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  • 1.
    Andersson, Henrik
    et al.
    Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Hartmanova (Andersson), Blanka
    Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Landfors, Mattias
    Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Matematik och matematisk statistik.
    Noppa, Laila
    FOI, Umeå (Swedish Defence Research Agency).
    Näslund, Linda
    Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
    Näslund, A.
    T A microarray analysis of the murine macrophage response to infection with Francisella tularensis LVS2006Ingår i: Journal of Medical Microbiology, ISSN 0022-2615, E-ISSN 1473-5644, Vol. 55, nr 8, s. 1023-1033Artikel i tidskrift (Refereegranskat)
  • 2.
    Andersson, Henrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Hartmanova, Blanka
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Bäck, Erik
    Universitetssjukhuset i Örebro.
    Eliasson, Henrik
    Universitetssjukhuset i Örebro.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Näslund, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Ryden, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Transcriptional profiling of the peripheral blood response during tularemia.2006Ingår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 7, nr 6, s. 503-513Artikel i tidskrift (Refereegranskat)
  • 3.
    Andersson, Henrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Hartmanova, Blanka
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Kuolee, R.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Conlan, Wayne
    NRC, Kanada.
    Chen, Wang
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Transcriptional profiling of the host responses in mouse lungs following aerosol2006Ingår i: Journal of Medical Microbiology, ISSN 0022-2615, E-ISSN 1473-5644, Vol. 55, nr 3, s. 263-271Artikel i tidskrift (Refereegranskat)
  • 4.
    Belyaev, Yu.K.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    On Non-Parametric Estimation of Poission Point Processes Related to Failure Stresses of Fibres2000Rapport (Övrigt vetenskapligt)
    Abstract [en]

    We consider statistical analysis of the reliability of fibres. The problem is to estimate the distribution law of random failure stresses of fibres (i.e. the critical level of stresses that destroy fibres) by using data obtained in a special kind of test, where several fibres are tested until they break. All new pieces resulting from this test will also be tested, if they are long enough. The test ends when all the remaining pieces are too short to be tested further. We refer to these as binary tree structured tests. We assume that the cumulative hazard function (c.h.f.) of the failure stresses of these fibres is continuous, and that the fibres are statistically identical. Under these assumptions we obtain, as the number of tested fibres increases, a strongly consistent Nelson-Aalen type estimator of the c.h.f. The functional central limit resampling theorem in Skorohod space is proved. It justifies the possibility of using resampling for estimating the accuracy of these estimators. The theorem shows that resampling can be used to asymptotically consistently estimate distribution laws of continuous functionals of the random deviations between the estimator and the true c.h.f.. For example, resampling can be used to estimate the distribution law of the maximum distance between estimators and estimands. Numerical examples suggest that resampling works well for a moderate number of tested fibres.

  • 5.
    Belyaev, Yuri K
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Non-parametric estimators of the distribution of tensile strengths of wires1997Rapport (Övrigt vetenskapligt)
  • 6.
    Chen, Changchun
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Huang, Bo
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Eliasson, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Byström, Anders S
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Elongator Complex Influences Telomeric Gene Silencing and DNA Damage Response by Its Role in Wobble Uridine tRNA Modification2011Ingår i: PLoS genetics, ISSN 1553-7404, Vol. 7, nr 9, s. e1002258-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Elongator complex is required for formation of the side chains at position 5 of modified nucleosides 5-carbamoylmethyluridine (ncm(5)U(34)), 5-methoxycarbonylmethyluridine (mcm(5)U(34)), and 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U(34)) at wobble position in tRNA. These modified nucleosides are important for efficient decoding during translation. In a recent publication, Elongator complex was implicated to participate in telomeric gene silencing and DNA damage response by interacting with proliferating cell nuclear antigen (PCNA). Here we show that elevated levels of tRNA(Lys) (s(2) ) (UUU), tRNA(Gln) (s(2) ) (UUG), and tRNA(Glu) (s(2) ) (UUC), which in a wild-type background contain the mcm(5)s(2)U nucleoside at position 34, suppress the defects in telomeric gene silencing and DNA damage response observed in the Elongator mutants. We also found that the reported differences in telomeric gene silencing and DNA damage response of various elp3 alleles correlated with the levels of modified nucleosides at U(34). Defects in telomeric gene silencing and DNA damage response are also observed in strains with the tuc2Δ mutation, which abolish the formation of the 2-thio group of the mcm(5)s(2)U nucleoside in tRNA(Lys) (mcm(5) (s(2) ) (UUU) ), tRNA(Gln) (mcm(5) (s(2) ) (UUG) ), and tRNA(Glu) (mcm(5) (s(2) ) (UUC) ). These observations show that Elongator complex does not directly participate in telomeric gene silencing and DNA damage response, but rather that modified nucleosides at U(34) are important for efficient expression of gene products involved in these processes. Consistent with this notion, we found that expression of Sir4, a silent information regulator required for assembly of silent chromatin at telomeres, was decreased in the elp3Δ mutants.

  • 7. De Pascalis, Roberto
    et al.
    Chou, Alicia Y.
    Ryden, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Kennett, Nikki J.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Elkins, Karen L.
    Models Derived from In Vitro Analyses of Spleen, Liver, and Lung Leukocyte Functions Predict Vaccine Efficacy against the Francisella tularensis Live Vaccine Strain (LVS)2014Ingår i: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 5, nr 2, artikel-id e00936Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Currently, there are no licensed vaccines and no correlates of protection against Francisella tularensis, which causes tularemia. We recently demonstrated that measuring in vitro control of intramacrophage bacterial growth by murine F. tularensis-immune splenocytes, as well as transcriptional analyses, discriminated Francisella vaccines of different efficacies. Further, we identified potential correlates of protection against systemic challenge. Here, we extended this approach by studying leukocytes derived from lungs and livers of mice immunized by parenteral and respiratory routes with F. tularensis vaccines. Liver and lung leukocytes derived from intradermally and intranasally vaccinated mice controlled in vitro Francisella Live Vaccine Strain (LVS) intramacrophage replication in patterns similar to those of splenocytes. Gene expression analyses of potential correlates also revealed similar patterns in liver cells and splenocytes. In some cases (e. g., tumor necrosis factor alpha [TNF-alpha], interleukin 22 [IL-22], and granulocyte-macrophage colony-stimulating factor [GM-CSF]), liver cells exhibited even higher relative gene expression, whereas fewer genes exhibited differential expression in lung cells. In contrast with their strong ability to control LVS replication, splenocytes from intranasally vaccinated mice expressed few genes with a hierarchy of expression similar to that of splenocytes from intradermally vaccinated mice. Thus, the relative levels of gene expression vary between cell types from different organs and by vaccination route. Most importantly, because studies comparing cell sources and routes of vaccination supported the predictive validity of this coculture and gene quantification approach, we combined in vitro LVS replication with gene expression data to develop analytical models that discriminated between vaccine groups and successfully predicted the degree of vaccine efficacy. Thus, this strategy remains a promising means of identifying and quantifying correlative T cell responses.

    IMPORTANCE

    Identifying and quantifying correlates of protection is especially challenging for intracellular bacteria, including Francisella tularensis. F. tularensis is classified as a category A bioterrorism agent, and no vaccines have been licensed in the United States, but tularemia is a rare disease. Therefore, clinical trials to test promising vaccines are impractical. In this report, we further evaluated a novel approach to developing correlates by assessing T cell immune responses in lungs and livers of differentially vaccinated mice; these nonprofessional immune tissues are colonized by Francisella. The relative degree of vaccine efficacy against systemic challenge was reflected by the ability of immune T cells, particularly liver T cells, to control the intramacrophage replication of bacteria in vitro and by relative gene expression of several immunological mediators. We therefore developed analytical models that combined bacterial replication data and gene expression data. Several resulting models provided excellent discrimination between vaccines of different efficacies.

