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  • 51.
    Esberg, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haworth, Simon
    Brunius, Carl
    Lif Holgerson, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Carbonic Anhydrase 6 Gene Variation influences Oral Microbiota Composition and Caries Risk in Swedish adolescents2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 452Article in journal (Refereed)
    Abstract [en]

    Carbonic anhydrase VI (CA6) catalyses the reversible hydration of carbon dioxide in saliva with possible pH regulation, taste perception, and tooth formation effects. This study assessed effects of variation in the CA6 gene on oral microbiota and specifically the acidophilic and caries-associated Streptococcus mutans in 17-year old Swedish adolescents (n = 154). Associations with caries status and secreted CA6 protein were also evaluated. Single Nucleotide Polymorphisms (27 SNPs in 5 haploblocks) and saliva and tooth biofilm microbiota from Illumina MiSeq 16S rDNA (V3-V4) sequencing and culturing were analysed. Haploblock 4 (rs10864376, rs3737665, rs12138897) CCC associated with low prevalence of S. mutans (OR (95% CI): 0.5 (0.3, 0.8)), and caries (OR 0.6 (0.3, 0.9)), whereas haploblock 4 TTG associated with high prevalence of S. mutans (OR: 2.7 (1.2, 5.9)) and caries (OR: 2.3 (1.2, 4.4)). The TTG-haploblock 4 (represented by rs12138897(G)) was characterized by S. mutans, Scardovia wiggsiae, Treponema sp. HOT268, Tannerella sp. HOT286, Veillonella gp.1 compared with the CCC-haploblock 4 (represented by rs12138897(C)). Secreted CA6 in saliva was weakly linked to CA6 gene variation. In conclusion, the results indicate that CA6 gene polymorphisms influence S. mutans colonization, tooth biofilm microbiota composition and risk of dental caries in Swedish adolescents.

  • 52.
    Escamez, Sacha
    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).
    Latha Gandla, Madhavi
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Derba-Maceluch, Marta
    Lundqvist, Sven-Olof
    Mellerowicz, Ewa J.
    Jönsson, Leif J.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Tuominen, Hannele
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    A collection of genetically engineered Populus trees reveals wood biomass traits that predict glucose yield from enzymatic hydrolysis2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 15798Article in journal (Refereed)
    Abstract [en]

    Wood represents a promising source of sugars to produce bio-based renewables, including biofuels. However, breaking down lignocellulose requires costly pretreatments because lignocellulose is recalcitrant to enzymatic saccharification. Increasing saccharification potential would greatly contribute to make wood a competitive alternative to petroleum, but this requires improving wood properties. To identify wood biomass traits associated with saccharification, we analyzed a total of 65 traits related to wood chemistry, anatomy and structure, biomass production and saccharification in 40 genetically engineered Populus tree lines. These lines exhibited broad variation in quantitative traits, allowing for multivariate analyses and mathematical modeling. Modeling revealed that seven wood biomass traits associated in a predictive manner with saccharification of glucose after pretreatment. Four of these seven traits were also negatively associated with biomass production, suggesting a trade-off between saccharification potential and total biomass, which has previously been observed to offset the overall sugar yield from whole trees. We therefore estimated the "total-wood glucose yield" (TWG) from whole trees and found 22 biomass traits predictive of TWG after pretreatment. Both saccharification and TWG were associated with low abundant, often overlooked matrix polysaccharides such as arabinose and rhamnose which possibly represent new markers for improved Populus feedstocks.

  • 53. Espín-Pérez, Almudena
    et al.
    Hebels, Dennie G. A. J.
    Kiviranta, Hannu
    Rantakokko, Panu
    Georgiadis, Panagiotis
    Botsivali, Maria
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Palli, Domenico
    Späth, Florentin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Chadeau-Hyam, Marc
    Kyrtopoulos, Soterios A
    Kleinjans, Jos C. S.
    de Kok, Theo M. C. M.
    Identification of Sex-Specific Transcriptome Responses to Polychlorinated Biphenyls (PCBs)2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 746Article in journal (Refereed)
    Abstract [en]

    PCBs are classified as xenoestrogens and carcinogens and their health risks may be sex-specific. To identify potential sex-specific responses to PCB-exposure we established gene expression profiles in a population study subdivided into females and males. Gene expression profiles were determined in a study population consisting of 512 subjects from the EnviroGenomarkers project, 217 subjects who developed lymphoma and 295 controls were selected in later life. We ran linear mixed models in order to find associations between gene expression and exposure to PCBs, while correcting for confounders, in particular distribution of white blood cells (WBC), as well as random effects. The analysis was subdivided according to sex and development of lymphoma in later life. The changes in gene expression as a result of exposure to the six studied PCB congeners were sex- and WBC type specific. The relatively large number of genes that are significantly associated with PCB-exposure in the female subpopulation already indicates different biological response mechanisms to PCBs between the two sexes. The interaction analysis between different PCBs and WBCs provides only a small overlap between sexes. In males, cancer-related pathways and in females immune system-related pathways are identified in association with PCBs and WBCs. Future lymphoma cases and controls for both sexes show different responses to the interaction of PCBs with WBCs, suggesting a role of the immune system in PCB-related cancer development.

  • 54. Eter, Wael A.
    et al.
    Parween, Saba
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Joosten, Lieke
    Frielink, Cathelijne
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Brom, Maarten
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gotthardt, Martin
    SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for beta-cell mass assessments2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 24576Article in journal (Refereed)
    Abstract [en]

    Single Photon Emission Computed Tomography (SPECT) has become a promising experimental approach to monitor changes in beta-cell mass (BCM) during diabetes progression. SPECT imaging of pancreatic islets is most commonly cross-validated by stereological analysis of histological pancreatic sections after insulin staining. Typically, stereological methods do not accurately determine the total beta-cell volume, which is inconvenient when correlating total pancreatic tracer uptake with BCM. Alternative methods are therefore warranted to cross-validate beta-cell imaging using radiotracers. In this study, we introduce multimodal SPECT - optical projection tomography (OPT) imaging as an accurate approach to cross-validate radionuclide-based imaging of beta-cells. Uptake of a promising radiotracer for beta-cell imaging by SPECT, In-111-exendin-3, was measured by ex vivo-SPECT and cross evaluated by 3D quantitative OPT imaging as well as with histology within healthy and alloxan-treated Brown Norway rat pancreata. SPECT signal was in excellent linear correlation with OPT data as compared to histology. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of In-111-exendin-3 and insulin positive beta-cell volumes between different pancreatic lobes, both visually and quantitatively. We propose ex vivo SPECT-OPT multimodal imaging as a highly accurate strategy for validating the performance of beta-cell radiotracers.

  • 55. Fanidi, Anouar
    et al.
    Muller, David C
    Midttun, Øivind
    Ueland, Per Magne
    Vollset, Stein Emil
    Relton, Caroline
    Vineis, Paolo
    Weiderpass, Elisabete
    Skeie, Guri
    Brustad, Magritt
    Palli, Domenico
    Tumino, Rosario
    Grioni, Sara
    Sacerdote, Carlotta
    Bueno-de-Mesquita, H B As
    Peeters, Petra H
    Boutron-Ruault, Marie-Christine
    Kvaskoff, Marina
    Cadeau, Claire
    Huerta, José María
    Sánchez, Maria-José
    Agudo, Antonio
    Lasheras, Cristina
    Quirós, J Ramón
    Chamosa, Saioa
    Riboli, Elio
    Travis, Ruth C
    Ward, Heather
    Murphy, Neil
    Khaw, Kay-Tee
    Trichopoulou, Antonia
    Lagiou, Pagona
    Papatesta, Eleni-Maria
    Boeing, Heiner
    Kuehn, Tilman
    Katzke, Verena
    Steffen, Annika
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Brennan, Paul
    Johansson, Mattias
    Circulating vitamin D in relation to cancer incidence and survival of the head and neck and oesophagus in the EPIC cohort2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 36017Article in journal (Refereed)
    Abstract [en]

    Experimental and epidemiological data suggest that vitamin D play a role in pathogenesis and progression of cancer, but prospective data on head and neck cancer (HNC) and oesophagus cancer are limited. The European Prospective Investigation into Cancer and Nutrition (EPIC) study recruited 385,747 participants with blood samples between 1992 and 2000. This analysis includes 497 case-control pairs of the head and neck and oesophagus, as well as 443 additional controls. Circulating 25(OH)D3 were measured in pre-diagnostic samples and evaluated in relation to HNC and oesophagus cancer risk and post-diagnosis all-cause mortality. After controlling for risk factors, a doubling of 25(OH)D3 was associated with 30% lower odds of HNC (OR 0.70, 95% confidence interval [95% CI] 0.56-0.88, Ptrend = 0.001). Subsequent analyses by anatomical sub-site indicated clear inverse associations with risk of larynx and hypopharynx cancer combined (OR 0.55, 95CI% 0.39-0.78) and oral cavity cancer (OR 0.60, 95CI% 0.42-0.87). Low 25(OH)D3 concentrations were also associated with higher risk of death from any cause among HNC cases. No clear association was seen with risk or survival for oesophageal cancer. Study participants with elevated circulating concentrations of 25(OH)D3 had decreased risk of HNC, as well as improved survival following diagnosis.

