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  • 1.
    Abdullah Nasir, Ahmad
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ligand-specific regulation of transforming growth factor beta superfamily factors by leucine-rich repeats and immunoglobulin-like domains proteins2023In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 8, article id e0289726Article in journal (Refereed)
    Abstract [en]

    Leucine-rich repeats and immunoglobulin-like domains (LRIG) are transmembrane proteins shown to promote bone morphogenetic protein (BMP) signaling in Caenorhabditis elegans, Drosophila melanogaster, and mammals. BMPs comprise a subfamily of the transforming growth factor beta (TGFβ) superfamily, or TGFβ family, of ligands. In mammals, LRIG1 and LRIG3 promote BMP4 signaling. BMP6 signaling, but not BMP9 signaling, is also regulated by LRIG proteins, although the specific contributions of LRIG1, LRIG2, and LRIG3 have not been investigated, nor is it known whether other mammalian TGFβ family members are regulated by LRIG proteins. To address these questions, we took advantage of Lrig-null mouse embryonic fibroblasts (MEFs) with doxycycline-inducible LRIG1, LRIG2, and LRIG3 alleles, which were stimulated with ligands representing all the major TGFβ family subgroups. By analyzing the signal mediators pSmad1/5 and pSmad3, as well as the induction of Id1 expression, we showed that LRIG1 promoted BMP2, BMP4, and BMP6 signaling and suppressed GDF7 signaling; LRIG2 promoted BMP2 and BMP4 signaling; and LRIG3 promoted BMP2, BMP4, BMP6, and GDF7 signaling. BMP9 and BMP10 signaling was not regulated by individual LRIG proteins, however, it was enhanced in Lrig-null cells. LRIG proteins did not regulate TGFβ1-induced pSmad1/5 signaling, or GDF11- or TGFβ1-induced pSmad3 signaling. Taken together, our results show that some, but not all, TGFβ family ligands are regulated by LRIG proteins and that the three LRIG proteins display differential regulatory effects. LRIG proteins thereby provide regulatory means for the cell to further diversify the signaling outcomes generated by a limited number of TGFβ family ligands and receptors.

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  • 2. Abel, Olubunmi
    et al.
    Powell, John F
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Al-Chalabi, Ammar
    Credibility analysis of putative disease-causing genes using bioinformatics2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 6, p. e64899-Article in journal (Refereed)
    Abstract [en]

    Background: Genetic studies are challenging in many complex diseases, particularly those with limited diagnostic certainty, low prevalence or of old age. The result is that genes may be reported as disease-causing with varying levels of evidence, and in some cases, the data may be so limited as to be indistinguishable from chance findings. When there are large numbers of such genes, an objective method for ranking the evidence is useful. Using the neurodegenerative and complex disease amyotrophic lateral sclerosis (ALS) as a model, and the disease-specific database ALSoD, the objective is to develop a method using publicly available data to generate a credibility score for putative disease-causing genes.

    Methods: Genes with at least one publication suggesting involvement in adult onset familial ALS were collated following an exhaustive literature search. SQL was used to generate a score by extracting information from the publications and combined with a pathogenicity analysis using bioinformatics tools. The resulting score allowed us to rank genes in order of credibility. To validate the method, we compared the objective ranking with a rank generated by ALS genetics experts. Spearman's Rho was used to compare rankings generated by the different methods.

    Results: The automated method ranked ALS genes in the following order: SOD1, TARDBP, FUS, ANG, SPG11, NEFH, OPTN, ALS2, SETX, FIG4, VAPB, DCTN1, TAF15, VCP, DAO. This compared very well to the ranking of ALS genetics experts, with Spearman's Rho of 0.69 (P = 0.009).

    Conclusion: We have presented an automated method for scoring the level of evidence for a gene being disease-causing. In developing the method we have used the model disease ALS, but it could equally be applied to any disease in which there is genotypic uncertainty.

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  • 3. Aboagye, Emmanuel
    et al.
    Hagberg, Jan
    Axén, Iben
    Kwak, Lydia
    Lohela-Karlsson, Malin
    Skillgate, Eva
    Dahlgren, Gunilla
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Jensen, Irene
    Individual preferences for physical exercise as secondary prevention for non-specific low back pain: a discrete choice experiment2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 12, article id e0187709Article in journal (Refereed)
    Abstract [en]

    Background: Exercise is effective in improving non-specific low back pain (LBP). Certain components of physical exercise, such as the type, intensity and frequency of exercise, are likely to influence participation among working adults with non-specific LBP, but the value and relative importance of these components remain unknown. The study's aim was to examine such specific components and their influence on individual preferences for exercise for secondary prevention of non-specific LBP among working adults. Methods: In a discrete choice experiment, working individuals with non-specific LBP answered a webbased questionnaire. Each respondent was given ten pairs of hypothetical exercise programs and asked to choose one option from each pair. The choices comprised six attributes of exercise (i.e., type of training, design, intensity, frequency, proximity and incentives), each with either three or four levels. A conditional logit regression that reflected the random utility model was used to analyze the responses. Results: The final study population consisted of 112 participants. The participants' preferred exercise option was aerobic (i.e., cardiovascular) rather than strength training, group exercise with trainer supervision, rather than individual or unsupervised exercise. They also preferred high intensity exercise performed at least once or twice per week. The most popular types of incentive were exercise during working hours and a wellness allowance rather than coupons for sports goods. The results show that the relative value of some attribute levels differed between young adults (age <= 44 years) and older adults (age <= 45 years) in terms of the level of trainer supervision required, exercise intensity, travel time to exercise location and financial incentives. For active study participants, exercise frequency (i.e., twice per week, 1.15; CI: 0.25; 2.06) influenced choice of exercise. For individuals with more than one child, travel time (i.e., 20 minutes, - 0.55; CI: 0.65; 3.26) was also an influential attribute for choice of exercise, showing that people with children at home preferred to exercise close to home. Conclusions: This study adds to our knowledge about what types of exercise working adults with back pain are most likely to participate in. The exercise should be a cardiovascular type of training carried out in a group with trainer supervision. It should also be of high intensity and preferably performed twice per week during working hours. Coupons for sports goods do not appear to motivate physical activity among workers with LBP. The findings of the study could have a substantial impact on the planning and development of exercise provision and promotion strategies to improve non-specific LBP. Providers and employers may be able to improve participation in exercise programs for adults with non-specific LBP by focusing on the exercise components which are the most attractive. This in turn would improve satisfaction and adherence to exercise interventions aimed at preventing recurrent non-specific LBP.

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  • 4.
    Abraha, Atakelti
    et al.
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Tigray Health Bureau, Tigray and Ethiopian Health Insurance Agency, Addis Ababa, Ethiopia.
    Myléus, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Byass, Peter
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Institutes of Applied Health Sciences, School of Medicine and Dentistry, University of Aberdeen, United Kingdom; MRC/Wits Rural Public Health and Health Transitions Research Unit, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Kahsay, Asmelash
    Tigray Health Bureau, Tigray and Ethiopian Health Insurance Agency, Addis Ababa, Ethiopia.
    Kinsman, John
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Department of Public Health Sciences, Global Health (IHCAR), Karolinska Institute, Stockholm, Sweden.
    Social determinants of under-5 child health: A qualitative study in Wolkayit Woreda, Tigray Region, Ethiopia2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 6, article id e0218101Article in journal (Refereed)
    Abstract [en]

    Despite the significant reductions seen in under-5 child mortality in Ethiopia over the last two decades, more than 10,000 children still die each year in Tigray Region alone, of whom 75% die from preventable diseases. Using an equity lens, this study aimed to investigate the social determinants of child health in one particularly vulnerable district as a means of informing the health policy decision-making process. An exploratory qualitative study design was adopted, combining focus group discussions and qualitative interviews. Seven Focus Group Discussions with mothers of young children, and 21 qualitative interviews with health workers were conducted in Wolkayit district in May-June 2015. Data were subjected to thematic analysis. Mothers’ knowledge regarding the major causes of child mortality appeared to be good, and they also knew about and trusted the available child health interventions. However, utilization and practice of these interventions was limited by a range of issues, including cultural factors, financial shortages, limited female autonomy on financial resources, seasonal mobility, and inaccessible or unaffordable health services. Our findings pointed to the importance of a multi-sectoral strategy to improve child health equity and reduce under-5 mortality in Wolkayit. Recommendations include further decentralizing child health services to local-level Health Posts, and increasing the number of Health Facilities based on local topography and living conditions.

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  • 5.
    Acuña Mora, Mariela
    et al.
    Institute of Health and Care Sciences, University of Gothenburg, Gothenburg, Sweden; Faculty of Caring Science, Work Life and Social Welfare, University of Borås, Borås, Sweden.
    Sparud-Lundin, Carina
    Institute of Health and Care Sciences, University of Gothenburg, Gothenburg, Sweden.
    Fernlund, Eva
    Division of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Crown Princess Victoria Children's Hospital, Linköping University Hospital, Linköping, Sweden.
    Fadl, Shalan
    Department of Children and Young Adults, University Hospital Örebro, Sweden.
    Kalliopi, Kazamia
    Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Burström, Åsa
    Karolinska Institute, Department of Neurobiology, Care Sciences and Society, Stockholm, Sweden.
    Hanseus, Katarina
    Children's Heart Center, Skåne University Hospital Lund, Lund, Sweden.
    Moons, Philip
    Institute of Health and Care Sciences, University of Gothenburg, Gothenburg, Sweden; Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium; Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.
    Bratt, Ewa-Lena
    Institute of Health and Care Sciences, University of Gothenburg, Gothenburg, Sweden; Department of Pediatric Cardiology, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    The longitudinal association between patient empowerment and patient-reported outcomes: what is the direction of effect?2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 11, article id e0277267Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Theoretical literature and cross-sectional studies suggest empowerment is associated with other patient-reported outcomes (PROs). However, it is not known if patient empowerment is leading to improvements in other PROs or vice versa. AIMS: The present study aimed to examine the direction of effects between patient empowerment and PROs in young persons with congenital heart disease (CHD). METHODS: As part of the STEPSTONES-CHD trial, adolescents with CHD from seven pediatric cardiology centers in Sweden were included in a longitudinal observational study (n = 132). Data were collected when patients were 16 (T0), 17 (T1) and 18 ½ years old (T2). The Gothenburg Young Persons Empowerment Scale (GYPES) was used to measure patient empowerment. Random intercepts cross-lagged panel models between patient empowerment and PROs (communication skills; patient-reported health; quality of life; and transition readiness) were undertaken. RESULTS: We found a significant cross-lagged effect of transition readiness over patient empowerment between T1 and T2, signifying that a higher level of transition readiness predicted a higher level of patient empowerment. No other significant cross-lagged relationships were found. CONCLUSION: Feeling confident before the transition to adult care is necessary before young persons with CHD can feel in control to manage their health and their lives. Clinicians interested in improving patient empowerment during the transitional period should consider targeting transition readiness.

