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- Verma, N., et al.
(författare)
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A beta efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas
- 2023
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Impairment of vascular pathways of cerebral beta-amyloid (A beta) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral A beta clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with A beta within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-A beta co-deposits. LRP1-mediated A beta transport across the blood-brain barrier and A beta clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by A beta deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and A beta pathology.
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- Coburn, J., et al.
(författare)
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First wall energy deposition during vertical displacement events on ITER
- 2020
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Ingår i: Physica Scripta. - : IOP Publishing. - 0031-8949 .- 1402-4896. ; T171:1
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Tidskriftsartikel (refereegranskat)abstract
- The beryllium (Be) first wall energy deposition and melt damage profiles resulting from the current quench phase of an unmitigated, 5 MA/1.8 T upward vertical displacement event for ITER are investigated. Time dependent 2D magnetic flux profiles are calculated with the DINA code and used as input for the SMITER 3D field line tracing software. 3D maps of the wetted area and perpendicular heat flux q(perpendicular to) show that the majority of the energy deposition occurs on the upper first wall panels #8 and #9 SMITER simulations predict q(perpendicular to,peak) approximate to 190 MW m(-2) on the surfaces of upper FWPs #8 and #9 at the end of the similar to 450 ms current quench. The surface heat flux maps generated by SMITER are used as input in the MEMOS-U code, which models Be melt formation and dynamics. Simulations reveal peak surface temperatures of similar to 2200 K, inward surface damage of similar to 0.5 mm in depth, and average melt velocities of similar to 2 m s(-1). Although VDEs are in principle the easiest disruptive instability to avoid, the analysis demonstrates that any non-mitigated events or intentional VDEs taking place during low I-p, early operational phases of ITER for the purposes of estimating disruption forces, must be kept to a low number.
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- Curtis, Michael W., et al.
(författare)
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Identification of amino acid domains of Borrelia burgdorferi P66 that are surface exposed and important for localization, oligomerization, and porin function of the protein
- 2022
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Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- P66, a bifunctional integral outer membrane protein, is necessary for Borrelia burgdorferi to establish initial infection and to disseminate in mice. The integrin binding function of P66 facilitates extravasation and dissemination, but the role of its porin function during murine infection has not been investigated. A limitation to studying P66 porin function during mammalian infection has been the lack of structural information for P66. In this study, we experimentally characterized specific domains of P66 with regard to structure and function. First, we aligned the amino acid sequences of P66 from Lyme disease-causing Borrelia and relapsing fever-causing Borrelia to identify conserved and unique domains between these disease-causing clades. Then, we examined whether specific domains of P66 are exposed on the surface of the bacteria by introducing c-Myc epitope tags into each domain of interest. The c-Myc epitope tag inserted C-terminally to E33 (highly conserved domain), to T187 (integrin binding region domain and a non-conserved domain), and to E334 (non-conserved domain) were all detected on the surface of Borrelia burgdorferi. The c-Myc epitope tag inserted C-terminally to E33 and D303 in conserved domains disrupted P66 oligomerization and porin function. In a murine model of infection, the E33 and D303 mutants exhibited decreased infectivity and dissemination. Taken together, these results suggest the importance of these conserved domains, and potentially P66 porin function, in vivo.
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- Huijben, Jilske A., et al.
(författare)
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Development of a quality indicator set to measure and improve quality of ICU care for patients with traumatic brain injury
- 2019
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Ingår i: Critical Care. - : BioMed Central. - 1364-8535 .- 1466-609X. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to develop a set of quality indicators for patients with traumatic brain injury (TBI) in intensive care units (ICUs) across Europe and to explore barriers and facilitators for implementation of these quality indicators.Methods: A preliminary list of 66 quality indicators was developed, based on current guidelines, existing practice variation, and clinical expertise in TBI management at the ICU. Eight TBI experts of the Advisory Committee preselected the quality indicators during a first Delphi round. A larger Europe-wide expert panel was recruited for the next two Delphi rounds. Quality indicator definitions were evaluated on four criteria: validity (better performance on the indicator reflects better processes of care and leads to better patient outcome), feasibility (data are available or easy to obtain), discriminability (variability in clinical practice), and actionability (professionals can act based on the indicator). Experts scored indicators on a 5-point Likert scale delivered by an electronic survey tool.Results. The expert panel consisted of 50 experts from 18 countries across Europe, mostly intensivists (N=24, 48%) and neurosurgeons (N=7, 14%). Experts agreed on a final set of 42 indicators to assess quality of ICU care: 17 structure indicators, 16 process indicators, and 9 outcome indicators. Experts are motivated to implement this finally proposed set (N=49, 98%) and indicated routine measurement in registries (N=41, 82%), benchmarking (N=42, 84%), and quality improvement programs (N=41, 82%) as future steps. Administrative burden was indicated as the most important barrier for implementation of the indicator set (N=48, 98%).Conclusions: This Delphi consensus study gives insight in which quality indicators have the potential to improve quality of TBI care at European ICUs. The proposed quality indicator set is recommended to be used across Europe for registry purposes to gain insight in current ICU practices and outcomes of patients with TBI. This indicator set may become an important tool to support benchmarking and quality improvement programs for patients with TBI in the future.
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