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- Schneider, K. M., et al.
(författare)
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Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6(-/-) mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy. Steatohepatitis is a chronic hepatic inflammation associated with increased risk of hepatocellular carcinoma progression. Here the authors show that intestinal dysbiosis in mice lacking the inflammasome sensor molecule NLRP6 aggravates steatohepatitis and accelerates liver cancer progression, a process that can be delayed by antibiotic treatment.
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| 4. |
- Lopez-Posadas, R., et al.
(författare)
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Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation
- 2016
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 126:2, s. 611-626
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Tidskriftsartikel (refereegranskat)abstract
- Although defects in intestinal barrier function are a key pathogenic factor in patients with inflammatory bowel diseases (IBDs), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we addressed this issue by characterizing the transcriptome of IECs from IBD patients using a genome-wide approach. We observed disease-specific alterations in IECs with markedly impaired Rho-A signaling in active IBD patients. Localization of epithelial Rho-A was shifted to the cytosol in IBDs, and inflammation was associated with suppressed Rho-A activation due to reduced expression of the Rho-A prenylation enzyme geranylgeranyltransferase-I (GGTase-l). Functionally, we found that mice with conditional loss of Rhoa or the gene encoding GGTase-1, Pggtlb, in IECs exhibit spontaneous chronic intestinal inflammation with accumulation of granulocytes and CD4(+) T cells. This phenotype was associated with cytoskeleton rearrangement and aberrant cell shedding, ultimately leading to loss of epithelial integrity and subsequent inflammation. These findings uncover deficient prenylation of Rho-A as a key player in the pathogenesis of IBDs. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-l-deficient IECs, our findings suggest new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients.
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- Horvath, I., et al.
(författare)
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Exhaled breath condensate: methodological recommendations and unresolved questions
- 2005
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Ingår i: Eur Respir J. ; 26:3
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Tidskriftsartikel (refereegranskat)abstract
- Collection of exhaled breath condensate (EBC) is a noninvasive method for obtaining samples from the lungs. EBC contains large number of mediators including adenosine, ammonia, hydrogen peroxide, isoprostanes, leukotrienes, nitrogen oxides, peptides and cytokines. Concentrations of these mediators are influenced by lung diseases and modulated by therapeutic interventions. Similarly EBC pH also changes in respiratory diseases. The aim of the American Thoracic Society/European Respiratory Society Task Force on EBC was to identify the important methodological issues surrounding EBC collection and assay, to provide recommendations for the measurements and to highlight areas where further research is required. Based on the currently available evidence and the consensus of the expert panel for EBC collection, the following general recommendations were put together for oral sample collection: collect during tidal breathing using a noseclip and a saliva trap; define cooling temperature and collection time (10 min is generally sufficient to obtain 1-2 mL of sample and well tolerated by patients); use inert material for condenser; do not use resistor and do not use filter between the subject and the condenser. These are only general recommendations and certain circumstances may dictate variation from them. Important areas for future research involve: ascertaining mechanisms and site of exhaled breath condensate particle formation; determination of dilution markers; improving reproducibility; employment of EBC in longitudinal studies; and determining the utility of exhaled breath condensate measures for the management of individual patients. These studies are required before recommending this technique for use in clinical practice.
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| 6. |
- Kronast, F., et al.
(författare)
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Element-specific magnetic hysteresis of individual 18 nm Fe nanocubes
- 2011
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Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6992 .- 1530-6984. ; 11:4, s. 1710-1715
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Tidskriftsartikel (refereegranskat)abstract
- Correlating the electronic structure and magnetic response with the morphology and crystal structure of the same single ferromagnetic nanoparticle has been up to now an unresolved challenge. Here, we present measurements of the element-specific electronic structure and magnetic response as a function of magnetic field amplitude and orientation for chemically synthesized single Fe nanocubes with 18 nm edge length. Magnetic states and interactions of monomers, dimers, and trimers are analyzed by X-ray photoemission electron microscopy for different particle arrangements. The element-specific electronic structure can be probed and correlated with the changes of magnetic properties. This approach opens new possibilities for a deeper understanding of the collective response of magnetic nanohybrids in multifunctional materials and in nanomagnetic colloidal suspensions used in biomedical and engineering technologies. © 2011 American Chemical Society.
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| 7. |
- Lopez-Posadas, R., et al.
