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  • 151. Perdersen, Martin Nors
    et al.
    Fodera, Vito
    Horvath, Istvan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    van Maarschalkerweerd, Andreas
    Toft, Katrine Norgaard
    Weise, Christoph
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wolf-Watz, Magnus
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Vestergaard, Bente
    Direct Correlation Between Ligand-Induced alpha-Synuclein Oligomers and Amyloid-like Fibril Growth2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 10422Article in journal (Refereed)
    Abstract [en]

    Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075: protein ratios, the oligomers appear to be on-pathway and modeling supports an 'oligomer stacking model' for alpha-synuclein fibril elongation.

  • 152. Peterson, Gunnel
    et al.
    Nilsson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Falla, Deborah
    Dedering, Åsa
    Wallman, Thorne
    Peolsson, Anneli
    Novel insights into the interplay between ventral neck muscles in individuals with whiplash-associated disorders2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15289Article in journal (Refereed)
    Abstract [en]

    Chronic whiplash-associated disorder (WAD) is common after whiplash injury, with considerable personal, social, and economic burden. Despite decades of research, factors responsible for continuing pain and disability are largely unknown, and diagnostic tools are lacking. Here, we report a novel model of mechanical ventral neck muscle function recorded from non-invasive, real-time, ultrasound measurements. We calculated the deformation area and deformation rate in 23 individuals with persistent WAD and compared them to 23 sex-and age-matched controls. Multivariate statistics were used to analyse interactions between ventral neck muscles, revealing different interplay between muscles in individuals with WAD and healthy controls. Although the cause and effect relation cannot be established from this data, for the first time, we reveal a novel method capable of detecting different neck muscle interplay in people with WAD. This non-invasive method stands to make a major breakthrough in the assessment and diagnosis of people following a whiplash trauma.

  • 153. Peterson, Gunnel
    et al.
    Nilsson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Peolsson, Anneli
    Neck-specific exercise improves impaired interactions between ventral neck muscles in chronic whiplash: A randomized controlled ultrasound study2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 9649Article in journal (Refereed)
    Abstract [en]

    Chronic pain and disability is common in whiplash-associated disorders (WAD), leading to personal suffering, sick leave, and social cost. The cervical spine is heavily dependent on muscular support and whiplash injury can cause damage to the neck muscles, but diagnostic tools to measure neck muscle impairment and evaluate exercise interventions are lacking. Therefore, the present study investigated ventral neck muscle interactions in 26 individuals with chronic WAD randomized to neck-specific exercise (NSE) or remaining on a waiting list (WL) in 3 months. We performed real-time, non-invasive ultrasound measurements with speckle tracking analysis and calculated the deformation area and deformation rate in three ventral neck muscles. Multivariate statistics were used to analyse interactions between the muscles. After 3 months of NSE, significant improvements were observed in neck muscle interactions and pain intensity in the NSE group compared to the WL group. Thus, this study demonstrates that non-invasive ultrasound can be a diagnostic tool for muscle impairment and used to evaluate exercise interventions in WAD and stands to make a breakthrough for better management in chronic WAD.

  • 154. Peterson, Gunnel
    et al.
    O'Leary, Shaun
    Nilsson, David
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Moodie, Katherine
    Tucker, Kylie
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Peolsson, Anneli
    Ultrasound imaging of dorsal neck muscles with speckle tracking analyses: the relationship between muscle deformation and force2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 13688Article in journal (Refereed)
    Abstract [en]

    The development of methods of non-invasive measurement of neck muscle function remains a priority in the clinical sciences. In this study, dorsal neck muscle deformation vs time curves (deformation area) were evaluated against incremental force, recorded from non-invasive real-time ultrasound measurement. The results revealed subject-specific moderate to strong linear or non-linear relationships between deformation and force. Test-retest variability showed strong reliability for all five neck muscles summed together and fair to good reliability for the five muscles evaluated separately. Multivariate statistics were used to analyse the interactions between the dorsal neck muscles during different percentages of maximal voluntary contraction (MVC). Low force (10-20% MVC) was related to muscle shortening; higher force (40-80% MVC) showed combination of shortening and elongation deformation in the muscle interactions. The muscle interactions during isometric MVC test were subject-specific, with different combinations and deformations of the five neck muscles. Force >= 40% MVC were associated with a forward movement of the cervical spine that affected the ultrasound measurement of the dorsal neck muscles. Ultrasound with speckle-tracking analyses may be best used to detect low levels (<40% MVC) of neck muscle activity.

  • 155. Peviani, Alessia
    et al.
    Lastdrager, Jeroen
    Hanson, Johannes
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Molecular Plant Physiology, Institute of Environmental Biology, Utrecht University, Utrecht, The Netherlands.
    Snel, Berend
    The phylogeny of C/S1 bZIP transcription factors reveals a shared algal ancestry and the pre-angiosperm translational regulation of S1 transcripts2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 30444Article in journal (Refereed)
    Abstract [en]

    Basic leucine zippers (bZIPs) form a large plant transcription factor family. C and S1 bZIP groups can heterodimerize, fulfilling crucial roles in seed development and stress response. S1 sequences also harbor a unique regulatory mechanism, termed Sucrose-Induced Repression of Translation (SIRT). The conservation of both C/S1 bZIP interactions and SIRT remains poorly characterized in non-model species, leaving their evolutionary origin uncertain and limiting crop research. In this work, we explored recently published plant sequencing data to establish a detailed phylogeny of C and S1 bZIPs, investigating their intertwined role in plant evolution, and the origin of SIRT. Our analyses clarified C and S1 bZIP orthology relationships in angiosperms, and identified S1 sequences in gymnosperms. We experimentally showed that the gymnosperm orthologs are regulated by SIRT, tracing back the origin of this unique regulatory mechanism to the ancestor of seed plants. Additionally, we discovered an earlier S ortholog in the charophyte algae Klebsormidium flaccidum, together with a C ortholog. This suggests that C and S groups originated by duplication from a single algal proto-C/S ancestor. Based on our observations, we propose a model wherein the C/S1 bZIP dimer network evolved in seed plants from pre-existing C/S bZIP interactions.

  • 156.
    Piltti, Juha
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Bygdell, Joakim
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fernández-Echevarría, Cecilia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marcellino, Daniel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center, Xi’an Jiaotong University.
    Rho-kinase inhibitor Y-27632 and hypoxia synergistically enhance chondrocytic phenotype and change the S100 protein profile in human chondrosarcoma cells2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3708Article in journal (Refereed)
    Abstract [en]

    Articular chondrocytes are slowly dividing cells that tend to lose their cell type-specific phenotype and ability to produce structurally and functionally correct cartilage tissue when cultured. Thus, culture conditions, which enhance the maintenance of chondrocyte phenotype would be very useful for cartilage research. Here we show that Rho-kinase inhibition by Y-27632 under hypoxic conditions efficiently maintains and even enhances chondrocyte-specific extracellular matrix production by chondrocytic cells. The effects of long-term Y-27632 exposure to human chondrosarcoma 2/8 cell phenotype maintenance and extracellular matrix production were studied at normoxia and at a 5% low oxygen atmosphere. Y-27632 treatment at normoxia induced ACAN and COL2A1 gene up-regulation and a minor increase of sulfated glycosaminoglycans (sGAGs), while type II collagen expression was not significantly up-regulated. A further increase in expression of ACAN and COL2A1 was achieved with Y-27632 treatment and hypoxia. The production of sGAGs increased by 65.8%, and ELISA analysis revealed a 6-fold up-regulation of type II collagen. Y-27632 also induced the up-regulation of S100-A1 and S100-B proteins and modified the expression of several other S100 protein family members, such as S100-A4, S100-A6, S100-A13 and S100-A16. The up-regulation of S100-A1 and S100-B proteins is suggested to enhance the chondrocytic phenotype of these cells.

  • 157.
    Piltti, Juha
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Bygdell, Joakim
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fernández-Echevarría, Cecilia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Marcellino, Daniel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). School of Public Health, Health Science Center of Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health and Family Planning Commission, Xi'an, China.
    Rho-kinase inhibitor Y-27632 and hypoxia synergistically enhance chondrocytic phenotype and modify S100 protein profiles in human chondrosarcoma cells2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3708Article in journal (Refereed)
    Abstract [en]

    Articular chondrocytes are slowly dividing cells that tend to lose their cell type-specific phenotype and ability to produce structurally and functionally correct cartilage tissue when cultured. Thus, culture conditions, which enhance the maintenance of chondrocyte phenotype would be very useful for cartilage research. Here we show that Rho-kinase inhibition by Y-27632 under hypoxic conditions efficiently maintains and even enhances chondrocyte-specific extracellular matrix production by chondrocytic cells. The effects of long-term Y-27632 exposure to human chondrosarcoma 2/8 cell phenotype maintenance and extracellular matrix production were studied at normoxia and at a 5% low oxygen atmosphere. Y-27632 treatment at normoxia induced ACAN and COL2A1 gene up-regulation and a minor increase of sulfated glycosaminoglycans (sGAGs), while type II collagen expression was not significantly up-regulated. A further increase in expression of ACAN and COL2A1 was achieved with Y-27632 treatment and hypoxia. The production of sGAGs increased by 65.8%, and ELISA analysis revealed a 6-fold up-regulation of type II collagen. Y-27632 also induced the up-regulation of S100-A1 and S100-B proteins and modified the expression of several other S100 protein family members, such as S100-A4, S100-A6, S100-A13 and S100-A16. The up-regulation of S100-A1 and S100-B proteins is suggested to enhance the chondrocytic phenotype of these cells.

