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- Lockhart, Samuel N, et al.
(författare)
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Amyloid and Tau PET Demonstrate Region-Specific Associations in Normal Older People.
- 2017
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Ingår i: NeuroImage. - : Elsevier BV. - 1095-9572 .- 1053-8119. ; 150, s. 191-199
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Tidskriftsartikel (refereegranskat)abstract
- β-amyloid (Aβ) and tau pathology become increasingly prevalent with age, however, the spatial relationship between the two pathologies remains unknown. We examined local (same region) and non-local (different region) associations between these 2 aggregated proteins in 46 normal older adults using [(18)F]AV-1451 (for tau) and [(11)C]PiB (for Aβ) positron emission tomography (PET) and 1.5T magnetic resonance imaging (MRI) images. While local voxelwise analyses showed associations between PiB and AV-1451 tracer largely in the temporal lobes, k-means clustering revealed that some of these associations were driven by regions with low tracer retention. We followed this up with a whole-brain region-by-region (local and non-local) partial correlational analysis. We calculated each participant's mean AV-1451 and PiB uptake values within 87 regions of interest (ROI). Pairwise ROI analysis demonstrated many positive PiB-AV-1451 associations. Importantly, strong positive partial correlations (controlling for age, sex, and global gray matter fraction, p < .01) were identified between PiB in multiple regions of association cortex and AV-1451 in temporal cortical ROIs. There were also less frequent and weaker positive associations of regional PiB with frontoparietal AV-1451 uptake. Particularly in temporal lobe ROIs, AV-1451 uptake was strongly predicted by PiB across multiple ROI locations. These data indicate that Aβ and tau pathology show significant local and non-local regional associations among cognitively normal elderly, with increased PiB uptake throughout the cortex correlating with increased temporal lobe AV-1451 uptake. The spatial relationship between Aβ and tau accumulation does not appear to be specific to Aβ location, suggesting a regional vulnerability of temporal brain regions to tau accumulation regardless of where Aβ accumulates.
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| 3. |
- Opassi, Giulia, 1988-
(författare)
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Accelerating the discovery of drugs for Neglected Tropical Diseases using biophysical methods
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Even though they account for 10% of the global disease burden and besides the new record of funding in 2018, tropical diseases are still neglected by the majority of pharmaceutical companies and public funding. The reason can be mostly found in the fact that for these diseases a conventional drug discovery process is often too expensive. The development of new approaches in the early stage of drug discovery has therefore a key role in fighting Neglected Tropical Diseases (NTD). AEGIS is a European network which relates on collaborations for a multidisciplinary approach, in order to “accelerate” drugs development – hence reducing the costs. As part of the network, this project is focused on a rational exploration of the chemical space, together with an in depth-analysis of molecular interactions for a better characterization of targets involved in NTD.One cost-efficient way for exploring pharmacologically relevant chemical space is fragment based lead discovery (FBLD). This approach requires an extensive understanding of the target properties; therefore, a pipeline of orthogonal methods was developed to validate the suitability of the target for FBLD.The choice of a fragment library has a significant impact on the experimental strategy. Not only the validation of the target, but also practical issues concerning technology, orthogonal validation and applicability have to be considered when initiating a fragment screening campaign.Another rational approach for the discovery of new drugs is looking at the target structure, especially when considering protein complexes interaction. Through the structural analysis of the protein-protein interface, several short peptides derived from the binding partner were analysed in their interaction with the target both in vitro and in cell. This allowed to identify the key sequence for the binding to the target and the internalization of the complex, both crucial information for a structure-based approach. The internalization process of the target was characterized by a real-time cell binding assay (RT-CBA), revealing a higher level of complexity than what was previously described.Implementing RT-CBA in the early stage is a strategy that might improve the success rate of drug development. The possibility to develop an intracellular time resolved molecular interaction assay between small molecules and a model target fused to a fluorescent protein was therefore explored.From a fragment screening campaign to a structure-based approach, culminating with a real time intracellular validation of hits, all the assays developed address the different possibilities for accelerating the drug discovery process in the early stages.
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| 4. |
- Isfoss, Björn, et al.
(författare)
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Distribution of aldehyde dehydrogenase 1-positive stem cells in benign mammary tissue from women with and without breast cancer.
- 2012
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Ingår i: Histopathology. - : Wiley. - 0309-0167. ; 60:4, s. 617-633
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Tidskriftsartikel (refereegranskat)abstract
- Isfoss B L, Holmqvist B, Alm P & Olsson H (2012) Histopathology Distribution of aldehyde dehydrogenase 1-positive stem cells in benign mammary tissue from women with and without breast cancer Aims: Aldehyde dehydrogenase 1 (ALDH1) in female breast tissue has been linked to stem cells, but little is known about the benign cellular organization in situ. We investigated the distribution of ALDH1-immunoreactive (ALDH1+) cells in histomorphologically benign breast tissue from 28 women with or without breast cancer. Methods and results: ALDH1+ cells were detected in benign tissue of women aged 20-72 years, located most commonly at the luminal and intermediate ductular levels and in the stroma. ALDH1+ cell populations and Ki67+ cell populations were present in separate ductules, both cell types rarely showing epithelial differentiation. ALDH1+ cells were non-reactive to Ki67 and oestrogen receptor. Stromal round/oval ALDH1+ non-leukocyte cells in both age groups expressed contractile protein. There was a lower concentration of luminal and intermediate ductular ALDH1+ cells in postmenopausal women than in premenopausal women, and in cancer patients than in non-cancer patients, and a higher concentration in women receiving exogenous hormones. Conclusions: This study provides further evidence for the stem cell character of ALDH1+ cells, here in benign breast tissue of cancer and non-cancer patients throughout non-lactating adult life, and contributes evidence of benign stromal ALDH1+ cells. The distribution of ductular ALDH1+ stem cells appears to be influenced by hormonal status.
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| 5. |
- Ogawa, Akihiro
(författare)
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Civil Society : Past, Present, and Future
- 2013
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Ingår i: Critical Issues in Contemporary Japan. - London; New York : Routledge. - 9780415857444 - 9780415857451 - 9780203797594 ; , s. 51-62
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Bokkapitel (refereegranskat)
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