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Biocenter Oulu

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Buler M.,University of Oulu | Buler M.,Medical Research Center Oulu | Aatsinki S.-M.,University of Oulu | Aatsinki S.-M.,Medical Research Center Oulu | And 5 more authors.
FASEB Journal | Year: 2014

The sirtuins (SIRTs; SIRT1-7) are a family of NAD+-dependent enzymes that dynamically regulate cellular physiology. Apart from SIRT1, the functions and regulatory mechanisms of the SIRTs are poorly defined. We explored regulation of the SIRT family by 2 energy metabolism-controlling factors: peroxisome proliferator-activated receptor y coactiva-tor 1-a (PGC-1α) and AMP-activated protein kinase (AMPK). Overexpression of PGC-1α in mouse primary hepatocytes increased SIRT5 mRNA expression 4-fold and also the protein in a peroxisome proliferator-activated receptor a (PPARa)- and estrogen-related receptor a (ERRa)-dependent manner. Furthermore, food withdrawal increased SIRT5 mRNA 1.3-fold in rat liver. Overexpression of AMPK in mouse hepatocytes increased expression of SIRT1, SIRT2, SIRT3, and SIRT6 < 2-fold. In contrast, SIRT5 mRNA was down-regulated by 58%. The antidiabetes drug metformin (1 mM), an established AMPK activator, reduced the mouse SIRT5 protein level by 44% in cultured hepatocytes and by 31% in liver in vivo (300 mg/kg, 7 d). Metformin also induced hypersuccinylation of mitochondrial proteins. Moreover, SIRT5 overexpression increased ATP synthesis and oxygen consumption in HepG2 cells, but did not affect mitochondrial biogenesis. In summary, our results identified SIRT5 as a novel factor that controls mitochondrial function. Moreover, SIRT5 levels are regulated by PGC-1α and AMPK which have opposite effects on its expression. © FASEB.


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.


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.


Li Z.,University of Helsinki | Sillanpaa M.J.,University of Helsinki | Sillanpaa M.J.,University of Oulu | Sillanpaa M.J.,Biocenter Oulu
Theoretical and Applied Genetics | Year: 2012

Quantitative trait loci (QTL)/association mapping aims at finding genomic loci associated with the phenotypes, whereas genomic selection focuses on breeding value prediction based on genomic data. Variable selection is a key to both of these tasks as it allows to (1) detect clear mapping signals of QTL activity, and (2) predict the genome-enhanced breeding values accurately. In this paper, we provide an overview of a statistical method called least absolute shrinkage and selection operator (LASSO) and two of its generalizations named elastic net and adaptive LASSO in the contexts of QTL mapping and genomic breeding value prediction in plants (or animals). We also briefly summarize the Bayesian interpretation of LASSO, and the inspired hierarchical Bayesian models. We illustrate the implementation and examine the performance of methods using three public data sets: (1) North American barley data with 127 individuals and 145 markers, (2) a simulated QTLMAS XII data with 5,865 individuals and 6,000 markers for both QTL mapping and genomic selection, and (3) a wheat data with 599 individuals and 1,279 markers only for genomic selection. © 2012 Springer-Verlag.


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.


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.


Lu N.,University of Bergen | Carracedo S.,University of Bergen | Ranta J.,Biocenter Oulu | Heuchel R.,Karolinska Hospital | And 2 more authors.
Matrix Biology | Year: 2010

