25 results on '"Sabrina Adam"'
Search Results
2. Methylation of recombinant mononucleosomes by DNMT3A demonstrates efficient linker DNA methylation and a role of H3K36me3
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Alexander Bröhm, Tabea Schoch, Michael Dukatz, Nora Graf, Franziska Dorscht, Evelin Mantai, Sabrina Adam, Pavel Bashtrykov, and Albert Jeltsch
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Biology (General) ,QH301-705.5 - Abstract
DNA methyltransferase 3A (DNMT3A) is shown to efficiently methylate recombinant mononucleosome linker DNA and a role for H3K36me3 in the stimulation of DNA methylation is revealed that is independent of its interaction with the PWWP domain. more...
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- 2022
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Catalog
3. Flanking sequences influence the activity of TET1 and TET2 methylcytosine dioxygenases and affect genomic 5hmC patterns
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Sabrina Adam, Julia Bräcker, Viviane Klingel, Bernd Osteresch, Nicole E. Radde, Jens Brockmeyer, Pavel Bashtrykov, and Albert Jeltsch
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Biology (General) ,QH301-705.5 - Abstract
Sabrina Adam et al. use a deep enzymology method to study the effect of neighboring DNA sequence variation on the in vitro activity of Tet1 and Tet2. Their results suggest that flanking sequences could represent an important parameter that influences genomic DNA modification patterns. more...
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- 2022
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4. Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms
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Linfeng Gao, Max Emperle, Yiran Guo, Sara A. Grimm, Wendan Ren, Sabrina Adam, Hidetaka Uryu, Zhi-Min Zhang, Dongliang Chen, Jiekai Yin, Michael Dukatz, Hiwot Anteneh, Renata Z. Jurkowska, Jiuwei Lu, Yinsheng Wang, Pavel Bashtrykov, Paul A. Wade, Gang Greg Wang, Albert Jeltsch, and Jikui Song more...
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Science - Abstract
In mammals, DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B. Here the authors report the crystal structures of DNMT3B in complex with both CpG and CpA DNA, providing insight into the substrate-recognition mechanism underpinning the divergent genomic methylation activities of DNMT3A and DNMT3B. more...
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- 2020
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5. DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation
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Sabrina Adam, Hiwot Anteneh, Maximilian Hornisch, Vincent Wagner, Jiuwei Lu, Nicole E. Radde, Pavel Bashtrykov, Jikui Song, and Albert Jeltsch
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Science - Abstract
DNA methylation is one of the major epigenetic mechanisms that critically influence gene expression, genomic stability and cell differentiation. Here, the authors study DNMT1 in complex with DNA substrates and systematically analyze the mechanism and specificity of DNMT1. more...
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- 2020
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6. The R736H cancer mutation in DNMT3A modulates the properties of the FF-subunit interface
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Stefan Kunert, Max Emperle, Sabrina Adam, Julia Bräcker, Jens Brockmeyer, Arumugam Rajavelu, and Albert Jeltsch
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General Medicine ,Biochemistry - Abstract
The DNMT3A DNA methyltransferase is an important epigenetic enzyme that is frequently mutated in cancers, particularly in AML. The heterozygous R736H mutation in the FF-interface of the tetrameric enzyme is the second most frequently observed DNMT3A cancer mutation, but its pathogenic mechanism is unclear. We show here that R736H leads to a moderate reduction in catalytic activity of 20-40% depending on the substrate, but no changes in CpG specificity, flanking sequence preferences and subnuclear localization. Strikingly, R736H showed a very strong stimulation by DNMT3L and the R736H/DNMT3L complex was 3-fold more active than WT/DNMT3L. Similarly, formation of mixed WT/R736H FF-interfaces led to an increased activity. R736H/DNMT3L and mixed R736H/DNMT3A WT FF-interfaces were less stable than interfaces not involving R736H, suggesting that an increased flexibility of the mixed interfaces stimulates catalytic activity. Our data suggest that aberrant activity of DNMT3A R736H may lead to DNA hypermethylation in cancer cells which could cause changes in gene expression. more...
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- 2023
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7. On the accuracy of the epigenetic copy machine: comprehensive specificity analysis of the DNMT1 DNA methyltransferase
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Sabrina Adam, Viviane Klingel, Nicole E Radde, Pavel Bashtrykov, and Albert Jeltsch
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Genetics - Abstract
The specificity of DNMT1 for hemimethylated DNA is a central feature for the inheritance of DNA methylation. We investigated this property in competitive methylation kinetics using hemimethylated (HM), hemihydroxymethylated (OH) and unmethylated (UM) substrates with single CpG sites in a randomized sequence context. DNMT1 shows a strong flanking sequence dependent HM/UM specificity of 80-fold on average, which is slightly enhanced on long hemimethylated DNA substrates. To explain this strong effect of a single methyl group, we propose a novel model in which the presence of the 5mC methyl group changes the conformation of the DNMT1-DNA complex into an active conformation by steric repulsion. The HM/OH preference is flanking sequence dependent and on average only 13-fold, indicating that passive DNA demethylation by 5hmC generation is not efficient in many flanking contexts. The CXXC domain of DNMT1 has a moderate flanking sequence dependent contribution to HM/UM specificity during DNA association to DNMT1, but not if DNMT1 methylates long DNA molecules in processive methylation mode. Comparison of genomic methylation patterns from mouse ES cell lines with various deletions of DNMTs and TETs with our data revealed that the UM specificity profile is most related to cellular methylation patterns, indicating that de novo methylation activity of DNMT1 shapes the DNA methylome in these cells. more...