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  • 6.
    Adamo, Hanibal Hani
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergström, Sofia Halin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Characterization of a Gene Expression Signature in Normal Rat Prostate Tissue Induced by the Presence of a Tumor Elsewhere in the Organ2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 6, article id e0130076Article in journal (Refereed)
    Abstract [en]

    Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating changes in the tumor-bearing organ, for example growth of the vasculature, an altered extracellular matrix, and influx of inflammatory cells. To investigate this response further, we compared prostate morphology and the gene expression profile of tumor-bearing normal rat prostate tissue (termed tumor-instructed/indicating normal tissue (TINT)) with that of prostate tissue from controls. Dunning rat AT-1 prostate cancer cells were injected into rat prostate and tumors were established after 10 days. As controls we used intact animals, animals injected with heat-killed AT-1 cells or cell culture medium. None of the controls showed morphological TINT-changes. A rat Illumina whole-genome expression array was used to analyze gene expression in AT-1 tumors, TINT, and in medium injected prostate tissue. We identified 423 upregulated genes and 38 downregulated genes (p<0.05, >= 2-fold change) in TINT relative to controls. Quantitative RT-PCR analysis verified key TINT-changes, and they were not detected in controls. Expression of some genes was changed in a manner similar to that in the tumor, whereas other changes were exclusive to TINT. Ontological analysis using GeneGo software showed that the TINT gene expression profile was coupled to processes such as inflammation, immune response, and wounding. Many of the genes whose expression is altered in TINT have well-established roles in tumor biology, and the present findings indicate that they may also function by adapting the surrounding tumor-bearing organ to the needs of the tumor. Even though a minor tumor cell contamination in TINT samples cannot be ruled out, our data suggest that there are tumor-induced changes in gene expression in the normal tumor-bearing organ which can probably not be explained by tumor cell contamination. It is important to validate these changes further, as they could hypothetically serve as novel diagnostic and prognostic markers of prostate cancer.

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  • 7.
    Adamo, Hanibal Hani
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Strömvall, Kerstin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nilsson, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Halin Bergström, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Adaptive (TINT) Changes in the Tumor Bearing Organ Are Related to Prostate Tumor Size and Aggressiveness2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 11, article id e0141601Article in journal (Refereed)
    Abstract [en]

    In order to grow, tumors need to induce supportive alterations in the tumor-bearing organ, by us named tumor instructed normal tissue (TINT) changes. We now examined if the nature and magnitude of these responses were related to tumor size and aggressiveness. Three different Dunning rat prostate tumor cells were implanted into the prostate of immune-competent rats; 1) fast growing and metastatic MatLyLu tumor cells 2) fast growing and poorly metastatic AT-1 tumor cells, and 3) slow growing and non-metastatic G tumor cells. All tumor types induced increases in macrophage, mast cell and vascular densities and in vascular cell-proliferation in the tumor-bearing prostate lobe compared to controls. These increases occurred in parallel with tumor growth. The most pronounced and rapid responses were seen in the prostate tissue surrounding MatLyLu tumors. They were, also when small, particularly effective in attracting macrophages and stimulating growth of not only micro-vessels but also small arteries and veins compared to the less aggressive AT-1 and G tumors. The nature and magnitude of tumor-induced changes in the tumor-bearing organ are related to tumor size but also to tumor aggressiveness. These findings, supported by previous observation in patient samples, suggest that one additional way to evaluate prostate tumor aggressiveness could be to monitor its effect on adjacent tissues.

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  • 8. Agogo, George O.
    et al.
    van der Voet, Hilko
    van't Veer, Pieter
    Ferrari, Pietro
    Leenders, Max
    Muller, David C.
    Sanchez-Cantalejo, Emilio
    Bamia, Christina
    Braaten, Tonje
    Knueppel, Sven
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    van Eeuwijk, Fred A.
    Boshuizen, Hendriek
    Use of Two-Part Regression Calibration Model to Correct for Measurement Error in Episodically Consumed Foods in a Single-Replicate Study Design: EPIC Case Study2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 11, p. e113160-Article in journal (Refereed)
    Abstract [en]

    In epidemiologic studies, measurement error in dietary variables often attenuates association between dietary intake and disease occurrence. To adjust for the attenuation caused by error in dietary intake, regression calibration is commonly used. To apply regression calibration, unbiased reference measurements are required. Short-term reference measurements for foods that are not consumed daily contain excess zeroes that pose challenges in the calibration model. We adapted twopart regression calibration model, initially developed for multiple replicates of reference measurements per individual to a single-replicate setting. We showed how to handle excess zero reference measurements by two-step modeling approach, how to explore heteroscedasticity in the consumed amount with variance-mean graph, how to explore nonlinearity with the generalized additive modeling (GAM) and the empirical logit approaches, and how to select covariates in the calibration model. The performance of two-part calibration model was compared with the one-part counterpart. We used vegetable intake and mortality data from European Prospective Investigation on Cancer and Nutrition (EPIC) study. In the EPIC, reference measurements were taken with 24-hour recalls. For each of the three vegetable subgroups assessed separately, correcting for error with an appropriately specified two-part calibration model resulted in about three fold increase in the strength of association with all-cause mortality, as measured by the log hazard ratio. Further found is that the standard way of including covariates in the calibration model can lead to over fitting the two-part calibration model. Moreover, the extent of adjusting for error is influenced by the number and forms of covariates in the calibration model. For episodically consumed foods, we advise researchers to pay special attention to response distribution, nonlinearity, and covariate inclusion in specifying the calibration model.

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  • 9.
    Aguilar, Ximena
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Schleucher, Jurgen
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Interaction Studies of the Human and Arabidopsis thaliana Med25-ACID Proteins with the Herpes Simplex Virus VP16-and Plant-Specific Dreb2a Transcription Factors2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 5, p. e98575-Article in journal (Refereed)
    Abstract [en]

    Mediator is an evolutionary conserved multi-protein complex present in all eukaryotes. It functions as a transcriptional coregulator by conveying signals from activators and repressors to the RNA polymerase II transcription machinery. The Arabidopsis thaliana Med25 (aMed25) ACtivation Interaction Domain (ACID) interacts with the Dreb2a activator which is involved in plant stress response pathways, while Human Med25-ACID (hMed25) interacts with the herpes simplex virus VP16 activator. Despite low sequence similarity, hMed25-ACID also interacts with the plant-specific Dreb2a transcriptional activator protein. We have used GST pull-down-, surface plasmon resonance-, isothermal titration calorimetry and NMR chemical shift experiments to characterize interactions between Dreb2a and VP16, with the hMed25 and aMed25-ACIDs. We found that VP16 interacts with aMed25-ACID with similar affinity as with hMed25-ACID and that the binding surface on aMed25-ACID overlaps with the binding site for Dreb2a. We also show that the Dreb2a interaction region in hMed25-ACID overlaps with the earlier reported VP16 binding site. In addition, we show that hMed25-ACID/Dreb2a and aMed25-ACID/Dreb2a display similar binding affinities but different binding energetics. Our results therefore indicate that interaction between transcriptional regulators and their target proteins in Mediator are less dependent on the primary sequences in the interaction domains but that these domains fold into similar structures upon interaction.

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  • 10.
    Ahmad, Irfan
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
    Karah, Nabil
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Nadeem, Aftab
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    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).
    Analysis of colony phase variation switch in Acinetobacter baumannii clinical isolates2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 1, article id e0210082Article in journal (Refereed)
    Abstract [en]

    Reversible switching between opaque and translucent colony formation is a novel feature of Acinetobacter baumannii that has been associated with variations in the cell morphology, surface motility, biofilm formation, antibiotic resistance and virulence. Here, we assessed a number of phenotypic alterations related to colony switching in A. baumannii clinical isolates belonging to different multi-locus sequence types. Our findings demonstrated that these phenotypic alterations were mostly strain-specific. In general, the translucent subpopulations of A. baumannii produced more dense biofilms, were more piliated, and released larger amounts of outer membrane vesicles (OMVs). In addition, the translucent subpopulations caused reduced fertility of Caenorhabditis elegans. When assessed for effects on the immune response in RAW 264.7 macrophages, the OMVs isolated from opaque subpopulations of A. baumannii appeared to be more immunogenic than the OMVs from the translucent form. However, also the OMVs from the translucent subpopulations had the potential to evoke an immune response. Therefore, we suggest that OMVs may be considered for development of new immunotherapeutic treatments against A. baumannii infections.

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  • 11. Al Nimer, Faiez
    et al.
    Thelin, Eric
    Nystrom, Harriet
    Dring, Ann M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Piehl, Fredrik
    Nelson, David W.
    Bellander, Bo-Michael
    Comparative Assessment of the Prognostic Value of Biomarkers in Traumatic Brain Injury Reveals an Independent Role for Serum Levels of Neurofilament Light2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 7, article id e0132177Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) is a common cause of death and disability, worldwide. Early determination of injury severity is essential to improve care. Neurofilament light (NF-L) has been introduced as a marker of neuroaxonal injury in neuroinflammatory/-degenerative diseases. In this study we determined the predictive power of serum (s-) and cerebrospinal fluid (CSF-) NF-L levels towards outcome, and explored their potential correlation to diffuse axonal injury (DAI). A total of 182 patients suffering from TBI admitted to the neurointensive care unit at a level 1 trauma center were included. S-NF-L levels were acquired, together with S100B and neuron-specific enolase (NSE). CSF-NF-L was measured in a subcohort (n = 84) with ventriculostomies. Clinical and neuro-radiological parameters, including computerized tomography (CT) and magnetic resonance imaging, were included in the analyses. Outcome was assessed 6 to 12 months after injury using the Glasgow Outcome Score (1-5). In univariate proportional odds analyses mean s-NF-L, -S100B and -NSE levels presented a pseudo-R-2 Nagelkerke of 0.062, 0.214 and 0.074 in correlation to outcome, respectively. In a multivariate analysis, in addition to a model including core parameters (pseudo-R-2 0.33 towards outcome; Age, Glasgow Coma Scale, pupil response, Stockholm CT score, abbreviated injury severity score, S100B), S-NF-L yielded an extra 0.023 pseudo-R-2 and a significantly better model (p = 0.006) No correlation between DAI or CT assessed-intracranial damage and NF-L was found. Our study thus demonstrates that SNF-L correlates to TBI outcome, even if used in models with S100B, indicating an independent contribution to the prediction, perhaps by reflecting different pathophysiological processes, not possible to monitor using conventional neuroradiology. Although we did not find a predictive value of NF-L for DAI, this cannot be completely excluded. We suggest further

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  • 12. Alarcon, Flora
    et al.
    Plante-Bordeneuve, Violaine
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Norrlands university hospital, NUS M31, Umeå, Sweden.
    Nuel, Gregory
    Non-parametric estimation of survival in age-dependent genetic disease and application to the transthyretin-related hereditary amyloidosis2018In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 9, article id e0203860Article in journal (Refereed)
    Abstract [en]

    In genetic diseases with variable age of onset, survival function estimation for the mutation carriers as well as estimation of the modifying factors effects are essential to provide individual risk assessment, both for mutation carriers management and prevention strategies. In practice, this survival function is classically estimated from pedigrees data where most genotypes are unobserved. In this article, we present a unifying Expectation-Maximization (EM) framework combining probabilistic computations in Bayesian networks with standard statistical survival procedures in order to provide mutation carrier survival estimates. The proposed approach allows to obtain previously published parametric estimates (e.g. Weibull survival) as particular cases as well as more general Kaplan-Meier non-parametric estimates, which is the main contribution. Note that covariates can also be taken into account using a proportional hazard model. The whole methodology is both validated on simulated data and applied to family samples with transthyretin-related hereditary amyloidosis (a rare autosomal dominant disease with highly variable age of onset), showing very promising results.

