| 1. |
- Aguilar-Calvo, Patricia, et al.
(författare)
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Generation of novel neuroinvasive prions following intravenous challenge
- 2018
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Ingår i: Brain Pathology. - : WILEY. - 1015-6305 .- 1750-3639. ; 28:6, s. 999-1011
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Tidskriftsartikel (refereegranskat)abstract
- Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.
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| 2. |
- Aguilar-Calvo, Patricia, et al.
(författare)
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Post-translational modifications in PrP expand the conformational diversity of prions in vivo
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Misfolded prion protein aggregates (PrPSc) show remarkable structural diversity and are associated with highly variable disease phenotypes. Similarly, other proteins, including amyloid-beta, tau, alpha-synuclein, and serum amyloid A, misfold into distinct conformers linked to different clinical diseases through poorly understood mechanisms. Here we use mice expressing glycophosphatidylinositol (GPI)anchorless prion protein, PrPC, together with hydrogen-deuterium exchange coupled with mass spectrometry (HXMS) and a battery of biochemical and biophysical tools to investigate how posttranslational modifications impact the aggregated prion protein properties and disease phenotype. Four GPI-anchorless prion strains caused a nearly identical clinical and pathological disease phenotype, yet maintained their structural diversity in the anchorless state. HXMS studies revealed that GPIanchorless PrPSc is characterized by substantially higher protection against hydrogen/deuterium exchange in the C-terminal region near the N-glycan sites, suggesting this region had become more ordered in the anchorless state. For one strain, passage of GPI-anchorless prions into wild type mice led to the emergence of a novel strain with a unique biochemical and phenotypic signature. For the new strain, histidine hydrogen-deuterium mass spectrometry revealed altered packing arrangements of beta-sheets that encompass residues 139 and 186 of PrPSc. These findings show how variation in posttranslational modifications may explain the emergence of new protein conformations in vivo and also provide a basis for understanding how the misfolded protein structure impacts the disease.
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| 3. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Monzó, Patricia, et al.
(författare)
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A novel numerical approach for imposing a temperature boundary condition at the borehole wall in borehole fields
- 2015
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Ingår i: Geothermics. - : Elsevier BV. - 0375-6505 .- 1879-3576. ; 56, s. 35-44
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Tidskriftsartikel (refereegranskat)abstract
- The design of a borehole field should be based on a long-term simulation of its thermal response for the intended energy loads. A well-known method to evaluate the response is based on a pre-calculated dimensionless function, the g-function. When calculating g-functions, there are two commonly used approaches for treating the boundary condition at the borehole wall: a constant heat flux at every instant of time, or a uniform temperature at a constant total heat flow to the borehole field. This paper is focused on a new approach to model the thermal process of borehole fields; in particular with a precise representation of a uniform temperature boundary condition at the borehole wall. The main purpose of this model is to be used as a research tool to either generate g-functions for particular cases or handle situations that cannot be addressed by others methods. First, the almost constant temperature along the borehole heat exchanger in operation requires a boundary condition of essentially isothermal boreholes along the depth. In a common case, the borehole heat exchangers are connected in parallel, thus all boreholes should have the same temperature. Also, the total heat flow to the borehole field should be constant over time. For this purpose, a numerical model in which the boreholes are filled with a hypothetical highly conductive material has been built, reproducing the isothermal condition. By thermally interconnecting the boreholes, the equal temperature condition is satisfied. Finally, the specified total heat flow is fed into one spot at the highly conductive material. The model is validated by generating g-functions of some simple borehole field configurations. The g-functions present, in general, a good agreement with the existing solutions for a similar boundary condition. Moreover, the model is also tested against real experimental data from a 2. ×. 3 borehole field at an office building. The simulated daily fluid temperatures are compared with measured daily fluid temperatures for the sixth year of operation. The simulated values present, in general, a good agreement with the measured data. The results show that there are no significant differences with regard to the boundary conditions at the borehole wall, which for this specific case is due to the fact that the system is thermally balanced.
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| 5. |
- Ruiz-Calvo, Félix, et al.
(författare)
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Coupling short-term (B2G model) and long-term (g-function) models for ground source heat exchanger simulation in TRNSYS. Application in a real installation
- 2016
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Ingår i: Applied Thermal Engineering. - : Elsevier. - 1359-4311 .- 1873-5606. ; 105, s. 720-732
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Tidskriftsartikel (refereegranskat)abstract
- Ground-source heat pump (GSHP) systems represent one of the most promising techniques for heating and cooling in buildings. These systems use the ground as a heat source/sink, allowing a better efficiency thanks to the low variations of the ground temperature along the seasons. The ground-source heat exchanger (GSHE) then becomes a key component for optimizing the overall performance of the system. Moreover, the short-term response related to the dynamic behaviour of the GSHE is a crucial aspect, especially from a regulation criteria perspective in on/off controlled GSHP systems. In this context, a novel numerical GSHE model has been developed at the Instituto de Ingeniería Energética, Universitat Politècnica de València. Based on the decoupling of the short-term and the long-term response of the GSHE, the novel model allows the use of faster and more precise models on both sides. In particular, the short-term model considered is the B2G model, developed and validated in previous research works conducted at the Instituto de Ingeniería Energética. For the long-term, the g-function model was selected, since it is a previously validated and widely used model, and presents some interesting features that are useful for its combination with the B2G model. The aim of the present paper is to describe the procedure of combining these two models in order to obtain a unique complete GSHE model for both short- and long-term simulation. The resulting model is then validated against experimental data from a real GSHP installation.
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