12 research outputs found
The large numbers of minicolumns in the primary visual cortex of humans, chimpanzees and gorillas are related to high visual acuity
Minicolumns are thought to be a fundamental neural unit in the neocortex and their replication may have formed the basis of the rapid cortical expansion that occurred during primate evolution. We sought evidence of minicolumns in the primary visual cortex (V-1) of three great apes, three rodents and representatives from three other mammalian orders: Eulipotyphla (European hedgehog), Artiodactyla (domestic pig) and Carnivora (ferret). Minicolumns, identified by the presence of a long bundle of radial, myelinated fibers stretching from layer III to the white matter of silver-stained sections, were found in the human, chimpanzee, gorilla and guinea pig V-1. Shorter bundles confined to one or two layers were found in the other species but represent modules rather than minicolumns. The inter-bundle distance, and hence density of minicolumns, varied systematically both within a local area that might represent a hypercolumn but also across the whole visual field. The distance between all bundles had a similar range for human, chimpanzee, gorilla, ferret and guinea pig: most bundles were 20–45 μm apart. By contrast, the space between bundles was greater for the hedgehog and pig (20–140 μm). The mean density of minicolumns was greater in tangential sections of the gorilla and chimpanzee (1,243–1,287 bundles/mm2) than in human (314–422 bundles/mm2) or guinea pig (643 bundles/mm2). The minicolumnar bundles did not form a hexagonal lattice but were arranged in thin curving and branched bands separated by thicker bands of neuropil/somata. Estimates of the total number of modules/minicolumns within V-1 were strongly correlated with visual acuity
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio
Transcriptomics and bioconcentration studies in fish to identify pharmaceuticals of environmental concern
Pharmaceuticals are frequently found in the aquatic environment. As they are most
often highly biologically active, quite persistent and may accumulate in aquatic organisms, i.e.
bioconcentrate, they may pose a risk to non-target organisms.
Current knowledge on environmental fate and effects of pharmaceuticals are limited,
and traditional risk assessment strategies are insufficient to capture all substances posing
risks for wildlife. In this thesis we explored the potential of two additional approaches to
assist in the identification of substances of environmental concern. The first involved readacross
between therapeutic plasma concentrations in humans and measured plasma levels of
pharmaceuticals in exposed fish, in order to predict the risks for pharmacological effects in
the fish. The second involved microarray analyses of gene expression to confirm
pharmacological interactions, find potential biomarkers and assess the mode of action of
pharmaceuticals in exposed fish.
We could show that waterborne diclofenac affects hepatic gene expression in exposed
fish at water concentrations reported in treated effluents and surface waters. Pharmacological
responses, resembling those found in mammals, were observed in fish at blood plasma
concentrations similar to human therapeutic plasma levels, indicating a similar potency and
mode of action in fish and humans. In contrast to some other reported results, the
bioconcentration factor of diclofenac in fish was found to be stable across exposure
concentrations.
Exposure of fish to ketoprofen at concentrations about 100 times higher than those
found in treated sewage effluents resulted in plasma concentrations below 1% of human
therapeutic plasma levels, suggesting low risk for effects in fish. Accordingly, no effects on
hepatic gene expression could be confirmed. However, exposure of fish to complex effluents
indicates a higher bioconcentration potential of NSAIDs than does exposure to single
substances. Thus, laboratory experiments may underestimate risks in the environment.
Microarray analyses revealed several differentially expressed genes after exposure to
conventionally treated effluents. These included estrogen-responsive genes and a biomarker
for dioxin-like exposure. Further results included indications of general stress after exposure
to all studied ozone treated effluents. Effluents treated with activated carbon resulted in the
least responses in exposed fish.
Exposure to the glucocorticoid beclomethasone-diproprionate affected plasma glucose
levels and caused oxidative stress in fish. Effects observed in fish resembled effects in
humans, supporting read-across between species. Exposure to free beclomethasone did not
result in any observed effects, most probably due to its inability to bioconcentrate.
Taken together, both read-across and microarray analyses have proven useful in
identifying pharmaceuticals of environmental concern
Multiple loci on 8q24 associated with prostate cancer susceptibility
Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility