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  1. Article ; Online: Structure of Amyloid Peptide Ribbons Characterized by Electron Microscopy, Atomic Force Microscopy, and Solid-State Nuclear Magnetic Resonance.

    Thurber, Kent R / Yau, Wai-Ming / Tycko, Robert

    The journal of physical chemistry. B

    2024  Volume 128, Issue 7, Page(s) 1711–1723

    Abstract: Polypeptides often self-assemble to form amyloid fibrils, which contain cross-β structural motifs and are typically 5-15 nm in width and micrometers in length. In many cases, short segments of longer amyloid-forming protein or peptide sequences also form ...

    Abstract Polypeptides often self-assemble to form amyloid fibrils, which contain cross-β structural motifs and are typically 5-15 nm in width and micrometers in length. In many cases, short segments of longer amyloid-forming protein or peptide sequences also form cross-β assemblies but with distinctive ribbon-like morphologies that are characterized by a well-defined thickness (on the order of 5 nm) in one lateral dimension and a variable width (typically 10-100 nm) in the other. Here, we use a novel combination of data from solid-state nuclear magnetic resonance (ssNMR), dark-field transmission electron microscopy (TEM), atomic force microscopy (AFM), and cryogenic electron microscopy (cryoEM) to investigate the structures within amyloid ribbons formed by residues 14-23 and residues 11-25 of the Alzheimer's disease-associated amyloid-β peptide (Aβ
    MeSH term(s) Microscopy, Atomic Force ; Electrons ; Protein Structure, Secondary ; Nuclear Magnetic Resonance, Biomolecular/methods ; Amyloid/chemistry ; Amyloidogenic Proteins ; Amyloid beta-Peptides/chemistry
    Chemical Substances Amyloid ; Amyloidogenic Proteins ; Amyloid beta-Peptides
    Language English
    Publishing date 2024-02-13
    Publishing country United States
    Document type Journal Article
    ISSN 1520-5207
    ISSN (online) 1520-5207
    DOI 10.1021/acs.jpcb.3c07867
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Editorial: Genomic imprinting and monoallelic gene expression mechanisms and applications.

    Oczkowicz, Maria / Tycko, Benjamin / Demars, Julie

    Frontiers in genetics

    2022  Volume 13, Page(s) 1067443

    Language English
    Publishing date 2022-11-10
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2606823-0
    ISSN 1664-8021
    ISSN 1664-8021
    DOI 10.3389/fgene.2022.1067443
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Structures of brain-derived 42-residue amyloid-β fibril polymorphs with unusual molecular conformations and intermolecular interactions.

    Lee, Myungwoon / Yau, Wai-Ming / Louis, John M / Tycko, Robert

    Proceedings of the National Academy of Sciences of the United States of America

    2023  Volume 120, Issue 11, Page(s) e2218831120

    Abstract: ... In type B fibrils, residues 2 to 42 adopt an υ-shaped conformation, with only intersubunit contacts and ... internal pores. Type A and type B fibrils have opposite helical handedness. Cryo-EM density maps and ... molecular dynamics simulations indicate intersubunit K16-A42 salt bridges in type B fibrils and partially occupied ...

    Abstract Fibrils formed by the 42-residue amyloid-β peptide (Aβ42), a main component of amyloid deposits in Alzheimer's disease (AD), are known to be polymorphic, i.e., to contain multiple possible molecular structures. Previous studies of Aβ42 fibrils, including fibrils prepared entirely in vitro or extracted from brain tissue and using solid-state NMR (ssNMR) or cryogenic electron microscopy (cryo-EM) methods, have found polymorphs with differences in amino acid sidechain orientations, lengths of structurally ordered segments, and contacts between cross-β subunit pairs within a single filament. Despite these differences, Aβ42 molecules adopt a common S-shaped conformation in all previously described high-resolution Aβ42 fibril structures. Here we report two cryo-EM-based structures of Aβ42 fibrils that are qualitatively different, in samples derived from AD brain tissue by seeded growth. In type A fibrils, residues 12 to 42 adopt a ν-shaped conformation, with both intra-subunit and intersubunit hydrophobic contacts to form a compact core. In type B fibrils, residues 2 to 42 adopt an υ-shaped conformation, with only intersubunit contacts and internal pores. Type A and type B fibrils have opposite helical handedness. Cryo-EM density maps and molecular dynamics simulations indicate intersubunit K16-A42 salt bridges in type B fibrils and partially occupied K28-A42 salt bridges in type A fibrils. The coexistence of two predominant polymorphs, with differences in N-terminal dynamics, is supported by ssNMR data, as is faithful propagation of structures from first-generation to second-generation brain-seeded Aβ42 fibril samples. These results demonstrate that Aβ42 fibrils can exhibit a greater range of structural variations than seen in previous studies.
    MeSH term(s) Humans ; Amyloid beta-Peptides/metabolism ; Alzheimer Disease/metabolism ; Magnetic Resonance Spectroscopy ; Brain/metabolism ; Molecular Conformation ; Amyloid/chemistry ; Peptide Fragments/metabolism
    Chemical Substances Amyloid beta-Peptides ; Amyloid ; Peptide Fragments
    Language English
    Publishing date 2023-03-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2218831120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Cancer epigenetics and targeted therapies.