  • 158. Prebil, Sara Drmota
    et al.
    Slapsak, Urska
    Pavsic, Miha
    Ilc, Gregor
    Puz, Vid
    Ribeiro, Euripedes de Almeida
    Anrather, Dorothea
    Hartl, Markus
    Backman, Lars
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Plavec, Janez
    Lenarcic, Brigita
    Djinovic-Carugo, Kristina
    Structure and calcium-binding studies of calmodulin-like domain of human non-muscle alpha-actinin-12016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 27383Article in journal (Refereed)
    Abstract [en]

    The activity of several cytosolic proteins critically depends on the concentration of calcium ions. One important intracellular calcium-sensing protein is alpha-actinin-1, the major actin crosslinking protein in focal adhesions and stress fibers. The actin crosslinking activity of alpha-actinin-1 has been proposed to be negatively regulated by calcium, but the underlying molecular mechanisms are poorly understood. To address this, we determined the first high-resolution NMR structure of its functional calmodulin-like domain (CaMD) in calcium-bound and calcium-free form. These structures reveal that in the absence of calcium, CaMD displays a conformationally flexible ensemble that undergoes a structural change upon calcium binding, leading to limited rotation of the N- and C-terminal lobes around the connecting linker and consequent stabilization of the calcium-loaded structure. Mutagenesis experiments, coupled with mass-spectrometry and isothermal calorimetry data designed to validate the calcium binding stoichiometry and binding site, showed that human non-muscle alpha-actinin-1 binds a single calcium ion within the N-terminal lobe. Finally, based on our structural data and analogy with other alpha-actinins, we provide a structural model of regulation of the actin crosslinking activity of alpha-actinin-1 where calcium induced structural stabilisation causes fastening of the juxtaposed actin binding domain, leading to impaired capacity to crosslink actin.

  • 159. Qian, Chaoju
    et al.
    Yin, Hengxia
    Shi, Yong
    Zhao, Jiecai
    Yin, Chengliang
    Luo, Wanyin
    Dong, Zhibao
    Chen, Guoxiong
    Yan, Xia
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Ma, Xiao-Fei
    Population dynamics of Agriophyllum squarrosum, a pioneer annual plant endemic to mobile sand dunes, in response to global climate change2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 26613Article in journal (Refereed)
    Abstract [en]

    Climate change plays an important role in the transition of ecosystems. Stratigraphic investigations have suggested that the Asian interior experienced frequent transitions between grassland and desert ecosystems as a consequence of global climate change. Using maternally and bi-parentally inherited markers, we investigated the population dynamics of Agriophyllum squarrosum (Chenopodiaceae), an annual pioneer plant endemic to mobile sand dunes. Phylogeographic analysis revealed that A. squarrosum could originate from Gurbantunggut desert since similar to 1.6 Ma, and subsequently underwent three waves of colonisation into other deserts and sandy lands corresponding to several glaciations. The rapid population expansion and distribution range shifts of A. squarrosum from monsoonal climate zones suggested that the development of the monsoonal climate significantly enhanced the population growth and gene flow of A. squarrosum. These data also suggested that desertification of the fragile grassland ecosystems in the Qinghai-Tibetan Plateau was more ancient than previously suggested and will be aggravated under global warming in the future. This study provides new molecular phylogeographic insights into how pioneer annual plant species in desert ecosystems respond to global climate change, and facilitates evaluation of the ecological potential and genetic resources of future crops for non-arable dry lands to mitigate climate change.

  • 160.
    Rajan, Anandi
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Persson, B. David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Olofsson, Annelie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Heino, Jyrki
    Department of Biochemistry, University of Turku, Finland.
    Takada, Yoshikazu
    Department of Dermatology, Biochemistry and Molecular Medicine, UC Davis School of Medicine, California, USA.
    Mould, A. Paul
    Biomolecular Analysis Core Facility, Faculty of Biology, Medicine and Health, University of Manchester, United Kingdom.
    Schnapp, Lynn M.
    Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, Charleston, USA.
    Gall, Jason
    Vaccine Research Center (VRC), NIAID, NIH, Bethesda, USA.
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Enteric species F human adenoviruses use laminin-binding integrins as co-receptors for infection of Ht-29 cells2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 10019Article in journal (Refereed)
    Abstract [en]

    The enteric species F human adenovirus types 40 and 41 (HAdV-40 and -41) are the third most common cause of infantile gastroenteritis in the world. Knowledge about HAdV-40 and -41 cellular infection is assumed to be fundamentally different from that of other HAdVs since HAdV-40 and -41 penton bases lack the αV-integrin-interacting RGD motif. This motif is used by other HAdVs mainly for internalization and endosomal escape. We hypothesised that the penton bases of HAdV-40 and -41 interact with integrins independently of the RGD motif. HAdV-41 transduction of a library of rodent cells expressing specific human integrin subunits pointed to the use of laminin-binding α2-, α3- and α6-containing integrins as well as other integrins as candidate co-receptors. Specific laminins prevented internalisation and infection, and recombinant, soluble HAdV-41 penton base proteins prevented infection of human intestinal HT-29 cells. Surface plasmon resonance analysis demonstrated that HAdV-40 and -41 penton base proteins bind to α6-containing integrins with an affinity similar to that of previously characterised penton base:integrin interactions. With these results, we propose that laminin-binding integrins are co-receptors for HAdV-40 and -41.

  • 161. Rivas, D. E.
    et al.
    Borot, A.
    Cardenas, D. E.
    Marcus, G.
    Gu, X.
    Herrmann, D.
    Xu, J.
    Tan, J.
    Kormin, D.
    Ma, G.
    Dallari, W.
    Tsakiris, G. D.
    Foldes, I. B.
    Chou, S. -w.
    Weidman, M.
    Bergues, B.
    Wittmann, T.
    Schroeder, H.
    Tzallas, P.
    Charalambidis, D.
    Razskazovskaya, O.
    Pervak, V.
    Krausz, F.
    Veisz, László
    Umeå University, Faculty of Science and Technology, Department of Physics. Max-Planck-Institut für Quantenoptik, Garching, Germany.
    Next Generation Driver for Attosecond and Laser-plasma Physics2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 5224Article in journal (Refereed)
    Abstract [en]

    The observation and manipulation of electron dynamics in matter call for attosecond light pulses, routinely available from high-order harmonic generation driven by few-femtosecond lasers. However, the energy limitation of these lasers supports only weak sources and correspondingly linear attosecond studies. Here we report on an optical parametric synthesizer designed for nonlinear attosecond optics and relativistic laser-plasma physics. This synthesizer uniquely combines ultra-relativistic focused intensities of about 10(20)W/cm(2) with a pulse duration of sub-two carrier-wave cycles. The coherent combination of two sequentially amplified and complementary spectral ranges yields sub-5-fs pulses with multi-TW peak power. The application of this source allows the generation of a broad spectral continuum at 100-eV photon energy in gases as well as high-order harmonics in relativistic plasmas. Unprecedented spatio-temporal confinement of light now permits the investigation of electric-field-driven electron phenomena in the relativistic regime and ultimately the rise of next-generation intense isolated attosecond sources.

  • 162.
    Rodriguez, Alvaro
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Zhang, Hanqing
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Klaminder, Jonatan
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Brodin, Tomas
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Andersson, Magnus
    Umeå University, Faculty of Science and Technology, Department of Physics.
    ToxId: an efficient algorithm to solve occlusions when tracking multiple animals2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 14774Article in journal (Refereed)
    Abstract [en]

    Video analysis of animal behaviour is widely used in fields such as ecology, ecotoxicology, and evolutionary research. However, when tracking multiple animals, occlusion and crossing are problematic, especially when the identity of each individual needs to be preserved. We present a new algorithm, ToxId, which preserves the identity of multiple animals by linking trajectory segments using their intensity histogram and Hu-moments. We verify the performance and accuracy of our algorithm using video sequences with different animals and experimental conditions. The results show that our algorithm achieves state-of-the-art accuracy using an efficient approach without the need of learning processes, complex feature maps or knowledge of the animal shape. ToxId is also computationally efficient, has low memory requirements, and operates without accessing future or past frames.

