15 research outputs found
John Frazer
No full textJohn Frazer, Professor, trained at the Architectural Association, taught first at Cambridge University and then the AA in the 1970s and again in the '90s. He was Head of School of Design Research History and Criticism at the University of Ulster in the 1980s, he also ran a systems and design consultancy with his wife Julia (including projects for Cedric Price and Walter Segal) and was founder and chairman of Autographics software. He is currently Swire Chair Professor and Head of School of Design in Hong Kong.-----\ud
\ud
This is a very personal perspective on a concept of universal and future significance. It is personal, both is the sense that it is an unashamedly biased view of both the significance of the project, and the nature of that significance and because the author was personally involved as one of the consultants on GENERATOR and subsequently involved Cedric Price in its educational application at the Architectural Association. GENERATOR is still very much alive and was still developing whilst this chapter was being written.\u
Control of anti-apoptotic and antioxidant pathways in neural cells
No full textOxidative stress is a feature of many chronic neurodegenerative diseases as well as a
contributing factor in acute disorders including stroke. Fork head class of
transcription factors (Foxos) play a key role in promoting oxidative stress-induced
apoptosis in neurons through the upregulation of a number of pro-apoptotic genes.
Here I demonstrate that synaptic NMDA receptor activity not only promotes Foxos
nuclear exclusion but also suppresses the expression of Foxo1 in a PI3K-dependent
fashion. I also found that Foxo1 is in fact, a Foxo target gene and that it is subject to
a feed-forward inhibition by synaptic activity, which is thought to result in longerterm
suppression of Foxo downstream gene expression than previously thought. The
nuclear factor (erythroid 2-related) factor 2 (Nrf2) is another transcription factor
involved in oxidative stress and the key regulator of many genes, whose products
form important intrinsic antioxidant systems. In the CNS, artificial activation of Nrf2
in astrocytes has been shown to protect nearby neurons from oxidative insults.
However, the extent to which Nrf2 in astrocytes could respond to endogenous signals
such as mild oxidative stress is less clear. The data presented herein, demonstrate for
the first time that endogenous Nrf2 could be activated by mild oxidative stress and
that this activation is restricted to astrocytes. Contrary to the established dogma, I
found that mild oxidative stress induces the astrocytic Nrf2 pathway in a manner
distinct from the classical Keap1 antagonism employed by prototypical Nrf2
inducers. The mechanism was found to involve direct regulation of Nrf2's
transactivation properties. Overall these results advance our knowledge of the
molecular mechanism(s) associated with the control of endogenous antioxidant
defences by physiological signals
Many happy returns, the presentation album of Gladys Moncrieff's farewell tour, 1959-1961 [picture] /
No full textTitle devised by cataloguer based on inscriptions and acquisitions documentation.; Inscriptions: "Many Happy Returns"--Embossed on front cover.; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn3807532; Also available in an electronic version via the internet at: http://nla.gov.au/nla.pic-vn3807532; Purchased at Charles Leski Auction, 2006 Lot 399. The album includes photographs of Gladys Moncrieff, principal and chorus performers and dancers. The farewell tour began in Sydney in 1959 and closed in Hamilton, New Zealand in 1961. Features of the photographs include choreography by Sheila Cruze, gowns and wardrobe by the Jesse Law Studio and scenery and design created by Dres Hardingham. The album includes images of Harry Wren the entrepreneur and the vaudeville star Jenny Howard
"A Symbol of the New African": Drum magazine, popular culture and the formation of black urban subjectivity in 1950s South Africa.
No full textPhDThis thesis examines the emergence of black urban subjectivity in South Africa
during the 1950s, focussing on the ways in which popular American genres were
utilised in the construction of black urban identities that served as a means of
resistance to apartheid. At the centre of this process was Drum magazine:
founded in South Africa in 1951 , it became the largest selling magazine on the
African continent in 1956. Drum's success was due to the way in which it
enabled the relocation of black identity from the "traditional" towards the
"modern'. The 1940s gave rise to widespread migration of black South Africans
from rural to urban areas and this newly urbanised community was seeking
models of black urban identity. Yet the Nationalist government was attempting
to curtail the emergence of a black urban proletariat, which posed a threat to
white political supremacy. Through apartheid legislation black identity was
constructed as essentially tribal and rural. As a means of resisting this, urbanised
black South Africans turned to, and appropriated, readily available forms of
American culture. Drum published Americanised images and stories: gangsters,
black detectives, black comic heroes, and pulp romances. This popular material
appeared alongside some of the finest investigative journalism ever published.