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  • 13.
    Alex, Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Fjellman-Wiklund, Anncristine
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Lundman, Berit
    Umeå University, Faculty of Medicine, Department of Nursing.
    Christianson, Monica
    Umeå University, Faculty of Medicine, Department of Nursing.
    Hammarström, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Beyond a Dichotomous View of the Concepts of 'Sex' and 'Gender' Focus Group Discussions among Gender Researchers at a Medical Faculty2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 11, p. e50275-Article in journal (Refereed)
    Abstract [en]

    Introduction: The concepts of 'sex' and 'gender' are both of vital importance in medicine and health sciences. However, the meaning of these concepts has seldom been discussed in the medical literature. The aim of this study was to explore what the concepts of 'sex' and 'gender' meant for gender researchers based in a medical faculty. Methods: Sixteen researchers took part in focus group discussions. The analysis was performed in several steps. The participating researchers read the text and discussed ideas for analysis in national and international workshops. The data were analysed using qualitative content analysis. The authors performed independent preliminary analyses, which were further developed and intensively discussed between the authors. Results: The analysis of meanings of the concepts of 'sex' and 'gender' for gender researchers based in a medical faculty resulted in three categories; "Sex as more than biology", with the subcategories 'sex' is not simply biological, 'sex' as classification, and 'sex' as fluid and changeable; "Gender as a multiplicity of power-related constructions", with the subcategories: 'gender' as constructions, 'gender' power dimensions, and 'gender' as doing femininities and masculinities; "'Sex and gender as interwoven", with the subcategories: 'sex' and 'gender' as inseparable and embodying 'sex' and 'gender'. Conclusions: Gender researchers within medicine pointed out the importance of looking beyond a dichotomous view of the concepts of 'sex' and 'gender'. The perception of the concepts was that 'sex' and 'gender' were intertwined. Further research is needed to explore how 'sex' and 'gender' interact.

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  • 14.
    Al-Furoukh, Natalie
    et al.
    Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
    Kardon, Julia R
    Krüger, Marcus
    Szibor, Marten
    Baker, Tania A
    Braun, Thomas
    NOA1, a novel ClpXP substrate, takes an unexpected nuclear detour prior to mitochondrial import.2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 7Article in journal (Refereed)
    Abstract [en]

    The mitochondrial matrix GTPase NOA1 is a nuclear encoded protein, essential for mitochondrial protein synthesis, oxidative phosphorylation and ATP production. Here, we demonstrate that newly translated NOA1 protein is imported into the nucleus, where it localizes to the nucleolus and interacts with UBF1 before nuclear export and import into mitochondria. Mutation of the nuclear localization signal (NLS) prevented both nuclear and mitochondrial import while deletion of the N-terminal mitochondrial targeting sequence (MTS) or the C-terminal RNA binding domain of NOA1 impaired mitochondrial import. Absence of the MTS resulted in accumulation of NOA1 in the nucleus and increased caspase-dependent apoptosis. We also found that export of NOA1 from the nucleus requires a leptomycin-B sensitive, Crm1-dependent nuclear export signal (NES). Finally, we show that NOA1 is a new substrate of the mitochondrial matrix protease complex ClpXP. Our results uncovered an unexpected, mandatory detour of NOA1 through the nucleolus before uptake into mitochondria. We propose that nucleo-mitochondrial translocation of proteins is more widespread than previously anticipated providing additional means to control protein bioavailability as well as cellular communication between both compartments.

  • 15. Ameh, Soter
    et al.
    D'Ambruoso, Lucia
    Gomez-Olive, Francesc Xavier
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Tollman, Stephen M.
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health.
    Klipstein-Grobusch, Kerstin
    Paradox of HIV stigma in an integrated chronic disease care in rural South Africa: Viewpoints of service users and providers2020In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 7, article id e0236270Article in journal (Refereed)
    Abstract [en]

    Background

    An integrated chronic disease management (ICDM) model was introduced by the National Department of Health in South Africa to tackle the dual burden of HIV/AIDS and non-communicable diseases. One of the aims of the ICDM model is to reduce HIV-related stigma. This paper describes the viewpoints of service users and providers on HIV stigma in an ICDM model in rural South Africa.

    Materials and methods

    A content analysis of HIV stigmatisation in seven primary health care (PHC) facilities and their catchment communities was conducted in 2013 in the rural Agincourt sub-district, South Africa. Eight Focus Group Discussions were used to obtain data from 61 purposively selected participants who were 18 years and above. Seven In-Depth Interviews were conducted with the nurses-in-charge of the facilities. The transcripts were inductively analysed using MAXQDA 2018 qualitative software.

    Results

    The emerging themes were HIV stigma, HIV testing and reproductive health-related concerns. Both service providers and users perceived implementation of the ICDM model may have led to reduced HIV stigma in the facilities. On the other hand, service users and providers thought HIV stigma increased in the communities because community members thought that home-based carers visited the homes of People living with HIV. Service users thought that routine HIV testing, intended for pregnant women, was linked with unwanted pregnancies among adolescents who wanted to use contraceptives but refused to take an HIV test as a precondition for receiving contraceptives.

    Conclusions

    Although the ICDM model was perceived to have contributed to reducing HIV stigma in the health facilities, it was linked with stigma in the communities. This has implications for practice in the community component of the ICDM model in the study setting and elsewhere in South Africa.

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  • 16.
    Amer, Ayad
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Costa, Tiago
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Farag, Salah
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Avican, Ummehan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Forsberg, Åke
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Francis, Matthew
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Genetically engineered frameshifted YopN-TyeA chimeras influence type III secretion system function in Yersinia pseudotuberculosis2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 10, article id e77767Article in journal (Refereed)
    Abstract [en]

    Type III secretion is a tightly controlled virulence mechanism utilized by many gram negative bacteria to colonize their eukaryotic hosts. To infect their host, human pathogenic Yersinia spp. translocate protein toxins into the host cell cytosol through a preassembled Ysc-Yop type III secretion device. Several of the Ysc-Yop components are known for their roles in controlling substrate secretion and translocation. Particularly important in this role is the YopN and TyeA heterodimer. In this study, we confirm that Y. pseudotuberculosis naturally produce a 42 kDa YopN-TyeA hybrid protein as a result of a +1 frame shift near the 3 prime of yopN mRNA, as has been previously reported for the closely related Y. pestis. To assess the biological role of this YopN-TyeA hybrid in T3SS by Y. pseudotuberculosis, we used in cis site-directed mutagenesis to engineer bacteria to either produce predominately the YopN-TyeA hybrid by introducing +1 frame shifts to yopN after codon 278 or 287, or to produce only singular YopN and TyeA polypeptides by introducing yopN sequence from Y. enterocolitica, which is known not to produce the hybrid. Significantly, the engineered 42 kDa YopN-TyeA fusions were abundantly produced, stable, and were efficiently secreted by bacteria in vitro. Moreover, these bacteria could all maintain functionally competent needle structures and controlled Yops secretion in vitro. In the presence of host cells however, bacteria producing the most genetically altered hybrids (+1 frameshift after 278 codon) had diminished control of polarized Yop translocation. This corresponded to significant attenuation in competitive survival assays in orally infected mice, although not at all to the same extent as Yersinia lacking both YopN and TyeA proteins. Based on these studies with engineered polypeptides, most likely a naturally occurring YopN-TyeA hybrid protein has the potential to influence T3S control and activity when produced during Yersinia-host cell contact.

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  • 17.
    Anan, Intissar
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Liszewska, Katarzyna
    Department of Medicine, Piteå Hospital, Piteå, Sweden.
    Baranda, Jorge Mejia
    Department of Medicine, Piteå Hospital, Piteå, Sweden.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wixner, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Ihse, Elisabet
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Amyloid fibril composition type is consistent over time in patients with Val30Met (p. Val50Met) transthyretin amyloidosis2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 3, article id e0266092Article in journal (Refereed)
    Abstract [en]

    Background: We have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses.

    Material and methods: Abdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot.

    Results: All 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies.

    Discussion: The result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.

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  • 18.
    Andersson, Agneta
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Marine Sciences Centre (UMF).
    Jurgensone, Iveta
    Rowe, Owen F.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Simonelli, Paolo
    Bignert, Anders
    Lundberg, Erik
    Umeå University, Faculty of Science and Technology, Umeå Marine Sciences Centre (UMF).
    Karlsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Can Humic Water Discharge Counteract Eutrophication in Coastal Waters?2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 4, p. e61293-Article in journal (Refereed)
    Abstract [en]

    A common and established view is that increased inputs of nutrients to the sea, for example via river flooding, will cause eutrophication and phytoplankton blooms in coastal areas. We here show that this concept may be questioned in certain scenarios. Climate change has been predicted to cause increased inflow of freshwater to coastal areas in northern Europe. River waters in these areas are often brown from the presence of high concentrations of allochthonous dissolved organic carbon ( humic carbon), in addition to nitrogen and phosphorus. In this study we investigated whether increased inputs of humic carbon can change the structure and production of the pelagic food web in the recipient seawater. In a mesocosm experiment unfiltered seawater from the northern Baltic Sea was fertilized with inorganic nutrients and humic carbon (CNP), and only with inorganic nutrients (NP). The system responded differently to the humic carbon addition. In NP treatments bacterial, phytoplankton and zooplankton production increased and the systems turned net autotrophic, whereas the CNP-treatment only bacterial and zooplankton production increased driving the system to net heterotrophy. The size-structure of the food web showed large variations in the different treatments. In the enriched NP treatments the phytoplankton community was dominated by filamentous >20 mu m algae, while in the CNP treatments the phytoplankton was dominated by picocyanobacteria <5 mu m. Our results suggest that climate change scenarios, resulting in increased humic-rich river inflow, may counteract eutrophication in coastal waters, leading to a promotion of the microbial food web and other heterotrophic organisms, driving the recipient coastal waters to net-heterotrophy.

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  • 19.
    Andersson, Gerhard
    et al.
    Department of Behavioural Sciences and Learning, Swedish Institute for Disability Research, Linköping University, Linkö ping, Sweden and Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden.
    Carlbring, Per
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Furmark, Tomas
    Department of Psychology, Uppsala University, Uppsala, Sweden.
    Therapist experience and knowledge acquisition in internet-delivered CBT for social anxiety disorder: a randomized controlled trial2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 5, p. e37411-Article in journal (Refereed)
    Abstract [en]

    Background: Guided internet-delivered cognitive behavior therapy (ICBT) has been tested in several trials on social anxiety disorder (SAD) with moderate to large effects. The aims of this study were threefold. First, to compare the effects of ICBT including online discussion forum with a moderated online discussion forum only. Second, to investigate if knowledge about SAD increased following treatment and third to compare the effects of inexperienced versus experienced therapists on patient outcomes.

    Methods: A total of 204 participants with a primary diagnosis of SAD were included and randomized to either guided ICBT or the control condition. ICBT consisted of a 9-week treatment program which was guided by either psychology students at MSc level (n = 6) or by licensed psychologists with previous experience of ICBT (n = 7). A knowledge test dealing with social anxiety was administered before and after treatment. Measures of social anxiety and secondary outcomes dealing with general anxiety, depression, and quality of life were administered before and after treatment. In addition, a 1-year follow-up was conducted on the treated individuals.

    Results: Immediately following treatment, the ICBT group showed superior outcome on the Liebowitz Social Anxiety Scale self-report version with a between group posttreatment Hedges geffect size ofg = 0.75. In addition, significant differences on all the secondary outcomes were observed. Gains were well maintained one year later. Knowledge, as assessed by the knowledge test, increased following treatment with little gain in the control group. Therapist experience did not result in different outcomes, but experienced therapists logged in less frequently compared to the inexperienced therapists, suggesting that they needed less time to support patients.

    Discussion: We conclude that guided ICBT reduce symptoms of SAD, increase knowledge about SAD and that therapist experience does not make a difference apart from the finding that experienced therapist may require less time to guide patients.