  • 163.
    Rutegård, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden.
    Lagergren, Pernilla
    Johar, Asif
    Rouvelas, Ioannis
    Lagergren, Jesper
    The prognostic role of coeliac node metastasis after resection for distal oesophageal cancer2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43744Article in journal (Refereed)
    Abstract [en]

    It is uncertain whether coeliac node metastasis precludes long-term survival in distal oesophageal cancer. This nationwide population-based cohort study included patients who underwent surgical resection for stage III or IV distal oesophageal cancer in 1987-2010 with follow-up until 2014. A minority (17.0%) had neoadjuvant therapy. The prognosis in patients with coeliac node metastasis was compared with patients with no such metastasis and patients with more distant metastasis. Multivariable Cox proportional-hazards regression models provided hazard ratios (HRs) with 95% confidence intervals (CIs) of disease-specific and overall mortality. Among 446 patients, 346 (77.6%) had no coeliac node metastasis, 56 (12.6%) had coeliac node metastasis, and 44 (9.9%) had more distant metastasis. Compared to coeliac node negative patients, coeliac node positive patients were at a 52% increased risk of disease-specific mortality (HR = 1.52, 95% CI 1.10-2.10), while patients with more distant metastasis had a 27% statistically non-significant increase (HR = 1.27, 95% CI 0.88-1.83). Patients with distant metastasis had no increase in disease-specific mortality compared to those with coeliac node metastasis (HR 0.71, 95% CI 0.40-1.27). Thus, patients with distal oesophageal cancer with coeliac node metastasis seem to have a similarly poor survival as patients with more distant metastasis, and thus may not benefit from surgery.

  • 164. Sahl, Jason W.
    et al.
    Del Franco, Mariateresa
    Pournaras, Spyros
    Colman, Rebecca E.
    Karah, Nabil
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dijkshoorn, Lenie
    Zarrilli, Raffaele
    Phylogenetic and genomic diversity in isolates from the globally distributed Acinetobacter baumannii ST25 lineage2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15188Article in journal (Refereed)
    Abstract [en]

    Acinetobacter baumannii is a globally distributed nosocomial pathogen that has gained interest due to its resistance to most currently used antimicrobials. Whole genome sequencing (WGS) and phylogenetics has begun to reveal the global genetic diversity of this pathogen. The evolution of A. baumannii has largely been defined by recombination, punctuated by the emergence and proliferation of defined clonal lineages. In this study we sequenced seven genomes from the sequence type (ST)25 lineage and compared them to 12 ST25 genomes deposited in public databases. A recombination analysis identified multiple genomic regions that are homoplasious in the ST25 phylogeny, indicating active or historical recombination. Genes associated with antimicrobial resistance were differentially distributed between ST25 genomes, which matched our laboratory-based antimicrobial susceptibility typing. Differences were also observed in biofilm formation between ST25 isolates, which were demonstrated to produce significantly more extensive biofilm than an isolate from the ST1 clonal lineage. These results demonstrate that within A. baumannii, even a fairly recently derived monophyletic lineage can still exhibit significant genotypic and phenotypic diversity. These results have implications for associating outbreaks with sequence typing as well as understanding mechanisms behind the global propagation of successful A. baumannii lineages.

  • 165. Samuel, Tinu Mary
    et al.
    Binia, Aristea
    de Castro, Carlos Antonio
    Thakkar, Sagar K.
    Billeaud, Claude
    Agosti, Massimo
    Al-Jashi, Isam
    Costeire, Maria Jose
    Marchinr, Giovanna
    Martínez-Costa, Cecilia
    Picaud, Jean-Charles
    Stiris, Tom
    Stoicescu, Silvia-Maria
    Vanpeé, Keine
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Austin, Sean
    Sprenger, Norbert
    Impact of maternal characteristics on human milk oligosaccharide composition over the first 4 months of lactation in a cohort of healthy European mothers2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 11767Article in journal (Refereed)
    Abstract [en]

    Human milk oligosaccharide (HMO) composition varies among lactating mothers and changes during the course of lactation period. Interindividua I variation is largely driven by fucosyltransferase (FUT2 and FUT3) polymorphisms resulting in 4 distinct milk groups. Little is known regarding whether maternal physiological status contributes to HMO variability. We characterized the trajectories of 20 major HMOs and explored whether maternal pre-pregnancy body mass index (ppBMI), mode of delivery, or parity may affect milk HMO composition. Using longitudinal breastmilk samples from healthy mothers (n = 290) across 7 European countries, we characterized HMO composion and employed mixed linear models to explore associations of maternal characteristics with individual HMOs. We observed HMO-specific temporal trajectories and milk group dependencies. We observed relatively small but significant differences in HMO concentrations based on maternal ppBMI, mode of delivery and parity. Our findings suggest that HMO composition to be regulated time-dependently by an enzyme as well as substrate availability and that ppBMI, mode of delivery, and parity may influence maternal physiology to affect glycosylation marginally within the initital period of lactation. Our observational study is the largest European standardized and longitudinal (up to 4 months) milk collection study assessing HMO concentrations and basic maternal characteristics. Time of lactation and milk groups had the biggest impact on HMO variation. Future studies need to elucidate these observations and assess the physiological significance for the breastfed infant.

  • 166. Schwartzbaum, Judith
    et al.
    Edlinger, Michael
    Zigmont, Victoria
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rempala, Grzegorz A.
    Nagel, Gabriele
    Hammar, Niklas
    Ulmer, Hanno
    Foeger, Bernhard
    Walldius, Goran
    Manjer, Jonas
    Malmstrom, Hakan
    Feychting, Maria
    Associations between prediagnostic blood glucose levels, diabetes, and glioma2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 1436Article in journal (Refereed)
    Abstract [en]

    Previous literature indicates that pre-diagnostic diabetes and blood glucose levels are inversely related to glioma risk. To replicate these findings and determine whether they could be attributed to excess glucose consumption by the preclinical tumour, we used data from the Apolipoprotein MOrtality RISk (AMORIS) (n = 528,580) and the Metabolic syndrome and Cancer project (Me-Can) cohorts (n = 269,365). We identified individuals who were followed for a maximum of 15 years after their first blood glucose test until glioma diagnosis, death, emigration or the end of follow-up. Hazard ratios (HRs), 95% confidence intervals (CIs) and their interactions with time were estimated using Cox time-dependent regression. As expected, pre-diagnostic blood glucose levels were inversely related to glioma risk (AMORIS, P-trend = 0.002; Me-Can, P-trend = 0.04) and pre-diagnostic diabetes (AMORIS, HR = 0.30, 95% CI 0.17 to 0.53). During the year before diagnosis, blood glucose was inversely associated with glioma in the AMORIS (HR = 0.78, 95% CI 0.66 to 0.93) but not the Me-Can cohort (HR = 0.99, 95% CI 0.63 to 1.56). This AMORIS result is consistent with our hypothesis that excess glucose consumption by the preclinical tumour accounts for the inverse association between blood glucose and glioma. We discuss additional hypothetical mechanisms that may explain our paradoxical findings.

  • 167.
    Sewe, Maquins Odhiambo
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya.
    Tozan, Yesim
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Using remote sensing environmental data to forecast malaria incidence at a rural district hospital in Western Kenya2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 2589Article in journal (Refereed)
    Abstract [en]

    Malaria surveillance data provide opportunity to develop forecasting models. Seasonal variability in environmental factors correlate with malaria transmission, thus the identification of transmission patterns is useful in developing prediction models. However, with changing seasonal transmission patterns, either due to interventions or shifting weather seasons, traditional modelling approaches may not yield adequate predictive skill. Two statistical models, a general additive model (GAM) and GAMBOOST model with boosted regression were contrasted by assessing their predictive accuracy in forecasting malaria admissions at lead times of one to three months. Monthly admission data for children under five years with confirmed malaria at the Siaya district hospital in Western Kenya for the period 2003 to 2013 were used together with satellite derived data on rainfall, average temperature and evapotranspiration(ET). There was a total of 8,476 confirmed malaria admissions. The peak of malaria season changed and malaria admissions reduced overtime. The GAMBOOST model at 1-month lead time had the highest predictive skill during both the training and test periods and thus can be utilized in a malaria early warning system.

