1,836 research outputs found
Bub1 maintains centromeric cohesion by activation of the spindle checkpoint.
Get PDFBub1 is a component of the spindle assembly checkpoint (SAC), a surveillance mechanism that ensures genome stability by delaying anaphase until all the chromosomes are stably attached to spindle microtubules via their kinetochores. To define Bub1's role in chromosome segregation, embryogenesis, and tissue homeostasis, we generated a mouse strain in which BUB1 can be inactivated by administration of tamoxifen, thereby bypassing the preimplantation lethality associated with the Bub1 null phenotype. We show that Bub1 is essential for postimplantation embryogenesis and proliferation of primary embryonic fibroblasts. Bub1 inactivation in adult males inhibits proliferation in seminiferous tubules, reducing sperm production and causing infertility. In culture, Bub1-deficient fibroblasts fail to align their chromosomes or sustain SAC function, yielding a highly aberrant mitosis that prevents further cell divisions. Centromeres in Bub1-deficient cells also separate prematurely; however, we show that this is a consequence of SAC dysfunction rather than a direct role for Bub1 in protecting centromeric cohesion
Raymond Gervais : 3 x 1
Get PDF"Raymond Gervais 3 X 1 traces and elucidates the important or little-known moments in the practice of Raymond Gervais, an artist who has explored the notion of the aural imagination since the mid 1970s. An erudite author, Gervais joins forces here with Nicole Gingras, a researcher and curator interested in what connects sound, image, and words. The first major publication on the work of a conceptual artist questioning whether thought is acoustic" -- p. [4] of cover
The collagens of hydra provide insight into the evolution of metazoan extracellular matrices
No full textA collagen-based extracellular matrix is one defining feature of all Metazoa. The thick sheet-like extracellular matrix (mesoglia) of the diploblast, hydra, has characteristics of both a basement membrane and an interstitial matrix. Several genes associated with mesoglea have been cloned including a basement membrane and fibrillar collagen and an A and B chain of laminin. Here we report the characterization of a further three fibrillar collagen genes (Hcol2, Hcol3, and Hcol5) and the partial sequence of a collagen gene with a unique structural organization consisting of multiple von Willebrand factor A domains interspersed with interrupted collagenous triple helices (Hcol6) from Hydra vulgaris. Hcol2 and -5 have major collagenous domains of classical length (∼1020 amino acid residues), whereas the equivalent domain in Hcol3 is shorter (969 residues). The N-propeptide of Hcol2 contains a whey acid protein four-cysteine repeat (WAP) domain, and the equivalent domain of Hcol3 contains two WAP and two von Willebrand factor A domains. Phylogenetic analyses reveal that the hydra fibrillar collagen genes form a distinct clade that appears related to the protostome/deuterostome A clade of fibrillar collagens. Data base searches reveal Hcol2, -5, and -6 are highly conserved in Hydra magnipapillata, which also provided preliminary evidence for the expression of a B-clade fibrillar collagen. All four of the H. vulgaris collagens are expressed specifically by the ectoderm. The expression pattern for Hcol2 is similar to that previously reported for Hcol1 (Deutzmann, R., Fowler, S., Zhang, X., Boone, K., Dexter, S., Boot-Handford, R. P., Rachel, R., and Sarras, M. P., Jr. (2000) Development 127, 4669-4680) but distinct from the pattern shared by Hcol3 and Hcol5. The characterization of multiple collagen genes in relatively simple diploblastic organisms provides new insights into the molecular evolution of collagens and the origins of the collagen-based extracellular matrix found throughout the multicellular animal kingdom. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc
Gene cloning to clinical trials-the trials and tribulations of a life with collagen
No full textThis review, based on the BSMB Fell‐Muir Lecture I presented in July 2018 at the Matrix Biology Europe Conference in Manchester, gives a personal perspective of my own laboratory's contributions to research into type X collagen, metaphyseal chondrodysplasia type Schmid and potential treatments for this disorder that are currently entering clinical trial. I have tried to set the advances made in the context of the scientific technologies available at the time and how these have changed over the more than three decades of this research
Raymond Williams and the limits of cultural materialism
Get PDFCultural materialism has become an influential discipline in recent
years, particularly so in 'Renaissance' studies, but also more generally in
'English', as well as departments defined as practising 'cultural' or
'communications' studies. The phrase is usually linked with the name of
Raymond Williams, but a cursory examination of Williams's own work
quickly establishes that it is a phrase he rarely uses, and only schematically
attempts to define. The thesis therefore takes the form of an investigation into
the way cultural materialism has come to be understood, by examining in
detail the trajectory of Raymond Williams's theoretical development, and how
his own engagement with various theoretical positions has helped to set
'limits' on the meaning of cultural materialism.