    Trial Registration: UMIN.ac.jp UMIN000001383

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  • 20.
    Andersson, Ida E
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, C David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Batsalova, Tsvetelina
    Medicinal Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Dzhambazov, Balik
    Medicinal Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Holmdahl, Rikard
    Medicinal Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Kihlberg, Jan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Linusson, Anna
    AstraZeneca R&D Mölndal, Mölndal.
    Design of glycopeptides used to investigate class II MHC binding and T-Cell responses associated with autoimmune arthritis2011In: PLOS ONE, E-ISSN 1932-6203, Vol. 6, no 3, p. e17881-Article in journal (Refereed)
    Abstract [en]

    The glycopeptide fragment CII259–273 from type II collagen (CII) binds to the murine Aq and human DR4 class II Major Histocompatibility Complex (MHC II) proteins, which are associated with development of murine collagen-induced arthritis (CIA) and rheumatoid arthritis (RA), respectively. It has been shown that CII259–273 can be used in therapeutic vaccination of CIA. This glycopeptide also elicits responses from T-cells obtained from RA patients, which indicates that it has an important role in RA as well. We now present a methodology for studies of (glyco)peptide-receptor interactions based on a combination of structure-based virtual screening, ligand-based statistical molecular design and biological evaluations. This methodology included the design of a CII259–273 glycopeptide library in which two anchor positions crucial for binding in pockets of Aq and DR4 were varied. Synthesis and biological evaluation of the designed glycopeptides provided novel structure-activity relationship (SAR) understanding of binding to Aq and DR4. Glycopeptides that retained high affinities for these MHC II proteins and induced strong responses in panels of T-cell hybridomas were also identified. An analysis of all the responses revealed groups of glycopeptides with different response patterns that are of high interest for vaccination studies in CIA. Moreover, the SAR understanding obtained in this study provides a platform for the design of second-generation glycopeptides with tuned MHC affinities and T-cell responses.

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  • 21.
    Andersson, Johanna
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Rosell, Michelle
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Kockum, Karin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lilja-Lund, Otto
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Soderstrom, Lars
    Laurell, Katarina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Prevalence of idiopathic normal pressure hydrocephalus: A prospective, population-based study2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 5, article id e0217705Article in journal (Refereed)
    Abstract [en]

    Background: Idiopathic normal pressure hydrocephalus (iNPH) causing gait impairment, dementia and urinary incontinence among the elderly, is probably under-diagnosed and under-treated. Despite being known since the 1960s, there is still a lack of prospective, population-based studies on the prevalence of iNPH. Such studies are warranted to minimize selection bias and estimate the true prevalence of the disease.

    Methods: The prevalence of iNPH was determined in a randomly selected sample of residents, aged 65 years and older, in the Swedish county of Jämtland. Out of 1,000 individuals invited to participate, 673 (67.3%) completed a questionnaire with seven questions on iNPH symptoms. A subgroup, with and without self-reported symptoms, participated in clinical and radiological evaluations and were diagnosed according to international guidelines. Measurement of cerebrospinal fluid opening pressure was not performed as it was considered too invasive.

    Results: Those who reported at least two symptoms in the questionnaire (n = 117) and 51 randomly selected individuals with 0–1 symptom participated in further examinations. Out of them, 25 individuals received the diagnosis probable iNPH according to American-European guidelines (except for the criterion of CSF opening pressure) corresponding to a prevalence of 3.7%. The prevalence of iNPH was four times higher among those aged 80 years and older (8.9%) than among those aged 65–79 years (2.1%) (p <0.001). The difference in prevalence between men (4.6%) and women (2.9%) was not significant (p = 0.24). When iNPH was diagnosed according to the Japanese guidelines the prevalence was 1.5%

    Conclusions: In this prospective, population-based study the prevalence of iNPH was 3.7% among individuals 65 years and older, and more common in the higher age group, 80 years and above. INPH should be increasingly recognized since it is a fairly common condition and an important cause of gait impairment and dementia among the elderly that can be effectively treated by shunt surgery.

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  • 22. Andersson, Jon
    et al.
    Hjältén, Joakim
    Dynesius, Mats
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Wood-Inhabiting Beetles in Low Stumps, High Stumps and Logs on Boreal Clear-Cuts: Implications for Dead Wood Management2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 3, article id e0118896Article in journal (Refereed)
    Abstract [en]

    The increasing demand for biofuels from logging residues require serious attention on the importance of dead wood substrates on clear-cuts for the many forestry-intolerant saproxylic (wood-inhabiting) species. In particular, the emerging harvest of low stumps motivates further study of these substrates. On ten clear-cuts we compared the species richness, abundance and species composition of saproxylic beetles hatching from four to nine year old low stumps, high stumps and logs of Norway spruce. By using emergence traps we collected a total of 2,670 saproxylic beetles among 195 species during the summers of 2006, 2007 and 2009. We found that the species assemblages differed significantly between high stumps and logs all three years. The species assemblages of low stumps, on the other hand, were intermediate to those found in logs and high stumps. There were also significant difference in species richness between the three examined years, and we found significant effect of substrate type on richness of predators and fungivores. As shown in previous studies of low stumps on clear-cuts they can sustain large numbers of different saproxylic beetles, including red-listed species. Our study does, in addition to this fact, highlight a possible problem in creating just one type of substrate as a tool for conservation in forestry. Species assemblages in high stumps did not differ significantly from those found in low stumps. Instead logs, which constitute a scarcer substrate type on clear-cuts, provided habitat for a more distinct assemblage of saproxylic species than high stumps. It can therefore be questioned whether high stumps are an optimal tool for nature conservation in clear-cutting forestry. Our results also indicate that low stumps constitute an equally important substrate as high stumps and logs, and we therefore suggest that stump harvesting is done after carefully evaluating measures to provide habitat for saproxylic organisms.

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  • 23. Andersson, Karin
    et al.
    Pokrzywa, M
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Inhibition of TTR aggregation-induced cell death: a new role for serum amyloid P component2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 2Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Serum amyloid P component (SAP) is a glycoprotein that is universally found associated with different types of amyloid deposits. It has been suggested that it stabilizes amyloid fibrils and therefore protects them from proteolytic degradation.

    METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we show that SAP binds not only to mature amyloid fibrils but also to early aggregates of amyloidogenic mutants of the plasma protein transthyretin (TTR). It does not inhibit fibril formation of TTR mutants, which spontaneously form amyloid in vitro at physiological pH. We found that SAP prevents cell death induced by mutant TTR, while several other molecules that are also known to decorate amyloid fibrils do not have such effect. Using a Drosophila model for TTR-associated amyloidosis, we found a new role for SAP as a protective factor in inhibition of TTR-induced toxicity. Overexpression of mutated TTR leads to a neurological phenotype with changes in wing posture. SAP-transgenic flies were crossed with mutated TTR-expressing flies and the results clearly confirmed a protective effect of SAP on TTR-induced phenotype, with an almost complete reduction in abnormal wing posture. Furthermore, we found in vivo that binding of SAP to mutated TTR counteracts the otherwise detrimental effects of aggregation of amyloidogenic TTR on retinal structure.

    CONCLUSIONS/SIGNIFICANCE: Together, these two approaches firmly establish the protective effect of SAP on TTR-induced cell death and degenerative phenotypes, and suggest a novel role for SAP through which the toxicity of early amyloidogenic aggregates is attenuated.

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  • 24. Ankarfeldt, Mikkel Z.
    et al.
    Ängquist, Lars
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Clinical Sciences in Malmö, Diabetes and Cardiovascular Diseases, Genetic Epidemiology, Lund University, Lund, Sweden.
    Jakobsen, Marianne U.
    Overvad, Kim
    Halkjær, Jytte
    Saris, Wim H. M.
    Astrup, Arne
    Sørensen, Thorkild I. A.
    Body characteristics, dietary protein and body weight regulation. Reconciling conflicting results from intervention and observational studies?2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 7, p. e101134-Article in journal (Refereed)
    Abstract [en]

    Background/Objectives: Physiological evidence indicates that high-protein diets reduce caloric intake and increase thermogenic response, which may prevent weight gain and regain after weight loss. Clinical trials have shown such effects, whereas observational cohort studies suggest an association between greater protein intake and weight gain. In both types of studies the results are based on average weight changes, and show considerable diversity in both directions. This study investigates whether the discrepancy in the evidence could be due to recruitment of overweight and obese individuals into clinical trials. Subjects/Methods: Data were available from the European Diet, Obesity and Genes (DiOGenes) post-weight-loss weight-maintenance trial and the Danish Diet, Cancer and Health (DCH) cohort. Participants of the DCH cohort were matched with participants from the DiOGenes trial on gender, diet, and body characteristics. Different subsets of the DCH-participants, comparable with the trial participants, were analyzed for weight maintenance according to the randomization status (high or low protein) of the matched trial participants. Results: Trial participants were generally heavier, had larger waist circumference and larger fat mass than the participants in the entire DCH cohort. A better weight maintenance in the high-protein group compared to the low protein group was observed in the subgroups of the DCH cohort matching body characteristics of the trial participants. Conclusion: This modified observational study, minimized the differences between the RCT and observational data with regard to dietary intake, participant characteristics and statistical analysis. Compared with low protein diet the high protein diet was associated with better weight maintenance when individuals with greater body mass index and waist circumference were analyzed. Selecting subsets of large-scale observational cohort studies with similar characteristics as participants in clinical trials may reconcile the otherwise conflicting results.

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  • 25. Annandale, Ellen
    et al.
    Hammarström, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Socialmedicin.
    Gender Inequality in the Couple Relationship and Leisure-Based Physical Exercise2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 7, article id e0133348Article in journal (Refereed)
    Abstract [en]

    Aims: To analyse whether gender inequality in the couple relationship was related to leisure-based physical activity, after controlling for earlier physical activity and confounders. Methods: Data drawn from the Northern Swedish Cohort of all pupils in their final year of compulsory schooling in a town in the North of Sweden. The sample consisted of 772 respondents (n = 381 men, n = 391 women) in the 26-year follow-up (in 2007, aged 42) who were either married or cohabiting. Ordinal regression, for men and women separately, was used to assess the association between gender inequality (measured as self-perceived equality in the couple relationship using dummy variables) and a measure of exercise frequency, controlling for prior exercise frequency, socioeconomic status, the presence of children in the home, and longer than usual hours in paid work. Results: The perception of greater gender equality in the couple relationship was associated with higher levels of physical activity for both men and women. This remained significant when the other variables were controlled for. Amongst men the confidence intervals were high. Conclusions: The results point to the potential of perceived gender equality in the couple relationship to counteract the general time poverty and household burden that often arises from the combination of paid work and responsibility for children and the home, especially for women. The high confidence intervals among men indicate the need for more research within the field with larger samples.

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  • 26.
    Antoniewicz, Lukasz
    et al.
    Division of Internal Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden; Division of Pulmonology, Department of Medicine II, Medical University of Vienna, Vienna, Austria.
    Kabele, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Nilsson, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Rankin, Gregory
    Bosson, Jenny A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundbäck, Magnus
    Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden.
    Chronic snus use in healthy males alters endothelial function and increases arterial stiffness2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 6, article id e0268746Article in journal (Refereed)
    Abstract [en]

    Background: Snus usage is commonly touted as a safer alternative to cigarette smoking. However, recent studies have demonstrated possible adverse cardiovascular effects in chronic snus users. The present study evaluates the effects of chronic snus use on vascular function by assessing central arterial stiffness and endothelial vasodilatory function in healthy chronic snus users as compared to matched non-users.

    Methods and results: Fifty healthy males (24 snus users, 26 age-matched controls) with a mean age of 44 years were included in the study. Arterial stiffness was assessed employing both pulse wave velocity and pulse wave analysis. Endothelial vasodilatory function was measured by venous occlusion plethysmography, utilizing intra-arterial administration of acetylcholine, glyceryl trinitrate and bradykinin to further gauge endothelium-dependent and -independent vasodilatory function. Arterial stiffness was significantly higher in chronic snus users as compared to controls: pulse wave velocity [m/s]: 6.6±0.8 vs 7.1±0.9 resp. (p = 0.026), augmentation index corrected for heart rate [%]: 0.1±13.2 vs 7.3±7.8 resp. (p = 0.023). Endothelial independent vasodilation, i.e. the reaction to glyceryl trinitrate, was significantly lower in snus users as measured by venous occlusion plethysmography.