While Drum magazine is widely acknowledged as having provided a platform
for the emergence of black South African writing in English, its popular content
has been dismissed by critics as apolitical escapism, imitation and capitulation to
American culture. This thesis challenges the dismissal of the popular that has
dominated analyses of Drum since the 1960s, arguing that such a position denies
the agency of local writers and audiences. My analysis reveals that American
forms were adopted in critically discerning ways and chosen for their ability to
convey local meaning and create positions from which to resist aparthei
Two Related but Distinct Chondroitin Sulfate Mimetope Octasaccharide Sequences Recognized by Monoclonal Antibody WF6
No full textChondroitin sulfate (CS) proteoglycans are major components of cartilage and other connective tissues. The monoclonal antibody (mAb) WF6, developed against embryonic shark cartilage CS, recognizes an epitope in CS chains, which is expressed in ovarian cancer and variably in joint diseases. To elucidate the structure of the epitope, we isolated oligosaccharide fractions from a partial chondroitinase ABC digest of shark cartilage CS-C and established their chain length, disaccharide composition, sulfate content and sulfation pattern. These structurally defined oligosaccharide fractions were characterized for binding to WF6 by enzyme-linked immunosorbent assay using an oligosaccharide microarray prepared with CS oligosaccharides derivatized with a fluorescent aminolipid. The lowest molecular weight fraction recognized by WF6 contained octasaccharides, which were split into five subfractions. The most reactive subfraction contained several distinct octasaccharide sequences. Two octasaccharides, **｣GD-C-C-C and ｣GC-C-A-D, were recognized by WF6, but other related octasaccharides, ｣GC-A-D-C and ｣GC-C-C-C, were not. The structure and sequences of both the binding and non-binding octasaccharides were compared by computer modeling, which revealed a remarkable similarity between the shape and distribution of the electrostatic potential in the two different octasaccharide sequences that bound to WF6 and which differed from the non-binding octasaccharides. The strong similarity in structure predicted for the two binding CS octasaccharides (｣GD-C-C-C and ｣GC-C-A-D) provided a possible explanation for their similar affinity for the WF6, although they differed in sequence and thus form two specific mimetopes for the antibody. **Abbreviations: A, GlcUAυ1-3GalNAc(4-O-sulfate); C, GlcUAυ1-3GalNAc(6-O-sulfate); D, GlcUA(2-O-sulfate)υ1-3GalNAc(6-O-sulfate); ｣GC, ｣G4,5HexUAτ1-3GalNAc(6-O-sulfate); ｣GD, ｣G4,5HexUA(2-O-sulfate)τ1-3GalNAc(6-O-sulfate)
Author response: Pro-death NMDA receptor signaling is promoted by the GluN2B C-terminus independently of Dapk1
No full textAssessment of IL-6, IL-8, bFGF, PDGF-BB, and VEGF-A as prognostic and predictive biomarkers for anti-VEGF in metastatic colorectal cancer (mCRC).
No full text 502 Background: There remains a need for predictive biomarkers in mCRC to better identify patients who clinically benefit from anti-VEGF therapy, in particular bevacizumab (BEV). The AGITG MAX trial compared capecitabine (C) with capecitabine (+/- mitomycin C (M)) and BEV and PFS was superior in the CB+/-M arm. Here we have taken a panel of pro-angiogenic proteins to assess whether there is a signal for a predictive factor for bevacizumab outcome in the MAX trial tissue population (TTP). Methods: Protein was isolated from FFPE tumour tissue and assayed using custom Bio-plex arrays to assess the expression levels of candidate tumour biomarkers IL-6, IL-8, bFGF, PDGF-BB and VEGF-A. As there are no accepted cutoff points for these analytes we chose the medians of distribution of each of these biomarkers as cutoff points for dichotomization into “high” v “low”. We then correlated levels of the biomarkers with objective response rate, disease-free and overall survival. Results: Total protein was isolated from FFPE tumour sections from 41.5% of patients (n=196) recruited into the MAX clinical trial and assayed for the proteins using a multiplex platform. Patients were generally balanced, tumour tissue population v intention to treat. Median follow up time is 30.2 mths. For patients receiving BEV there was no relationship between the level of IL-6, IL-8, bFGF, PDGF-BB and VEGF-A and PFS and OS. In patients treated with BEV/C vs. C alone, low tumor VEGF-A was predictive of better ORR as compared to those with a high level (ORR 53% vs 38%, p = 0.03). Multivariate analyses showed low VEGF-A expression level was a significant prognostic factor for longer progression free survival (median PFS 9.3 months low VEGF-A v 7.2 months high VEGF-A, multivariate adjusted HR 1.55 (95% CI 1.12-2.13), p = 0.008). Conclusions: We have shown that the chosen panel of pro-angiogenic proteins was not predictive for PFS or OS outcomes when B is added to C in mCRC. However low VEGF-A level did predict for higher ORR and was an independent prognostic marker for PFS in this cohort. </jats:p
Correction: Author Correction: Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism
No full textNature Communications 8: Article number: 15132 (2017); Published: 2 May 2017; Updated: 6 February 2018 Michel Goedert, who developed the Thy1-P301S transgenic mouse, was inadvertently omitted from the Acknowledgments section of this Article. The Acknowledgements should have included the following: ‘We thank Michel Goedert for providing the Thy1-P301S transgenic mouse that was used in this study.</jats:p
Enhanced hippocampal LTP but normal NMDA receptor and AMPA receptor function in a rat model of CDKL5 deficiency disorder
No full text\ua9 The Author(s) 2024. Background: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5−/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5−/y rats. Methods: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. Results: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5−/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5−/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. Conclusions: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. Limitations: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD
