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  • Ahlberg, Erik, et al. (författare)
  • "Vi klimatforskare stödjer Greta och skolungdomarna"
  • Ingår i: Dagens nyheter (DN debatt). - 1101-2447.
  • Tidskriftsartikel (populärvet., debatt m.m.)abstract
    • DN DEBATT 15/3. Sedan industrialiseringens början har vi använt omkring fyra femtedelar av den mängd fossilt kol som får förbrännas för att vi ska klara Parisavtalet. Vi har bara en femtedel kvar och det är bråttom att kraftigt reducera utsläppen. Det har Greta Thunberg och de strejkande ungdomarna förstått. Därför stödjer vi deras krav, skriver 270 klimatforskare.
  • Guan, Jikui, et al. (författare)
  • Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.
  • 2018
  • Ingår i: Cold Spring Harbor molecular case studies. - 2373-2873. ; 4:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Tumors with Anaplastic Lymphoma Kinase (ALK) fusion rearrangements, including non-small cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. While mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, due to lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germ-line FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Mono-therapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 months treatment, residual primary tumor was surgically removed and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 months treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.
  • Gustafsson, Nina M. S., et al. (författare)
  • Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination
  • 2018
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anticancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-gamma H2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.
  • Johnson, Tomas, 1979, et al. (författare)
  • A Multi-Scale Simulation Method for the Prediction of Edge Wicking in Multi-Ply Paperboard
  • 2015
  • Ingår i: Nordic Pulp and Paper Research Journal. - 0283-2631. ; 30:4, s. 640-650
  • Tidskriftsartikel (refereegranskat)abstract
    • When liquid packaging board is made aseptic in the filling machine the unsealed edges of the board are exposed to a mixture of water and hydrogen peroxide. A high level of liquid penetration may lead to aesthetic as well as functional defects. To be able to make a priori predictions of the edge wicking properties of a certain paperboard material is therefore of great interest to the paper industry as well as to packaging manufacturers. In this paper an extended multi-scale model of edge wicking in multi-ply paperboard is presented. The geometric and physical properties of the paperboard are modeled on the micro-scale, and include fillers and fines. The absolute air permeabilities and pore size distributions are validated with experimental and tomographic values. On the macro-scale random porosity and sizing distributions, time and sizing dependent contact angles, and inter-ply dependence are modeled. Arbitrary shapes of the paperboard are handled through an unstructured 3D surface mesh. Stationary and transient edge wicking simulations are validated against experiments with excellent agreement. The simulations show that the diffusive menisci between the liquid and air phases together with the two-ply model is necessary to achieve good agreement with the transient edge wicking experiments.
  • Lundgren, Hanna, et al. (författare)
  • HLA-DR7 and HLA-DQ2 : Transgenic mouse strains tested as a model system for ximelagatran hepatotoxicity
  • 2017
  • Ingår i: PLoS ONE. - San Francisco, United States : Public Library of Science. - 1932-6203 .- 1932-6203. ; 12:9
  • Tidskriftsartikel (refereegranskat)abstract
    • The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients. An immunemediated pathogenesis was suggested. Here, we evaluated whether HLA transgenic mice models could be used to investigate whether the expression of relevant HLA molecules was enough to reproduce the DILI effects in humans. In silico modelling performed in this study revealed association of both ximelagatran (pro-drug) and melagatran (active drug) to the antigen-presenting groove of the homology modelled HLA-DR7 molecule suggesting "altered repertoire" as a key initiating event driving development of DILI in humans. Transgenic mouse strains (tgms) expressing HLA of serotype HLA-DR7 (HLA-DRB1*0701, -DRA*0102), and HLA-DQ2 (HLA-DQB1*0202, -DQA1*0201) were created. These two lines were crossed with a human (h) CD4 transgenic line, generating the two tgms DR7xhCD4 and DQ2xhCD4. To investigate whether the DILI effects observed in humans could be reproduced in tgms, the mice were treated for 28 days with ximelagatran. Results revealed no signs of DILI when biomarkers for liver toxicity were measured and histopathology was evaluated. In the ximelagatran case, presence of relevant HLA-expression in a preclinical model did not fulfil the prerequisite for reproducing DILI observed in patients. Nonetheless, for the first time an HLA-transgenic mouse model has been investigated for use in HLA-associated DILI induced by a low molecular weight compound. This study shows that mimicking of genetic susceptibility, expressed as DILI-associated HLA-types in mice, is not sufficient for reproducing the complex pathogenesis leading to DILI in man.