  • 168.
    Sharma, Sandeep K
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Steneberg, Pär
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Vernersson-Lindahl, Emma
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Edlund, Helena
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Insulin-degrading enzyme prevents alpha-synuclein fibril formation in a nonproteolytical manner2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 12531Article in journal (Refereed)
    Abstract [en]

    The insulin-degrading enzyme (IDE) degrades amyloidogenic proteins such as Amyloid β (Aβ) and Islet Amyloid Polypeptide (IAPP), i.e. peptides associated with Alzheimer's disease and type 2 diabetes, respectively. In addition to the protease activity normally associated with IDE function an additional activity involving the formation of stable, irreversible complexes with both Aβ and α-synuclein, an amyloidogenic protein involved in Parkinson's disease, was recently proposed. Here, we have investigated the functional consequences of IDE-α-synuclein interactions in vitro. We demonstrate that IDE in a nonproteolytic manner and at sub-stoichiometric ratios efficiently inhibits α-synuclein fibril formation by binding to α-synuclein oligomers making them inert to amyloid formation. Moreover, we show that, within a defined range of α-synuclein concentrations, interaction with α-synuclein oligomers increases IDE's proteolytic activity on a fluorogenic substrate. We propose that the outcomes of IDE-α-synuclein interactions, i.e. protection against α-synuclein amyloid formation and stimulated IDE protease activity, may be protective in vivo.

  • 169. Silva, L. N.
    et al.
    Da Hora, G. C. A.
    Soares, T. A.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Univ Fed Pernambuco, Dept Quim Fundamental, Recife, Brazil.
    Bojer, M. S.
    Ingmer, H.
    Macedo, A. J.
    Trentin, D. S.
    Myricetin protects Galleria mellonella against Staphylococcus aureus infection and inhibits multiple virulence factors2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 2823Article in journal (Refereed)
    Abstract [en]

    Staphylococcus aureus is an opportunistic pathogen related to a variety of life-threatening infections but for which antimicrobial resistance is liming the treatment options. We report here that myricetin, but not its glycosylated form, can remarkably decrease the production of several S. aureus virulence factors, including adhesion, biofilm formation, hemolysis and staphyloxanthin production, without interfering with growth. Myricetin affects both surface proteins and secreted proteins which indicate that its action is unrelated to inhibition of the agr quorum sensing system. Analysis of virulence related gene expression and computational simulations of pivotal proteins involved in pathogenesis demonstrate that myricetin downregulates the saeR global regulator and interacts with sortase A and alpha-hemolysin. Furthermore, Myr confers a significant degree of protection against staphylococcal infection in the Galleria mellonella model. The present findings reveal the potential of Myr as an alternative multi-target antivirulence candidate to control S. aureus pathogenicity.

  • 170.
    Singh, Bhupender
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Mortezaei, Narges
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Savarino, Stephen
    Bullitt, Esther
    Andersson, Magnus
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Antibody-mediated disruption of the mechanics of CS20 fimbriae of enterotoxigenic Escherichia coli2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 13678Article in journal (Refereed)
    Abstract [en]

    Preventive vaccines against enterotoxigenic Escherichia coli (ETEC) are being developed, many of which target common fimbrial colonization factors as the major constituent, based on empirical evidence that these function as protective antigens. Particularly, passive oral administration of ETEC anti-fimbrial antibodies prevent ETEC diarrhea. Little is, however, known regarding the specific mechanisms by which intestinal antibodies against ETEC fimbriae function to prevent disease. Using coli surface antigen 20 (CS20) fimbriae as a model ETEC colonization factor, we show using force spectroscopy that anti-fimbrial antibodies diminish fimbrial elasticity by inhibiting their natural capacity to unwind and rewind. In the presence of anti-CS20 antibodies the force required to unwind a single fimbria was increased several-fold and the extension length was shortened several-fold. Similar measurements in the presence of anti-CS20 Fab fragments did not show any effect, indicating that bivalent antibody binding is required to reduce fimbrial elasticity. Based on these findings, we propose a model for an in-vivo mechanism whereby antibody-mediated disruption of the biomechanical properties of CS20 fimbriae impedes sustained adhesion of ETEC to the intestinal mucosal surface. Further elucidation of the role played by intestinal antibodies in mechanical disruption of fimbrial function may provide insights relevant to ETEC vaccine development.

  • 171.
    Sjöström, Annika E
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Membrane vesicle-mediated release of bacterial RNA2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15329Article in journal (Refereed)
    Abstract [en]

    Many Gram-negative bacterial species release outer membrane vesicles (OMVs) that interact with the host by delivering virulence factors. Here, we report for the first time that RNA is among the wide variety of bacterial components that are associated with OMVs. To characterize the RNA profiles of bacterial OMVs, we performed RNA deep sequencing analysis using OMV samples isolated from a wild type Vibrio cholerae O1 El Tor strain. The results showed that RNAs originating from intergenic regions were the most abundant. Our findings reveal a hitherto unrecognised feature of OMVs mimicking eukaryotic exosomes and highlight a need to evaluate the potential role of RNA-containing bacterial membrane vesicles in bacteria-host interactions.

  • 172. Skoog, Emma C.
    et al.
    Padra, Medea
    Åberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gideonsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Obi, Ikenna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Quintana-Hayashi, Macarena P.
    Arnqvist, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Linden, Sara K.
    BabA dependent binding of Helicobacter pylori to human gastric mucins cause aggregation that inhibits proliferation and is regulated via ArsS2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 40656Article in journal (Refereed)
    Abstract [en]

    Mucins in the gastric mucus layer carry a range of glycan structures, which vary between individuals, can have antimicrobial effect or act as ligands for Helicobacter pylori. Mucins from various individuals and disease states modulate H. pylori proliferation and adhesin gene expression differently. Here we investigate the relationship between adhesin mediated binding, aggregation, proliferation and adhesin gene expression using human gastric mucins and synthetic adhesin ligand conjugates. By combining measurements of optical density, bacterial metabolic activity and live/dead stains, we could distinguish bacterial aggregation from viability changes, enabling elucidation of mechanisms behind the anti-prolific effects that mucins can have. Binding of H. pylori to Leb-glycoconjugates inhibited the proliferation of the bacteria in a BabA dependent manner, similarly to the effect of mucins carrying Leb. Furthermore, deletion of arsS lead to a decrease in binding to Leb-glycoconjugates and Leb-decorated mucins, accompanied by decreased aggregation and absence of anti-prolific effect of mucins and Leb-glycoconjugates. Inhibition of proliferation caused by adhesin dependent binding to mucins, and the subsequent aggregation suggests a new role of mucins in the host defense against H. pylori. This aggregating trait of mucins may be useful to incorporate into the design of adhesin inhibitors and other disease intervention molecules.

  • 173. Slupsky, Carolyn M.
    et al.
    He, Xuan
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Andersson, Yvonne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rudolph, Colin
    Lönnerdal, Bo
    West, Christina E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Postprandial metabolic response of breast-fed infants and infants fed lactose-free vs regular infant formula: a randomized controlled trial2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3640Article in journal (Refereed)
    Abstract [en]

    Lactose intolerance is a major concern driving the growth of lactose-free foods including lactose-free infant formula. It is unknown what the metabolic consequence is of consumption of a formula where lactose has been replaced with corn syrup solids (CSS). Here, a randomized double-blinded intervention study was conducted where exclusively formula-fed infants were fed formula containing either lactose or CSS-based infant formula and compared with an equal number of exclusively breast-fed infants. Plasma metabolites and insulin were measured at baseline, 15, 30, 60, 90 and 120 min after feeding. Differences in plasma metabolite profiles for formula-fed infants included a rapid increase in circulating amino acids, creatinine and urea compared with breast-fed infants. At 120 min post-feeding, insulin was significantly elevated in formula-fed compared with breast-fed infants. Infants fed lactose-based formula had the highest levels of glucose at 120 min, and leucine, isoleucine, valine and proline at 90 and 120 min, whereas infants fed CSS-based formula had the lowest levels of non-esterified fatty acids at all time points, and glucose at 120 min. Overall, these differences highlight that changes in infant formula composition impact infant metabolism, and show that metabolomics is a powerful tool to help with development of improved infant formulas.

  • 174.
    Sobhy, Haitham
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Kumar, Rajendra
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Lewerentz, Jacob
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lizana, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Division of CBRN Security and Defence, FOI–Swedish Defence Research Agency, Umeå, Sweden.
    Highly interacting regions of the human genome are enriched with enhancers and bound by DNA repair proteins2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4577Article in journal (Refereed)
    Abstract [en]

    In specific cases, chromatin clearly forms long-range loops that place distant regulatory elements in close proximity to transcription start sites, but we have limited understanding of many loops identified by Chromosome Conformation Capture (such as Hi-C) analyses. In efforts to elucidate their characteristics and functions, we have identified highly interacting regions (HIRs) using intra-chromosomal Hi-C datasets with a new computational method based on looking at the eigenvector that corresponds to the smallest eigenvalue (here unity). Analysis of these regions using ENCODE data shows that they are in general enriched in bound factors involved in DNA damage repair and have actively transcribed genes. However, both highly transcribed regions as well as transcriptionally inactive regions can form HIRs. The results also indicate that enhancers and super-enhancers in particular form long-range interactions within the same chromosome. The accumulation of DNA repair factors in most identified HIRs suggests that protection from DNA damage in these regions is essential for avoidance of detrimental rearrangements.

