14 results on '"Sears, Renee L."'
Search Results
2. Human placental cytotrophoblast epigenome dynamics over gestation and alterations in placental disease
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Zhang, Bo, Kim, M Yvonne, Elliot, GiNell, Zhou, Yan, Zhao, Guangfeng, Li, Daofeng, Lowdon, Rebecca F, Gormley, Matthew, Kapidzic, Mirhan, Robinson, Joshua F, McMaster, Michael T, Hong, Chibo, Mazor, Tali, Hamilton, Emily, Sears, Renee L, Pehrsson, Erica C, Marra, Marco A, Jones, Steven JM, Bilenky, Misha, Hirst, Martin, Wang, Ting, Costello, Joseph F, and Fisher, Susan J
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Biological Sciences ,Genetics ,Human Genome ,Clinical Research ,Pediatric Research Initiative ,Contraception/Reproduction ,Biotechnology ,Pediatric ,1.1 Normal biological development and functioning ,Aetiology ,Underpinning research ,2.1 Biological and endogenous factors ,Reproductive health and childbirth ,Good Health and Well Being ,Acetylation ,DNA Methylation ,Enhancer Elements ,Genetic ,Epigenome ,Female ,Gene Expression Regulation ,Developmental ,Gestational Age ,Histones ,Humans ,Lysine ,Placenta Diseases ,Pre-Eclampsia ,Pregnancy ,Protein Processing ,Post-Translational ,Trophoblasts ,DNA methylation ,H3K27ac ,H3K9me3 ,chorionic villi ,cytotrophoblast ,gestational regulation ,histone modification ,human placenta ,placental disease ,preeclampsia ,Medical and Health Sciences ,Developmental Biology ,Biochemistry and cell biology - Abstract
The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring's health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.
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- 2021
3. Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer’s disease
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Yokoyama, Jennifer S, Bonham, Luke W, Sears, Renee L, Klein, Eric, Karydas, Anna, Kramer, Joel H, Miller, Bruce L, and Coppola, Giovanni
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Neurodegenerative ,Genetics ,Brain Disorders ,Aging ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Clinical Research ,Human Genome ,Genetic Testing ,Dementia ,2.1 Biological and endogenous factors ,Aetiology ,Aged ,Aged ,80 and over ,Algorithms ,Alleles ,Alzheimer Disease ,Apolipoprotein E4 ,Cohort Studies ,Decision Trees ,Female ,Genetic Markers ,Genotype ,Humans ,Male ,Neurologic Examination ,Phenotype ,Risk Assessment ,Risk Factors ,Alzheimer's disease ,Decision tree analysis ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
BackgroundHeritability of Alzheimer's disease (AD) is estimated at 74% and genetic contributors have been widely sought. The ε4 allele of apolipoprotein E (APOE) remains the strongest common risk factor for AD, with numerous other common variants contributing only modest risk for disease. Variability in clinical presentation of AD, which is typically amnestic (AmnAD) but can less commonly involve visuospatial, language and/or dysexecutive syndromes (atypical or AtAD), further complicates genetic analyses. Taking a multi-locus approach may increase the ability to identify individuals at highest risk for any AD syndrome. In this study, we sought to develop and investigate the utility of a multi-variant genetic risk assessment on a cohort of phenotypically heterogeneous patients with sporadic AD clinical diagnoses.MethodsWe genotyped 75 variants in our cohort and, using a two-staged study design, we developed a 17-marker AD risk score in a Discovery cohort (n = 59 cases, n = 133 controls) then assessed its utility in a second Validation cohort (n = 126 cases, n = 150 controls). We also performed a data-driven decision tree analysis to identify genetic and/or demographic criteria that are most useful for accurately differentiating all AD cases from controls.ResultsWe confirmed APOE ε4 as a strong risk factor for AD. A 17-marker risk panel predicted AD significantly better than APOE genotype alone (P
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- 2015
4. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export.
