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Oulu, Finland

Kobayashi H.,University of Cambridge | Kobayashi H.,Toho University | Isohanni M.,University of Oulu | Jaaskelainen E.,University of Oulu | And 9 more authors.
Schizophrenia Bulletin | Year: 2014

Neurodevelopmental and neurodegenerative theories may be viewed as incompatible accounts that compete to explain the pathogenesis of schizophrenia. However, it is possible that neurodevelopmental and neurodegenerative processes could both reflect common underlying causal mechanisms. We hypothesized that cognitive dysfunction would gradually deteriorate over time in schizophrenia and the degree of this deterioration in adulthood would be predicted by an infant measure of neurodevelopment. We aimed to examine the association between age of learning to stand in infancy and deterioration of cognitive function in adulthood. Participants were nonpsychotic control subjects (n = 76) and participants with schizophrenia (n = 36) drawn from the Northern Finland 1966 Birth Cohort study. The schizophrenia group showed greater deterioration in abstraction with memory than controls, but there were no differences between schizophrenia and controls in rate of change of other cognitive measures. Age of learning to stand in infancy significantly inversely predicted later deterioration of abstraction with memory in adult schizophrenia (later infant development linked to greater subsequent cognitive deterioration during adulthood), possibly suggesting a link between abnormal neurodevelopmental and neurodegenerative processes in schizophrenia. © 2014 © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. Source


Katritch V.,Scripps Research Institute | Katritch V.,University of California at San Diego | Jaakola V.-P.,Scripps Research Institute | Jaakola V.-P.,Biocenter Oulu | And 10 more authors.
Journal of Medicinal Chemistry | Year: 2010

The recent progress in crystallography of G-protein coupled receptors opens an, unprecedented venue for structure-based GPCR drug discovery. To test efficiency of the structure-based approach, we performed molecular docking and virtual ligand screening (VLS) of more than 4 million commercially available "drug-like " and "lead-like " compounds against the A 2AAR 2.6 Å resolution crystal structure. Out of 56 high ranking compounds tested, in A2AAR binding assays, 23 showed, affinities under 10μM, 11 of those had sub-μM affinities and, two compounds had affinities under 60 nM. The identified hits represent at least 9 different chemical scaffolds and are characterized by very high ligand efficiency (0.3-0.5 kcal/mol per heavy atom). Significant A2AAR antagonist activities were confirmed for 10 out of 13 ligands tested in, functional assays. High success rate, novelty, and diversity of the chemical scaffolds and strong ligand efficiency of the A2A,AR antagonists identified in this study suggest practical applicability of receptor-based VLS in GPCR drug discovery. © 2010 American Chemical Society. Source


Hakkola J.,University of Oulu | Rysa J.,University of Eastern Finland | Hukkanen J.,University of Oulu | Hukkanen J.,Biocenter Oulu
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2016

The pregnane X receptor (PXR) is a nuclear receptor that is traditionally thought to be specialized for sensing xenobiotic exposure. In concurrence with this feature PXR was originally identified to regulate drug-metabolizing enzymes and transporters. During the last ten years it has become clear that PXR harbors broader functions. Evidence obtained both in experimental animals and humans indicate that ligand-activated PXR regulates hepatic glucose and lipid metabolism and affects whole body metabolic homeostasis. Currently, the consequences of PXR activation on overall metabolic health are not yet fully understood and varying results on the effect of PXR activation or knockout on metabolic disorders and weight gain have been published in mouse models. Rifampicin and St. John's wort, the prototypical human PXR agonists, impair glucose tolerance in healthy volunteers. Chronic exposure to PXR agonists could potentially represent a risk factor for diabetes and metabolic syndrome. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. © 2016. Source


Li Z.,University of Helsinki | Sillanpaa M.J.,University of Oulu | Sillanpaa M.J.,Biocenter Oulu
Genetics | Year: 2013

In biology, many quantitative traits are dynamic in nature. They can often be described by some smooth functions or curves. A joint analysis of all the repeated measurements of the dynamic traits by functional quantitative trait loci (QTL) mapping methods has the benefits to (1) understand the genetic control of the whole dynamic process of the quantitative traits and (2) improve the statistical power to detect QTL. One crucial issue in functional QTL mapping is how to correctly describe the smoothness of trajectories of functional valued traits. We develop an efficient Bayesian nonparametric multiple-loci procedure for mapping dynamic traits. The method uses the Bayesian P-splines with (nonparametric) B-spline bases to specify the functional form of a QTL trajectory and a random walk prior to automatically determine its degree of smoothness. An efficient deterministic variational Bayes algorithm is used to implement both (1) the search of an optimal subset of QTL among large marker panels and (2) estimation of the genetic effects of the selected QTL changing over time. Our method can be fast even on some large-scale data sets. The advantages of our method are illustrated on both simulated and real data sets. © 2013 by the Genetics Society of America. Source


Li Z.,University of Helsinki | Hallingback H.R.,University of Helsinki | Abrahamsson S.,Swedish University of Agricultural Sciences | Fries A.,Swedish University of Agricultural Sciences | And 4 more authors.
G3: Genes, Genomes, Genetics | Year: 2014

Quantitative trait loci (QTL) mapping of wood properties in conifer species has focused on single time point measurements or on trait means based on heterogeneous wood samples (e.g., increment cores), thus ignoring systematic within-tree trends. In this study, functional QTL mapping was performed for a set of important wood properties in increment cores from a 17-yr-old Scots pine (Pinus sylvestris L.) full-sib family with the aim of detecting wood trait QTL for general intercepts (means) and for linear slopes by increasing cambial age. Two multi-locus functional QTL analysis approaches were proposed and their performances were compared on trait datasets comprising 2 to 9 time points, 91 to 455 individual tree measurements and genotype datasets of amplified length polymorphisms (AFLP), and single nucleotide polymorphism (SNP) markers. The first method was a multilevel LASSO analysis whereby trend parameter estimation and QTL mapping were conducted consecutively; the second method was our Bayesian linear mixed model whereby trends and underlying genetic effects were estimated simultaneously. We also compared several different hypothesis testing methods under either the LASSO or the Bayesian framework to perform QTL inference. In total, five and four significant QTL were observed for the intercepts and slopes, respectively, across wood traits such as earlywood percentage, wood density, radial fiberwidth, and spiral grain angle. Four of these QTL were represented by candidate gene SNPs, thus providing promising targets for future research in QTL mapping and molecular function. Bayesian and LASSO methods both detected similar sets of QTL given datasets that comprised large numbers of individuals. © 2014 Li et al. Source

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