  • 175. Souza, Pedro P. C.
    et al.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lundgren, Inger
    Umeå University, Faculty of Medicine, Department of Odontology.
    Magalhäes, Fernando A. C.
    Costa-Neto, Claudio M.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology. Centre for Bone and Arthritis Research at Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Activation of Toll-like receptor 2 induces B1 and B2 kinin receptors in human gingival fibroblasts and in mouse gingiva2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 2973Article in journal (Refereed)
    Abstract [en]

    The regulation of the kallikrein-kinin system is an important mechanism controlling vasodilation and promoting inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) in regulating kinin B1 and B2 receptor expression in human gingival fibroblasts and in mouse gingiva. Both P. gingivalis LPS and the synthetic TLR2 agonist Pam2CSK4 increased kinin receptor transcripts. Silencing of TLR2, but not of TLR4, inhibited the induction of kinin receptor transcripts by both P. gingivalis LPS and Pam2CSK4. Human gingival fibroblasts (HGF) exposed to Pam2CSK4 increased binding sites for bradykinin (BK, B2receptor agonist) and des-Arg10-Lys-bradykinin (DALBK, B1 receptor agonist). Pre-treatment of HGF for 24 h with Pam2CSK4 resulted in increased PGE2 release in response to BK and DALBK. The increase of B1 and B2 receptor transcripts by P. gingivalis LPS was not blocked by IL-1β neutralizing antibody; TNF-α blocking antibody did not affect Breceptor up-regulation, but partially blocked increase of B2 receptor mRNA. Injection of P. gingivalis LPS in mouse gingiva induced an increase of B1 and B2 receptor mRNA. These data show that activation of TLR2 in human gingival fibroblasts as well as in mouse gingival tissue leads to increase of B1 and B2 receptor mRNA and protein.

  • 176.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Henning, Petra
    Klar, Joakim
    McDermott, Emma
    Stecksen-Blicks, Christina
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sandström, Per-Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Kellgren, Therese G
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lönnerholm, Torsten
    Ameur, Adam
    Helfrich, Miep H
    Coxon, Fraser P
    Dahl, Niklas
    Wikström, Johan
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology. Centre for Bone and Arthritis Research, Department of internal medicine and clinical nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3012Article in journal (Refereed)
    Abstract [en]

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

  • 177.
    Stojkovic, Gorazd
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Makarova, Alena V.
    Wanrooij, Paulina H.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
    Forslund, Josefin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Burgers, Peter M.
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
    Oxidative DNA damage stalls the human mitochondrial replisome2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 28942Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is capable of causing damage to various cellular constituents, including DNA. There is however limited knowledge on how oxidative stress influences mitochondrial DNA and its replication. Here, we have used purified mtDNA replication proteins, i.e. DNA polymerase. holoenzyme, the mitochondrial single-stranded DNA binding protein mtSSB, the replicative helicase Twinkle and the proposed mitochondrial translesion synthesis polymerase PrimPol to study lesion bypass synthesis on oxidative damage-containing DNA templates. Our studies were carried out at dNTP levels representative of those prevailing either in cycling or in non-dividing cells. At dNTP concentrations that mimic those in cycling cells, the replication machinery showed substantial stalling at sites of damage, and these problems were further exacerbated at the lower dNTP concentrations present in resting cells. PrimPol, the translesion synthesis polymerase identified inside mammalian mitochondria, did not promote mtDNA replication fork bypass of the damage. This argues against a conventional role for PrimPol as a mitochondrial translesion synthesis DNA polymerase for oxidative DNA damage; however, we show that Twinkle, the mtDNA replicative helicase, is able to stimulate PrimPol DNA synthesis in vitro, suggestive of an as yet unidentified role of PrimPol in mtDNA metabolism.

  • 178.
    Sunde, Johanna
    et al.
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Carl, Tamario
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Tibblin, Petter
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Larsson, Per
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Forsman, Anders
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Variation in salinity tolerance between and within anadromous subpopulations of pike (Esox lucius)2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 22Article in journal (Refereed)
    Abstract [en]

    Environmental heterogeneity is a key determinant of genetic and phenotypic diversity. Stable andhomogenous environments tends to result in evolution of specialism and local adaptations, whiletemporally unpredictable environments may maintain a diversity of specialists, promote generaliststrategies, or favour diversified bet hedging strategies. We compared salinity tolerance between twoanadromous subpopulations of pike (Esox Lucius) that utilize freshwater spawning sites with differentsalinity regimes. Eggs from each population were artificially fertilized and incubated in a salinitygradient (0, 3, 5, 7, and 9 psu) using a split-brood design. Effects on embryonic development, hatchingsuccess, survival of larvae, and fry body length were compared between populations and families.The population naturally spawning in the stable freshwater habitat showed signs of specialization forfreshwater spawning. The population exposed to fluctuating selective pressure in a spawning area withoccasional brackish water intrusions tolerated higher salinities and displayed considerable variation inreaction norms. Genetic differences and plasticity of salinity tolerance may enable populations to copewith changes in salinity regimes associated with future climate change. That geographically adjacentsubpopulations can constitute separate units with different genetic characteristics must be consideredin management and conservation efforts to avoid potentially negative effects of genetic admixture onpopulation fitness and persistence.

  • 179.
    Sundkvist, Anneli
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bodén, Stina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Enroth, Stefan
    Gyllensten, Ulf
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Targeted plasma proteomics identifies a novel, robust association between cornulin and Swedish moist snuff2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 2320Article in journal (Refereed)
    Abstract [en]

    Lifestyle behaviors are believed to influence the body's inflammatory state. Chronic low-grade inflammation contributes to the development of major non-communicable diseases such as diabetes, cardiovascular disease and cancer. Inflammation may thus be an important link between lifestyle and disease. We evaluated self-reported physical activity, tobacco use and alcohol consumption in relation to plasma levels of 160 validated inflammatory and cancer biomarkers. The study included 138 participants from a population-based cohort, all with repeated sampling of plasma and data ten years apart, allowing consideration of both intra- and inter-individual variation. Of 17 relationships identified, the strongest was an independent, positive association between cornulin (CRNN) and Swedish moist snuff (snus) use. We replicated the finding in a second cohort of 501 individuals, in which a dose-response relationship was also observed. Snus explained approximately one fifth of the variance in CRNN levels in both sample sets (18% and 23%). In conclusion, we identified a novel, independent, dose-dependent association between CRNN and snus use. Further study is warranted, to evaluate the performance of CRNN as a potential snus biomarker. The putative importance of lifestyle behaviors on a wide range of protein biomarkers illustrates the need for more personalized biomarker cut-offs.

  • 180.
    Sundqvist, Bertil
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Mapping intermolecular bonding in C602014In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 4, p. 06171-Article in journal (Refereed)
    Abstract [en]

    The formation of intermolecular bonds in C60 has been investigated in detail at pressures below 2.2 GPa and up to 750 K. Fullerene samples were heated in a temperature gradient to obtain data on the formation of dimers and low-dimensional polymers along isobars. Intermolecular bonding was analyzed ex situ by Raman scattering, using both intramolecular modes and intermolecular stretching modes. Semi-quantitative reaction maps are given for the formation of dimers and chains. The activation energy for dimer formation decreases by 0.2 meV pm-1 when intermolecular distances decrease and dimer formation is noticeably affected by the rotational state of molecules. Above 400-450 K larger oligomers are formed; below 1.4 GPa most of these are disordered, with small domains of linear chains, but above this the appearance of stretching modes indicates the existence of ordered one-dimensional polymers. At the highest pressures and temperatures two-dimensional polymers are also observed.

  • 181.
    Söderholm, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Javadi, Ala
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sierra Flores, Isabel
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Flärdh, Klas
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Affinity to cellulose is a shared property among coiled-coil domains of intermediate filaments and prokaryotic intermediate filament-like proteins2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 16524Article in journal (Refereed)
    Abstract [en]

    Coiled-coil domains of intermediate filaments (IF) and prokaryotic IF-like proteins enable oligomerisation and filamentation, and no additional function is ascribed to these coiled-coil domains. However, an IF-like protein from Streptomyces reticuli was reported to display cellulose affinity. We demonstrate that cellulose affinity is an intrinsic property of the IF-like proteins FilP and Scy and the coiled-coil protein DivIVA from the genus Streptomyces. Furthermore, IF-like proteins and DivIVA from other prokaryotic species and metazoan IF display cellulose affinity despite having little sequence homology. Cellulose affinity-based purification is utilised to isolate native FilP protein from the whole cell lysate of Scoelicolor. Moreover, cellulose affinity allowed for the isolation of IF and IF-like protein from the whole cell lysate of Ccrescentus and a mouse macrophage cell line. The binding to cellulose is mediated by certain combinations of coiled-coil domains, as demornstrated for FilP and lamin. Fusions of target proteins to cellulose-binding coiled-coil domains allowed for cellulose-based protein purification. The data presented show that cellulose affinity is a novel function of certain coiled-coil domains of IF and IF-like proteins from evolutionary diverse species.

