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| 2. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 4. |
- Korenblik, R., et al.
(författare)
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Dragon 1 Protocol Manuscript : Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy
- 2022
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Ingår i: Cardiovascular and Interventional Radiology. - : Springer. - 0174-1551 .- 1432-086X. ; 45, s. 1391-1398
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Tidskriftsartikel (refereegranskat)abstract
- Study Purpose The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. Methods The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. Results Not applicable. Conclusion DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR.
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| 5. |
- Johannesson, M, et al.
(författare)
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A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock
- 2009
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1088-9051. ; 19:1, s. 150-158
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Tidskriftsartikel (refereegranskat)abstract
- The laboratory rat (Rattus norvegicus) is a key tool for the study of medicine and pharmacology for human health. A large database of phenotypes for integrated fields such as cardiovascular, neuroscience, and exercise physiology exists in the literature. However, the molecular characterization of the genetic loci that give rise to variation in these traits has proven to be difficult. Here we show how one obstacle to progress, the fine-mapping of quantitative trait loci (QTL), can be overcome by using an outbred population of rats. By use of a genetically heterogeneous stock of rats, we map a locus contributing to variation in a fear-related measure (two-way active avoidance in the shuttle box) to a region on chromosome 5 containing nine genes. By establishing a protocol measuring multiple phenotypes including immunology, neuroinflammation, and hematology, as well as cardiovascular, metabolic, and behavioral traits, we establish the rat HS as a new resource for the fine-mapping of QTLs contributing to variation in complex traits of biomedical relevance.
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| 6. |
- Louzolo, A, et al.
(författare)
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Enhanced Instructed Fear Learning in Delusion-Proneness
- 2022
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Ingår i: Frontiers in psychology. - : Frontiers Media SA. - 1664-1078. ; 13, s. 786778-
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Tidskriftsartikel (refereegranskat)abstract
- Psychosis is associated with distorted perceptions and deficient bottom-up learning such as classical fear conditioning. This has been interpreted as reflecting imprecise priors in low-level predictive coding systems. Paradoxically, overly strong beliefs, such as overvalued beliefs and delusions, are also present in psychosis-associated states. In line with this, research has suggested that patients with psychosis and associated phenotypes rely more on high-order priors to interpret perceptual input. In this behavioural and fMRI study we studied two types of fear learning, i.e., instructed fear learning mediated by verbal suggestions about fear contingencies and classical fear conditioning mediated by low level associative learning, in delusion proneness—a trait in healthy individuals linked to psychotic disorders. Subjects were shown four faces out of which two were coupled with an aversive stimulation (CS+) while two were not (CS-) in a fear conditioning procedure. Before the conditioning, subjects were informed about the contingencies for two of the faces of each type, while no information was given for the two other faces. We could thereby study the effect of both classical fear conditioning and instructed fear learning. Our main outcome variable was evaluative rating of the faces. Simultaneously, fMRI-measurements were performed to study underlying mechanisms. We postulated that instructed fear learning, measured with evaluative ratings, is stronger in psychosis-related phenotypes, in contrast to classical fear conditioning that has repeatedly been shown to be weaker in these groups. In line with our hypothesis, we observed significantly larger instructed fear learning on a behavioural level in delusion-prone individuals (n = 20) compared to non-delusion-prone subjects (n = 23; n = 20 in fMRI study). Instructed fear learning was associated with a bilateral activation of lateral orbitofrontal cortex that did not differ significantly between groups. However, delusion-prone subjects showed a stronger functional connectivity between right lateral orbitofrontal cortex and regions processing fear and pain. Our results suggest that psychosis-related states are associated with a strong instructed fear learning in addition to previously reported weak classical fear conditioning. Given the similarity between nocebo paradigms and instructed fear learning, our results also have an impact on understanding why nocebo effects differ between individuals.
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| 10. |
- Economides, M., et al.
(författare)
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Arbitration between controlled and impulsive choices
- 2015
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Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 109, s. 206-216
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Tidskriftsartikel (refereegranskat)abstract
- The impulse to act for immediate reward often conflicts with more deliberate evaluations that support long-term benefit. The neural architecture that negotiates this conflict remains unclear. One account proposes a single neural circuit that evaluates both immediate and delayed outcomes, while another outlines separate impulsive and patient systems that compete for behavioral control. Here we designed a task in which a complex payout structure divorces the immediate value of acting from the overall long-term value, within the same outcome modality. Using model-based fMRI in humans, we demonstrate separate neural representations of immediate and long-term values, with the former tracked in the anterior caudate (AC) and the latter in the ventromedial prefrontal cortex (vmPFC). Crucially, when subjects' choices were compatible with long-run consequences, value signals in AC were down-weighted and those in vmPFC were enhanced, while the opposite occurred when choice was impulsive. Thus, our data implicate a trade-off in value representation between AC and vmPFC as underlying controlled versus impulsive choice.