  • 8. De Pascalis, Roberto
    et al.
    Hahn, Andrew
    Brook, Helen M.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Donart, Nathaniel
    Mittereder, Lara
    Frey, Blake
    Wu, Terry H.
    Elkins, Karen L.
    A panel of correlates predicts vaccine-induced protection of rats against respiratory challenge with virulent Francisella tularensis2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 5, artikel-id e0198140Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There are no defined correlates of protection for any intracellular pathogen, including the bacterium Francisella tularensis, which causes tularemia. Evaluating vaccine efficacy against sporadic diseases like tularemia using field trials is problematic, and therefore alternative strategies to test vaccine candidates like the Francisella Live Vaccine Strain (LVS), such as testing in animals and applying correlate measurements, are needed. Recently, we described a promising correlate strategy that predicted the degree of vaccine-induced protection in mice given parenteral challenges, primarily when using an attenuated Francisella strain. Here, we demonstrate that using peripheral blood lymphocytes (PBLs) in this approach predicts LVS-mediated protection against respiratory challenge of Fischer 344 rats with fully virulent F. tularensis, with exceptional sensitivity and specificity. Rats were vaccinated with a panel of LVS-derived vaccines and subsequently given lethal respiratory challenges with Type A F. tularensis. In parallel, PBLs from vaccinated rats were evaluated for their functional ability to control intramacrophage Francisella growth in in vitro co-culture assays. PBLs recovered from co-cultures were also evaluated for relative gene expression using a large panel of genes identified in murine studies. In vitro control of LVS intramacrophage replication reflected the hierarchy of protection. Further, despite variability between individuals, 22 genes were significantly more up-regulated in PBLs from rats vaccinated with LVS compared to those from rats vaccinated with the variant LVS-R or heat killed LVS, which were poorly protective. These genes included IFN-gamma, IL-21, NOS2, LTA, T-bet, IL-12rβ2, and CCL5. Most importantly, combining quantifications of intramacrophage growth control with 5-7 gene expression levels using multivariate analyses discriminated protected from non-protected individuals with greater than 95% sensitivity and specificity. The results therefore support translation of this approach to non-human primates and people to evaluate new vaccines against Francisella and other intracellular pathogens.

  • 9.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Siwicki, Jan Konrad
    Revie, John
    Borssen, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Evelönn, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Chrzanowska, Krystyna H.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Keith, W. Nicol
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias2014Ingår i: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, nr 7, s. 606-615Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.

  • 10.
    Del Peso-Santos, Teresa
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Landfors, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Skärfstad, Eleonore
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Shingler, Victoria
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Pr is a member of a restricted class of σ70-dependent promoters that lack a recognizable -10 element2012Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 40, nr 22, s. 11308-11320Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Pr promoter is the first verified member of a class of bacterial σ(70)-promoters that only possess a single match to consensus within its -10 element. In its native context, the activity of this promoter determines the ability of Pseudomonas putida CF600 to degrade phenolic compounds, which provides proof-of-principle for the significance of such promoters. Lack of identity within the -10 element leads to non-detection of Pr-like promoters by current search engines, because of their bias for detection of the -10 motif. Here, we report a mutagenesis analysis of Pr that reveals strict sequence requirements for its activity that includes an essential -15 element and preservation of non-consensus bases within its -35 and -10 elements. We found that highly similar promoters control plasmid- and chromosomally- encoded phenol degradative systems in various Pseudomonads. However, using a purpose-designed promoter-search algorithm and activity analysis of potential candidate promoters, no bona fide Pr-like promoter could be found in the entire genome of P. putida KT2440. Hence, Pr-like σ(70)-promoters, which have the potential to be a widely distributed class of previously unrecognized promoters, are in fact highly restricted and remain in a class of their own.

  • 11.
    Desvars, Amélie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Furberg, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Hjertqvist, Marika
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Epidemiology and Ecology of Tularemia in Sweden2015Ingår i: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, s. 58-58Artikel i tidskrift (Övrigt vetenskapligt)
  • 12.
    Desvars, Amélie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Furberg, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Hjertqvist, Marika
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Rydén, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Epidemiology and Ecology of Tularemia in Sweden, 1984-20122015Ingår i: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 21, nr 1, s. 32-39Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The zoonotic disease tularemia is endemic in large areas of the Northern Hemisphere, but research is lacking on patterns of spatial distribution and connections with ecologic factors. To describe the spatial epidemiology of and identify ecologic risk factors for tularemia incidence in Sweden, we analyzed surveillance data collected over 29 years (1984-2012). A total of 4,830 cases were notified, of which 3,524 met all study inclusion criteria. From the first to the second half of the study period, mean incidence increased 10-fold, from 0.26/100,000 persons during 1984-1998 to 2.47/100,000 persons during 1999 2012 (p<0.001). The incidence of tularemia was higher than expected in the boreal and alpine ecologic regions (p<0.001), and incidence was positively correlated with the presence of lakes and rivers (p<0.001). These results provide a comprehensive epidemiologic description of tularemia in Sweden and illustrate that incidence is higher in locations near lakes and rivers.

  • 13.
    Desvars-Larrive, Amélie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Liu, X.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Hjertqvist, M.
    Sjöstedt, A.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Johansson, A.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    High-risk regions and outbreak modelling of tularemia in humans2017Ingår i: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 145, nr 3, s. 482-490Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Sweden reports large and variable numbers of human tularemia cases, but the high-risk regions are anecdotally defined and factors explaining annual variations are poorly understood. Here, high-risk regions were identified by spatial cluster analysis on disease surveillance data for 1984-2012. Negative binomial regression with five previously validated predictors (including predicted mosquito abundance and predictors based on local weather data) was used to model the annual number of tularemia cases within the high-risk regions. Seven high-risk regions were identified with annual incidences of 3.8-44 cases/100 000 inhabitants, accounting for 56.4% of the tularemia cases but only 9.3% of Sweden's population. For all high-risk regions, most cases occurred between July and September. The regression models explained the annual variation of tularemia cases within most high-risk regions and discriminated between years with and without outbreaks. In conclusion, tularemia in Sweden is concentrated in a few high-risk regions and shows high annual and seasonal variations. We present reproducible methods for identifying tularemia high-risk regions and modelling tularemia cases within these regions. The results may help health authorities to target populations at risk and lay the foundation for developing an early warning system for outbreaks.

  • 14.
    Eneslätt, Kjell
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Golovliov, Igor
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Vaccine-mediated mechanisms controlling replication of Francisella tularensis in human peripheral blood mononuclear cells using a co-culture system2018Ingår i: Frontiers in Cellular and Infection Microbiology, E-ISSN 2235-2988, Vol. 8, artikel-id 27Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cell-mediated immunity (CMI) is normally required for efficient protection against intracellular infections, however, identification of correlates is challenging and they are generally lacking. Francisella tularensis is a highly virulent, facultative intracellular bacterium and CMI is critically required for protection against the pathogen, but how this is effectuated in humans is poorly understood. To understand the protective mechanisms, we established an in vitro co-culture assay to identify how control of infection of F. tularensis is accomplished by human cells and hypothesized that the model will mimic in vivo immune mechanisms. Non-adherent peripheral blood mononuclear cells (PBMCs) were expanded with antigen and added to cultures with adherent PBMC infected with the human vaccine strain, LVS, or the highly virulent SCHU S4 strain. Intracellular numbers of F. tularensis was followed for 72 h and secreted and intracellular cytokines were analyzed. Addition of PBMC expanded from naïve individuals, i.e., those with no record of immunization to F. tularensis, generally resulted in little or no control of intracellular bacterial growth, whereas addition of PBMC from a majority of F. tularensis-immune individuals executed static and sometimes cidal effects on intracellular bacteria. Regardless of infecting strain, statistical differences between the two groups were significant, P < 0.05. Secretion of 11 cytokines was analyzed after 72 h of infection and significant differences with regard to secretion of IFN-γ, TNF, and MIP-1β was observed between immune and naïve individuals for LVS-infected cultures. Also, in LVS-infected cultures, CD4 T cells from vaccinees, but not CD8 T cells, showed significantly higher expression of IFN-γ, MIP-1β, TNF, and CD107a than cells from naïve individuals. The co-culture system appears to identify correlates of immunity that are relevant for the understanding of mechanisms of the protective host immunity to F. tularensis.