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Legati, Andrea, Giovannini, Donatella, Nicolas, Gaël, López-Sánchez, Uriel, Quintáns, Beatriz, Oliveira, João RM, Sears, Renee L, Ramos, Eliana Marisa, Spiteri, Elizabeth, Sobrido, María-Jesús, Carracedo, Ángel, Castro-Fernández, Cristina, Cubizolle, Stéphanie, Fogel, Brent L, Goizet, Cyril, Jen, Joanna C, Kirdlarp, Suppachok, Lang, Anthony E, Miedzybrodzka, Zosia, Mitarnun, Witoon, Paucar, Martin, Paulson, Henry, Pariente, Jérémie, Richard, Anne-Claire, Salins, Naomi S, Simpson, Sheila A, Striano, Pasquale, Svenningsson, Per, Tison, François, Unni, Vivek K, Vanakker, Olivier, Wessels, Marja W, Wetchaphanphesat, Suppachok, Yang, Michele, Boller, Francois, Campion, Dominique, Hannequin, Didier, Sitbon, Marc, Geschwind, Daniel H, Battini, Jean-Luc, and Coppola, Giovanni
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Humans ,Brain Diseases ,Metabolic ,Inborn ,Neurodegenerative Diseases ,Calcinosis ,Genetic Predisposition to Disease ,Receptors ,G-Protein-Coupled ,Receptors ,Virus ,Pedigree ,DNA Mutational Analysis ,Lod Score ,Mutation ,Missense ,Middle Aged ,Female ,Male ,Genetic Association Studies ,HEK293 Cells ,Xenotropic and Polytropic Retrovirus Receptor ,Neurosciences ,Rare Diseases ,2.1 Biological and endogenous factors ,Aetiology ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC.
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- 2015
5. A Multiancestral Genome-Wide Exome Array Study of Alzheimer Disease, Frontotemporal Dementia, and Progressive Supranuclear Palsy
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Chen, Jason A, Wang, Qing, Davis-Turak, Jeremy, Li, Yun, Karydas, Anna M, Hsu, Sandy C, Sears, Renee L, Chatzopoulou, Doxa, Huang, Alden Y, Wojta, Kevin J, Klein, Eric, Lee, Jason, Beekly, Duane L, Boxer, Adam, Faber, Kelley M, Haase, Claudia M, Miller, Josh, Poon, Wayne W, Rosen, Ami, Rosen, Howard, Sapozhnikova, Anna, Shapira, Jill, Varpetian, Arousiak, Foroud, Tatiana M, Levenson, Robert W, Levey, Allan I, Kukull, Walter A, Mendez, Mario F, Ringman, John, Chui, Helena, Cotman, Carl, DeCarli, Charles, Miller, Bruce L, Geschwind, Daniel H, and Coppola, Giovanni
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- 2015
6. An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy.
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Li, Yun, Chen, Jason A, Sears, Renee L, Gao, Fuying, Klein, Eric D, Karydas, Anna, Geschwind, Michael D, Rosen, Howard J, Boxer, Adam L, Guo, Weilong, Pellegrini, Matteo, Horvath, Steve, Miller, Bruce L, Geschwind, Daniel H, and Coppola, Giovanni
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Brain ,Chromosomes ,Human ,Pair 17 ,Humans ,Supranuclear Palsy ,Progressive ,Neurodegenerative Diseases ,Tauopathies ,Genetic Predisposition to Disease ,tau Proteins ,Risk Factors ,DNA Methylation ,Epigenesis ,Genetic ,Haplotypes ,Genetic Association Studies ,Frontotemporal Dementia ,Developmental Biology ,Genetics - Abstract
Little is known about how changes in DNA methylation mediate risk for human diseases including dementia. Analysis of genome-wide methylation patterns in patients with two forms of tau-related dementia--progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD)--revealed significant differentially methylated probes (DMPs) in patients versus unaffected controls. Remarkably, DMPs in PSP were clustered within the 17q21.31 region, previously known to harbor the major genetic risk factor for PSP. We identified and replicated a dose-dependent effect of the risk-associated H1 haplotype on methylation levels within the region in blood and brain. These data reveal that the H1 haplotype increases risk for tauopathy via differential methylation at that locus, indicating a mediating role for methylation in dementia pathophysiology.
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- 2014
7. Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification
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Hsu, Sandy Chan, Sears, Renee L, Lemos, Roberta R, Quintáns, Beatriz, Huang, Alden, Spiteri, Elizabeth, Nevarez, Lisette, Mamah, Catherine, Zatz, Mayana, Pierce, Kerrie D, Fullerton, Janice M, Adair, John C, Berner, Jon E, Bower, Matthew, Brodaty, Henry, Carmona, Olga, Dobricić, Valerija, Fogel, Brent L, García-Estevez, Daniel, Goldman, Jill, Goudreau, John L, Hopfer, Suellen, Janković, Milena, Jaumà, Serge, Jen, Joanna C, Kirdlarp, Suppachok, Klepper, Joerg, Kostić, Vladimir, Lang, Anthony E, Linglart, Agnès, Maisenbacher, Melissa K, Manyam, Bala V, Mazzoni, Pietro, Miedzybrodzka, Zofia, Mitarnun, Witoon, Mitchell, Philip B, Mueller, Jennifer, Novaković, Ivana, Paucar, Martin, Paulson, Henry, Simpson, Sheila A, Svenningsson, Per, Tuite, Paul, Vitek, Jerrold, Wetchaphanphesat, Suppachok, Williams, Charles, Yang, Michele, Schofield, Peter R, de Oliveira, João RM, Sobrido, María-Jesús, Geschwind, Daniel H, and Coppola, Giovanni
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Neurodegenerative ,Human Genome ,Clinical Research ,Neurosciences ,Genetic Testing ,Prevention ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adult ,Aged ,Amino Acid Sequence ,Basal Ganglia Diseases ,Calcinosis ,Cohort Studies ,DNA Mutational Analysis ,Family ,Female ,Humans ,Linkage Disequilibrium ,Male ,Middle Aged ,Models ,Biological ,Molecular Sequence Data ,Mutation ,Neurodegenerative Diseases ,Retrospective Studies ,Sodium-Phosphate Cotransporter Proteins ,Type III ,Basal ganglia calcification ,Fahr's ,Sequencing ,Mutations ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.
