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  • 251.
    Hugosson, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sjögren, Camilla
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hedlund, Ludmilla
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Eriksson, Therese
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Palmer, Ruth H.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The Drosophila Midkine/Pleiotrophin Homologues Miple1 and Miple2 Affect Adult Lifespan but Are Dispensable for Alk Signaling during Embryonic Gut Formation2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112250-Article in journal (Refereed)
    Abstract [en]

    Midkine (MDK) and Pleiotrophin (PTN) are small heparin-binding cytokines with closely related structures. The Drosophila genome harbours two genes encoding members of the MDK/PTN family of proteins, known as miple1 and miple2. We have investigated the role of Miple proteins in vivo, in particular with regard to their proposed role as ligands for the Alk receptor tyrosine kinase (RTK). Here we show that Miple proteins are neither required to drive Alk signaling during Drosophila embryogenesis, nor are they essential for development in the fruit fly. Additionally we show that neither MDK nor PTN can activate hALK in vivo when ectopically co-expressed in the fly. In conclusion, our data suggest that Alk is not activated by MDK/PTN related growth factors Miple1 and Miple 2 in vivo.

  • 252. Hussain-Alkhateeb, Laith
    et al.
    Kroeger, Axel
    Olliaro, Piero
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Institute of Public Health, Heidelberg University, Heidelberg, Germany.
    Sewe, Maquins Odhiambo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Tejeda, Gustavo
    Benitez, David
    Gill, Balvinder
    Hakim, S. Lokman
    Carvalho, Roberta Gomes
    Bowman, Leigh
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Petzold, Max
    Early warning and response system (EWARS) for dengue outbreaks: recent advancements towards widespread applications in critical settings2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 5, article id e0196811Article in journal (Refereed)
    Abstract [en]

    Background: Dengue outbreaks are increasing in frequency over space and time, affecting people's health and burdening resource-constrained health systems. The ability to detect early emerging outbreaks is key to mounting an effective response. The early warning and response system (EWARS) is a toolkit that provides countries with early-warning systems for efficient and cost-effective local responses. EWARS uses outbreak and alarm indicators to derive prediction models that can be used prospectively to predict a forthcoming dengue outbreak at district level.

    Methods: We report on the development of the EWARS tool, based on users' recommendations into a convenient, user-friendly and reliable software aided by a user's workbook and its field testing in 30 health districts in Brazil, Malaysia and Mexico.

    Findings: 34 Health officers from the 30 study districts who had used the original EWARS for 7 to 10 months responded to a questionnaire with mainly open-ended questions. Qualitative content analysis showed that participants were generally satisfied with the tool but preferred open-access vs. commercial software. EWARS users also stated that the geographical unit should be the district, while access to meteorological information should be improved. These recommendations were incorporated into the second-generation EWARS-R, using the free R software, combined with recent surveillance data and resulted in higher sensitivities and positive predictive values of alarm signals compared to the first-generation EWARS. Currently the use of satellite data for meteorological information is being tested and a dashboard is being developed to increase user-friendliness of the tool. The inclusion of other Aedes borne viral diseases is under discussion.

    Conclusion: EWARS is a pragmatic and useful tool for detecting imminent dengue outbreaks to trigger early response activities.

  • 253.
    Hvidsten, Torgeir
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Laegreid, Astrid
    Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, St. Olavs Hospital HF, Trondheim, Norway.
    Kryshtafovych, Andriy
    UC Davis Genome Center, Davis, California, United States of America.
    Andersson, Gunnar
    The Linnaeus Centre for Bioinformatics, Uppsala University and The Swedish University for Agricultural Sciences, Uppsala, Sweden.
    Fidelis, Krzysztof
    UC Davis Genome Center, Davis, California, United States of America.
    Komorowski, Jan
    The Linnaeus Centre for Bioinformatics, Uppsala University and The Swedish University for Agricultural Sciences, Uppsala, Sweden.
    A comprehensive analysis of the structure-function relationship in proteins based on local structure similarity2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 7, p. e6266-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Sequence similarity to characterized proteins provides testable functional hypotheses for less than 50% of the proteins identified by genome sequencing projects. With structural genomics it is believed that structural similarities may give functional hypotheses for many of the remaining proteins. METHODOLOGY/PRINCIPAL FINDINGS: We provide a systematic analysis of the structure-function relationship in proteins using the novel concept of local descriptors of protein structure. A local descriptor is a small substructure of a protein which includes both short- and long-range interactions. We employ a library of commonly reoccurring local descriptors general enough to assemble most existing protein structures. We then model the relationship between these local shapes and Gene Ontology using rule-based learning. Our IF-THEN rule model offers legible, high resolution descriptions that combine local substructures and is able to discriminate functions even for functionally versatile folds such as the frequently occurring TIM barrel and Rossmann fold. By evaluating the predictive performance of the model, we provide a comprehensive quantification of the structure-function relationship based only on local structure similarity. Our findings are, among others, that conserved structure is a stronger prerequisite for enzymatic activity than for binding specificity, and that structure-based predictions complement sequence-based predictions. The model is capable of generating correct hypotheses, as confirmed by a literature study, even when no significant sequence similarity to characterized proteins exists. CONCLUSIONS/SIGNIFICANCE: Our approach offers a new and complete description and quantification of the structure-function relationship in proteins. By demonstrating how our predictions offer higher sensitivity than using global structure, and complement the use of sequence, we show that the presented ideas could advance the development of meta-servers in function prediction.

  • 254.
    Hägg, David
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Sundström, Anders
    Schmitt-Egenolf, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    The higher proportion of men with psoriasis treated with biologics may be explained by more severe disease in men2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e63619-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Moderate to severe psoriasis, once regarded as merely a skin disease, is today seen as an inflammatory systemic disease. The sex ratio of the prevalence of psoriasis is balanced. In recent years several reports have documented that men receive more systemic or UV treatment than women, and different hypotheses were made. In PsoReg, the national registry for systemic treatment of psoriasis in Sweden, we have, like other European registries, observed a predominance of men (59%), especially of men treated with biologics (63%). Biologics are a relatively new group of very effective but high-priced drugs. The objective of this study was to analyse if women are discriminated by not having the same access to the high-priced biologics.

    DESIGN: Population based cohort study using data from a nationwide quality register of psoriasis patients.

    POPULATION: 2294 patients with moderate to severe psoriasis receiving systemic treatment from a specialist in dermatology.

    MAIN OUTCOME MEASURES: Time to initiation of biologic treatment. A multiple Cox proportional hazard's regression was performed, with time to initiating a biologic treatment as the outcome in order to assess the independent role of the patient's sex in initiating such therapy. The psoriasis severity was defined as a time-varying variable.

    RESULTS: Men had more severe psoriasis than women according to the Psoriasis Area and Severity Index (PASI), regardless of age at enrolment, and throughout the study period. The analysis in the multiple Cox regression show that age, psoriasis severity and psoriasis arthropathy were relevant factors for initiating biologic therapy, whereas sex is not.

    CONCLUSIONS: Although as many women as men are believed to suffer from psoriasis, men seem to be more severely affected by psoriasis. The asymmetry in allocation of biologic therapy thereby probably reflects the differing disease activity between the sexes, and is not a discrimination against women per se.

  • 255.
    Hägglund, Anna-Carin
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Berghard, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Canonical Wnt/beta-Catenin Signalling Is Essential for Optic Cup Formation2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e81158-Article in journal (Refereed)
    Abstract [en]

    A multitude of signalling pathways are involved in the process of forming an eye. Here we demonstrate that beta-catenin is essential for eye development as inactivation of beta-catenin prior to cellular specification in the optic vesicle caused anophthalmia in mice. By achieving this early and tissue-specific beta-catenin inactivation we find that retinal pigment epithelium (RPE) commitment was blocked and eye development was arrested prior to optic cup formation due to a loss of canonical Wnt signalling in the dorsal optic vesicle. Thus, these results show that Wnt/beta-catenin signalling is required earlier and play a more central role in eye development than previous studies have indicated. In our genetic model system a few RPE cells could escape beta-catenin inactivation leading to the formation of a small optic rudiment. The optic rudiment contained several neural retinal cell classes surrounded by an RPE. Unlike the RPE cells, the neural retinal cells could be beta-catenin- negative revealing that differentiation of the neural retinal cell classes is beta-catenin-independent. Moreover, although dorsoventral patterning is initiated in the mutant optic vesicle, the neural retinal cells in the optic rudiment displayed almost exclusively ventral identity. Thus, beta-catenin is required for optic cup formation, commitment to RPE cells and maintenance of dorsal identity of the retina.

  • 256.
    Hägglund, Anna-Carin
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Dahl, Lina
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lhx2 is required for patterning and expansion of a distinct progenitor cell population committed to eye development2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23387-Article in journal (Refereed)
    Abstract [en]

    Progenitor cells committed to eye development become specified in the prospective forebrain and develop subsequently into the optic vesicle and the optic cup. The optic vesicle induces formation of the lens placode in surface ectoderm from which the lens develops. Numerous transcription factors are involved in this process, including the eye-field transcription factors. However, many of these transcription factors also regulate the patterning of the anterior neural plate and their specific role in eye development is difficult to discern since eye-committed progenitor cells are poorly defined. By using a specific part of the Lhx2 promoter to regulate Cre recombinase expression in transgenic mice we have been able to define a distinct progenitor cell population in the forebrain solely committed to eye development. Conditional inactivation of Lhx2 in these progenitor cells causes an arrest in eye development at the stage when the optic vesicle induces lens placode formation in the surface ectoderm. The eye-committed progenitor cell population is present in the Lhx2(-/-) embryonic forebrain suggesting that commitment to eye development is Lhx2-independent. However, re-expression of Lhx2 in Lhx2(-/-) progenitor cells only promotes development of retinal pigment epithelium cells, indicating that Lhx2 promotes the acquisition of the oligopotent fate of these progenitor cells. This approach also allowed us to identify genes that distinguish Lhx2 function in eye development from that in the forebrain. Thus, we have defined a distinct progenitor cell population in the forebrain committed to eye development and identified genes linked to Lhx2’s function in the expansion and patterning of these progenitor cells.

  • 257.
    Hägglöf, Christina
    et al.
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Paulsson, Janna
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Östman, Arne
    Stromal PDGFRbeta expression in prostate tumors and non-malignant prostate tissue predicts prostate cancer survival2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 5, p. e10747-Article in journal (Refereed)
    Abstract [en]

    The study revealed a number of novel associations between stromal PDGFRbeta expression in prostate tumors and several important clinical characteristics, including survival.

