42,758 research outputs found
L'intégration monétaire dans une perspective historique
No full textHamada Koichi, Porteous David. L'intégration monétaire dans une perspective historique. In: Revue d'économie financière, n°22, 1992. L’indépendance des Banques centrales . pp. 77-92
Recommended from our members
The David W. Fentress Family Letters, 1856-1969
No full textTranscript of a letter by an unidentified author to David Fentress regarding sharing federal newspapers and the banning of federal newspapers in some areas. The author passes on the news of the war including the destruction of the Federal merchantmen by the Confederate fleet. He passes along world news: Russia preparing to go to War with Europe and how that could negatively affect the Confederacy. There is also speculation on the future of the war
The David W. Fentress Family Letters, 1856-1969
No full textTranscript of a letter by an unidentified author to David Fentress regarding sharing federal newspapers and the banning of federal newspapers in some areas. The author passes on the news of the war including the destruction of the Federal merchantmen by the Confederate fleet. He passes along world news: Russia preparing to go to War with Europe and how that could negatively affect the Confederacy. There is also speculation on the future of the war
Portrait of author David Foster at the National Library of Australia, Canberra, 8 June 2011 /
No full textTitle from acquisitions documentation.; Part of the collection: Portraits of author David Foster at the National Library of Australia, Canberra, 8 June 2011.; Acquired in digital format; access copy available online.; Mode of access: Online.; Photographed by a staff member of the National Library of Australia
Author David Foster with academic Jeff Doyle at the National Library of Australia, Canberra, 8 June 2011 /
No full textTitle from acquisitions documentation.; Part of the collection: Portraits of author David Foster at the National Library of Australia, Canberra, 8 June 2011.; Acquired in digital format; access copy available online.; Mode of access: Online.; Photographed by a staff member of the National Library of Australia
DISC1 & GSK3β modulate PDE4 activity: functional integration of psychiatric associated signalling pathways
No full textFollowing the discovery of the DISC1 gene in 2000, subsequent research has led to
DISC1 becoming one of the most promising candidate genes for psychiatric disorders.
Acting as a scaffold protein, DISC1 has a large number of interacting proteins and is
involved in a series of intracellular signalling pathways. Amongst these binding proteins
are two enzymes, PDE4 and GSK3β, that were originally implicated in psychiatric
disease by virtue of their inhibition by psychoactive drugs. PDE4 enzymes are inhibited
by rolipram, which possesses anti-depressant and anti-psychotic activity, while GSK3β
is one of the major targets of lithium, a potent mood stabiliser. Both these enzymes are
intricately involved in the PI3K/AKT, cAMP, and MAPK signalling pathways, all of
which have a number of downstream outcomes with potential relevance to psychiatric
disorders. The Millar and Porteous laboratory had established that DISC1 modulates
PDE4 activity, but this predated awareness of GSK3 as another DISC1 interactor
whose binding site overlapped with that of PDE4. Since cAMP is a key regulator of
signalling pathways in the brain, I hypothesised that not only DISC1, but also GSK3β
may be involved in the regulation of PDE4 activity to control local cAMP levels and
gradients.
To investigate this hypothesis, I characterised SHSY5Y cells as a model for measuring
PDE4 activity, and performed a series of genetic and pharmacological manipulations on
this system. Inhibition of GSK3β resulted in a decrease of basal PDE4 activity that was
amplified by DISC1 overexpression. Wild type cells that were treated with forskolin
exhibited a significant increase in PDE4 activity, which was suppressed by GSK3β
inhibition and both overexpression and knockdown of DISC1. Further experiments
confirmed that none of these changes were a result of differences in PDE4 mRNA or
protein expression. Thus I have provided evidence that suggests tonic activation of
PDE4 by GSK3β and evidence for modulation of PDE4 activity by DISC1. I provide
evidence for the localisation of PDE4B & PDE4D with key psychiatric associated
receptors in structures resembling developing dendritic spines; furthermore, agonism of
NMDA receptors results in a significant increase in PDE4 activity in primary neurons.
These results are a simple demonstration of an emerging principle in psychiatric
research: that none of the signalling pathways implicated in psychiatric disease are
acting in isolation. There are likely to be multiple points of integration between these
pathways, with the demonstrated DISC1-GSK3β-PDE4 interaction forming one of these
points. My results add an important new element to the understanding of how the
DISC1 complex may regulate intracellular signalling in response to extracellular cues
Author David Foster and academic Jeff Doyle at the National Library of Australia, Canberra, 8 June 2011 /
No full textTitle from acquisitions documentation.; Part of the collection: Portraits of author David Foster at the National Library of Australia, Canberra, 8 June 2011.; Acquired in digital format; access copy available online.; Mode of access: Online.; Photographed by a staff member of the National Library of Australia
- …
