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  • 1.
    Achour, Cyrinne
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Long non-coding RNA and Polycomb: an intricate partnership in cancer biology2018In: Frontiers in Bioscience, ISSN 1093-9946, E-ISSN 1093-4715, Vol. 23, p. 2106-2132Article in journal (Refereed)
    Abstract [en]

    High-throughput analyses have revealed that the vast majority of the transcriptome does not code for proteins. These non-translated transcripts, when larger than 200 nucleotides, are termed long non-coding RNAs (lncRNAs), and play fundamental roles in diverse cellular processes. LncRNAs are subject to dynamic chemical modification, adding another layer of complexity to our understanding of the potential roles that lncRNAs play in health and disease. Many lncRNAs regulate transcriptional programs by influencing the epigenetic state through direct interactions with chromatin-modifying proteins. Among these proteins, Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) have been shown to be recruited by lncRNAs to silence target genes. Aberrant expression, deficiency or mutation of both lncRNA and Polycomb have been associated with numerous human diseases, including cancer. In this review, we have highlighted recent findings regarding the concerted mechanism of action of Polycomb group proteins (PcG), acting together with some classically defined lncRNAs including X-inactive specific transcript (XIST), antisense non-coding RNA in the INK4 locus (ANRIL), metastasis associated lung adenocarcinoma transcript 1 (MALAT1), and HOX transcript antisense RNA (HOTAIR).

  • 2.
    Aguilo, Francesca
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
    Walsh, Martin J.
    The N6-Methyladenosine RNA modification in pluripotency and reprogramming2017In: Current Opinion in Genetics and Development, ISSN 0959-437X, E-ISSN 1879-0380, Vol. 46, p. 77-82Article, review/survey (Refereed)
    Abstract [en]

    Chemical modifications of RNA provide a direct and rapid way to manipulate the existing transcriptome, allowing rapid responses to the changing environment further enriching the regulatory capacity of RNA. N-6-Methyladenosine(m(6)A) has been identified as the most abundant internal modification of messenger RNA in eukaryotes, linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. M(6)A modification affects a broad spectrum of cellular functions, including maintenance of the pluripotency of embryonic stem cells (ESCs) and the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). In this review, we summarize the most recent findings on m(6)A modification with special focus on the different studies describing how m(6)A is implicated in ESC self-renewal, cell fate specification and iPSC generation.

  • 3. Aspberg, Johan
    et al.
    Heijl, Anders
    Jóhannesson, Gauti
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Linden, Christina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Andersson-Geimer, Sabina
    Bengtsson, Boel
    Intraocular Pressure Lowering Effect of Latanoprost as First-line Treatment for Glaucoma2018In: Journal of glaucoma, ISSN 1057-0829, E-ISSN 1536-481X, Vol. 27, no 11, p. 976-980Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The purpose of this study was to assess the intraocular pressure (IOP) - reducing effect of latanoprost in treatment-naïve patients with newly detected open-angle glaucoma with no restriction of the level of untreated IOP.

    METHODS: Eighty-six patients (105 eyes) with a diagnosis of open-angle glaucoma received IOP-lowering therapy with latanoprost. The IOP reduction 1 and 3 months after initiation of treatment was recorded.

    RESULTS: Mean untreated IOP for all eyes was 26.2 mm Hg (ranging from 10 to 51 mm Hg). The mean pressure reduction was 7.9 mm Hg (28%), with equivalent average levels at 1 and 3 months. The reduction in IOP ranged from -2.3 to 25.3 mm Hg after 1 month, and from -1.3 to 33.3 mm Hg after 3 months. The pressure-lowering effect was considerably more pronounced in eyes with higher untreated IOP; the reduction increased by 0.55 mm Hg per mm Hg higher untreated IOP. Four eyes, with untreated IOP within statistically normal limits, had no or negative IOP-reduction. A regression model predicted that IOP reduction ended at untreated IOP≤16 mm Hg. Multiple regression analysis showed that an additional IOP-lowering effect of 1.28 mm Hg was achieved in eyes with pseudoexfoliation glaucoma.

    CONCLUSIONS: To the best of our knowledge, this paper is the first to report the IOP-reducing effect of latanoprost treatment at all untreated IOP levels in newly detected glaucoma patients. The effect was proportional to the untreated IOP at all levels above 16 mm Hg and better at higher untreated IOP levels, also in relative terms. Our results further confirm the indication of latanoprost as a first-line therapy for glaucoma.