  • 258.
    Hägglöf, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Strömvall, Kerstin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Egevad, Lars
    Josefsson, Andreas
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Granfors, Torvald
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TMPRSS2-ERG Expression Predicts Prostate Cancer Survival and Associates with Stromal Biomarkers2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e86824-Article in journal (Refereed)
    Abstract [en]

    The TMPRSS2-ERG gene fusion is found in approximately half of all prostate cancers. The functional and prognostic significance of TMPRSS2-ERG is, however, not fully understood. Based on a historical watchful waiting cohort, an association between TMPRSS2-ERG, evaluated as positive immune staining, and shorter survival of prostate cancer patients was identified. Expression of ERG was also associated with clinical markers such as advanced tumor stage, high Gleason score, presence of metastasis and prognostic tumor cell markers such as high Ki67, pEGFR and pAkt. Novel associations between TMPRSS2-ERG and alterations in the tumor stroma, for example, increased vascular density, hyaluronan and PDGFR beta and decreased Caveolin-1, all known to be associated with an aggressive disease, were found. The present study suggests that the TMPRSS2-ERG fusion gene is associated with a more aggressive prostate cancer phenotype, supported by changes in the tumor stroma.

  • 259.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rapp, Kilian
    Univ Ulm, Inst Epidemiol & Med Biometry, D-89069 Ulm, Germany.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Manjer, Jonas
    Lund Univ, Skåne Univ Hosp, Dept Surg, Malmö, Sweden.
    Bjørge, Tone
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Ulmer, Hanno
    Med Univ Innsbruck, Dept Med Stat Informat & Hlth Econ, A-6020 Innsbruck, Austria.
    Engeland, Anders
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Almqvist, Martin
    Lund Univ, Skåne Univ Hosp, Dept Surg, Malmö, Sweden.
    Concin, Hans
    Agcy Prevent & Social Med, Bregenz, Australia.
    Selmer, Randi
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tretli, Steinar
    Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway.
    Nagel, Gabriele
    Univ Ulm, Inst Epidemiol & Med Biometry, D-89069 Ulm, Germany.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Metabolic factors associated with risk of renal cell carcinoma2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, p. e57475-Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that obesity and hypertension are associated with increased risk of renal cell carcinoma (RCC), but less is known about the association to other metabolic factors. In the Metabolic Syndrome and Cancer project (Me-Can) data on body mass index (BMI, kg/m2), blood pressure, and circulating levels of glucose, cholesterol, and triglycerides were collected from 560,388 men and women in cohorts from Norway, Austria, and Sweden. By use of Cox proportional hazard models, hazard ratios (HR) were calculated for separate and composite metabolic exposures. During a median follow-up of 10 years, 592 men and 263 women were diagnosed with RCC. Among men, we found an increased risk of RCC for BMI, highest vs. lowest quintile, (HR = 1.51, 95% CI 1.13-2.03), systolic blood pressure, (HR = 3.40, 95% CI 1.91-6.06), diastolic blood pressure, (HR = 3.33, 95% CI 1.85-5.99), glucose, (HR = 3.75, 95% CI 1.46-9.68), triglycerides, (HR = 1.79, 95% CI 1.00-3.21) and a composite score of these metabolic factors, (HR = 2.68, 95% CI 1.75-4.11). Among women we found an increased risk of RCC for BMI, highest vs. lowest quintile, (HR = 2.21, 95% CI 1.32-3.70) and the composite score, (HR = 2.29, 95% CI 1.12-4.68). High levels of the composite score were also associated with risk of death from RCC among both men and women. No multiplicative statistical or biological interactions between metabolic factors on risk of RCC were found. High levels of BMI, blood pressure, glucose and triglycerides among men and high BMI among women were associated with increased risk of RCC.

  • 260.
    Håglin, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Törnkvist, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Bäckman, Lennart
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Obesity, smoking habits, and serum phosphate levels predicts mortality after life-style intervention2020In: PLoS ONE, E-ISSN 1932-6203, Vol. 15, no 1, article id e0227692Article in journal (Refereed)
    Abstract [en]

    Background: Life-style interventions, including smoking cessation and weight control are of importance for managing future escalating prevalence of obesity. Smoking habits and obesity have jointly great impact on mortality, however mechanisms behind the effect and variables involved in the obesity paradox is still unknown.

    Objectives: This study examines risk factors for all-cause, cardiovascular, and cancer mortality in males and females with high cardiovascular risk, mediated by smoking habits, body mass index (BMI, kg/m2), and serum phosphate (S-P) levels.

    Methods: Patients were admitted to the Vindeln Patient Education Center in groups of 30 for a four-week residential comprehensive program (114 hours) focusing on smoking cessation, stress reduction, food preferences and selections, and physical exercise. The follow-up, in years from 1984 to 2014 corresponds to 30 years. This study included 2,504 patients (1,408 females and 1,096 males). Cox regression analysis was used to assess mortality risk associated with smoking habits, low and high BMI, and low and high S-P levels.

    Results: High BMI (>34,2 kg/m2), current smoking, type 2 diabetes mellitus (T2DM), high serum calcium (S-Ca), mmol/L and high systolic blood pressure (SBP, mmHg) were associated with all-cause mortality irrespective of sex. Former and current smoking females had a high all-cause mortality (adjusted hazard ratio [HR] 1.581; 95% CI 1.108–2.256, adjusted hazard ratio [HR] 1.935; 95% CI 1.461–2.562, respectively) while current smoking and high BMI increased risk for cardiovascular mortality (adjusted hazard ratio [HR] 3.505; 95% CI 2.140–5.740 and [HR] 1.536; 95% CI 1.058–2.231, respectively). Neither low nor high levels of S-P predicted all-cause, cardiovascular disease (CVD) and cancer mortality in males or females while low levels of S-P predicted all-cause mortality in smokers (adjusted hazard ratio [HR] 1.713; 95% CI 1.211–2.424). In non-smokers, low BMI (<27.6 kg/m2) was protecting and high BMI a risk for all-cause mortality. In males, ischemic heart disease (IHD), and low serum albumin (S-Alb) were associated with all-cause mortality. In females, an interaction between high BMI and smoking (HbmiSM) decreased the cardiovascular mortality (adjusted hazard ratio [HR] 0.410; 95% CI 0.179–0.937, respectively).

    Conclusions: High BMI and current smoking were associated with all-cause mortality in both males and females in the present high cardiovascular-risk cohort. In current smokers and non-smokers, T2DM and high S-Ca were associated with an increase in all-cause mortality, while low S-P was associated with all-cause mortality in smokers. Interaction between high BMI and smoking contribute to the obesity paradox by being protective for cardiovascular mortality in females.

  • 261.
    Höglund Åberg, Carola
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Antonoglou, Georgios
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Haubek, Dorte
    Section for Pediatric Dentistry, Department of Dentistry, Health, Århus University, Århus, Denmark.
    Kwamin, Francis
    Dental School University of Ghana, Accra, Ghana.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Cytolethal distending toxin in isolates of Aggregatibacter actinomycetemcomitans from Ghanaian adolescents and association with serotype and disease progression 2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e65781-Article in journal (Refereed)
    Abstract [en]

    Background and Objectives: The cytolethal distending toxin (Cdt) is a highly conserved exotoxin that are produced by a number of Gram negative bacteria, including Aggregatibacter actinomycetemcomitans, and affects mammalian cells by inhibiting cell division and causing apoptosis. A complete cdt-operon is present in the majority of A. actinomycetemcomitans, but the proportion of isolates that lack cdt-encoding genes (A, B and C) varies according to the population studied. The objectives of this study were to examine serotype, Cdt-genotype, and Cdt-activity in isolates of A. actinomycetemcomitans collected from an adolescent West African population and to examine the association between the carrier status of A. actinomycetemcomitans and the progression of attachment loss (AL).

    Material and Methods: A total of 249 A. actinomycetemcomitans isolates from 200 Ghanaian adolescents were examined for serotype and cdt-genotype by PCR. The activity of the Cdt-toxin was examined by DNA-staining of exposed cultured cells and documented with flow cytometry. The periodontal status of the participants was examined at baseline and at a two-year follow-up.

    Results: Presence of all three cdt-encoding genes was detected in 79% of the examined A. actinomycetemcomitans isolates. All these isolates showed a substantial Cdt-activity. The two different cdt-genotypes (with and without presence of all three cdt-encoding genes) showed a serotype-dependent distribution pattern. Presence of A. actinomycetemcomitans was significantly associated with progression of AL (OR = 5.126; 95% CI = [2.994 - 8.779], p < 0.001).

    Conclusion: A. actinomycetemcomitans isolated from the Ghanaian adolescents showed a distribution of serotype and cdt-genotype in line with results based on other previously studied populations. Presence of A. actinomycetemcomitans was significantly associated with disease progression, in particular the b serotype, whereas the association with disease progression was not particularly related to cdt-genotype, and Cdt-activity.

  • 262.
    Höglund Åberg, Carola
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haubek, Dorte
    Århus University.
    Kwamin, Francis
    Ghana University.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Leukotoxic activity of Aggregatibacter actinomycetemcomitans and periodontal attachment loss2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e104095-Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans is a Gram-negative periodontitis-associated bacterium that expresses a toxin that selectively affects leukocytes. This leukotoxin is encoded by an operon belonging to the core genome of this bacterial species. Variations in the expression of the leukotoxin have been reported, and a well-characterized specific clonal type (JP2) of this bacterium with enhanced leukotoxin expression has been isolated. In particular, the presence of the JP2 genotype significantly increases the risk for the progression of periodontal attachment loss (AL). Based on these findings we hypothesized that variations in the leukotoxicity are linked to disease progression in infected individuals. In the present study, the leukotoxicity of 239 clinical isolates of A. actinomycetemcomitans was analysed with different bioassays, and the genetic peculiarities of the isolates were related to their leukotoxicity based on examination with molecular techniques. The periodontal status of the individuals sampled for the presence of A. actinomycetemcomitans was examined longitudinally, and the importance of the observed variations in leukotoxicity was evaluated in relation to disease progression. Our data show that high leukotoxicity correlates with an enhanced risk for the progression of AL. The JP2 genotype isolates were all highly leukotoxic, while the isolates with an intact leukotoxin promoter (non-JP2 genotypes) showed substantial variation in leukotoxicity. Genetic characterization of the non-JP2 genotype isolates indicated the presence of highly leukotoxic genotypes of serotype b with similarities to the JP2 genotype. Based on these results, we conclude that A. actinomycetemcomitans harbours other highly virulent genotypes besides the previously described JP2 genotype. In addition, the results from the present study further highlight the importance of the leukotoxin as a key virulence factor in aggressive forms of periodontitis.

  • 263.
    Hörnberg, Emma
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bovinder Ylitalo, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 4, p. e19059-Article in journal (Refereed)
    Abstract [en]

    Background: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote  the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.

    Methodology/Principal Findings: Hormone-naı¨ve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from  40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival.

    Conclusions/Significance: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.

