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- Affatato, Oreste, et al.
(författare)
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Assessing volumetric brain differences in migraine and depression patients : a UK Biobank study
- 2023
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Ingår i: BMC Neurology. - : BMC. - 1471-2377. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Migraine and depression are two of the most common and debilitating conditions. From a clinical perspective, they are mostly prevalent in women and manifest a partial overlapping symptomatology. Despite the high level of comorbidity, previous studies hardly investigated possible common patterns in brain volumetric differences compared to healthy subjects. Therefore, the current study investigates and compares the volumetric difference patterns in sub-cortical regions between participants with migraine or depression in comparison to healthy controls.Methods: The study included data from 43 930 participants of the large UK Biobank cohort. Using official ICD10 diagnosis, we selected 712 participants with migraine, 1 853 with depression and 23 942 healthy controls. We estimated mean volumetric difference between the groups for the different sub-cortical brain regions using generalized linear regression models, conditioning the model within the levels of BMI, age, sex, ethnical background, diastolic blood pressure, current tobacco smoking, alcohol intake frequency, Assessment Centre, Indices of Multiple Deprivation, comorbidities and total brain volume.Results: We detected larger overall volume of the caudate (mean difference: 66, 95% CI [-3, 135]) and of the thalamus (mean difference: 103 mm(3), 95% CI [-2, 208]) in migraineurs than healthy controls. We also observed that individuals with depression appear to have also larger overall (mean difference: 47 mm(3), 95% CI [-7, 100]) and gray matter (mean difference: 49 mm(3), 95% CI [2, 95]) putamen volumes than healthy controls, as well as larger amygdala volume (mean difference: 17 mm(3), 95% CI [-7, 40]).Conclusion: Migraineurs manifested larger overall volumes at the level of the nucleus caudate and of the thalamus, which might imply abnormal pain modulation and increased migraine susceptibility. Larger amygdala and putamen volumes in participants with depression than controls might be due to increased neuronal activity in these regions.
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| 2. |
- Amarasinghe, Kosala N., et al.
(författare)
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Sensor dimer disruption as a new mode of action to block the IRE1-mediated unfolded protein response
- 2022
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Ingår i: Computational and Structural Biotechnology Journal. - : Elsevier BV. - 2001-0370. ; 20, s. 1584-1592
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Tidskriftsartikel (refereegranskat)abstract
- The unfolded protein response (UPR) is activated to cope with an accumulation of improperly folded proteins in the Endoplasmic reticulum (ER). The Inositol requiring enzyme 1 alpha (IRE1 alpha) is the most evolutionary conserved transducer of the UPR. Activated IRE1 forms 'back-to-back'-dimers that enables the unconventional splicing of X-box Binding Protein 1 (XBP1) mRNA. The spliced XBP1 (XBP1s) mRNA is translated into a transcription factor controlling the expression of UPR target genes. Herein, we report a detailed in silico screening specifically targeting for the first time the dimer interface at the IRE1 RNase region. Using the database of FDA approved drugs, we identified four compounds (neomycin, pemetrexed, quercitrin and rutin) that were able to bind to and distort IRE1 RNase cavity. The activity of the compounds on IRE1 phosphorylation was evaluated in HEK293T cells and on IRE1 RNase activity using an in vitro fluorescence assay. These analyzes revealed sub-micromolar IC50 values. The current study reveals a new and unique mode of action to target and block the IRE1-mediated UPR signaling, whereby we may avoid problems associated with selectivity occurring when targeting the IRE1 kinase pocket as well as the inherent reactivity of covalent inhibitors targeting the RNase pocket. (C)& nbsp;2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.& nbsp;
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| 3. |
- Amarasinghe, Kosala N., et al.
(författare)
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Virtual Screening Expands the Non-Natural Amino Acid Palette for Peptide Optimization
- 2022
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 62:12, s. 2999-3007
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Tidskriftsartikel (refereegranskat)abstract
- Peptides are an important modality in drug discovery. While current peptide optimization focuses predominantly on the small number of natural and commercially available non-natural amino acids, the chemical spaces available for small molecule drug discovery are in the billions of molecules. In the present study, we describe the development of a large virtual library of readily synthesizable non-natural amino acids that can power the virtual screening protocols and aid in peptide optimization. To that end, we enumerated nearly 380 thousand amino acids and demonstrated their vast chemical diversity compared to the 20 natural and commercial residues. Furthermore, we selected a diverse ten thousand amino acid subset to validate our virtual screening workflow on the Keap1-Neh2 complex model system. Through in silico mutations of Neh2 peptide residues to those from the virtual library, our docking-based protocol identified a number of possible solutions with a significantly higher predicted affinity toward the Keap1 protein. This protocol demonstrates that the non-natural amino acid chemical space can be massively extended and virtually screened with a reasonable computational cost.