  • 4.
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Regulating the dynamic interactions between herpes simplex viruses and cell -surface glycosaminoglycans2019In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 48, p. S41-S41Article in journal (Other academic)
    Abstract [en]

    Virus entry is a complex dynamic multistep process requiring a series of fine-tuned events mediating virus diffusion through the glycocalyx, its attachment to the cell membrane and lateral diffusion to the point of entry. A number of enveloped viruses, including herpes simplex viruses (HSV) attach to susceptible host cells via interaction between their glycoproteins and cell-surface glycosaminoglycans (GAGs). In our work, we study the molecular and physical mechanisms modulating HSV binding, diffusion and release from cell-surface glycosaminoglycans. Using single virus tracking in combination with either in vitro minimal models of the cell surface or live cell microscopy, we gain insights into the modulatory function of protein glycosylation (the presence of mucin-like regions on viral glycoproteins) and interrogate the role of GAG sulfation in the process. We show that mucin-like regions found on the glycoproteins of HSV-1 and HSV-2 play an important role in modulating the interaction, an observation further supported by cell experiments. We further show that the diffusion of virions on the surface depends on the type of GAGs and their degree of sulfation. Taken together, our research contributes to a better understanding of the mechanisms underlying the interaction between a virus and the surface of its host. Such insights will without doubt facilitate the design of more efficient antiviral drugs or vaccines.

  • 5.
    Bodén, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Shivappa, Nitin
    Hébert, James R
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    The inflammatory potential of diet in determining cancer risk: a prospective investigation of two dietary pattern scores2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4, article id e0214551Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Inflammation-related mechanisms may contribute to the link between diet and cancer. We sought to investigate the inflammatory impact of diet on cancer risk using the Dietary inflammatory index (DII) and an adapted Mediterranean diet score (MDS).

    METHODS: This population-based, prospective cohort study used self-reported dietary data from the Västerbotten Intervention Programme, including 100,881 participants, of whom 35,393 had repeated measures. Associations between dietary patterns and cancer risk were evaluated using Cox proportional hazards regression. We also used restricted cubic splines to test for potential non-linear associations.

    RESULTS: A total of 9,250 incident cancer cases were diagnosed during a median follow-up of 15 years. The two dietary patterns were moderately correlated to each other and had similar associations with cancer risk, predominantly lung cancer in men (DII per tertile decrease: Hazard ratio (HR) 0.81 (0.66-0.99), MDS per tertile increase: HR 0.86 (0.72-1.03)), and gastric cancer in men (DII: 0.73 (0.53-0.99), MDS: 0.73 (0.56-0.96)). Associations were, in general, found to be linear. We found no longitudinal association between 10-year change in diet and cancer risk.

    CONCLUSION: We confirm small, but consistent and statistically significant associations between a more anti-inflammatory or healthier diet and reduced risk of cancer, including a lower risk of lung and gastric cancer in men. The dietary indexes produced similar associations with respect to the risk of cancer.

  • 6. Bruening, Janina
    et al.
    Lasswitz, Lisa
    Banse, Pia
    Kahl, Sina
    Marinach, Carine
    Vondran, Florian W.
    Kaderali, Lars
    Silvie, Olivier
    Pietschmann, Thomas
    Meissner, Felix
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Insitute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Hepatitis C virus enters liver cells using the CD81 receptor complex proteins calpain-5 and CBLB2018In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 14, no 7, article id e1007111Article in journal (Refereed)
    Abstract [en]

    Hepatitis C virus (HCV) and the malaria parasite Plasmodium use the membrane protein CD81 to invade human liver cells. Here we mapped 33 host protein interactions of CD81 in primary human liver and hepatoma cells using high-resolution quantitative proteomics. In the CD81 protein network, we identified five proteins which are HCV entry factors or facilitators including epidermal growth factor receptor (EGFR). Notably, we discovered calpain-5 (CAPN5) and the ubiquitin ligase Casitas B-lineage lymphoma proto-oncogene B (CBLB) to form a complex with CD81 and support HCV entry. CAPN5 and CBLB were required for a post-binding and pre-replication step in the HCV life cycle. Knockout of CAPN5 and CBLB reduced susceptibility to all tested HCV genotypes, but not to other enveloped viruses such as vesicular stomatitis virus and human coronavirus. Furthermore, Plasmodium sporozoites relied on a distinct set of CD81 interaction partners for liver cell entry. Our findings reveal a comprehensive CD81 network in human liver cells and show that HCV and Plasmodium highjack selective CD81 interactions, including CAPN5 and CBLB for HCV, to invade cells.