    Tycko, Benjamin

    Oncology (Williston Park, N.Y.)

    2011  Volume 25, Issue 3, Page(s) 228, 231

    MeSH term(s) Antineoplastic Agents/therapeutic use ; DNA Methylation ; Epigenesis, Genetic ; Humans ; Neoplasms/diagnosis ; Neoplasms/genetics ; Neoplasms/therapy
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2011-03
    Publishing country United States
    Document type Comment ; Journal Article ; Review
    ZDB-ID 1067950-9
    ISSN 0890-9091
    ISSN 0890-9091
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: CloudASM: an ultra-efficient cloud-based pipeline for mapping allele-specific DNA methylation.

    Dumont, Emmanuel L P / Tycko, Benjamin / Do, Catherine

    Bioinformatics (Oxford, England)

    2020  Volume 36, Issue 11, Page(s) 3558–3560

    Abstract: Summary: Methods for quantifying the imbalance in CpG methylation between alleles genome-wide have been described but their algorithmic time complexity is quadratic and their practical use requires painstaking attention to infrastructure choice, ... ...

    Abstract Summary: Methods for quantifying the imbalance in CpG methylation between alleles genome-wide have been described but their algorithmic time complexity is quadratic and their practical use requires painstaking attention to infrastructure choice, implementation and execution. To solve this problem, we developed CloudASM, a scalable, ultra-efficient, turn-key, portable pipeline on Google Cloud Platform (GCP) that uses a novel pipeline manager and GCP's serverless enterprise data warehouse.
    Availability and implementation: CloudASM is freely available in the GitHub repository https://github.com/TyckoLab/CloudASM and a sample dataset and its results are also freely available at https://console.cloud.google.com/storage/browser/cloudasm.
    Contact: emmanuel.dumont@hmh-cdi.org.
    MeSH term(s) Alleles ; Cloud Computing ; DNA Methylation ; Software
    Language English
    Publishing date 2020-02-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1422668-6
    ISSN 1367-4811 ; 1367-4803
    ISSN (online) 1367-4811
    ISSN 1367-4803
    DOI 10.1093/bioinformatics/btaa149
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Prodromal Alzheimer's disease can affect activities of daily living for adults with Down syndrome.

    Listwan, Tracy A / Krinsky-McHale, Sharon J / Kovacs, Cynthia M / Lee, Joseph H / Pang, Deborah I / Schupf, Nicole / Tycko, Benjamin / Zigman, Warren B / Silverman, Wayne

    Alzheimer's & dementia (Amsterdam, Netherlands)

    2024  Volume 16, Issue 1, Page(s) e12562

    Abstract: Introduction: Alzheimer's disease (AD) affecting adults with Down syndrome (DS-AD), like late-onset AD (LOAD) in the neurotypical population, has preclinical, prodromal, and more advanced stages. Only tasks placing high demands on cognition are expected ...