  • 182.
    Taheri, Nayyer
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Mahmud, A K M Firoj
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Fällman, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Campylobacter jejuni bile exposure influences outer membrane vesicles protein content and bacterial interaction with epithelial cells2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 16996Article in journal (Refereed)
    Abstract [en]

    Campylobacter jejuni is a prevalent human pathogen and a major cause of bacterial gastroenteritis in the world. In humans, C. jejuni colonizes the intestinal tract and its tolerance to bile is crucial for bacteria to survive and establish infection. C. jejuni produces outer membrane vesicles (OMVs) which have been suggested to be involved in virulence. In this study, the proteome composition of C. jejuni OMVs in response to low concentration of bile was investigated. We showed that exposure of C. jejuni to low concentrations of bile, similar to the concentration in cecum, induced significant changes in the protein profile of OMVs released during growth without affecting the protein profile of the bacteria. This suggests that bile influences a selective packing of the OMVs after bacterial exposure to low bile. A low concentration of bile was found to increase bacterial adhesion to intestinal epithelial cells, likely by an enhanced hydrophobicity of the cell membrane following exposure to bile. The increased bacterial adhesiveness was not associated with increased invasion, instead bile exposure decreased C. jejuni invasion. OMVs released from bacteria upon exposure to low bile showed to increase both adhesion and invasion of non-bile-exposed bacteria into intestinal epithelial cells. These findings suggest that C. jejuni in environments with low concentrations of bile produce OMVs that facilitates colonization of the bacteria, and this could potentially contribute to virulence of C. jejuni in the gut.

  • 183. Takahashi, Hannah
    et al.
    Cornish, Alex J.
    Sud, Amit
    Law, Philip J.
    Kinnersley, Ben
    Ostrom, Quinn T.
    Labreche, Karim
    Eckel-Passow, Jeanette E.
    Armstrong, Georgina N.
    Claus, Elizabeth B.
    Il'yasova, Dora
    Schildkraut, Joellen
    Barnholtz-Sloan, Jill S.
    Olson, Sara H.
    Bernstein, Jonine L.
    Lai, Rose K.
    Schoemaker, Minouk J.
    Simon, Matthias
    Hoffmann, Per
    Nöthen, Markus M.
    Joeckel, Karl-Heinz
    Chanock, Stephen
    Rajaraman, Preetha
    Johansen, Christoffer
    Jenkins, Robert B.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wrensch, Margaret R.
    Sanson, Marc
    Bondy, Melissa L.
    Turnbull, Clare
    Houlston, Richard S.
    Mendelian randomisation study of the relationship between vitamin D and risk of glioma2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 2339Article in journal (Refereed)
    Abstract [en]

    To examine for a causal relationship between vitamin D and glioma risk we performed an analysis of genetic variants associated with serum 25-hydroxyvitamin D (25(OH) D) levels using Mendelian randomisation (MR), an approach unaffected by biases from confounding. Two-sample MR was undertaken using genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with 25(OH) D levels were used as instrumental variables (IVs). We calculated MR estimates for the odds ratio (OR) for 25(OH) D levels with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighted (IVW) and maximum likelihood estimation (MLE) methods. A non-significant association between 25(OH) D levels and glioma risk was shown using both the IVW (OR = 1.21, 95% confidence interval [CI] = 0.90-1.62, P = 0.201) and MLE (OR = 1.20, 95% CI = 0.98-1.48, P = 0.083) methods. In an exploratory analysis of tumour subtype, an inverse relationship between 25(OH)D levels and glioblastoma (GBM) risk was identified using the MLE method (OR = 0.62, 95% CI = 0.43-0.89, P = 0.010), but not the IVW method (OR = 0.62, 95% CI = 0.37-1.04, P = 0.070). No statistically significant association was shown between 25(OH) D levels and non-GBM glioma. Our results do not provide evidence for a causal relationship between 25(OH) D levels and all forms of glioma risk. More evidence is required to explore the relationship between 25(OH) D levels and risk of GBM.

  • 184. Teichmann, S. M.
    et al.
    Racz, P.
    Ciappina, M. F.
    Perez-Hernandez, J. A.
    Thai, A.
    Fekete, J.
    Elezzabi, A. Y.
    Veisz, László
    Max-Planck-Institut für Quantenoptik, D-85748 Garching, Germany.
    Biegert, J.
    Dombi, P.
    Strong-field plasmonic photoemission inthe mid-IR at <1 GW/cm2 intensity2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 7584Article in journal (Refereed)
    Abstract [en]

    We investigated nonlinear photoemission from plasmonic films with femtosecond, mid-infrared pulses at 3.1 μm wavelength. Transition between regimes of multi-photon-induced and tunneling emission is demonstrated at an unprecedentedly low intensity of <1 GW/cm2. Thereby, strong-field nanophysics can be accessed at extremely low intensities by exploiting nanoscale plasmonic field confinement, enhancement and ponderomotive wavelength scaling at the same time. Results agree well with quantum mechanical modelling. Our scheme demonstrates an alternative paradigm and regime in strong-field physics.

  • 185. Thomsen, Hauke
    et al.
    da Silva Filho, Miguel Inacio
    Woltmann, Andrea
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Eyfjord, Jorunn E.
    Hamann, Ute
    Manjer, Jonas
    Enquist-Olsson, Kerstin
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Cancer Center Stockholm Gotland, Stockholm, Sweden.
    Herms, Stefan
    Hoffmann, Per
    Chen, Bowang
    Huhn, Stefanie
    Hemminki, Kari
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Foersti, Asta
    Inbreeding and homozygosity in breast cancer survival2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 16467Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWASs) help to understand the effects of single nucleotide polymorphisms (SNPs) on breast cancer (BC) progression and survival. We performed multiple analyses on data from a previously conducted GWAS for the influence of individual SNPs, runs of homozygosity (ROHs) and inbreeding on BC survival. (I.) The association of individual SNPs indicated no differences in the proportions of homozygous individuals among short-time survivors (STSs) and long-time survivors (LTSs). (II.) The analysis revealed differences among the populations for the number of ROHs per person and the total and average length of ROHs per person and among LTSs and STSs for the number of ROHs per person. (III.) Common ROHs at particular genomic positions were nominally more frequent among LTSs than in STSs. Common ROHs showed significant evidence for natural selection (iHS, Tajima's D, Fay-Wu's H). Most regions could be linked to genes related to BC progression or treatment. (IV.) Results were supported by a higher level of inbreeding among LTSs. Our results showed that an increased level of homozygosity may result in a preference of individuals during BC treatment. Although common ROHs were short, variants within ROHs might favor survival of BC and may function in a recessive manner.

  • 186.
    Tibblin, Petter
    et al.
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Berggren, Hanna
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Nordahl, Oscar
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Larsson, Per
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Forsman, Anders
    Linnéuniversitetet, Institutionen för biologi och miljö (BOM).
    Causes and consequences of intra-specific variation in vertebral number2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 26372Article in journal (Refereed)
    Abstract [en]

    Intraspecific variation in vertebral number is taxonomically widespread. Much scientific attention hasbeen directed towards understanding patterns of variation in vertebral number among individualsand between populations, particularly across large spatial scales and in structured environments.However, the relative role of genes, plasticity, selection, and drift as drivers of individual variation andpopulation differentiation remains unknown for most systems. Here, we report on patterns, causesand consequences of variation in vertebral number among and within sympatric subpopulations ofpike (Esox lucius). Vertebral number differed among subpopulations, and common garden experimentsindicated that this reflected genetic differences. A QST-FST comparison suggested that populationdifferences represented local adaptations driven by divergent selection. Associations with fitness traitsfurther indicated that vertebral counts were influenced both by stabilizing and directional selectionwithin populations. Overall, our study enhances the understanding of adaptive variation, which iscritical for the maintenance of intraspecific diversity and species conservation.

