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- Blom, S, et al.
(författare)
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Systems pathology by multiplexed immunohistochemistry and whole-slide digital image analysis
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 15580-
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Tidskriftsartikel (refereegranskat)abstract
- The paradigm of molecular histopathology is shifting from a single-marker immunohistochemistry towards multiplexed detection of markers to better understand the complex pathological processes. However, there are no systems allowing multiplexed IHC (mIHC) with high-resolution whole-slide tissue imaging and analysis, yet providing feasible throughput for routine use. We present an mIHC platform combining fluorescent and chromogenic staining with automated whole-slide imaging and integrated whole-slide image analysis, enabling simultaneous detection of six protein markers and nuclei, and automatic quantification and classification of hundreds of thousands of cells in situ in formalin-fixed paraffin-embedded tissues. In the first proof-of-concept, we detected immune cells at cell-level resolution (n = 128,894 cells) in human prostate cancer, and analysed T cell subpopulations in different tumour compartments (epithelium vs. stroma). In the second proof-of-concept, we demonstrated an automatic classification of epithelial cell populations (n = 83,558) and glands (benign vs. cancer) in prostate cancer with simultaneous analysis of androgen receptor (AR) and alpha-methylacyl-CoA (AMACR) expression at cell-level resolution. We conclude that the open-source combination of 8-plex mIHC detection, whole-slide image acquisition and analysis provides a robust tool allowing quantitative, spatially resolved whole-slide tissue cytometry directly in formalin-fixed human tumour tissues for improved characterization of histology and the tumour microenvironment.
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| 9. |
- Chartkunchand, K. C., et al.
(författare)
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Lifetimes of bound excited states of Pt-
- 2017
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Ingår i: Journal of Physics: Conference Series, Vol. 875, no. 022051. - : IOP Publishing. - 1742-6588.
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Konferensbidrag (refereegranskat)abstract
- Measurements of the radiative lifetimes of the two excited states of the platinum anion Pt- are presented. Pt- ions stored in the cryogenic ion storage ring DESIREE were photodetached at different photon wavelengths and the resulting yield of neutral Pt measured as a function of time was recorded. Analysis of the neutral decay curves show a 2.54 +/- 0.10 s lifetime for the higher-lying 5d(10)6(s) S-2(1/2) excited state and a lifetime in the range of 50-200 ms for the lower- lying 5d(9)6(s)(2) D-2(3/2) excited state. This is the first study to report the lifetime of a bound anion excited state with an electron configuration different from that of the anion ground state.
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| 13. |
- Henje Blom, Eva, 1962-, et al.
(författare)
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Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.
- 2015
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.
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| 14. |
- Ho, Tiffany C., et al.
(författare)
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Fusiform gyrus dysfunction is associated with perceptual processing efficiency to emotional faces in adolescent depression : a model-based approach
- 2016
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Ingår i: Frontiers in Psychology. - Lausanne : Frontiers Media S.A.. - 1664-1078. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- While the extant literature has focused on major depressive disorder (MDD) as being characterized by abnormalities in processing affective stimuli (e.g., facial expressions), little is known regarding which specific aspects of cognition influence the evaluation of affective stimuli, and what are the underlying neural correlates. To investigate these issues, we assessed 26 adolescents diagnosed with MDD and 37 well-matched healthy controls (HCL) who completed an emotion identification task of dynamically morphing faces during functional magnetic resonance imaging (fMRI). We analyzed the behavioral data using a sequential sampling model of response time (RT) commonly used to elucidate aspects of cognition in binary perceptual decision making tasks: the Linear Ballistic Accumulator (LBA) model. Using a hierarchical Bayesian estimation method, we obtained group-level and individual-level estimates of LBA parameters on the facial emotion identification task. While the MDD and HCL groups did not differ in mean RT, accuracy, or group-level estimates of perceptual processing efficiency (i.e., drift rate parameter of the LBA), the MDD group showed significantly reduced responses in left fusiform gyrus compared to the HCL group during the facial emotion identification task. Furthermore, within the MDD group, fMRI signal in the left fusiform gyrus during affective face processing was significantly associated with greater individual-level estimates of perceptual processing efficiency. Our results therefore suggest that affective processing biases in adolescents with MDD are characterized by greater perceptual processing efficiency of affective visual information in sensory brain regions responsible for the early processing of visual information. The theoretical, methodological, and clinical implications of our results are discussed.
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| 15. |
- Kaminska, M, et al.
