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- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Emery, Samantha J., et al.
(författare)
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Differential protein expression and post-translational modifications in metronidazole-resistant Giardia duodenalis
- 2018
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Ingår i: GigaScience. - : OXFORD UNIV PRESS. - 2047-217X. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Metronidazole (Mtz) is the frontline drug treatment for multiple anaerobic pathogens, including the gastrointestinal protist, Giardia duodenalis. However, treatment failure is common and linked to in vivo drug resistance. In Giardia, in vitro drug-resistant lines allow controlled experimental interrogation of resistance mechanisms in isogenic cultures. However, resistance-associated changes are inconsistent between lines, phenotypic data are incomplete, and resistance is rarely genetically fixed, highlighted by reversion to sensitivity after drug selection ceases or via passage through the life cycle. Comprehensive quantitative approaches are required to resolve isolate variability, fully define Mtz resistance phenotypes, and explore the role of post-translational modifications therein. Findings: We performed quantitative proteomics to describe differentially expressed proteins in 3 seminal Mtz-resistant lines compared to their isogenic, Mtz-susceptible, parental line. We also probed changes in post-translational modifications including protein acetylation, methylation, ubiquitination, and phosphorylation via immunoblotting. We quantified more than 1,000 proteins in each genotype, recording substantial genotypic variation in differentially expressed proteins between isotypes. Our data confirm substantial changes in the antioxidant network, glycolysis, and electron transport and indicate links between protein acetylation and Mtz resistance, including cross-resistance to deacetylase inhibitor trichostatin A in Mtz-resistant lines. Finally, we performed the first controlled, longitudinal study of Mtz resistance stability, monitoring lines after cessation of drug selection, revealing isolate-dependent phenotypic plasticity. Conclusions: Our data demonstrate understanding that Mtz resistance must be broadened to post-transcriptional and post-translational responses and that Mtz resistance is polygenic, driven by isolate-dependent variation, and is correlated with changes in protein acetylation networks.
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| 6. |
- Seyednazari, Salar, et al.
(författare)
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Error and stability estimates of a least-squares variational kernel-based method for second order elliptic PDEs
- 2021
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Ingår i: Computers and Mathematics with Applications. - : Elsevier. - 0898-1221 .- 1873-7668. ; 103, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- We consider a least-squares variational kernel-based method for numerical solution of second order elliptic partial differential equations on a multi-dimensional domain. In this setting it is not assumed that the differential operator is self-adjoint or positive definite as it should be in the Rayleigh-Ritz setting. However, the new scheme leads to a symmetric and positive definite algebraic system of equations. Moreover, the resulting method does not rely on certain subspaces satisfying the boundary conditions. The trial space for discretization is provided via standard kernels that reproduce the Sobolev spaces as their native spaces. The error analysis of the method is given, but it is partly subjected to an inverse inequality on the boundary which is still an open problem. The condition number of the final linear system is approximated in terms of the smoothness of the kernel and the discretization quality. Finally, the results of some computational experiments support the theoretical error bounds.
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| 7. |
- Thananthirige, Kanishka Pushpitha Maha, et al.
(författare)
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Tau modulation through AAV9 therapy augments Akt/Erk survival signalling in glaucoma mitigating the retinal degenerative phenotype
- 2024
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The microtubule-associated protein Tau is a key player in various neurodegenerative conditions, including Alzheimer's disease (AD) and Tauopathies, where its hyperphosphorylation disrupts neuronal microtubular lattice stability. Glaucoma, a neurodegenerative disorder affecting the retina, leads to irreversible vision loss by damaging retinal ganglion cells and the optic nerve, often associated with increased intraocular pressure. Prior studies have indicated Tau expression and phosphorylation alterations in the retina in both AD and glaucoma, yet the causative or downstream nature of Tau protein changes in these pathologies remains unclear. This study investigates the impact of Tau protein modulation on retinal neurons under normal and experimental glaucoma conditions. Employing AAV9-mediated gene therapy for Tau overexpression and knockdown, both manipulations were found to adversely affect retinal structural and functional measures as well as neuroprotective Akt/Erk survival signalling in healthy conditions. In the experimental glaucoma model, Tau overexpression intensified inner retinal degeneration, while Tau silencing provided significant protection against these degenerative changes. These findings underscore the critical role of endogenous Tau protein levels in preserving retinal integrity and emphasize the therapeutic potential of targeting Tau in glaucoma pathology.
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