435 research outputs found
Editorial on state representative Annette Hoglund, D-Portland, and her failure t
No full textEditorial on state representative Annette Hoglund, D-Portland, and her failure to follow state and federal regulations regarding wetlands. Hoglund\u27s company, Euclid Ambler Associates, filled as much as 18 acres of wetlands in developing subdivisions in Portland
Recognition of beta 2-microglobulin-negative (beta 2m-) T-cell blasts by natural killer cells from normal but not from beta 2m- mice: nonresponsiveness controlled by beta 2m- bone marrow in chimeric mice
No full textThe role of major histocompatibility complex (MHC) class I expression in control of the sensitivity of normal cells to natural killer (NK) cells was studied by the use of mutant mice made deficient for expression of beta 2-microglobulin (beta 2m) through homologous recombination in embryonal stem cells. T-cell blasts from beta 2m-deficient (beta 2m -/-) mice were killed by NK cells from normal mice in vitro, while beta 2m +/- blasts were resistant. The beta 2m defect also affected the NK effector cell repertoire: NK cells from beta 2m -/- mice failed to kill beta 2m -/- blasts, while they retained the ability to kill the prototype NK cell target lymphoma YAC-1, although at reduced levels. The inability to recognize beta 2m -/- blasts could be transferred with beta 2m -/- bone marrow to irradiated beta 2m-expressing mice. In contrast, the development of CD8+ T cells (deficient in beta 2m -/- mice) was restored in such chimera. These results indicate that loss of MHC class I/beta 2m expression is sufficient to render normal cells sensitive to NK cells, and that the same defect in the hemopoietic system of a mouse renders its NK cells tolerant to beta 2m-deficient but otherwise normal cells. In the beta 2m -/- mice, NK cells may be selected or educated by other bone marrow cells to tolerate the MHC class I deficiency. Alternatively, the specificity may be controlled directly by the class I molecules on the NK cells themselves
Denitrification by rhizobia: A possible factor contributing to nitrogen losses from soils
No full textThe intensive pastoral farming system on which New Zealand animal production is based is almost completely dependent upon the rhizobium-legurne symbiosis for the fixed nitrogen required for pasture production. The average annual fixation has been measured as 184 kg nitrogen/ha in developed lowland pastures Hoglund et cii., 1979 and about 13 kg nitrogen/ha in poorly developed bill country pastures (Grant and Lambert, 1979). From these figures it can be estimated that rhizobia in New Zealand pastures fix in excess of one million tonnes of nitrogen an nually. The current annual application of fertilizer nitrogen to pastures is about 12 500 tonnes (O'Connor, 1979)
Including the effects of pressure and stress in thermodynamic functions
No full textMost applications of thermodynamic databases to materials design are limited to ambient pressure. The consideration of elastic contributions to thermodynamic stability is highly desirable but not straight-forward to realise. We present examples of existing physical models for pressure-dependent thermodynamic functions and discuss the requirements for future implementations given the existing results of experiments and first-principles calculations. We briefly summarize the calculation of elastic constants and point out examples of nonlinear variation with pressure, temperature and chemical composition that would need to be accounted for in thermodynamic databases. This is particularly the case if a system melts from different phases at different pressures. Similar relations exist between pressure and magnetism and hence set the need to also include magnetic effects in thermodynamic databases for finite pressure. We present examples to illustrate that the effect of magnetism on stability is strongly coupled to pressure, temperature, and external fields. As a further complication we discuss dynamical instabilities that may appear at finite pressure. While imaginary phonon frequencies may render a structure unstable and destroy a crystal lattice, the anharmonic effects may stabilize it again at finite temperature. Finally, we also outline a possible implementation scheme for strain effects in thermodynamic databases. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
A novel three-colour fluorescence in situ hybridization approach for the detection of t(7;12)(q36;p13) in acute myeloid leukaemia reveals new cryptic three way translocation t(7;12;16)
No full text© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).The t(7;12)(q36;p13) translocation is a recurrent chromosome abnormality that involves the ETV6 gene on chromosome 12 and has been identified in 20–30% of infant patients with acute myeloid leukaemia (AML). The detection of t(7;12) rearrangements relies on the use of fluorescence in situ hybridization (FISH) because this translocation is hardly visible by chromosome banding methods. Furthermore, a fusion transcript HLXB9-ETV6 is found in approximately 50% of t(7;12) cases, making the reverse transcription PCR approach not an ideal screening method. Considering the report of few cases of variant translocations harbouring a cryptic t(7;12) rearrangement, we believe that the actual incidence of this abnormality is higher than reported to date. The clinical outcome of t(7;12) patients is believed to be poor, therefore an early and accurate diagnosis is important in the clinical management and treatment. In this study, we have designed and tested a novel three-colour FISH approach that enabled us not only to confirm the presence of the t(7;12) in a number of patients studied previously, but also to identify a cryptic t(7;12) as part of a complex rearrangement. This new approach has proven to be an efficient and reliable method to be used in the diagnostic setting