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| 5. |
- Cooke, Janice E. K., et al.
(författare)
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The dynamic nature of bud dormancy in trees : environmental control and molecular mechanisms
- 2012
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Ingår i: Plant, Cell and Environment. - : Wiley. - 0140-7791 .- 1365-3040. ; 35:10, s. 1707-1728
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Tidskriftsartikel (refereegranskat)abstract
- In tree species native to temperate and boreal regions, the activity-dormancy cycle is an important adaptive trait both for survival and growth. We discuss recent research on mechanisms controlling the overlapping developmental processes that define the activity-dormancy cycle, including cessation of apical growth, bud development, induction, maintenance and release of dormancy, and bud burst. The cycle involves an extensive reconfiguration of metabolism. Environmental control of the activity-dormancy cycle is based on perception of photoperiodic and temperature signals, reflecting adaptation to prevailing climatic conditions. Several molecular actors for control of growth cessation have been identified, with the CO/FT regulatory network and circadian clock having important coordinating roles in control of growth and dormancy. Other candidate regulators of bud set, dormancy and bud burst have been identified, such as dormancy-associated MADS-box factors, but their exact roles remain to be discovered. Epigenetic mechanisms also appear to factor in control of the activity-dormancy cycle. Despite evidence for gibberellins as negative regulators in growth cessation, and ABA and ethylene in bud formation, understanding of the roles that plant growth regulators play in controlling the activity-dormancy cycle is still very fragmentary. Finally, some of the challenges for further research in bud dormancy are discussed.
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| 9. |
- Kanchiralla, Fayas Malik, 1989
(författare)
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Life cycle navigation through future energy carriers and propulsion options for the energy transition in shipping
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The shipping industry's heavy reliance on fossil fuels has a detrimental effect on the global climate, human health, and the natural environment. The shipping sector now relies on the use of cheap and energy-dense heavy fuel oil and is perceived as ‘difficult-to-decarbonize’. Presently the shipping sector is adopting incremental emission reduction measures related to operational and technological energy efficiency solutions. However, to meet the global climate target, the transition from fossil-based marine fuels to renewable energy carriers is needed. Electro-fuels, which are produced from low-carbon electricity, or direct use of electricity with battery storage, are two pathways for energy transition included in this thesis. This thesis aims to assess the possible influence of the above two decarbonization paths based on energy demand, environmental performance, and economic performance across the whole life cycle of ships. The assessment is performed for hydrogen, ammonia, methanol, and battery-electric on three case study vessels using prospective life cycle assessment (pLCA) and life cycle costing (LCC). The pLCA is based on systems thinking used for the environmental assessment of emerging technologies that are in an early stage of development, and the LCC is used for the economic assessment of technologies over the life cycle based on the same systems thinking. To understand the environmental and economic tradeoffs for decision making an integrated assessment of pLCA and LCC is employed in the thesis. Considering the complexity and challenges of integration, a framework termed ‘integrated life cycle framework’ is developed for this thesis, allowing for consistent assessment to understand tradeoffs. This framework can be useful for other transport sectors. The study shows that there is a substantial potential for reducing the environmental impact of shipping through the studied pathways; however, this depends on the carbon intensity of the electricity used in fuel production. Technically, not all fuels are suitable for all vessels. Their suitability is primarily determined by the amount of fuel required for bunkering and the amount of space available onboard. Reduced climate impact comes at the expense of several other impact categories, such as human toxicity, water use, and resource use (minerals and metals). For the same type of fuel, fuel cells have greater impact reduction potential than engine options; however, engines are more cost competitive. Fuel price and utilization rate also influence cost competitiveness. The total life cycle cost of all the studied options is significantly higher than the conventional diesel option, and the critical parameter is the cost of the fuel. The cost of fuel is sensitive to the price of electricity. The carbon abatement cost estimated in this study shows that policies should be designed to imply at least a cost of 250–300 €/tCO2eq for emitting greenhouse gases to make the assessed fuel options cost competitive.
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| 10. |
- Muzaka, Valbona, Dr.
(författare)
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Food, Health and the Knowledge Economy : The State and Intellectual Property in India and Brazil
- 2018
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- This book opens a window into how two ambitious countries, India and Brazil, are seeking to become knowledge powers in the 21st century. As the knowledge economy became the preferred way of conceptualising the economy and its future direction in the more economically-advanced countries, our search for understanding also followed the same direction, generating a body of work that has neglected countries that, like India and Brazil, are attempting to make the leap into knowledge economies. The book explores these ambitions and the ways in which they have inspired a number of institutional reforms in India and Brazil. It offers an investigation of the role the state in shaping the respective intellectual property systems pertaining to the pharmaceutical and agro-biotechnology sectors and the multiple social conflicts that have unfolded as a result.
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