  • 15.
    Eneslätt, Kjell
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rietz, Cecilia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    House, Robert V
    Wolfraim, Lawrence A
    Tärnvik, Arne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Persistence of cell-mediated immunity three decades after vaccination with the live vaccine strain of Francisella tularensis2011Ingår i: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 41, nr 4, s. 974-980Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The efficacy of many vaccines against intracellular bacteria depends on the generation of cell-mediated immunity, but studies to determine the duration of immunity are usually confounded by re-exposure. The causative agent of tularemia, Francisella tularensis, is rare in most areas and, therefore, tularemia vaccination is an interesting model for studies of the longevity of vaccine-induced cell-mediated immunity. Here, lymphocyte proliferation and cytokine production in response to F. tularensis were assayed in two groups of 16 individuals, vaccinated 1-3 or 27-34 years previously. As compared to naïve individuals, vaccinees of both groups showed higher proliferative responses and, out of 17 cytokines assayed, higher levels of MIP-1β, IFN-γ, IL-10, and IL-5 in response to recall stimulation. The responses were very similar in the two groups of vaccinees. A statistical model was developed to predict the immune status of the individuals and by use of two parameters, proliferative responses and levels of IFN-γ, 91.1% of the individuals were correctly classified. Using flow cytometry analysis, we demonstrated that during recall stimulation, expression of IFN-γ by CD4(+) CCR7(+) , CD4(+) CD62L(+) , CD8(+) CCR7(+) , and CD8(+) CD62L(+) cells significantly increased in samples from vaccinated donors. In conclusion, cell-mediated immunity was found to persist three decades after tularemia vaccination without evidence of decline.

  • 16.
    Fahlén, Jessica
    et al.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Landfors, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Freyhult, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
    Bylesjö, Max
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hvidsten, Torgeir
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Bioinformatics strategies for cDNA-microarray data processing2009Ingår i: Batch effects and noise in microarray experiments: sources and solutions / [ed] Scherer, Andreas, Wiley and Sons , 2009, 1, , s. 272s. 61-74Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    

    Pre-processing plays a vital role in cDNA-microarray data analysis. Without proper pre-processing it is likely that the biological conclusions will be misleading. However, there are many alternatives and in order to choose a proper pre-processing procedure it is necessary to understand the effect of different methods. This chapter discusses several pre-processing steps, including image analysis, background correction, normalization, and filtering. Spike-in data are used to illustrate how different procedures affect the analytical ability to detect differentially expressed genes and estimate their regulation. The result shows that pre-processing has a major impact on both the experiment’s sensitivity andits bias. However, general recommendations are hard to give, since pre-processing consists of several actions that are highly dependent on each other. Furthermore, it is likely that pre-processing have a major impact on downstream analysis, such as clustering and classification, and pre-processing methods should be developed and evaluated with this in mind.

  • 17.
    Fahlén, Jessica
    et al.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Rentoft, Matilda
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    MicroRNA-microarray data analysis in the precence of FFPE storage time effects2010Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: The standard method for preserving patient samples for diagnostic purposes is fixation in formalin followed by embedding in paraffin (FFPE). The use of FFPE blocks makes it possible to include a large number of patients in the experimental studies since millions of FFPE blocks are stored around the world. However, FFPE storage can cause degradation and modifi­cations of nucleic acids. In order to draw reliable biological conclusions it is therefore important to know what effect FFPE-storage have on the tissues and to have procedures that normalize this effect. In this paper, we study the effect that FFPE-storage has on microRNA-microarray data from tongue-cancer patients and propose a novel procedure for normalizing the bias intro­duced by FFPE-storage.

    Results: MicroRNA-microarray data from 21 tongue-cancer patients and 8 control patients were used. The samples were stored in FFPE blocks and had been in storage for up to 11 years. The data contained a large amount of biological relevant variation, yet the largest variation was due to the samples storage times. The storage effect was shown to be significant and some results suggested that it may be causal. Moreover, the microRNAs were unequally affected by storage and this could partially be explained by sequence characteristics. The novel normaliza­tion procedure was shown to have a large impact in the analysis ability to identify differentially expressed microRNAs between young and old cancer patients as well as between cancer and control patients. The p-values for the top microRNAs candidates were much lower for the pro­posed novel normalization compared to a standard normalization procedure which suggested that the novel normalization made the analysis more efficient.

    Conclusions: MicroRNA-microarray data can be seriously affected by FFPE-storage and the introduced variation cannot be removed by standard normalizations. The proposed normaliza­tion removes the bias introduced by FFPE-storage and gives higher sensitivity than the standard normalization.

  • 18.
    Freyhult, Eva
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Önskog, Jenny
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Hvidsten, Torgeir R.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Challenges in microarray class discovery: a comprehensive examination of normalization, gene selection and clustering2010Ingår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 11, artikel-id 503Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Cluster analysis, and in particular hierarchical clustering, is widely used to extract information from gene expression data. The aim is to discover new classes, or sub-classes, of either individuals or genes. Performing a cluster analysis commonly involve decisions on how to; handle missing values, standardize the data and select genes. In addition, pre processing, involving various types of filtration and normalization procedures, can have an effect on the ability to discover biologically relevant classes. Here we consider cluster analysis in a broad sense and perform a comprehensive evaluation that covers several aspects of cluster analyses, including normalization.

    Result: We evaluated 2780 cluster analysis methods on seven publicly available 2-channel microarray data sets with common reference designs. Each cluster analysis method differed in data normalization (5 normalizations were considered), missing value imputation (2), standardization of data (2), gene selection (19) or clustering method (11). The cluster analyses are evaluated using known classes, such as cancer types, and the adjusted Rand index. The performances of the different analyses vary between the data sets and it is difficult to give general recommendations. However, normalization, gene selection and clustering method are all variables that have a significant impact on the performance. In particular, gene selection is important and it is generally necessary to include a relatively large number of genes in order to get good performance. Selecting genes with high standard deviation or using principal component analysis are shown to be the preferred gene selection methods. Hierarchical clustering using Ward's method, k-means clustering and Mclust are the clustering methods considered in this paper that achieves the highest adjusted Rand. Normalization can have a significant positive impact on the ability to cluster individuals, and there are indications that background correction is preferable, in particular if the gene selection is successful. However, this is an area that needs to be studied further in order to draw any general conclusions.

    Conclusions: The choice of cluster analysis, and in particular gene selection, has a large impact on the ability to cluster individuals correctly based on expression profiles. Normalization has a positive effect, but the relative performance of different normalizations is an area that needs more research. In summary, although clustering, gene selection and normalization are considered standard methods in bioinformatics, our comprehensive analysis shows that selecting the right methods, and the right combinations of methods, is far from trivial and that much is still unexplored in what is considered to be the most basic analysis of genomic data.

  • 19. Griffin, Robert M.
    et al.
    Dean, Rebecca
    Grace, Jaime L.
    Ryden, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Friberg, Urban
    The Shared Genome Is a Pervasive Constraint on the Evolution of Sex-Biased Gene Expression2013Ingår i: Molecular biology and evolution, ISSN 0737-4038, E-ISSN 1537-1719, Vol. 30, nr 9, s. 2168-2176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Males and females share most of their genomes, and differences between the sexes can therefore not evolve through sequence divergence in protein coding genes. Sexual dimorphism is instead restricted to occur through sex-specific expression and splicing of gene products. Evolution of sexual dimorphism through these mechanisms should, however, also be constrained when the sexes share the genetic architecture for regulation of gene expression. Despite these obstacles, sexual dimorphism is prevalent in the animal kingdom and commonly evolves rapidly. Here, we ask whether the genetic architecture of gene expression is plastic and easily molded by sex-specific selection, or if sexual dimorphism evolves rapidly despite pervasive genetic constraint. To address this question, we explore the relationship between the intersexual genetic correlation for gene expression (r(MF)), which captures how independently genes are regulated in the sexes, and the evolution of sex-biased gene expression. Using transcriptome data from Drosophila melanogaster, we find that most genes have a high r(MF) and that genes currently exposed to sexually antagonistic selection have a higher average r(MF) than other genes. We further show that genes with a high r(MF) have less pronounced sex-biased gene expression than genes with a low r(MF) within D. melanogaster and that the strength of the r(MF) in D. melanogaster predicts the degree to which the sex bias of a gene's expression has changed between D. melanogaster and six other species in the Drosophila genus. In sum, our results show that a shared genome constrains both short- and long-term evolution of sexual dimorphism.

  • 20.
    Jonsson, Frida
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Byström, Berit
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Davidson, Alice E.
    UCL Institute of Ophthalmology, London, UK.
    Backman, Ludvig J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Kellgren, Therese
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Tuft, Stephen J.
    UCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK.
    Koskela, Timo
    Koskelas Eye Clinic, Umeå, Sweden.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sandgren, Ola
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Oftalmiatrik.
    Danielson, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Hardcastle, Alison J.
    UCL Institute of Ophthalmology, London, UK.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Mutations in Collagen, Type XVII, Alpha 1 (COL17A1) Cause Epithelial Recurrent Erosion Dystrophy (ERED)2015Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 4, s. 463-473Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.