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- 2013
8. WashU Epigenome Browser update 2019
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Li, Daofeng, primary, Hsu, Silas, additional, Purushotham, Deepak, additional, Sears, Renee L, additional, and Wang, Ting, additional
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- 2019
- Full Text
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9. Bioinformatics Approaches to Stem Cell Research
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Zhou, Jia, primary and Sears, Renee L., additional
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- 2018
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10. Tissue-specific DNA methylation is conserved across human, mouse, and rat, and driven by primary sequence conservation
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Zhou, Jia, primary, Sears, Renee L., additional, Xing, Xiaoyun, additional, Zhang, Bo, additional, Li, Daofeng, additional, Rockweiler, Nicole B., additional, Jang, Hyo Sik, additional, Choudhary, Mayank N.K., additional, Lee, Hyung Joo, additional, Lowdon, Rebecca F., additional, Arand, Jason, additional, Tabers, Brianne, additional, Gu, C. Charles, additional, Cicero, Theodore J., additional, and Wang, Ting, additional
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- 2017
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11. Epigenomic annotation of genetic variants using the Roadmap Epigenome Browser
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Zhou, Xin, primary, Li, Daofeng, additional, Zhang, Bo, additional, Lowdon, Rebecca F, additional, Rockweiler, Nicole B, additional, Sears, Renee L, additional, Madden, Pamela A F, additional, Smirnov, Ivan, additional, Costello, Joseph F, additional, and Wang, Ting, additional
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- 2015
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12. Tissue-specific DNA methylation is conserved across human, mouse, and rat, and driven by primary sequence conservation.
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Jia Zhou, Sears, Renee L., Xiaoyun Xing, Bo Zhang, Daofeng Li, Rockweiler, Nicole B., Hyo Sik Jang, Choudhary, Mayank N. K., Hyung Joo Lee, Lowdon, Rebecca F., Arand, Jason, Tabers, Brianne, Gu, C. Charles, Cicero, Theodore J., and Ting Wang
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DNA methylation , *PHENOTYPES , *GENETICS , *SPECIES , *GENES - Abstract
Background: Uncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. While studies have confirmed DNA methylation as a conserved epigenetic mechanism in mammalian development, little is known about the conservation of tissue-specific genome-wide DNA methylation patterns. Results: Using a comparative epigenomics approach, we identified and compared the tissue-specific DNAmethylation patterns of rat against those of mouse and human across three shared tissue types. We confirmed that tissue-specific differentially methylated regions are strongly associated with tissue-specific regulatory elements. Comparisons between species revealed that at a minimum 11-37% of tissue-specific DNA methylation patterns are conserved, a phenomenon that we define as epigenetic conservation. Conserved DNA methylation is accompanied by conservation of other epigenetic marks including histone modifications. Although a significant amount of locus-specific methylation is epigenetically conserved, the majority of tissue-specific DNA methylation is not conserved across the species and tissue types that we investigated. Examination of the genetic underpinning of epigenetic conservation suggests that primary sequence conservation is a driving force behind epigenetic conservation. In contrast, evolutionary dynamics of tissue-specific DNA methylation are best explained by the maintenance or turnover of binding sites for important transcription factors. Conclusions: Our study extends the limited literature of comparative epigenomics and suggests a new paradigm for epigenetic conservation without genetic conservation through analysis of transcription factor binding sites. [ABSTRACT FROM AUTHOR]
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- 2017