T cell responses and NK cell function in experimental autoimmune diabetes
No full textThe immune system is regulated by several complex mechanisms to maintain self tolerance and prevent autoimmune diseases. However, genetic as well as environmental factors can increase the risk of breaking self tolerance. Autoimmune diabetes is a polygenic disorder characterized by the selective destruction of pancreatic beta cells. Self-reactive T cells mediate the disease, but other cells including B cells, macrophages, dendritic cells (DC) , natural killer (NK) cells, NKT cells and regulatory T cells have been suggested to influence disease development.The aim of this thesis has been to characterize the regulation of T cell responses and the function of NK cells in autoimmune diabetes. CD8+ T cells are major producers of IFN-gamma, a key cytokine in autoimmune diabetes. The regulation of IFN-gamma production by CD8+ T cells was studied in relation to stimulatory strength. IFN-gamma secretion in stimulated naïve CD8+ T cells varied inversely with proliferation. Low concentrations of antigenic peptide and low levels of costimulation resulted in weak T cell proliferation, but substantial IFN-gamma production. Our unpublished data showed that CD8+ T cells from NOD mice (that spontaneously develop diabetes) are predisposed to increased IFNgamma responses, suggesting a possible role for IFN-gamma produced by self-reactive CD8+ T cells in the initiation phase of autoimmune diabetes.We also evaluated the role of the signaling adapter molecule DAP12 in a CD4+ T cell transgenic diabetes mouse model. Previously, it was shown that DAP 12 knock out mice were protected from experimental autoimmune encephalitis (EAE). Protection from EAE was associated with diminished priming of autoreactive CD4+ T cells in the mutant mice. We showed that DAP12 had an adverse effect in our model of autoimmune diabetes. In the absence of a functional DAP12 molecule, both diabetes and the activation of autoreactive CD4+ T cells were increased. This increased disease pathogenicity was accompanied by reduced suppression by antigen-specific CD4+CD25+ regulatory T cells. DAP 12 mutated mice had a different composition of DC, with an increased frequency of plasmacytoid DC (pDC), suggesting an interesting link between pDC and activation of regulatory T cells.NK cells may be involved in autoimmmunity and have been suggested to serve as regulatory cells in T cell mediated autoimmune diseases. A comprehensive analysis of NK cell function in NOD mice was made. NK cells in NOD mice could be identified by the combination of two monoclonal antibodies, TMbeta-1 (recognizing the beta-chain of the IL-2 receptor) and DX5 (recognizing CD49b integrin). Using these antibodies we demonstrated that there were no abnormalities in the size of NK cell populations in NOD mice compared to non-diabetogenic strains. However, NOD NK cell functions were broadly impaired due to defects in multiple activation pathways. This NK cell deficiency could be partially restored by NK cell activation in vivo, and after IL-12 and IL-18 stimulation in vitro.Furthermore, treating NOD mice with the TMbeta-1 antibody prevented disease. We confirmed, by flow cytometry, that all NK cells were depleted by this treatment. NK cell depletion was also confirmed by the complete lack of NK killing ability in antibody treated mice. A fraction of NKT cells was also depleted. In addition, a small population of CD8+ T cells, some of which co-expressed NKG2D, disappeared after treatment. TMbeta-1 treated mice could mount a normal primary CD8+ T cell response, but it is still possible that this small population of CD8+ T cells is important for diabetes development.A particularly interesting finding in this study was that disease was blocked when the antibody was administered late in disease pathogenesis. Even when given to prediabetic mice at 15 weeks of age, most mice were protected from diabetes, suggesting that the TMbeta-1 antibody targets effector cell/s responsible for a late, perhaps direct beta cell cytotoxic, effect in disease. This finding opens up the possibility for future development of new late-acting drugs against this disease.List of scientific papersI. Hall HT, Petrovic J, Hoglund P (2004). Reduced antigen concentration and costimulatory blockade increase IFN-gamma secretion in naive CD8(+) T cells. Eur J Immunol. 34(11): 3091-101. https://pubmed.ncbi.nlm.nih.gov/15384046II. Hal HTL, Sjolin H, Tomasello E, Vivier E, Hoglund P (2004). KARAP/DAP12-deficiency promotes diabetes development and prevents the activity of CD4+CD25+ BDC2.5 transgenic regulatory T cells in the pancreatic lymph nodes. [Manuscript]III. Johansson SE, Hall H, Bjorklund J, Hoglund P (2004). Broadly impaired NK cell function in non-obese diabetic mice is partially restored by NK cell activation in vivo and by IL-12/IL-18 in vitro. Int Immunol. 16(1): 1-11. https://pubmed.ncbi.nlm.nih.gov/14688055IV. Hall HTL, Johansson SE, Flodstrom-Tullberg M, Hoglund P (2004). Depletion of IL-2Rbeta+ cells prevents diabetes in non-obese mice. [Manuscript]</p
Investigating powerful jets in radio-loud narrow-line Seyfert 1s