  • 264.
    Hörnberg, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Sundström, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Innala, Lena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Wållberg-Jonsson, Solveig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Aerobic capacity over 16 years in patients with rheumatoid arthritis: relationship to disease activity and risk factors for cardiovascular disease2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0190211Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to analyse the change in aerobic capacity from disease onset of rheumatoid arthritis (RA) over 16.2 years, and its associations with disease activity and cardiovascular risk factors. Twenty-five patients (20 f/5 m), diagnosed with RA 1995-2002 were tested at disease onset and after mean 16.2 years. Parameters measured were: sub-maximal ergometer test for aerobic capacity, functional ability, self-efficacy, ESR, CRP and DAS28. At follow-up, cardiovascular risk factors were assessed as blood lipids, glucose concentrations, waist circumference, body mass index (BMI), body composition, pulse wave analysis and carotid intima-media thickness. Aerobic capacity [median (IQR)] was 32.3 (27.9-42.1) ml O2/kg x min at disease onset, and 33.2 (28.4-38.9) at follow-up (p>0.05). Baseline aerobic capacity was associated with follow-up values of: BMI (rs = -.401, p = .047), waist circumference (rs = -.498, p = .011), peripheral pulse pressure (rs = -.415, p = .039) self-efficacy (rs = .420, p = .037) and aerobic capacity (rs = .557, p = .004). In multiple regression models adjusted for baseline aerobic capacity, disease activity at baseline and over time predicted aerobic capacity at follow-up (AUC DAS28, 0-24 months; β = -.14, p = .004). At follow-up, aerobic capacity was inversely associated with blood glucose levels (rs = -.508, p = .016), BMI (rs = -.434, p = .030), body fat% (rs = -.419, p = .037), aortic pulse pressure (rs = -.405, p = .044), resting heart rate (rs = -.424, p = .034) and self-efficacy (rs = .464, p = .020) at follow-up. We conclude that the aerobic capacity was maintained over 16 years. High baseline aerobic capacity associated with favourable measures of cardiovascular risk factors at follow-up. Higher disease activity in early stages of RA predicted lower aerobic capacity after 16.2 years.

  • 265.
    Hörnblad, Andreas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Sock, Elisabeth
    Hill, Robert
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Impaired spleen formation perturbs morphogenesis of the gastric lobe of the pancreas2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, p. e21753-Article in journal (Refereed)
    Abstract [en]

    Despite the extensive use of the mouse as a model for studies of pancreas development and disease, the development of the gastric pancreatic lobe has been largely overlooked. In this study we use optical projection tomography to provide a detailed three-dimensional and quantitative description of pancreatic growth dynamics in the mouse. Hereby, we describe the epithelial and mesenchymal events leading to the formation of the gastric lobe of the pancreas. We show that this structure forms by perpendicular growth from the dorsal pancreatic epithelium into a distinct lateral domain of the dorsal pancreatic mesenchyme. Our data support a role for spleen organogenesis in the establishment of this mesenchymal domain and in mice displaying perturbed spleen development, including Dh +/-, Bapx1-/- and Sox11-/-, gastric lobe development is disturbed. We further show that the expression profile of markers for multipotent progenitors is delayed in the gastric lobe as compared to the splenic and duodenal pancreatic lobes. Altogether, this study provides new information regarding the developmental dynamics underlying the formation of the gastric lobe of the pancreas and recognizes lobular heterogeneities regarding the time course of pancreatic cellular differentiation. Collectively, these data are likely to constitute important elements in future interpretations of the developing and/or diseased pancreas.

  • 266.
    Iakovleva, Irina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Begum, Afshan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wijsekera, Alexandra
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Nilsson, Lina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Zhang, Jin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, Patrik L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sauer-Eriksson, A. Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Tetrabromobisphenol A Is an Efficient Stabilizer of the Transthyretin Tetramer2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0153529Article in journal (Refereed)
    Abstract [en]

    Amyloid formation of the human plasma protein transthyretin (TTR) is associated with several human disorders, including familial amyloidotic polyneuropathy (FAP) and senile systemic amyloidosis. Dissociation of TTR’s native tetrameric assembly is the rate-limiting step in the conversion into amyloid, and this feature presents an avenue for intervention because binding of an appropriate ligand to the thyroxin hormone binding sites of TTR stabilizes the native tetrameric assembly and impairs conversion into amyloid. The desired features for an effective TTR stabilizer include high affinity for TTR, high selectivity in the presence of other proteins, no adverse side effects at the effective concentrations, and a long half-life in the body. In this study we show that the commonly used flame retardant tetrabromobisphenol A (TBBPA) efficiently stabilizes the tetrameric structure of TTR. The X-ray crystal structure shows TBBPA binding in the thyroxine binding pocket with bromines occupying two of the three halogen binding sites. Interestingly, TBBPA binds TTR with an extremely high selectivity in human plasma, and the effect is equal to the recently approved drug tafamidis and better than diflunisal, both of which have shown therapeutic effects against FAP. TBBPA consequently present an interesting scaffold for drug design. Its absorption, metabolism, and potential side-effects are discussed.

  • 267.
    Iakovleva, Irina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Begum, Afshan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pokrzywa, Malgorzata
    Walfridsson, Malin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sauer-Eriksson, A Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    The flavonoid luteolin, but not luteolin-7-o-glucoside, prevents a transthyretin mediated toxic response2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0128222Article in journal (Refereed)
    Abstract [en]

    Transthyretin (TTR) is a homotetrameric plasma protein with amyloidogenic properties that has been linked to the development of familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy, and senile systemic amyloidosis. The in vivo role of TTR is associated with transport of thyroxine hormone T4 and retinol-binding protein. Loss of the tetrameric integrity of TTR is a rate-limiting step in the process of TTR amyloid formation, and ligands with the ability to bind within the thyroxin binding site (TBS) can stabilize the tetramer, a feature that is currently used as a therapeutic approach for FAP. Several different flavonoids have recently been identified that impair amyloid formation. The flavonoid luteolin shows therapeutic potential with low incidence of unwanted side effects. In this work, we show that luteolin effectively attenuates the cytotoxic response to TTR in cultured neuronal cells and rescues the phenotype of a Drosophila melanogaster model of FAP. The plant-derived luteolin analogue cynaroside has a glucoside group in position 7 of the flavone A-ring and as opposed to luteolin is unable to stabilize TTR tetramers and thus prevents a cytotoxic effect. We generated high-resolution crystal-structures of both TTR wild type and the amyloidogenic mutant V30M in complex with luteolin. The results show that the A-ring of luteolin, in contrast to what was previously suggested, is buried within the TBS, consequently explaining the lack of activity from cynaroside. The flavonoids represent an interesting group of drug candidates for TTR amyloidosis. The present investigation shows the potential of luteolin as a stabilizer of TTR in vivo. We also show an alternative orientation of luteolin within the TBS which could represent a general mode of binding of flavonoids to TTR and is of importance concerning the future design of tetramer stabilizing drugs.

  • 268.
    Ibañez, Cristian
    et al.
    Centro de Biotecnología y Genómica de Plantas, Departamento de Biotecnología, Universidad Politécnica de Madrid, E. T. S. Ingenieros de Montes, Madrid, Spain.
    Ramos, Alberto
    Acebo, Paloma
    Contreras, Angela
    Casado, Rosa
    Allona, Isabel
    Aragoncillo, Cipriano
    Overall alteration of circadian clock gene expression in the chestnut cold response2008In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 3, no 10, p. e3567-Article in journal (Refereed)
    Abstract [en]

    Cold acclimation in woody plants may have special features compared to similar processes in herbaceous plants. Recent studies have shown that circadian clock behavior in the chestnut tree (Castanea sativa) is disrupted by cold temperatures and that the primary oscillator feedback loop is not functional at 4 degrees C or in winter. In these conditions, CsTOC1 and CsLHY genes are constantly expressed. Here, we show that this alteration also affects CsPRR5, CsPRR7 and CsPRR9. These genes are homologous to the corresponding Arabidopsis PSEUDO-RESPONSE REGULATOR genes, which are also components of the circadian oscillator feedback network. The practically constant presence of mRNAs of the 5 chestnut genes at low temperature reveals an unknown aspect of clock regulation and suggests a mechanism regulating the transcription of oscillator genes as a whole.

  • 269.
    Irewall, Anna-Lotta
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ögren, Joachim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Public Health and Clinical Medicine, Östersund, Sweden.
    Bergström, Lisa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Public Health and Clinical Medicine, Östersund, Sweden.
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Söderström, Lars
    Unit of Research, Development and Education, Region Jämtland Härjedalen, Östersund Hospital, Östersund, Sweden.
    Mooe, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nurse-Led, Telephone-Based, Secondary Preventive Follow-Up after Stroke or Transient Ischemic Attack Improves Blood Pressure and LDL Cholesterol: Results from the First 12 Months of the Randomized, Controlled NAILED Stroke Risk Factor Trial2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, article id e0139997Article in journal (Refereed)
    Abstract [en]

    Background: Enhanced secondary preventive follow-up after stroke or transient ischemic attack (TIA) is necessary for improved adherence to recommendations regarding blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels. We investigated whether nurse-led, telephone-based follow-up was more efficient than usual care at improving BP and LDL-C levels at 12 months after hospital discharge.

    Methods: We randomized 537 patients to either nurse-led, telephone-based follow-up (intervention) or usual care (control). BP and LDL-C measurements were performed at 1 month (baseline) and 12 months post-discharge. Intervention group patients who did not meet target values at baseline received additional follow-up, including titration of medication and lifestyle counselling, to reach treatment goals (BP < 140/90 mmHg, LDL-C < 2.5 mmol/L).

    Results: At 12 months, mean systolic BP, diastolic BP and LDL-C was 3.3 (95% CI 0.3 to 6.3) mmHg, 2.3 mmHg (95% CI 0.5 to 4.2) and 0.3 mmol/L (95% CI 0.1 to 0.4) lower in the intervention group compared to controls. Among participants with values above the treatment goal at baseline, the difference in systolic BP and LDL-C was more pronounced (8.0 mmHg, 95% CI 4.0 to 12.1, and 0.6 mmol/L, 95% CI 0.4 to 0.9). A larger proportion of the intervention group reached the treatment goal for systolic BP (68.5 vs. 56.8%, p = 0.008) and LDL-C (69.7% vs. 50.4%, p < 0.001).

    Conclusions: Nurse-led, telephone-based secondary preventive follow-up, including medication adjustment, was significantly more efficient than usual care at improving BP and LDL-C levels by 12 months post-discharge.

  • 270.
    Ishikawa, Takahiko
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rompikuntal, Pramod Kumar
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lindmark, Barbro
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Milton, Debra L.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Wai, Sun Nyunt
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Quorum sensing regulation of the two hcp alleles in Vibrio cholerae O1 strains2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 8, article id e6734Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The type VI secretion system (T6SS) has emerged as a protein secretion system important to several gram-negative bacterial species. One of the common components of the system is Hcp, initially described as a hemolysin co-regulated protein in a serotype O17 strain of Vibrio cholerae. Homologs to V. cholerae hcp genes have been found in all characterized type VI secretion systems and they are present also in the serotype O1 strains of V. cholerae that are the cause of cholera diseases but seemed to have non-functional T6SS.

    METHODOLOGY/PRINCIPAL FINDINGS: The serotype O1 V. cholerae strain A1552 was shown to express detectable levels of Hcp as determined by immunoblot analyses using polyclonal anti-Hcp antiserum. We found that the expression of Hcp was growth phase dependent. The levels of Hcp in quorum sensing deficient mutants of V. cholerae were compared with the levels in wild type V. cholerae O1 strain A1552. The expression of Hcp was positively and negatively regulated by the quorum sensing regulators HapR and LuxO, respectively. In addition, we observed that expression of Hcp was dependent on the cAMP-CRP global transcriptional regulatory complex and required the RpoN sigma factor.

