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- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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- Andersson, Henrik, et al.
(författare)
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Economic Analysis and Investment Priorities in Sweden's Transport Sector
- 2018
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Ingår i: Journal of Benefit-Cost Analysis. - : Cambridge University Press. - 2194-5888 .- 2152-2812. ; 9:1, s. 120-146
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Tidskriftsartikel (refereegranskat)abstract
- Beginning as a planning tool within Sweden's national road administration some 50 years ago, benefit-cost analysis (BCA) has come to be a pillar of the national transport policy because of subsequent strategic choices made by the national parliament. These choices made it necessary to widen the analysis of costs to include also externalities and a foregone conclusion was that efficient investment priorities should be made based on BCA. But no one asked whether the political decision makers or the BCA models were up to that task. This paper reviews the institutional framework and practice of BCA in Sweden for transport infrastructure investment, and considers design issues that have been and still are debated, such as whether the discount rate should include a risk term and how to account for the marginal cost of public funds. A main concern with BCA results is the underestimation of construction costs, making transport sector projects look better than they are. Several ex post analyses have established that a higher NPV ratio increases the probability of being included in the investment program proposal prepared by the agency. The requirement to let projects undergo BCA seems to make planners trim project proposals by trying to reduce investment costs without significantly reducing benefits. This relationship is weaker among profitable projects. Moreover, there is no correlation between rate of return and the probability of being included in the final program, which is established on political grounds.
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- Dini, Hoda, 1984-, et al.
(författare)
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Optimization and validation of a dislocation density based constitutive model for as-cast Mg-9%Al-1%Zn
- 2018
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Ingår i: Materials Science & Engineering. - : Elsevier. - 0921-5093 .- 1873-4936. ; 710, s. 17-26
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Tidskriftsartikel (refereegranskat)abstract
- A dislocation density-based constitutive model, including effects of microstructure scale and temperature, was calibrated to predict flow stress of an as-cast AZ91D (Mg-9%Al-1%Zn) alloy. Tensile stress-strain data, for strain rates from 10-4 up to 10-1 s-1 and temperatures from room temperature up to 190 °C were used for model calibration. The used model accounts for the interaction of various microstructure features with dislocations and thereby on the plastic properties. It was shown that the Secondary Dendrite Arm Spacing (SDAS) size was appropriate as an initial characteristic microstructural scale input to the model. However, as strain increased the influence of subcells size and total dislocation density dominated the flow stress. The calibrated temperature-dependent parameters were validated through a correlation between microstructure and the physics of the deforming alloy. The model was validated by comparison with dislocation density obtained by using Electron Backscattered Diffraction (EBSD) technique.
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- Michaëlsson, Henrik, et al.
(författare)
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The novel antidepressant ketamine enhances dentate gyrus proliferation with no effects on synaptic plasticity or hippocampal function in depressive-like rats
- 2019
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 225:4
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Tidskriftsartikel (refereegranskat)abstract
- Aim Major depressive disorder is a common and debilitating condition with substantial economic impact. Treatment options, although effective, are aimed at relieving the symptoms with limited disease modification. Ketamine, a commonly used anaesthetic, has received substantial attention as it shows rapid antidepressant effects clinically. We studied the effects of ketamine on hippocampal function and dentate gyrus proliferation in rats showing a depressive-like phenotype. Methods Adolescent and adult animals were pre-natally exposed to the glucocorticoid analog dexamethasone, and we verified a depressive-like phenotype using behavioural tests, such as the sucrose preference. We subsequently studied the effects of ketamine on hippocampal synaptic transmission, plasticity and dentate gyrus proliferation. In addition, we measured hippocampal glutamate receptor expression. We also tested the ketamine metabolite hydroxynorketamine for NMDA-receptor independent effects. Results Surprisingly, our extensive experimental survey revealed limited effects of ketamine or its metabolite on hippocampal function in control as well as depressive-like animals. We found no effects on synaptic efficacy or induction of long-term potentiation in adolescent and adult animals. Also there was no difference when comparing the dorsal and ventral hippocampus. Importantly, however, ketamine 24 hours prior to experimentation significantly increased the dentate gyrus proliferation, as revealed by Ki-67 immunostaining, in the depressive-like phenotype. Conclusion We find limited effects of ketamine on hippocampal glutamatergic transmission. Instead, alterations in dentate gyrus proliferation could explain the antidepressant effects of ketamine.
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