  • 7. Delguste, Martin
    et al.
    Peerboom, Nadia
    Le Brun, Gregoire
    Trybala, Edward
    Olofsson, Sigvard
    Bergström, Tomas
    Alsteens, David
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Regulatory Mechanisms of the Mucin-Like Region on Herpes Simplex Virus during Cellular Attachment2019In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 14, no 3, p. 534-542Article in journal (Refereed)
    Abstract [en]

    Mucin-like regions, characterized by a local high density of O-linked glycosylation, are found on the viral envelope glycoproteins of many viruses. Herpes simplex virus type 1 (HSV-1), for example, exhibits a mucin-like region on its glycoprotein gC, a viral protein involved in initial recruitment of the virus to the cell surface via interaction with sulfated glycosaminoglycans. So far, this mucin-like region has been proposed to play a key role in modulating the interactions with cellular glycosaminoglycans, and in particular to promote release of HSV-1 virions from infected cells. However, the molecular mechanisms and the role as a pathogenicity factor remains unclear. Using single virus particle tracking, we show that the mobility of chondroitin sulfate-bound HSV-1 virions is decreased in absence of the mucin-like region. This decrease in mobility correlates with an increase in HSV-1-chondroitin sulfate binding forces as observed using atomic force microscopy-based force spectroscopy. Our data suggest that the mucin-like region modulates virus-glycosaminoglycan interactions by regulating the affinity, type, and number of glycoproteins involved in the virus glycosaminoglycan interaction. This study therefore presents new evidence for a role of the mucin-like region in balancing the interaction of HSV-1 with glycosaminoglycans and provides further insights into the molecular mechanisms used by the virus to ensure both successful cell entry and release from the infected cell.

  • 8. Emilsson, Gustav
    et al.
    Röder, Evelyn
    Malekian, Bita
    Xiong, Kunli
    Manzi, John
    Tsai, Feng-Ching
    Cho, Nam-Joon
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Dahlin, Andreas
    Nanoplasmonic Sensor Detects Preferential Binding of IRSp53 to Negative Membrane Curvature2019In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 7, article id 1Article in journal (Refereed)
    Abstract [en]

    Biosensors based on plasmonic nanostructures are widely used in various applications and benefit from numerous operational advantages. One type of application where nanostructured sensors provide unique value in comparison with, for instance, conventional surface plasmon resonance, is investigations of the influence of nanoscale geometry on biomolecular binding events. In this study, we show that plasmonic "nanowells" conformally coated with a continuous lipid bilayer can be used to detect the preferential binding of the insulin receptor tyrosine kinase substrate protein (IRSp53) I-BAR domain to regions of negative surface curvature, i.e., the interior of the nanowells. Two different sensor architectures with and without an additional niobium oxide layer are compared for this purpose. In both cases, curvature preferential binding of IRSp53 (at around 0.025 nm(-1) and higher) can be detected qualitatively. The high refractive index niobium oxide influences the near field distribution and makes the signature for bilayer formation less clear, but the contrast for accumulation at regions of negative curvature is slightly higher. This work shows the first example of analyzing preferential binding of an average-sized and biologically important protein to negative membrane curvature in a label-free manner and in real-time, illustrating a unique application for nanoplasmonic sensors.

  • 9.
    Franklin, Oskar
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Billing, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Berglund, Anette
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Herdenberg, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wang, Wanzhong
    Department of Pathology/Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Novel prognostic markers within the CD44-stromal ligand network in pancreatic cancer2019In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 5, no 2, p. 130-141Article in journal (Refereed)
    Abstract [en]

    The dense stroma in pancreatic cancer tumours is rich in secreted extracellular matrix proteins and proteoglycans. Secreted hyaluronan, osteopontin and type IV collagen sustain oncogenic signalling by interactions with CD44s and its variant isoform CD44v6 on cancer cell membranes. Although well established in animal and in vitro models, this oncogenic CD44-stromal ligand network is less explored in human cancer. Here, we use a pancreatic cancer tissue microarray from 69 primary tumours and 37 metastatic lymph nodes and demonstrate that high tumour cell expression of CD44s and, surprisingly, low stromal deposition of osteopontin correlate with poor survival independent of established prognostic factors for pancreatic cancer. High stromal expression of hyaluronan was a universal trait of both primary tumours and metastatic lymph nodes. However, hyaluronan species of different molecular mass are known to function differently in pancreatic cancer biology and immunohistochemistry cannot distinguish between them. Using gas-phase electrophoretic molecular mobility analysis, we uncover a shift towards high molecular mass hyaluronan in pancreatic cancer tissue compared to normal pancreas and at a transcriptional level, we find that hyaluronan synthesising HAS2 correlates positively with CD44. The resulting prediction that high molecular mass hyaluronan would then correlate with poor survival in pancreatic cancer was confirmed in serum samples, where we demonstrate that hyaluronan >27 kDa measured before surgery is an independent predictor of postoperative survival. Our findings confirm the prognostic value of CD44 tissue expression and highlight osteopontin tissue expression and serum high molecular mass hyaluronan as novel prognostic markers in pancreatic cancer.