    Abstract Introduction: Alzheimer's disease (AD) affecting adults with Down syndrome (DS-AD), like late-onset AD (LOAD) in the neurotypical population, has preclinical, prodromal, and more advanced stages. Only tasks placing high demands on cognition are expected to be affected during the prodromal stage, with activities of daily living (ADLs) typically being spared. However, cognitive demands of ADLs could be high for adults with DS and may be affected during prodromal DS-AD.
    Methods: Cognitively stable cases that subsequently developed prodromal DS-AD were identified within a set of archived data from a previous longitudinal study. Measures of ADLs and multiple cognitive domains were examined over time.
    Results: Clear declines in ADLs accompanied cognitive declines with prodromal DS-AD while stability in all measures was verified during preclinical DS-AD.
    Discussion: Operationally defining prodromal DS-AD is essential to disease staging in this high-risk population and for informing treatment options and timing as new disease-modifying drugs become available.
    Highlights: Cognitive and functional stability were demonstrated prior to the onset of prodromal DS-AD.ADL declines accompanied cognitive declines as adults with DS transitioned to prodromal AD.Declines in ADLs should be a defining feature of prodromal AD for adults with DS.Better characterization of prodromal DS-AD can improve AD diagnosis and disease staging.Improvements in DS-AD diagnosis and staging could also inform the timing of interventions.
    Language English
    Publishing date 2024-03-11
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2832898-X
    ISSN 2352-8729
    ISSN 2352-8729
    DOI 10.1002/dad2.12562
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Temperature-Dependent Nuclear Spin Relaxation Due to Paramagnetic Dopants Below 30 K: Relevance to DNP-Enhanced Magnetic Resonance Imaging.

    Chen, Hsueh-Ying / Tycko, Robert

    The journal of physical chemistry. B

    2018  Volume 122, Issue 49, Page(s) 11731–11742

    Abstract: Dynamic nuclear polarization (DNP) can increase nuclear magnetic resonance (NMR) signal strengths by factors of 100 or more at low temperatures. In magnetic resonance imaging (MRI), signal enhancements from DNP potentially lead to enhancements in image ... ...

    Abstract Dynamic nuclear polarization (DNP) can increase nuclear magnetic resonance (NMR) signal strengths by factors of 100 or more at low temperatures. In magnetic resonance imaging (MRI), signal enhancements from DNP potentially lead to enhancements in image resolution. However, the paramagnetic dopants required for DNP also reduce nuclear spin relaxation times, producing signal losses that may cancel the signal enhancements from DNP. Here we investigate the dependence of
    MeSH term(s) Magnetic Resonance Imaging ; Nitrogen Oxides/chemistry ; Nuclear Magnetic Resonance, Biomolecular ; Temperature
    Chemical Substances Nitrogen Oxides
    Language English
    Publishing date 2018-10-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ISSN 1520-5207
    ISSN (online) 1520-5207
    DOI 10.1021/acs.jpcb.8b07958
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Allele-specific DNA methylation: beyond imprinting.

    Tycko, Benjamin

    Human molecular genetics

    2010  Volume 19, Issue R2, Page(s) R210–20

    Abstract: Allele-specific DNA methylation (ASM) and allele-specific gene expression (ASE) have long been studied in genomic imprinting and X chromosome inactivation. But these types of allelic asymmetries, along with allele-specific transcription factor binding ( ... ...

    Abstract Allele-specific DNA methylation (ASM) and allele-specific gene expression (ASE) have long been studied in genomic imprinting and X chromosome inactivation. But these types of allelic asymmetries, along with allele-specific transcription factor binding (ASTF), have turned out to be far more pervasive-affecting many non-imprinted autosomal genes in normal human tissues. ASM, ASE and ASTF have now been mapped genome-wide by microarray-based methods and NextGen sequencing. Multiple studies agree that all three types of allelic asymmetries, as well as the related phenomena of expression and methylation quantitative trait loci, are mostly accounted for by cis-acting regulatory polymorphisms. The precise mechanisms by which this occurs are not yet understood, but there are some testable hypotheses and already a few direct clues. Future challenges include achieving higher resolution maps to locate the epicenters of cis-regulated ASM, using this information to test mechanistic models, and applying genome-wide maps of ASE/ASM/ASTF to pinpoint functional regulatory polymorphisms influencing disease susceptibility.
    MeSH term(s) Alleles ; Binding Sites/genetics ; DNA Methylation/genetics ; Genomic Imprinting/genetics ; Humans ; Transcription Factors/metabolism
    Chemical Substances Transcription Factors
    Language English
    Publishing date 2010-09-20
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddq376
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  9. Article ; Online: Stress and DNA Methylation of Blood Leukocytes among Pregnant Latina Women.