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| 15. |
- Adams, Rick A., et al.
(författare)
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Variability in Action Selection Relates to Striatal Dopamine 2/3 Receptor Availability in Humans : A PET Neuroimaging Study Using Reinforcement Learning and Active Inference Models
- 2020
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Ingår i: Cerebral Cortex. - : Oxford University Press (OUP). - 1047-3211 .- 1460-2199. ; 30:6, s. 3573-3589
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Tidskriftsartikel (refereegranskat)abstract
- Choosing actions that result in advantageous outcomes is a fundamental function of nervous systems. All computational decision-making models contain a mechanism that controls the variability of (or confidence in) action selection, but its neural implementation is unclear-especially in humans. We investigated this mechanism using two influential decision-making frameworks: active inference (AI) and reinforcement learning (RL). In AI, the precision (inverse variance) of beliefs about policies controls action selection variability-similar to decision 'noise' parameters in RL-and is thought to be encoded by striatal dopamine signaling. We tested this hypothesis by administering a 'go/no-go' task to 75 healthy participants, and measuring striatal dopamine 2/3 receptor (D2/3R) availability in a subset (n = 25) using [C-11]-(+)-PHNO positron emission tomography. In behavioral model comparison, RL performed best across the whole group but AI performed best in participants performing above chance levels. Limbic striatal D2/3R availability had linear relationships with AI policy precision (P = 0.029) as well as with RL irreducible decision 'noise' (P = 0.020), and this relationship with D2/3R availability was confirmed with a 'decision stochasticity' factor that aggregated across both models (P = 0.0006). These findings are consistent with occupancy of inhibitory striatal D(2/3)Rs decreasing the variability of action selection in humans.
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| 16. |
- Badia, Rosa M., et al.
(författare)
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Demonstration of the OPTIMIS Toolkit for Cloud Service Provisioning
- 2011
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Ingår i: Towards a Service-Based Internet. - Berlin, Heidelberg : Springer Berlin/Heidelberg. - 9783642247545 - 9783642247552 ; , s. 331-333
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Konferensbidrag (refereegranskat)abstract
- We demonstrate the OPTIMIS toolkit for scalable and dependable service platforms and architectures that enable flexible and dynamic provisioning of Cloud services. The innovations demonstrated are aimed at optimizing Cloud services and infrastructures based on aspects such as trust, risk, eco-efficiency, cost, performance and legal constraints. Adaptive self-preservation is part of the toolkit to meet predicted and unforeseen changes in resource requirements. By taking into account the whole service life cycle, the multitude of future Cloud architectures, and a by taking a holistic approach to sustainable service provisioning, the toolkit provides a foundation for a reliable, sustainable, and trustful Cloud computing industry.
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| 18. |
- Fernandez-Anez, Nieves, et al.
(författare)
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Current Wildland Fire Patterns and Challenges in Europe : A Synthesis of National Perspectives
- 2021
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Ingår i: Air, Soil and Water Research. - : SAGE Publications. - 1178-6221. ; 14, s. 1-19
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Forskningsöversikt (refereegranskat)abstract
- Changes in climate, land use, and land management impact the occurrence and severity of wildland fires in many parts of the world. This is particularly evident in Europe, where ongoing changes in land use have strongly modified fire patterns over the last decades. Although satellite data by the European Forest Fire Information System provide large-scale wildland fire statistics across European countries, there is still a crucial need to collect and summarize in-depth local analysis and understanding of the wildland fire condition and associated challenges across Europe. This article aims to provide a general overview of the current wildland fire patterns and challenges as perceived by national representatives, supplemented by national fire statistics (2009–2018) across Europe. For each of the 31 countries included, we present a perspective authored by scientists or practitioners from each respective country, representing a wide range of disciplines and cultural backgrounds. The authors were selected from members of the COST Action “Fire and the Earth System: Science & Society” funded by the European Commission with the aim to share knowledge and improve communication about wildland fire. Where relevant, a brief overview of key studies, particular wildland fire challenges a country is facing, and an overview of notable recent fire events are also presented. Key perceived challenges included (1) the lack of consistent and detailed records for wildland fire events, within and across countries, (2) an increase in wildland fires that pose a risk to properties and human life due to high population densities and sprawl into forested regions, and (3) the view that, irrespective of changes in management, climate change is likely to increase the frequency and impact of wildland fires in the coming decades. Addressing challenge (1) will not only be valuable in advancing national and pan-European wildland fire management strategies, but also in evaluating perceptions (2) and (3) against more robust quantitative evidence.