(författare)
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Inhibiting PGGT1B Disrupts Function of RHOA, Resulting in T-cell Expression of Integrin alpha 4 beta 7 and Development of Colitis in Mice
- 2019
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085. ; 157:5, s. 1293-1309
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: It is not clear how regulation of T-cell function is altered during development of inflammatory bowel diseases (IBD). We studied the mechanisms by which geranylgeranyltransferase-mediated prenylation controls T-cell localization to the intestine and chronic inflammation. METHODS: We generated mice with T-cell-specific disruption of the geranylgeranyltransferase type I, beta subunit gene (Pggt1b), called Pggt1b(Delta CD4) mice, or the ras homolog family member A gene (Rhoa), called Rhoa(Delta CD4) mice. We also studied mice with knockout of CDC42 or RAC1 and wild-type mice (controls). Intestinal tissues were analyzed by histology, multiphoton and confocal microscopy, and real-time polymerase chain reaction. Activation of CDC42, RAC1, and RHOA were measured with G-LISA, cell fractionation, and immunoblots. T cells and lamina propria mononuclear cells from mice were analyzed by flow cytometry or transferred to Rag1(-/-) mice. Mice were given injections of antibodies against integrin alpha4beta7 or gavaged with the RORC antagonist GSK805. We obtained peripheral blood and intestinal tissue samples from patients with and without IBD and analyzed them by flow cytometry. RESULTS: Pggt1b(Delta CD4) mice developed spontaneous colitis, characterized by thickening of the intestinal wall, edema, fibrosis, accumulation of T cells in the colon, and increased expression of inflammatory cytokines. Compared with control CD4+ T cells, PGGT1B-deficient CD4+ T cells expressed significantly higher levels of integrin alpha4beta7, which regulates their localization to the intestine. Inflammation induced by transfer of PGGT1B-deficient CD4+ T cells to Rag1(-/-) mice was blocked by injection of an antibody against integrin alpha4beta7. Lamina propria of Pggt1b(Delta CD4) mice had increased numbers of CD4+ T cells that expressed RORC and higher levels of cytokines produced by T-helper 17 cells (granulocyte-macrophage colony-stimulating factor, interleukin [IL]17A, IL17F, IL22, and tumor necrosis factor [TNF]). The RORC inverse agonist GSK805, but not antibodies against IL17A or IL17F, prevented colitis in Pggt1b(Delta CD4) mice. PGGT1B-deficient CD4+ T cells had decreased activation of RHOA. RhoA(Delta CD4) mice had a similar phenotype to Pggt1b(Delta CD4) mice, including development of colitis, increased numbers of CD4+ T cells in colon, increased expression of integrin alpha4beta7 by CD4+ T cells, and increased levels of IL17A and other inflammatory cytokines in lamina propria. T cells isolated from intestinal tissues from patients with IBD had significantly lower levels of PGGT1B than tissues from individuals without IBD. CONCLUSION: Loss of PGGT1B from T cells in mice impairs RHOA function, increasing CD4+ T-cell expression of integrin alpha4beta7 and localization to colon, resulting in increased expression of inflammatory cytokines and colitis. T cells isolated from gut tissues from patients with IBD have lower levels of PGGT1B than tissues from patients without IBD.
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| 8. |
- Wirtz, L., et al.
(författare)
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Curve-Crossing Analysis for Potential Sputtering of Insulators
- 2000
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Ingår i: Surface Science. - 0039-6028 .- 1879-2758. ; 451:1-3, s. 197-202
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Tidskriftsartikel (refereegranskat)abstract
- We develop a theoretical model for the recently observed threshold for potential sputtering of LiF by slow singly and doubly charged ions. The threshold coincides with the potential energy to create a cold hole in the valence band of LiF by resonant neutralization. We calculate the level shift of the incident ion and the deformation of the valence band under the influence of the projectile. Resonant neutralization becomes possible for ions with recombination energies larger than 10 eV in agreement with the experimental findings.
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| 9. |
- Wirtz, L., et al.
(författare)
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Vertical incidence of slow Ne10+ ions on an LiF surface: Suppression of the trampoline effect
- 2001
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Ingår i: Nuclear Instruments and Methods in Physics Research Section B. - 0168-583X .- 1872-9584. ; 182:1-4, s. 36-40
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Tidskriftsartikel (refereegranskat)abstract
- We present a Monte Carlo simulation of the neutralization of a slow Ne10+ ion in vertical incidence on an LiF(100) surface. The rates for resonant electron transfer between surface F- ions and the projectile are calculated using a classical trajectory Monte Carlo simulation. We investigate the influence of the hole mobility on the neutralization sequence. It is shown that backscattering above the surface due to the local positive charge up of the surface ("trampoline effect") does not take place.