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- 2023
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8. DNA methyltransferase DNMT3A forms interaction networks with the CpG site and flanking sequence elements for efficient methylation
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Michael, Dukatz, Marianna, Dittrich, Elias, Stahl, Sabrina, Adam, Alex, de Mendoza, Pavel, Bashtrykov, and Albert, Jeltsch
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Guanine ,Mutation ,CpG Islands ,DNA ,DNA Methylation ,DNA Modification Methylases ,DNA Methyltransferase 3A - Abstract
Specific DNA methylation at CpG and non-CpG sites is essential for chromatin regulation. The DNA methyltransferase DNMT3A interacts with target sites surrounded by variable DNA sequences with its TRD and RD loops, but the functional necessity of these interactions is unclear. We investigated CpG and non-CpG methylation in a randomized sequence context using WT DNMT3A and several DNMT3A variants containing mutations at DNA-interacting residues. Our data revealed that the flanking sequence of target sites between the -2 and up to the +8 position modulates methylation rates100-fold. Non-CpG methylation flanking preferences were even stronger and favor C(+1). R836 and N838 in concert mediate recognition of the CpG guanine. R836 changes its conformation in a flanking sequence-dependent manner and either contacts the CpG guanine or the +1/+2 flank, thereby coupling the interaction with both sequence elements. R836 suppresses activity at CNT sites but supports methylation of CAC substrates, the preferred target for non-CpG methylation of DNMT3A in cells. N838 helps to balance this effect and prevent the preference for C(+1) from becoming too strong. Surprisingly, we found L883 reduces DNMT3A activity despite being highly conserved in evolution. However, mutations at L883 disrupt the DNMT3A-specific DNA interactions of the RD loop, leading to altered flanking sequence preferences. Similar effects occur after the R882H mutation in cancer cells. Our data reveal that DNMT3A forms flexible and interdependent interaction networks with the CpG guanine and flanking residues that ensure recognition of the CpG and efficient methylation of the cytosine in contexts of variable flanking sequences. more...
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- 2022
9. Preferential Self-interaction of DNA Methyltransferase DNMT3A Subunits Containing the R882H Cancer Mutation Leads to Dominant Changes of Flanking Sequence Preferences
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Alexandra Mack, Max Emperle, Philipp Schnee, Sabrina Adam, Jürgen Pleiss, Pavel Bashtrykov, and Albert Jeltsch
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Leukemia, Myeloid, Acute ,Structural Biology ,Mutation ,Terminal Repeat Sequences ,Humans ,DNA Methylation ,Molecular Biology ,DNA Methyltransferase 3A - Abstract
Somatic R882H DNMT3A mutations occur frequently in AML, but their pathogenic mechanism is unclear. As R882H mutations usually are heterozygous, wildtype (WT) and R882H subunits co-exist in affected cells. R882 is located in the RD interface of DNMT3A tetramers, which forms the DNA binding site. R882H causes strong changes in the flanking sequence preferences of DNMT3A. Here, we analyzed flanking sequence preferences for CGNNNN sites showing that most disfavored sites are methylated 4-5 fold slower by R882H than WT, while it methylates most preferred sites 2-fold faster. Overall, R882H was more active than WT at 13% and less active at 52% of all CGNNNN sites. We prepared mixed DNMT3A heterotetramers containing WT and R882H subunits and show that mixed complexes preferentially assemble with an R882H/R882H RD interface. Structural comparisons and MD simulations confirmed the conclusion that the R882H RD interface is more stable than that of WT, in part because H882 forms an inter-subunit contact in the RD interface, while R882 contacts the DNA. As the subunits at the RD interface contribute the two active centers to the DNMT3A tetramer, R882H characteristic flanking sequence preferences of DNMT3A were observed in mixed tetrameric complexes containing WT and R882H subunits, and they are not diluted by the "averaged" effects of mixed or WT interfaces. Hence, R882H has a dominant effect on the flanking sequence preferences and other catalytic properties of DNMT3A in samples containing WT and R882H subunits, which may explain its pathogenic effect in heterozygous state. more...
