1,278 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
Norman Porteous as I Remember Him
No full textThis paper describes the period (1960-67) the author spent working with Norman Porteous in the department of Old Testament at New College, Edinburgh. He describes this as a time when Porteous was at the peak of his reputation as the foremost scholar of Old Testament Theology in Great Britain. However, the magnum opus that he might have been expected to produce at this point never appeared, in particular because the publication of von Rad’s Old Testament Theology made him realise that, with an already crowded schedule, he would not be able to devote sufficient time to be able to engage properly with such a major departure from the established ways of working in biblical theology. The paper does however give us insights into Porteous’ thinking on the subject around this time, based on a report of his Stone Lectures and from one-to-one interaction with the author
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
Supporting offenders who are also victims [Blog post]
No full textIn, May 2015, the London Mayoral Office for Policing and Crime published research undertaken at Middlesex University into the development of support services for young people who have offended but have themselves been a victim of crime, abuse and violence. One of the authors of the report, Associate Professor in Criminology at Middlesex University Dr David Porteous, considers the issues raised by the study
Copy Number Variants in the human genome and their association with quantitative traits
No full textCopy number Variants (CNVs), which comprise deletions, insertions and inversions of genomic
sequence, are a main form of genetic variation between individual genomes. CNVs are
commonly present in the genomes of human and other species. However, they have not been
extensively characterized as their ascertainment is challenging.
I reviewed current CNV studies and CNV discovery methods, especially the algorithms which
infer CNVs from whole genome Single Nucleotide Polymorphism (SNP) arrays and compared
the performance of three analytical tools in order to identify the best method of CNV
identification. Then I applied this method to identify CNV events in three European population
isolates—the island of Vis in Croatia, the islands of Orkney in Scotland and villages in the South
Tyrol in Italy - from Illumina genome-wide array data with more than 300,000 SNPs. I analyzed
and compared CNV features across these three populations, including CNV frequencies, genome
distribution, gene content, segmental duplication overlap and GC content. With the pedigree
information for each population, I investigated the inheritance and segregation of CNVs in
families. I also looked at association between CNVs and quantitative traits measured in the study
samples.
CNVs were widely found in study samples and reference genomes. Discrepancies were found
between sets of CNVs called by different analytical tools. I detected 4016 CNVs in 1964
individuals, out of a total of 2789 participants from the three population isolates, which clustered
into 743 copy number variable regions (CNVRs). Features of these CVNRs, including frequency
and distribution, were compared and were shown to differ significantly between the Orcadian, South Tyrolean and Dalmatian population samples. Consistent with the inference that this
indicated population-specific CNVR identity and origin, it was also demonstrated that CNV
variation within each population can be used to measure genetic relatedness. Finally, I
discovered that individuals who had extreme values of some metabolic traits possessed rare
CNVs which overlapped with known genes more often than in individuals with moderate trait
values
Identification of polymorphic and off-target probe binding sites on the Illumina Infinium MethylationEPIC BeadChip
No full textGenome-wide analysis of DNA methylation has now become a relatively inexpensive technique thanks to array-based methylation profiling technologies. The recently developed Illumina Infinium MethylationEPIC BeadChip interrogates methylation at over 850,000 sites across the human genome, covering 99% of RefSeq genes. This array supersedes the widely used Infinium HumanMethylation450 BeadChip, which has permitted insights into the relationship between DNA methylation and a wide range of conditions and traits. Previous research has identified issues with certain probes on both the HumanMethylation450 BeadChip and its predecessor, the Infinium HumanMethylation27 BeadChip, which were predicted to affect array performance. These issues concerned probe-binding specificity and the presence of polymorphisms at target sites. Using in silico methods, we have identified probes on the Infinium MethylationEPIC BeadChip that are predicted to (i) measure methylation at polymorphic sites and (ii) hybridise to multiple genomic regions. We intend these resources to be used for quality control procedures when analysing data derived from this platform
School Days in Haddington, East Lothian: The Boyhood and Youth of Norman Porteous
No full textA brief account of Porteous’ schooling at the Knox institute, Haddingto
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