  • 56. Georgiadis, Panagiotis
    et al.
    Hebels, Dennie G
    Valavanis, Ioannis
    Liampa, Irene
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palli, Domenico
    Chadeau-Hyam, Marc
    Chatziioannou, Aristotelis
    Jennen, Danyel G J
    Krauskopf, Julian
    Jetten, Marlon J
    Kleinjans, Jos C S
    Vineis, Paolo
    Kyrtopoulos, Soterios A
    Omics for prediction of environmental health effects: Blood leukocyte-based cross-omic profiling reliably predicts diseases associated with tobacco smoking.2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 20544Article in journal (Refereed)
    Abstract [en]

    The utility of blood-based omic profiles for linking environmental exposures to their potential health effects was evaluated in 649 individuals, drawn from the general population, in relation to tobacco smoking, an exposure with well-characterised health effects. Using disease connectivity analysis, we found that the combination of smoking-modified, genome-wide gene (including miRNA) expression and DNA methylation profiles predicts with remarkable reliability most diseases and conditions independently known to be causally associated with smoking (indicative estimates of sensitivity and positive predictive value 94% and 84%, respectively). Bioinformatics analysis reveals the importance of a small number of smoking-modified, master-regulatory genes and suggest a central role for altered ubiquitination. The smoking-induced gene expression profiles overlap significantly with profiles present in blood cells of patients with lung cancer or coronary heart disease, diseases strongly associated with tobacco smoking. These results provide proof-of-principle support to the suggestion that omic profiling in peripheral blood has the potential of identifying early, disease-related perturbations caused by toxic exposures and may be a useful tool in hazard and risk assessment.

  • 57. Ginley, Brandon G
    et al.
    Emmons, Tiffany
    Lutnick, Brendon
    Urban, Constantin F
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Segal, Brahm H
    Sarder, Pinaki
    Computational detection and quantification of human and mouse neutrophil extracellular traps in flow cytometry and confocal microscopy2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 17755Article in journal (Refereed)
    Abstract [en]

    Neutrophil extracellular traps (NETs) are extracellular defense mechanisms used by neutrophils, where chromatin is expelled together with histones and granular/cytoplasmic proteins. They have become an immunology hotspot, implicated in infections, but also in a diverse array of diseases such as systemic lupus erythematosus, diabetes, and cancer. However, the precise assessment of in vivo relevance in different disease settings has been hampered by limited tools to quantify occurrence of extracellular traps in experimental models and human samples. To expedite progress towards improved quantitative tools, we have developed computational pipelines to identify extracellular traps from an in vitro human samples visualized using the ImageStream® platform (Millipore Sigma, Darmstadt, Germany), and confocal images of an in vivo mouse disease model of aspergillus fumigatus pneumonia. Our two in vitro methods, tested on n = 363/n =145 images respectively, achieved holdout sensitivity/specificity 0.98/0.93 and 1/0.92. Our unsupervised method for thin lung tissue sections in murine fungal pneumonia achieved sensitivity/specificity 0.99/0.98 in n = 14 images. Our supervised method for thin lung tissue classified NETs with sensitivity/specificity 0.86/0.90. We expect that our approach will be of value for researchers, and have application in infectious and inflammatory diseases.

  • 58. Gonoskov, A.
    et al.
    Wallin, Erik
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Polovinkin, A.
    Meyerov, I.
    Employing machine learning for theory validation and identification of experimental conditions in laserplasma physics2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 7043Article in journal (Refereed)
    Abstract [en]

    The validation of a theory is commonly based on appealing to clearly distinguishable and describable features in properly reduced experimental data, while the use of ab-initio simulation for interpreting experimental data typically requires complete knowledge about initial conditions and parameters. We here apply the methodology of using machine learning for overcoming these natural limitations. We outline some basic universal ideas and show how we can use them to resolve long-standing theoretical and experimental difficulties in the problem of high-intensity laser-plasma interactions. In particular we show how an artificial neural network can "read" features imprinted in laser-plasma harmonic spectra that are currently analysed with spectral interferometry.

  • 59. Groenning, Minna
    et al.
    Campos, Raul I
    Hirschberg, Daniel
    IFM – Department of Chemistry, Linköping University, Linköping, Sweden.
    Hammarström, Per
    Vestergaard, Bente
    Considerably Unfolded Transthyretin Monomers Preceed and Exchange with Dynamically Structured Amyloid Protofibrils2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 11443Article in journal (Refereed)
    Abstract [en]

    Despite numerous studies, a detailed description of the transthyretin (TTR) self-assembly mechanism and fibril structure in TTR amyloidoses remains unresolved. Here, using a combination of primarily small -angle X-ray scattering (SAXS) and hydrogen exchange mass spectrometry (HXMS) analysis, we describe an unexpectedly dynamic TTR protofibril structure which exchanges protomers with highly unfolded monomers in solution. The protofibrils only grow to an approximate final size of 2,900 kDa and a length of 70 nm and a comparative HXMS analysis of native and aggregated samples revealed a much higher average solvent exposure of TTR upon fibrillation. With SAXS, we reveal the continuous presence of a considerably unfolded TTR monomer throughout the fibrillation process, and show that a considerable fraction of the fibrillating protein remains in solution even at a late maturation state. Together, these data reveal that the fibrillar state interchanges with the solution state. Accordingly, we suggest that TTR fibrillation proceeds via addition of considerably unfolded monomers, and the continuous presence of amyloidogenic structures near the protofibril surface offers a plausible explanation for secondary nucleation. We argue that the presence of such dynamic structural equilibria must impact future therapeutic development strategies.

  • 60.
    Gu, Xiaolian
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boldrup, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, Philip J
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. RECAMO, Masaryk Memorial Cancer Institute, Brno, Czech Republic; Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, Paris, France.
    Nylander, Elisabet
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Norberg-Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Gärskog, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Epigenetic regulation of OAS2 shows disease-specific DNA methylation profiles at individual CpG sites2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 32579Article in journal (Refereed)
    Abstract [en]

    Epigenetic modifications are essential regulators of biological processes. Decreased DNA methylation of OAS2 (2'-5'-Oligoadenylate Synthetase 2), encoding an antiviral protein, has been seen in psoriasis. To provide further insight into the epigenetic regulation of OAS2, we performed pyrosequencing to detect OAS2 DNA methylation status at 11 promoter and first exon located CpG sites in psoriasis (n = 12) and two common subtypes of squamous cell carcinoma (SCC) of the head and neck: tongue (n = 12) and tonsillar (n = 11). Compared to corresponding controls, a general hypomethylation was seen in psoriasis. In tongue and tonsillar SCC, hypomethylation was found at only two CpG sites, the same two sites that were least demethylated in psoriasis. Despite differences in the specific residues targeted for methylation/demethylation, OAS2 expression was upregulated in all conditions and correlations between methylation and expression were seen in psoriasis and tongue SCC. Distinctive methylation status at four successively located CpG sites within a genomic area of 63 bp reveals a delicately integrated epigenetic program and indicates that detailed analysis of individual CpGs provides additional information into the mechanisms of epigenetic regulation in specific disease states. Methylation analyses as clinical biomarkers need to be tailored according to disease-specific sites.

