| 1. |
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| 2. |
- Kreins, AY, et al.
(författare)
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Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome
- 2015
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 212:10, s. 1641-1662
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17+ T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.
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| 3. |
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| 4. |
- Ogishi, M, et al.
(författare)
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Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency
- 2022
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:10
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Tidskriftsartikel (refereegranskat)abstract
- Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
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| 5. |
- Edgar, Graham J., et al.
(författare)
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Global conservation outcomes depend on marine protected areas with five key features
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 506:7487, s. 216-
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Tidskriftsartikel (refereegranskat)abstract
- In line with global targets agreed under the Convention on Biological Diversity, the number of marine protected areas (MPAs) is increasing rapidly, yet socio-economic benefits generated by MPAs remain difficult to predict and under debate(1,2). MPAs often fail to reach their full potential as a consequence of factors such as illegal harvesting, regulations that legally allow detrimental harvesting, or emigration of animals outside boundaries because of continuous habitat or inadequate size of reserve(3-5). Here we show that the conservation benefits of 87 MPAs investigated worldwide increase exponentially with the accumulation of five key features: no take, well enforced, old (>10 years), large (>100 km(2)), and isolated by deep water or sand. Using effective MPAs with four or five key features as an unfished standard, comparisons of underwater survey data from effective MPAs with predictions based on survey data from fished coasts indicate that total fish biomass has declined about two-thirds from historical baselines as a result of fishing. Effective MPAs also had twice as many large (>250 mm total length) fish species per transect, five times more large fish biomass, and fourteen times more shark biomass than fished areas. Most (59%) of the MPAs studied had only one or two key features and were not ecologically distinguishable from fished sites. Our results show that global conservation targets based on area alone will not optimize protection of marine biodiversity. More emphasis is needed on better MPA design, durable management and compliance to ensure that MPAs achieve their desired conservation value.
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| 6. |
- Oikonomou, Vasileios, et al.
(författare)
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The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1.
- 2024
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Ingår i: The New England journal of medicine. - 1533-4406. ; 390:20, s. 1873-1884
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood.We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses.Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients.Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
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| 7. |
- Warwick, J., et al.
(författare)
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Experimental Observation of a Current-Driven Instability in a Neutral Electron-Positron Beam
- 2017
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Ingår i: Physical Review Letters. - : AMER PHYSICAL SOC. - 0031-9007 .- 1079-7114. ; 119:18
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Tidskriftsartikel (refereegranskat)abstract
- We report on the first experimental observation of a current-driven instability developing in a quasineutral matter-antimatter beam. Strong magnetic fields (amp;gt;= 1 T) are measured, via means of a proton radiography technique, after the propagation of a neutral electron-positron beam through a background electron-ion plasma. The experimentally determined equipartition parameter of epsilon(B) approximate to 10(-3) is typical of values inferred from models of astrophysical gamma-ray bursts, in which the relativistic flows are also expected to be pair dominated. The data, supported by particle-in-cell simulations and simple analytical estimates, indicate that these magnetic fields persist in the background plasma for thousands of inverse plasma frequencies. The existence of such long-lived magnetic fields can be related to analog astrophysical systems, such as those prevalent in lepton-dominated jets.
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| 8. |
- Aguilar, Helena, et al.
(författare)
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VAV3 mediates resistance to breast cancer endocrine therapy
- 2014
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Ingår i: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 16:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.
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| 9. |
- Araoz Ramos, Joseph A., et al.
(författare)
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Numerical simulation for the design analysis of kinematic Stirling engines
- 2015
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Ingår i: Applied Energy. - : Elsevier BV. - 0306-2619 .- 1872-9118. ; 159, s. 633-650
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Tidskriftsartikel (refereegranskat)abstract
- The Stirling engine is a closed-cycle regenerative system that presents good theoretical properties. These include a high thermodynamic efficiency, low emissions levels thanks to a controlled external heat source, and multi-fuel capability among others. However, the performance of actual prototypes largely differs from the mentioned theoretical potential. Actual engine prototypes present low electrical power outputs and high energy losses. These are mainly attributed to the complex interaction between the different components of the engine, and the challenging heat transfer and fluid dynamics requirements. Furthermore, the integration of the engine into decentralized energy systems such as the Combined Heat and Power systems (CHP) entails additional complications. These has increased the need for engineering tools that could assess design improvements, considering a broader range of parameters that would influence the engine performance when integrated within overall systems. Following this trend, the current work aimed to implement an analysis that could integrate the thermodynamics, and the thermal and mechanical interactions that influence the performance of kinematic Stirling engines. In particular for their use in Combined Heat and Power systems. The mentioned analysis was applied for the study of an engine prototype that presented very low experimental performance. The numerical methodology was selected for the identification of possible causes that limited the performance. This analysis is based on a second order Stirling engine model that was previously developed and validated. The simulation allowed to evaluate the effect that different design and operational parameters have on the engine performance, and consequently different performance curves were obtained. These curves allowed to identify ranges for the charged pressure, temperature ratio, heat exchangers dimensions, crank phase angle and crank mechanical effectiveness, where the engine performance was improved. In addition, the curves also permitted to recognise ranges were the design parameters could drastically reduce the brake power and efficiency. The results also showed that the design of the engine is affected by the conditions imposed by the CHP interactions, and that the engine could reach a brake power closer to 832 W with a corresponding brake efficiency of 26% when the adequate design parameters were considered. On the other hand, the performance could also be very low; as the reported in experimental tests, with brake power measurements ranging 52-120W.