    CONCLUSION/SIGNIFICANCE: Our results show that serotype O1 strains of V. cholerae do express Hcp which is regarded as one of the important T6SS components and is one of the secreted substrates in non-O1 non-O139 V. cholerae isolates. We found that expression of Hcp was strictly regulated by the quorum sensing system in the V. cholerae O1 strain. In addition, the expression of Hcp required the alternative sigma factor RpoN and the cAMP-CRP global regulatory complex. Interestingly, the environmental isolates of V. cholerae O1 strains that showed higher levels of the HapR quorum sensing regulator in comparison with our laboratory standard serotype O1 strain A1552 where also expressing higher levels of Hcp.

  • 271. Ito, Yuki
    et al.
    Vela, Jose Luis
    Matsumura, Fumiko
    Hoshino, Hitomi
    Tyznik, Aaron
    Lee, Heeseob
    Girardi, Enrico
    Zajonc, Dirk M
    Liddington, Robert
    Kobayashi, Motohiro
    Bao, Xingfeng
    Bugaytsova, Jeanna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Borén, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Jin, Rongsheng
    Zong, Yinong
    Seeberger, Peter H
    Nakayama, Jun
    Kronenberg, Mitchell
    Fukuda, Minoru
    Helicobacter pylori Cholesteryl α-Glucosides Contribute to Its Pathogenicity and Immune Response by Natural Killer T Cells2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, article id e78191Article in journal (Refereed)
    Abstract [en]

    Approximately 10-15% of individuals infected with Helicobacter pylori will develop ulcer disease (gastric or duodenal ulcer), while most people infected with H. pylori will be asymptomatic. The majority of infected individuals remain asymptomatic partly due to the inhibition of synthesis of cholesteryl α-glucosides in H. pylori cell wall by α1,4-GlcNAc-capped mucin O-glycans, which are expressed in the deeper portion of gastric mucosa. However, it has not been determined how cholesteryl α-glucosyltransferase (αCgT), which forms cholesteryl α-glucosides, functions in the pathogenesis of H. pylori infection. Here, we show that the activity of αCgT from H. pylori clinical isolates is highly correlated with the degree of gastric atrophy. We investigated the role of cholesteryl α-glucosides in various aspects of the immune response. Phagocytosis and activation of dendritic cells were observed at similar degrees in the presence of wild-type H. pylori or variants harboring mutant forms of αCgT showing a range of enzymatic activity. However, cholesteryl α-glucosides were recognized by invariant natural killer T (iNKT) cells, eliciting an immune response in vitro and in vivo. Following inoculation of H. pylori harboring highly active αCgT into iNKT cell-deficient (Jα18(-/-)) or wild-type mice, bacterial recovery significantly increased in Jα18(-/-) compared to wild-type mice. Moreover, cytokine production characteristic of Th1 and Th2 cells dramatically decreased in Jα18(-/-) compared to wild-type mice. These findings demonstrate that cholesteryl α-glucosides play critical roles in H. pylori-mediated gastric inflammation and precancerous atrophic gastritis.

  • 272.
    Jagarlamudi, Krishna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Liu, Lian
    Department of Chemotherapy, Cancer Center, Qilu Hospital, Shandong University, Jinan, China.
    Adhikari, Deepak
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Reddy, Pradeep
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ottander, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Oocyte-specific deletion of Pten in mice reveals a stage-specific function of PTEN/PI3K signaling in oocytes in controlling follicular activation2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 7, p. e6186-Article in journal (Refereed)
    Abstract [en]

    Immature ovarian primordial follicles are essential for maintenance of the reproductive lifespan of female mammals. Recently, it was found that overactivation of the phosphatidylinositol 3-kinase (PI3K) signaling in oocytes of primordial follicles by an oocyte-specific deletion of Pten (phosphatase and tensin homolog deleted on chromosome ten), the gene encoding PI3K negative regulator PTEN, results in premature activation of the entire pool of primordial follicles, indicating that activation of the PI3K pathway in oocytes is important for control of follicular activation. To investigate whether PI3K signaling in oocytes of primary and further developed follicles also plays a role at later stages in follicular development and ovulation, we conditionally deleted the Pten gene from oocytes of primary and further developed follicles by using transgenic mice expressing zona pellucida 3 (Zp3) promoter-mediated Cre recombinase. Our results show that Pten was efficiently deleted from oocytes of primary and further developed follicles, as indicated by the elevated phosphorylation of the major PI3K downstream component Akt. However, follicular development was not altered and oocyte maturation was also normal, which led to normal fertility with unaltered litter size in the mutant mice. Our data indicate that properly controlled PTEN/PI3K-Akt signaling in oocytes is essential for control of the development of primordial follicles whereas overactivation of PI3K signaling in oocytes does not appear to affect the development of growing follicles. This suggests that there is a stage-specific function of PTEN/PI3K signaling in mouse oocytes that controls follicular activation.

  • 273. Jefferson, Amanda
    et al.
    Leonard, Helen
    Siafarikas, Aris
    Woodhead, Helen
    Fyfe, Sue
    Ward, Leanne M.
    Munns, Craig
    Motil, Kathleen
    Tarquinio, Daniel
    Shapiro, Jay R.
    Brismar, Torkel
    Ben-Zeev, Bruria
    Bisgaard, Anne-Marie
    Coppola, Giangennaro
    Ellaway, Carolyn
    Freilinger, Michael
    Geerts, Suzanne
    Humphreys, Peter
    Jones, Mary
    Lane, Jane
    Larsson, Gunilla
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Swedish National Rett Centre, Frösön, Sweden.
    Lotan, Meir
    Percy, Alan
    Pineda, Mercedes
    Skinner, Steven
    Syhler, Birgit
    Thompson, Sue
    Weiss, Batia
    Witt Engerström, Ingegerd
    Downs, Jenny
    Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 2, article id e0146824Article in journal (Refereed)
    Abstract [en]

    ObjectivesWe developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians.

    MethodsAn initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions.

    ResultsAgreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended.

    ConclusionA clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

  • 274.
    Jernberg, Emma
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bovinder Ylitalo, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e77407-Article in journal (Refereed)
    Abstract [en]

    Background: Intra-tumoral steroidogenesis and constitutive androgen receptor (AR) activity have been associated withcastration-resistant prostate cancer (CRPC). This study aimed to examine if CRPC bone metastases expressed higher levels ofsteroid-converting enzymes than untreated bone metastases. Steroidogenic enzyme levels were also analyzed in relation toexpression of constitutively active AR variants (AR-Vs) and to clinical and pathological variables.

    Methodology/Principal Findings: Untreated, hormone-naıve (HN, n = 9) and CRPC bone metastases samples (n = 45) wereobtained from 54 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13prostatectomy specimens. Transcript and protein levels were analyzed by real-time RT-PCR, immunohistochemistry andimmunoblotting. No differences in steroidogenic enzyme levels were detected between CRPC and HN bone metastases.Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases thanin non-malignant and/or malignant prostate tissue, while the CYP11A1, CYP17A1, HSD3B2, SRD5A2, and HSD17B6 mRNAlevels in metastases were significantly lower. A sub-group of metastases expressed very high levels of AKR1C3, which wasnot due to gene amplification as examined by copy number variation assay. No association was found between AKR1C3expression and nuclear AR staining, tumor cell proliferation or patient outcome after metastases surgery. With only oneexception, high AR-V protein levels were found in bone metastases with low AKR1C3 levels, while metastases with highAKR1C3 levels primarily contained low AR-V levels, indicating distinct mechanisms behind castration-resistance in individualbone metastases.

    Conclusions/Significance: Induced capacity of converting adrenal-gland derived steroids into more potent androgens wasindicated in a sub-group of PC bone metastases. This was not associated with CRPC but merely with the advanced stage ofmetastasis. Sub-groups of bone metastases could be identified according to their expression levels of AKR1C3 and AR-Vs,which might be of relevance for patient response to 2nd line androgen-deprivation therapy.

  • 275. Johansson, Ann-Sofi
    et al.
    Vestling, Monika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lang, Lisa
    Leinartaite, Lina
    Karlstrom, Mikael
    Danielsson, Jens
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Oliveberg, Mikael
    Cytotoxicity of Superoxide Dismutase 1 in Cultured Cells Is Linked to Zn2+ Chelation2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e36104-Article in journal (Refereed)
    Abstract [en]

    Neurodegeneration in protein-misfolding disease is generally assigned to toxic function of small, soluble protein aggregates. Largely, these assignments are based on observations of cultured neural cells where the suspect protein material is titrated directly into the growth medium. In the present study, we use this approach to shed light on the cytotoxic action of the metalloenzyme Cu/Zn superoxide dismutase 1 (SOD1), associated with misfolding and aggregation in amyotrophic lateral sclerosis (ALS). The results show, somewhat unexpectedly, that the toxic species of SOD1 in this type of experimental setting is not an aggregate, as typically observed for proteins implicated in other neuro-degenerative diseases, but the folded and fully soluble apo protein. Moreover, we demonstrate that the toxic action of apoSOD1 relies on the protein's ability to chelate Zn2+ ions from the growth medium. The decreased cell viability that accompanies this extraction is presumably based on disturbed Zn2+ homeostasis. Consistently, mutations that cause global unfolding of the apoSOD1 molecule or otherwise reduce its Zn2+ affinity abolish completely the cytotoxic response. So does the addition of surplus Zn2+. Taken together, these observations point at a case where the toxic response of cultured cells might not be related to human pathology but stems from the intrinsic limitations of a simplified cell model. There are several ways proteins can kill cultured neural cells but all of these need not to be relevant for neurodegenerative disease.

  • 276.
    Johansson, Frank
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Lederer, Baptiste
    Lind, Martin I
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Trait performance correlations across life stages under environmental stress conditions in the common frog, Rana temporaria2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 7, p. e11680-Article in journal (Refereed)
    Abstract [en]

    If an organism's juvenile and adult life stages inhabit different environments, certain traits may need to be independently adapted to each environment. In many organisms, a move to a different environment during ontogeny is accompanied by metamorphosis. In such organisms phenotypic induction early in ontogeny can affect later phenotypes. In laboratory experiments we first investigated correlations between body morphology and the locomotor performance traits expressed in different life stages of the common frog, Rana temporaria: swimming speed and acceleration in tadpoles; and jump-distance in froglets. We then tested for correlations between these performances across life stages. We also subjected tadpoles to unchanging or decreasing water levels to explore whether decreasing water levels might induce any carry-over effects. Body morphology and performance were correlated in tadpoles; morphology and performance were correlated in froglets: hence body shape and morphology affect performance within each life stage. However, performance was decoupled across life stages, as there was no correlation between performance in tadpoles and performance in froglets. While size did not influence tadpole performance, it was correlated with performance of the metamorphosed froglets. Experiencing decreasing water levels accelerated development time, which resulted in smaller tadpoles and froglets, i.e., a carry-over effect. Interestingly, decreasing water levels positively affected the performance of tadpoles, but negatively affected froglet performance. Our results suggest that performance does not necessarily have to be correlated between life stages. However, froglet performance is size dependent and carried over from the tadpole stage, suggesting that some important size-dependent characters cannot be decoupled via metamorphosis.