  • 61.
    Gustafsson, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Jacobsson, Stig OP
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Effects of cannabinoids on the development of chick embryos in ovo2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 13486Article in journal (Refereed)
    Abstract [en]

    We have examined the effects of the synthetic cannabinoids HU 210 and HU 211, the plant-derived cannabidiol and the endogenous cannabinoid anandamide on the viability and development of chick embryos. Fertilized White Leghorn chicken eggs were injected with the test compounds or carrier vehicle, via a drilled small hole in the egg, directly into the egg yolk. After nine days of exposure, the embryonal viability, length and wet weight of embryos, and wet weight of brains were measured, and the development stages were assessed according to the Hamburger and Hamilton (HH) scale. The potent synthetic cannabinoid receptor agonist HU 210 and the non-psychotropic cannabidiol were embryotoxic at the highest concentrations examined (10µM and 50µM, respectively), with no viable embryos after the HU 210 injection, and 20% viability after the cannabidiol injections. The efects of HU 210 on the chick embryo were attenuated by α-tocopherol and the cannabinoid receptor antagonist AM251, whereas only α-tocopherol gave a statistically signifcant protection against the embryotoxic efects of cannabidiol. This study shows that exposure to plant-derived or synthetic cannabinoids during early embryonal development decreases embryonal viability. Extrapolation of data across species is of course difcult, but the data would argue against the use of cannabinoids, be it recreationally or therapeutically, during pregnancy

  • 62.
    Hadrevi, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Bjorklund, Martin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Kosek, E.
    Hallgren, Solveig
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Professionell Development.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fahlstrom, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Professionell Development.
    Hellstrom, F.
    Systemic differences in serum metabolome: a cross sectional comparison of women with localised and widespread pain and controls2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15925Article in journal (Refereed)
    Abstract [en]

    Chronic musculoskeletal pain exists either as localised to a single region or as widespread to multiple sites in several quadrants of the body. Prospective studies indicate that widespread pain could act as a far end of a continuum of musculoskeletal pain that started with chronic localised pain. The mechanism by which the transition from localised pain to widespread occurs is not clear, although many studies suggest it to be an altered metabolism. In this study, systemic metabolic differences between women with chronic localised neck-shoulder pain (NP), women with chronic widespread pain (CWP) and women who were healthy (CON) were assessed. Blood samples were analysed taking a metabolomics approach using gas chromatography mass spectrometry (GC-MS) and orthogonal partial least square discriminant analysis (OPLS-DA). The metabolomics analysis showed a clear systematic difference in the metabolic profiles between the subjects with NP and the CON but only a weak systematic difference between the subjects with CWP and the CON. This most likely reflects a difference in the portion of the metabolome influenced by the two pain conditions. In the NP group, the overall metabolic profile suggests that processes related to energy utilisation and lipid metabolism could be central aspects of mechanisms maintaining disorder.

  • 63. Haglund, Axel
    et al.
    Lindh, Asa U.
    Lysell, Henrik
    Renberg, Ellinor Salander
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
    Waern, Margda
    Runeson, Bo
    Interpersonal violence and the prediction of short-term risk of repeat suicide attempt2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 36892Article in journal (Refereed)
    Abstract [en]

    In this multi-center cohort study, suicide attempters presenting to hospital (N = 355, 63% women) were interviewed using the Karolinska Interpersonal Violence Scale (KIVS) and followed-up by medical record review. Main outcome was non-fatal or fatal repeat suicide attempt within six months. Also, repeat attempt using a violent method was used as an additional outcome in separate analyses. Data were analyzed for the total group and for men and women separately. Repeat attempts were observed within six months in 78 persons (22%) and 21 (6%) of these used a violent method. KIVS total score of 6 or more was associated with repeat suicide attempt within six months (OR = 1.81, CI 1.08-3.02) and predicted new attempts with a sensitivity of 62% and a specificity of 53%. A three-fold increase in odds ratio was observed for repeat attempt using a violent method (OR = 3.40, CI 1.22-9.49). An association between exposure to violence in adulthood and violent reattempt was seen in women (OR = 1.38, CI 1.06-1.82). The overall conclusions are that information about interpersonal violence may help predict short-term risk for repeat suicide attempt, and that structured assessment of interpersonal violence may be of value in risk assessment after attempted suicide.

  • 64.
    Halin Bergström, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 31805Article in journal (Refereed)
    Abstract [en]

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer.

  • 65.
    Hall, Michael
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hasegawa, Yoshiaki
    Yoshimura, Fuminobu
    Persson, Karina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Structural and functional characterization of shaft, anchor, and tip proteins of the Mfa1 fimbria from the periodontal pathogen Porphyromonas gingivalis2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 1793Article in journal (Refereed)
    Abstract [en]

    Very little is known about how fimbriae of Bacteroidetes bacteria are assembled. To shed more light on this process, we solved the crystal structures of the shaft protein Mfa1, the regulatory protein Mfa2, and the tip protein Mfa3 from the periodontal pathogen Porphyromonas gingivalis. Together these build up part of the Mfa1 fimbria and represent three of the five proteins, Mfa1-5, encoded by the mfa1 gene cluster. Mfa1, Mfa2 and Mfa3 have the same overall fold i.e., two β-sandwich domains. Upon polymerization, the first β-strand of the shaft or tip protein is removed by indigenous proteases. Although the resulting void is expected to be filled by a donor-strand from another fimbrial protein, the mechanism by which it does so is still not established. In contrast, the first β-strand in Mfa2, the anchoring protein, is firmly attached by a disulphide bond and is not cleaved. Based on the structural information, we created multiple mutations in P. gingivalis and analysed their effect on fimbrial polymerization and assembly in vivo. Collectively, these data suggest an important role for the C-terminal tail of Mfa1, but not of Mfa3, affecting both polymerization and maturation of downstream fimbrial proteins.

  • 66.
    Hamdan, Mohammed
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Byström, Pär
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Hotchkiss, Erin R.
    Al-Haidarey, Mohammed J.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Ask, Jenny
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Karlsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Carbon dioxide stimulates lake primary production2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 10878Article in journal (Refereed)
    Abstract [en]

    Gross primary production (GPP) is a fundamental ecosystem process that sequesters carbon dioxide (CO2) and forms the resource base for higher trophic levels. Still, the relative contribution of different controls on GPP at the whole-ecosystem scale is far from resolved. Here we show, by manipulating CO2 concentrations in large-scale experimental pond ecosystems, that CO2 availability is a key driver of whole-ecosystem GPP. This result suggests we need to reformulate past conceptual models describing controls of lake ecosystem productivity and include our findings when developing models used to predict future lake ecosystem responses to environmental change.

  • 67.
    Hassan, Emadeldeen
    et al.
    Umeå University, Faculty of Science and Technology, Department of Computing Science. Department of electronics and electrical communications, Menoufia University, Menouf, 32952, Egypt.
    Noreland, Daniel
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Wadbro, Eddie
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Berggren, Martin
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Topology Optimisation of Wideband Coaxial-to-Waveguide Transitions2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 45110Article in journal (Refereed)
    Abstract [en]

    To maximize the matching between a coaxial cable and rectangular waveguides, we present a computational topology optimisation approach that decides for each point in a given domain whether to hold a good conductor or a good dielectric. The conductivity is determined by a gradient-based optimisation method that relies on finite-difference time-domain solutions to the 3D Maxwell’s equations. Unlike previously reported results in the literature for this kind of problems, our design algorithm can efficiently handle tens of thousands of design variables that can allow novel conceptual waveguide designs. We demonstrate the effectiveness of the approach by presenting optimised transitions with reflection coefficients lower than −15dB over more than a 60% bandwidth, both for right-angle and end-launcher configurations. The performance of the proposed transitions is crossverified with a commercial software, and one design case is validated experimentally.

  • 68. He, Xuan
    et al.
    Parenti, Mariana
    Grip, Tove
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lonnerdal, Bo
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Timby, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Slupsky, Carolyn M.
    Metabolic phenotype of breast-fed infants, and infants fed standard formula or bovine MFGM supplemented formula: a randomized controlled trial2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 339Article in journal (Refereed)
    Abstract [en]

    Formula-fed (FF) infants exhibit a different metabolic profile than breast-fed (BF) infants. Two potential mechanisms are the higher protein level in formula compared with breast milk and the removal of the milk fat and associated milk fat globule membranes (MFGM) during production of infant formula. To determine whether MFGM may impact metabolism, formula-fed infants were randomly assigned to receive either an MFGM isolate-supplemented experimental formula (EF) or a standard formula (SF) from 2 until 6 months and compared with a BF reference group. Infants consuming EF had higher levels of fatty acid oxidation products compared to infants consuming SF. Although the protein level in the study formula was approximately 12 g/L (lower than most commercial formulas), a metabolic difference between FF and BF remained such that FF infants had higher levels of amino acid catabolism by-products and a low efficiency of amino acid clearance (preference for protein metabolism). BF infants had higher levels of fatty acid oxidation products (preference for fat metabolism). These unique, energy substrate-driven metabolic outcomes did not persist after diet was shifted to weaning foods and appeared to be disrupted by complementary feeding. Our results suggest that MFGM may have a role in directing infant metabolism.