(författare)
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Storing keV negative ions for hours: Lifetime measurements in new time domains
- 2015
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 635
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Konferensbidrag (refereegranskat)abstract
- We have used one of the cryogenic ion storage rings of DESIREE to measure the lifetime of the 2P o 1/2 level in the sulfur anion to be 503 ± 43 seconds. This is orders of magnitude longer than any previously measured lifetime in a negatively charged ion.
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| 16. |
- Mellin, Pelle, et al.
(författare)
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A proposed Swedish national standard and best practice for detection of Ar in PM hip material
- 2018
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Ingår i: Euro PM 2018 Congress and Exhibition. - : European Powder Metallurgy Association (EPMA). - 9781899072507
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Konferensbidrag (refereegranskat)abstract
- Ar in metal is present as gaseous voids which affect the material performance; most notably the mechanical properties. In agreement with literature findings, our investigation confirms this for 316L steel produced by PM HIP. Detecting the Ar is possible by microscopy, but more reliably with inert gas fusion followed by gas chromatography or mass spectrometry. The users of these techniques have accumulated experience over the years and consider them robust, especially in terms of distinguishing a presence or absence of Ar. Since consensus has emerged, a standard is now possible. We propose firstly a national standard. It may be used as a quality agreement between the purchaser and provider of the PM HIP service. The proposed standard considers the distinctiveness of PM HIP. For example that Ar tends to segregate in PM HIP cans. In fact, consensus has also been reached on how to reliably sample from PM HIP cans. © European Powder Metallurgy Association (EPMA).
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| 17. |
- Mellin, Pelle, et al.
(författare)
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Detecting argon trapped in reference samples made by hot isostatic pressing
- 2016
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Ingår i: World PM 2016 Congress and Exhibition. - : European Powder Metallurgy Association (EPMA). - 9781899072484
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Konferensbidrag (refereegranskat)abstract
- We reveal in this paper a procedure to make reference materials containing a known level of Ar. Risk assessment when detecting Ar in a production material is based on the content relative to a specified safety limit (usually 50 ngAr/gsteel). Hence we only need to know if a production material contains more or less than this limit. Now, we can produce material at this limit. To evaluate, we use two types of instruments, on the following contents: 24, 48, 71, 95 and ngAr/gsteel. We found that all instruments could distinguish a higher and a lower level, from the safety limit. These contents are close to the lowest detectable limit for both instruments. The instruments are a G8 Galileo from Bruker Elemental and an ELTRA-Werf (several units) from Takon AB. The mechanisms of Argon segregation are reflected upon as the need for a uniform distribution in reference samples is important. Especially if one would do the instrument calibration solely based on reference samples in the future.
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| 18. |
- Mohlin, Frida, et al.
(författare)
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Functional characterization of two novel non-synonymous alterations in CD46 and a Q950H change in factor H found in atypical hemolytic uremic syndrome patients.
- 2015
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Ingår i: Molecular Immunology. - : Elsevier BV. - 1872-9142 .- 0161-5890. ; 65:2, s. 367-376
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Tidskriftsartikel (refereegranskat)abstract
- Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation, characterized by hemolytic anemia, thrombocytopenia and acute renal failure. Mutations in complement inhibitors are major risk factors for development of aHUS. The three aHUS patients reported in this study had several previously identified alterations in complement inhibitors; e.g. risk haplotypes in CD46 and factor H but we also identified two novel heterozygous non-synonymous CD46 alterations (p.E142Q and p.G259V). Presence of G259V caused decreased expression of the recombinant mutant CD46 compared to wild type (WT). Western blot analysis showed that the majority of the expressed G259V protein was in the precursor form, suggesting that it is processed less efficiently than WT. Low CD46 expression on the surface of the patient's neutrophils confirmed the in vitro results. Further, G259V had a substantially impaired ability to act as a cofactor to factor I, in the degradation of both C3b and C4b. The E142Q mutant showed neither decreased expression nor impaired function. Two of the patients also had a heterozygous non-synonymous alteration in factor H (p.Q950H), reported previously in aHUS but not functionally tested. This variant showed moderately impaired function in hemolytic assays, both using patient sera and recombinant proteins. The recombinant Q950H also showed a somewhat decreased expression compared to WT but the complement inhibitory function in fluid phase was normal. Taken together, we report a novel CD46 alteration showing both a decreased protein expression and substantially impaired cofactor function (G259V) and another without an effect on expression or cofactor function (E142Q). Moreover, mild consequences of a previously reported aHUS associated rare variant in factor H (Q950H) was also revealed, underlining the clear need for functional characterization of each new aHUS associated mutation.
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| 19. |
- Mossmark, Fredrik, 1975, et al.