Integrin α11β1 is expressed by ectomesenchymally- and mesodermally-derived fibroblasts and is the major collagen receptor on embryonic fibroblasts. We have previously characterized a 3. kb human α11 promoter region in vitro. In the current study we generated promoter-LacZ reporter transgenic mice to examine the ability of the 3. kb α11 promoter to drive tissue-specific expression also in vivo. Our data show that the 3 kb α11 promoter contains most of the regulatory elements that direct ectomesenchymal and mesodermal fibroblast-specific expression.Not much is known about integrin α11 regulation by TGF-β family members and the potential role of α11 in TGF-β1 driven processes such as fibrosis and wound contraction. In the current study we show that TGF-β1 induces α11 transcription in the fibrosarcoma cell line HT1080 as well as in primary fibroblasts. Co-transfection of an expression plasmid encoding constitutively active ALK5 together with α11 promoter-luciferase reporter constructs demonstrated that TGF-β1 responsive elements are located within the 3. kb α11 promoter. Serial deletions located TGF-β1 responsiveness to the proximal promoter (nt -176/+25) as well as to the region extending to nt -330. Transfection and expression of the inhibitory Smad7 in the cells attenuated the TGF-β1-dependent α11 induction both at the RNA and the protein level. Mutation and deletion analyses identified a Smad-binding element, SBE2 (nt -182/-176), as an important Smad3-binding site in this part of the promoter. Further analyses suggested that the Sp1-binding site SBS1 (nt -140/-134) takes part in the responsiveness to TGF-β1 in a Smad2-dependent manner.In summary, our data confirm that 3. kb of the α11 promoter is efficient in driving tissue-specific expression in vivo. We also demonstrate that this promoter confers TGF-β1 responsiveness which appears to rely on both a Smad-binding element at nt -182/-176 and a Sp1-binding site at nt -140/-134. Our data furthermore indicate that additional elements needed for TGF-β1 responsiveness are located upstream in the -2962/-330 promoter region. © 2009 International Society of Matrix Biology.


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.


Li Z.,Biocenter Oulu | Li Z.,University of Oulu | Sillanpaa M.J.,Biocenter Oulu | Sillanpaa M.J.,University of Oulu
Trends in Plant Science | Year: 2015

Advanced platforms have recently become available for automatic and systematic quantification of plant growth and development. These new techniques can efficiently produce multiple measurements of phenotypes over time, and introduce time as an extra dimension to quantitative trait locus (QTL) studies. Functional mapping utilizes a class of statistical models for identifying QTLs associated with the growth characteristics of interest. A major benefit of functional mapping is that it integrates information over multiple timepoints, and therefore could increase the statistical power for QTL detection. We review the current development of computationally efficient functional mapping methods which provide invaluable tools for analyzing large-scale timecourse data that are readily available in our post-genome era. High-throughput imaging techniques are capable of measuring time-series of plant phenotypes, which may potentially facilitate the QTL analysis of developmental and growth related traits.A major benefit of functional mapping is that it integrates information over multiple timepoints, and therefore could increase the statistical power for QTL detection.To handle high-dimensional genotyping and phenotyping data, computational efficiency is the focus of the novel statistical methods for dynamic QTL analysis. © 2015 Elsevier Ltd.


Halt K.,Matrix | Halt K.,Biocenter Oulu | Halt K.,University of Oulu | Vainio S.,Matrix | And 2 more authors.
Pediatric Nephrology | Year: 2014

Several Wnt proteins are expressed in the embryonic kidney during various stages of development. Gene knockout models and ex vivo studies have provided strong evidence that Wnt-mediated signals are essential in renal ontogeny. Perhaps the most critical factors, Wnt9b and Wnt4, function during the early phase when the cap mesenchyme is induced to undergo morphogenesis into a nephron. Wnt11 controls early ureteric bud branching and contributes to the final kidney size. In addition to its inductive role, later on Wnt9b plays a significant role in the convergent extension of the tubular epithelial cells, while Wnt4 signaling controls smooth muscle cell fates in the medulla. Wnt7b has a specific function together with its likely antagonist Dkk1 in controlling the morphogenesis of the renal medulla. The signal-transduction mechanisms of the Wnts in kidney ontogeny have not been resolved, but studies characterizing the downstream signaling pathways are emerging. Aberrant Wnt signaling may lead to kidney diseases ranging from fatal kidney agenesis to more benign phenotypes. Wnt-mediated signaling regulates several critical aspects of kidney development from the early inductive stages to later steps of tubular epithelial maturation. © 2014 The Author(s).

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