    Conclusions: The results of this study show an increased arterial stiffness and an underlying endothelial dysfunction in daily snus users as compared to matched non-tobacco controls. These findings indicate that long-term use of snus may alter the function of the endothelium and therefore reinforces the assertion that chronic snus use is correlated to an increased risk of development of cardiovascular disease.

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  • 27.
    Antoniewicz, Lukasz
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Karolinska Institutet, Department of Clinical Sciences, Division of Internal Medicine, Danderyd Hospital, Stockholm, Sweden.
    Novo, Mirza
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Bosson, Jenny A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Lundbäck, Magnus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Brief exposure to Swedish snus causes divergent vascular responses in healthy male and female volunteers2018In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 4, article id e0195493Article in journal (Refereed)
    Abstract [en]

    Introduction: The use of Swedish oral moist snuff, known as snus, has for a long time been limited to the Scandinavian countries. With declining cigarette sales in the western world, tobacco companies have looked to the development of alternative tobacco products. In 2006 snus products were launched in the US. Even though several studies have demonstrated negative health effects, snus is often depicted as harmless.

    The aim of the present study was to investigate acute vascular effects of snus as measured by arterial stiffness as well as blood pressure and heart rate.

    Methods: Two separate randomized double-blind crossover studies with the same study design were pooled for analysis. Twenty-nine healthy snus-users (17 females, 12 males) were included. Snus (Göteborgs Rapé) and tobacco free snus (Onico) were administered in a randomized order at two separate visits. Arterial stiffness, blood pressure and heart rate were measured at baseline as well as every five minutes for 40 minutes during exposure. Following snus removal, measurements continued for 30 minutes post exposure. Arterial stiffness was measured using pulse wave velocity (Vicorder) and pulse wave analysis (Sphygmocor).

    Results: Compared to placebo, snus significantly increased systolic and diastolic blood pressure as well as heart rate, however, only in females (p = 0.004, p = 0.006 and p<0.001 respectively). No changes were seen in arterial stiffness measurements in either gender.

    Conclusion: We observed an increase in blood pressure and heart rate only in females, but not in males due to snus usage as compared to placebo. This novel finding was surprising and needs to be further investigated considering most of the earlier studies have mainly focused on male snus users and the increasing usage of snus among females.

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  • 28.
    Antti, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Näsström, Elin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kouremenos, Konstantinos
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sundén-Cullberg, Jonas
    Guo, Yongzhi
    Moritz, Thomas
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Fällman, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Metabolic profiling for detection of staphylococcus aureus infection and antibiotic resistance2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 2, article id e56971Article in journal (Refereed)
    Abstract [en]

    Due to slow diagnostics, physicians must optimize antibiotic therapies based on clinical evaluation of patients without specific information on causative bacteria. We have investigated metabolomic analysis of blood for the detection of acute bacterial infection and early differentiation between ineffective and effective antibiotic treatment. A vital and timely therapeutic difficulty was thereby addressed: the ability to rapidly detect treatment failures because of antibiotic-resistant bacteria. Methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) were used and for infecting mice, while natural MSSA infection was studied in humans. Samples of bacterial growth media, the blood of infected mice and of humans were analyzed with combined Gas Chromatography/Mass Spectrometry. Multivariate data analysis was used to reveal the metabolic profiles of infection and the responses to different antibiotic treatments. experiments resulted in the detection of 256 putative metabolites and mice infection experiments resulted in the detection of 474 putative metabolites. Importantly, ineffective and effective antibiotic treatments were differentiated already two hours after treatment start in both experimental systems. That is, the ineffective treatment of MRSA using cloxacillin and untreated controls produced one metabolic profile while all effective treatment combinations using cloxacillin or vancomycin for MSSA or MRSA produced another profile. For further evaluation of the concept, blood samples of humans admitted to intensive care with severe sepsis were analyzed. One hundred thirty-three putative metabolites differentiated severe MSSA sepsis (n = 6) from severe sepsis (n = 10) and identified treatment responses over time. Combined analysis of human, , and mice samples identified 25 metabolites indicative of effective treatment of sepsis. Taken together, this study provides a proof of concept of the utility of analyzing metabolite patterns in blood for early differentiation between ineffective and effective antibiotic treatment in acute infections.

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  • 29.
    Antti, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sellstedt, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Metabolic effects of an aspartate aminotransferase-inhibitor on two T-cell lines2018In: PLOS ONE, E-ISSN 1932-6203, Vol. 13, no 12, article id e0208025Article in journal (Refereed)
    Abstract [en]

    An emerging method to help elucidate the mode of action of experimental drugs is to use untargeted metabolomics of cell-systems. The interpretations of such screens are however complex and more examples with inhibitors of known targets are needed. Here two T-cell lines were treated with an inhibitor of aspartate aminotransferase and analyzed with untargeted GC-MS. The interpretation of the data was enhanced by the use of two different cell-lines and supports aspartate aminotransferase as a target. In addition, the data suggest an unexpected off-target effect on glutamate decarboxylase. The results exemplify the potency of metabolomics to provide insight into both mode of action and off-target effects of drug candidates.

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  • 30.
    Arvidsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Westermark, Per
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Amyloid Cardiomyopathy in Hereditary Transthyretin V30M Amyloidosis - Impact of Sex and Amyloid Fibril Composition2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 11, article id e0143456Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Transthyretin V30M (ATTR V30M) amyloidosis is a phenotypically diverse disease with symptoms ranging from predominant neuropathy to exclusive cardiac manifestations. The aims of this study were to determine the dispersion of the two types of fibrils found in Swedish ATTR V30M patients -Type A consisting of a mixture of truncated and full length ATTR fibrils and type B fibrils consisting of full length fibrils, and to estimate the severity of cardiac dysfunction in relation to fibril composition and sex.

    MATERIAL AND METHODS: Echocardiographic data were analysed in 107 Swedish ATTR V30M patients with their fibril composition determined as either type A or type B. Measurements of left ventricular (LV) dimensions and evaluation of systolic and diastolic function including speckle tracking derived strain were performed. Patients were grouped according to fibril type and sex. Multivariate linear regression was utilised to determine factors of significant impact on LV thickness.

    RESULTS: There was no significant difference in proportions of the two types of fibrils between men and women. In patients with type A fibrils, women had significantly lower median septal (p = 0.007) and posterior wall thicknesses (p = 0.010), lower median LV mass indexed to height (p = 0.008), and higher septal strain (p = 0.037), as compared to males. These differences were not apparent in patients with type B fibrils. Multiple linear regression analysis revealed that fibril type, sex and age all had significant impact on LV septal thickness.

    CONCLUSION: This study demonstrates a clear difference between sexes in the severity of amyloid heart disease in ATTR V30M amyloidosis patients. Even though type A fibrils were associated with more advanced amyloid heart disease compared to type B, women with type A fibrils generally developed less cardiac infiltration than men. The differences may explain the better outcome for liver transplanted late-onset female patients compared to males.

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  • 31. Asaf, Sajjad
    et al.
    Khan, Abdul Latif
    Aaqil Khan, Muhammad
    Imran, Qari Muhammad
    School of Applied Biosciences, Kyungpook National University, Daegu, Republic of Korea.
    Kang, Sang-Mo
    Al-Hosni, Khdija
    Jeong, Eun Ju
    Lee, Ko Eun
    Lee, In-Jung
    Comparative analysis of complete plastid genomes from wild soybean (Glycine soja) and nine other Glycine species2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 8Article in journal (Refereed)
    Abstract [en]

    The plastid genomes of different plant species exhibit significant variation, thereby providing valuable markers for exploring evolutionary relationships and population genetics. Glycine soja (wild soybean) is recognized as the wild ancestor of cultivated soybean (G. max), representing a valuable genetic resource for soybean breeding programmes. In the present study, the complete plastid genome of Gsoja was sequenced using Illumina paired-end sequencing and then compared it for the first time with previously reported plastid genome sequences from nine other Glycine species. The Gsoja plastid genome was 152,224 bp in length and possessed a typical quadripartite structure, consisting of a pair of inverted repeats (IRa/IRb; 25,574 bp) separated by small (178,963 bp) and large (83,181 bp) single-copy regions, with a 51-kb inversion in the large single-copy region. The genome encoded 134 genes, including 87 protein-coding genes, eight ribosomal RNA genes, and 39 transfer RNA genes, and possessed 204 randomly distributed microsatellites, including 15 forward, 25 tandem, and 34 palindromic repeats. Whole-plastid genome comparisons revealed an overall high degree of sequence similarity between Gmax and Ggracilis and some divergence in the intergenic spacers of other species. Greater numbers of indels and SNP substitutions were observed compared with Gcyrtoloba. The sequence of the accD gene from Gsoja was highly divergent from those of the other species except for Gmax and Ggracilis. Phylogenomic analyses of the complete plastid genomes and 76 shared genes yielded an identical topology and indicated that Gsoja is closely related to Gmax and Ggracilis. The complete Gsoja genome sequenced in the present study is a valuable resource for investigating the population and evolutionary genetics of Glycine species and can be used to identify related species.

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  • 32. Asghar, Naveed
    et al.
    Lindblom, Pontus
    Melik, Wessam
    Lindqvist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Haglund, Mats
    Forsberg, Pia
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Andreassen, Åshild
    Lindgren, Per-Eric
    Johansson, Magnus
    Tick-borne encephalitis virus sequenced directly from questing and blood-feeding ticks reveals quasispecies variance2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 7, p. e103264-Article in journal (Refereed)
    Abstract [en]

    The increased distribution of the tick-borne encephalitis virus (TBEV) in Scandinavia highlights the importance of characterizing novel sequences within the natural foci. In this study, two TBEV strains: the Norwegian Mandal 2009 (questing nymphs pool) and the Swedish Saringe 2009 (blood-fed nymph) were sequenced and phylogenetically characterized. Interestingly, the sequence of Mandal 2009 revealed the shorter form of the TBEV genome, similar to the highly virulent Hypr strain, within the 3' non-coding region (3'NCR). A different genomic structure was found in the 3'NCR of Saringe 2009, as in-depth analysis demonstrated TBEV variants with different lengths within the poly(A) tract. This shows that TBEV quasispecies exists in nature and indicates a putative shift in the quasispecies pool when the virus switches between invertebrate and vertebrate environments. This prompted us to further sequence and analyze the 3'NCRs of additional Scandinavian TBEV strains and control strains, Hypr and Neudoerfl. Toro 2003 and Habo 2011 contained mainly a short (A) 3C(A)6 poly(A) tract. A similar pattern was observed for the human TBEV isolates 1993/783 and 1991/4944; however, one clone of 1991/4944 contained an (A) 3C(A)11 poly(A) sequence, demonstrating that quasispecies with longer poly(A) could be present in human isolates. Neudoerfl has previously been reported to contain a poly(A) region, but to our surprise the resequenced genome contained two major quasispecies variants, both lacking the poly(A) tract. We speculate that the observed differences are important factors for the understanding of virulence, spread, and control of the TBEV.

