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  • 1
    Online Resource
    Online Resource
    Divalproex sodium regulates ataxin-3 translocation likely by an importin α1-dependent pathway
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  NeuroReport Vol. 30, No. 11 ( 2019-08-7), p. 760-764
    Details
    In: NeuroReport, Ovid Technologies (Wolters Kluwer Health), Vol. 30, No. 11 ( 2019-08-7), p. 760-764
    Type of Medium: Online Resource
    ISSN: 0959-4965
    URL: Article
    DOI: 10.1097/WNR.0000000000001246
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2031485-1
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  • 2
    Online Resource
    Online Resource
    The impact of an audience response system on a summative assessment, a controlled field study
    Springer Science and Business Media LLC ; 2020
    In:  BMC Medical Education Vol. 20, No. 1 ( 2020-12)
    Details
    In: BMC Medical Education, Springer Science and Business Media LLC, Vol. 20, No. 1 ( 2020-12)
    Abstract: Audience response systems allow to activate the audience and to receive a direct feedback of participants during lectures. Modern systems do not require any proprietary hardware anymore. Students can directly respond on their smartphone. Several studies reported about a high level of satisfaction of students when audience response systems are used, however their impact on learning success is still unclear. Methods In order to evaluate the impact of an audience response system on the learning success we implemented the audience response system eduVote into a seminar series and performed a controlled crossover study on its impact on assessments. One hundred fifty-four students in nine groups were taught the same content. In four groups, eduVote was integrated for the first topic while five groups were taught this topic without the audience response systems. For a second topic, the groups were switched: Those groups who were taught before using eduVote were now taught without the audience response system and vice versa. We then analysed the impact of the audience response system on the students’ performance in a summative assessment and specifically focused on questions dealing with the topic, for which the audience response system was used during teaching. We further assessed the students’ perception on the use of eduVote using questionnaires. Results In our controlled crossover study we could not confirm an impact of the audience response system eduVote on long-term persistence i.e. the students’ performance in the summative assessment. Our evaluation revealed that students assessed the use of eduVote very positively, felt stronger engaged and better motivated to deal with the respective topics and would prefer their integration into additional courses as well. In particular we identified that students who feel uncomfortable with answering questions in front of others profit from the use of an audience response system during teaching. Conclusions Audience response systems motivate and activate students and increase their engagement during classes. However, their impact on long-term persistence and summative assessments may be limited. Audience response systems, however, specifically allow activating students which cannot be reached by the traditional way of asking questions without such an anonymous tool.
    Type of Medium: Online Resource
    ISSN: 1472-6920
    URL: Article
    DOI: 10.1186/s12909-020-02130-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2044473-4
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  • 3
    Online Resource
    Online Resource
    Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease
    Springer Science and Business Media LLC ; 2023
    In:  Molecular Neurodegeneration Vol. 18, No. 1 ( 2023-07-04)
    Details
    In: Molecular Neurodegeneration, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2023-07-04)
    Abstract: Braak’s hypothesis states that sporadic Parkinson’s disease (PD) follows a specific progression of pathology from the peripheral to the central nervous system, and this progression can be monitored by detecting the accumulation of alpha-Synuclein (α-Syn) protein. Consequently, there is growing interest in understanding how the gut (commensal) microbiome can regulate α-Syn accumulation, as this could potentially lead to PD. Methods We used 16S rRNA and shotgun sequencing to characterise microbial diversity. 1 H-NMR was employed to understand the metabolite production and intestinal inflammation estimated using ELISA and RNA-sequencing from feces and the intestinal epithelial layer respectively. The Na + channel current and gut permeability were measured using an Ussing chamber. Immunohistochemistry and immunofluorescence imaging were applied to detect the α-Syn protein. LC-MS/MS was used for characterization of proteins from metabolite treated neuronal cells. Finally, Metascape and Ingenuity Pathway Analysis (IPA) bioinformatics tools were used for identification of dysregulated pathways. Results We studied a transgenic (TG) rat model overexpressing the human SNCA gene and found that a progressive gut microbial composition alteration characterized by the reduction of Firmicutes to Bacteroidetes ratio could be detected in the young TG rats. Interestingly, this ratio then increased with ageing. The dynamics of Lactobacillus and Alistipes were monitored and reduced Lactobacillus and increased Alistipes abundance was discerned in ageing TG rats. Additionally, the SNCA gene overexpression resulted in gut α-Syn protein expression and increased with advanced age. Further, older TG animals had increased intestinal inflammation, decreased Na + current and a robust alteration in metabolite production characterized by the increase of succinate levels in feces and serum. Manipulation of the gut bacteria by short-term antibiotic cocktail treatment revealed a complete loss of short-chain fatty acids and a reduction in succinate levels. Although antibiotic cocktail treatment did not change α-Syn expression in the enteric nervous system of the colon, however, reduced α-Syn expression was detected in the olfactory bulbs (forebrain) of the TG rats. Conclusion Our data emphasize that the gut microbiome dysbiosis synchronous with ageing leads to a specific alteration of gut metabolites and can be modulated by antibiotics which may affect PD pathology.