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- 2021
10. Mutations of R882 change flanking sequence preferences of the DNA methyltransferase DNMT3A and cellular methylation patterns
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Christoph Plass, Pavel Bashtrykov, Michael Dukatz, Philipp Rathert, Stefan Kunert, Annika Baude, Albert Jeltsch, Sabrina Adam, and Max Emperle
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5' Flanking Region ,Somatic cell ,DNMT3B ,Mutation, Missense ,Biology ,Arginine ,DNA methyltransferase ,DNA Methyltransferase 3A ,Substrate Specificity ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Catalytic Domain ,Neoplasms ,Genetics ,Humans ,Histidine ,DNA (Cytosine-5-)-Methyltransferases ,Gene ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Nucleic Acid Enzymes ,Methylation ,DNA Methylation ,HCT116 Cells ,Amino Acid Substitution ,chemistry ,CpG site ,030220 oncology & carcinogenesis ,embryonic structures ,DNA methylation ,CpG Islands ,DNA - Abstract
Somatic DNMT3A mutations at R882 are frequently observed in AML patients including the very abundant R882H, but also R882C, R882P and R882S. Using deep enzymology, we show here that DNMT3A-R882H has more than 70-fold altered flanking sequence preferences when compared with wildtype DNMT3A. The R882H flanking sequence preferences mainly differ on the 3′ side of the CpG site, where they resemble DNMT3B, while 5′ flanking sequence preferences resemble wildtype DNMT3A, indicating that R882H behaves like a DNMT3A/DNMT3B chimera. Investigation of the activity and flanking sequence preferences of other mutations of R882 revealed that they cause similar effects. Bioinformatic analyses of genomic methylation patterns focusing on flanking sequence effects after expression of wildtype DNMT3A and R882H in human cells revealed that genomic methylation patterns reflect the details of the altered flanking sequence preferences of R882H. Concordantly, R882H specific hypermethylation in AML patients was strongly correlated with the R882H flanking sequence preferences. R882H specific DNA hypermethylation events in AML patients were accompanied by R882H specific mis-regulation of several genes with strong cancer connection, which are potential downstream targets of R882H. In conclusion, our data provide novel and detailed mechanistic understanding of the pathogenic mechanism of the DNMT3A R882H somatic cancer mutation. more...
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- 2019
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11. Structural and biochemical insight into the mechanism of dual CpG site binding and methylation by the DNMT3A DNA methyltransferase
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Ingrid Tessmer, Hannah S. Heil, Pavel Bashtrykov, Katrin G. Heinze, Albert Jeltsch, Disha M. Bangalore, Stefan Kunert, Sabrina Adam, and Max Emperle
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AcademicSubjects/SCI00010 ,DNMT3A Gene ,Biology ,DNA methyltransferase ,DNA Methyltransferase 3A ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Tetramer ,Protein Domains ,Genetics ,Dna bending ,Humans ,DNA (Cytosine-5-)-Methyltransferases ,DNA Modification Methylases ,030304 developmental biology ,0303 health sciences ,Binding Sites ,Nucleic Acid Enzymes ,Methylation ,DNA ,DNA Methylation ,Heterotetramer ,chemistry ,CpG site ,embryonic structures ,Biophysics ,CpG Islands ,030217 neurology & neurosurgery - Abstract
DNMT3A/3L heterotetramers contain two active centers binding CpG sites at 12 bp distance, however their interaction with DNA not containing this feature is unclear. Using randomized substrates, we observed preferential co-methylation of CpG sites with 6, 9 and 12 bp spacing by DNMT3A and DNMT3A/3L. Co-methylation was favored by AT bases between the 12 bp spaced CpG sites consistent with their increased bending flexibility. SFM analyses of DNMT3A/3L complexes bound to CpG sites with 12 bp spacing revealed either single heterotetramers inducing 40° DNA bending as observed in the X-ray structure, or two heterotetramers bound side-by-side to the DNA yielding 80° bending. SFM data of DNMT3A/3L bound to CpG sites spaced by 6 and 9 bp revealed binding of two heterotetramers and 100° DNA bending. Modeling showed that for 6 bp distance between CpG sites, two DNMT3A/3L heterotetramers could bind side-by-side on the DNA similarly as for 12 bp distance, but with each CpG bound by a different heterotetramer. For 9 bp spacing our model invokes a tetramer swap of the bound DNA. These additional DNA interaction modes explain how DNMT3A and DNMT3A/3L overcome their structural preference for CpG sites with 12 bp spacing during the methylation of natural DNA., Graphical Abstract Graphical AbstractNGS methylation analysis with pool of randomized CpG double site substrates and SFM imaging of enzyme-DNA complexes with example substrates revealed novel interaction modes of DNMT3A and DNMT3A/3L with CpG double site substrates. more...
