47 research outputs found

    SOX9 Governs Differentiation Stage-Specific Gene Expression in Growth Plate Chondrocytes via Direct Concomitant Transactivation and Repression

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    Cartilage and endochondral bone development require SOX9 activity to regulate chondrogenesis, chondrocyte proliferation, and transition to a non-mitotic hypertrophic state. The restricted and reciprocal expression of the collagen X gene, Col10a1, in hypertrophic chondrocytes and Sox9 in immature chondrocytes epitomise the precise spatiotemporal control of gene expression as chondrocytes progress through phases of differentiation, but how this is achieved is not clear. Here, we have identified a regulatory element upstream of Col10a1 that enhances its expression in hypertrophic chondrocytes in vivo. In immature chondrocytes, where Col10a1 is not expressed, SOX9 interacts with a conserved sequence within this element that is analogous to that within the intronic enhancer of the collagen II gene Col2a1, the known transactivation target of SOX9. By analysing a series of Col10a1 reporter genes in transgenic mice, we show that the SOX9 binding consensus in this element is required to repress expression of the transgene in non-hypertrophic chondrocytes. Forced ectopic Sox9 expression in hypertrophic chondrocytes in vitro and in mice resulted in down-regulation of Col10a1. Mutation of a binding consensus motif for GLI transcription factors, which are the effectors of Indian hedgehog signaling, close to the SOX9 site in the Col10a1 regulatory element, also derepressed transgene expression in non-hypertrophic chondrocytes. GLI2 and GLI3 bound to the Col10a1 regulatory element but not to the enhancer of Col2a1. In addition to Col10a1, paired SOX9–GLI binding motifs are present in the conserved non-coding regions of several genes that are preferentially expressed in hypertrophic chondrocytes and the occurrence of pairing is unlikely to be by chance. We propose a regulatory paradigm whereby direct concomitant positive and negative transcriptional control by SOX9 ensures differentiation phase-specific gene expression in chondrocytes. Discrimination between these opposing modes of transcriptional control by SOX9 may be mediated by cooperation with different partners such as GLI factors

    A Comprehensive Microarray-Based DNA Methylation Study of 367 Hematological Neoplasms

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    Background: Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required. Methodology/Principal Findings: Here, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system. Using appropriate controls of B-, T-, or myeloid cellular origin, we identified a total of 220 genes hypermethylated in at least one HN entity. In general, promoter hypermethylation was more frequent in lymphoid malignancies than in myeloid malignancies, being germinal center mature B-cell lymphomas as well as B and T precursor lymphoid neoplasias those entities with highest frequency of gene-associated DNA hypermethylation. We also observed a significant correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. Most of the genes becoming hypermethylated contained promoters with high CpG content, and a significant fraction of them are targets of the polycomb repressor complex. Interestingly, T-cell prolymphocytic leukemias show low levels of DNA hypermethylation and a comparatively large number of hypomethylated genes, many of them showing an increased gene expression. Conclusions/Significance: We have characterized the DNA methylation profile of a wide range of different HNs entities. As well as identifying genes showing aberrant DNA methylation in certain HN subtypes, we also detected six genes DBC1, DIO3, FZD9, HS3ST2, MOS, and MYOD1 that were significantly hypermethylated in B-cell, T-cell, and myeloid malignancies. These might therefore play an important role in the development of different HNs

    Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

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    Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions

    Epigenetic associations in relation to cardiovascular prevention and therapeutics

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    Whole body ultrasound in the operating room and intensive care unit

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    Whole body ultrasound can be used to improve the speed and accuracy of evaluation of an increasing number of organ systems in the critically ill. Cardiac and abdominal ultrasound can be used to identify the mechanisms and etiology of hemodynamic instability. In hypoxemia or hypercarbia, lung ultrasound can rapidly identify the etiology of the condition with an accuracy that is equivalent to that of computed tomography. For encephalopathy, ocular ultrasound and transcranial Doppler can identify elevated intracranial pressure and midline shift. Renal and bladder ultrasound can identify the mechanisms and etiology of renal failure. Ultrasound can also improve the accuracy and safety of percutaneous procedures and should be currently used routinely for central vein catheterization and percutaneous tracheostomy

    The United Kingdom and Ireland experience of the Haemodialysis Reliable Outflow graft for vascular access

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    Objectives: To describe the UK and Ireland experience of the Haemodialysis Reliable Outflow graft in complex vascular access. Design: Observational, multi-centre case series. Methods: Data from any patient undergoing Haemodialysis Reliable Outflow graft were collected from eight UK and one Irish centre. Any Haemodialysis Reliable Outflow procedure between July 2013 and May 2016 was included. Demographics, primary and secondary patency rates, and complications were analysed. Results: A total of 52 patients underwent Haemodialysis Reliable Outflow graft insertion. Median age was 55 (20–86) years, 24 (46%) were male and 66% were Caucasian. Median follow-up was 290 (10–966) days and patient survival was 41/52 (79%). In total, 48 procedures were in the upper limb with 39 using the brachial artery as inflow (75%). The internal jugular vein and subclavian vein were most frequently used as access for outflow insertion. Primary patency rates at 6, 12, and 24 months were 51.2% (95% confidence interval, 38.8%–67.4%), 40.9% (95% confidence interval, 28.7%–58.2%), and 33.4% (95% confidence interval, 21.3%–52.5%), respectively. Secondary patency rates at 6, 12, and 24 months were 84.8% (95% confidence interval, 75%–95.9%), 76.5% (95% confidence interval, 64.5%–90.6%), and 70.6% (95% confidence interval, 56%–88.9%), respectively. There were 65 surgical and 49 radiological interventions resulting in 2.30 interventions per year to retain patency. Complications included four infections and two episodes of steal syndrome. Conclusion: The Haemodialysis Reliable Outflow graft provides acceptable 12-month secondary patency rates and acceptable complication rates in a UK and Ireland multi-centre series of complex access patients. Haemodialysis Reliable Outflow should be considered in patients with central pathology as a potential alternative to lower limb grafts and long-term central venous catheters.</p
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