No full textWe report results on multiband observations from radio to gamma-rays of the two radio-loud narrow-line Seyfert 1 (NLSy1) galaxies PKS 2004-447 and J1548+3511. Both sources show a core-jet structure on parsec scale, while they are unresolved at the arcsecond scale. The high core dominance and the high variability brightness temperature make these NLSy1 galaxies good gamma-ray source candidates. Fermi-Large Area Telescope detected gamma-ray emission only from PKS 2004-447, with a gamma-ray luminosity comparable to that observed in blazars. No gamma-ray emission is observed for J1548+ 3511. Both sources are variable in X-rays. J1548+ 3511 shows a hardening of the spectrum during high activity states, while PKS 2004-447 has no spectral variability. A spectral steepening likely related to the soft excess is hinted below 2 keV for J1548+ 3511, while the X-ray spectra of PKS 2004-447 collected by XMM-Newton in 2012 are described by a single power law without significant soft excess. No additional absorption above the Galactic column density or the presence of an Fe line is detected in the X-ray spectra of both sources
Analysis and manipulation of autoreactive and tumor-specific T cell responses
No full textThe focus of this work has been on the analysis and manipulation of T cell responses. One emphasis has been on T cells involved in autoimmune diabetes and another on T cells in tumor immunity. Primary activation of T cells as well as the role of the proteasome in T cell responses has been overlapping themes.Non obese diabetic (NOD) mice represent a mouse model for human Type I diabetes. Diabetes at NOD mice starts at around two weeks of age, when naïve autoreactive T cells encounter beta cell-derived antigen, in the pancreatic lymph nodes (PLN). Activated T cells proliferate at this site and subsequently leave the PLN and infiltrate the pancreas. Lymphocytes first appear in the pancreas at 3 weeks of age and diabetes occurs around 12 weeks of age.In an attempt to identify disease-initiating T cells, we studied the length of the CDR3 region on T cells isolated from the PLN of very young NOD mice. Immunoscope analysis of lymph node RNA from different time points (10, 14, 18 and 22 days of age), revealed subtle and transient oligoclonal expansion of TCRVbeta5.1-Jbeta1.5, TCRVbeta5.1-Jbeta1.3, TCRVbeta5.2Jbeta1.5 and TCRVbeta5.2-Jbeta1.6 in the PLN in comparison to the inguinal lymph node (ILN). Targeting those specific TCR species may offer novel treatment strategies in autoimmune diabetes.The subtleness of the initiating events in the PLN suggested that variation in activation thresholds could affect rate-limiting steps in order for T cell activation to proceeds. One such threshold may be stimulation needed for individual T cells to initiate IFN-gamma secretion. We found that naïve CD8+ T cells are geared towards IFN-gamma production when stimulated with low amounts of peptide, suggesting that they may play a role in early phases of immune responses in peripheral lymphoid organs.Another important focus of this thesis has been attempts to manipulate T cell responses using, proteasome inhibitors. Proteasome inhibitors affect peptide presentation but also modulate cytokine production, proliferation and survival of T cells.Applying proteasome inhibitor MG132 in a diabetes transfer model reduced diabetes with 76% in inhibitor treated mice compared with control recipients. The calpain inhibitor z-LeuLeu-H was without protective effect suggesting that MG132 acted via inhibition of the proteasome. Leukocyte infiltration of the pancreatic islets was not dramatically altered. However, our analysis revealed a decrease in proliferation of the transferred T cells in the PLN of the recipient mice, suggesting that the link between PLN proliferation and islet infiltration may reflect qualitative rather than quantitative effects.The use of proteasome inhibitors in a tumor system revealed a role of the proteasome in the production of certain tumor antigens. When tumor cells were adapted to grow in the presence of proteasome inhibitors they became more efficient in avoiding immunological reaction and formed more tumors in vivo. This phenotype might be preferentially selected in tumors to allow immune escape.Together, the studies presented in this thesis contribute to the understanding of T cell activation in autoimmune diabetes and cancer and propose different possibilities of modulation activation, proliferation and effector function of T cells.List of scientific papersI. Kessler B, Hong X, Petrovic J, Borodovsky A, Dantuma NP, Bogyo M, Overkleeft HS, Ploegh H, Glas R (2003). Pathways accessory to proteasomal proteolysis are less efficient in major histocompatibility complex class I antigen production. J Biol Chem. 278(12): 10013-21. Epub 2002 Dec 16 https://pubmed.ncbi.nlm.nih.gov/12488316II. Petrovic J, Hall H, Mehr R, Glas R, Hoglund P (2004). Inhibition of the proteasome reduces transfer-induced diabetes in nonobese diabetic mice. Scand J Immunol. 60(1-2): 134-42. https://pubmed.ncbi.nlm.nih.gov/15238082III. Petrovic J, Ferrandiz M, hall H, Cazenave PA, Six A, Hoglund P (2004). T cell receptor usage in the pancreatic lymph nodes of young non-obese diabetes mice. [Manuscript]IV. Hall HT, Petrovic J, Hoglund P (2004). Reduced antigen concentration and costimulatory blockade increase IFN-gamma secretion in naive CD8+ T cells. Eur J Immunol. 34(11): 3091-101. https://pubmed.ncbi.nlm.nih.gov/15384046</p
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