Discussion on Walker, Damien, Laud and Smith

models. In practice, it is likely that these algorithms will not be commonly used and I am going to concentrate my remarks on the other two constructions presented for which prior to posterior computations are fairly straightforward. Note that both P'olya trees (PT) and Bernoulli trips (BT) involve in fine some arbitrary discretization, PT will be partially specified up to a level M , while BT rely on discrete time. P'olya tree priors require a binary tree partitioning of the space. In contrast to the DP, it has long been recognized (Ferguson 1974) that the points of subdivisions play a part in the posterior properties of the process, which is an undesirable feature. On the other hand, in comparison to the DP, P'olya trees are more flexible since they allow choice of ff ffl0 ; ff ffl1 at each level, whereas for the DP ff ffl = ff ffl0 + ff<F14

APOE is a potential modifier gene in an autosomal dominant form of frontotemporal dementia (IBMPFD)

PurposeInclusion-body myopathy, Paget's disease of bone and frontotemporal dementia is an adult-onset autosomal dominant illness (IBMPFD) caused by mutations in the valosin-containing protein (VCP) on chromosome 9p21.1-p12. The penetrance of the gene is 82% for myopathy, 49% for Paget's disease, but may be as low as 30% for frontotemporal dementia. Modifier genes could account for decreased frontotemporal dementia penetrance. In this study apolipoprotein-E (APOE) was evaluated for this role in IBMPFD families based on its known modifier effect in Alzheimer's disease.MethodsFrom a database of 231 members of 15 families, 174 had APOE genotype available for analysis. Logistic regressions on APOE genotype and frontotemporal dementia were performed, using appropriate covariates.Results and conclusionFTD was associated with APOE 4 genotype (P=0.0002), myopathy (P=0.0006), and age (P=0.01), but not microtubule associated protein tau (MAPT) H2 haplotype (P=0.5) or gender (0.09) after adjustment for membership in pedigrees with at least one APOE 4 genotype. These data suggest a potential link between APOE 4 genotype and the specific form of frontotemporal dementia found in IBMPFD. The molecular basis of this link bears further investigation. We did not observe an association of frontotemporal dementia and H2 MAPT haplotype

Epigenetic modulation of adult hippocampal neurogenesis by extremely low-frequency electromagnetic fields.

Throughout life adult neurogenesis generates new neurons in the dentate gyrus of hippocampus that have a critical role in memory formation. Strategies able to stimulate this endogenous process have raised considerable interest because of their potential use to treat neurological disorders entailing cognitive impairment. We previously reported that mice exposed to extremely low-frequency electromagnetic fields (ELFEFs) showed increased hippocampal neurogenesis. Here we demonstrate that the ELFEF-dependent enhancement of hippocampal neurogenesis improves spatial learning and memory. To gain insights on the molecular mechanisms underlying ELFEFs\u2019 effects we extended our studies to an in vitro model of neural stem cells (NSCs) isolated from the hippocampi of newborn mice. We found that ELFEFs enhanced proliferation and neuronal differentiation of hippocampal NSCs by regulation of epigenetic mechanisms leading to pro-neuronal gene expression. Upon ELFEF stimulation of NSCs, we observed a significant enhancement of expression of the pro-proliferative gene Hes1 and the neuronal determination genes NeuroD1 and Neurogenin1. These events were preceded by increased acetylation of H3K9 and binding of the phosphorylated transcription factor cAMP response element-binding protein (CREB) on the regulatory sequence of these genes. Such ELFEF-dependent epigenetic modifications were prevented by the Cav1-channel blocker nifedipine, and were associated with increased occupancy of CREB binding protein (CBP) to the same loci within the analyzed promoters. Our results unravel the molecular mechanisms underlying the ELFEFs\u2019 ability to improve endogenous neurogenesis, pointing to histone acetylation\u2013related chromatin remodeling as a critical determinant. These findings could pave the way to the development of novel therapeutic approaches in regenerative medicin