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| 10. |
- Ashton, Nicholas J., et al.
(författare)
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A plasma protein classifier for predicting amyloid burden for preclinical Alzheimer's disease.
- 2019
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Ingår i: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- A blood-based assessment of preclinical disease would have huge potential in the enrichment of participants for Alzheimer's disease (AD) therapeutic trials. In this study, cognitively unimpaired individuals from the AIBL and KARVIAH cohorts were defined as Aβ negative or Aβ positive by positron emission tomography. Nontargeted proteomic analysis that incorporated peptide fractionation and high-resolution mass spectrometry quantified relative protein abundances in plasma samples from all participants. A protein classifier model was trained to predict Aβ-positive participants using feature selection and machine learning in AIBL and independently assessed in KARVIAH. A 12-feature model for predicting Aβ-positive participants was established and demonstrated high accuracy (testing area under the receiver operator characteristic curve = 0.891, sensitivity = 0.78, and specificity = 0.77). This extensive plasma proteomic study has unbiasedly highlighted putative and novel candidates for AD pathology that should be further validated with automated methodologies.
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| 11. |
- Bueno-Alejo, Carlos J., et al.
(författare)
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Supramolecular Transcription of Guanosine Monophosphate into Mesostructured Silica
- 2014
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 53:45, s. 12106-12110
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Tidskriftsartikel (refereegranskat)abstract
- There is large interest in replicating biological supramolecular structures in inorganic materials that are capable of mimicking biological properties. The use of 5-guanosine monophosphate in the presence of Na+ and K+ ions as a supramolecular template for the synthesis of well-ordered mesostructured materials is reported here. Mesostructured particles with the confined template exhibit high structural order at both meso-and atomic scales, with a lower structural symmetry in the columnar mesophase. Although a chiral space group can not be deduced from X-ray diffraction, analysis by electron microscopy and circular dichroism confirms a chiral stacking arrangement along the c-axis. Guanosine monophosphate based mesophases thus illustrate the possibility for specific molecular imprinting of mesoporous materials by genetic material and the potential for higher definition in molecular recognition.
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| 12. |
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| 13. |
- Pulecio, Julian, et al.
(författare)
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Direct Conversion of Fibroblasts to Megakaryocyte Progenitors
- 2016
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 17:3, s. 671-683
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Tidskriftsartikel (refereegranskat)abstract
- Current sources of platelets for transfusion are insufficient and associated with risk of alloimmunization and blood-borne infection. These limitations could be addressed by the generation of autologous megakaryocytes (MKs) derived in vitro from somatic cells with the ability to engraft and differentiate in vivo. Here, we show that overexpression of a defined set of six transcription factors efficiently converts mouse and human fibroblasts into MK-like progenitors. The transdifferentiated cells are CD41(+), display polylobulated nuclei, have ploidies higher than 4N, form MK colonies, and give rise to platelets in vitro. Moreover, transplantation of MK-like murine progenitor cells into NSG mice results in successful engraftment and further maturation in vivo. Similar results are obtained using disease-corrected fibroblasts from Fanconi anemia patients. Our results combined demonstrate that functional MK progenitors with clinical potential can be obtained in vitro, circumventing the use of hematopoietic progenitors or pluripotent stem cells.
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| 14. |
- Shi, Liu, et al.
(författare)
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Replication study of plasma proteins relating to Alzheimer's pathology.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 17:9, s. 1452-1464
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Tidskriftsartikel (refereegranskat)abstract
- This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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| 15. |
- Tudisco, Erika, et al.
(författare)
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Neutron imaging of rock mechanics experiments
- 2015
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Ingår i: Integrating Innovations of Rock Mechanics : Proceedings of the 8th South American Congress on Rock Mechanics, 15–18 November 2015, Buenos Aires, Argentina - Proceedings of the 8th South American Congress on Rock Mechanics, 15–18 November 2015, Buenos Aires, Argentina. - 9781614996040 - 9781614996057 ; , s. 231-236
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Konferensbidrag (refereegranskat)abstract
- Understanding the mechanical behaviour of porous rocks and how this influences the fluid flow is key in a number of resource engineering challenges, in particular hydrocarbon production and CO2 sequestration. Deformation in these porous materials is, in general, not homogeneous, as deformation localises into narrow shear or compaction bands, which might then evolve into fractures. These local deformation features can act as barriers or conduits for fluid flow, depending on their evolution and resultant properties. This work focusses on achieving quantitative understanding of how localised deformation (shear or compaction bands and fractures) can change (local and global) permeability in porous rocks. In particular the aim is to overcome limitations of traditional methods for permeability measurement, which consider bulk sample measurements, and do not provide a good understanding of the permeability variations in the presence of material heterogeneity, e.g., localised deformations. Better understanding of the controlling factors on permeability evolution due to localised deformation requires mapping of the full permeability and strain fields through test specimens. Neutron tomography, in combination with 3D-volumetric Digital Image Correlation (3DDIC) is used to measure deformation and fast neutron radiography is used to visualise fluid-flow through the characterised deformed samples.
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