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  • 1
    Online Resource
    Online Resource
    Using common genetic variants to find drugs for common epilepsies
    Oxford University Press (OUP) ; 2021
    In:  Brain Communications Vol. 3, No. 4 ( 2021-10-01)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 3, No. 4 ( 2021-10-01)
    Abstract: Better drugs are needed for common epilepsies. Drug repurposing offers the potential of significant savings in the time and cost of developing new treatments. In order to select the best candidate drug(s) to repurpose for a disease, it is desirable to predict the relative clinical efficacy that drugs will have against the disease. Common epilepsy can be divided into different types and syndromes. Different antiseizure medications are most effective for different types and syndromes of common epilepsy. For predictions of antiepileptic efficacy to be clinically translatable, it is essential that the predictions are specific to each form of common epilepsy, and reflect the patterns of drug efficacy observed in clinical studies and practice. These requirements are not fulfilled by previously published drug predictions for epilepsy. We developed a novel method for predicting the relative efficacy of drugs against any common epilepsy, by using its Genome-Wide Association Study summary statistics and drugs’ activity data. The methodological advancement in our technique is that the drug predictions for a disease are based upon drugs’ effects on the function and abundance of proteins, and the magnitude and direction of those effects, relative to the importance, degree and direction of the proteins’ dysregulation in the disease. We used this method to predict the relative efficacy of all drugs, licensed for any condition, against each of the major types and syndromes of common epilepsy. Our predictions are concordant with findings from real-world experience and randomized clinical trials. Our method predicts the efficacy of existing antiseizure medications against common epilepsies; in this prediction, our method outperforms the best alternative existing method: area under receiver operating characteristic curve (mean ± standard deviation) 0.83 ± 0.03 and 0.63 ± 0.04, respectively. Importantly, our method predicts which antiseizure medications are amongst the more efficacious in clinical practice, and which antiseizure medications are amongst the less efficacious in clinical practice, for each of the main syndromes of common epilepsy, and it predicts the distinct order of efficacy of individual antiseizure medications in clinical trials of different common epilepsies. We identify promising candidate drugs for each of the major syndromes of common epilepsy. We screen five promising predicted drugs in an animal model: each exerts a significant dose-dependent effect upon seizures. Our predictions are a novel resource for selecting suitable candidate drugs that could potentially be repurposed for each of the major syndromes of common epilepsy. Our method is potentially generalizable to other complex diseases.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcab287
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 3020013-1
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  • 2
    Online Resource
    Online Resource
    Polyphenolic Allelochemicals from the Aquatic Angiosperm Myriophyllum spicatum Inhibit Photosystem II
    Oxford University Press (OUP) ; 2002
    In:  Plant Physiology Vol. 130, No. 4 ( 2002-12-01), p. 2011-2018
    Details
    In: Plant Physiology, Oxford University Press (OUP), Vol. 130, No. 4 ( 2002-12-01), p. 2011-2018
    Abstract: Myriophyllum spicatum (Haloragaceae) is a highly competitive freshwater macrophyte that produces and releases algicidal and cyanobactericidal polyphenols. Among them, β-1,2,3-tri-O-galloyl-4,6-(S)-hexahydroxydiphenoyl-d-glucose (tellimagrandin II) is the major active substance and is an effective inhibitor of microalgal exoenzymes. However, this mode of action does not fully explain the strong allelopathic activity observed in bioassays. Lipophilic extracts of M. spicatum inhibit photosynthetic oxygen evolution of intact cyanobacteria and other photoautotrophs. Fractionation of the extract provided evidence for tellimagrandin II as the active compound. Separate measurements of photosystem I and II activity with spinach (Spinacia oleracea) thylakoid membranes indicated that the site of inhibition is located at photosystem II (PSII). In thermoluminescence measurements with thylakoid membranes and PSII-enriched membrane fragments M. spicatum extracts shifted the maximum temperature of the B-band (S2QB  −recombination) to higher temperatures. Purified tellimagrandin II in concentrations as low as 3 μm caused a comparable shift of the B-band. This demonstrates that the target site of this inhibitor is different from the QB-binding site, a common target of commercial herbicides like 3-(3,4-dichlorophenyl)-1,1-dimethylurea. Measurements with electron paramagnetic resonance spectroscopy suggest a higher redox midpoint potential for the non-heme iron, located between the primary and the secondary quinone electron acceptors, QA and QB. Thus, tellimagrandin II has at least two modes of action, inhibition of exoenzymes and inhibition of PSII. Multiple target sites are a common characteristic of many potent allelochemicals.