  • 187.
    Toreti, Andrea
    et al.
    European Commission, Ispra (VA), Italy.
    Cronie, Ottmar
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Zampieri, Matteo
    European Commission, Ispra (VA), Italy.
    Concurrent climate extremes in the key wheat producing regions of the world2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5493Article in journal (Refereed)
    Abstract [en]

    Climate extremes have profound impacts on key socio-economic sectors such as agriculture. In a changing climate context, characterised by an intensification of these extremes and where the population is expected to grow, exposure and vulnerability must be accurately assessed. However, most risk assessments analyse extremes independently, thus potentially being overconfident in the resilience of the socio-economic sectors. Here, we propose a novel approach to defining and characterising concurrent climate extremes (i.e. extremes occurring within a specific temporal lag), which is able toidentify spatio-temporal dependences without making any strict assumptions. the method is applied to large-scale heat stress and drought events in the key wheat producing regions of the world, as these extremes can cause serious yield losses and thus trigger market shocks. Wheat regions likely to haveconcurrent extremes (heat stress and drought events) are identified, as well as regions independent ofeach other or inhibiting each other in terms of these extreme events. this tool may be integrated in all risk assessments but could also be used to explore global climate teleconnections.

  • 188. Trentin, Danielle S
    et al.
    Silva, Denise B
    Frasson, Amanda P
    Rzhepishevska, Olena
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    da Silva, Márcia V
    Pulcini, Elinor de L
    James, Garth
    Soares, Gabriel V
    Tasca, Tiana
    Ramstedt, Madeleine
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Giordani, Raquel B
    Lopes, Norberto P
    Macedo, Alexandre J
    Natural green coating inhibits adhesion of clinically important bacteria2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 8287-Article in journal (Refereed)
    Abstract [en]

    Despite many advances, biomaterial-associated infections continue to be a major clinical problem. In order to minimize bacterial adhesion, material surface modifications are currently being investigated and natural products possess large potential for the design of innovative surface coatings. We report the bioguided phytochemical investigation of Pityrocarpa moniliformis and the characterization of tannins by mass spectrometry. It was demonstrated that B-type linked proanthocyanidins-coated surfaces, here termed Green coatings, reduced Gram-positive bacterial adhesion and supported mammalian cell spreading. The proposed mechanism of bacterial attachment inhibition is based on electrostatic repulsion, high hydrophilicity and the steric hindrance provided by the coating that blocks bacterium-substratum interactions. This work shows the applicability of a prototype Green-coated surface that aims to promote necessary mammalian tissue compatibility, while reducing bacterial colonization.

  • 189. Tsatrafyllis, N.
    et al.
    Bergues, B.
    Schroeder, H.
    Veisz, László
    Umeå University, Faculty of Science and Technology, Department of Physics. Max-Planck-Institut für Quantenoptik, Garching, Germany.
    Skantzakis, E.
    Gray, D.
    Bodi, B.
    Kuhn, S.
    Tsakiris, G. D.
    Charalambidis, D.
    Tzallas, P.
    The ion microscope as a tool for quantitative measurements in the extreme ultraviolet2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 21556Article in journal (Refereed)
    Abstract [en]

    We demonstrate a tool for quantitative measurements in the extreme ultraviolet (EUV) spectral region measuring spatially resolved atomic ionization products at the focus of an EUV beam. The ionizing radiation is a comb of the 11th-15th harmonics of a Ti:Sapphire femtosecond laser beam produced in a Xenon gas jet. The spatial ion distribution at the focus of the harmonics is recorded using an ion microscope. Spatially resolved single-and two-photon ionization products of Argon and Helium are observed. From such ion distributions single-and two-photon generalized cross sections can be extracted by a self-calibrating method. The observation of spatially resolved two-EUV-photon ionization constitutes an initial step towards future single-shot temporal characterization of attosecond pulses.

  • 190. Tükenmez, Hasan
    et al.
    Edström, Isabel
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Ummanni, Ramesh
    Fick, Stina Berglund
    Sundin, Charlotta
    Elofsson, Mikael
    Larsson, Christer
    Mycobacterium tuberculosis virulence inhibitors discovered by Mycobacterium marinum high-throughput screening2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 26Article in journal (Refereed)
    Abstract [en]

    High-throughput screening facilities do not generally support biosafety level 3 organisms such as Mycobacterium tuberculosis. To discover not only antibacterials, but also virulence inhibitors with either bacterial or host cell targets, an assay monitoring lung fibroblast survival upon infection was developed and optimized for 384-plate format and robotic liquid handling. By using Mycobacterium marinum as surrogate organism, 28,000 compounds were screened at biosafety level 2 classification, resulting in 49 primary hits. Exclusion of substances with unfavourable properties and known antimicrobials resulted in 11 validated hits of which 7 had virulence inhibiting properties and one had bactericidal effect also in wild type Mycobacterium tuberculosis. This strategy to discover virulence inhibitors using a model organism in high-throughput screening can be a valuable tool for other researchers working on drug discovery against tuberculosis and other biosafety level 3 infectious agents.

  • 191. Urdaneta, Veronica
    et al.
    Hernandez, Sara B.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.
    Casadesus, Josep
    Mutational and non mutational adaptation of Salmonella enterica to the gall bladder2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5203Article in journal (Refereed)
    Abstract [en]

    During systemic infection of susceptible hosts, Salmonella enterica colonizes the gall bladder, which contains lethal concentrations of bile salts. Recovery of Salmonella cells from the gall bladder of infected mice yields two types of isolates: (i) bile-resistant mutants; (ii) isolates that survive lethal selection without mutation. Bile-resistant mutants are recovered at frequencies high enough to suggest that increased mutation rates may occur in the gall bladder, thus providing a tentative example of stress-induced mutation in a natural environment. However, most bile-resistant mutants characterized in this study show defects in traits that are relevant for Salmonella colonization of the animal host. Mutation may thus permit short-term adaptation to the gall bladder at the expense of losing fitness for transmission to new hosts. In contrast, non mutational adaptation may have evolved as a fitness-preserving strategy. Failure of RpoS(-) mutants to colonize the gall bladder supports the involvement of the general stress response in non mutational adaptation.

  • 192. van Krieken, Pim P.
    et al.
    Dicker, Andrea
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Herrera, Pedro L.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Berggren, Per-Olof
    Ilegems, Erwin
    Kinetics of functional beta cell mass decay in a diphtheria toxin receptor mouse model of diabetes2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 12440Article in journal (Refereed)
    Abstract [en]

    Functional beta cell mass is an essential biomarker for the diagnosis and staging of diabetes. It has however proven technically challenging to study this parameter during diabetes progression. Here we have detailed the kinetics of the rapid decline in functional beta cell mass in the RIP-DTR mouse, a model of hyperglycemia resulting from diphtheria toxin induced beta cell ablation. A novel combination of imaging modalities was employed to study the pattern of beta cell destruction. Optical projection tomography of the pancreas and longitudinal in vivo confocal microscopy of islets transplanted into the anterior chamber of the eye allowed to investigate kinetics and tomographic location of beta cell mass decay in individual islets as well as at the entire islet population level. The correlation between beta cell mass and function was determined by complementary in vivo and ex vivo characterizations, demonstrating that beta cell function and glucose tolerance were impaired within the first two days following treatment when more than 50% of beta cell mass was remaining. Our results illustrate the importance of acquiring quantitative functional and morphological parameters to assess the functional status of the endocrine pancreas.

  • 193. Van Rijn, S.
    et al.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Noske, D. P.
    Peter Vandertop, W.
    Tannous, B. A.
    Würdinger, T.
    Functional multiplex reporter assay using tagged Gaussia luciferase2013In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 3, article id 1046Article in journal (Refereed)
    Abstract [en]

    We have developed a multiplex reporter system to monitor multiple biological variables in real-time. The secreted Gaussia luciferase was fused to ten different epitope tags (Gluc tag), each expressed in different tumor cells. By immunobinding of the tags followed by Gluc tag detection, this system allowed the independent and real-time monitoring of mixed cell cultures in vitro and of mixed subcutaneous and intracranial tumor subpopulations in vivo.

  • 194.
    Varik, Vallo
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). 1University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia.
    Oliveira, Sofia Raquel Alves
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). 1University of Tartu, Institute of Technology, Nooruse 1, 50411 Tartu, Estonia.
    Tenson, Tanel
    Composition of the outgrowth medium modulates wake-up kinetics and ampicillin sensitivity of stringent and relaxed Escherichia coli2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 22308Article in journal (Refereed)
    Abstract [en]

    The transition of Escherichia coli from the exponential into the stationary phase of growth induces the stringent response, which is mediated by the rapid accumulation of the alarmone nucleotide (p)ppGpp produced by the enzyme RelA. The significance of RelA's functionality during the transition in the opposite direction, i.e. from the stationary phase into new exponential growth, is less well understood. Here we show that the relaxed strain, i.e. lacking the relA gene, displays a relative delay in regrowth during the new exponential growth phase in comparison with the isogenic wild type strain. The severity of the effect is a function of both the carbon source and amino acid composition of the outgrowth media. As a result, the loss of RelA functionality increases E. coli tolerance to the bactericidal antibiotic ampicillin during growth resumption in fresh media in a medium-specific way. Taken together, our data underscore the crucial role of medium composition and growth conditions for studies of the role of individual genes and regulatory networks in bacterial phenotypic tolerance to antibiotics.