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13. Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice
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Keller, Annika, Westenberger, Ana, Sobrido, Maria J., Garcia-Murias, Maria, Domingo, Aloysius, Sears, Renee L., Lemos, Roberta R., Ordonez-Ugalde, Andres, Nicolas, Gael, Gomes da Cunha, Jose E., Rushing, Elisabeth J., Hugelshofer, Michael, Wurnig, Moritz C., Kaech, Andres, Reimann, Regina, Lohmann, Katja, Dobricic, Valerija, Carracedo, Angel, Petrovic, Igor, Miyasaki, Janis M., Abakumova, Irina, Mäe, Maarja Andaloussi, Raschperger, Elisabeth, Zatz, Mayana, Zschiedrich, Katja, Klepper, Jorg, Spiteri, Elizabeth, Prieto, Jose M., Navas, Inmaculada, Preuss, Michael, Dering, Carmen, Jankovic, Milena, Paucar, Martin, Svenningsson, Per, Saliminejad, Kioomars, Khorshid, Hamid R. K., Novakovic, Ivana, Aguzzi, Adriano, Boss, Andreas, Le Ber, Isabelle, Defer, Gilles, Hannequin, Didier, Kostic, Vladimir S., Campion, Dominique, Geschwind, Daniel H., Coppola, Giovanni, Betsholtz, Christer, Klein, Christine, Oliveira, Joao R. M., Keller, Annika, Westenberger, Ana, Sobrido, Maria J., Garcia-Murias, Maria, Domingo, Aloysius, Sears, Renee L., Lemos, Roberta R., Ordonez-Ugalde, Andres, Nicolas, Gael, Gomes da Cunha, Jose E., Rushing, Elisabeth J., Hugelshofer, Michael, Wurnig, Moritz C., Kaech, Andres, Reimann, Regina, Lohmann, Katja, Dobricic, Valerija, Carracedo, Angel, Petrovic, Igor, Miyasaki, Janis M., Abakumova, Irina, Mäe, Maarja Andaloussi, Raschperger, Elisabeth, Zatz, Mayana, Zschiedrich, Katja, Klepper, Jorg, Spiteri, Elizabeth, Prieto, Jose M., Navas, Inmaculada, Preuss, Michael, Dering, Carmen, Jankovic, Milena, Paucar, Martin, Svenningsson, Per, Saliminejad, Kioomars, Khorshid, Hamid R. K., Novakovic, Ivana, Aguzzi, Adriano, Boss, Andreas, Le Ber, Isabelle, Defer, Gilles, Hannequin, Didier, Kostic, Vladimir S., Campion, Dominique, Geschwind, Daniel H., Coppola, Giovanni, Betsholtz, Christer, Klein, Christine, and Oliveira, Joao R. M.
- Abstract
Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait ( idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor beta (PDGF-R beta) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-R beta. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans., These authors jointly directed and contributed equally to this work:Annika Keller, Ana Westenberger, Maria J Sobrido, Christer Betsholtz, Christine Klein & Joao R M Oliveira
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- 2013
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14. Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice
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Keller, Annika, primary, Westenberger, Ana, additional, Sobrido, Maria J, additional, García-Murias, Maria, additional, Domingo, Aloysius, additional, Sears, Renee L, additional, Lemos, Roberta R, additional, Ordoñez-Ugalde, Andres, additional, Nicolas, Gael, additional, da Cunha, José E Gomes, additional, Rushing, Elisabeth J, additional, Hugelshofer, Michael, additional, Wurnig, Moritz C, additional, Kaech, Andres, additional, Reimann, Regina, additional, Lohmann, Katja, additional, Dobričić, Valerija, additional, Carracedo, Angel, additional, Petrović, Igor, additional, Miyasaki, Janis M, additional, Abakumova, Irina, additional, Mäe, Maarja Andaloussi, additional, Raschperger, Elisabeth, additional, Zatz, Mayana, additional, Zschiedrich, Katja, additional, Klepper, Jörg, additional, Spiteri, Elizabeth, additional, Prieto, Jose M, additional, Navas, Inmaculada, additional, Preuss, Michael, additional, Dering, Carmen, additional, Janković, Milena, additional, Paucar, Martin, additional, Svenningsson, Per, additional, Saliminejad, Kioomars, additional, Khorshid, Hamid R K, additional, Novaković, Ivana, additional, Aguzzi, Adriano, additional, Boss, Andreas, additional, Le Ber, Isabelle, additional, Defer, Gilles, additional, Hannequin, Didier, additional, Kostić, Vladimir S, additional, Campion, Dominique, additional, Geschwind, Daniel H, additional, Coppola, Giovanni, additional, Betsholtz, Christer, additional, Klein, Christine, additional, and Oliveira, Joao R M, additional
- Published
- 2013
- Full Text
- View/download PDF
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