  • 69. He, Xuan
    et al.
    Parenti, Mariana
    Grip, Tove
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Lönnerdal, Bo
    Timby, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Slupsky, Carolyn M.
    Fecal microbiome and metabolome of infants fed bovine MFGM supplemented formula or standard formula with breast-fed infants as reference: a randomized controlled trial2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 11589Article in journal (Refereed)
    Abstract [en]

    Human milk delivers an array of bioactive components that safeguard infant growth and development and maintain healthy gut microbiota. Milk fat globule membrane (MFGM) is a biologically functional fraction of milk increasingly linked to beneficial outcomes in infants through protection from pathogens, modulation of the immune system and improved neurodevelopment. In the present study, we characterized the fecal microbiome and metabolome of infants fed a bovine MFGM supplemented experimental formula (EF) and compared to infants fed standard formula (SF) and a breast-fed reference group. The impact of MFGM on the fecal microbiome was moderate; however, the fecal metabolome of EF-fed infants showed a significant reduction of several metabolites including lactate, succinate, amino acids and their derivatives from that of infants fed SF. Introduction of weaning food with either human milk or infant formula reduces the distinct characteristics of breast-fed- or formula-fed-like infant fecal microbiome and metabolome profiles. Our findings support the hypothesis that higher levels of protein in infant formula and the lack of human milk oligosaccharides promote a shift toward amino acid fermentation in the gut. MFGM may play a role in shaping gut microbial activity and function.

  • 70. Hedman, Daniel
    et al.
    Barzegar, Hamid Reza
    Umeå University, Faculty of Science and Technology, Department of Physics. Department of Physics, University of California and the Lawrence Berkeley National Laboratory, USA.
    Rosen, Arne
    Wågberg, Thomas
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Larsson, J. Andreas
    On the Stability and Abundance of Single Walled Carbon Nanotubes2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 16850Article in journal (Refereed)
    Abstract [en]

    Many nanotechnological applications, using single-walled carbon nanotubes (SWNTs), are only possible with a uniform product. Thus, direct control over the product during chemical vapor deposition (CVD) growth of SWNT is desirable, and much effort has been made towards the ultimate goal of chirality-controlled growth of SWNTs. We have used density functional theory (DFT) to compute the stability of SWNT fragments of all chiralities in the series representing the targeted products for such applications, which we compare to the chiralities of the actual CVD products from all properly analyzed experiments. From this comparison we find that in 84% of the cases the experimental product represents chiralities among the most stable SWNT fragments (within 0.2 eV) from the computations. Our analysis shows that the diameter of the SWNT product is governed by the well-known relation to size of the catalytic nanoparticles, and the specific chirality is normally determined by the product's relative stability, suggesting thermodynamic control at the early stage of product formation. Based on our findings, we discuss the effect of other experimental parameters on the chirality of the product. Furthermore, we highlight the possibility to produce any tube chirality in the context of recent published work on seeded-controlled growth.

  • 71.
    Hjorth, Therese
    et al.
    Department of Internal Medicine and Clinical Nutrition, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Huseinovic, Ena
    Department of Internal Medicine and Clinical Nutrition, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Hallström, Elinor
    Department of Agrifood and Bioscience, RISE- Research Institutes of Sweden, Gothenburg, Sweden..
    Strid, Anna
    Department of Internal Medicine and Clinical Nutrition, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Sonesson, Ulf
    Department of Agrifood and Bioscience, RISE- Research Institutes of Sweden, Gothenburg, Sweden..
    Winkvist, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health. Department of Internal Medicine and Clinical Nutrition, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden..
    Changes in dietary carbon footprint over ten years relative to individual characteristics and food intake in the Västerbotten Intervention Programme2020In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 10, no 1, article id 20Article in journal (Refereed)
    Abstract [en]

    The objective was to examine 10-year changes in dietary carbon footprint relative to individual characteristics and food intake in the unique longitudinal Västerbotten Intervention Programme, Sweden. Here, 14 591 women and 13 347 men had been followed over time. Food intake was assessed via multiple two study visits 1996-2016, using a 64-item food frequency questionnaire. Greenhouse gas emissions (GHGE) related to food intake, expressed as kg carbon dioxide equivalents/1000 kcal and day, were estimated. Participants were classified into GHGE quintiles within sex and 10-year age group strata at both visits. Women and men changing from lowest to highest GHGE quintile exhibited highest body mass index within their quintiles at first visit, and the largest increase in intake of meat, minced meat, chicken, fish and butter and the largest decrease in intake of potatoes, rice and pasta. Women and men changing from highest to lowest GHGE quintile exhibited basically lowest rates of university degree and marriage and highest rates of smoking within their quintiles at first visit. Among these, both sexes reported the largest decrease in intake of meat, minced meat and milk, and the largest increase in intake of snacks and, for women, sweets. More research is needed on how to motivate dietary modifications to reduce climate impact and support public health.

  • 72.
    Holm, Linus
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Wadenholt, Gustaf
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Schrater, Paul
    Episodic curiosity for avoiding asteroids: Per-trial information gain for choice outcomes drive information seeking2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 11265Article in journal (Refereed)
    Abstract [en]

    Humans often appear to desire information for its own sake, but it is presently unclear what drives this desire. The important role that resolving uncertainty plays in stimulating information seeking has suggested a tight coupling between the intrinsic motivation to gather information and performance gains, construed as a drive for long-term learning. Using an asteroid-avoidance game that allows us to study learning and information seeking at an experimental time-scale, we show that the incentive for information-seeking can be separated from a long-term learning outcome, with information-seeking best predicted by per-trial outcome uncertainty. Specifically, participants were more willing to take time penalties to receive feedback on trials with increasing uncertainty in the outcome of their choices. We found strong group and individual level support for a linear relationship between feedback request rate and information gain as determined by per-trial outcome uncertainty. This information better reflects filling in the gaps of the episodic record of choice outcomes than long-term skill acquisition or assessment. Our results suggest that this easy to compute quantity can drive information-seeking, potentially allowing simple organisms to intelligently gather information for a diverse episodic record of the environment without having to anticipate the impact on future performance.

  • 73.
    Holme, Petter
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Liljeros, Fredrik
    Birth and death of links control disease spreading in empirical contact networks2014In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 4, p. 4999-Article in journal (Refereed)
    Abstract [en]

    We investigate what structural aspects of a collection of twelve empirical temporal networks of human contacts are important to disease spreading. We scan the entire parameter spaces of the two canonical models of infectious disease epidemiology-the Susceptible-Infectious-Susceptible (SIS) and Susceptible-Infectious-Removed (SIR) models. The results from these simulations are compared to reference data where we eliminate structures in the interevent intervals, the time to the first contact in the data, or the time from the last contact to the end of the sampling. The picture we find is that the birth and death of links, and the total number of contacts over a link, are essential to predict outbreaks. On the other hand, the exact times of contacts between the beginning and end, or the interevent interval distribution, do not matter much. In other words, a simplified picture of these empirical data sets that suffices for epidemiological purposes is that links are born, is active with some intensity, and die.

  • 74. Houston, Catriona M.
    et al.
    Diamanti, Efthymia
    Diamantaki, Maria
    Kutsarova, Elena
    Cook, Anna
    Sultan, Fahad
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Department Cognitive Neurology, HertieInstitute for Clinical Brain Research, University of Tübingen, Germany.
    Brickley, Stephen G.
    Exploring the significance of morphological diversity for cerebellar granule cell excitability2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46147Article in journal (Refereed)
    Abstract [en]

    The relatively simple and compact morphology of cerebellar granule cells (CGCs) has led to the view that heterogeneity in CGC shape has negligible impact upon the integration of mossy fibre (MF) information. Following electrophysiological recording, 3D models were constructed from high-resolution imaging data to identify morphological features that could influence the coding of MF input patterns by adult CGCs. Quantification of MF and CGC morphology provided evidence that CGCs could be connected to the multiple rosettes that arise from a single MF input. Predictions from our computational models propose that MF inputs could be more densely encoded within the CGC layer than previous models suggest. Moreover, those MF signals arriving onto the dendrite closest to the axon will generate greater CGC excitation. However, the impact of this morphological variability on MF input selectivity will be attenuated by high levels of CGC inhibition providing further flexibility to the MF. CGC pathway. These features could be particularly important when considering the integration of multimodal MF sensory input by individual CGCs.

  • 75.
    Huber, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Wikén, Christian
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Henriksson, Robin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Söderström, Lars
    Mooe, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Statin treatment after acute coronary syndrome: Adherence and reasons for non-adherence in a randomized controlled intervention trial2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 12079Article in journal (Refereed)
    Abstract [en]

    Studies of secondary prevention for cardiovascular disease show low fulfilment of guidelinere-commended targets. This study explored whether nurse-led follow-up could increase adherence to statins over time and reasons for discontinuation. All patients admitted for acute coronary syndrome at Ostersund hospital between 2010-2014 were screened for the randomized controlled NAILED-ACS trial. The trial comprises two groups, one with nurse-led annual follow-up and medical titration by telephone to reach set intervention targets and one with usual care. All discontinuations of statins were recorded prospectively for at least 36 months and categorized as avoidable or unavoidable. Kaplan-Meier estimates were conducted for first and permanent discontinuations. Predictors for discontinuation were analysed using multivariate Cox regression, statin type and mean LDL-C at end of follow-up. Female gender was a predictor for discontinuation. Allocation in the intervention group predicted increased risk for a first but decreased risk for permanent discontinuation. A nurse-led telemedical secondary prevention programme in a relatively unselected ACS cohort leads to increased adherence to statins over time, greater percentage on potent treatment and lower LDL-C compared to usual care. An initially increased tendency toward early discontinuation in the intervention group stresses the importance of a longer duration of structured follow-up.

