Altered expression of caspases-4 and -5 during inflammatory bowel disease and colorectal cancer : diagnostic and therapeutic potential

Caspases are a group of proteolytic enzymes involved in the co-ordination of cellular processes, including cellular homeostasis, inflammation and apoptosis. Altered activity of caspases, particularly caspase-1, has been implicated in the development of intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, the involvement of two related inflammatory caspase members, caspases-4 and -5, during intestinal homeostasis and disease has not yet been established. This study demonstrates that caspases-4 and -5 are involved in IBD-associated intestinal inflammation. Furthermore, we found a clear correlation between stromal caspase-4 and -5 expression levels, inflammation and disease activity in ulcerative colitis patients. Deregulated intestinal inflammation in IBD patients is associated with an increased risk of developing CRC. We found robust expression of caspases-4 and -5 within intestinal epithelial cells, exclusively within neoplastic tissue, of colorectal tumours. An examination of adjacent normal, inflamed and tumour tissue from patients with colitis-associated CRC confirmed that stromal expression of caspases-4 and -5 is increased in inflamed and dysplastic tissue, while epithelial expression is restricted to neoplastic tissue. In addition to identifying caspases-4 and -5 as potential targets for limiting intestinal inflammation, this study has identified epithelial-expressed caspases-4 and -5 as biomarkers with diagnostic and therapeutic potential in CRC

Maf1, a New Player in the Regulation of Human RNA Polymerase III Transcription

BACKGROUND: Human RNA polymerase III (pol III) transcription is regulated by several factors, including the tumor suppressors P53 and Rb, and the proto-oncogene c-Myc. In yeast, which lacks these proteins, a central regulator of pol III transcription, called Maf1, has been described. Maf1 is required for repression of pol III transcription in response to several signal transduction pathways and is broadly conserved in eukaryotes. METHODOLOGY/PRINCIPAL FINDINGS: We show that human endogenous Maf1 can be co-immunoprecipitated with pol III and associates in vitro with two pol III subunits, the largest subunit RPC1 and the α-like subunit RPAC2. Maf1 represses pol III transcription in vitro and in vivo and is required for maximal pol III repression after exposure to MMS or rapamycin, treatments that both lead to Maf1 dephosphorylation. CONCLUSIONS/SIGNIFICANCE: These data suggest that Maf1 is a major regulator of pol III transcription in human cells

Function of TFIIIC, RNA polymerase III initiation factor, in activation and repression of tRNA gene transcription

Transcription of transfer RNA genes by RNA polymerase III (Pol III) is controlled by general factors, TFIIIB and TFIIIC, and a negative regulator, Maf1. Here we report the interplay between TFIIIC and Maf1 in controlling Pol III activity upon the physiological switch of yeast from fermentation to respiration. TFIIIC directly competes with Pol III for chromatin occupancy as demonstrated by inversely correlated tDNA binding. The association of TFIIIC with tDNA was stronger under unfavorable respiratory conditions and in the presence of Maf1. Induction of tDNA transcription by glucose-activated protein kinase A (PKA) was correlated with the down-regulation of TFIIIC occupancy on tDNA. The conditions that activate the PKA signaling pathway promoted the binding of TFIIIB subunits, Brf1 and Bdp1, with tDNA, but decreased their interaction with TFIIIC. Association of Brf1 and Bdp1 with TFIIIC was much stronger under repressive conditions, potentially restricting TFIIIB recruitment to tDNA and preventing Pol III recruitment. Altogether, we propose a model in which, depending on growth conditions, TFIIIC promotes activation or repression of tDNA transcription

The Manufacture of Popular Graphic Images in Years 1870–1940. Technology, Embellishment and Framing

The main goal of the article is to draw attention to the underestimated phenomenon of printed paintings. Due to the extensiveness of the matter, the considerations are limited to the study of the production technology (primarily lithography, secondarily photolithography and offset printing), as well as variations of embellishments and framing. The study of the subject was based on field and museum researches, while bibliographic research based primarily on texts of German researchers. This results from the fact, that at the time German producers of graphic images were potentates on the European market. What is more, manufacture and distribution of painting reproductions spread so widely, that without exaggeration, we can use the expressions like “the manufacture” or “the manufactured painting”. The history of the most popular series of paintings were connected with the technological progress. Thanks to the development of printing-techniques the images could be produced in wholesale-quantities. Quickly and naturally the manufactured painting became a representative art of peasantry and blue-collar workers.Celem niniejszego artykułu jest zwrócenie uwagi na niedoceniany fenomen obrazów fabrycznych. Ze względu na obszerność materii rozważania ograniczono do przybliżenia technik produkcji (litografii, fotolitografii, offsetu), a także wariantów zdobień i ramowania. Pracę nad tematem oparto na badaniach terenowych i muzealnych, zaś badania bibliograficzne – na tekstach badaczy niemieckich. Wynika to z faktu, że niemieccy wytwórcy obrazów byli w swoim czasie potentatami na rynku europejskim. Wyrób reprodukcji obrazkowych rozpowszechnił się tak dalece, że bez przesady można w tym przypadku stosować sformułowania typu produkcja czy obraz fabryczny. Historia popularnych wydawnictw związana była z postępem technologicznym. Dzięki rozwojowi technik poligraficznych obrazy zaczęto wykonywać w ilościach hurtowych. Szybko i naturalnie obrazy fabryczne stały się reprezentacyjną sztuką chłopów i robotników