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| 19. |
- Ferrer, Ana Juan, et al.
(författare)
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OPTIMIS : A holistic approach to cloud service provisioning
- 2012
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Ingår i: Future generations computer systems. - Amsterdam : North-Holland. - 0167-739X .- 1872-7115. ; 28:1, s. 66-77
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Tidskriftsartikel (refereegranskat)abstract
- We present fundamental challenges for scalable and dependable service platforms and architectures that enable flexible and dynamic provisioning of cloud services. Our findings are incorporated in a toolkit targeting the cloud service and infrastructure providers. The innovations behind the toolkit are aimed at optimizing the whole service life cycle, including service construction, deployment, and operation, on a basis of aspects such as trust, risk, eco-efficiency and cost. Notably, adaptive self-preservation is crucial to meet predicted and unforeseen changes in resource requirements. By addressing the whole service life cycle, taking into account several cloud architectures, and by taking a holistic approach to sustainable service provisioning, the toolkit aims to provide a foundation for a reliable, sustainable, and trustful cloud computing industry.
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| 20. |
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| 21. |
- Gershman, SJ, et al.
(författare)
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Neural signatures of arbitration between Pavlovian and instrumental action selection
- 2021
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Ingår i: PLoS computational biology. - : Public Library of Science (PLoS). - 1553-7358. ; 17:2, s. e1008553-
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Tidskriftsartikel (refereegranskat)abstract
- Pavlovian associations drive approach towards reward-predictive cues, and avoidance of punishment-predictive cues. These associations “misbehave” when they conflict with correct instrumental behavior. This raises the question of how Pavlovian and instrumental influences on behavior are arbitrated. We test a computational theory according to which Pavlovian influence will be stronger when inferred controllability of outcomes is low. Using a model-based analysis of a Go/NoGo task with human subjects, we show that theta-band oscillatory power in frontal cortex tracks inferred controllability, and that these inferences predict Pavlovian action biases. Functional MRI data revealed an inferior frontal gyrus correlate of action probability and a ventromedial prefrontal correlate of outcome valence, both of which were modulated by inferred controllability.
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| 24. |
- Guitart-Masip, Marc, et al.
(författare)
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Differential, but not opponent, effects of L-DOPA and citalopram on action learning with reward and punishment
- 2014
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 231:5, s. 955-966
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Tidskriftsartikel (refereegranskat)abstract
- Decision-making involves two fundamental axes of control namely valence, spanning reward and punishment, and action, spanning invigoration and inhibition. We recently exploited a go/no-go task whose contingencies explicitly decouple valence and action to show that these axes are inextricably coupled during learning. This results in a disadvantage in learning to go to avoid punishment and in learning to no-go to obtain a reward. The neuromodulators dopamine and serotonin are likely to play a role in these asymmetries: Dopamine signals anticipation of future rewards and is also involved in an invigoration of motor responses leading to reward, but it also arbitrates between different forms of control. Conversely, serotonin is implicated in motor inhibition and punishment processing. To investigate the role of dopamine and serotonin in the interaction between action and valence during learning. We combined computational modeling with pharmacological manipulation in 90 healthy human volunteers, using levodopa and citalopram to affect dopamine and serotonin, respectively. We found that, after administration of levodopa, action learning was less affected by outcome valence when compared with the placebo and citalopram groups. This highlights in this context a predominant effect of levodopa in controlling the balance between different forms of control. Citalopram had distinct effects, increasing participants' tendency to perform active responses independent of outcome valence, consistent with a role in decreasing motor inhibition. Our findings highlight the rich complexities of the roles played by dopamine and serotonin during instrumental learning.
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| 29. |
- Johansson, Jarkko, et al.
(författare)
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Biphasic patterns of age-related differences in dopamine D1 receptors across the adult lifespan
- 2023
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Ingår i: Cell Reports. - 2211-1247. ; 42:9
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Tidskriftsartikel (refereegranskat)abstract
- Age-related alterations in D1-like dopamine receptor (D1DR) have distinct implications for human cognition and behavior during development and aging, but the timing of these periods remains undefined. Enabled by a large sample of in vivo assessments (n = 180, age 20 to 80 years of age, 50% female), we discover that age-related D1DR differences pivot at approximately 40 years of age in several brain regions. Focusing on the most age-sensitive dopamine-rich region, we observe opposing pre- and post-forties interrelations among caudate D1DR, cortico-striatal functional connectivity, and memory. Finally, particularly caudate D1DR differences in midlife and beyond, but not in early adulthood, associate with manifestation of white matter lesions. The present results support a model by which excessive dopamine modulation in early adulthood and insufficient modulation in aging are deleterious to brain function and cognition, thus challenging a prevailing view of monotonic D1DR function across the adult lifespan.
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