103 research outputs found

    Galnt11 Is A Novel Galnac-Transferase That Glycosylates Notch1 Receptor To Specify Between Motor And Sensory Ciliary Fates In The Vertebrate Left-Right Organizer

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    Heterotaxy is a disease of abnormal left-right (LR) body patterning associated with congenital heart disease that has very poor outcomes. Despite advances in surgical management, the two most severe forms of heterotaxy, right and left atrial isomerism, have a 29% and 64% 5-year survival rate, respectively. Through copy number variant analysis of heterotaxy patients, GALNT11 was recently identified as a novel gene important in human LR development. However, the mechanism by which Galnt11 causes heterotaxy has not been elucidated. In order to discover the mechanism of GALNT11 in patterning the LR axis, I performed loss of function and gain of function studies in Xenopus tropicalis and expression analysis in Mus musculus. In Xenopus, knockdown of galnt11 = induced heart looping defects that were successfully rescued with human GALNT11 mRNA indicating that the phenotype was specific to Galnt11. Via immunohistochemistry, Galnt11 protein strongly localizes to the crown cells surrounding the LRO. Manipulations of Galnt11 altered the density of ciliated epidermal cells, but based on gliding assays and ultrastructural analysis did not alter the cilia. Galnt11 and Notch effects on epidermal ciliated epidermal cell density, heart looping, as well as PitX2 and Coco expression were very similar, and Galnt11 morphants were rescued with Notch ICD and Su(H)-Ank, but not Delta suggesting that galnt11 acts in the notch pathway downstream of the ligand. GALNT11 RNA no longer had any effect on heart looping or PitX2 expression following a conservative point mutation of its catalytic glycosylation domain. Galnt11 morphants had significantly narrower LROs, and much stronger expression of motile ciliary markers FoxJ1 and RFX2, while GALNT11 RNA injected embryos had almost no detectable FoxJ1 and RFX2. Taken together, these results indicate that Galnt11 is a GalNAc-transferase that is necessary for proper left-right axis establishment and heart looping. Its function is to specify between motile and sensory cell fates at the Left-Right Organizer by glycosylating Notch receptor and modifying Notch signaling

    GIS model of the basic geological map as a basis for Geodatabase of the Republic of Macedonia

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    This paper presents the process of digitalization of the Basic Geological Map with scale 1:200 000 of the Republic of Macedonia in software package Maplnfo professional 8.0 as a basis for preparing geodatabase for the Republic of Macedonia. The procedure of design and implementation of a GIS project for the Basic Geological Map of the Republic of Macedonia is given, starting with the design of the database table, selecting attributes and entering vector graphical objects. Model of geodatabase is developed using latest information technologies, GIS and integrated database, allowing further development and upgrade. A list of digital data and maps that are included in the geodatabase is shown, together with the logical structure for entering data into the geodatabase and the service architecture of applications and data redundancy

    Synchronization of overburden dumping in Bucim open pit mine in function of minimal costs

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    Overburden exploatation in open pit “Bucim” is performed from 3 (three) ore bodies, with least 2 (two) excavating zone. Overburden dumping is in 3 dump: two external and one internal. The need for synchronization of work is imminent, given that it is the same transport machinery - 12 trucks. In this paper it was made an attempt for mathematical modeling of synchronization of transporting and overburden dumping in three dumps

    Notch/Her12 signalling modulates, motile/immotile cilia ratio downstream of Foxjla in zebrafish left-right organizer

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    undacao para a Ciencia e a Tecnologia PTDC/BEX-BID/1411/2014 Susana Santos Lopes Fundacao para a Ciencia e a Tecnologia FCT-ANR/BEX-BID/0153/2012 Sara Pestana Fundacao para a Ciencia e a Tecnologia PTDC/SAU-OBD/103981/2008 Andreia Vaz Fundacao para a Ciencia e a Tecnologia PD/BD/52420/2013 Raquel Jacinto Fundacao para a Ciencia e a Tecnologia SFRH/BPD/77258/2011 Barbara Tavares Fundacao para a Ciencia e a Tecnologia SFRH/BD/111611/2015 Pedro Sampaio Fundacao para a Ciencia e a Tecnologia IF/00951/2012 Susana Santos Lopes The funders had no role in study design, data collection and interpretation, or the on the decision to submit the work for publication.publishersversionpublishe

    Signaling through the primary cilium

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    © 2018 Wheway, Nazlamova and Hancock. The presence of single, non-motile "primary" cilia on the surface of epithelial cells has been well described since the 1960s. However, for decades these organelles were believed to be vestigial, with no remaining function, having lost their motility. It wasn't until 2003, with the discovery that proteins responsible for transport along the primary cilium are essential for hedgehog signaling in mice, that the fundamental importance of primary cilia in signal transduction was realized. Little more than a decade later, it is now clear that the vast majority of signaling pathways in vertebrates function through the primary cilium. This has led to the adoption of the term "the cells's antenna" as a description for the primary cilium. Primary cilia are particularly important during development, playing fundamental roles in embryonic patterning and organogenesis, with a suite of inherited developmental disorders known as the "ciliopathies" resulting from mutations in genes encoding cilia proteins. This review summarizes our current understanding of the role of these fascinating organelles in a wide range of signaling pathways

    A conserved major facilitator superfamily member orchestrates a subset of O-glycosylation to aid macrophage tissue invasion

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    Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on proteins in pathways previously linked to cancer, most strongly on the sulfhydryl oxidase Qsox1 which we show is required for macrophage tissue entry. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate a program governing migration steps important for both development and cancer metastasis

    GIS model of the basic geological map as a basis for Geodatabase of the Republic of Macedonia

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    This paper presents the process of digitalization of the Basic Geological Map with scale 1:200 000 of the Republic of Macedonia in software package Maplnfo professional 8.0 as a basis for preparing geodatabase for the Republic of Macedonia. The procedure of design and implementation of a GIS project for the Basic Geological Map of the Republic of Macedonia is given, starting with the design of the database table, selecting attributes and entering vector graphical objects. Model of geodatabase is developed using latest information technologies, GIS and integrated database, allowing further development and upgrade. A list of digital data and maps that are included in the geodatabase is shown, together with the logical structure for entering data into the geodatabase and the service architecture of applications and data redundancy

    Rock mass properties in minimizing of general slope in surface mining of metals

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    Exploitation of ore and overburden is done from working environments with different characteristics such as physical-mechanical and technical – technological aspect. Heterogeneity and anizotropic are one of the main features that directly effect of the determination of the geotechnical characteristics of working environment. In this paper it was made an attempt based on the large number of theoretical and empirical studies to define the dependence between the characteristics of the work environment and maximizing general angle in surface mining of metals
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