  • 277.
    Johansson, Gunnar
    et al.
    Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan .
    Peng, Po-Chun
    Huang, Po-Yuan
    Chien, Hsiung-Fei
    Hua, Kuo-Tai
    Kuo, Min-Liang
    Chen, Chin-Tin
    Lee, Ming-Jen
    Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, article id e115916Article in journal (Refereed)
    Abstract [en]

    Neurofibromatosis type 1 (NF1) is the most common tumor predisposition disorder affecting 1/3500 worldwide. Patients are at risk of developing benign (neurofibromas) and malignant peripheral nerve sheath tumors (MPNST). The AXL receptor tyrosine kinase has been implicated in several kinds of cancers, but so far no studies have investigated the role of AXL in NF1 related tumorigenesis. Recently, the soluble fraction from the extracellular domain of AXL (sAXL) has been found in human plasma, and its level was correlated to poor prognosis in patients with renal cancer. Compared to normal human Schwann cells, a significantly high expression level of AXL was found in three of the four MPNST cell lines and two of the three primary MPNST tissues. Similarly, the level of sAXL in conditioned media corresponded to the protein and mRNA levels of AXL in the MPNST cell lines. Furthermore, in two different human MPNST xenograft models, the human sAXL could be detected in the mouse plasma. Its level was proportionate to the size of the xenograft tumors, while no human sAXL was detect prior to the formation of the tumors. Treatment with a newly developed photodynamic therapy, prevented further tumor growth and resulted in drastically reduced the levels of sAXL compared to that of the control group. Finally, the level of sAXL was significantly increased in patients with plexiform tumors compared to patients with only dermal neurofibromas, further supporting the role of sAXL as a marker for NF1 related tumor burden.

  • 278.
    Johansson, Ingegerd
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Esberg, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Eriksson, Linda
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haworth, Simon
    Lif Holgerson, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Self-reported bovine milk intake is associated with oral microbiota composition2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 3, article id e0193504Article in journal (Refereed)
    Abstract [en]

    Bovine milk intake has been associated with various disease outcomes, with modulation of the gastro-intestinal microbiome being suggested as one potential mechanism. The aim of the present study was to explore the oral microbiota in relation to variation in self-reported milk intake. Saliva and tooth biofilm microbiota was characterized by 16S rDNA sequencing, PCR and cultivation in 154 Swedish adolescents, and information on diet and other lifestyle markers were obtained from a questionnaire, and dental caries from clinical examination. A replication cohort of 31,571 adults with similar information on diet intake, other lifestyle markers and caries was also studied. Multivariate partial least squares (PLS) modelling separated adolescents with low milk intake (lowest tertile with <0.4 servings/day) apart from those with high intake of milk (≥3.7 servings/day) based on saliva and tooth biofilm, respectively. Taxa in several genera contributed to this separation, and milk intake was inversely associated with the caries causing Streptococcus mutans in saliva and tooth biofilm samples by sequencing, PCR and cultivation. Despite the difference in S. mutans colonization, caries prevalence did not differ between milk consumption groups in the adolescents or the adults in the replication cohort, which may reflect that a significant positive association between intake of milk and sweet products was present in both the study and replication group. It was concluded that high milk intake correlates with different oral microbiota and it is hypothesized that milk may confer similar effects in the gut. The study also illustrated that reduction of one single disease associated bacterial species, such as S. mutans by milk intake, may modulate but not prevent development of complex diseases, such as caries, due to adverse effects from other causal factors, such as sugar intake in the present study.

  • 279.
    Johansson Jänkänpää, Hanna
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Frenkel, Martin
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Zulfugarov, Ismayil
    Institute of Botany, Azerbaijan National Academy of Sciences, Baku, Azerbaijan.
    Reichelt, Michael
    Department of Biochemistry, Max Planck Institute for Chemical Ecology, Jena, Germany.
    Krieger-Liszkay, Anja
    CEA, Institut de Biologie et Technologies de Saclay, Service de Bioénergétique Biologie Structurale et Mécanisme, Gif-sur-Yvette, France.
    Mishra, Yogesh
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Gershenzon, Jonathan
    Department of Biochemistry, Max Planck Institute for Chemical Ecology, Jena, Germany.
    Moen, Jon
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Lee, Choon-Hwan
    Department of Molecular Biology, Pusan National University, Busan, Republic of Korea.
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Non-photochemical quenching capacity in arabidopsis thaliana affects herbivore behaviour2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e53232-Article in journal (Refereed)
    Abstract [en]

    Under natural conditions, plants have to cope with numerous stresses, including light-stress and herbivory. This raises intriguing questions regarding possible trade-offs between stress defences and growth. As part of a program designed to address these questions we have compared herbivory defences and damage in wild type Arabidopsis thaliana and two "photoprotection genotypes", npq4 and oePsbS, which respectively lack and overexpress PsbS (a protein that plays a key role in qE-type non-photochemical quenching). In dual-choice feeding experiments both a specialist (Plutella xylostella) and a generalist (Spodoptera littoralis) insect herbivore preferred plants that expressed PsbS most strongly. In contrast, although both herbivores survived equally well on each of the genotypes, for oviposition female P. xylostella adults preferred plants that expressed PsbS least strongly. However, there were no significant differences between the genotypes in levels of the 10 most prominent glucosinolates; key substances in the Arabidopsis anti-herbivore chemical defence arsenal. After transfer from a growth chamber to the field we detected significant differences in the genotypes' metabolomic profiles at all tested time points, using GC-MS, but no consistent "metabolic signature'' for the lack of PsbS. These findings suggest that the observed differences in herbivore preferences were due to differences in the primary metabolism of the plants rather than their contents of typical "defence compounds". A potentially significant factor is that superoxide accumulated most rapidly and to the highest levels under high light conditions in npq4 mutants. This could trigger changes in planta that are sensed by herbivores either directly or indirectly, following its dismutation to H2O2.

  • 280.
    Johansson, Robert
    et al.
    Department of Behavioural Sciences and Learning, Linköping University, Linköping,.
    Ekbladh, Sigrid
    Department of Behavioural Sciences and Learning, Linköping University, Linköping,.
    Herbert, Amanda
    Department of Behavioural Sciences and Learning, Linköping University, Linköping,.
    Lindström, Malin
    Department of Behavioural Sciences and Learning, Linköping University, Linköping,.
    Möller, Sara
    Department of Behavioural Sciences and Learning, Linköping University, Linköping,.
    Petitt, Eleanor
    Department of Behavioural Sciences and Learning, Linköping University, Linköping,.
    Poysti, Stephanie
    Department of Behavioural Sciences and Learning, Linköping University, Linköping,.
    Holmqvist Larsson, Mattias
    Department of Behavioural Sciences and Learning, Linköping University, Linköping,.
    Rousseau, Andréas
    Psychiatric Clinic, University Hospital of Linköping, Linköping, Sweden,.
    Carlbring, Per
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Cuijpers, Pim
    Department of Clinical Psychology and EMGO Institute, Vrije Universiteit, Amsterdam, The Netherlands.
    Andersson, Gerhard
    Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden, Swedish Institute for Disability Research, Linköping University, Linköping, Sweden, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden.
    Psychodynamic Guided Self-Help for Adult Depression through the Internet: A Randomised Controlled Trial2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e38021-Article in journal (Refereed)
    Abstract [en]

    Abstract

    Background and aims: Psychodynamic psychotherapy (PDT) is an effective treatment for major depressive disorder (MDD), but not all clients with MDD can receive psychotherapy. Using the Internet to provide psychodynamic treatments is one way of improving access to psychological treatments for MDD. The aim of this randomised controlled trial was to investigate the efficacy of an Internet-based psychodynamic guided self-help treatment for MDD.

    Methods: Ninety-two participants who were diagnosed with MDD according to the Mini-International Neuropsychiatric Interview were randomised to treatment or an active control. The treatment consisted of nine treatment modules based on psychodynamic principles with online therapist contact. The active control condition was a structured support intervention and contained psychoeducation and scheduled weekly contacts online. Both interventions lasted for 10 weeks. The primary outcome measure was the Beck Depression Inventory-II (BDI-II).

    Results: Mixed-effects model analyses of all randomised participants showed that participants receiving Internet-based PDT made large and superior improvements compared with the active control group on the BDI-II (between-group Cohen’s d = 1.11). Treatment effects were maintained at a 10-month follow-up.

    Conclusions: Internet-based psychodynamic guided self-help is an efficacious treatment for MDD that has the potential to increase accessibility and availability of PDT for MDD.

  • 281.
    Johansson, Robert
    et al.
    Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden,.
    Sjöberg, Elin
    Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden,.
    Sjögren, Magnus
    Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden,.
    Johansson, Erik
    Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden,.
    Carlbring, Per
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Andersson, Therese
    Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden .
    Rousseau, Andréas
    Psychiatric Clinic, University Hospital of Linköping, Linköping, Sweden.
    Andersson, Gerhard
    Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden; Swedish Institute for Disability Research, Linköping University, Linköping, Sweden; Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden .
    Tailored vs. Standardized Internet-Based Cognitive Behavior Therapy for Depression and Comorbid Symptoms: A Randomized Controlled Trial2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e36905-Article in journal (Refereed)
    Abstract [en]

    Background and Aims:Major depression can be treated by means of cognitive behavior therapy, delivered via the Internet as guided self-help. Individually tailored guided self-help treatments have shown promising results in the treatment of anxiety disorders. This randomized controlled trial tested the efficacy of an Internet-based individually tailored guided selfhelp treatment which specifically targeted depression with comorbid symptoms. The treatment was compared both to standardized (non-tailored) Internet-based treatment and to an active control group in the form of a monitored online discussion group. Both guided self-help treatments were based on cognitive behavior therapy and lasted for 10 weeks. The discussion group consisted of weekly discussion themes related to depression and the treatment of depression.

    Methods:A total of 121 participants with diagnosed major depressive disorder and with a range of comorbid symptoms were randomized to three groups. The tailored treatment consisted of a prescribed set of modules targeting depression as well as comorbid problems. The standardized treatment was a previously tested guided self-help program for depression.

    Results:From pre-treatment to post-treatment, both treatment groups improved on measures of depression, anxiety and quality of life. The results were maintained at a 6-month follow-up. Subgroup analyses showed that the tailored treatment was more effective than the standardized treatment among participants with higher levels of depression at baseline and more comorbidity, both in terms of reduction of depressive symptoms and on recovery rates. In the subgroup with lower baseline scores of depression, few differences were seen between treatments and the discussion group.

    Conclusions:This study shows that tailored Internet-based treatment for depression is effective and that addressing comorbidity by tailoring may be one way of making guided self-help treatments more effective than standardized approaches in the treatment of more severe depression.

