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  1. Article ; Online: Genome integrity and inflammation in the nervous system.

    Aditi / McKinnon, Peter J

    DNA repair

    2022  Volume 119, Page(s) 103406

    Abstract: Preservation of genomic integrity is crucial for nervous system development and function. DNA repair deficiency results in several human diseases that are characterized by both neurodegeneration and neuroinflammation. Recent research has highlighted a ... ...

    Abstract Preservation of genomic integrity is crucial for nervous system development and function. DNA repair deficiency results in several human diseases that are characterized by both neurodegeneration and neuroinflammation. Recent research has highlighted a role for compromised genomic integrity as a key factor driving neuropathology and triggering innate immune signaling to cause inflammation. Here we review the mechanisms by which DNA damage engages innate immune signaling and how this may promote neurological disease. We also consider the contributions of different neural cell types towards DNA damage-driven neuroinflammation. A deeper knowledge of genome maintenance mechanisms that prevent aberrant immune activation in neural cells will guide future therapies to ameliorate neurological disease.
    MeSH term(s) DNA Damage ; Humans ; Inflammation/pathology ; Nervous System Diseases/genetics ; Neurons/pathology
    Language English
    Publishing date 2022-09-14
    Publishing country Netherlands
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2071608-4
    ISSN 1568-7856 ; 1568-7864
    ISSN (online) 1568-7856
    ISSN 1568-7864
    DOI 10.1016/j.dnarep.2022.103406
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    Zs.A 5555: Show issues Location:
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  2. Book ; Online ; E-Book: The application of science in environmental impact assessment

    MacKinnon, Aaron J. / Duinker, Peter N. / Walker, Tony R.

    (Routledge focus on environment and sustainability)

    2018  

    Author's details Aaron J. MacKinnon, Peter N. Duinker and Tony R. Walker
    Series title Routledge focus on environment and sustainability
    Language English
    Size 1 Online-Ressource (vii, 141 Seiten)
    Publisher Routledge, Taylor & Francis Group
    Publishing place London
    Publishing country Great Britain
    Document type Book ; Online ; E-Book
    Remark Zugriff für angemeldete ZB MED-Nutzerinnen und -Nutzer
    HBZ-ID HT019601381
    ISBN 978-1-351-17343-8 ; 978-1-351-17344-5 ; 9780815387299 ; 1-351-17343-X ; 1-351-17344-8 ; 0815387296
    Database ZB MED Catalogue: Medicine, Health, Nutrition, Environment, Agriculture

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  3. Article ; Online: Out of LINE: Transposons, genome integrity, and neurodegeneration.

    Dumitrache, Lavinia C / McKinnon, Peter J

    Neuron

    2022  Volume 110, Issue 20, Page(s) 3217–3219

    Abstract: Abnormal activity of LINE-1 transposable elements has been associated with neurological disease. In this issue of Neuron, Takahashi et al. (2022) show that L1 hyperactivity occurs in the neurodegenerative syndrome ataxia telangiectasia and causes ataxia ... ...

    Abstract Abnormal activity of LINE-1 transposable elements has been associated with neurological disease. In this issue of Neuron, Takahashi et al. (2022) show that L1 hyperactivity occurs in the neurodegenerative syndrome ataxia telangiectasia and causes ataxia and cerebellar degeneration in mice.
    MeSH term(s) Animals ; Mice ; DNA Transposable Elements/genetics ; Ataxia Telangiectasia/genetics ; Neurons ; Neurodegenerative Diseases/genetics ; Ataxia/genetics
    Chemical Substances DNA Transposable Elements
    Language English
    Publishing date 2022-10-07
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2022.09.026
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    Zs.A 2496: Show issues Location:
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  4. Article ; Online: Genome integrity and disease prevention in the nervous system.

    McKinnon, Peter J

    Genes & development

    2017  Volume 31, Issue 12, Page(s) 1180–1194

    Abstract: Multiple DNA repair pathways maintain genome stability and ensure that DNA remains essentially unchanged over the life of a cell. Various human diseases occur if DNA repair is compromised, and most of these impact the nervous system, in some cases ... ...