(författare)
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Environmental impact of underground construction from a hydrological and hydrochemical disturbance perspective
- 2018
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Ingår i: ISRM International Symposium - 10th Asian Rock Mechanics Symposium, ARMS 2018.
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Konferensbidrag (refereegranskat)abstract
- In most projects involving underground construction, impact to hydrogeological conditions is monitored through measurements of groundwater levels. In contrast, hydrological and hydrochemical changes are rarely monitored throughout a project and the assessment of environmental resilience is often limited to an evaluation that broadly links the behavior of groundwater levels with a large number of engineering geological and ecological parameters. An ongoing field research project in Sweden is based on monitoring the recovery of hydrogeological, hydrological and hydrochemical conditions after a long-term groundwater extraction. The groundwater discharge was intended to simulate effects of underground construction. Groundwater was extracted during a period of five years from fractured igneous rock in a previously glaciated area with thin soil cover. During this time the hydrogeological and hydrological conditions were altered with lowered groundwater levels and the surface runoff from the area decreased by nearly 50%. Meanwhile significant hydrochemical changes were observed with spikes in sulfate and lowered pH in groundwater as well as in surface water. Preliminary results show that hydrological recovery after the groundwater extraction took more than three years, despite apparent quick recovery of groundwater levels with runoff volumes remaining lower than in a nearby reference area. Meanwhile, hydrochemical conditions did not return to those that existed prior to groundwater extraction. During the first three years of recovery, sulfate remained higher in shallow groundwater bodies, whereas base cations were lower compared to before the extraction started. After ten years of recovery sulfate concentrations have decreased by 30% to 60%, in both surface water and groundwater bodies, whereas chloride concentrations have increased compared to before the extraction. By restricting monitoring to only groundwater levels, some environmental impacts due to underground constructions may be missed.
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| 21. |
- Pellinen, T, et al.
(författare)
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ITGB1-dependent upregulation of Caveolin-1 switches TGFβ signalling from tumour-suppressive to oncogenic in prostate cancer
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 2338-
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Tidskriftsartikel (refereegranskat)abstract
- Caveolin-1 (CAV1) is over-expressed in prostate cancer (PCa) and is associated with adverse prognosis, but the molecular mechanisms linking CAV1 expression to disease progression are poorly understood. Extensive gene expression correlation analysis, quantitative multiplex imaging of clinical samples, and analysis of the CAV1-dependent transcriptome, supported that CAV1 re-programmes TGFβ signalling from tumour suppressive to oncogenic (i.e. induction of SLUG, PAI-1 and suppression of CDH1, DSP, CDKN1A). Supporting such a role, CAV1 knockdown led to growth arrest and inhibition of cell invasion in prostate cancer cell lines. Rationalized RNAi screening and high-content microscopy in search for CAV1 upstream regulators revealed integrin beta1 (ITGB1) and integrin associated proteins as CAV1 regulators. Our work suggests TGFβ signalling and beta1 integrins as potential therapeutic targets in PCa over-expressing CAV1, and contributes to better understand the paradoxical dual role of TGFβ in tumour biology.
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| 23. |
- Schedin-Weiss, Sophia, et al.
(författare)
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Super-resolution microscopy reveals gamma-secretase at both sides of the neuronal synapse
- 2016
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Ingår i: Acta neuropathologica communications. - : BioMed Central. - 2051-5960. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- The transmembrane protein assembly gamma-secretase is a key protease in regulated intramembrane processing (RIP) of around 100 type-1 transmembrane proteins. Importantly, it has a pathological role in Alzheimer disease (AD) as it generates the neurotoxic amyloid beta-peptide from the amyloid precursor protein (APP). Studies on gamma-secretase location are therefore crucial both from a biological and a therapeutic perspective. Despite several years of efforts in many laboratories, it is not clear where in the neuron gamma-secretase exerts it's activities. Technical challenges include the fact that the active enzyme contains four protein components and that most subcellular compartments cannot be spatially resolved by traditional light microscopy. Here, we have used a powerful combination of the two nanoscopy techniques STORM and STED microscopy to visualize the location of gamma-secretase in neurons using an active-site specific probe, with a focus on the synapse. We show that gamma-secretase is present in both the pre-and postsynaptic compartments. We further show that the enzyme is enriched very close to the synaptic cleft in the postsynaptic membrane, as well as to NMDA receptors, demonstrating that gamma-secretase is present in the postsynaptic plasma membrane. Importantly, the expression of gamma-secretase increased in the pre-and postsynaptic compartments with the size of the synapse, suggesting a correlation between gamma-secretase activity and synapse maturation. Thus, our data shows the synaptic location with high precision in three dimensions and settles the long-lasting debate on the synaptic location of gamma-secretase.
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