  • 21. Kheir, Sahar M.
    et al.
    Kafi, Shamsoun K.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Elbir, Haitham
    Soliman, Mohammed A.
    Ali, Shima
    Abulikailik, Ramy
    Ahamed, Khadega
    Abu-Aisha, Hasan
    Results of application of the ISPD guidelines to the management of peritoneal dialysis in a single center in Sudan2017Ingår i: Journal of Infection and Public Health, ISSN 1876-0341, E-ISSN 1876-035X, Vol. 10, nr 3, s. 348-352Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The culture negative peritonitis in Sudan 2010 was 46% exceeding 20% of the recommended ISPD (International Society for Peritoneal Dialysis) guidelines. This study reports an update after applying the standard ISPD protocol. The routine method was replaced by ISPD protocol. The culture negative rate using the ISPD guidelines dropped from 46% in the year 2010, to 39% in the year 2011, to 5% in the 2012 and to zero percent in the year 2013. Bacterial and fungal species represent (86.76%) and (13.23%) of infection and most isolates showed low resistance rate to antibiotics. Touch contamination added significantly (p = 0.0006) to the risk of contracting Peritonitis. The risk of contracting Peritonitis was 1.53 times higher in the group exposed by touch contamination. None of the other risk factors contributed significantly to Peritonitis. The study highlights the importance of implementing high hygiene practice. (C) 2016 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Limited. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

  • 22.
    Källberg, David
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Belyaev, Yuri
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    A moment-distance hybrid method for estimating a mixture of two symmetric densities2018Ingår i: Modern Stochastics: Theory and Applications, ISSN 2351-6054, Vol. 5, nr 1, s. 1-36Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In clustering of high-dimensional data a variable selection is commonly applied to obtain an accurate grouping of the samples. For two-class problems this selection may be carried out by fitting a mixture distribution to each variable. We propose a hybrid method for estimating a parametric mixture of two symmetric densities. The estimator combines the method of moments with the minimum distance approach. An evaluation study including both extensive simulations and gene expression data from acute leukemia patients shows that the hybrid method outperforms a maximum-likelihood estimator in model-based clustering. The hybrid estimator is flexible and performs well also under imprecise model assumptions, suggesting that it is robust and suited for real problems.

  • 23.
    Landfors, Mattias
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Fahlén, Jessica
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Rydén, Patrik
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    MC-normalization: a novel method for dye-normalization of two-channel microarray data2009Ingår i: Statistical Applications in Genetics and Molecular Biology, ISSN 1544-6115, E-ISSN 1544-6115, Vol. 8, nr 1, s. 42-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Motivation: Pre-processing plays a vital role in two-color microarray data analysis. An analysis is characterized by its ability to identify differentially expressed genes (its sensitivity) and its ability to provide unbiased estimators of the true regulation (its bias). It has been shown that microarray experiments regularly underestimate the true regulation of differentially expressed genes. We introduce the MC-normalization, where C stands for channel-wise normalization, with considerably lower bias than the commonly used standard methods.

    Methods: The idea behind the MC-normalization is that the channels’ individual intensities determine the correction, rather than the average intensity which is the case for the widely used MA-normalization. The two methods were evaluated using spike-in data from an in-house produced cDNA-experiment and a public available Agilent-experiment. The methods were applied on background corrected and non-background corrected data. For the cDNA-experiment the methods were either applied separately on data from each of the print-tips or applied on the complete array data. Altogether 24 analyses were evaluated. For each analysis the sensitivity, the bias and two variance measures were estimated.

    Results: We prove that the MC-normalization has lower bias than the MA-normalization. The spike-in data confirmed the theoretical result and suggest that the difference is significant. Furthermore, the empirical data suggest that the MC-and MA-normalization have similar sensitivity. A striking result is that print-tip normalizations did have considerably higher sensitivity than analyses using the complete array data.

  • 24.
    Landfors, Mattias
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Philip, Philge
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Stenberg, Per
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Normalization of high dimensional genomics data where the distribution of the altered variables is skewed2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 11, s. e27942-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome-wide analysis of gene expression or protein binding patterns using different array or sequencing based technologies is now routinely performed to compare different populations, such as treatment and reference groups. It is often necessary to normalize the data obtained to remove technical variation introduced in the course of conducting experimental work, but standard normalization techniques are not capable of eliminating technical bias in cases where the distribution of the truly altered variables is skewed, i.e. when a large fraction of the variables are either positively or negatively affected by the treatment. However, several experiments are likely to generate such skewed distributions, including ChIP-chip experiments for the study of chromatin, gene expression experiments for the study of apoptosis, and SNP-studies of copy number variation in normal and tumour tissues. A preliminary study using spike-in array data established that the capacity of an experiment to identify altered variables and generate unbiased estimates of the fold change decreases as the fraction of altered variables and the skewness increases. We propose the following work-flow for analyzing high-dimensional experiments with regions of altered variables: (1) Pre-process raw data using one of the standard normalization techniques. (2) Investigate if the distribution of the altered variables is skewed. (3) If the distribution is not believed to be skewed, no additional normalization is needed. Otherwise, re-normalize the data using a novel HMM-assisted normalization procedure. (4) Perform downstream analysis. Here, ChIP-chip data and simulated data were used to evaluate the performance of the work-flow. It was found that skewed distributions can be detected by using the novel DSE-test (Detection of Skewed Experiments). Furthermore, applying the HMM-assisted normalization to experiments where the distribution of the truly altered variables is skewed results in considerably higher sensitivity and lower bias than can be attained using standard and invariant normalization methods.

  • 25.
    Larsson, Miriam
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Uvell, Hanna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sandström, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Selth, Luke A.
    Mechanisms of Transcription Laboratory, Clare Hall Laboratories, Cancer Research UK London Research Institute.
    Björklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Functional Studies of the Yeast Med5, Med15 and Med16 Mediator Tail Subunits2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 8, s. e73137-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The yeast Mediator complex can be divided into three modules, designated Head, Middle and Tail. Tail comprises the Med2, Med3, Med5, Med15 and Med16 protein subunits, which are all encoded by genes that are individually non-essential for viability. In cells lacking Med16, Tail is displaced from Head and Middle. However, inactivation of MED5/MED15 and MED15/MED16 are synthetically lethal, indicating that Tail performs essential functions as a separate complex even when it is not bound to Middle and Head. We have used the N-Degron method to create temperature-sensitive (ts) mutants in the Mediator tail subunits Med5, Med15 and Med16 to study the immediate effects on global gene expression when each subunit is individually inactivated, and when Med5/15 or Med15/16 are inactivated together. We identify 25 genes in each double mutant that show a significant change in expression when compared to the corresponding single mutants and to the wild type strain. Importantly, 13 of the 25 identified genes are common for both double mutants. We also find that all strains in which MED15 is inactivated show down-regulation of genes that have been identified as targets for the Ace2 transcriptional activator protein, which is important for progression through the G1 phase of the cell cycle. Supporting this observation, we demonstrate that loss of Med15 leads to a G1 arrest phenotype. Collectively, these findings provide insight into the function of the Mediator Tail module.

  • 26.
    Monsen, Tor
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi. Umeå university hospital.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    A new concept and a comprehensive evaluation of SYSMEX UF-1000i flow cytometer to identify culture-negative urine specimens in patients with UTI2017Ingår i: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 36, nr 9, s. 1691-1703Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Urinary tract infections (UTIs) are among the most common bacterial infections in men and urine culture is gold standard for diagnosis. Considering the high prevalence of culture-negative specimens, any method that identifies such specimens is of interest. The aim was to evaluate a new screening concept for flow cytometry analysis (FCA). The outcomes were evaluated against urine culture, uropathogen species and three conventional screening methods. A prospective, consecutive study examined 1,312 urine specimens, collected during January and February 2012. The specimens were analyzed using the Sysmex UF1000i FCA. Based on the FCA data culture negative specimens were identified in a new model by use of linear discriminant analysis (FCA-LDA). In total 1,312 patients were included. In- and outpatients represented 19.6% and 79.4%, respectively; 68.3% of the specimens originated from women. Of the 610 culture-positive specimens, Escherichia coli represented 64%, enterococci 8% and Klebsiella spp. 7%. Screening with FCA-LDA at 95% sensitivity identified 42% (552/1312) as culture negative specimens when UTI was defined according to European guidelines. The proposed screening method was either superior or similar in comparison to the three conventional screening methods. In conclusion, the proposed/suggested and new FCA-LDA screening method was superior or similar to three conventional screening methods. We recommend the proposed screening method to be used in clinic to exclude culture negative specimens, to reduce workload, costs and the turnaround time. In addition, the FCA data may add information that enhance handling and support diagnosis of patients with suspected UTI pending urine culture.