  • 76.
    Huch, Susanne
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gommlich, Jessie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Muppavarapu, Mridula
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Beckham, Carla
    Nissan, Tracy
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Membrane-association of mRNA decapping factors is independent of stress in budding yeast2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 25477Article in journal (Refereed)
    Abstract [en]

    Recent evidence has suggested that the degradation of mRNA occurs on translating ribosomes or alternatively within RNA granules called P bodies, which are aggregates whose core constituents are mRNA decay proteins and RNA. In this study, we examined the mRNA decapping proteins, Dcp1, Dcp2, and Dhh1, using subcellular fractionation. We found that decapping factors co-sediment in the polysome fraction of a sucrose gradient and do not alter their behaviour with stress, inhibition of translation or inhibition of the P body formation. Importantly, their localisation to the polysome fraction is independent of the RNA, suggesting that these factors may be constitutively localised to the polysome. Conversely, polysomal and post-polysomal sedimentation of the decapping proteins was abolished with the addition of a detergent, which shifts the factors to the non-translating RNP fraction and is consistent with membrane association. Using a membrane otation assay, we observed the mRNA decapping factors in the lower density fractions at the buoyant density of membrane-associated proteins. These observations provide further evidence that mRNA decapping factors interact with subcellular membranes, and we suggest a model in which the mRNA decapping factors interact with membranes to facilitate regulation of mRNA degradation. 

  • 77.
    Huch, Susanne
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Nissan, Tracy
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    An mRNA decapping mutant deficient in P body assembly limits mRNA stabilization in response to osmotic stress2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 44395Article in journal (Refereed)
    Abstract [en]

    Yeast is exposed to changing environmental conditions and must adapt its genetic program to provide a homeostatic intracellular environment. An important stress for yeast in the wild is high osmolarity. A key response to this stress is increased mRNA stability primarily by the inhibition of deadenylation. We previously demonstrated that mutations in decapping activators (edc3∆ lsm4∆C), which result in defects in P body assembly, can destabilize mRNA under unstressed conditions. We wished to examine whether mRNA would be destabilized in the edc3∆ lsm4∆C mutant as compared to the wild-type in response to osmotic stress, when P bodies are intense and numerous. Our results show that the edc3∆ lsm4∆C mutant limits the mRNA stability in response to osmotic stress, while the magnitude of stabilization was similar as compared to the wild-type. The reduced mRNA stability in the edc3∆ lsm4∆C mutant was correlated with a shorter PGK1 poly(A) tail. Similarly, the MFA2 mRNA was more rapidly deadenylated as well as significantly stabilized in the ccr4∆ deadenylation mutant in the edc3∆ lsm4∆C background. These results suggest a role for these decapping factors in stabilizing mRNA and may implicate P bodies as sites of reduced mRNA degradation.

  • 78. Ilegems, E.
    et al.
    van Krieken, P. P.
    Edlund, P. K.
    Dicker, A.
    Alanentalo, T.
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mandic, S.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Berggren, P. -O
    Light scattering as an intrinsic indicator for pancreatic islet cell mass and secretion2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 10740Article in journal (Refereed)
    Abstract [en]

    The pancreatic islet of Langerhans is composed of endocrine cells producing and releasing hormones from secretory granules in response to various stimuli for maintenance of blood glucose homeostasis. In order to adapt to a variation in functional demands, these islets are capable of modulating their hormone secretion by increasing the number of endocrine cells as well as the functional response of individual cells. A failure in adaptive mechanisms will lead to inadequate blood glucose regulation and thereby to the development of diabetes. It is therefore necessary to develop tools for the assessment of both pancreatic islet mass and function, with the aim of understanding cellular regulatory mechanisms and factors guiding islet plasticity. Although most of the existing techniques rely on the use of artificial indicators, we present an imaging methodology based on intrinsic optical properties originating from mature insulin secretory granules within endocrine cells that reveals both pancreatic islet mass and function. We demonstrate the advantage of using this imaging strategy by monitoring in vivo scattering signal from pancreatic islets engrafted into the anterior chamber of the mouse eye, and how this versatile and noninvasive methodology permits the characterization of islet morphology and plasticity as well as hormone secretory status.

  • 79.
    Islam, Md. Koushikul
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Strand, Mårten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Saleeb, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Richard
    Baranczewski, Pawel
    Artursson, Per
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Anti-Rift Valley fever virus activity in vitro, pre-clinical pharmacokinetics and oral bioavailability of benzavir-2, a broad-acting antiviral compound2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 1925Article in journal (Refereed)
    Abstract [en]

    Rift Valley fever virus (RVFV) is a mosquito-borne hemorrhagic fever virus affecting both humans and animals with severe morbidity and mortality and is classified as a potential bioterror agent due to the possible aerosol transmission. At present there is no human vaccine or antiviral therapy available. Thus, there is a great need to develop new antivirals for treatment of RVFV infections. Benzavir-2 was previously identified as potent inhibitor of human adenovirus, herpes simplex virus type 1, and type 2. Here we assess the anti-RVFV activity of benzavir-2 together with four structural analogs and determine pre-clinical pharmacokinetic parameters of benzavir-2. In vitro, benzavir-2 efficiently inhibited RVFV infection, viral RNA production and production of progeny viruses. In vitro, benzavir-2 displayed satisfactory solubility, good permeability and metabolic stability. In mice, benzavir-2 displayed oral bioavailability with adequate maximum serum concentration. Oral administration of benzavir-2 formulated in peanut butter pellets gave high systemic exposure without any observed toxicity in mice. To summarize, our data demonstrated potent anti-RVFV activity of benzavir-2 in vitro together with a promising pre-clinical pharmacokinetic profile. This data support further exploration of the antiviral activity of benzavir-2 in in vivo efficacy models that may lead to further drug development for human use.

  • 80. Jalali, Ali
    et al.
    Amirian, E. Susan
    Bainbridge, Matthew N.
    Armstrong, Georgina N.
    Liu, Yanhong
    Tsavachidis, Spyros
    Jhangiani, Shalini N.
    Plon, Sharon E.
    Lau, Ching C.
    Claus, Elizabeth B.
    Barnholtz-Sloan, Jill S.
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S.
    Jenkins, Robert B.
    Lachance, Daniel
    Olson, Sara H.
    Bernstein, Jonine L.
    Merrell, Ryan T.
    Wrensch, Margaret R.
    Davis, Faith G.
    Lai, Rose
    Shete, Sanjay
    Aldape, Kenneth
    Amos, Christopher I.
    Muzny, Donna M.
    Gibbs, Richard A.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa L.
    Targeted sequencing in chromosome 17q linkage region identifies familial glioma candidates in the Gliogene Consortium2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 8278-Article in journal (Refereed)
    Abstract [en]

    Glioma is a rare, but highly fatal, cancer that accounts for the majority of malignant primary brain tumors. Inherited predisposition to glioma has been consistently observed within non-syndromic families. Our previous studies, which involved non-parametric and parametric linkage analyses, both yielded significant linkage peaks on chromosome 17q. Here, we use data from next generation and Sanger sequencing to identify familial glioma candidate genes and variants on chromosome 17q for further investigation. We applied a filtering schema to narrow the original list of 4830 annotated variants down to 21 very rare (<0.1% frequency), non-synonymous variants. Our findings implicate the MYO19 and KIF18B genes and rare variants in SPAG9 and RUNDC1 as candidates worthy of further investigation. Burden testing and functional studies are planned.