  • 282.
    Jonsson, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    San Sebastian, Miguel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Stromsten, Lotta M. J.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hammarstrom, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Social medicine.
    Gustafsson, Per E
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Life Course Pathways of Adversities Linking Adolescent Socioeconomic Circumstances and Functional Somatic Symptoms in Mid-Adulthood: A Path Analysis Study2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0155963Article in journal (Refereed)
    Abstract [en]

    While research examining the health impact of early socioeconomic conditions suggests that effects may exist independently of or jointly with adult socioeconomic position, studies exploring other potential pathways are few. Following a chain of risk life course model, this prospective study seeks to examine whether pathways of occupational class as well as material and social adversities across the life course link socioeconomic disadvantage in adolescent to functional somatic symptoms in mid-adulthood. Applying path analysis, a multiple mediator model was assessed using prospective data collected during 26 years through the Northern Swedish Cohort. The sample contained 987 individuals residing in the municipality of Lulea, Sweden, who participated in questionnaire surveys at age 16, 21, 30 and 42. Socioeconomic conditions (high/low) in adolescence (age 16) were operationalized using the occupation of the parents, while occupational class in adulthood (manual/nonmanual) was measured using the participant's own occupation at age 21 and 30. The adversity measurements were constructed as separate age specific parcels at age 21 and 30. Social adversity included items pertaining to stressful life events that could potentially harm salient relationships, while material adversity was operationalized using items concerning unfavorable financial and material circumstances. Functional somatic symptoms at age 42 was a summary measure of self-reported physical symptoms, palpitation and sleeping difficulties that had occurred during the last 12 months. An association between socioeconomic conditions at age 16 and functional somatic symptoms at age 42 (r = 0.068) which was partially explained by people's own occupational class at age 21 and then material as well as social adversity at age 30 was revealed. Rather than proposing a direct and independent health effect of the socioeconomic conditions of the family, the present study suggests that growing up in an unfavorable socioeconomic environment might be a source for a chain of adverse material and social living situations, which in turn affects adult health.

  • 283.
    Jonsson, Samuel
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Rebecca
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    McGrath, Aleksandra M
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Effect of delayed peripheral nerve repair on nerve regeneration, Schwann cell function and target muscle recovery2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, article id e56484Article in journal (Refereed)
    Abstract [en]

    Despite advances in surgical techniques for peripheral nerve repair, functional restitution remains incomplete. The timing of surgery is one factor influencing the extent of recovery but it is not yet clearly defined how long a delay may be tolerated before repair becomes futile. In this study, rats underwent sciatic nerve transection before immediate (0) or 1, 3, or 6 months delayed repair with a nerve graft. Regeneration of spinal motoneurons, 13 weeks after nerve repair, was assessed using retrograde labeling. Nerve tissue was also collected from the proximal and distal stumps and from the nerve graft, together with the medial gastrocnemius (MG) muscles. A dramatic decline in the number of regenerating motoneurons and myelinated axons in the distal nerve stump was observed in the 3- and 6-months delayed groups. After 3 months delay, the axonal number in the proximal stump increased 2-3 folds, accompanied by a smaller axonal area. RT-PCR of distal nerve segments revealed a decline in Schwann cells (SC) markers, most notably in the 3 and 6 month delayed repair samples. There was also a progressive increase in fibrosis and proteoglycan scar markers in the distal nerve with increased delayed repair time. The yield of SC isolated from the distal nerve segments progressively fell with increased delay in repair time but cultured SC from all groups proliferated at similar rates. MG muscle at 3- and 6-months delay repair showed a significant decline in weight (61% and 27% compared with contra-lateral side). Muscle fiber atrophy and changes to neuromuscular junctions were observed with increased delayed repair time suggestive of progressively impaired reinnervation. This study demonstrates that one of the main limiting factors for nerve regeneration after delayed repair is the distal stump. The critical time point after which the outcome of regeneration becomes too poor appears to be 3-months.

  • 284. Jonsson, Ulf
    et al.
    Bertilsson, Goran
    Allard, Per
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Gyllensvard, Harald
    Soderlund, Anne
    Tham, Anne
    Andersson, Gerhard
    Psychological Treatment of Depression in People Aged 65 Years and Over: A Systematic Review of Efficacy, Safety, and Cost-Effectiveness2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160859Article in journal (Refereed)
    Abstract [en]

    Objectives Depression in elderly people is a major public health concern. As response to antidepressants is often unsatisfactory in this age group, there is a need for evidence-based non-pharmacological treatment options. Our objectives were twofold: firstly, to synthesize published trials evaluating efficacy, safety and cost-effectiveness of psychological treatment of depression in the elderly and secondly, to assess the quality of evidence. Method The electronic databases PubMed, EMBASE, Cochrane Library, CINAL, Scopus, and Psyc-INFO were searched up to 23 May 2016 for randomized controlled trials (RCTs) of psychological treatment for depressive disorders or depressive symptoms in people aged 65 years and over. Two reviewers independently assessed relevant studies for risk of bias. Where appropriate, the results were synthesized in meta-analyses. The quality of the evidence was graded according to GRADE (Grading of Recommendations Assessment, Development and Evaluation). Results Twenty-two relevant RCTs were identified, eight of which were excluded from the synthesis due to a high risk of bias. Of the remaining trials, six evaluated problem-solving therapy (PST), five evaluated other forms of cognitive behavioural therapy (CBT), and three evaluated life review/reminiscence therapy. In frail elderly with depressive symptoms, the evidence supported the efficacy of PST, with large but heterogeneous effect sizes compared with treatment as usual. The results for life-review/reminiscence therapy and CBT were also promising, but because of the limited number of trials the quality of evidence was rated as very low. Safety data were not reported in any included trial. The only identified cost-effectiveness study estimated an incremental cost per additional point reduction in Beck Depression Inventory II score for CBT compared with talking control and treatment as usual. Conclusion Psychological treatment is a feasible option for frail elderly with depressive symptoms. However, important questions about efficacy, generalizability, safety and cost-effectiveness remain.

  • 285.
    Jäger, Gunilla
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Chen, Peng
    Björk, Glenn R.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Transfer RNA Bound to MnmH Protein Is Enriched with Geranylated tRNA - A Possible Intermediate in Its Selenation?2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0153488Article in journal (Refereed)
    Abstract [en]

    The wobble nucleoside 5-methylaminomethyl-2-thio-uridine (mnm(5)s(2)U) is present in bacterial tRNAs specific for Lys and Glu and 5-carboxymethylaminomethyl-2-thio-uridine (cmnm(5)s(2)U) in tRNA specific for Gln. The sulfur of (c) mnm(5)s(2)U may be exchanged by selenium (Se)-a reaction catalyzed by the selenophosphate-dependent tRNA 2-selenouridine synthase encoded by the mnmH (ybbB, selU, sufY) gene. The MnmH protein has a rhodanese domain containing one catalytic Cys (C97) and a P-loop domain containing a Walker A motif, which is a potential nucleotide binding site. We have earlier isolated a mutant of Salmonella enterica, serovar Typhimurium with an alteration in the rhodanese domain of the MnmH protein (G67E) mediating the formation of modified nucleosides having a geranyl (ge)-group (C10H17-fragment) attached to the s(2) group of mnm(5)s(2)U and of cmnm(5)s(2)U in tRNA. To further characterize the structural requirements to increase the geranylation activity, we here report the analysis of 39 independently isolated mutants catalyzing the formation of mnm(5)ges(2)U. All these mutants have amino acid substitutions in the rhodanese domain demonstrating that this domain is pivotal to increase the geranylation activity. The wild type form of MnmH(+) also possesses geranyltransferase activity in vitro although only a small amount of the geranyl derivatives of (c) mnm(5)s(2)U is detected in vivo. The selenation activity in vivo has an absolute requirement for the catalytic Cys97 in the rhodanese domain whereas the geranylation activity does not. Clearly, MnmH has two distinct enzymatic activities for which the rhodanese domain is pivotal. An intact Walker motif in the P-loop domain is required for the geranylation activity implying that it is the binding site for geranylpyrophosphate (GePP), which is the donor molecule in vitro in the geranyltransfer reaction. Purified MnmH from wild type and from the MnmH(G67E) mutant have bound tRNA, which is enriched with geranylated tRNA. This in conjunction with earlier published data, suggests that this bound geranylated tRNA may be an intermediate in the selenation of the tRNA.

  • 286.
    Jäger, Gunilla
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nilsson, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Björk, Glenn R.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The Phenotype of Many Independently Isolated+1 Frameshift Suppressor Mutants Supports a Pivotal Role of the P-Site in Reading Frame Maintenance2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4, p. e60246-Article in journal (Refereed)
    Abstract [en]

    The main features of translation are similar in all organisms on this planet and one important feature of it is the way the ribosome maintain the reading frame. We have earlier characterized several bacterial mutants defective in tRNA maturation and found that some of them correct a +1 frameshift mutation; i.e. such mutants possess an error in reading frame maintenance. Based on the analysis of the frameshifting phenotype of such mutants we proposed a pivotal role of the ribosomal grip of the peptidyl-tRNA to maintain the correct reading frame. To test the model in an unbiased way we first isolated many (467) independent mutants able to correct a +1 frameshift mutation and thereafter tested whether or not their frameshifting phenotypes were consistent with the model. These 467+1 frameshift suppressor mutants had alterations in 16 different loci of which 15 induced a defective tRNA by hypo- or hypermodifications or altering its primary sequence. All these alterations of tRNAs induce a frameshift error in the P-site to correct a +1 frameshift mutation consistent with the proposed model. Modifications next to and 39 of the anticodon (position 37), like 1-methylguanosine, are important for proper reading frame maintenance due to their interactions with components of the ribosomal P-site. Interestingly, two mutants had a defect in a locus (rpsI), which encodes ribosomal protein S9. The C-terminal of this protein contacts position 32-34 of the peptidyl-tRNA and is thus part of the P-site environment. The two rpsI mutants had a C-terminal truncated ribosomal protein S9 that destroys its interaction with the peptidyl-tRNA resulting in +1 shift in the reading frame. The isolation and characterization of the S9 mutants gave strong support of our model that the ribosomal grip of the peptidylt-RNA is pivotal for the reading frame maintenance.