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  • 33. Atherton, Sarah
    et al.
    Jondelius, Ulf
    A taxonomic review and revisions of Microstomidae (Platyhelminthes: Macrostomorpha)2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 4, article id e0212073Article, review/survey (Refereed)
    Abstract [en]

    Microstomidae (Platyhelminthes: Macrostomorpha) diversity has been almost entirely ignored within recent years, likely due to inconsistent and often old taxonomic literature and a general rarity of sexually mature collected specimens. Herein, we reconstruct the phylogenetic relationships of the group using both previously published and new 18S and CO1 gene sequences. We present some taxonomic revisions of Microstomidae and further describe 8 new species of Microstomum based on both molecular and morphological evidence. Finally, we briefly review the morphological taxonomy of each species and provide a key to aid in future research and identification that is not dependent on reproductive morphology. Our goal is to clarify the taxonomy and facilitate future research into an otherwise very understudied group of tiny (but important) flatworms.

  • 34. Audet, Carolyn M.
    et al.
    Ngobeni, Sizzy
    Graves, Erin
    Wagner, Ryan G.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Agincourt Research Unit, School of Public Health, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.
    Mixed methods inquiry into traditional healers' treatment of mental, neurological and substance abuse disorders in rural South Africa2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 12, article id e0188433Article in journal (Refereed)
    Abstract [en]

    Background: Traditional healers are acceptable and highly accessible health practitioners throughout sub-Saharan Africa. Patients in South Africa often seek concurrent traditional and allopathic treatment leading to medical pluralism. Methods & findings: We studied the cause of five traditional illnesses known locally as "Mavabyi ya nhloko" (sickness of the head), by conducting 27 in-depth interviews and 133 surveys with a randomly selected sample of traditional healers living and working in rural, northeastern South Africa. These interviews were carried out to identify treatment practices of mental, neurological, and substance abuse (MNS) disorders. Participating healers were primarily female (77%), older in age (median: 58.0 years; interquartile range [IQR]: 50-67), had very little formal education (median: 3.7 years; IQR: 3.2-4.2), and had practiced traditional medicine for many years (median: 17 years; IQR: 9.5-30). Healers reported having the ability to successfully treat: seizure disorders (47%), patients who have lost touch with reality (47%), paralysis on one side of the body (59%), and substance abuse (21%). Female healers reported a lower odds of treating seizure disorders (Odds Ratio (OR): 0.47), patients who had lost touch with reality (OR: 0.26; p-value<0.05), paralysis of one side of the body (OR: 0.36), and substance abuse (OR: 0.36) versus males. Each additional year of education received was found to be associated with lower odds, ranging from 0.13-0.27, of treating these symptoms. Each additional patient seen by healers in the past week was associated with roughly 1.10 higher odds of treating seizure disorders, patients who have lost touch with reality, paralysis of one side of the body, and substance abuse. Healers charged a median of 500 South African Rand (similar to US$35) to treat substance abuse, 1000 Rand (similar to US$70) for seizure disorders or paralysis of one side of the body, and 1500 Rand (similar to US$105) for patients who have lost touch with reality. Conclusions: While not all healers elect to treat MNS disorders, many continue to do so, delaying allopathic health services to acutely ill patients.

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  • 35.
    Ayeni, Oluwatosin A.
    et al.
    Faculty of Health Sciences, Division of Epidemiology and biostatistics, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa.
    Walaza, Sibongile
    Faculty of Health Sciences, Division of Epidemiology and biostatistics, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; National Institute for Communicable Diseases of the National Health Laboratory Service, Centre for Respiratory Diseases and Meningitis, Johannesburg, South Africa.
    Tempia, Stefano
    Faculty of Health Sciences, Division of Epidemiology and biostatistics, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; Influenza Division, Centers for Disease Control and Prevention, GA, Atlanta, United States; Influenza Programme, Centers for Disease Control and Prevention-South Africa, Pretoria, South Africa; Mass Genics, GA, Duluth, United States.
    Groome, Michelle
    Faculty of Health Sciences, Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Technology, National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa.
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Epidemiology and Global Health. Faculty of Health Sciences, MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; INDEPTH Network, Accra, Ghana.
    Madhi, Shabir A.
    National Institute for Communicable Diseases of the National Health Laboratory Service, Centre for Respiratory Diseases and Meningitis, Johannesburg, South Africa; Faculty of Health Sciences, Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa; Department of Science and Technology, National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa.
    Cohen, Adam L.
    Influenza Division, Centers for Disease Control and Prevention, GA, Atlanta, United States; Influenza Programme, Centers for Disease Control and Prevention-South Africa, Pretoria, South Africa.
    Moyes, Jocelyn
    National Institute for Communicable Diseases of the National Health Laboratory Service, Centre for Respiratory Diseases and Meningitis, Johannesburg, South Africa.
    Venter, Marietjie
    Department of Medical Virology, University of Pretoria, Pretoria, South Africa.
    Pretorius, Marthi
    National Institute for Communicable Diseases of the National Health Laboratory Service, Centre for Respiratory Diseases and Meningitis, Johannesburg, South Africa; Department of Medical Virology, University of Pretoria, Pretoria, South Africa.
    Treurnicht, Florette
    National Institute for Communicable Diseases of the National Health Laboratory Service, Centre for Respiratory Diseases and Meningitis, Johannesburg, South Africa.
    Hellferscee, Orienka
    Faculty of Health Sciences, Division of Epidemiology and biostatistics, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; School of Pathology, University of the Witwatersrand, Johannesburg, South Africa.
    Von Gottberg, Anne
    National Institute for Communicable Diseases of the National Health Laboratory Service, Centre for Respiratory Diseases and Meningitis, Johannesburg, South Africa; School of Pathology, University of the Witwatersrand, Johannesburg, South Africa; Division of Infectious Diseases, Hubert Department of Global Health, Rollins School of Public Health, School of Medicine, Emory University, GA, Atlanta, United States.
    Wolter, Nicole
    National Institute for Communicable Diseases of the National Health Laboratory Service, Centre for Respiratory Diseases and Meningitis, Johannesburg, South Africa; School of Pathology, University of the Witwatersrand, Johannesburg, South Africa.
    Cohen, Cheryl
    Faculty of Health Sciences, Division of Epidemiology and biostatistics, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; National Institute for Communicable Diseases of the National Health Laboratory Service, Centre for Respiratory Diseases and Meningitis, Johannesburg, South Africa.
    Mortality in children aged <5 years with severe acute respiratory illness in a high HIV-prevalence urban and rural areas of South Africa, 2009–20132021In: PLOS ONE, E-ISSN 1932-6203, Vol. 16, no 8, article id e0255941Article in journal (Refereed)
    Abstract [en]

    Background: Severe acute respiratory illness (SARI) is an important cause of mortality in young children, especially in children living with HIV infection. Disparities in SARI death in children aged <5 years exist in urban and rural areas.

    Objective: To compare the factors associated with in-hospital death among children aged <5 years hospitalized with SARI in an urban vs. a rural setting in South Africa from 2009–2013.

    Methods: Data were collected from hospitalized children with SARI in one urban and two rural sentinel surveillance hospitals. Nasopharyngeal aspirates were tested for ten respiratory viruses and blood for pneumococcal DNA using polymerase chain reaction. We used multivariable logistic regression to identify patient and clinical characteristics associated with in-hospital death.

    Results: From 2009 through 2013, 5,297 children aged <5 years with SARI-associated hospital admission were enrolled; 3,811 (72%) in the urban and 1,486 (28%) in the rural hospitals. In-hospital case-fatality proportion (CFP) was higher in the rural hospitals (6.9%) than the urban hospital (1.3%, p<0.001), and among HIV-infected than the HIV-uninfected children (9.6% vs. 1.6%, p<0.001). In the urban hospital, HIV infection (odds ratio (OR):11.4, 95% confidence interval (CI):5.4–24.1) and presence of any other underlying illness (OR: 3.0, 95% CI: 1.0–9.2) were the only factors independently associated with death. In the rural hospitals, HIV infection (OR: 4.1, 95% CI: 2.3–7.1) and age <1 year (OR: 3.7, 95% CI: 1.9–7.2) were independently associated with death, whereas duration of hospitalization ≥5 days (OR: 0.5, 95% CI: 0.3–0.8) and any respiratory virus detection (OR: 0.4, 95% CI: 0.3–0.8) were negatively associated with death.

    Conclusion: We found that the case-fatality proportion was substantially higher among children admitted to rural hospitals and HIV infected children with SARI in South Africa. While efforts to prevent and treat HIV infections in children may reduce SARI deaths, further efforts to address health care inequality in rural populations are needed.

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  • 36.
    Backeström, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Papadopoulos, Konstantin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Blennow, Kaj
    Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at University of Gothenburg, Mö lndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mö lndal, Sweden.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mö lndal, Sweden; Department of Neurodegenerative Disease, Ucl Institute of Neurology, Queen Square, London, United Kingdom; UK Dementia Research Institute at Ucl, London, United Kingdom.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Acute hyperglycaemia leads to altered frontal lobe brain activity and reduced working memory in type 2 diabetes2021In: PLOS ONE, E-ISSN 1932-6203, Vol. 16, no 3, article id e0247753Article in journal (Refereed)
    Abstract [en]

    How acute hyperglycaemia affects memory functions and functional brain responses in individuals with and without type 2 diabetes is unclear. Our aim was to study the association between acute hyperglycaemia and working, semantic, and episodic memory in participants with type 2 diabetes compared to a sex- A nd age-matched control group. We also assessed the effect of hyperglycaemia on working memory-related brain activity. A total of 36 participants with type 2 diabetes and 34 controls (mean age, 66 years) underwent hyperglycaemic clamp or placebo clamp in a blinded and randomised order. Working, episodic, and semantic memory were tested. Overall, the control group had higher working memory (mean z-score 33.15 ± 0.45) than the group with type 2 diabetes (mean z-score 31.8 ± 0.44, p = 0.042) considering both the placebo and hyperglycaemic clamps. Acute hyperglycaemia did not influence episodic, semantic, or working memory performance in either group. Twenty-two of the participants (10 cases, 12 controls, mean age 69 years) were randomly invited to undergo the same clamp procedures to challenge working memory, using 1-, 2-, and 3-back, while monitoring brain activity by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). The participants with type 2 diabetes had reduced working memory during the 1- A nd 2-back tests. fMRI during placebo clamp revealed increased BOLD signal in the left lateral frontal cortex and the anterior cingulate cortex as a function of working memory load in both groups (3>2>1). During hyperglycaemia, controls showed a similar load-dependent fMRI response, whereas the type 2 diabetes group showed decreased BOLD response from 2-to 3-back. These results suggest that impaired glucose metabolism in the brain affects working memory, possibly by reducing activity in important frontal brain areas in persons with type 2 diabetes.

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  • 37.
    Backman, Ludvig
    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, Sports Medicine.
    Fong, Gloria
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Andersson, Gustav
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Scott, Alexander
    Vancouver Coastal Health and Research Institute, University of British Columbia, Vancouver.
    Danielson, Patrik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Substance P is a mechanoresponsive, autocrine regulator of human tenocyte proliferation2011In: PLOS ONE, E-ISSN 1932-6203, Vol. 6, no 11, p. e27209-Article in journal (Refereed)
    Abstract [en]

    It has been hypothesised that substance P (SP) may be produced by primary fibroblastic tendon cells (tenocytes), and that this production, together with the widespread distribution of the neurokinin-1 receptor (NK-1 R) in tendon tissue, could play an important role in the development of tendinopathy, a condition of chronic tendon pain and thickening. The aim of this study was to examine the possibility of endogenous SP production and the expression of NK-1 R by human tenocytes. Because tendinopathy is related to overload, and because the predominant tissue pathology (tendinosis) underlying early tendinopathy is characterized by tenocyte hypercellularity, the production of SP in response to loading/strain and the effects of exogenously administered SP on tenocyte proliferation were also studied. A cell culture model of primary human tendon cells was used. The vast majority of tendon cells were immunopositive for the tenocyte/fibroblast markers tenomodulin and vimentin, and immunocytochemical counterstaining revealed that positive immunoreactions for SP and NK-1 R were seen in a majority of these cells. Gene expression analyses showed that mechanical loading (strain) of tendon cell cultures using the FlexCell (R) technique significantly increased the mRNA levels of SP, whereas the expression of NK-1 R mRNA decreased in loaded as compared to unloaded tendon cells. Reduced NK-1 R protein was also observed, using Western blot, after exogenously administered SP at a concentration of 10(-7) M. SP exposure furthermore resulted in increased cell metabolism, increased cell viability, and increased cell proliferation, all of which were found to be specifically mediated via the NK-1 R; this in turn involving a common mitogenic cell signalling pathway, namely phosphorylation of ERK1/2. This study indicates that SP, produced by tenocytes in response to mechanical loading, may regulate proliferation through an autocrine loop involving the NK-1 R.