  • 81. Jiguet, Frederic
    et al.
    Burgess, Malcolm
    Thorup, Kasper
    Conway, Greg
    Arroyo Matos, Jose Luis
    Barber, Lee
    Black, John
    Burton, Niall
    Castello, Joan
    Clewley, Gary
    Luis Copete, Jose
    Czajkowski, Michel Alexandre
    Dale, Svein
    Davis, Tony
    Dombrovski, Valery
    Drew, Mike
    Elts, Jaanus
    Gilson, Vicky
    Grzegorczyk, Emilienne
    Henderson, Ian
    Holdsworth, Michael
    Husbands, Rob
    Lorrilliere, Romain
    Marja, Riho
    Minkevicius, Simonas
    Moussy, Caroline
    Olsson, Peter
    Onrubia, Alejandro
    Perez, Marc
    Piacentini, Joseph
    Piha, Markus
    Pons, Jean-Marc
    Prochazka, Petr
    Rakovic, Marko
    Robins, Harriet
    Seimola, Tuomas
    Selstam, Gunnar
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Agricultural Research in Northern Sweden, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Skierczynski, Michal
    Sondell, Jan
    Thibault, Jean-Claude
    Tottrup, Anders P.
    Walker, Justin
    Hewson, Chris
    Desert crossing strategies of migrant songbirds vary between and within species2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 20248Article in journal (Refereed)
    Abstract [en]

    Each year, billions of songbirds cross large ecological barriers during their migration. Understanding how they perform this incredible task is crucial to predict how global change may threaten the safety of such journeys. Earlier studies based on radar suggested that most songbirds cross deserts in intermittent flights at high altitude, stopping in the desert during the day, while recent tracking with light loggers suggested diurnal prolongation of nocturnal flights and common non-stop flights for some species. We analyzed light intensity and temperature data obtained from geolocation loggers deployed on 130 individuals of ten migratory songbird species, and show that a large variety of strategies for crossing deserts exists between, but also sometimes within species. Diurnal stopover in the desert is a common strategy in autumn, while most species prolonged some nocturnal flights into the day. Nonstop flights over the desert occurred more frequently in spring than in autumn, and more frequently in foliage gleaners. Temperature recordings suggest that songbirds crossed deserts with flight bouts performed at various altitudes according to species and season, along a gradient ranging from low above ground in autumn to probably >2000 m above ground level, and possibly at higher altitude in spring. High-altitude flights are therefore not the general rule for crossing deserts in migrant songbirds. We conclude that a diversity of migration strategies exists for desert crossing among songbirds, with variations between but also within species.

  • 82. Jin, Yuqing
    et al.
    Ma, Yongpeng
    Wang, Shun
    Hu, Xian-Ge
    Huang, Li-Sha
    Li, Yue
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). 1National Engineering Laboratory for Tree Breeding, Key Laboratory of Genetics and Breeding in Forest Trees and Ornamental Plants, Ministry of Education, College of Biological Sciences and Technology, Beijing Forestry University, Beijing, China.
    Mao, Jian-Feng
    Genetic evaluation of the breeding population of a valuable reforestation conifer Platycladus orientalis (Cupressaceae)2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 34821Article in journal (Refereed)
    Abstract [en]

    Platycladus orientalis, a widespread conifer with long lifespan and significant adaptability. It is much used in reforestation in north China and commonly planted in central Asia. With the increasing demand for plantation forest in central to north China, breeding programs are progressively established for this species. Efficient use of breeding resources requires good understanding of the genetic value of the founder breeding materials. This study investigated the distribution of genetic variation in 192 elite trees collected for the breeding program for the central range of the species. We developed first set of 27 polymorphic EST-derived SSR loci for the species from transcriptome/genome data. After examination of amplification quality, 10 loci were used to evaluate the genetic variation in the breeding population. We found moderate genetic diversity (average H-e = 0.348) and low population differentiation (Fst = 0.011). Extensive admixture and no significant geographic population structure characterized this set of collections. Our analyses of the diversity and population structure are important steps toward a long-term sustainable deployment of the species and provide valuable genetic information for conservation and breeding applications.

  • 83. Joers, Arvi
    et al.
    Vind, Kristiina
    Hernandez, Sara B.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Maruste, Regina
    Pereira, Marta
    Brauer, Age
    Remm, Maido
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Tenson, Tanel
    Muropeptides Stimulate Growth Resumption from Stationary Phase in Escherichia coli2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 18043Article in journal (Refereed)
    Abstract [en]

    When nutrients run out, bacteria enter a dormant metabolic state. This low or undetectable metabolic activity helps bacteria to preserve their scant reserves for the future needs, yet it also diminishes their ability to scan the environment for new growth-promoting substrates. However, neighboring microbial growth is a reliable indicator of a favorable environment and can thus serve as a cue for exiting dormancy. Here we report that for Escherichia coli and Pseudomonas aeruginosa this cue is provided by the basic peptidoglycan unit (i.e. muropeptide). We show that several forms of muropeptides from a variety of bacterial species can stimulate growth resumption of dormant cells and the sugar-peptide bond is crucial for this activity. These results, together with previous research that identifies muropeptides as a germination signal for bacterial spores, and their detection by mammalian immune cells, show that muropeptides are a universal cue for bacterial growth.

  • 84.
    Jones, Iwan
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Yelhekar, Tushar D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wiberg, Rebecca
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Johansson, Staffan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Carlsson, Leif
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Development and validation of an in vitro model system to study peripheral sensory neuron development and injury2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 15961Article in journal (Refereed)
    Abstract [en]

    The ability to discriminate between diverse types of sensation is mediated by heterogeneous populations of peripheral sensory neurons. Human peripheral sensory neurons are inaccessible for research and efforts to study their development and disease have been hampered by the availability of relevant model systems. The in vitro differentiation of peripheral sensory neurons from human embryonic stem cells therefore provides an attractive alternative since an unlimited source of biological material can be generated for studies that specifically address development and injury. The work presented in this study describes the derivation of peripheral sensory neurons from human embryonic stem cells using small molecule inhibitors. The differentiated neurons express canonical- and modality-specific peripheral sensory neuron markers with subsets exhibiting functional properties of human nociceptive neurons that include tetrodotoxin-resistant sodium currents and repetitive action potentials. Moreover, the derived cells associate with human donor Schwann cells and can be used as a model system to investigate the molecular mechanisms underlying neuronal death following peripheral nerve injury. The quick and efficient derivation of genetically diverse peripheral sensory neurons from human embryonic stem cells offers unlimited access to these specialised cell types and provides an invaluable in vitro model system for future studies.

  • 85.
    Josefsson, Maria
    et al.
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Larsson, Maria
    Nordin, Steven
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Olofsson, Jonas
    APOE-ɛ4 effects on longitudinal decline in olfactory and non-olfactory cognitive abilities in middle-aged and old adults2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 1286Article in journal (Refereed)
    Abstract [en]

    Characterizing aging-related decline trajectories in mental abilities, and relationships of the ɛ4 allele of the Apolipoprotein gene, helps to identify individuals at high risk for dementia. However, longitudinal changes in olfactory and non-olfactory cognitive abilities have not been investigated in relation to the ɛ4 allele. In the present study, participants from a large population-based study (657 middle-aged and 556 old) were tested over 10 years on their performance on an odor identification task and three non-olfactory cognitive tasks; MMSE, episodic memory, and semantic memory. Our key finding is that in middle-aged participants, odor identification declined twice as fast for ɛ4/4 homozygotes, compared to non-carriers. However, in old participants, the ɛ4/4 homozygotes showed an impaired odor identification ability, but they declined at a similar rate as the non-carriers. Furthermore, in old participants all assessments displayed aging-related declines, but exaggerated declines in ɛ4-carriers were found only in MMSE and episodic memory assessments. In sum, we present evidence that odor identification ability starts to decline already in middle-aged, and that carriers of ɛ4/4, who are at highest risk of developing dementia, decline twice as fast. Our results may have implications for use of odor identification assessment in detection of early-stage dementia.

  • 86. Kable, Mary E.
    et al.
    Hansen, Lori M.
    Styer, Cathy M.
    Deck, Samuel L.
    Rakhimova, Olena
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Shevtsova, Anna
    Eaton, Kathryn A.
    Martin, Miriam E.
    Gideonsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Borén, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Solnick, Jay V.
    Host Determinants of Expression of the Helicobacter pylori BabA Adhesin2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46499Article in journal (Refereed)
    Abstract [en]

    Expression of the Helicobacter pylori blood group antigen binding adhesin A (BabA) is more common in strains isolated from patients with peptic ulcer disease or gastric cancer, rather than asymptomatic colonization. Here we used mouse models to examine host determinants that affect H. pylori BabA expression. BabA expression was lost by phase variation as frequently in WT mice as in RAG2-/- mice that do not have functional B or T cells, and in MyD88-/-, TLR2-/- and TLR4-/- mice that are defective in toll like receptor signaling. The presence of other bacteria had no effect on BabA expression as shown by infection of germ free mice. Moreover, loss of BabA expression was not dependent on Le(b) expression or the capacity of BabA to bind Leb. Surprisingly, gender was the host determinant most associated with loss of BabA expression, which was maintained to a greater extent in male mice and was associated with greater bacterial load. These results suggest the possibility that loss of BabA expression is not driven by adaptive immunity or toll-like receptor signaling, and that BabA may have other, unrecognized functions in addition to serving as an adhesin that binds Le(b).