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- 2021
12. Methylation of recombinant mononucleosomes by DNMT3A demonstrates efficient linker DNA methylation and a role of H3K36me3
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Alexander, Bröhm, Tabea, Schoch, Michael, Dukatz, Nora, Graf, Franziska, Dorscht, Evelin, Mantai, Sabrina, Adam, Pavel, Bashtrykov, and Albert, Jeltsch
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DNA ,DNA (Cytosine-5-)-Methyltransferases ,DNA Methylation ,DNA Methyltransferase 3A ,Protein Binding - Abstract
Recently, the structure of the DNMT3A2/3B3 heterotetramer complex bound to a mononucleosome was reported. Here, we investigate DNA methylation of recombinant unmodified, H3K
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- 2021
13. Complex DNA sequence readout mechanisms of the DNMT3B DNA methyltransferase
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Jikui Song, Mahamaya Biswal, Sabrina Adam, Pavel Bashtrykov, Albert Jeltsch, and Michael Dukatz
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Methyltransferase ,AcademicSubjects/SCI00010 ,Context (language use) ,Biology ,DNA methyltransferase ,DNA sequencing ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Catalytic Domain ,Information and Computing Sciences ,Genetics ,Humans ,DNA (Cytosine-5-)-Methyltransferases ,030304 developmental biology ,0303 health sciences ,Base Sequence ,Gene regulation, Chromatin and Epigenetics ,Methylation ,DNA ,DNA Methylation ,Biological Sciences ,CpG site ,chemistry ,DNA methylation ,CpG Islands ,030217 neurology & neurosurgery ,Environmental Sciences ,Protein Binding ,Developmental Biology - Abstract
DNA methyltransferases interact with their CpG target sites in the context of variable flanking sequences. We investigated DNA methylation by the human DNMT3B catalytic domain using substrate pools containing CpX target sites in randomized flanking context and identified combined effects of CpG recognition and flanking sequence interaction together with complex contact networks involved in balancing the interaction with different flanking sites. DNA methylation rates were more affected by flanking sequences at non-CpG than at CpG sites. We show that T775 has an essential dynamic role in the catalytic mechanism of DNMT3B. Moreover, we identify six amino acid residues in the DNA-binding interface of DNMT3B (N652, N656, N658, K777, N779, and R823), which are involved in the equalization of methylation rates of CpG sites in favored and disfavored sequence contexts by forming compensatory interactions to the flanking residues including a CpG specific contact to an A at the +1 flanking site. Non-CpG flanking preferences of DNMT3B are highly correlated with non-CpG methylation patterns in human cells. Comparison of the flanking sequence preferences of human and mouse DNMT3B revealed subtle differences suggesting a co-evolution of flanking sequence preferences and cellular DNMT targets. more...
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- 2020
14. DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation
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Albert Jeltsch, Maximilian Hornisch, Hiwot Anteneh, Jikui Song, Nicole Radde, Pavel Bashtrykov, Sabrina Adam, Jiuwei Lu, and Vincent Wagner
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0301 basic medicine ,Models, Molecular ,Protein Conformation ,Oligonucleotides ,General Physics and Astronomy ,Crystallography, X-Ray ,environment and public health ,Substrate Specificity ,chemistry.chemical_compound ,Mice ,Gene Knockout Techniques ,0302 clinical medicine ,Models ,Catalytic Domain ,lcsh:Science ,Genetics ,Mice, Knockout ,Multidisciplinary ,Crystallography ,DNA methylation ,Methylation ,DNA-Binding Proteins ,CpG site ,030220 oncology & carcinogenesis ,embryonic structures ,Enzyme mechanisms ,DNA (Cytosine-5-)-Methyltransferase 1 ,Science ,Knockout ,1.1 Normal biological development and functioning ,General Biochemistry, Genetics and Molecular Biology ,DNA sequencing ,Article ,03 medical and health sciences ,Underpinning research ,Animals ,X-ray crystallography ,Cofactor binding ,Base Sequence ,Oligonucleotide ,urogenital system ,Human Genome ,Molecular ,General Chemistry ,DNA ,DNA Methylation ,Kinetics ,030104 developmental biology ,DNA demethylation ,chemistry ,X-Ray ,Nucleic Acid Conformation ,lcsh:Q ,Generic health relevance - Abstract
DNA methylation maintenance by DNMT1 is an essential process in mammals but molecular mechanisms connecting DNA methylation patterns and enzyme activity remain elusive. Here, we systematically analyzed the specificity of DNMT1, revealing a pronounced influence of the DNA sequences flanking the target CpG site on DNMT1 activity. We determined DNMT1 structures in complex with preferred DNA substrates revealing that DNMT1 employs flanking sequence-dependent base flipping mechanisms, with large structural rearrangements of the DNA correlating with low catalytic activity. Moreover, flanking sequences influence the conformational dynamics of the active site and cofactor binding pocket. Importantly, we show that the flanking sequence preferences of DNMT1 highly correlate with genomic methylation in human and mouse cells, and 5-azacytidine triggered DNA demethylation is more pronounced at CpG sites with flanks disfavored by DNMT1. Overall, our findings uncover the intricate interplay between CpG-flanking sequence, DNMT1-mediated base flipping and the dynamic landscape of DNA methylation., DNA methylation is one of the major epigenetic mechanisms that critically influence gene expression, genomic stability and cell differentiation. Here, the authors study DNMT1 in complex with DNA substrates and systematically analyze the mechanism and specificity of DNMT1. more...