  • 10.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden; .
    A Hierarchical Bayesian Mixture Modeling Approach for Analysis of Resting-State Functional Brain Connectivity: An Alternative to ThresholdingManuscript (preprint) (Other academic)
  • 11.
    Gorbach, Tetiana
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lundquist, Anders
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    de Luna, Xavier
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden..
    Bayesian mixture modeling for longitudinal fMRI connectivity studies with dropoutManuscript (preprint) (Other academic)
  • 12.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lång, Kenneth
    Ihse, Elisabet
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Olsson, Malin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Lundgren, Hans-Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Westermark, Per
    Wixner, Jonas
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, p. 1-5Article in journal (Refereed)
    Abstract [en]

    For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

  • 13. Herrador, Antonio
    et al.
    Fedeli, Chiara
    Radulovic, Emilia
    Campbell, Kevin P.
    Moreno, Hector
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology. TWINCORE - Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Kunz, Stefan
    Dynamic Dystroglycan Complexes Mediate Cell Entry of Lassa Virus2019In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 10, no 2, article id e02869-18Article in journal (Refereed)
    Abstract [en]

    Recognition of functional receptors by viruses is a key determinant for their host range, tissue tropism, and disease potential. The highly pathogenic Lassa virus (LASV) currently represents one of the most important emerging pathogens. The major cellular receptor for LASV in human cells is the ubiquitously expressed and evolutionary highly conserved extracellular matrix receptor dystroglycan (DG). In the host, DG interacts with many cellular proteins in a tissue-specific manner. The resulting distinct supramolecular complexes likely represent the functional units for viral entry, and preexisting protein-protein interactions may critically influence DG's function in productive viral entry. Using an unbiased shotgun proteomic approach, we define the largely unknown molecular composition of DG complexes present in highly susceptible epithelial cells that represent important targets for LASV during viral transmission. We further show that the specific composition of cellular DG complexes can affect DG's function in receptor-mediated endocytosis of the virus. Under steady-state conditions, epithelial DG complexes underwent rapid turnover via an endocytic pathway that shared some characteristics with DG-mediated LASV entry. However, compared to steady-state uptake of DG, LASV entry via DG occurred faster and critically depended on additional signaling by receptor tyrosine kinases and the downstream effector p21-activating kinase. In sum, we show that the specific molecular composition of DG complexes in susceptible cells is a determinant for productive virus entry and that the pathogen can manipulate the existing DG-linked endocytic pathway. This highlights another level of complexity of virus-receptor interaction and provides possible cellular targets for therapeutic antiviral intervention.

    Importance: Recognition of cellular receptors allows emerging viruses to break species barriers and is an important determinant for their disease potential. Many virus receptors have complex tissue-specific interactomes, and preexisting protein-protein interactions may influence their function. Combining shotgun proteomics with a biochemical approach, we characterize the molecular composition of the functional receptor complexes used by the highly pathogenic Lassa virus (LASV) to invade susceptible human cells. We show that the specific composition of the receptor complexes affects productive entry of the virus, providing proof-of-concept. In uninfected cells, these functional receptor complexes undergo dynamic turnover involving an endocytic pathway that shares some characteristics with viral entry. However, steady-state receptor uptake and virus endocytosis critically differ in kinetics and underlying signaling, indicating that the pathogen can manipulate the receptor complex according to its needs. Our study highlights a remarkable complexity of LASV-receptor interaction and identifies possible targets for therapeutic antiviral intervention.

  • 14.
    Holmgren, Klas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Haapamäki, Markku M.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Matthiessen, Peter
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Anterior resection for rectal cancer in Sweden: validation of a registry-based method to determine long-term stoma outcome2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 12, p. 1631-1638Article in journal (Refereed)
    Abstract [en]

    Background: A permanent stoma after anterior resection for rectal cancer is common. Nationwide registries provide sufficient power to evaluate factors influencing this phenomenon, but validation is required to ensure the quality of registry-based stoma outcomes.