  • 87. Karlsson, Anna
    et al.
    Cirenajwis, Helena
    Ericson-Lindquist, Kajsa
    Brunnström, Hans
    Reuterswärd, Christel
    Jönsson, Mats
    Ortiz-Villalon, Cristian
    Hussein, Aziz
    Bergman, Bengt
    Vikström, Anders
    Monsef, Nastaran
    Branden, Eva
    Koyi, Hirsh
    de Petris, Luigi
    Micke, Patrick
    Patthey, Annika
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Planck, Maria
    Staaf, Johan
    A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5207Article in journal (Refereed)
    Abstract [en]

    Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.

  • 88. Karlsson, E.
    et al.
    Larkeryd, A.
    Sjödin, Andreas
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Swedish Defence Research Agency, Umeå, Sweden.
    Forsman, M.
    Stenberg, Per
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Swedish Defence Research Agency, Umeå, Sweden; Department of Chemistry, Computational Life Science Cluster (CLiC), Umeå University, Umeå, Sweden.
    Scaffolding of a bacterial genome using MinION nanopore sequencing2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 11996Article in journal (Refereed)
    Abstract [en]

    Second generation sequencing has revolutionized genomic studies. However, most genomes contain repeated DNA elements that are longer than the read lengths achievable with typical sequencers, so the genomic order of several generated contigs cannot be easily resolved. A new generation of sequencers offering substantially longer reads is emerging, notably the Pacific Biosciences (PacBio) RS II system and the MinION system, released in early 2014 by Oxford Nanopore Technologies through an early access program. The latter has highly advantageous portability and sequences samples by measuring changes in ionic current when single-stranded DNA molecules are translocated through nanopores. We show that the MinION system produces long reads with high mapability that can be used for scaffolding bacterial genomes, despite currently producing substantially higher error rates than PacBio reads. With further development we anticipate that MinION will be useful not only for assembling genomes, but also for rapid detection of organisms, potentially in the field.

  • 89.
    Kasari, Villu
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Margus, Tonu
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Johansson, Marcus J. O.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). 3 University of Tartu, Institute of Technology, Tartu, Estonia.
    Ribosome profiling analysis of eEF3-depleted Saccharomyces cerevisiae2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 3037Article in journal (Refereed)
    Abstract [en]

    In addition to the standard set of translation factors common in eukaryotic organisms, protein synthesis in the yeast Saccharomyces cerevisiae requires an ABCF ATPase factor eEF3, eukaryotic Elongation Factor 3. eEF3 is an E-site binder that was originally identified as an essential factor involved in the elongation stage of protein synthesis. Recent biochemical experiments suggest an additional function of eEF3 in ribosome recycling. We have characterised the global effects of eEF3 depletion on translation using ribosome profiling. Depletion of eEF3 results in decreased ribosome density at the stop codon, indicating that ribosome recycling does not become rate limiting when eEF3 levels are low. Consistent with a defect in translation elongation, eEF3 depletion causes a moderate redistribution of ribosomes towards the 5' part of the open reading frames. We observed no E-site codon-or amino acid-specific ribosome stalling upon eEF3 depletion, supporting its role as a general elongation factor. Surprisingly, depletion of eEF3 leads to a relative decrease in P-site proline stalling, which we hypothesise is a secondary effect of generally decreased translation and/or decreased competition for the E-site with eIF5A.

  • 90. Khalil, Hussein
    et al.
    Ecke, Frauke
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Magnusson, Magnus
    Hornfeldt, Birger
    Declining ecosystem health and the dilution effect2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 31314Article in journal (Refereed)
    Abstract [en]

    The "dilution effect" implies that where species vary in susceptibility to infection by a pathogen, higher diversity often leads to lower infection prevalence in hosts. For directly transmitted pathogens, non-host species may "dilute" infection directly (1) and indirectly (2). Competitors and predators may (1) alter host behavior to reduce pathogen transmission or (2) reduce host density. In a well-studied system, we tested the dilution of the zoonotic Puumala hantavirus (PUUV) in bank voles (Myodes glareolus) by two competitors and a predator. Our study was based on long-term PUUV infection data (2003-2013) in northern Sweden. The field vole (Microtus agrestis) and the common shrew (Sorex araneus) are bank vole competitors and Tengmalm's owl (Aegolius funereus) is a main predator of bank voles. Infection probability in bank voles decreased when common shrew density increased, suggesting that common shrews reduced PUUV transmission. Field voles suppressed bank vole density in meadows and clear-cuts and indirectly diluted PUUV infection. Further, Tengmalm's owl decline in 1980-2013 may have contributed to higher PUUV infection rates in bank voles in 2003-2013 compared to 1979-1986. Our study provides further evidence for dilution effect and suggests that owls may have an important role in reducing disease risk.

  • 91. Khemiri, Lotfi
    et al.
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Runeson, Bo
    Jayaram-Lindstrom, Nitya
    Suicide Risk Associated with Experience of Violence and Impulsivity in Alcohol Dependent Patients2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 19373Article in journal (Refereed)
    Abstract [en]

    Alcohol dependence (AD) and aggression-impulsivity are both associated with increased suicide risk. There is a need to evaluate clinical tools in order to improve suicide risk assessment of AD patients. The present study consisted of 95 individuals with a diagnosis of AD, consecutively admitted for addiction treatment, compared with 95 healthy controls. Suicidal risk was assessed together with exposure of violence and impulsivity. AD patients reported significantly higher rates of exposure to violence in childhood, as measured by the Karolinska Interpersonal Violence Scale (KIVS), compared to HC. Within the AD group, individuals with history of suicidal ideation and suicidal behavior reported higher levels of violence experience compared to AD individuals without such history. AD patients with previous suicidal ideation scored higher on self-reported impulsivity as assessed by the Barratt Impulsivity Scale (BIS). Our main finding was that experience of trauma and expression of violent behavior, coupled with increased impulsivity are associated with an elevated suicide risk in AD patients. Future longitudinal studies assessing these traits are needed to evaluate their potential role in identifying AD patients at risk of future suicide.

  • 92. Kimanius, D.
    et al.
    Lindahl, E.
    Andersson, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Uptake dynamics in the Lactose permease (LacY) membrane protein transporter2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 14324Article in journal (Refereed)
    Abstract [en]

    The sugar transporter Lactose permease (LacY) of Escherichia coli has become a prototype to understand the underlying molecular details of membrane transport. Crystal structures have trapped the protein in sugar-bound states facing the periplasm, but with narrow openings unable to accommodate sugar. Therefore, the molecular details of sugar uptake remain elusive. In this work, we have used extended simulations and metadynamics sampling to explore a putative sugar-uptake pathway and associated free energy landscape. We found an entrance at helix-pair 2 and 11, which involved lipid head groups and residues Gln 241 and Gln 359. Furthermore, the protein displayed high flexibility on the periplasmic side of Phe 27, which is located at the narrowest section of the pathway. Interactions to Phe 27 enabled passage into the binding site, which was associated with a 24 ± 4 kJ/mol binding free energy in excellent agreement with an independent binding free energy calculation and experimental data. Two free energy minima corresponding to the two possible binding poses of the lactose analog β-D-galactopyranosyl-1-thio-β-D-galactopyranoside (TDG) were aligned with the crystal structure-binding pocket. This work outlines the chemical environment of a putative periplasmic sugar pathway and paves way for understanding substrate affinity and specificity in LacY.

  • 93.
    Kindstedt, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Koskinen Holm, Cecilia
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Martinez-Carrasco, Irene
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    CCL11, a novel mediator of inflammatory bone resorption2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 5334Article in journal (Refereed)
    Abstract [en]

    Normal bone homeostasis, which is regulated by bone-resorbing osteoclasts and bone-forming osteoblasts is perturbed by inflammation. Inchronic inflammatory disease with disturbed bone remodelling, e.g. rheumatoid arthritis, patients show increased serum levels of the chemokine eotaxin-1 (CCL11). Herein, we demonstrate an inflammatory driven expression of CCL11 in bone tissue and a novel role of CCL11 in osteoclast migration and resorption. Using an inflammatory bone lesion model and primary cell cultures, we discovered that osteoblasts express CCL11 in vivo and in vitro and that expression increased during inflammatory conditions. Osteoclasts did not express CCL11, but the high affinity receptor CCR3 was significantly upregulated during osteoclast differentiation and found to colocalise with CCL11. Exogenous CCL11 was internalised in osteoclast and stimulated the migration of pre-osteoclast and concomitant increase in bone resorption. Our data pinpoints that the CCL11/CCR3 pathway could be a new target for treatment of inflammatory bone resorption.