  • 27.
    Monsen, Tor
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Flow Cytometry Analysis Using Sysmex UF-1000i Classifies Uropathogens Based on Bacterial, Leukocyte, and Erythrocyte Counts in Urine Specimens among Patients with Urinary Tract Infections2015Ingår i: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 53, nr 2, s. 539-545Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Urinary tract infections (UTIs) are the second most common bacterial infection. Urine culture is the gold standard for diagnosis, but new techniques, such as flow cytometry analysis (FCA), have been introduced. The aim of the present study was to evaluate FCA characteristics regarding bacteriuria, leukocyturia, and erythrocyturia in relation to cultured uropathogens in specimens from patients with a suspected UTI. We also wanted to evaluate whether the FCA characteristics can identify uropathogens prior to culture. From a prospective study, 1,587 consecutive urine specimens underwent FCA prior to culture during January and February 2012. Outpatients and inpatients (79.6% and 19.4%, respectively) were included, of whom women represented 67.5%. In total, 620 specimens yielded growth, of which Escherichia coli represented 65%, Enterococcus spp.8%, Klebsiella spp. 7%, and Staphylococcus spp. 5%. For the uropathogens, the outcome of FCA was compared against the results for specimens with E. coli and those with a negative culture. E. coli had high bacterial (median, 17,914/mu l), leukocyte (median, 348/mu l), and erythrocyte (median, 23/mu l) counts. With the exception of Klebsiella spp., the majority of the uropathogens had considerable or significantly lower bacterial counts than that of E. coli. High leukocyte counts were found in specimens with Staphylococcus aureus, Proteus mirabilis, Pseudomonas aeruginosa, and group C streptococci. Elevated erythrocyte counts were found for P. vulgaris, P. aeruginosa, and group C streptococci, as well as for Staphylococcus saprophyticus. In essence, FCA adds new information about the bacterial, leukocyte, and erythrocyte counts in urine specimens for different uropathogens. Based on FCA characteristics, uropathogens can be classified and identified prior to culture. E. coli and Klebsiella spp. have similar FCA characteristics.

  • 28.
    Rentoft, Matilda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Fahlén, Jessica
    Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Coates, PJ
    Laurell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Sjöström, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    miRNA analysis of formalin-fixed squamous cell carcinomas of the tongue is affected by age of the samples2011Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 38, nr 1, s. 61-69Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Global miRNA expression arrays were used for analysis of 836 miRNAs in formalin-fixed paraffin-embedded samples from 21 tongue cancer patients and 8 controls. Samples had been stored for one to eleven years. Results separated tumour samples from controls, however, the largest variation was correlated to sample storage time, detectable already after one year. With the use of a linear regression model we could adjust for the storage-dependent effect, leading to the identification of 54 differentially expressed miRNAs in tongue cancer, compared to 16 when using standard normalization, including up-regulation of a novel miRNA, miR-424.

  • 29.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Matematisk statistik.
    Estimation of the reliability of systems described by the Daniels Load-Sharing Model1999Licentiatavhandling, monografi (Övrigt vetenskapligt)
    Abstract [en]

    We consider the problem of estimating the failure stresses of bundles (i.e. the tensile forces that destroy the bundles), constructed of several statisti-cally similar fibres, given a particular kind of censored data. Each bundle consists of several fibres which have their own independent identically dis-tributed failure stresses, and where the force applied on a bundle at any moment is distributed equally between the unbroken fibres in the bundle. A bundle with these properties is an example of an equal load-sharing sys-tem, often referred to as the Daniels failure model. The testing of several bundles generates a special kind of censored data, which is complexly struc-tured. Strongly consistent non-parametric estimators of the distribution laws of bundles are obtained by applying the theory of martingales, and by using the observed data. It is proved that random sampling, with replace-ment from the statistical data related to each tested bundle, can be used to obtain asymptotically correct estimators for the distribution functions of deviations of non-parametric estimators from true values. In the case when the failure stresses of the fibres are described by a Weibull distribution, we obtain strongly consistent parametric maximum likelihood estimators of the distribution functions of failure stresses of bundles, by using the complexly structured data. Numerical examples illustrate the behavior of the obtained estimators.

  • 30.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Matematisk statistik.
    Statistical analysis and simulation methods related to load-sharing models.2000Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    We consider the problem of estimating the reliability of bundles constructed of several fibres, given a particular kind of censored data. The bundles consist of several fibres which have their own independent identically dis-tributed failure stresses (i.e.the forces that destroy the fibres). The force applied to a bundle is distributed between the fibres in the bundle, accord-ing to a load-sharing model. A bundle with these properties is an example of a load-sharing system. Ropes constructed of twisted threads, compos-ite materials constructed of parallel carbon fibres, and suspension cables constructed of steel wires are all examples of load-sharing systems. In par-ticular, we consider bundles where load-sharing is described by either the Equal load-sharing model or the more general Local load-sharing model.

    In order to estimate the cumulative distribution function of failure stresses of bundles, we need some observed data. This data is obtained either by testing bundles or by testing individual fibres. In this thesis, we develop several theoretical testing methods for both fibres and bundles, and related methods of statistical inference.

    Non-parametric and parametric estimators of the cumulative distribu-tion functions of failure stresses of fibres and bundles are obtained from different kinds of observed data. It is proved that most of these estimators are consistent, and that some are strongly consistent estimators. We show that resampling, in this case random sampling with replacement from sta-tistically independent portions of data, can be used to assess the accuracy of these estimators. Several numerical examples illustrate the behavior of the obtained estimators. These examples suggest that the obtained estimators usually perform well when the number of observations is moderate.

  • 31.
    Rydén, Patrik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Björk, Rafael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Schäfer, Martina L
    Lundström, Jan O
    Petersén, Bodil
    Lindblom, Anders
    Forsman, Mats
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Outbreaks of tularemia in a boreal forest region depends on mosquito prevalence2012Ingår i: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 205, nr 2, s. 297-304Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. We aimed to evaluate the potential association of mosquito prevalence in a boreal forest area with transmission of the bacterial disease tularemia to humans, and model the annual variation of disease using local weather data.

    Methods. A prediction model for mosquito abundance was built using weather and mosquito catch data. Then a negative binomial regression model based on the predicted mosquito abundance and local weather data was built to predict annual numbers of humans contracting tularemia in Dalarna County, Sweden.

    Results. Three hundred seventy humans were diagnosed with tularemia between 1981 and 2007, 94% of them during 7 summer outbreaks. Disease transmission was concentrated along rivers in the area. The predicted mosquito abundance was correlated (0.41, P < .05) with the annual number of human cases. The predicted mosquito peaks consistently preceded the median onset time of human tularemia (temporal correlation, 0.76; P < .05). Our final predictive model included 5 environmental variables and identified 6 of the 7 outbreaks.

    Conclusions. This work suggests that a high prevalence of mosquitoes in late summer is a prerequisite for outbreaks of tularemia in a tularemia-endemic boreal forest area of Sweden and that environmental variables can be used as risk indicators.

  • 32.
    Rydén, Patrik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Effects of climate change on tularemia disease activity in Sweden2009Ingår i: Global Health Action, ISSN 1654-9880, Vol. 2Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tularaemia is a vector-borne infectious disease. A large majority of cases transmitted to humans by bloodfeeding arthropods occur during the summer season and is linked to increased temperatures. Therefore, the effect of climate change is likely to have an effect on tularaemia transmission patterns in highly endemic areas of Sweden. In this report, we use simulated climate change scenario data and empirical data of temperatures critical to tularaemia transmission to forecast tularaemia outbreak activity. The five high-endemic counties: Dalarna, Gävleborg, Norrbotten, Värmland and Örebro represent only 14.6% of the total population of Sweden, but have recorded 40.1-81.1% of the number of annual human tularaemia in Sweden from 1997 until 2008. We project here earlier starts and a later termination of future tularaemia outbreaks for the time period 2010-2100. For five localised outbreak areas; Gagnef (Dalarna), Ljusdal (Gävleborg), Harads (Norrbotten), Karlstad (Värmland) and Örebro municipality (Örebro), the climate scenario suggests an approximately 2°C increase in monthly average summer temperatures leading to increases in outbreak durations ranging from 3.5 weeks (Harads) to 6.6 weeks (Karlstad) between 2010 and 2100. In contrast, an analysis of precipitation scenarios indicates fairly stable projected levels of precipitation during the summer months. Thus, there should not be an increased abundance of late summer mosquitoes that are believed to be main vectors for transmission to humans in these areas. In conclusion, the results indicate that the future climate changes will lead to an increased burden of tularaemia in high-endemic areas of Sweden during the coming decades.