  • 195.
    Varik, Vallo
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Nooruse 1, 50411, Tartu, Estonia.
    Oliveira, Sofia Raquel Alves
    Hauryliuk, Vasili
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). University of Tartu, Institute of Technology, Nooruse 1, 50411, Tartu, Estonia.
    Tenson, Tanel
    HPLC-based quantification of bacterial housekeeping nucleotides and alarmone messengers ppGpp and pppGpp2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 11022Article in journal (Refereed)
    Abstract [en]

    Here we describe an HPLC-based method to quantify bacterial housekeeping nucleotides and the signaling messengers ppGpp and pppGpp. We have replicated and tested several previously reported HPLC-based approaches and assembled a method that can process 50 samples in three days, thus making kinetically resolved experiments feasible. The method combines cell harvesting by rapid filtration, followed by acid extraction, freeze-drying with chromatographic separation. We use a combination of C18 IPRP-HPLC (GMP unresolved and co-migrating with IMP; GDP and GTP; AMP, ADP and ATP; CTP; UTP) and SAX-HPLC in isocratic mode (ppGpp and pppGpp) with UV detection. The approach is applicable to bacteria without the requirement of metabolic labelling with 32P-labelled radioactive precursors. We applied our method to quantify nucleotide pools in Escherichia coli BW25113 K12-strain both throughout the growth curve and during acute stringent response induced by mupirocin. While ppGpp and pppGpp levels vary drastically (40-and >= 8-fold, respectively) these changes are decoupled from the quotients of the housekeeping pool and guanosine and adenosine housekeeping nucleotides: NTP/NDP/NMP ratio remains stable at 6/1/0.3 during both normal batch culture growth and upon acute amino acid starvation.

  • 196.
    Vdovikova, Svitlana
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Gilfillan, Siv
    Wang, Shixiong
    Dongre, Mitesh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Hurtado, Antonio
    Modulation of gene transcription and epigenetics of colon carcinoma cells by bacterial membrane vesicles2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 7434Article in journal (Refereed)
    Abstract [en]

    Interactions between bacteria and colon cancer cells infuence the transcription of the host cell. Yet is it undetermined whether the bacteria itself or the communication between the host and bacteria is responsible for the genomic changes in the eukaryotic cell. Now, we have investigated the genomic and epigenetic consequences of co-culturing colorectal carcinoma cells with membrane vesicles from pathogenic bacteria Vibrio cholerae and non-pathogenic commensal bacteria Escherichia coli. Our study reveals that membrane vesicles from pathogenic and commensal bacteria have a global impact on the gene expression of colon-carcinoma cells. The changes in gene expression correlate positively with both epigenetic changes and chromatin accessibility of promoters at transcription start sites of genes induced by both types of membrane vesicles. Moreover, we have demonstrated that membrane vesicles obtained only from V. cholerae induced the expression of genes associated with epithelial cell diferentiation. Altogether, our study suggests that the observed genomic changes in host cells might be due to specifc components of membrane vesicles and do not require communication by direct contact with the bacteria.

  • 197. Vinci, Walter
    et al.
    Markström, Klas
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Boixo, Sergio
    Roy, Aidan
    Spedalieri, Federico M.
    Warburton, Paul A.
    Severini, Simone
    Hearing the shape of the Ising model with a programmable superconducting-flux annealer2014In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 4, p. 5703-Article in journal (Refereed)
    Abstract [en]

    Two objects can be distinguished if they have different measurable properties. Thus, distinguishability depends on the Physics of the objects. In considering graphs, we revisit the Ising model as a framework to define physically meaningful spectral invariants. In this context, we introduce a family of refinements of the classical spectrum and consider the quantum partition function. We demonstrate that the energy spectrum of the quantum Ising Hamiltonian is a stronger invariant than the classical one without refinements. For the purpose of implementing the related physical systems, we perform experiments on a programmable annealer with superconducting flux technology. Departing from the paradigm of adiabatic computation, we take advantage of a noisy evolution of the device to generate statistics of low energy states. The graphs considered in the experiments have the same classical partition functions, but different quantum spectra. The data obtained from the annealer distinguish non-isomorphic graphs via information contained in the classical refinements of the functions but not via the differences in the quantum spectra.

  • 198.
    Vollmer, Tino
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin-Brandenburg School for Regenerative Therapies (BSRT) & Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Jankowski, Vera
    Jankowski, Joachim
    Glorieux, Griet
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    An in-vitro assay using human spermatozoa to detect toxicity of biologically active substances2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 14525Article in journal (Refereed)
    Abstract [en]

    Identifying the key toxic players within an in-vivo toxic syndrome is crucial to develop targeted therapies. Here, we established a novel method that characterizes the effect of single substances by means of an ex-vivo incubation set-up. We found that primary human spermatozoa elicit a distinct motile response on a (uremic) toxic milieu. Specifically, this approach describes the influence of a bulk toxic environment (uremia) as well as single substances (uremic toxins) by real-time analyzing motile cellular behavior. We established the human spermatozoa-based toxicity testing (HSTT) for detecting single substance-induced toxicity to be used as a screening tool to identify in-vivo toxins. Further, we propose an application of the HSTT as a method of clinical use to evaluate toxin-removing interventions (hemodialysis).

  • 199. Voskarides, Konstantinos
    et al.
    Chatzittofis, Andreas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Medical School, University of Cyprus, Nicosia, Cyprus.
    GWAS studies reveal a possible genetic link between cancer and suicide attempt2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 18290Article in journal (Refereed)
    Abstract [en]

    Inuit is the population with the highest incidence of suicide attempt and cancer in the world. Previous studies reported that people attempted suicide have a higher future risk for cancer. In view of these data, the largest available genome wide association studies (GWAS) for four major mental disorder groups were screened here for any common genes with all known cancer associated genes and oncogenes/tumor suppressor genes. A common genetic background came out only between suicide attempt and cancer (cancer associated genes analysis: RR = 1.64, p = 7.83 × 10−5; oncogenes/tumor suppressor genes analysis: RR = 2.55, p = 2.82 × 10−22), this supporting existing epidemiological data. Incidence/prevalence of both conditions was found to correlate with extreme cold geographical regions (adjusted R2 = 0.135, p = 3.00 × 10−4); this is not the case for other mental disorders. Our results show a possible genetic link between suicide attempt and cancer and a possible evolutionary connection of both diseases with extreme cold environments. These data are useful for future molecular studies or even for investigation of possible therapeutic protocols.

  • 200.
    Wang, Chao
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Iashchishyn, Igor
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of General Chemistry, Sumy State University, Sumy, 40000, Ukraine.
    Pansieri, Jonathan
    Nyström, Sofie
    Klementieva, Oxana
    Kara, John
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Horvath, Istvan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Moskalenko, Roman
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Pathology, Sumy State University, Sumy, 40000, Ukraine.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gouras, Gunnar
    Kovacs, Gabor G.
    Shankar, S. K.
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    S100A9-Driven Amyloid-Neuroinflammatory Cascade in Traumatic Brain Injury as a Precursor State for Alzheimer's Disease2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 12836Article in journal (Refereed)
    Abstract [en]

    Pro-inflammatory and amyloidogenic S100A9 protein is an important contributor to Alzheimer's disease (AD) pathology. Traumatic brain injury (TBI) is viewed as a precursor state for AD. Here we have shown that S100A9-driven amyloid-neuroinflammatory cascade was initiated in TBI and may serve as a mechanistic link between TBI and AD. By analyzing the TBI and AD human brain tissues, we demonstrated that in post-TBI tissues S100A9, produced by neurons and microglia, becomes drastically abundant compared to A beta and contributes to both precursor-plaque formation and intracellular amyloid oligomerization. Conditions implicated in TBI, such as elevated S100A9 concentration, acidification and fever, provide strong positive feedback for S100A9 nucleation-dependent amyloid formation and delay in its proteinase clearance. Consequently, both intracellular and extracellular S100A9 oligomerization correlated with TBI secondary neuronal loss. Common morphology of TBI and AD plaques indicated their similar initiation around multiple aggregation centers. Importantly, in AD and TBI we found S100A9 plaques without A beta. S100A9 and A beta plaque pathology was significantly advanced in AD cases with TBI history at earlier age, signifying TBI as a risk factor. These new findings highlight the detrimental consequences of prolonged post-TBI neuroinflammation, which can sustain S100A9-driven amyloid-neurodegenerative cascade as a specific mechanism leading to AD development.

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