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| 14. |
- Baral, SD, et al.
(författare)
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The highest attainable standard of evidence (HASTE) for HIV/AIDS interventions: toward a public health approach to defining evidence
- 2012
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Ingår i: Public health reports (Washington, D.C. : 1974). - : SAGE Publications. - 1468-2877 .- 0033-3549. ; 127:6, s. 572-584
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Tidskriftsartikel (refereegranskat)abstract
- Evidence-driven decisions have become a standard for health interventions, policy, and programs. While randomized controlled trials (RCTs) are encouraged for public health interventions, there are limitations with RCTs as the gold standard of evidence for HIV interventions. We developed a novel system of evaluating evidence for assessing HIV preventive interventions termed the Highest Attainable Standard of Evidence (HASTE). Methods. The HASTE system focuses on triangulation of three distinct categories of evidence: efficacy data, implementation data, and plausibility. We conducted systematic reviews, including experimental and observational data, to assess all available interventions for men who have sex with men (MSM). We collected implementation and programmatic data using a global electronic consultation, Internet searches, and in-person consultations. We assessed plausibility with expert analyses of both biological and public health evidence. Results. HASTE includes four grades of evidence: Strong (Grade 1), Conditional (Grade 2), Insufficient (Grade 3), and Inappropriate (Grade 4). We used the HASTE system to evaluate the evidence for HIV interventions for MSM in low- and middle-income countries. Several differences emerged in the strength of recommendation with the use of the HASTE system, including strong recommendations for voluntary counseling and testing and for structural interventions. Conclusions. The HASTE system addresses a need for an evidence evaluation tool that is specific for HIV interventions and facilitates an evaluation of biomedical, behavioral, and structural approaches using the highest standard of attainable evidence. HASTE represents a tool that balances scientific integrity and practicality in assessing the quality of evidence of preventive interventions targeting the most-at-risk populations for HIV.
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| 20. |
- Corre, Y., et al.
(författare)
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Testing of ITER-grade plasma facing units in the WEST tokamak: Progress in understanding heat loading and damage mechanisms
- 2023
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Ingår i: Nuclear Materials and Energy. - : Elsevier BV. - 2352-1791. ; 37
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Tidskriftsartikel (refereegranskat)abstract
- Assessing the performance of the ITER design for the tungsten (W) divertor Plasma Facing Units (PFUs) in a tokamak environment is a high priority issue to ensure efficient plasma operation. This paper reviews the most recent results derived from experiments and post-mortem analysis of the ITER-grade PFUs exposed in the WEST tokamak and the associated modelling, with a focus on understanding heat loading and damage evolution. Several shaping options, sharp or chamfered leading edge (LE), unshaped or shaped blocks with a toroidal bevel as foreseen in ITER, were investigated, under steady state heat fluxes of up to 120 MW⋅m−2 and 6 MW⋅m−2 on the sharp LE and top surface of the block, respectively. A very high spatial resolution (VHR) infrared (IR) camera (0.1 mm/pixel) was used to derive the temporal and surface distribution of the temperature and heat load on the castellated tungsten blocks for different geometric alignment and plasma conditions. Photonic modelling was required to reproduce the IR measurements in particular in the toroidal and poloidal gaps of the mono-block (MB) stacks where high apparent temperatures are observed. Specular reflection is found to be the dominant emitter in these parts of the blocks. W-cracking was observed on the leading edge of the blocks already within the first phase of plasma operation, during which the divertor was equipped with unshaped PFUs, including some intentionally misaligned blocks. Numerical analysis taking into account softening processes and mechanical stresses, revealed brittle failure due to transients as the dominant failure mechanisms. Ductile failure was observed in one particular block used for the melting experiment, therefore under extremely high steady state heat load conditions. W-melting achieved on actively cooled PFU exhibits specific features: shallow melting and slow melt displacement. Plasma exposure of pre-damaged PFUs at various damage levels (crack network and melted droplets) was carried out under high heat load conditions with several hours of cumulated plasma duration. IR data and preliminary surface analyses show no evidence of significant degradation damage progression under these conditions.
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