  • 33.
    Rydén, Patrik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Twine, Susan
    Shen, Hua
    Harris, Gregory
    Chen, Wangxue
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Conlan, Wayne
    Correlates of protection following vaccination of mice with gene deletion mutants of Francisella tularensis subspecies tularensis strain, SCHU S4 that elicit varying degrees of immunity to systemic and respiratory challenge with wild-type bacteria2013Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 54, nr 1, s. 58-67Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Francisella tularensis subspecies tularensis is an extremely virulent facultative intracellular bacterial pathogen capable of causing significant mortality in humans when inhaled. Consequently, subspecies tularensis was developed as a biological weapon more than 50 years ago. To counter this threat the US Army empirically developed a live vaccine strain, F. tularensis LVS, from the less virulent holarctica subspecies. In human experiments LVS afforded substantial protection against transdermal challenge with clinical subspecies tularensis strain, SCHU S4, but lesser protection against infection initiated by inhalation of the pathogen. Several regulatory and clinical issues remain unresolved for this vaccine, including the absence of a robust correlate of protection. To try to address this, we have developed several defined gene deletion mutants of SCHU S4 that elicit varying degrees of protection in a mouse dermal or respiratory challenge model. In the present study, we have examined whether host immune responses to immunization with such live vaccine candidates can serve as correlates of protection. Antibody responses were unable to distinguish between effective and ineffective vaccine strains. However, several cytokine responses to vaccination showed some promise. Especially, serum levels of TNFα, IFNγ, and MCP-1 between days 4 and 7 after vaccination appear to correlate with protection against respiratory challenge.

  • 34.
    Schelin, Lina
    et al.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Fysioterapi.
    Tengman, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Fysioterapi.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Häger, Charlotte
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Fysioterapi.
    A statistically compiled test battery for feasible evaluation of knee function after rupture of the Anterior Cruciate Ligament - derived from long-term follow-up data.2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 5, artikel-id e0176247Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: Clinical test batteries for evaluation of knee function after injury to the Anterior Cruciate Ligament (ACL) should be valid and feasible, while reliably capturing the outcome of rehabilitation. There is currently a lack of consensus as to which of the many available assessment tools for knee function that should be included. The present aim was to use a statistical approach to investigate the contribution of frequently used tests to avoid redundancy, and filter them down to a proposed comprehensive and yet feasible test battery for long-term evaluation after ACL injury.

    METHODS: In total 48 outcome variables related to knee function, all potentially relevant for a long-term follow-up, were included from a cross-sectional study where 70 ACL-injured (17-28 years post injury) individuals were compared to 33 controls. Cluster analysis and logistic regression were used to group variables and identify an optimal test battery, from which a summarized estimator of knee function representing various functional aspects was derived.

    RESULTS: As expected, several variables were strongly correlated, and the variables also fell into logical clusters with higher within-correlation (max ρ = 0.61) than between clusters (max ρ = 0.19). An extracted test battery with just four variables assessing one-leg balance, isokinetic knee extension strength and hop performance (one-leg hop, side hop) were mathematically combined to an estimator of knee function, which acceptably classified ACL-injured individuals and controls. This estimator, derived from objective measures, correlated significantly with self-reported function, e.g. Lysholm score (ρ = 0.66; p<0.001).

    CONCLUSIONS: The proposed test battery, based on a solid statistical approach, includes assessments which are all clinically feasible, while also covering complementary aspects of knee function. Similar test batteries could be determined for earlier phases of ACL rehabilitation or to enable longitudinal monitoring. Such developments, established on a well-grounded consensus of measurements, would facilitate comparisons of studies and enable evidence-based rehabilitation.

  • 35. Shen, Hua
    et al.
    Harris, Gregory
    Chen, Wangxue
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Conlan, Wayne
    NRC, CKanada.
    Molecular immune responses to aerosol challenge with Francisella tularensis in mice inoculated with live vaccine candidates of varying efficacy2010Ingår i: PloS one, ISSN 1932-6203, Vol. 5, nr 10, s. e13349-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This is the first report characterizing local and systemic cytokine and chemokine responses in mice immunized with vaccines with different efficacies against aerosol challenge with virulent F. tularensis subsp. tularensis. It shows that increases in the levels of most of these immunomodulators, including those known to be critical for protective immunity, do not superficially correlate with protection unless adjusted for the effects of bacterial burden. Additionally, several cytokines were selectively suppressed in the lungs of naïve mice, suggesting that one mechanism of vaccine action is to overcome this pathogen-induced immunosuppression.

  • 36.
    Simonyté Sjödin, Kotryna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hammarström, Marie-Louise
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Sjödin, A.
    Hernell, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Engstrand, L.
    West, Christina E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Temporal and long-term gut microbiota variation in allergic disease: a prospective study from infancy to school age2019Ingår i: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 74, nr 1, s. 176-185Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Compositional changes in the early‐life gut microbiota have been implicated in IgE‐associated allergic diseases, but there is lack of longitudinal studies. We examined gut microbiota development from infancy to school age in relation to onset of IgE‐associated allergic diseases. At 8 years of age, we also examined the relationship between gut microbiota and T‐cell regulation, estimated as responses to polyclonal T‐cell activation.

    Methods: Stool samples were collected from 93 children at 4, 6, 13 months, and 8 years of age. The gut microbiota was profiled using 16S rRNA gene sequencing. Peripheral blood was drawn from all children, and mononuclear cells were polyclonally activated. Levels of IL‐10 and FOXP3 mRNA copies were determined using real‐time quantitative reverse transcriptase‐PCR.

    Results: At 8 years of age, 21 children were diagnosed with IgE‐associated allergic disease and 90% displayed allergic comorbidity. Seventy‐two children were nonallergic and nonsensitized. Statistical tests with multiple testing corrections demonstrated temporal underrepresentation of Ruminococcus and consistent underrepresentation of Bacteroides, Prevotella, and Coprococcus in allergic compared to nonallergic children from infancy to school age. The gut microbiota of the allergic 8‐year‐olds was enriched in Bifidobacteriumand depleted of Lactobacillus, Enterococcus, and Lachnospira. In allergic 8‐year-olds, Faecalibacterium correlated with IL‐10 mRNA levels (rs = 0.49, Padj = 0.02) with the same trend for FOXP3 (rs = 0.39, Padj = 0.08).

    Conclusions: We identified both temporal and long‐term variation in the differential abundance of specific bacterial genera in children developing IgE‐associated allergic disease. Improved dietary interventions aiming at expanding immune‐modulatory taxa could be studied for prevention of allergic disease.

  • 37.
    Sjödin, Kotryna Simonyte
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    West, Christina E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Emerging evidence of the role of gut microbiota in the development of allergic diseases2016Ingår i: Current Opinion in Allergy and Clinical Immunology, ISSN 1528-4050, E-ISSN 1473-6322, Vol. 16, nr 4, s. 390-395Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Purpose of review The purpose is to review recent studies examining the role of gut microbiota in allergic diseases and asthma.

    Recent findings Work in experimental models gives further evidence that a disturbed gut microbiota influences the propensity to develop allergic manifestations, and that changing the gut microbiota by dietary means (high fiber/acetate or prebiotics) in pregnancy may reduce the risk of allergic airways disease and food allergy in the offspring, respectively. The gut microbiome in established allergic disease and prior to disease onset has also been assessed in clinical trials. One study demonstrated a strong association between high abundance of Faecalibacterium prausnitzii and decreased levels of butyrate and propionate, and established eczema. Lower relative abundance of Ruminococcaceae appears to be implicated in food sensitization and to precede the development of atopic eczema. Decreased relative abundance of Lachnospira, Veillonella, Faecalibacterium, and Rothia in early infancy was reported to be associated with increased asthma risk. Inoculation of germ-free mice with these genera decreased airway inflammation in their offspring thereby proposing a causal role of bacteria in preventing allergic airways disease.

    Summary Gut microbiome research is an actively developing field. Although candidate bacterial taxa have been reported it still remains unclear which bacteria (or other microbes), in which numbers and combinations, and when during the gut colonization process may prevent allergic diseases and asthma. There is still a call for standardized approaches that will enable direct comparison of different studies.