    Abstract Multiple DNA repair pathways maintain genome stability and ensure that DNA remains essentially unchanged over the life of a cell. Various human diseases occur if DNA repair is compromised, and most of these impact the nervous system, in some cases exclusively. However, it is often unclear what specific endogenous damage underpins disease pathology. Generally, the types of causative DNA damage are associated with replication, transcription, or oxidative metabolism; other direct sources of endogenous lesions may arise from aberrant topoisomerase activity or ribonucleotide incorporation into DNA. This review focuses on the etiology of DNA damage in the nervous system and the genome stability pathways that prevent human neurologic disease.
    MeSH term(s) DNA Damage ; DNA Repair ; Genomic Instability ; Humans ; Nervous System/physiopathology ; Nervous System Diseases/etiology ; Nervous System Diseases/genetics ; Nervous System Diseases/physiopathology ; Nervous System Diseases/prevention & control
    Language English
    Publishing date 2017-06-15
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.301325.117
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    Zs.A 2292: Show issues Location:
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  5. Article ; Online: Drug-induced olfactory and gustatory dysfunction: Analysis of FDA adverse events reporting system.

    Debbaneh, Peter / McKinnon, Louis / Haidari, Muhib / Liang, Jonathan

    Auris, nasus, larynx

    2023  Volume 50, Issue 4, Page(s) 558–564

    Abstract: Objectives: With the COVID-19 pandemic, there is growing interest and research in olfactory and gustatory dysfunction (OGD). Drug-induced dysfunction is an often overlooked etiology. While several medications include smell or taste disturbance as a side ...

    Abstract Objectives: With the COVID-19 pandemic, there is growing interest and research in olfactory and gustatory dysfunction (OGD). Drug-induced dysfunction is an often overlooked etiology. While several medications include smell or taste disturbance as a side effect, there are no publications describing which medications are most frequently implicated. We aim to describe the patterns of these adverse drug reactions (ADRs) using the FDA Adverse Events Reporting System (FAERS).
    Methods: The FAERS database was queried from 2011 to 2021 for terms describing ADRs related to OGD. Terms included anosmia, hyposmia, olfactory test abnormal, olfactory nerve disorder, hallucination olfactory, parosmia, ageusia, hypogeusia, dysgeusia, and taste disorder. We identified the top reported medications associated with general smell dysfunction, general taste dysfunction, reduced smell, and altered smell.
    Results: From 2011 to 2021, 16,091 ADRs were reported with OGD, of which13,641 (84.8%) and 2,450 (15.2%) were associated with gustatory and olfactory reactions, respectively. Zinc products (370 reports) and fluticasone propionate (214) were most commonly associated with olfactory dysfunction, specifically reduced olfaction. Varenicline (24) and fluticasone propionate (23) were most commonly associated with altered smell. Lenalidomide (490) and sunitinib (468) were most commonly associated with gustatory dysfunction. Antineoplastic and immunomodulating medications accounted for 21.6% and 36.3% of olfactory and gustatory ADRs, respectively. Among this category, immunoglobulin drugs were the most commonly associated with OGD ADRs.
    Conclusion: Gustatory dysfunction is more commonly reported ADR compared with olfactory dysfunction. Immunologic/rheumatologic medications are the leading culprit of reported OGD. With increasing numbers of patients presenting to otolaryngologists for OGD, it is important to consider drug-induced etiology.
    Level of evidence: III.
    MeSH term(s) Humans ; Smell ; COVID-19/complications ; Pandemics ; SARS-CoV-2 ; Taste Disorders/chemically induced ; Taste Disorders/epidemiology ; Ageusia/chemically induced ; Ageusia/epidemiology ; Dysgeusia/chemically induced ; Dysgeusia/epidemiology ; Olfaction Disorders/chemically induced ; Olfaction Disorders/epidemiology ; Anosmia
    Language English
    Publishing date 2023-01-20
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 604552-2
    ISSN 1879-1476 ; 0385-8146
    ISSN (online) 1879-1476
    ISSN 0385-8146
    DOI 10.1016/j.anl.2022.12.012
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    Zs.A 1675: Show issues Location:
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  6. Article ; Online: Topoisomerases and the regulation of neural function.