    Barcelona, Veronica / Abuaish, Sameera / Lee, Seonjoo / Harkins, Sarah / Butler, Ashlie / Tycko, Benjamin / Baccarelli, Andrea A / Walsh, Kate / Monk, Catherine E

    Epigenomes

    2023  Volume 7, Issue 4

    Abstract: Latinas experience physical and psychological stressors in pregnancy leading to increased morbidity and higher risk for adverse birth outcomes. Epigenetic changes, including DNA methylation (DNAm), have been proposed as markers to create more refined ... ...

    Abstract Latinas experience physical and psychological stressors in pregnancy leading to increased morbidity and higher risk for adverse birth outcomes. Epigenetic changes, including DNA methylation (DNAm), have been proposed as markers to create more refined risk stratification, yet few of these studies have examined these changes in Latinas. We conducted a secondary analysis of stored blood leukocytes of Latina women (n = 58) enrolled in a larger National Institutes of Health funded R01 project (2011-2016). We examined DNAm on eight candidate stress genes to compare physically and psychologically stressed participants to healthy (low stress) participants. We found unique CpGs that were differentially methylated in stressed women early- and mid-pregnancy compared to the healthy group, though none remained significant after FDR correction. Both physical and psychological stress were associated with hypomethylation at two consecutive CpG sites on NR3C1 in early pregnancy and one CpG site on NR3C1 in mid-pregnancy before adjustment. Stress was also associated with hypomethylation at two CpG sites on FKBP5 in early and mid-pregnancy but were no longer significant after FDR adjustment. Though we did not find statistically significant differences in DNAm during pregnancy between stressed and healthy women in this sample, signals were consistent with previous findings. Future work in larger samples should further examine the associations between stress and DNAm in pregnancy as this mechanism may explain underlying perinatal health inequities.
    Language English
    Publishing date 2023-11-01
    Publishing country Switzerland
    Document type Journal Article
    ISSN 2075-4655
    ISSN (online) 2075-4655
    DOI 10.3390/epigenomes7040027
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  10. Article ; Online: Mapping allele-specific DNA methylation: a new tool for maximizing information from GWAS.

    Tycko, Benjamin

    American journal of human genetics

    2009  Volume 86, Issue 2, Page(s) 109–112

    Abstract: In this issue of The Journal, an article by Schalkwyk et al.(1) shows the landscape of allele-specific DNA methylation (ASM) in the human genome. ASM has long been studied as a hallmark of imprinted genes, and a chromosome-wide version of this phenomenon ...

    Abstract In this issue of The Journal, an article by Schalkwyk et al.(1) shows the landscape of allele-specific DNA methylation (ASM) in the human genome. ASM has long been studied as a hallmark of imprinted genes, and a chromosome-wide version of this phenomenon occurs, in a random fashion, during X chromosome inactivation in female cells. But the type of ASM motivating the study by Schalkwyk et al. is different. They used a high-resolution, methylation-sensitive SNP array (MSNP) method for genome-wide profiling of ASM in total peripheral-blood leukocytes (PBL) and buccal cells from a series of monozygotic twin pairs. Their data bring a new level of detail to our knowledge of a newly recognized phenomenon-nonimprinted, sequence-dependent ASM. They document the widespread occurrence of this phenomenon among human genes and discuss its basic implications for gene regulation and genetic-epigenetic interactions. But this paper and recent work from other laboratories(2,3) raises the possibility of a more immediate and practical application for ASM mapping, namely to help extract maximum information from genome-wide association studies.
    MeSH term(s) Alleles ; Animals ; Base Sequence ; Chromosome Mapping ; DNA Methylation/genetics ; Epigenesis, Genetic ; Genome-Wide Association Study/methods ; Humans ; Mice ; Polymorphism, Single Nucleotide/genetics
    Language English
    Publishing date 2009-11-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 219384-x
    ISSN 1537-6605 ; 0002-9297
    ISSN (online) 1537-6605
    ISSN 0002-9297
    DOI 10.1016/j.ajhg.2010.01.021
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