  • 38. Srivastava, Vaibhav
    et al.
    Obudulu, Ogonna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational life science cluster (CLiC), Umeå University and Swedish University of Agricultural Sciences.
    Bygdell, Joakim
    Löfstedt, Tommy
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational life science cluster (CLiC), Umeå University.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational life science cluster (CLiC), Umeå University.
    Nilsson, Robert
    Ahnlund, Maria
    Johansson, Annika
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational life science cluster (CLiC), Umeå University.
    Freyhult, Eva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi. Computational life science cluster (CLiC), Umeå University.
    Qvarnström, Johanna
    Karlsson, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Melzer, Michael
    Moritz, Thomas
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational life science cluster (CLiC), Umeå University.
    Hvidsten, Torgeir R
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Computational life science cluster (CLiC), Umeå University and Department of Chemistry, Biotechnology; Food Science, Norwegian, University of Life Sciences, Ås Norwegian, Norway.
    Wingsle, Gunnar
    OnPLS integration of transcriptomic, proteomic and metabolomic data shows multi-level oxidative stress responses in the cambium of transgenic hipI- superoxide dismutase Populus plants2013Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, artikel-id 893Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Reactive oxygen species (ROS) are involved in the regulation of diverse physiological processes in plants, including various biotic and abiotic stress responses. Thus, oxidative stress tolerance mechanisms in plants are complex, and diverse responses at multiple levels need to be characterized in order to understand them. Here we present system responses to oxidative stress in Populus by integrating data from analyses of the cambial region of wild-type controls and plants expressing high-isoelectric-point superoxide dismutase (hipI-SOD) transcripts in antisense orientation showing a higher production of superoxide. The cambium, a thin cell layer, generates cells that differentiate to form either phloem or xylem and is hypothesized to be a major reason for phenotypic perturbations in the transgenic plants. Data from multiple platforms including transcriptomics (microarray analysis), proteomics (UPLC/QTOF-MS), and metabolomics (GC-TOF/MS, UPLC/MS, and UHPLC-LTQ/MS) were integrated using the most recent development of orthogonal projections to latent structures called OnPLS. OnPLS is a symmetrical multi-block method that does not depend on the order of analysis when more than two blocks are analysed. Significantly affected genes, proteins and metabolites were then visualized in painted pathway diagrams.

    RESULTS: The main categories that appear to be significantly influenced in the transgenic plants were pathways related to redox regulation, carbon metabolism and protein degradation, e.g. the glycolysis and pentose phosphate pathways (PPP). The results provide system-level information on ROS metabolism and responses to oxidative stress, and indicate that some initial responses to oxidative stress may share common pathways.

    CONCLUSION: The proposed data evaluation strategy shows an efficient way of compiling complex, multi-platform datasets to obtain significant biological information.

  • 39.
    Stattin, Eva-Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Henning, Petra
    Klar, Joakim
    McDermott, Emma
    Stecksen-Blicks, Christina
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Sandström, Per-Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Kellgren, Therese G
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Lönnerholm, Torsten
    Ameur, Adam
    Helfrich, Miep H
    Coxon, Fraser P
    Dahl, Niklas
    Wikström, Johan
    Lerner, Ulf H
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Centre for Bone and Arthritis Research, Department of internal medicine and clinical nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 3012Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.

  • 40.
    Stenberg, Per
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Lundberg, Lina E.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Johansson, Anna-Mia
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Svensson, Malin J.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Larsson, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
    Buffering of segmental and chromosomal aneuploidies in Drosophila melanogaster2009Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 5, nr 5Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chromosomal instability, which involves the deletion and duplication of chromosomes or chromosome parts, is a common feature of cancers, and deficiency screens are commonly used to detect genes involved in various biological pathways. However, despite their importance, the effects of deficiencies, duplications, and chromosome losses on the regulation of whole chromosomes and large chromosome domains are largely unknown. Therefore, to explore these effects, we examined expression patterns of genes in several Drosophila deficiency hemizygotes and a duplication hemizygote using microarrays. The results indicate that genes expressed in deficiency hemizygotes are significantly buffered, and that the buffering effect is general rather than being mainly mediated by feedback regulation of individual genes. In addition, differentially expressed genes in haploid condition appear to be generally more strongly buffered than ubiquitously expressed genes in haploid condition, but, among genes present in triploid condition, ubiquitously expressed genes are generally more strongly buffered than differentially expressed genes. Furthermore, we show that the 4th chromosome is compensated in response to dose differences. Our results suggest general mechanisms have evolved that stimulate or repress gene expression of aneuploid regions as appropriate, and on the 4th chromosome of Drosophila this compensation is mediated by Painting of Fourth (POF).

  • 41. Sundqvist, Martin
    et al.
    Granholm, Susanne
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Naseer, Umaer
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Brolund, Alma
    Sundsfjord, Arnfinn
    Kahlmeter, Gunnar
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Within-population distribution of trimethoprim resistance in Escherichia coli before and after a community-wide intervention on trimethoprim use2014Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, nr 12, s. 7492-7500Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A 2-year prospective intervention on the prescription of trimethoprim reduced the use by 85% in a health care region with 178,000 inhabitants. Here, we performed before-and-after analyses of the within-population distribution of trimethoprim resistance in Escherichia coli. Phylogenetic and population genetic methods were applied to multilocus sequence typing data of 548 consecutively collected E. coli isolates from clinical urinary specimens. Results were analyzed in relation to antibiotic susceptibility and the presence and genomic location of different trimethoprim resistance gene classes. A total of 163 E. coli sequence types (STs) were identified, of which 68 were previously undescribed. The isolates fell into one of three distinct genetic clusters designated BAPS 1 (E. coli phylogroup B2), BAPS 2 (phylogroup A and B1), and BAPS 3 (phylogroup D), each with a similar frequency before and after the intervention. BAPS 2 and BAPS 3 were positively and BAPS 1 was negatively associated with trimethoprim resistance (odds ratios of 1.97, 3.17, and 0.26, respectively). In before-and-after analyses, trimethoprim resistance frequency increased in BAPS 1 and decreased in BAPS 2. Resistance to antibiotics other than trimethoprim increased in BAPS 2. Analysis of the genomic location of different trimethoprim resistance genes in isolates of ST69, ST58, and ST73 identified multiple independent acquisition events in isolates of the same ST. The results show that despite a stable overall resistance frequency in E. coli before and after the intervention, marked within-population changes occurred. A decrease of resistance in one major genetic cluster was masked by a reciprocal increase in another major cluster.

  • 42.
    Svensson, Per
    et al.
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Williams, Cecilia
    Lundeberg, Joakim
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Bergqvist, Ingela
    Edlund, Helena
    Umeå universitet, Medicinska fakulteten, Umeå centrum för molekylär medicin (UCMM).
    Gene array identification of Ipf1/Pdx1 -/- regulated genes in pancreatic progenitor cells.2007Ingår i: BMC Developmental Biology, ISSN 1471-213X, E-ISSN 1471-213X, Vol. 7, nr 1, s. 129-Artikel i tidskrift (Refereegranskat)
  • 43.
    Thysell, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Iglesias-Gato, Diego
    Flores-Morales, Amilcar
    Stattin, Pär
    Egevad, Lars
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor2019Ingår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 13, nr 8, s. 1763-1777Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bone metastasis is the lethal end-stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome-wide expression profiles of bone metastases from untreated patients (n = 12) and patients treated with androgen-deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors (n = 52) and in transurethral resected prostate (TUR-P) tissue of a separate cohort (n = 59). Three molecular subtypes of bone metastases (MetA-C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor-regulated genes, including prostate-specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma-epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR-P samples was able to differentiate MetA-like (high PSA, low Ki67) from MetB-like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.