    McKinnon, Peter J

    Nature reviews. Neuroscience

    2016  Volume 17, Issue 11, Page(s) 673–679

    Abstract: Topoisomerases are unique enzymes that regulate torsional stress in DNA to enable essential genome functions, including DNA replication and transcription. Although all cells in an organism require topoisomerases to maintain normal function, the nervous ... ...

    Abstract Topoisomerases are unique enzymes that regulate torsional stress in DNA to enable essential genome functions, including DNA replication and transcription. Although all cells in an organism require topoisomerases to maintain normal function, the nervous system in particular shows a vital need for these enzymes. Indeed, a range of inherited human neurologic syndromes, including neurodegeneration, schizophrenia and intellectual impairment, are associated with aberrant topoisomerase function. Much remains unknown regarding the tissue-specific function of neural topoisomerases or the connections between these enzymes and disease aetiology. Precisely how topoisomerases regulate genome dynamics within the nervous system is therefore a crucial research question.
    MeSH term(s) Animals ; DNA Damage/physiology ; DNA Replication/physiology ; DNA Topoisomerases/genetics ; DNA Topoisomerases/metabolism ; Humans ; Nervous System Diseases/genetics ; Nervous System Diseases/metabolism ; Neurons/physiology ; Transcription, Genetic/physiology
    Chemical Substances DNA Topoisomerases (EC 5.99.1.-)
    Language English
    Publishing date 2016
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2034150-7
    ISSN 1471-0048 ; 1471-0048 ; 1471-003X
    ISSN (online) 1471-0048
    ISSN 1471-0048 ; 1471-003X
    DOI 10.1038/nrn.2016.101
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    Zs.A 5473: Show issues Location:
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  7. Article ; Online: Next-generation bromodomain inhibitors of the SWI/SNF complex enhance DNA damage and cell death in glioblastoma.

    Yang, Chuanhe / He, Yali / Wang, Yinan / McKinnon, Peter J / Shahani, Vijay / Miller, Duane D / Pfeffer, Lawrence M

    Journal of cellular and molecular medicine

    2023  Volume 27, Issue 18, Page(s) 2770–2781

    Abstract: Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis. While surgical resection is the primary treatment, adjuvant temozolomide (TMZ) chemotherapy and radiotherapy only provide slight improvement in disease course and outcome. ... ...

    Abstract Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis. While surgical resection is the primary treatment, adjuvant temozolomide (TMZ) chemotherapy and radiotherapy only provide slight improvement in disease course and outcome. Unfortunately, most treated patients experience recurrence of highly aggressive, therapy-resistant tumours and eventually succumb to the disease. To increase chemosensitivity and overcome therapy resistance, we have modified the chemical structure of the PFI-3 bromodomain inhibitor of the BRG1 and BRM catalytic subunits of the SWI/SNF chromatin remodelling complex. Our modifications resulted in compounds that sensitized GBM to the DNA alkylating agent TMZ and the radiomimetic bleomycin. We screened these chemical analogues using a cell death ELISA with GBM cell lines and a cellular thermal shift assay using epitope tagged BRG1 or BRM bromodomains expressed in GBM cells. An active analogue, IV-129, was then identified and further modified, resulting in new generation of bromodomain inhibitors with distinct properties. IV-255 and IV-275 had higher bioactivity than IV-129, with IV-255 selectively binding to the bromodomain of BRG1 and not BRM, while IV-275 bound well to both BRG1 and BRM bromodomains. In contrast, IV-191 did not bind to either bromodomain or alter GBM chemosensitivity. Importantly, both IV-255 and IV-275 markedly increased the extent of DNA damage induced by TMZ and bleomycin as determined by nuclear γH2AX staining. Our results demonstrate that these next-generation inhibitors selectively bind to the bromodomains of catalytic subunits of the SWI/SNF complex and sensitize GBM to the anticancer effects of TMZ and bleomycin. This approach holds promise for improving the treatment of GBM.
    MeSH term(s) Humans ; Glioblastoma/drug therapy ; Glioblastoma/genetics ; Protein Domains ; Temozolomide/pharmacology ; Cell Death ; Bleomycin/pharmacology ; DNA Damage
    Chemical Substances Temozolomide (YF1K15M17Y) ; Bleomycin (11056-06-7)
    Language English
    Publishing date 2023-08-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2074559-X
    ISSN 1582-4934 ; 1582-4934 ; 1582-1838
    ISSN (online) 1582-4934
    ISSN 1582-4934 ; 1582-1838
    DOI 10.1111/jcmm.17907
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  8. Article ; Online: TDP2 keeps the brain healthy.