Morphologie de l'onde P du signal électrocardiographique. Analyse de forme des signaux bidimensionnels: mesure d'effets pharmacologiques sur les ondes P, QRS et T en représentation temps-fréquence

The aim of this work is to develop a signal processing methodology in order to improve fine studies of the cardiac signal, and specially of P wave, particularly focusing the measurement of shape variations. After a review of cardiac signal characteristics, a description of its physiological and pathological variability and of the different recording techniques, a critical study of cardiac signal processing methods is performed: noise reduction, specific filtering, signal averaging and jitter estimation. An interactive and practical software for ECO, particularly devoted to P wave studies, has been developed, with special algorithms of preprocessing and processing, concerning signal averaging procedure and shape comparison. In fact, the most important part of this work is devoted to a new and personal approach of measuring shape differences of bidimensional signaIs. This method is an extension to two dimensions of the distribution function method (DFM), called DFM-2D. The method is described and it is demonstrated that it can be applied to time-frequency representations of monodimensional signaIs. Through simulations applied on gaussian curves, it is clearly showed that DFM-2D performances are better than DFM-ID ones, on noisy as weIl as non-noisy signals. DFM-2D can also be applied to image processing, as it is proved by examples of histologic sections processing. Precise and early detection of electrophysiological action of drugs (such as Cibenzoline or Quinidine) on ECO waves (P, QRS, T) is an interesting application ofDFM-2D in pharmacology. The presented results demonstrate the abililty of this method to measure shape variations and to distinguish them from wave duration fluctuations.Cette thèse a pour objet la recherche d'une méthodologie de traitement du signal pour améliorer l'étude fine du signal cardiaque (électrocardiogramme ou ECG), en particulier de l'onde P (d'origine auriculaire), avec pour intérêt privilégié la mesure des variations de forme. Après le rappel des propriétés du signal cardiaque, de sa grande variabilité physiologique et pathologique, ainsi que de ses différentes techniques de recueil, une étude critique des méthodes existantes de traitement de ce signal est effectuée: réduction du bruit, filtrages spécifiques, sommation synchrone et estimation du "jitter". Un logiciel convivial et interactif de prétraitement et traitement (sommation-moyennage, comparaison de forme) de l'ECG, et de l'onde P en particulier, a été développé. Mais la partie principale de ce travail concerne une nouvelle approche de mesure des écarts de forme des signaux bidimensionnels. Cette méthode est une extension à deux dimensions de la méthode des fonctions de répartition (MFR), notée MFR-2D. La théorie de la méthode est exposée, et, en particulier, la possibilité de l'appliquer aux représentations temps-fréquence des signaux monodimensionnels est démontrée. Au travers de simulations sur des gaussiennes, sa supériorité par rapport à la MFR-1D est soulignée, que le signal soit ou non bruité. Elle s'avère aussi capable, sur des exemples de coupes histologiques, d'être employée au traitement d'images. Appliquée aux spectrogrammes des ondes ECG (P, QRS et T), elle est utilisable pour la détection précoce des actions électrophysiologiques de médicaments (Cibenzoline, Quinidine). Les résultats obtenus montrent l'efficacité de la méthode à mesurer des variations de forme en les distinguant des fluctuations de durée des ondes

New approach in management of vitreo-retinal interface disorders with ocriplasmine

Nieprawidłowości powierzchni styku ciało szkliste–siatkówka w postaci objawowej prowadzą do powstania trakcji obszaru plamki i formowania otworu w plamce. Standardem postępowania w takich przypadkach jest witrektomia. Okryplazmina jako enzym proteolityczny może być zastosowana w leczeniu tych schorzeń, dając możliwość uniknięcia witrektomii jako procedury chirurgicznej w wybranych przypadkach.Symptomatic diseases of vitreo-retinal interface can result in traction and macular hole. Standard treatment for these disorders is pars plana vitrectomy. Ocriplasmine is a proteolytic enzyme that can cause resolution of the symptoms and replace surgical procedure in selected cases

Investigating the role of inflammatory caspases during disease-associated inflammation

THESIS 11066Caspases are a group of proteolytic enzymes involved in the co-ordination of cellular processes such as inflammation and apoptosis. Functional mechanisms surrounding the activation and signalling pathways mediated by inflammatory caspases (such as caspase-1, -4 and -5) are being intensively researched at present. It is well established that canonical inflammasome mediated caspase-1 activation promotes the maturation and secretion of pro-inflammatory cytokines such as IL-1? and IL-18, which further amplifies the pro-inflammatory immune response. However, activation of the non-canonical inflammasome (mediated by human caspase-4 and -5 or their murine homolog, caspase-11), serves as an additional pathway for enhancing canonical inflammasome activation in response to Gram-negative bacterial infection. This highlights the crucial importance of these caspases during the host immune response and caspase-1 regulation. As canonical activation of inflammasome signalling is a critical modulator of immune system homeostasis, its dysregulation leads to the development of a multitude of inflammatory disorders and also inflammatory associated cancers. Altered activity of caspase-1 and the canonical inflammasome has been implicated in the development of intestinal inflammatory diseases such as inflammatory bowel disease (IBD) and colitis associated cancer (CAC). However, there is still little known regarding the role of murine caspase-11 and human caspase-4 and -5 during acute and chronic disease associated inflammation of the gastrointestinal tract (GI)