  • 44.
    Tiensuu, Teresa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Andersson, Christopher
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Johansson, Jörgen
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Cycles of light and dark co-ordinate reversible colony differentiation in Listeria monocytogenes2013Ingår i: Molecular Microbiology, ISSN 0950-382X, E-ISSN 1365-2958, Vol. 87, nr 4, s. 909-924Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recently, several light receptors have been identified in non-phototrophic bacteria, but their physiological roles still remain rather elusive. Here we show that colonies of the saprophytic bacterium Listeria monocytogenes undergo synchronized multicellular behaviour on agar plates, in response to oscillating light/dark conditions, giving rise to alternating ring formation (opaque and translucent rings). On agar plates, bacteria from opaque rings survive increased levels of reactive oxygen species (ROS), as well as repeated cycles of light and dark, better than bacteria from translucent rings. The ring formation is strictly dependent on a blue-light receptor, Lmo0799, acting through the stress-sigma factor, sigma B. A transposon screening identified 48 mutants unable to form rings at alternating light conditions, with several of them showing a decreased sigma B activity/level. However, some of the tested mutants displayed a varied sigma B activity depending on which of the two stress conditions tested (light or H2O2 exposure). Intriguingly, the transcriptional regulator PrfA and the virulence factor ActA were shown to be required for ring formation by a mechanism involving activation of sigma B. All in all, this suggests a distinct pathway for Lmo0799 that converge into a common signalling pathway for sigma B activation. Our results show that night and day cycles co-ordinate a reversible differentiation of a L.monocytogenes colony at room temperature, by a process synchronized by a blue-light receptor and sigma B.

  • 45. Twine, Susan
    et al.
    Shen, Hua
    Harris, Gregory
    Chen, Wangxue
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Conlan, Wayne
    BALB/c mice, but not C57BL/6 mice immunized with a Delta clpB mutant of Francisella tularensis subspecies tularensis are protected against respiratory challenge with wild-type bacteria: Association of protection with post-vaccination and post-challenge immune responses2012Ingår i: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 30, nr 24, s. 3634-3645Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Francisella tularensis subspecies tularensis is highly virulent for humans especially when it is inhaled. Therefore, it has the potential to be used as a biothreat agent. Vaccines against F. tularensis will need to be approved in accordance with the FDA Animal Rule. This will require identification of robust correlates of protection in experimental animals and the demonstration that similar immune responses are generated in vaccinated humans. Towards this goal, we have developed an experimental live vaccine strain by deleting the gene, clpB, encoding a heat shock protein from virulent subsp. tularensis strain, SCHU S4. SCHU S4 Delta clpB administered intradermally protects BALB/c, but not C57BL/6 mice from subsequent respiratory challenge with wildtype SCHU S4. A comparison of post-vaccination and post-challenge immune responses in these two mouse strains shows an association between several antibody and cytokine responses and protection. In particular, elevated IFN gamma levels in the skin 2 days after vaccination, sero-conversion to hypothetical membrane protein ETT_778c, and to 30S ribosomal protein Si (FTT_0183c) of F. tularensis after 30 days of vaccination, and elevated levels of pulmonary IL-17 on day 7 after respiratory challenge with SCHU S4 were all associated with protection. (C) 2012 Wayne Conlan. Published by Elsevier Ltd. All rights reserved.

  • 46.
    Vonkavaara, Malin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Telepnev, Maxim V
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Samhällsvetenskapliga fakulteten, Statistiska institutionen. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Sjöstedt, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Stöven, Svenja
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk bakteriologi.
    Drosophila melanogaster as a model for elucidating the pathogenicity of Francisella tularensis2008Ingår i: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 10, nr 6, s. 1327-1338Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Drosophila melanogaster is a widely used model organism for research on innate immunity and serves as an experimental model for infectious diseases. The aetiological agent of the zoonotic disease tularaemia, Francisella tularensis, can be transmitted by ticks and mosquitoes and Drosophila might be a useful, genetically amenable model host to elucidate the interactions between the bacterium and its arthropod vectors. We found that the live vaccine strain of F. tularensis was phagocytosed by Drosophila and multiplied in fly haemocytes in vitro and in vivo. Bacteria injected into flies resided both inside haemocytes and extracellularly in the open circulatory system. A continuous activation of the humoral immune response, i.e. production of antimicrobial peptides under control of the imd/Relish signalling pathway, was observed and it may have contributed to the relative resistance to F. tularensis as flies defective in the imd/Relish pathway died rapidly. Importantly, bacterial strains deficient for genes of the F. tularensis intracellular growth locus or the macrophage growth locus were attenuated in D. melanogaster. Our results demonstrate that D. melanogaster is a suitable model for the analysis of interactions between F. tularensis and its arthropod hosts and that it can also be used to identify F. tularensis virulence factors relevant for mammalian hosts.

  • 47.
    West, Christina E.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Lundin, D.
    Engstrand, L.
    Tulic, M. K.
    Prescott, S. L.
    Gut microbiome and innate immune response patterns in IgE-associated eczema2015Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 45, nr 9, s. 1419-1429Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BackgroundGut microbiome patterns have been associated with predisposition to eczema potentially through modulation of innate immune signalling. ObjectiveWe examined gut microbiome development in the first year of life in relation to innate immune responses and onset of IgE-associated eczema over the first 2.5years in predisposed children due to maternal atopy [, trial ID ACTRN12606000280505]. MethodsMicrobial composition and diversity were analysed with barcoded 16S rRNA 454 pyrosequencing in stool samples in pregnancy and at ages 1week, 1month and 12months in infants (n=10) who developed IgE-associated eczema and infants who remained free of any allergic symptoms at 2.5years of age (n=10). Microbiome data at 1week and 1month were analysed in relation to previously assessed immune responses to TLR 2 and 4 ligands at 6months of age. ResultsThe relative abundance of Gram-positive Ruminococcaceae was lower at 1week of age in infants developing IgE-associated eczema, compared with controls (P=0.0047). At that age, the relative abundance of Ruminococcus was inversely associated with TLR2 induced IL-6 (-0.567, P=0.042) and TNF- (-0.597, P=0.032); there was also an inverse association between the abundance of Proteobacteria (comprising Gram-negative taxa) and TLR4-induced TNF- (rs=-0.629, P=0.024). This relationship persisted at 1month, with inverse associations between the relative abundance of Enterobacteriaceae (within the Proteobacteria phylum) and TLR4-induced TNF- (rs=-0.697, P=0.038) and Enterobacteriaceae and IL-6 (rs=-0.709, P=0.035). Mothers whose infants developed IgE-associated eczema had lower -diversity of Bacteroidetes (P=0.04) although this was not seen later in their infants. At 1year, -diversity of Actinobacteria was lower in infants with IgE-associated eczema compared with controls (P=0.002). Conclusion and clinical relevanceOur findings suggest that reduced relative abundance of potentially immunomodulatory gut bacteria is associated with exaggerated inflammatory cytokine responses to TLR-ligands and subsequent development of IgE-associated eczema.

  • 48.
    Wibom, Carl
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ghasimi, Soma
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Van Loo, P.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergenheim, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    EGFR gene variants are associated with specific somatic aberrations in glioma2012Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, nr Suppl. 3, s. 46-46Artikel i tidskrift (Övrigt vetenskapligt)
  • 49.
    Wibom, Carl
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ghasimi, Soma
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Van Loo, Peter
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lau, Ching
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergenheim, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    EGFR gene variants are associated with specific somatic aberrations in glioma2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 12, s. e47929-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A number of gene variants have been associated with an increased risk of developing glioma. We hypothesized that the reported risk variants may be associated with tumor genomic instability. To explore potential correlations between germline risk variants and somatic genetic events, we analyzed matched tumor and blood samples from 95 glioma patients by means of SNP genotyping. The generated genotype data was used to calculate genome-wide allele-specific copy number profiles of the tumor samples. We compared the copy number profiles across samples and found two EGFR gene variants (rs17172430 and rs11979158) that were associated with homozygous deletion at the CDKN2A/B locus. One of the EGFR variants (rs17172430) was also associated with loss of heterozygosity at the EGFR locus. Our findings were confirmed in a separate dataset consisting of matched blood and tumor samples from 300 glioblastoma patients, compiled from publically available TCGA data. These results imply there is a functional effect of germline EGFR variants on tumor progression.

  • 50.
    Wibom, Carl
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Sjöström, Sara
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Broholm, Helle
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Johansen, Christoffer
    Collatz-Laier, Helle
    Hepworth, Sara
    McKinney, Patricia A
    Bethke, Lara
    Houlston, Richard S
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice S
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    DNA-repair gene variants are associated with glioblastoma survival2012Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, nr 3, s. 325-332Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patient outcome from glioma may be influenced by germline variation. Considering the importance of DNA repair in cancer biology as well as in response to treatment, we studied the relationship between 1458 SNPs, which captured the majority of the common genetic variation in 136 DNA repair genes, in 138 glioblastoma samples from Sweden and Denmark. We confirmed our findings in an independent cohort of 121 glioblastoma patients from the UK. Our analysis revealed nine SNPs annotating MSH2, RAD51L1 and RECQL4 that were significantly (p < 0.05) associated with glioblastoma survival.

12 1 - 50 av 52
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