169 research outputs found

    For Parents: Using Literature to Stretch Your Children\u27s Thinking

    Get PDF

    Listening in the Content Areas

    Get PDF

    Quantitative proteomics screen identifies a substrate repertoire of rhomboid protease RHBDL2 in human cells and implicates it in epithelial homeostasis

    Get PDF
    This deposit is composed by the main article plus the supplementary materials of the publication.Rhomboids are intramembrane serine proteases conserved in all kingdoms of life. They regulate epidermal growth factor receptor signalling in Drosophila by releasing signalling ligands from their transmembrane tethers. Their functions in mammals are poorly understood, in part because of the lack of endogenous substrates identified thus far. We used a quantitative proteomics approach to investigate the substrate repertoire of rhomboid protease RHBDL2 in human cells. We reveal a range of novel substrates that are specifically cleaved by RHBDL2, including the interleukin-6 receptor (IL6R), cell surface protease inhibitor Spint-1, the collagen receptor tyrosine kinase DDR1, N-Cadherin, CLCP1/DCBLD2, KIRREL, BCAM and others. We further demonstrate that these substrates can be shed by endogenously expressed RHBDL2 and that a subset of them is resistant to shedding by cell surface metalloproteases. The expression profiles and identity of the substrates implicate RHBDL2 in physiological or pathological processes affecting epithelial homeostasis.Academy of Sciences of the Czech Republic grant: (Purkyne Fellowship); EMBO grant: (Installation Grant no. 2329); Ministry of Education, Youth and Sports of the Czech Republic grants: (projects no. LK11206 and LO1302); Marie Curie Career Integration grant: (project no. 304154); National Subvention for Development of Research Organisations grant: (RVO: 61388963); Institute of Organic Chemistry and Biochemistry; Fundação Calouste Gulbenkian; Worldwide Cancer Research grant: (14–1289); Marie Curie Career Integration grant: (project no. 618769); Fundação para a Ciência e Tecnologica (FCT, PTDC/BEX-BCM/3015/2014); European Crohn’s and Colitis organization (ECCO); COST BM1406; Wellcome Trust grant: (101035/Z/13/Z); Medical Research Council grant: (programme number MC_U105178780).info:eu-repo/semantics/publishedVersio

    Bub1 Kinase and Sgo1 Modulate Pericentric Chromatin in Response to Altered Microtubule Dynamics

    Get PDF
    Tension sensing of bi-oriented chromosomes is essential for the fidelity of chromosome segregation. The spindle assembly checkpoint (SAC) conveys lack of tension or attachment to the anaphase promoting complex. Components of the SAC (Bub1) phosphorylate histone H2A (S121) and recruit the protector of cohesin, Shugoshin (Sgo1) to the inner centromere. How the chromatin structural modifications of the inner centromere are integrated into the tension sensing mechanisms and the checkpoint are not known

    Tension-dependent nucleosome remodeling at the pericentromere in yeast

    Get PDF
    Dynamics of histones under tension in the pericentromere depends on RSC and ISW2 chromatin remodeling. The underlying pericentromeric chromatin forms a platform that is required to maintain kinetochore structure when under spindle-based tension.Nucleosome positioning is important for the structural integrity of chromosomes. During metaphase the mitotic spindle exerts physical force on pericentromeric chromatin. The cell must adjust the pericentromeric chromatin to accommodate the changing tension resulting from microtubule dynamics to maintain a stable metaphase spindle. Here we examine the effects of spindle-based tension on nucleosome dynamics by measuring the histone turnover of the chromosome arm and the pericentromere during metaphase in the budding yeast Saccharomyces cerevisiae. We find that both histones H2B and H4 exhibit greater turnover in the pericentromere during metaphase. Loss of spindle-based tension by treatment with the microtubule-depolymerizing drug nocodazole or compromising kinetochore function results in reduced histone turnover in the pericentromere. Pericentromeric histone dynamics are influenced by the chromatin-remodeling activities of STH1/NPS1 and ISW2. Sth1p is the ATPase component of the Remodels the Structure of Chromatin (RSC) complex, and Isw2p is an ATP-dependent DNA translocase member of the Imitation Switch (ISWI) subfamily of chromatin-remodeling factors. The balance between displacement and insertion of pericentromeric histones provides a mechanism to accommodate spindle-based tension while maintaining proper chromatin packaging during mitosis

    Associations between metabolic syndrome components and markers of inflammation in Welsh school children

    Get PDF
    We investigated the multivariate dimensionality and strength of the relationship between metabolic syndrome (MetS) and inflammation in children. Caucasian school children (N = 229; 12-14 yr) from Wales were tested on several health indicators including measures of body composition, inflammation, fasting glucose regulation, blood pressure and lipids. The multivariate associationbetween MetS and inflammation was investigated via canonical correlation analysis. Data were corrected for non-normality by log transformation, and sex-specific z-scores computed for variables where there was a significant sex difference. Structure r’s were interpreted to determine the dimensions of MetS and inflammation responsible for significant canonical variates. The overallmultivariate association between MetS and inflammation was significant (Wilks’ Lambda = 0.54, p < 0.001). The relationship was explained primarily by the waist circumference dimension of MetS (CC = 0.87) and inflammatory markers of fibrinogen (CC = 0.52) and C-reactive protein (CC = 0.50). The pattern of results was similar regardless of whether variables were adjusted for sex differences.Conclusions: Central adiposity is the strongest predictor of the inflammatory aspect of cardiovascular disease risk in Caucasian adolescents. Future research into MetS and cardiometabolic risk should consider multivariate statistical approaches, in order to identify the separate contributions of each dimension in interrelationships and to identify which dimensions are influenced by preventive interventions

    A 3D Map of the Yeast Kinetochore Reveals the Presence of Core and Accessory Centromere-Specific Histone

    Get PDF
    The budding yeast kinetochore is ~68nm in length with a diameter slightly larger than a 25nm microtubule [1]. The kinetochores from the 16 chromosomes are organized in a stereotypic cluster encircling central spindle microtubules. Quantitative analysis of the inner kinetochore cluster (Cse4, COMA) reveals structural features not apparent in singly attached kinetochores. The cluster of Cse4 containing kinetochores is physically larger perpendicular to the spindle axis relative to the cluster of Ndc80 molecules [2]. If there were a single Cse4 (molecule or nucleosome) at the kinetochore attached to each microtubule plus-end, the cluster of Cse4 would appear geometrically identical to Ndc80. Thus, the structure of the inner kinetochore at the surface of the chromosomes remains unsolved
    • …
    corecore