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- 2020
15. Deep Enzymology Studies on DNA Methyltransferases Reveal Novel Connections between Flanking Sequences and Enzyme Activity
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Pavel Bashtrykov, Albert Jeltsch, Michael Dukatz, Sabrina Adam, and Max Emperle
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Models, Molecular ,Methyltransferase ,Protein Conformation ,Bisulfite sequencing ,DNA ,Computational biology ,Methylation ,Biology ,DNA methyltransferase ,Mice ,genomic DNA ,chemistry.chemical_compound ,CpG site ,chemistry ,Structural Biology ,DNA methylation ,Animals ,Humans ,CpG Islands ,DNA (Cytosine-5-)-Methyltransferases ,Molecular Biology - Abstract
DNA interacting enzymes recognize their target sequences embedded in variable flanking sequence context. The influence of flanking sequences on enzymatic activities of DNA methyltransferases (DNMTs) can be systematically studied with “deep enzymology” approaches using pools of double-stranded DNA substrates, which contain target sites in random flanking sequence context. After incubation with DNMTs and bisulfite conversion, the methylation states and flanking sequences of individual DNA molecules are determined by NGS. Deep enzymology studies with different human and mouse DNMTs revealed strong influences of flanking sequences on their CpG and non-CpG methylation activity and the structures of DNMT-DNA complexes. Differences in flanking sequence preferences of DNMT3A and DNMT3B were shown to be related to the prominent role of DNMT3B in the methylation of human SATII repeat elements. Mutational studies in DNMT3B discovered alternative interaction networks between the enzyme and the DNA leading to a partial equalization of the effects of different flanking sequences. Structural studies in DNMT1 revealed striking correlations between enzymatic activities and flanking sequence dependent conformational changes upon DNA binding. Correlation of the biochemical data with cellular methylation patterns demonstrated that flanking sequence preferences are an important parameter that influences genomic DNA methylation patterns together with other mechanisms targeting DNMTs to genomic sites. more...
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- 2021
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16. Engineering of Effector Domains for Targeted DNA Methylation with Reduced Off-Target Effects
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Albert Jeltsch, Laura Laistner, Sabrina Adam, Julian Broche, Pavel Bashtrykov, and Daniel Hofacker
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targeted DNA methylation ,Computational biology ,SunTag ,Protein Engineering ,Article ,Catalysis ,DNA sequencing ,DNA Methyltransferase 3A ,lcsh:Chemistry ,Inorganic Chemistry ,dCas9 ,chemistry.chemical_compound ,Protein Domains ,Epigenome editing ,Humans ,Cellular Reprogramming Techniques ,DNA (Cytosine-5-)-Methyltransferases ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,Gene ,Spectroscopy ,DNMT3A-DNMT3L ,Chemistry ,Cas9 ,Organic Chemistry ,General Medicine ,Methylation ,DNA Methylation ,Computer Science Applications ,HEK293 Cells ,Gene Expression Regulation ,lcsh:Biology (General) ,lcsh:QD1-999 ,DNA methylation ,epigenome editing ,Reprogramming ,DNA ,Genome-Wide Association Study - Abstract
Epigenome editing is a promising technology, potentially allowing the stable reprogramming of gene expression profiles without alteration of the DNA sequence. Targeted DNA methylation has been successfully documented by many groups for silencing selected genes, but recent publications have raised concerns regarding its specificity. In the current work, we developed new EpiEditors for programmable DNA methylation in cells with a high efficiency and improved specificity. First, we demonstrated that the catalytically deactivated Cas9 protein (dCas9)-SunTag scaffold, which has been used earlier for signal amplification, can be combined with the DNMT3A-DNMT3L single-chain effector domain, allowing for a strong methylation at the target genomic locus. We demonstrated that off-target activity of this system is mainly due to untargeted freely diffusing DNMT3A-DNMT3L subunits. Therefore, we generated several DNMT3A-DNMT3L variants containing mutations in the DNMT3A part, which reduced their endogenous DNA binding. We analyzed the genome-wide DNA methylation of selected variants and confirmed a striking reduction of untargeted methylation, most pronounced for the R887E mutant. For all potential applications of targeted DNA methylation, the efficiency and specificity of the treatment are the key factors. By developing highly active targeted methylation systems with strongly improved specificity, our work contributes to future applications of this approach. more...
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- 2020
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17. Mutations of R882 in DNMT3A change flanking sequence preferences and cellular methylation patterns in AML
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Philipp Rathert, Stefan Kunert, Christoph Plass, Pavel Bashtrykov, Sabrina Adam, Max Emperle, Michael Dukatz, Albert Jeltsch, and Annika Baude
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Genetics ,Chimera (genetics) ,CpG site ,Flanking maneuver ,embryonic structures ,DNA methylation ,DNMT3B ,Wild type ,Methylation ,Biology ,Gene - Abstract
DNMT3A R882 mutations are frequently observed in AML including the abundant R882H and the rare R882C, R882P and R882S. Using deep enzymology we show here that the DNMT3A-R882H has more than 70-fold altered flanking sequence preferences when compared with wildtype DNMT3A. The R882H flanking sequence preferences mainly differ on the 3’ side of the CpG site, where they resemble DNMT3B, while 5’ flanking sequence preferences of R882H resemble wildtype DNMT3A, indicating that R882H behaves like a DNMT3A/DNMT3B chimera. Activities and flanking sequence preferences of R882C, R882P and R882S were determined as well. Genomic methylation patterns after expression of wildtype DNMT3A and R882H in human cells reflect the flanking sequence preferences. R882H specific hypermethylation in AML patients are correlated with R882H flanking sequence preferences. The hypermethylation events are accompanied by R882H specific misregulation of several genes with strong cancer connection in AML patients, which are potential downstream targets of R882H. more...