    Type of Medium: Online Resource
    ISSN: 1532-2548 , 0032-0889
    URL: Article
    DOI: 10.1104/pp.011593
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2002
    detail.hit.zdb_id: 2004346-6
    detail.hit.zdb_id: 208914-2
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Concise Review: Macrophages: Versatile Gatekeepers During Pancreatic β-Cell Development, Injury, and Regeneration
    Oxford University Press (OUP) ; 2015
    In:  Stem Cells Translational Medicine Vol. 4, No. 6 ( 2015-06-01), p. 555-563
    Details
    In: Stem Cells Translational Medicine, Oxford University Press (OUP), Vol. 4, No. 6 ( 2015-06-01), p. 555-563
    Abstract: Macrophages are classically considered detrimental for pancreatic β-cell survival and function, thereby contributing to β-cell failure in both type 1 (T1D) and 2 (T2D) diabetes mellitus. In addition, adipose tissue macrophages negatively influence peripheral insulin signaling and promote obesity-induced insulin resistance in T2D. In contrast, recent data unexpectedly uncovered that macrophages are not only able to protect β cells during pancreatitis but also to orchestrate β-cell proliferation and regeneration after β-cell injury. Moreover, by altering their activation state, macrophages are able to improve insulin resistance in murine models of T2D. This review will elaborate on current insights in macrophage heterogeneity and on the evolving role of pancreas macrophages during organogenesis, tissue injury, and repair. Additional identification of macrophage subtypes and of their secreted factors might ultimately translate into novel therapeutic strategies for both T1D and T2D. Significance Diabetes mellitus is a pandemic disease, characterized by severe acute and chronic complications. Macrophages have long been considered prime suspects in the pathogenesis of both type 1 and 2 diabetes mellitus. In this concise review, current insights in macrophage heterogeneity and on the, as yet, underappreciated role of alternatively activated macrophages in insulin sensing and β-cell development/repair are reported. Further identification of macrophage subtypes and of their secreted factors might ultimately translate into novel therapeutic strategies for diabetes mellitus.
    Type of Medium: Online Resource
    ISSN: 2157-6564 , 2157-6580
    URL: Article
    DOI: 10.5966/sctm.2014-0272
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2015
    detail.hit.zdb_id: 2642270-0
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  • 4
    Online Resource
    Online Resource
    Ice-related seasonality in zooplankton community composition in a high Arctic fjord
    Oxford University Press (OUP) ; 2013
    In:  Journal of Plankton Research Vol. 35, No. 4 ( 2013-07-01), p. 831-842
    Details
    In: Journal of Plankton Research, Oxford University Press (OUP), Vol. 35, No. 4 ( 2013-07-01), p. 831-842
    Type of Medium: Online Resource
    ISSN: 1464-3774 , 0142-7873
    URL: Article
    DOI: 10.1093/plankt/fbt031
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2013
    detail.hit.zdb_id: 756271-8
    detail.hit.zdb_id: 1474909-9
    SSG: 12
    SSG: 21,3
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  • 5
    Online Resource
    Online Resource
    Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A
    Oxford University Press (OUP) ; 2013
    In:  Brain Vol. 136, No. 10 ( 2013-10-01), p. 3140-3150
    Details
    In: Brain, Oxford University Press (OUP), Vol. 136, No. 10 ( 2013-10-01), p. 3140-3150
    Type of Medium: Online Resource
    ISSN: 1460-2156 , 0006-8950
    URL: Article
    DOI: 10.1093/brain/awt233
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2013
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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