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  • 38.
    Baek, Seung Ki
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Choi, Jung-Kyoo
    Kim, Beom Jun
    Dworkin's Paradox2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 6, p. e38529-Article in journal (Refereed)
    Abstract [en]

    How to distribute welfare in a society is a key issue in the subject of distributional justice, which is deeply involved with notions of fairness. Following a thought experiment by Dworkin, this work considers a society of individuals with different preferences on the welfare distribution and an official to mediate the coordination among them. Based on a simple assumption that an individual's welfare is proportional to how her preference is fulfilled by the actual distribution, we show that an egalitarian preference is a strict Nash equilibrium and can be favorable even in certain inhomogeneous situations. These suggest how communication can encourage and secure a notion of fairness.

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  • 39. Bahnan, Wael
    et al.
    Boettner, Douglas R.
    Westermark, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Fällman, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Schesser, Kurt
    Pathogenic Yersinia Promotes Its Survival by Creating an Acidic Fluid-Accessible Compartment on the Macrophage Surface2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 8, article id e0133298Article in journal (Refereed)
    Abstract [en]

    Microbial pathogens and host immune cells each initiate events following their interaction in an attempt to drive the outcome to their respective advantage. Here we show that the bacterial pathogen Yersinia pseudotuberculosis sustains itself on the surface of a macrophage by forming acidic fluid-accessible compartments that are partially bounded by the host cell plasma membrane. These Yersinia-containing acidic compartments (YACs) are bereft of the early endosomal marker EEA1 and the lysosomal antigen LAMP1 and readily form on primary macrophages as well as macrophage-like cell lines. YAC formation requires the presence of the Yersinia virulence plasmid which encodes a type III secretion system. Unexpectedly, we found that the initial formation of YACs did not require translocation of the type III effectors into the host cell cytosol; however, the duration of YACs was markedly greater in infections using translocation-competent Y. pseudotuberculosis strains as well as strains expressing the effector YopJ. Furthermore, it was in this translocation- and YopJ-dependent phase of infection that the acidic environment was critical for Y. pseudotuberculosis survival during its interaction with macrophages. Our findings indicate that during its extracellular phase of infection Y. pseudotuberculosis initiates and then, by a separate mechanism, stabilizes the formation of a highly intricate structure on the surface of the macrophage that is disengaged from the endocytic pathway.

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  • 40.
    Bandau, Franziska
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Decker, Vicki Huizu Guo
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Gundale, Michael J.
    Department of Forest Ecology and Management, Swedish University of Agricultural Sciences, SE 90183 Umeå, Sweden.
    Albrectsen, Benedicte Riber
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Department of Plant and Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, DK 1871 Frederiksberg C, Denmark.
    Genotypic tannin levels in Populus tremula impact the way nitrogen enrichment affects growth and allocation responses for some traits and not for others2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 10, article id e0140971Article in journal (Refereed)
    Abstract [en]

    Plant intraspecific variability has been proposed as a key mechanism by which plants adapt to environmental change. In boreal forests where nitrogen availability is strongly limited, nitrogen addition happens indirectly through atmospheric N deposition and directly through industrial forest fertilization. These anthropogenic inputs of N have numerous environmental consequences, including shifts in plant species composition and reductions in plant species diversity. However, we know less about how genetic differences within plant populations determine how species respond to eutrophication in boreal forests. According to plant defense theories, nitrogen addition will cause plants to shift carbon allocation more towards growth and less to chemical defense, potentially enhancing vulnerability to antagonists. Aspens are keystone species in boreal forests that produce condensed tannins to serve as chemical defense. We conducted an experiment using ten Populus tremula genotypes from the Swedish Aspen Collection that express extreme levels of baseline investment into foliar condensed tannins. We investigated whether investment into growth and phenolic defense compounds in young plants varied in response to two nitrogen addition levels, corresponding to atmospheric N deposition and industrial forest fertilization. Nitrogen addition generally caused growth to increase, and tannin levels to decrease; however, individualistic responses among genotypes were found for height growth, biomass of specific tissues, root: shoot ratios, and tissue lignin and N concentrations. A genotype's baseline ability to produce and store condensed tannins also influenced plant responses to N, although this effect was relatively minor. High-tannin genotypes tended to grow less biomass under low nitrogen levels and more at the highest fertilization level. Thus, the ability in aspen to produce foliar tannins is likely associated with a steeper reaction norm of growth responses, which suggests a higher plasticity to nitrogen addition, and potentially an advantage when adapting to higher concentrations of soil nitrogen.

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  • 41.
    Barajas-Lopez, Juan de Dios
    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).
    Kremnev, Dmitry
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Shaikhali, Jehad
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Pinas-Fernandez, Aurora
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Strand, Åsa
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    PAPP5 is involved in the tetrapyrrole mediated plastid signalling during chloroplast development2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 3, article id e60305Article in journal (Refereed)
    Abstract [en]

    The initiation of chloroplast development in the light is dependent on nuclear encoded components. The nuclear genes encoding key components in the photosynthetic machinery are regulated by signals originating in the plastids. These plastid signals play an essential role in the regulation of photosynthesis associated nuclear genes (PhANGs) when proplastids develop into chloroplasts. One of the plastid signals is linked to the tetrapyrrole biosynthesis and accumulation of the intermediates the Mg-ProtoIX and its methyl ester Mg-ProtoIX-ME. Phytochrome-Associated Protein Phosphatase 5 (PAPP5) was isolated in a previous study as a putative Mg-ProtoIX interacting protein. In order to elucidate if there is a biological link between PAPP5 and the tetrapyrrole mediated signal we generated double mutants between the Arabidopsis papp5 and the crd mutants. The crd mutant over-accumulates Mg-ProtoIX and Mg-ProtoIX-ME and the tetrapyrrole accumulation triggers retrograde signalling. The crd mutant exhibits repression of PhANG expression, altered chloroplast morphology and a pale phenotype. However, in the papp5crd double mutant, the crd phenotype is restored and papp5crd accumulated wild type levels of chlorophyll, developed proper chloroplasts and showed normal induction of PhANG expression in response to light. Tetrapyrrole feeding experiments showed that PAPP5 is required to respond correctly to accumulation of tetrapyrroles in the cell and that PAPP5 is most likely a component in the plastid signalling pathway down stream of the tetrapyrrole Mg-ProtoIX/Mg-ProtoIX-ME. Inhibition of phosphatase activity phenocopied the papp5crd phenotype in the crd single mutant demonstrating that PAPP5 phosphatase activity is essential to mediate the retrograde signal and to suppress PhANG expression in the crd mutant. Thus, our results suggest that PAPP5 receives an inbalance in the tetrapyrrole biosynthesis through the accumulation of Mg-ProtoIX and acts as a negative regulator of PhANG expression during chloroplast biogenesis and development.

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  • 42.
    Barcena-Uribarri, Ivan
    et al.
    Universität Würzburg, Germany.
    Thein, Marcus
    Universität Würzburg and Jacobs University Bremen, Germany.
    Maier, Elke
    Universität Würzburg, Germany.
    Bonde, Mari
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bergström, Sven
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Benz, Roland
    Universität Würzburg, Germany.
    Use of Nonelectrolytes Reveals the Channel Size and Oligomeric Constitution of the Borrelia burgdorferi P66 Porin2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 11, p. e78272-Article in journal (Refereed)
    Abstract [en]

    In the Lyme disease spirochete Borrelia burgdorferi, the outer membrane protein P66 is capable of pore formation with an atypical high single-channel conductance of 11 nS in 1 M KCl, which suggested that it could have a larger diameter than 'normal' Gram-negative bacterial porins. We studied the diameter of the P66 channel by analyzing its single-channel conductance in black lipid bilayers in the presence of different nonelectrolytes with known hydrodynamic radii. We calculated the filling of the channel with these nonelectrolytes and the results suggested that nonelectrolytes (NEs) with hydrodynamic radii of 0.34 nm or smaller pass through the pore, whereas neutral molecules with greater radii only partially filled the channel or were not able to enter it at all. The diameter of the entrance of the P66 channel was determined to be <= 1.9 nm and the channel has a central constriction of about 0.8 nm. The size of the channel appeared to be symmetrical as judged from one-sidedness of addition of NEs. Furthermore, the P66-induced membrane conductance could be blocked by 80-90% by the addition of the nonelectrolytes PEG 400, PEG 600 and maltohexaose to the aqueous phase in the low millimolar range. The analysis of the power density spectra of ion current through P66 after blockage with these NEs revealed no chemical reaction responsible for channel block. Interestingly, the blockage of the single-channel conductance of P66 by these NEs occurred in about eight subconductance states, indicating that the P66 channel could be an oligomer of about eight individual channels. The organization of P66 as a possible octamer was confirmed by Blue Native PAGE and immunoblot analysis, which both demonstrated that P66 forms a complex with a mass of approximately 460 kDa. Two dimension SDS PAGE revealed that P66 is the only polypeptide in the complex.

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  • 43. Barman, Malin
    et al.
    Johansson, Sara
    Hesselmar, Bill
    Wold, Agnes E.
    Sandberg, Ann-Sofie
    Sandin, Anna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    High Levels of Both n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids in Cord Serum Phospholipids Predict Allergy Development2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 7, p. e67920-Article in journal (Refereed)
    Abstract [en]

    Background: Long-chain polyunsaturated fatty acids (LCPUFAs) reduce T-cell activation and dampen inflammation. They might thereby counteract the neonatal immune activation and hamper normal tolerance development to harmless environmental antigens. We investigated whether fatty acid composition of cord serum phospholipids affects allergy development up to age 13 years. Methods: From a population-based birth-cohort born in 1996/7 and followed until 13 years of age (n = 794), we selected cases with atopic eczema (n = 37) or respiratory allergy (n = 44), as well as non-allergic non-sensitized controls (n = 48) based on diagnosis at 13 years of age. Cord and maternal sera obtained at delivery from cases and controls were analysed for proportions of saturated, monounsaturated and polyunsaturated fatty acids among serum phospholipids. Results: The cord serum phospholipids from subject who later developed either respiratory allergy or atopic eczema had significantly higher proportions of 5/8 LCPUFA species, as well as total n-3 LCPUFA, total n-6 LCPUFA and total LCPUFA compared to cord serum phospholipids from controls who did not develop allergy (P < 0.001 for all comparisons). Conversely, individuals later developing allergy had lower proportion of the monounsaturated fatty acid 18:1n-9 as well as total MUFA (p < 0.001) among cord serum phospholipids. The risk of respiratory allergy at age 13 increased linearly with the proportion of n-3 LCPUFA (P-trend < 0.001), n-6 LCPUFA (P-trend = 0.001), and total LCPUFA (P-trend < 0.001) and decreased linearly with the proportions of total MUFA (P-trend = 0.025) in cord serum phospholipids. Furthermore, Kaplan-Meier estimates of allergy development demonstrated that total LCPUFA proportion in cord serum phospholipids was significantly associated with respiratory allergy (P = 0.008) and sensitization (P = 0.002), after control for sex and parental allergy. Conclusion: A high proportion of long-chain PUFAs among cord serum phospholipids may predispose to allergy development. The mechanism is unknown, but may involve dampening of the physiologic immune activation in infancy needed for proper maturation of the infant's immune system.