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- 2019
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18. Mittelstandsanleihen in Deutschland
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Johannes Klein, Leonard Stuckenborg, Jan-André Pramann, and Sabrina Adam
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- 2018
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19. White matter hyperintensities and smaller cortical thickness are associated with neuropsychiatric symptoms in neurodegenerative and cerebrovascular diseases
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Miracle Ozzoude, Brenda Varriano, Derek Beaton, Joel Ramirez, Sabrina Adamo, Melissa F. Holmes, Christopher J. M. Scott, Fuqiang Gao, Kelly M. Sunderland, Paula McLaughlin, Maged Goubran, Donna Kwan, Angela Roberts, Robert Bartha, Sean Symons, Brian Tan, Richard H. Swartz, Agessandro Abrahao, Gustavo Saposnik, Mario Masellis, Anthony E. Lang, Connie Marras, Lorne Zinman, Christen Shoesmith, Michael Borrie, Corinne E. Fischer, Andrew Frank, Morris Freedman, Manuel Montero-Odasso, Sanjeev Kumar, Stephen Pasternak, Stephen C. Strother, Bruce G. Pollock, Tarek K. Rajji, Dallas Seitz, David F. Tang-Wai, John Turnbull, Dar Dowlatshahi, Ayman Hassan, Leanne Casaubon, Jennifer Mandzia, Demetrios Sahlas, David P. Breen, David Grimes, Mandar Jog, Thomas D. L. Steeves, Stephen R. Arnott, Sandra E. Black, Elizabeth Finger, Jennifer Rabin, ONDRI Investigators, and Maria Carmela Tartaglia more...
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White matter hyperintensities ,Cortical thickness ,Neuropsychiatric symptoms ,Neurodegenerative disease ,Cerebrovascular disease ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases. Methods Five hundred thirteen participants with one of these conditions, i.e. Alzheimer’s Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson’s Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory – Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss. Results Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson’s disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities. Conclusions In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed. more...
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- 2023
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20. EFFECTS OF VASCULAR BURDEN ON COGNITION ARE MEDIATED BY ATROPHY, AMYLOID, AND GLUCOSE METABOLISM: A MULTI-CENTRE MIXED COHORT OF SMALL VESSEL DISEASE AND ALZHEIMER'S PATHOLOGY
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Julie Ottoy, LC Campbell, Miracle Ozzoude, LC Campbell, Katherine Zukotynski, LC Campbell, Sabrina Adamo, LC Campbell, Christopher Scott, LC Campbell, Vincent Gaudet, Joel Ramirez, LC Campbell, Walter Swardfager, Hugo Cogo-Moreira, LC Campbell, Benjamin Lam, LC Campbell, Aparna Bhan, LC Campbell, Parisa Mojiri, LC Campbell, Min Su Kang, Jennifer Rabin, LC Campbell, Alex Kiss, Stephen Strother, Christian Bocti, Michael Borrie, Howard Chertkow, Richard Frayne, Robin Hsiung, Robert Laforce, Jr., Michael D. Noseworthy, Frank S. Prato, Demetrios J. Sahlas, Eric E. Smith, Phillip H. Kuo, Vesna Sossi, Alexander Thiel, Jean-Paul Soucy, Jean-Claude Tardif, Sandra E. Black, LC Campbell, and Maged Goubran, LC Campbell more...
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Specialties of internal medicine ,RC581-951 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2024
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21. Retinal nerve fiber layer in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
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Bryan M. Wong, Christopher Hudson, Emily Snook, Faryan Tayyari, Hyejung Jung, Malcolm A. Binns, Saba Samet, Richard W. Cheng, Carmen Balian, Efrem D. Mandelcorn, Edward Margolin, Elizabeth Finger, Sandra E. Black, David F. Tang-Wai, Lorne Zinman, Brian Tan, Wendy Lou, Mario Masellis, Agessandro Abrahao, Andrew Frank, Derek Beaton, Kelly M. Sunderland, Stephen R. Arnott, ONDRI Investigators, Maria Carmela Tartaglia, Wendy V. Hatch, Sabrina Adamo, Stephen Arnott, Rob Bartha, Courtney Berezuk, Alanna Black, Alisia Bonnick, David Breen, Don Brien, Susan Bronskill, Dennis Bulman, Leanne Casaubon, Ying Chen, Marvin Chum, Brian Coe, Ben Cornish, Jane Lawrence Dewar, Roger A. Dixon, Sherif El-Defrawy, Sali M.K. Farhan, Frederico Faria, Julia Fraser, Mahdi Ghani, Barry Greenberg, Hassan Haddad, Wendy Hatch, Melissa Holmes, Chris Hudson, Peter Kleinstiver, Donna Kwan, Elena Leontieva, Brian Levine, Ed Margolin, Connie Marras, Bill McIlroy, Paula McLaughlin, Manuel Montero Odasso, Doug Munoz, David Munoz, Nuwan Nanayakkara, JB Orange, Miracle Ozzoude, Alicia Peltsch, Pradeep Raamana, Joel Ramirez, Natalie Rashkovan, Angela Roberts, Yanina Sarquis Adamson, Christopher Scott, Michael Strong, Stephen Strothers, Sujeevini Sujanthan, Sean Symons, Athena Theyers, Angela Troyer, Abiramy Uthirakumaran, Karen Van Ooteghem, John Woulfe, Mojdeh Zamyadi, and Guangyong (GY) Zou more...
