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Sökning: WFRF:(Calvo Patricia)

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  • Klionsky, Daniel J., et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • Ingår i: Autophagy. - : Landes Bioscience. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • Forskningsöversikt (refereegranskat)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
  • Hudson, Thomas J., et al. (författare)
  • International network of cancer genome projects
  • 2010
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
  • Tidskriftsartikel (refereegranskat)abstract
    • The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
  • Patel, Yash, et al. (författare)
  • Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.
  • 2020
  • Ingår i: JAMA psychiatry. - 2168-6238.
  • Tidskriftsartikel (refereegranskat)abstract
    • Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.Interregional profiles of group difference in cortical thickness between cases and controls.A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
  • Aguilar-Calvo, Patricia, et al. (författare)
  • Generation of novel neuroinvasive prions following intravenous challenge
  • 2018
  • Ingår i: Brain Pathology. - : WILEY. - 1015-6305 .- 1750-3639. ; 28:6, s. 999-1011
  • 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.
  • Aguilar-Calvo, Patricia, et al. (författare)
  • Post-translational modifications in PrP expand the conformational diversity of prions in vivo
  • 2017
  • Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
  • 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.
  • Aguilar-Calvo, Patricia, et al. (författare)
  • Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions
  • 2020
  • Ingår i: Acta Neuropathologica. - : SPRINGER. - 0001-6322 .- 1432-0533. ; 139:3, s. 527-546
  • Tidskriftsartikel (refereegranskat)abstract
    • Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1(+/-)) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.
  • Monzó, Patricia, et al. (författare)
  • A novel numerical approach for imposing a temperature boundary condition at the borehole wall in borehole fields
  • 2015
  • Ingår i: Geothermics. - 0375-6505 .- 1879-3576. ; 56, s. 35-44
  • 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.
  • Monzó, Patricia, et al. (författare)
  • Experimental Validation of a Numerical Model for the Thermal Response of a Borehole Field
  • 2014
  • Ingår i: ASHRAE TRANSACTIONS 2014, VOL 120, PT 2. - : ASHRAE.
  • Konferensbidrag (refereegranskat)abstract
    • The design of borehole fields for ground coupled-heat pump systems is often based on so-called g-functions, a pre-calculated dimensionless temperature response to a step heat load. The g-function is specific to the borehole field geometry. For a long-term analysis of a particular borehole field, the average borehole wall temperature is obtained from the g-function and a temporal superposition of its thermal load steps. There are two accepted provisions for the g-function regarding the boundary condition used at (and along) the borehole wall: a constant heat flux at every instant of time, or a uniform temperature at constant total heat flow to the borehole field, respectively. In this paper, a numerical model is built up according to the geometrical characteristics and ground thermal properties of a 2x3 borehole demo site at the Universitat Politecnica de Valencia, Spain. The model is separately studied with regard to the two boundary conditions. The models are first compared in terms of their g-function, which are verified against reference solutions. Then, the daily fluid temperatures are obtained from each of these models with measured daily loads during a six year period. The results 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. The simulated temperatures are more accurate during cooling periods.
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