  • 287. Järhult, Josef D
    et al.
    Muradrasoli, Shaman
    Wahlgren, John
    Söderström, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Orozovic, Goran
    Gunnarsson, Gunnar
    Brojer, Caroline
    Latorre-Margalef, Neus
    Fick, Jerker
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Grabic, Roman
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lennerstrand, Johan
    Waldenstrom, Jonas
    Lundkvist, Åke
    Olsen, Björn
    Environmental levels of the antiviral oseltamivir induce development of resistance mutation H274Y in influenza A/H1N1 virus in mallards2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e24742-Article in journal (Refereed)
    Abstract [en]

    Oseltamivir (Tamiflu (R)) is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008-2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried the mutation H274Y in the neuraminidase gene which causes resistance to the drug. The active metabolite of oseltamivir, oseltamivir carboxylate (OC), is poorly degraded in sewage treatment plants and surface water and has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance. To assess if resistance can develop under these circumstances, we infected mallards with influenza A/H1N1 virus and exposed the birds to 80 ng/L, 1 mu g/L and 80 mu g/L of OC through their sole water source. By sequencing the neuraminidase gene from fecal samples, we found that H274Y occurred at 1 mu g/L of OC and rapidly dominated the viral population at 80 mu g/L. IC(50) for OC was increased from 2-4 nM in wild-type viruses to 400-700 nM in H274Y mutants as measured by a neuraminidase inhibition assay. This is consistent with the decrease in sensitivity to OC that has been noted among human clinical isolates carrying H274Y. Environmental OC levels have been measured to 58-293 ng/L during seasonal outbreaks and are expected to reach mu g/L-levels during pandemics. Thus, resistance could be induced in influenza viruses circulating among wild ducks. As influenza viruses can cross species barriers, oseltamivir resistance could spread to human-adapted strains with pandemic potential disabling oseltamivir, a cornerstone in pandemic preparedness planning. We propose surveillance in wild birds as a measure to understand the resistance situation in nature and to monitor it over time. Strategies to lower environmental levels of OC include improved sewage treatment and, more importantly, a prudent use of antivirals.

  • 288.
    Kadzhaev, Konstantin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Golovliov, Igor
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bolanowski, Mark
    Shen, Hua
    Conlan, Wayne
    NRC/ Canada.
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Identification of genes contributing to the virulence of Francisella tularensis SCHU S4 in a mouse intradermal infection model2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 5, p. e5463-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Francisella tularensis is a highly virulent human pathogen. The most virulent strains belong to subspecies tularensis and these strains cause a sometimes fatal disease. Despite an intense recent research effort, there is very limited information available that explains the unique features of subspecies tularensis strains that distinguish them from other F. tularensis strains and that explain their high virulence. Here we report the use of targeted mutagenesis to investigate the roles of various genes or pathways for the virulence of strain SCHU S4, the type strain of subspecies tularensis.

    METHODOLOGY/PRINCIPAL FINDINGS: The virulence of SCHU S4 mutants was assessed by following the outcome of infection after intradermal administration of graded doses of bacteria. By this route, the LD(50) of the SCHU S4 strain is one CFU. The virulence of 20 in-frame deletion mutants and 37 transposon mutants was assessed. A majority of the mutants did not show increased prolonged time to death, among them notably Delta pyrB and Delta recA. Of the remaining, mutations in six unique targets, tolC, rep, FTT0609, FTT1149c, ahpC, and hfq resulted in significantly prolonged time to death and mutations in nine targets, rplA, wbtI, iglB, iglD, purL, purF, ggt, kdtA, and glpX, led to marked attenuation with an LD(50) of > 10(3) CFU. In fact, the latter seven mutants showed very marked attenuation with an LD(50) of > or = 10(7) CFU.

    CONCLUSIONS/SIGNIFICANCE: The results demonstrate that the characterization of targeted mutants yielded important information about essential virulence determinants that will help to identify the so far little understood extreme virulence of F. tularensis subspecies tularensis.

  • 289.
    Kaján, Gyõzõ L.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute for Veterinary Medical Research, Centre for Agricultural Research, Hungarian Academy of Sciences, Budapest, Hungary.
    Lipiec, Agnieszka
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Bartha, Daniel
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    A multigene typing system for human adenoviruses reveals a new genotype in a collection of Swedish clinical isolates2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209038Article in journal (Refereed)
    Abstract [en]

    Human adenoviruses (HAdVs) are common pathogens that can cause respiratory, gastrointestinal, urogenital, and ocular infections. They are divided into seven species containing 85 genotypes. Straightforward typing systems might help epidemiological investigations. As homologous recombination frequently shapes the evolution of HAdVs, information on a single gene is seldom sufficient to allow accurate and precise typing, and complete genome-based methods are recommended. Even so, complete genome analyses are not always easy to perform for practical reasons, and in such cases a multigene system can provide considerably more information about the strain under investigation than single-gene-based methods. Here we present a rapid, generic, multigene typing system for HAdVs based on three main deterministic regions of these viruses. Three PCR systems were used to amplify the genes encoding the DNA polymerase, the penton base hypervariable Arg-Gly-Asp-containing loop, and the hexon loop 1 (hypervariable region 1–6). Using this system, we typed 281 clinical isolates, detected members of six out of seven HAdV species (Human mastadenovirus AF), and could also detect not only divergent strains of established types but also a new recombinant strain with a previously unpublished combination of adenovirus genomes. This strain was accepted by the Human Adenovirus Working Group as a novel genotype: HAdV-86. Seven strains that could not be typed with sufficient accuracy were also investigated using a PCR based on part of the fiber gene. By analysis of corresponding sequences of the 86 known HAdV genotypes, we determined that the proposed typing system should be able to distinguish all non-recombinant types, and with additional fiber information, all known HAdV genotypes.

  • 290.
    Kalezic, Ivana
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Centre for Musculoskeletal Research, University of Gävle, Umeå, Sweden.
    Steffens, Heinz
    Institute of Physiology, University of Göttingen, Göttingen, Germany.
    Changes in Tetrodotoxin-Resistant C-Fibre Activity during Fatiguing Isometric Contractions in the Rat2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e73980-Article in journal (Refereed)
    Abstract [en]

    It is by now well established that tetrodotoxin-resistant (TTX-R) afferent fibres from muscle in the rat exhibit a multisensitive profile, including nociception. TTX-R afferent fibres play an important role in motor control, via spinal and supraspinal loops, but their activation and function during muscle exercise and fatigue are still unknown. Therefore, the specific effect of isometric fatiguing muscle contraction on the responsiveness of TTX-R C-fibres has been investigated in this study. To quantify the TTX-R afferent input we recorded the cord dorsum potential (CDP), which is the result of the electrical fields set up within the spinal cord by the depolarisation of the interneurons located in the dorsal horn, activated by an incoming volley of TTX-R muscle afferents. The changes in TTX-R CDP size before, during and after fatiguing electrical stimulation of the gastrocnemius-soleus (GS) muscle have been taken as a measure of TTX-R C-unit activation. At the end of the fatiguing protocol, following an exponential drop in force, TTX-R CDP area decreased in the majority of trials (9/14) to 0.75 +/- 0.03% (mean +/- SEM) of the pre-fatigue value. Recovery to the control size of the TTX-R CDP was incomplete after 10 min. Furthermore, fatiguing trials could sensitise a fraction of the TTX-R C-fibres responding to muscle pinch. The results suggest a long-lasting activation of the TTX-R muscle afferents after fatiguing stimulation. The role of this behaviour in chronic muscle fatigue in connection with pain development is discussed. Accumulation of metabolites released into the interstitium during fatiguing stimulation might be one of the reasons underlying the C-fibres' long-lasting activation.

  • 291. Kalis, Martins
    et al.
    Bolmeson, Caroline
    Esguerra, Jonathan LS
    Gupta, Shashank
    Edlund, Anna
    Tormo-Badia, Neivis
    Speidel, Dina
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mayans, Sofia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Khoo, Nelson KS
    Wendt, Anna
    Eliasson, Lena
    Cilio, Corrado M
    Beta-cell specific deletion of dicer1 leads to defective insulin secretion and diabetes mellitus2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, p. e29166-Article in journal (Refereed)
    Abstract [en]

    Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting beta-cells, we have generated mice with a beta-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Delta/wt)), RIP-Cre(+/-) Dicer1(flox/flox) mice (RIP-Cre Dicer1(Delta/Delta)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased beta-cell mass, reduced numbers of granules within the beta-cells and reduced granule docking in adult RIP-Cre Dicer1(Delta/Delta) mice. beta-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal beta-cell development as 2-week old RIP-Cre Dicer1(Delta/Delta) mice showed ultrastructurally normal beta-cells and intact insulin secretion. In conclusion, we have demonstrated that a beta-cell specific disruption of the miRNAs network, although allowing for apparently normal beta-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.

  • 292.
    Kalpouzos, Gregoria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Memory Self-Efficacy Beliefs Modulate Brain Activity when Encoding Real-World Future Intentions2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e73850-Article in journal (Refereed)
    Abstract [en]

    Background: While the use of different cognitive strategies when encoding episodic memory information has been extensively investigated, modulation of brain activity by memory self-efficacy beliefs has not been studied yet.

    Methodology/Principal Findings: Sixteen young adults completed the prospective and retrospective metamemory questionnaire, providing individual subjective judgments of everyday memory function. The day after, using functional magnetic resonance imaging, the participants had to memorize real-world intentions (e. g., return a book to the library), which were performed later on in a virtual environment. Participants also performed offline cognitive tasks evaluating executive functions, working memory, and attention. During encoding, activity was found in medial temporal lobe, left prefrontal cortex, medial parietal regions, occipital areas, and regions involved in (pre) motor processes. Based on results from the questionnaire, the group was split into low and high memory self-efficacy believers. Comparison of encoding-related brain activity between the 2 groups revealed that the low memory self-efficacy believers activated more the hippocampus bilaterally, right posterior parahippocampal cortex, precuneus, and left lateral temporal cortex. By contrast, more activity was found in dorsal anterior cingulate gyrus for the high-memory believers. In addition, the low-memory believers performed more poorly at feature binding and (at trend) manipulating visuospatial information in working memory.

    Conclusion/Significance: Overall, these findings indicate that memory self-efficacy beliefs modulate brain activity during intentional encoding. Low memory self-efficacy believers activated more brain areas involved in visuospatial operations such as the hippocampus. Possibly, this increase reflects attempts to compensate for poor performance of certain neurocognitive processes, such as feature binding. By contrast, high-memory believers seemed to rely more on executive-like processes involved in cognitive control.

  • 293.
    Kalpouzos, Grégoria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Eriksson, Johan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Sjölie, Daniel
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Molin, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Neurocognitive systems related to real-world prospective memory2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 10, p. e13304-Article in journal (Refereed)
    Abstract [en]

    Taken together, these findings show how brain systems complementary interact during real-world PM, and support a more complete model of PM that can be applied to naturalistic PM tasks and that we named PROspective MEmory DYnamic (PROMEDY) model because of its dynamics on both multi-phase iteration and the interactions of distinct neurocognitive networks.