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retinal nerve fibre layer ,optical coherence tomography ,tauopathy ,TDP-43 proteinopathy ,frontotemporal lobar degeneration ,amyotrophic lateral sclerosis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
PurposeTauopathy and transactive response DNA binding protein 43 (TDP-43) proteinopathy are associated with neurodegenerative diseases. These proteinopathies are difficult to detect in vivo. This study examined if spectral-domain optical coherence tomography (SD-OCT) can differentiate in vivo the difference in peripapillary retinal nerve fibre layer (pRNFL) thickness and macular retinal thickness between participants with presumed tauopathy (progressive supranuclear palsy) and those with presumed TDP-43 proteinopathy (amyotrophic lateral sclerosis and semantic variant primary progressive aphasia).Study designProspective, multi-centre, observational study.Materials and methodspRNFL and macular SD-OCT images were acquired in both eyes of each participant using Heidelberg Spectralis SD-OCT. Global and pRNFL thickness in 6 sectors were analyzed, as well as macular thickness in a central 1 mm diameter zone and 4 surrounding sectors. Linear mixed model methods adjusting for baseline differences between groups were used to compare the two groups with respect to pRNFL and macular thickness.ResultsA significant difference was found in mean pRNFL thickness between groups, with the TDP-43 group (n = 28 eyes) having a significantly thinner pRNFL in the temporal sector than the tauopathy group (n = 9 eyes; mean difference = 15.46 μm, SE = 6.98, p = 0.046), which was not significant after adjusting for multiple comparisons. No other significant differences were found between groups for pRNFL or macular thickness.ConclusionThe finding that the temporal pRNFL in the TDP-43 group was on average 15.46 μm thinner could potentially have clinical significance. Future work with larger sample sizes, longitudinal studies, and at the level of retinal sublayers will help to determine the utility of SD-OCT to differentiate between these two proteinopathies. more...
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- 2022
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22. Kutane Lymphome in Deutschland. Eine Analyse des Zentralregisters 'Kutane Lymphome der Deutschen Dermatologischen Gesellschaft (DDG)'
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Anette Stein, Edgar Dippel, Chalid Assaf, Esther A. Coors, André Koch, Sylke Gellrich, Wolfram Sterry, Claus-Detlev Klemke, Sabrina Adam-Murati, Rudolf Stadler, Franca Weiße, Dorothee Nashan, Matthias Steinhoff, Ulrike Henke, and Philippa Gollin more...
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Dermatology - Published
- 2007
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23. Cutaneous lymphomas in Germany: an analysis of the Central Cutaneous Lymphoma Registry of the German Society of Dermatology (DDG)
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Anette Stein, Edgar Dippel, Ulrike Henke, Dorothee Nashan, Wolfram Sterry, Rudolf Stadler, Chalid Assaf, Claus-Detlev Klemke, Esther A. Coors, Matthias Steinhoff, Philippa Gollin, André Koch, Sylke Gellrich, Sabrina Adam-Murati, and Franca Weiße more...
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Adult ,Male ,medicine.medical_specialty ,Skin Neoplasms ,Lymphoma ,Population ,Disease ,Dermatology ,Risk Assessment ,Cutaneous lymphoma ,German ,Risk Factors ,hemic and lymphatic diseases ,Germany ,Epidemiology ,medicine ,Prevalence ,Humans ,Registries ,Stage (cooking) ,education ,Societies, Medical ,Aged ,Aged, 80 and over ,education.field_of_study ,Mycosis fungoides ,business.industry ,Middle Aged ,medicine.disease ,language.human_language ,language ,Female ,business - Abstract
Summary Background: Primary cutaneous lymphomas form a heterogenous group of lymphatic neoplasias.They manifest themselves on the skin and are the second most frequent group of non-Hodgkin lymphoma (NHL) following gastrointestinal lymphomas.The number of epidemiologic studies is small due to limited availability and limited comparability on population-based data. Patients and methods: In the present study the first evaluation of the German Central Registry for Cutaneous Lymphomas (ZRKL) of the German Society of Dermatology (DDG) is undertaken on the basis of 998 patients.The epidemiology of cutaneous lymphomas in Germany is compared to other national or regional lymphoma registries. Results: Based on the registration of 998 patients from 26 clinics in Germany,a clear predominance of cutaneous T-cell lymphomas (85 %) in comparison to cutaneous B-cell lymphomas (14 %) is seen.The most frequent representative of CTCL is mycosis fungoides,composing 62 % of cases with a slight predominance of men (M:F = 1.6:1).Differences are also seen in stage of the disease at first presentation of patients with cutaneous lymphomas.While, for example, 80 % of patients with mycosis fungoides in Germany present in early stages (I–IIA),in the USA 34 % of patients are in the tumor stage or have organ involvement at presentation. Conclusions: The ZRKL of the DDG for the first time presents epidemiologic data from Germany, allowing comparison with other nations for the study of etio-logical factors and socioeconomic influences. Further, the ZRKL supports the development of uniform and quality-oriented diagnostic criteria and therapeutic options. Finally, the ZRKL provides a foundation for future intensive study of clinical and scientific questions regarding cutaneous T- and B-cell lym-phomas. more...