    Type of Medium: Online Resource
    ISSN: 1750-1326
    URL: Article
    DOI: 10.1186/s13024-023-00628-1
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2244557-2
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  • 4
    Online Resource
    Online Resource
    KPNB1 modulates the Machado–Joseph disease protein ataxin-3 through activation of the mitochondrial protease CLPP
    Springer Science and Business Media LLC ; 2022
    In:  Cellular and Molecular Life Sciences Vol. 79, No. 8 ( 2022-08)
    Details
    In: Cellular and Molecular Life Sciences, Springer Science and Business Media LLC, Vol. 79, No. 8 ( 2022-08)
    Abstract: Machado–Joseph disease (MJD) is characterized by a pathological expansion of the polyglutamine (polyQ) tract within the ataxin-3 protein. Despite its primarily cytoplasmic localization, polyQ-expanded ataxin-3 accumulates in the nucleus and forms intranuclear aggregates in the affected neurons. Due to these histopathological hallmarks, the nucleocytoplasmic transport machinery has garnered attention as an important disease relevant mechanism. Here, we report on MJD cell model-based analysis of the nuclear transport receptor karyopherin subunit beta-1 (KPNB1) and its implications in the molecular pathogenesis of MJD. Although directly interacting with both wild-type and polyQ-expanded ataxin-3, modulating KPNB1 did not alter the intracellular localization of ataxin-3. Instead, overexpression of KPNB1 reduced ataxin-3 protein levels and the aggregate load, thereby improving cell viability. On the other hand, its knockdown and inhibition resulted in the accumulation of soluble and insoluble ataxin-3. Interestingly, the reduction of ataxin-3 was apparently based on protein fragmentation independent of the classical MJD-associated proteolytic pathways. Label-free quantitative proteomics and knockdown experiments identified mitochondrial protease CLPP as a potential mediator of the ataxin-3-degrading effect induced by KPNB1. We confirmed reduction of KPNB1 protein levels in MJD by analyzing two MJD transgenic mouse models and induced pluripotent stem cells (iPSCs) derived from MJD patients. Our results reveal a yet undescribed regulatory function of KPNB1 in controlling the turnover of ataxin-3, thereby highlighting a new potential target of therapeutic value for MJD.
    Type of Medium: Online Resource
    ISSN: 1420-682X , 1420-9071
    URL: Article
    DOI: 10.1007/s00018-022-04372-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1458497-9
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Pathophysiological interplay between O -GlcNAc transferase and the Machado–Joseph disease protein ataxin-3
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 47 ( 2021-11-23)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 47 ( 2021-11-23)
    Abstract: Aberrant O -GlcNAcylation, a protein posttranslational modification defined by the O -linked attachment of the monosaccharide N -acetylglucosamine ( O -GlcNAc), has been implicated in neurodegenerative diseases. However, although many neuronal proteins are substrates for O -GlcNAcylation, this process has not been extensively investigated in polyglutamine disorders. We aimed to evaluate the enzyme O -GlcNAc transferase (OGT), which attaches O -GlcNAc to target proteins, in Machado–Joseph disease (MJD). MJD is a neurodegenerative condition characterized by ataxia and caused by the expansion of a polyglutamine stretch within the deubiquitinase ataxin-3, which then present increased propensity to aggregate. By analyzing MJD cell and animal models, we provide evidence that OGT is dysregulated in MJD, therefore compromising the O -GlcNAc cycle. Moreover, we demonstrate that wild-type ataxin-3 modulates OGT protein levels in a proteasome-dependent manner, and we present OGT as a substrate for ataxin-3. Targeting OGT levels and activity reduced ataxin-3 aggregates, improved protein clearance and cell viability, and alleviated motor impairment reminiscent of ataxia of MJD patients in zebrafish model of the disease. Taken together, our results point to a direct interaction between OGT and ataxin-3 in health and disease and propose the O -GlcNAc cycle as a promising target for the development of therapeutics in the yet incurable MJD.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2025810118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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