  • 294.
    Karah, Nabil
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Jolley, Keith A.
    Hall, Ruth M.
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Database for the ampC alleles in Acinetobacter baumannii2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0176695Article in journal (Refereed)
    Abstract [en]

    Acinetobacter baumannii is a troublesome opportunistic pathogen with a high capacity for clonal dissemination. We announce the establishment of a database for the ampC locus in A. baumannii, in which novel ampC alleles are differentiated based on the occurrence of >= 1 nucleotide change, regardless of whether it is silent or missense. The database is openly accessible at the pubmlst platform for A. baumannii (http://pubmlst.org/abaumannii/). Forty-eight distinctive alleles of the ampC locus have so far been identified and deposited in the database. Isolates from clonal complex 1 (CC1), according to the Pasteur multilocus sequence typing scheme, had a variety of the ampC locus alleles, including alleles 1, 3, 4, 5, 6, 7, 8, 13, 14, 17, and 18. On the other hand, isolates from CC2 had the ampC alleles 2, 3, 19, 20, 21, 22, 23, 24, 26, 27, 28, and 46. Allele 3 was characteristic for sequence types ST3 or ST32. The ampC alleles 10, 16, and 25 were characteristic for CC10, ST16, and CC25, respectively. Our study points out that novel gene databases, in which alleles are numbered based on differences in their nucleotide identities, should replace traditional records that use amino acid substitutions to define new alleles.

  • 295.
    Karah, Nabil
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Samuelsen, Ørjan
    Zarrilli, Raffaele
    Sahl, Jason W.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    CRISPR-cas subtype I-Fb in Acinetobacter baumannii: evolution and utilization for strain subtyping2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 2, article id e0118205Article in journal (Refereed)
    Abstract [en]

    Clustered regularly interspaced short palindromic repeats (CRISPR) are polymorphic elements found in the genome of some or all strains of particular bacterial species, providing them with a system of acquired immunity against invading bacteriophages and plasmids. Two CRISPR-Cas systems have been identified in Acinetobacter baumannii, an opportunistic pathogen with a remarkable capacity for clonal dissemination. In this study, we investigated the mode of evolution and diversity of spacers of the CRISPR-cas subtype I-Fb locus in a global collection of 76 isolates of A. baumannii obtained from 14 countries and 4 continents. The locus has basically evolved from a common ancestor following two main lineages and several pathways of vertical descent. However, this vertical passage has been interrupted by occasional events of horizontal transfer of the whole locus between distinct isolates. The isolates were assigned into 40 CRISPR-based sequence types (CST). CST1 and CST23-24 comprised 18 and 9 isolates, representing two main sub-clones of international clones CC1 and CC25, respectively. Epidemiological data showed that some of the CST1 isolates were acquired or imported from Iraq, where it has probably been endemic for more than one decade and occasionally been able to spread to USA, Canada, and Europe. CST23-24 has shown a remarkable ability to cause national outbreaks of infections in Sweden, Argentina, UAE, and USA. The three isolates of CST19 were independently imported from Thailand to Sweden and Norway, raising a concern about the prevalence of CST19 in Thailand. Our study highlights the dynamic nature of the CRISPR-cas subtype I-Fb locus in A. baumannii, and demonstrates the possibility of using a CRISPR-based approach for subtyping a significant part of the global population of A. baumannii.

  • 296.
    Karalija, Amar
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Neuroprotective Effects of N-Acetyl-Cysteine and Acetyl-L-Carnitine after Spinal Cord Injury in Adult Rats2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41086-Article in journal (Refereed)
    Abstract [en]

    Following the initial acute stage of spinal cord injury, a cascade of cellular and inflammatory responses will lead to progressive secondary damage of the nerve tissue surrounding the primary injury site. The degeneration is manifested by loss of neurons and glial cells, demyelination and cyst formation. Injury to the mammalian spinal cord results in nearly complete failure of the severed axons to regenerate. We have previously demonstrated that the antioxidants N-acetyl-cysteine (NAC) and acetyl-L-carnitine (ALC) can attenuate retrograde neuronal degeneration after peripheral nerve and ventral root injury. The present study evaluates the effects of NAC and ALC on neuronal survival, axonal sprouting and glial cell reactions after spinal cord injury in adult rats. Tibial motoneurons in the spinal cord were pre-labeled with fluorescent tracer Fast Blue one week before lumbar L5 hemisection. Continuous intrathecal infusion of NAC (2.4 mg/day) or ALC (0.9 mg/day) was initiated immediately after spinal injury using Alzet 2002 osmotic minipumps. Neuroprotective effects of treatment were assessed by counting surviving motoneurons and by using quantitative immunohistochemistry and Western blotting for neuronal and glial cell markers 4 weeks after hemisection. Spinal cord injury induced significant loss of tibial motoneurons in L4-L6 segments. Neuronal degeneration was associated with decreased immunostaining for microtubular-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker GFAP and microglial marker OX42 was increased. Treatment with NAC and ALC rescued approximately half of the motoneurons destined to die. In addition, antioxidants restored MAP2 and synaptophysin immunoreactivity. However, the perineuronal synaptophysin labeling was not recovered. Although both treatments promoted axonal sprouting, there was no effect on reactive astrocytes. In contrast, the microglial reaction was significantly attenuated. The results indicate a therapeutic potential for NAC and ALC in the early treatment of traumatic spinal cord injury.

  • 297.
    Karalija, Amar
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Differentiation of pre- and postganglionic nerve injury using MRI of the spinal cord2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0168807Article in journal (Refereed)
    Abstract [en]

    Brachial plexus injury (BPI) is a devastating type of nerve injury, potentially causing loss of motor and sensory function. Principally, BPI is either categorized as preganglionic or post- ganglionic, with the early establishment of injury level being crucial for choosing the correct treatment strategy. Despite diagnostic advances, the need for a reliable, non-invasive method for establishing the injury level remains. We studied the usefulness of in vivo mag- netic resonance imaging (MRI) of the spinal cord for determination of injury level. The find- ings were related to neuronal and glial changes. Rats underwent unilateral L4 & L5 ventral roots avulsion or sciatic nerve axotomy. The injuries served as models for pre- and postgan- glionic BPI, respectively. MRI of the L4/L5 spinal cord segments 4 weeks after avulsion showed ventral horn (VH) shrinkage on the injured side compared to the uninjured side. Axotomy induced no change in the VH size on MRI. Following avulsion, histological sections of L4/L5 revealed shrinkage in the VH grey matter area occupied by NeuN-positive neurons, loss of microtubular-associated protein-2 positive dendritic branches (MAP2), pan-neurofila- ment positive axons (PanNF), synaptophysin-positive synapses (SYN) and increase in immunoreactivity for the microglial OX42 and astroglial GFAP markers. Axotomy induced no changes in NeuN-reactivity, modest decrease of MAP2 immunoreactivity, no changes in SYN and PanNF labelling, and a modest increase in OX42 and SYN labeling. Histological and radiological findings were congruent when assessing changes after axotomy, while MRI somewhat underestimated the shrinkage. This study indicates a potential diagnostic value of structural spinal cord MRI following BPI. 

  • 298. Karat, Aaron S.
    et al.
    Tlali, Mpho
    Fielding, Katherine L.
    Charalambous, Salome
    Chihota, Violet N.
    Churchyard, Gavin J.
    Hanifa, Yasmeen
    Johnson, Suzanne
    McCarthy, Kerrigan
    Martinson, Neil A.
    Omar, Tanvier
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa ; INDEPTH Network, Accra, Ghana.
    Chandramohan, Daniel
    Grant, Alison D.
    Measuring mortality due to HIV-associated tuberculosis among adults in South Africa: Comparing verbal autopsy, minimally-invasive autopsy, and research data2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id e0174097Article in journal (Refereed)
    Abstract [en]

    Background The World Health Organization (WHO) aims to reduce tuberculosis (TB) deaths by 95% by 2035; tracking progress requires accurate measurement of TB mortality. International Classification of Diseases (ICD) codes do not differentiate between HIV-associated TB and HIV more generally. Verbal autopsy (VA) is used to estimate cause of death (CoD) patterns but has mostly been validated against a suboptimal gold standard for HIV and TB. This study, conducted among HIV-positive adults, aimed to estimate the accuracy of VA in ascertaining TB and HIV CoD when compared to a reference standard derived from a variety of clinical sources including, in some, minimally-invasive autopsy (MIA). Methods and findings Decedents were enrolled into a trial of empirical TB treatment or a cohort exploring diagnostic algorithms for TB in South Africa. The WHO 2012 instrument was used; VA CoD were assigned using physician-certified VA (PCVA), InterVA-4, and SmartVA-Analyze. Reference CoD were assigned using MIA, research, and health facility data, as available. 259 VAs were completed: 147 (57%) decedents were female; median age was 39 (interquartile range [IQR] 33-47) years and CD4 count 51 (IQR 22-102) cells/mu L. Compared to reference CoD that included MIA (n = 34), VA underestimated mortality due to HIV/AIDS (94% reference, 74% PCVA, 47% InterVA-4, and 41% SmartVA-Analyze; chance-corrected concordance [CCC] 0.71, 0.42, and 0.31, respectively) and HIV-associated TB (41% reference, 32% PCVA; CCC 0.23). For individual decedents, all VA methods agreed poorly with reference CoD that did not include MIA (n = 259; overall CCC 0.14, 0.06, and 0.15 for PCVA, InterVA-4, and SmartVA-Analyze); agreement was better at population level (cause-specific mortality fraction accuracy 0.78, 0.61, and 0.57, for the three methods, respectively). Conclusions Current VA methods underestimate mortality due to HIV-associated TB. ICD and VA methods need modifications that allow for more specific evaluation of HIV-related deaths and direct estimation of mortality due to HIV-associated TB.

  • 299. Karhula, Sakari
    et al.
    Finnilä, Mikko
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center of Xi'an Jiaotong University; Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, P. R. China.
    Ylärinne, Janne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kauppinen, Sami
    Rieppo, Lassi
    Pritzker, Kenneth P H
    Nieminen, Heikki
    Saarakkala, Simo
    Effects of articular cartilage constituents on phosphotungstic acid enhanced micro-computed tomography2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0171075Article in journal (Refereed)
    Abstract [en]

    Contrast-enhanced micro-computed tomography (CEμCT) with phosphotungstic acid (PTA) has shown potential for detecting collagen distribution of articular cartilage. However, the selectivity of the PTA staining to articular cartilage constituents remains to be elucidated. The aim of this study was to investigate the dependence of PTA for the collagen content in bovine articular cartilage. Adjacent bovine articular cartilage samples were treated with chondroitinase ABC and collagenase to degrade the proteoglycan and the collagen constituents in articular cartilage, respectively. Enzymatically degraded samples were compared to the untreated samples using CEμCT and reference methods, such as Fourier-transform infrared imaging. Decrease in the X-ray attenuation of PTA in articular cartilage and collagen content was observed in cartilage depth of 0-13% and deeper in tissue after collagen degradation. Increase in the X-ray attenuation of PTA was observed in the cartilage depth of 13-39% after proteoglycan degradation. The X-ray attenuation of PTA-labelled articular cartilage in CEμCT is associated mainly with collagen content but the proteoglycans have a minor effect on the X-ray attenuation of the PTA-labelled articular cartilage. In conclusion, the PTA labeling provides a feasible CEμCT method for 3D characterization of articular cartilage.

  • 300.
    Karlsson, Jessica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Inhibition of Endocannabinoid Metabolism by the Metabolites of Ibuprofen and Flurbiprofen2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e103589-Article in journal (Refereed)
    Abstract [en]

    Background: In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. Methodology/Principal Findings:COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. Conclusions/Significance: It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

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