- Published
- 2007
24. Comparison of Diffusion Tensor Imaging Metrics in Normal-Appearing White Matter to Cerebrovascular Lesions and Correlation with Cerebrovascular Disease Risk Factors and Severity
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Seyyed M. H. Haddad, Christopher J. M. Scott, Miracle Ozzoude, Courtney Berezuk, Melissa Holmes, Sabrina Adamo, Joel Ramirez, Stephen R. Arnott, Nuwan D. Nanayakkara, Malcolm Binns, Derek Beaton, Wendy Lou, Kelly Sunderland, Sujeevini Sujanthan, Jane Lawrence, Donna Kwan, Brian Tan, Leanne Casaubon, Jennifer Mandzia, Demetrios Sahlas, Gustavo Saposnik, Ayman Hassan, Brian Levine, Paula McLaughlin, J. B. Orange, Angela Roberts, Angela Troyer, Sandra E. Black, Dar Dowlatshahi, Stephen C. Strother, Richard H. Swartz, Sean Symons, Manuel Montero-Odasso, null ONDRI Investigators, and Robert Bartha more...
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Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Medical technology ,R855-855.5 - Abstract
Alterations in tissue microstructure in normal-appearing white matter (NAWM), specifically measured by diffusion tensor imaging (DTI) fractional anisotropy (FA), have been associated with cognitive outcomes following stroke. The purpose of this study was to comprehensively compare conventional DTI measures of tissue microstructure in NAWM to diverse vascular brain lesions in people with cerebrovascular disease (CVD) and to examine associations between FA in NAWM and cerebrovascular risk factors. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured in cerebral tissues and cerebrovascular anomalies from 152 people with CVD participating in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). Ten cerebral tissue types were segmented including NAWM, and vascular lesions including stroke, periventricular and deep white matter hyperintensities, periventricular and deep lacunar infarcts, and perivascular spaces (PVS) using T1-weighted, proton density-weighted, T2-weighted, and fluid attenuated inversion recovery MRI scans. Mean DTI metrics were measured in each tissue region using a previously developed DTI processing pipeline and compared between tissues using multivariate analysis of covariance. Associations between FA in NAWM and several CVD risk factors were also examined. DTI metrics in vascular lesions differed significantly from healthy tissue. Specifically, all tissue types had significantly different MD values, while FA was also found to be different in most tissue types. FA in NAWM was inversely related to hypertension and modified Rankin scale (mRS). This study demonstrated the differences between conventional DTI metrics, FA, MD, AD, and RD, in cerebral vascular lesions and healthy tissue types. Therefore, incorporating DTI to characterize the integrity of the tissue microstructure could help to define the extent and severity of various brain vascular anomalies. The association between FA within NAWM and clinical evaluation of hypertension and disability provides further evidence that white matter microstructural integrity is impacted by cerebrovascular function. more...
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- 2022
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25. Ontario Neurodegenerative Disease Research Initiative (ONDRI): Structural MRI Methods and Outcome Measures
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Joel Ramirez, Melissa F. Holmes, Christopher J. M. Scott, Miracle Ozzoude, Sabrina Adamo, Gregory M. Szilagyi, Maged Goubran, Fuqiang Gao, Stephen R. Arnott, Jane M. Lawrence-Dewar, Derek Beaton, Stephen C. Strother, Douglas P. Munoz, Mario Masellis, Richard H. Swartz, Robert Bartha, Sean Symons, Sandra E. Black, and The ONDRI Investigators more...
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MRI ,Alzheimer ,Parkinson ,amyotrophic lateral sclerosis ,frontotemporal dementia ,cerebrovascular disease ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
The Ontario Neurodegenerative Research Initiative (ONDRI) is a 3 years multi-site prospective cohort study that has acquired comprehensive multiple assessment platform data, including 3T structural MRI, from neurodegenerative patients with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and cerebrovascular disease. This heterogeneous cross-section of patients with complex neurodegenerative and neurovascular pathologies pose significant challenges for standard neuroimaging tools. To effectively quantify regional measures of normal and pathological brain tissue volumes, the ONDRI neuroimaging platform implemented a semi-automated MRI processing pipeline that was able to address many of the challenges resulting from this heterogeneity. The purpose of this paper is to serve as a reference and conceptual overview of the comprehensive neuroimaging pipeline used to generate regional brain tissue volumes and neurovascular marker data that will be made publicly available online. more...
- Published
- 2020
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