    McKinnon, Peter J

    Nature genetics

    2014  Volume 46, Issue 5, Page(s) 419–421

    MeSH term(s) Abnormalities, Multiple/genetics ; Animals ; Antigens, Neoplasm/metabolism ; Ataxia/genetics ; DNA Topoisomerases, Type II/metabolism ; DNA-Binding Proteins/metabolism ; Humans ; Intellectual Disability/genetics ; Nuclear Proteins/genetics ; Phosphoric Diester Hydrolases ; Seizures/genetics ; Transcription Factors/genetics ; Transcription, Genetic/genetics
    Chemical Substances Antigens, Neoplasm ; DNA-Binding Proteins ; Nuclear Proteins ; Transcription Factors ; Phosphoric Diester Hydrolases (EC 3.1.4.-) ; TDP2 protein, human (EC 3.1.4.-) ; DNA Topoisomerases, Type II (EC 5.99.1.3)
    Language English
    Publishing date 2014-04-25
    Publishing country United States
    Document type News ; Comment
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/ng.2967
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  9. Article ; Online: Assessment of Joint Angle and Reach Envelope Demands Using a Video-Based Physical Demands Description Tool.

    McKinnon, Colin D / Sonne, Michael W / Keir, Peter J

    Human factors

    2020  Volume 64, Issue 3, Page(s) 568–578

    Abstract: Background: Current methods for describing physical work demands often lack detail and format standardization, require technical training and expertise, and are time-consuming to complete. A video-based physical demands description (PDD) tool may ... ...

    Abstract Background: Current methods for describing physical work demands often lack detail and format standardization, require technical training and expertise, and are time-consuming to complete. A video-based physical demands description (PDD) tool may improve time and accuracy concerns associated with current methods.
    Methods: Ten simulated occupational tasks were synchronously recorded using a motion capture system and digital video. The tasks included a variety of industrial tasks from lifting to drilling to overhead upper extremity tasks of different cycle times. The digital video was processed with a novel video-based assessment tool to produce 3D joint trajectories (PDAi), and joint angle and reach envelope measures were calculated and compared between both data sources.
    Results: Root mean squared error between video-based and motion capture posture estimated ranged from 89.0 mm to 118.6 mm for hand height and reach distance measures, and from 13.5° to 21.6° for trunk, shoulder, and elbow angle metrics. Continuous data were reduced to time-weighted bins, and video-based posture estimates showed 75% overall agreement and quadratic-weight Cohen's kappa scores ranging from 0.29 to 1.0 compared to motion capture data across all posture metrics.
    Conclusion and application: The substantial level of agreement between time-weighted bins for video-based and motion capture measures suggest that video-based job task assessment may be a viable approach to improve accuracy and standardization of field physical demands descriptions and minimize error in joint posture and reach envelope estimates compared to traditional pen-and-paper methods.
    MeSH term(s) Biomechanical Phenomena ; Hand ; Humans ; Posture ; Shoulder ; Upper Extremity
    Keywords covid19
    Language English
    Publishing date 2020-09-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 212725-8
    ISSN 1547-8181 ; 0018-7208
    ISSN (online) 1547-8181
    ISSN 0018-7208
    DOI 10.1177/0018720820951349
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  10. Article: Ptch2 is a Potential Regulator of Mesenchymal Stem Cells.

    Juuri, Emma / Tikka, Pauli / Domanskyi, Andrii / Corfe, Ian / Morita, Wataru / Mckinnon, Peter J / Jandova, Nela / Balic, Anamaria

    Frontiers in physiology

    2022  Volume 13, Page(s) 877565

    Abstract: Ptch receptors 1 and 2 mediate Hedgehog signaling pivotal for organ development and homeostasis. In contrast to embryonic ... ...

    Abstract Ptch receptors 1 and 2 mediate Hedgehog signaling pivotal for organ development and homeostasis. In contrast to embryonic lethal
    Language English
    Publishing date 2022-04-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2022.877565
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