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- Hansson, Magnus, et al.
(författare)
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Cyclophilin D-sensitive mitochondrial permeability transition in adult human brain and liver mitochondria.
- 2011
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 28, s. 143-153
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Tidskriftsartikel (refereegranskat)abstract
- The mitochondrial permeability transition (mPT) is considered to be a major cause of cell death under a variety of pathophysiological conditions of the CNS and other organs. Pharmacological inhibition or genetic knock-out of the matrix protein cyclophilin D (CypD) prevents mPT and cell degeneration in several models of brain injury. Provided that findings in animal models can be translatable to human disease, pharmacological inhibition of mPT offers a promising therapeutic target. The objective of this study was to validate the presence of a CypD-sensitive mPT in adult human brain and liver mitochondria. In order to perform functional characterization of human mitochondria, fresh tissue samples were obtained during hemorrhage or tumor surgery and mitochondria were rapidly isolated. Mitochondrial calcium retention capacity, a quantitative assay for mPT, was significantly increased by the CypD inhibitor cyclosporin A in both human brain and liver mitochondria, whereas thiol-reactive compounds and oxidants sensitized mitochondria to calcium-induced mPT. Brain mitochondria underwent swelling upon calcium overload, which was reversible upon calcium removal. To further explore mPT of human mitochondria, liver mitochondria were demonstrated to exhibit several classical features of the mPT phenomenon such as calcium-induced loss of membrane potential and respiratory coupling, as well as release of the pro-apoptotic protein cytochrome c. It is concluded that adult viable human brain and liver mitochondria possess an active CypD-sensitive mPT. The present findings support the rationale of CypD and mPT inhibition as pharmacological targets in acute and chronic neurodegeneration.
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- Niimi, Yoshiki, et al.
(författare)
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Combining plasma Aβ and p-tau217 improves detection of brain amyloid in non-demented elderly
- 2024
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Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer’s disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-β (Aβ)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aβ-positron emission tomography (PET) in the preclinical and prodromal AD. Methods: We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aβ and p-tau217 assessments, and Aβ-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aβ(1-42) (Aβ42) and Aβ(1-40) (Aβ40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly). Results: Aβ-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aβ42/Aβ40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aβ-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aβ42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aβ42/Aβ40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aβ42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aβ42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aβ42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914). Conclusions: Combination of plasma Aβ-related biomarkers and p-tau217 exhibits high performance when predicting Aβ-PET positivity. Adding basic clinical information (i.e., age, sex, APOE ε genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aβ-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.
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- Uchino, Hiroyuki, et al.
(författare)
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Cyclophilin-D inhibition in neuroprotection : dawn of a new era of mitochondrial medicine
- 2013
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Ingår i: Acta Neurochirurgica. Supplementum. - Vienna : Springer Vienna. - 0065-1419. ; 118, s. 5-311
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury and ischemia can result in marked neuronal degeneration and residual impairment of cerebral function. However, no effective pharmacological treatment directed at tissues of the central nervous system (CNS) for acute intervention has been developed. The detailed pathophysiological cascade leading to -neurodegeneration in these conditions has not been elucidated, but cellular calcium overload and mitochondrial dysfunction have been implicated in a wide range of animal models involving degeneration of the CNS. In particular, activation of the calcium-induced mitochondrial permeability transition (mPT) is considered to be a major cause of cell death inferred by the broad and potent neuroprotective effects of -pharmacological inhibitors of mPT, especially modulators of cyclophilin activity and, more specifically, genetic inactivation of the mitochondrial cyclophilin, cyclophilin D. Reviewed are evidence and challenges that could bring on the dawning of mitochondrial medicine aimed at safeguarding energy supply following acute injury to the CNS.
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| 5. |
- Yamamoto, Kohei, et al.
(författare)
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Ultrafast demagnetization of Pt magnetic moment in L1(0)-FePt probed by magnetic circular dichroism at a hard x-ray free electron laser
- 2019
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Ingår i: New Journal of Physics. - : IOP PUBLISHING LTD. - 1367-2630. ; 21:12
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Tidskriftsartikel (refereegranskat)abstract
- Unraveling the origin of ultrafast demagnetization in multisublattice ferromagnetic materials requires femtosecond x-ray techniques to trace the magnetic moment dynamics on individual elements, but this could not yet be achieved in the hard x-ray regime. We demonstrate here the first ultrafast demagnetization dynamics in the ferromagnetic heavy 5d-transition metal Pt using circularly-polarized hard x-rays at an x-ray free electron laser (XFEL). The decay time of laser-induced demagnetization of L1(0)-FePt is determined to be tau(Pt) = 0.61 +/- 0.04 ps using time-resolved x-ray magnetic circular dichroism at the Pt L-3 edge, whereas magneto-optical Kerr measurements indicate the decay time for the total magnetization as tau(total) < 0.1 ps. A transient magnetic state with a photomodulated ratio of the 3d and 5d magnetic moments is demonstrated for pump-probe delays larger than 1 ps. We explain this distinct photo-modulated transient magnetic state by the induced-moment behavior of the Pt atom and the x-ray probing depth. Our findings pave the way for the future use of XFELs to disentangle atomic spin dynamics contributions.
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