Chapters 1 and 2 deal with some of Williams's earliest work,
particularly Reading and Criticism, as a way of investigating how reasonable
it is to tag him as a 'Left-Leavisite', arguing that Leavis's undoubted
influence is resisted (though not entirely rejected) from a very early stage. The
first chapter considers in detail Leavis's work at Cambridge, the influence of
Eliot, and the significance of the 'Organic Community'. Chapter 2, which is
based around a comparative analysis of Williams's and Leavis's readings of
Dickens, argues that Williams rejects the 'organic community' in favour of his
'knowable community'. Chapters 4 and 5 deal with specific 'theoretical'
issues: the first, based around a reading of Terry Eagleton's critique of
Williams's use of the Marxist metaphor of 'base and superstructure', shows
some of the problems which arise from Williams's cultural model, as well as
suggesting refinements; the second deals with the influence of Volosinov's
theories on Williams. Chapter 6 comes out of Williams's readings of the
'Country-House' poems in The Country and the City, showing how his
practice of literary criticism relies on an acceptance of 'ideology' apparently
denied in his more 'theoretical' writings. This analysis is extended as a result
of investigations into the 'De L'Isle' manuscripts relating to the Penshurst
estate. Chapter 7 argues that it is possible to see the work of Fredric Jameson
as developing Williams's cultural materialism into Jameson's debates on
postmodernism.
In the Introduction and Conclusion, I have taken the opportunity to
look briefly at the activity of cultural materialism as it has developed since
Raymond Williams's death in 1988. The Introduction emphasizes what I see
to be important methodological differences between 'cultural materialism'
and 'new historicism'; the Conclusion deals with the continuing debate over
the value of a cultural materialist approach by considering the 'appropriation'
of Shakespeare
Project Venezia-Gondola (A Framework for P-Commerce)
Get PDFA novel project named Venezia-Gondola (Project V-G) was presented, which describes an application platform that enables the activities of Peer-to-Peer commerce (P-Commerce). A new pattern called the Inverted Model-View-Controller (IMVC) pattern was claimed that is suitable for P-Commerce. The author also explains the principles of the Project V-G and possible architecture for future development
The unfolded protein response and its relevance to connective tissue diseases
Get PDFThe unfolded protein response (UPR) has evolved to counter the stresses that occur in the endoplasmic reticulum (ER) as a result of misfolded proteins. This sophisticated quality control system attempts to restore homeostasis through the action of a number of different pathways that are coordinated in the first instance by the ER stress-senor proteins IRE1, ATF6 and PERK. However, prolonged ER-stress-related UPR can have detrimental effects on cell function and, in the longer term, may induce apoptosis. Connective tissue cells such as fibroblasts, osteoblasts and chondrocytes synthesise and secrete large quantities of proteins and mutations in many of these gene products give rise to heritable disorders of connective tissues. Until recently, these mutant gene products were thought to exert their effect through the assembly of a defective extracellular matrix that ultimately disrupted tissue structure and function. However, it is now becoming clear that ER stress and UPR, because of the expression of a mutant gene product, is not only a feature of, but may be a key mediator in the initiation and progression of a whole range of different connective tissue diseases. This review focuses on ER stress and the UPR that characterises an increasing number of connective tissue diseases and highlights novel therapeutic opportunities that may arise
Carbamazepine reduces disease severity in a mouse model of metaphyseal chondrodysplasia type Schmid caused by a premature stop codon (Y632X) in the Col10a1 gene.
No full textMutations, mostly in the region of the COL10A1 gene encoding the C-terminal non-collagenous domain, cause the dwarfism metaphyseal chondrodysplasia type Schmid. In most cases, the disease mechanism involves the misfolding of the mutant protein causing increased ER stress and an unfolded protein response (UPR). However, in an iliac crest biopsy, the COL10A1p.Y632X mutation was found to produce instability of the mutant mRNA such that very little mutant protein may be produced. To investigate the disease mechanism further, a gene targeted mouse model of the Col10a1p.Y632X mutation was generated. In this model, the mutant mRNA showed no instability and in mice heterozygous for the mutation, mutant and wild type mRNA was present at equal concentration. Protein was translated from the mutant allele and retained within the cell triggering increased ER stress and an UPR. The mutation produced a relatively severe form of MCDS. Nevertheless, treatment of the mice with carbamazepine, (CBZ) a drug which stimulates intracellular proteolysis and alleviates ER stress effectively reduced the disease severity in this model of MCDS caused by a premature stop codon in the Col10a1 gene. Specifically, the drug reduced ER stress in the growth plate, restored growth plate architecture toward the wild type state, significantly increased bone growth, and within 2 weeks of treatment corrected the MCDS-induced hip distortion. These results indicate that CBZ is likely to be effective in ongoing clinical trials against all forms of MCDS whether caused by premature stop codons or substitutions
Recommendation for Raymond P. Kaighn (June 1, 1891)
No full textThis is a recommendation for Raymond P. Kaighn for admission to the International YMCA Training School, now Springfield College. The form is dated June 1, 1891. The exact name of the author is hard to work out from the writing. The form still has the old name for the school on the top, "The School For Christian Workers." The form asks questions about his personality, health, religious practices, and general impressions
- …