  • 94.
    Kloppsteck, Patrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hall, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hasegawa, Yoshiaki
    Persson, Karina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Structure of the fimbrial protein Mfa4 from Porphyromonas gingivalis in its precursor form: implications for a donor-strand complementation mechanism2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 22945Article in journal (Refereed)
    Abstract [en]

    Gingivitis and periodontitis are chronic inflammatory diseases that can lead to tooth loss. One of the causes of these diseases is the Gram-negative Porphyromonas gingivalis. This periodontal pathogen is dependent on two fimbriae, FimA and Mfa1, for binding to dental biofilm, salivary proteins, and host cells. These fimbriae are composed of five proteins each, but the fimbriae assembly mechanism and ligands are unknown. Here we reveal the crystal structure of the precursor form of Mfa4, one of the accessory proteins of the Mfa1 fimbria. Mfa4 consists of two β-sandwich domains and the first part of the structure forms two well-defined β-strands that run over both domains. This N-terminal region is cleaved by gingipains, a family of proteolytic enzymes that encompass arginine- and lysine-specific proteases. Cleavage of the N-terminal region generates the mature form of the protein. Our structural data allow us to propose that the new N-terminus of the mature protein may function as a donor strand in the polymerization of P. gingivalis fimbriae.

  • 95.
    Kolan, Shrikant S
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lidström, Tommy
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Mediavilla, Tomás
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Dernstedt, Andy
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Björk, Karl
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Marcellino, Daniel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4276Article in journal (Refereed)
    Abstract [en]

    A majority of lymphomas are derived from B cells and novel treatments are required to treat refractory disease. Neurotransmitters such as serotonin and dopamine influence activation of B cells and the effects of a selective serotonin 1A receptor (5HT1A) antagonist on growth of a number of B cell-derived lymphoma cell lines were investigated. We confirmed the expression of 5HT1A in human lymphoma tissue and in several well-defined experimental cell lines. We discovered that the pharmacological inhibition of 5HT1A led to the reduced proliferation of B cell-derived lymphoma cell lines together with DNA damage, ROS-independent caspase activation and apoptosis in a large fraction of cells. Residual live cells were found ‘locked’ in a non-proliferative state in which a selective transcriptional and translational shutdown of genes important for cell proliferation and metabolism occurred (e.g., AKT, GSK-3β, cMYC and p53). Strikingly, inhibition of 5HT1A regulated mitochondrial activity through a rapid reduction of mitochondrial membrane potential and reducing dehydrogenase activity. Collectively, our data suggest 5HT1A antagonism as a novel adjuvant to established cancer treatment regimens to further inhibit lymphoma growth.

  • 96.
    Kolar, Mallappa Kadappa
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Itte, Vinay N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Kelk, Peyman
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    The neurotrophic effects of different human dental mesenchymal stem cells2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 12605Article in journal (Refereed)
  • 97. Koukalova, Alena
    et al.
    Amaro, Mariana
    Aydogan, Gokcan
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Williamson, Philip T. F.
    Mikhalyov, Ilya
    Hof, Martin
    Sachl, Radek
    Lipid Driven Nanodomains in Giant Lipid Vesicles are Fluid and Disordered2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 5460Article in journal (Refereed)
    Abstract [en]

    It is a fundamental question in cell biology and biophysics whether sphingomyelin (SM)-and cholesterol (Chol)-driven nanodomains exist in living cells and in model membranes. Biophysical studies on model membranes revealed SM and Chol driven micrometer-sized liquid-ordered domains. Although the existence of such microdomains has not been proven for the plasma membrane, such lipid mixtures have been often used as a model system for 'rafts'. On the other hand, recent super resolution and single molecule results indicate that the plasma membrane might organize into nanocompartments. However, due to the limited resolution of those techniques their unambiguous characterization is still missing. In this work, a novel combination of Forster resonance energy transfer and Monte Carlo simulations (MC-FRET) identifies directly 10 nm large nanodomains in liquid-disordered model membranes composed of lipid mixtures containing SM and Chol. Combining MC-FRET with solidstate wide-line and high resolution magic angle spinning NMR as well as with fluorescence correlation spectroscopy we demonstrate that these nanodomains containing hundreds of lipid molecules are fluid and disordered. In terms of their size, fluidity, order and lifetime these nanodomains may represent a relevant model system for cellular membranes and are closely related to nanocompartments suggested to exist in cellular membranes.

  • 98. Krauskopf, Julian
    et al.
    de Kok, Theo M
    Hebels, Dennie G
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Spaeth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kiviranta, Hannu
    Rantakokko, Panu
    Kyrtopoulos, Soterios A
    Kleinjans, Jos C
    MicroRNA profile for health risk assessment: environmental exposure to persistent organic pollutants strongly affects the human blood microRNA machinery2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 9262Article in journal (Refereed)
    Abstract [en]

    Persistent organic pollutants (POPs) are synthetic chemical substances that accumulate in our environment. POPs such as polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB) and dichlorodiphenyltrichloroethane (DDT) have been classified as carcinogenic to humans and animals. Due to their resistance to biodegradation humans are still exposed to these compounds worldwide. We aim to evaluate the miRNA and transcriptomic response of a human population exposed to POPs. The miRNA and transcriptomic response was measured in blood of healthy subjects by microarray technology and associated with the serum concentrations of six PCB congeners, DDE (a common DDT metabolite), and HCB. A total of 93 miRNA levels appeared significantly associated with the POP-exposure (FDR < 0.05). The miRNA profile includes four tumor suppressor miRNAs, namely miR-193a-3p, miR-152, miR-31-5p and miR-34a-5p. Integration of the miRNA profile with the transcriptome profile suggests an interaction with oncogenes such as MYC, CCND1, BCL2 and VEGFA. We have shown that exposure to POPs is associated with human miRNA and transcriptomic responses. The identified miRNAs and target genes are related to various types of cancer and involved in relevant signaling pathways like wnt and p53. Therefore, these miRNAs may have great potential to contribute to biomarker-based environmental health risk assessment.

  • 99.
    Kuhn, McKenzie
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Department of Renewable Resources, University of Alberta, 116 St & 85 Ave, Edmonton, AB, CA, T6G 2R3, Canada.
    Lundin, Erik J
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Swedish Polar Research Secretariat, Abisko Scientific Research Station, SE-981 07, Abisko, Sweden.
    Giesler, Reiner
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Johansson, Margareta
    Karlsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Emissions from thaw ponds largely offset the carbon sink of northern permafrost wetlands2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 9535Article in journal (Refereed)
    Abstract [en]

    Northern regions have received considerable attention not only because the effects of climate change are amplified at high latitudes but also because this region holds vast amounts of carbon (C) stored in permafrost. These carbon stocks are vulnerable to warming temperatures and increased permafrost thaw and the breakdown and release of soil C in the form of carbon dioxide (CO2) and methane (CH4). The majority of research has focused on quantifying and upscaling the effects of thaw on CO2 and CH4 emissions from terrestrial systems. However, small ponds formed in permafrost wetlands following thawing have been recognized as hotspots for C emissions. Here, we examined the importance of small ponds for C fluxes in two permafrost wetland ecosystems in northern Sweden. Detailed flux estimates of thaw ponds during the growing season show that ponds emit, on average (±SD), 279 ± 415 and 7 ± 11 mmol C m−2 d−1 of CO2 and CH4, respectively. Importantly, addition of pond emissions to the total C budget of the wetland decreases the C sink by ~39%. Our results emphasize the need for integrated research linking C cycling on land and in water in order to make correct assessments of contemporary C balances.

  • 100. Kunsmann, Lisa
    et al.
    Rueter, Christian
    Bauwens, Andreas
    Greune, Lilo
    Glueder, Malte
    Kemper, Bjoern
    Fruth, Angelika
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    He, Xiaohua
    Lloubes, Roland
    Schmidt, M. Alexander
    Dobrindt, Ulrich
    Mellmann, Alexander
    Karch, Helge
    Bielaszewska, Martina
    Virulence from vesicles: Novel mechanisms of host cell injury by Escherichia coli O104:H4 outbreak strain2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 13252Article in journal (Refereed)
    Abstract [en]

    The highly virulent Escherichia coli O104:H4 that caused the large 2011 outbreak of diarrhoea and haemolytic uraemic syndrome secretes blended virulence factors of enterohaemorrhagic and enteroaggregative E. coli, but their secretion pathways are unknown. We demonstrate that the outbreak strain releases a cocktail of virulence factors via outer membrane vesicles (OMVs) shed during growth. The OMVs contain Shiga toxin (Stx) 2a, the major virulence factor of the strain, Shigella enterotoxin 1, H4 flagellin, and O104 lipopolysaccharide. The OMVs bind to and are internalised by human intestinal epithelial cells via dynamin-dependent and Stx2a-independent endocytosis, deliver the OMV-associated virulence factors intracellularly and induce caspase-9-mediated apoptosis and interleukin-8 secretion. Stx2a is the key OMV component responsible for the cytotoxicity, whereas flagellin and lipopolysaccharide are the major interleukin-8 inducers. The OMVs represent novel ways for the E. coli O104: H4 outbreak strain to deliver pathogenic cargoes and injure host cells.

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