  • Malinovskiy, Dmitry, et al. (författare)
  • Variations in the isotopic composition of molybdenum in freshwater lake systems
  • 2007
  • Ingår i: Chemical Geology. - : Elsevier. - 0009-2541 .- 1872-6836. ; 236:3-4, s. 181-198
  • Tidskriftsartikel (refereegranskat)abstract
    • Variations in molybdenum isotopic composition, spanning the range of ≈ 2.3‰ in the terms of 97Mo/95Mo ratio, have been measured in sediment cores from three lakes in northern Sweden and north-western Russia. These variations have been produced by both isotopically variable input of Mo into the lakes due to Mo isotopic heterogeneity of bedrock in the drainage basins and fractionation in the lake systems due to temporal variations in limnological conditions. Mo isotope abundances of bedrock in the lake drainage basins have been documented by analysis of Mo isotope ratios of a suite of molybdenite occurrences collected in the studied area and of detrital fractions of the lake sediment cores. The median δ97Mo value of the investigated molybdenites is 0.26‰ with standard deviation of 0.43‰ (n = 19), whereas the median δ97Mo value of detrital sediment fractions from two lakes is - 0.40‰ with standard deviation of 0.36‰ (n = 15). The isotopic composition of Mo in the sediment cores has been found to be dependent on redox conditions of the water columns and the dominant type of scavenging phases. Hydrous Fe oxides have been shown to be an efficient scavenger of Mo from porewater under oxic conditions. Oxidative precipitation of Fe(II) in the sediments resulted in co-precipitation of Mo and significant authigenic enrichment at the redox boundary. In spite of a pronounced increase in Mo concentration associated with Fe oxides at the redox boundary the isotopic composition of Mo in this zone varies insignificantly, suggesting little or no isotope fractionation during scavenging of Mo by hydrous Fe oxides. In a lake with anoxic bottom water a chironomid-inferred reconstruction of O2 conditions in the bottom water through the Holocene indicates that increased O2 concentrations are generally associated with low δ97Mo/95Mo values of the sediments, whereas lowered O2 contents of the bottom water are accompanied by relatively high δ97Mo/95Mo values, thus confirming the potential of Mo isotope data to be a proxy for redox conditions of overlying waters. However, it is pointed out that other processes including input of isotopically heterogeneous Mo and Mn cycling in the redox-stratified water column can be a primary cause of variations in Mo isotopic compositions of lake sediments.
  • Martinsson, J., et al. (författare)
  • Carbonaceous aerosol source apportionment using the Aethalometer model - evaluation by radiocarbon and levoglucosan analysis at a rural background site in southern Sweden
  • 2017
  • Ingår i: Atmospheric Chemistry and Physics. - : Copernicus Gesellschaft mbH. - 1680-7316. ; 17, s. 4265-4281
  • Tidskriftsartikel (refereegranskat)abstract
    • With the present demand on fast and inexpensive aerosol source apportionment methods, the Aethalometer model was evaluated for a full seasonal cycle (June 2014June 2015) at a rural atmospheric measurement station in southern Sweden by using radiocarbon and levoglucosan measurements. By utilizing differences in absorption of UV and IR, the Aethalometer model apportions carbon mass into wood burning (WB) and fossil fuel combustion (FF) aerosol. In this study, a small modification in the model in conjunction with carbon measurements from thermal-optical analysis allowed apportioned non-light-absorbing biogenic aerosol to vary in time. The absorption differences between WB and FF can be quantified by the absorption angstrom ngstrom exponent (AAE). In this study AAE(WB) was set to 1.81 and AAE(FF) to 1.0. Our observations show that the AAE was elevated during winter (1.36 +/- 0.07) compared to summer (1.12 +/- 0.07). Quantified WB aerosol showed good agreement with levoglucosan concentrations, both in terms of correlation (R-2 = 0 : 70) and in comparison to reference emission inventories. WB aerosol showed strong seasonal variation with high concentrations during winter (0.65 mu gm(-3), 56% of total carbon) and low concentrations during summer (0.07 mu gm(-3), 6% of total carbon). FF aerosol showed less seasonal dependence; however, black carbon (BC) FF showed clear diurnal patterns corresponding to traffic rush hour peaks. The presumed non-light-absorbing biogenic carbonaceous aerosol concentration was high during summer (1.04 mu gm(-3), 72% of total carbon) and low during winter (0.13 mu gm(-3), 8% of total carbon). Aethalometer model results were further compared to radiocarbon and levoglucosan source apportionment results. The comparison showed good agreement for apportioned mass of WB and biogenic carbonaceous aerosol, but discrepancies were found for FF aerosol mass. The Aethalometer model overestimated FF aerosol mass by a factor of 1.3 compared to radiocarbon and levoglucosan source apportionment. A performed sensitivity analysis suggests that this discrepancy can be explained by interference of non-light-absorbing biogenic carbon during winter. In summary, the Aethalometer model offers a costeffective yet robust high-time-resolution source apportionment at rural background stations compared to a radiocarbon and levoglucosan alternative.
  • Martinsson, Johan, et al. (författare)
  • Evaluation of delta C-13 in Carbonaceous Aerosol Source Apportionment at a Rural Measurement Site
  • 2017
  • Ingår i: Aerosol and Air Quality Research. - 1680-8584 .- 2071-1409. ; 17:8, s. 2081-2094
  • Tidskriftsartikel (refereegranskat)abstract
    • The stable isotope of carbon, C-13, has been used in several studies for source characterization of carbonaceous aerosol since there are specific signatures for different sources. In rural areas, the influence of different sources is complex and the application of delta C-13 for source characterization of the total carbonaceous aerosol (TC) can therefore be difficult, especially the separation between biomass burning and biogenic sources. We measured delta C-13 from 25 filter samples collected during one year at a rural background site in southern Sweden. Throughout the year, the measured delta C-13 showed low variability (-26.73 to -25.64%). We found that the measured delta C-13 did not correlate with other commonly used source apportionment tracers (C-14, levoglucosan). delta C-13 values showed lower variability during the cold months compared to the summer, and this narrowing of the delta C-13 values together with elevated levoglucosan concentrations may indicate contribution from sources with lower delta C-13 variation, such as biomass or fossil fuel combustion. Comparison of two Monte Carlo based source apportionment models showed no significant difference in results when delta C-13 was incorporated in the model. The insignificant change of redistributed fraction of carbon between the sources was mainly a consequence of relatively narrow range of delta C-13 values and was complicated by an unaccounted kinetic isotopic effect and overlapping delta C-13 end-member values for biomass burning and biogenic sources.
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