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  • 44. Barrenas, Fredrik
    et al.
    Chavali, Sreenivas
    Holme, Petter
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Mobini, Reza
    Benson, Mikael
    Network properties of complex human disease genes identified through genome-wide association studies2009In: PLOS ONE, E-ISSN 1932-6203, Vol. 4, no 11, p. e8090-Article in journal (Refereed)
    Abstract [en]

    Background Previous studies of network properties of human disease genes have mainly focused on monogenic diseases or cancers and have suffered from discovery bias. Here we investigated the network properties of complex disease genes identified by genome-wide association studies (GWAs), thereby eliminating discovery bias.

    Principal findings We derived a network of complex diseases (n = 54) and complex disease genes (n = 349) to explore the shared genetic architecture of complex diseases. We evaluated the centrality measures of complex disease genes in comparison with essential and monogenic disease genes in the human interactome. The complex disease network showed that diseases belonging to the same disease class do not always share common disease genes. A possible explanation could be that the variants with higher minor allele frequency and larger effect size identified using GWAs constitute disjoint parts of the allelic spectra of similar complex diseases. The complex disease gene network showed high modularity with the size of the largest component being smaller than expected from a randomized null-model. This is consistent with limited sharing of genes between diseases. Complex disease genes are less central than the essential and monogenic disease genes in the human interactome. Genes associated with the same disease, compared to genes associated with different diseases, more often tend to share a protein-protein interaction and a Gene Ontology Biological Process.

    Conclusions This indicates that network neighbors of known disease genes form an important class of candidates for identifying novel genes for the same disease.

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  • 45.
    Barros, Guilherme W. F.
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Performance of modeling and balancing approach methods when using weights to estimate treatment effects in observational time-to-event settings2023In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 12, article id e0289316Article in journal (Refereed)
    Abstract [en]

    In observational studies weighting techniques are often used to overcome bias due to confounding. Modeling approaches, such as inverse propensity score weighting, are popular, but often rely on the correct specification of a parametric model wherein neither balance nor stability are targeted. More recently, balancing approach methods that directly target covariate imbalances have been proposed, and these allow the researcher to explicitly set the desired balance constraints. In this study, we evaluate the finite sample properties of different modeling and balancing approach methods, when estimating the marginal hazard ratio, through Monte Carlo simulations. The use of the different methods is also illustrated by analyzing data from the Swedish stroke register to estimate the effect of prescribing oral anticoagulants on time to recurrent stroke or death in stroke patients with atrial fibrillation. In simulated scenarios with good overlap and low or no model misspecification the balancing approach methods performed similarly to the modeling approach methods. In scenarios with bad overlap and model misspecification, the modeling approach method incorporating variable selection performed better than the other methods. The results indicate that it is valuable to use methods that target covariate balance when estimating marginal hazard ratios, but this does not in itself guarantee good performance in situations with, e.g., poor overlap, high censoring, or misspecified models/balance constraints.

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  • 46.
    Bartels, Pia
    et al.
    Department of Ecology and Genetics, Limnology, Uppsala University, Uppsala, Sweden.
    Hirsch, Philipp E.
    Department of Ecology and Genetics, Limnology, Uppsala University, Uppsala, Sweden.
    Svanbäck, Richard
    Department of Ecology and Genetics, Limnology, Uppsala University, Uppsala, Sweden.
    Eklöv, Peter
    Department of Ecology and Genetics, Limnology, Uppsala University, Uppsala, Sweden.
    Water transparency drives intra-population divergence in Eurasian perch (Perca fluviatilis)2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 8, article id e43641Article in journal (Refereed)
    Abstract [en]

    Trait combinations that lead to a higher efficiency in resource utilization are important drivers of divergent natural selection and adaptive radiation. However, variation in environmental features might constrain foraging in complex ways and therefore impede the exploitation of critical resources. We tested the effect of water transparency on intra-population divergence in morphology of Eurasian perch (Perca fluviatilis) across seven lakes in central Sweden. Morphological divergence between near-shore littoral and open-water pelagic perch substantially increased with increasing water transparency. Reliance on littoral resources increased strongly with increasing water transparency in littoral populations, whereas littoral reliance was not affected by water transparency in pelagic populations. Despite the similar reliance on pelagic resources in pelagic populations along the water transparency gradient, the utilization of particular pelagic prey items differed with variation in water transparency in pelagic populations. Pelagic perch utilized cladocerans in lakes with high water transparency and copepods in lakes with low water transparency. We suggest that under impaired visual conditions low utilization of littoral resources by littoral perch and utilization of evasive copepods by pelagic perch may lead to changes in morphology. Our findings indicate that visual conditions can affect population divergence in predator populations through their effects on resource utilization.

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  • 47.
    Bastos, Vasco
    et al.
    Faculty of Physical Education and Sport (ULHT), Lusófona University, Lisbon, Portugal; Research Center in Sport, Physical Education, Exercise and Health (CIDEFES), Lisbon, Portugal.
    Rodrigues, Filipe
    Quality of Life Research Center (CIEQV), Santarém, Portugal.
    Davis, Paul A.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Teixeira, Diogo Santos
    Faculty of Physical Education and Sport (ULHT), Lusófona University, Lisbon, Portugal; Research Center in Sport, Physical Education, Exercise and Health (CIDEFES), Lisbon, Portugal.
    Assessing affective valence and activation in resistance training with the feeling scale and the felt arousal scale: a systematic review2023In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 11, article id e0294529Article in journal (Refereed)
    Abstract [en]

    Evidence suggests affective responses to exercise can influence exercise adherence. However, there is a limited understanding of how and when to measure core affect in resistance training. As such, the objective of this systematic review was to analyze how the Feeling Scale and/or the Felt Arousal Scale have been used in resistance training to assess core affect. Focus was given to the contextual feasibility, timing, and frequency of assessment. A search in PubMed, SPORTDiscus, and PsycINFO databases was conducted (last search date July, 2022) with the purpose of including experimental and non-experimental studies, utilizing the Feeling Scale and/or the Felt Arousal Scale in resistance training, and focused on apparently healthy individuals of any age. Twenty-seven studies (N = 718 participants) published between 2009-2022 were qualitatively analyzed. Both scales appeared to be able to detect core affect within a wide array of intensities, ages, and equipment. As for the timing and frequency of measurement, no apparent standardization was evident. The use of the Feeling Scale, the Felt Arousal Scale, or both, to measure core affect appears to be feasible in resistance training practices. However, a lack of methodological background raises concerns regarding the quality of previous studies' assessments and comparisons of results across studies.

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  • 48. Bawah, Ayaga
    et al.
    Houle, Brian
    Alam, Nurul
    Razzaque, Abdur
    Streatfield, Peter Kim
    Debpuur, Cornelius
    Welaga, Paul
    Oduro, Abraham
    Hodgson, Abraham
    Tollman, Stephen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Rural Public Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa ; INDEPTH Network, Accra, Ghana.
    Collinson, Mark
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Rural Public Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa ; INDEPTH Network, Accra, Ghana.
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. MRC/Wits Rural Public Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa ; INDEPTH Network, Accra, Ghana.
    Toan, Tran Khan
    Phuc, Ho Dang
    Chuc, Nguyen Thi Kim
    Sankoh, Osman
    Clark, Samuel J.
    The Evolving Demographic and Health Transition in Four Low- and Middle-Income Countries: Evidence from Four Sites in the INDEPTH Network of Longitudinal Health and Demographic Surveillance Systems2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 6, article id e0157281Article in journal (Refereed)
    Abstract [en]

    This paper contributes evidence documenting the continued decline in all-cause mortality and changes in the cause of death distribution over time in four developing country populations in Africa and Asia. We present levels and trends in age-specific mortality (all-cause and cause-specific) from four demographic surveillance sites: Agincourt (South Africa), Navrongo (Ghana) in Africa; Filabavi (Vietnam), Matlab (Bangladesh) in Asia. We model mortality using discrete time event history analysis. This study illustrates how data from INDEPTH Network centers can provide a comparative, longitudinal examination of mortality patterns and the epidemiological transition. Health care systems need to be reconfigured to deal simultaneously with continuing challenges of communicable disease and increasing incidence of non-communicable diseases that require long-term care. In populations with endemic HIV, long-term care of HIV patients on ART will add to the chronic care needs of the community.

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  • 49.
    Bellieny-Rabelo, Daniel
    et al.
    Laborato´rio de Quı´mica e Func¸a˜o de Proteı´nas e Peptı´deos, Centro de Biocieˆncias e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, Rio de Janeiro, Brazil.
    Oliveira, Antônia Elenir Amâncio
    Venancio, Thiago Motta
    Impact of whole-genome and tandem duplications in the expansion and functional diversification of the F-box family in legumes (Fabaceae)2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 2, article id e55127Article in journal (Refereed)
    Abstract [en]

    F-box proteins constitute a large gene family that regulates processes from hormone signaling to stress response. F-box proteins are the substrate recognition modules of SCF E3 ubiquitin ligases. Here we report very distinct trends in family size, duplication, synteny and transcription of F-box genes in two nitrogen-fixing legumes, Glycine max (soybean) and Medicago truncatula (alfafa). While the soybean FBX genes emerged mainly through segmental duplications (including whole-genome duplications), M. truncatula genome is dominated by locally-duplicated (tandem) F-box genes. Many of these young FBX genes evolved complex transcriptional patterns, including preferential transcription in different tissues, suggesting that they have probably been recruited to important biochemical pathways (e.g. nodulation and seed development).

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  • 50. Bengtsson, Anders A.
    et al.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wuttge, Dirk M.
    Sturfelt, Gunnar
    Theander, Elke
    Donten, Magdalena
    Moritz, Thomas
    Sennbro, Carl-Johan
    Torell, Frida
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lood, Christian
    Surowiec, Izabella
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rännar, Stefan
    Lundstedt, Torbjörn
    Metabolic Profiling of Systemic Lupus Erythematosus and Comparison with Primary Sjögren’s Syndrome and Systemic Sclerosis2016In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 7, article id e0159384Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease which can affect most organ systems including skin, joints and the kidney. Clinically, SLE is a heterogeneous disease and shares features of several other rheumatic diseases, in particular primary Sjögrens syndrome (pSS) and systemic sclerosis (SSc), why it is difficult to diag- nose The pathogenesis of SLE is not completely understood, partly due to the heterogeneity of the disease. This study demonstrates that metabolomics can be used as a tool for improved diagnosis of SLE compared to other similar autoimmune diseases. We observed differences in metabolic profiles with a classification specificity above 67% in the comparison of SLE with pSS, SSc and a matched group of healthy individuals. Selected metabolites were also significantly different between studied diseases. Biochemical pathway analysis was conducted to gain understanding of underlying pathways involved in the SLE pathogenesis. We found an increased oxidative activity in SLE, supported by increased xanthine oxidase activity and an increased turnover in the urea cycle. The most discriminatory metabolite observed was tryptophan, with decreased levels in SLE patients compared to control groups. Changes of tryptophan levels were related to changes in the activity of the aromatic amino acid decarboxylase (AADC) and/or to activation of the kynurenine pathway. 

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