    Methods: Patients who underwent anterior resection for rectal cancer in the Northern healthcare region of Sweden between 1 January 2007 and 31 December 2013 were reviewed by medical records and followed until 31 December 2014 with regard to stoma outcome. A registry-based method to determine nationwide long-term stoma outcomes, using data from the National Patient Registry and the Swedish Colorectal Cancer Registry, was developed and internally validated using the chart reviewed reference cohort. Accuracy was evaluated with positive and negative predictive values and Kappa values. Following validation, the stoma outcome in all patients treated with an anterior resection for rectal cancer in Sweden during the study period was estimated. Possible regional differences in determined stoma outcomes between the six Swedish healthcare regions were subsequently evaluated with the χ2 test.

    Results: With 312 chart reviewed patients as reference, stoma outcome was accurately predicted through the registry-based method in 299 cases (95.8%), with a positive predictive value of 85.1% (95% CI 75.8%-91.8%), and a negative predictive value of 100.0% (95% CI 98.4%-100.0%), while the Kappa value was 0.89 (95% CI 0.82-0.95). In Sweden, 4768 patients underwent anterior resection during the study period, of which 942 (19.8%) were determined to have a permanent stoma. The stoma rate varied regionally between 17.8-29.2%, to a statistically significant degree (p = .001).

    Conclusion: Using data from two national registries to determine long-term stoma outcome after anterior resection for rectal cancer proved to be reliable in comparison to chart review. Permanent stoma prevalence after such surgery remains at a significant level, while stoma outcomes vary substantially between different healthcare regions in Sweden.

  • 15.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Damber, Jan-Erik
    Welen, Karin
    AR-V7 expression in circulating tumor cells as a potential prognostic marker in metastatic hormone-sensitive prostate cancer2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226XArticle in journal (Refereed)
    Abstract [en]

    Treatment of patients with metastatic hormone-sensitive (mHSPC) depends on androgen deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling. Although the majority of patients respond well to ADT, castration-resistant prostate cancer (CRPC) inevitably develops. Addition of docetaxel, abiraterone acetate, or enzalutamide, to ADT significantly increases cancer-specific survival (CSS) [1–3]. The drawback is that not all patients respond to the therapies equally well and biomarkers to enable personalized treatment are urgently needed. Prostate-specific antigen (PSA) is a powerful biomarker for diagnosis of PC, but there are no validated biomarkers to prognosticate prognosis, let alone prediction of therapy response, of metastatic disease prior to ADT. Mechanisms important for resistance to ADT and development of CRPC include increased AR levels, constitutively active AR variants such as AR-V7, and intratumoral steroid production to sustain AR signaling despite castrate levels of steroids [4–7]. Although these changes mainly have been reported in CRPC, inherent expression could indicate predisposition for CRPC and poor response to ADT and other therapies targeting AR signaling.

    To identify patients with optimal therapeutic benefit from drugs with conceptually different targets, their metastatic disease needs to be characterized. Given the difficulty to access metastatic tissue for analysis, circulating tumor cells (CTCs) have a potential to provide phenotypic information of the tumor, in addition to the prognostic value associated with their abundance [8]. We have demonstrated that gene expression in circulating tumor cells (CTCs) reflects the phenotype of prostate cancer metastases [9]. It has also been suggested that detection of AR-V7 mRNA and AR-V7 localization to the nucleus in CTCs predict poor response to drugs targeting the androgen signaling axis, such as abiraterone acetate and enzalutamide, in patients with CRPC [10,11]. Although the biomarker potential of CTCs mostly has been evaluated in CRPC [10,12,13], two studies have described the presence of CTCs as a prognostic marker for overall survival, progression-free survival (PFS), and time to CRPC also in mHSPC [14,15]. In addition, we previously showed that detection of EGFR mRNA in CTCs is a negative prognostic biomarker for CSS in mHSPC [16].

    The present study investigates expression of genes associated with development of CRPC [17] for their prognostic value in mHSPC response to ADT. We showed that mRNA for the steroidogenic enzymes AKR1C3 and CYP17A1 can be detected in CTCs in high volume mHSPC, and that the detection of mRNA for AR-V7 in CTCs before ADT has prognostic value.

  • 16.
    Jóhannesson, Gauti
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Eklund, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Linden, Christina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Intracranial and Intraocular Pressure at the Lamina Cribrosa: Gradient Effects2018In: Current Neurology and Neuroscience Reports, ISSN 1528-4042, E-ISSN 1534-6293, Vol. 18, no 5, article id 25Article, review/survey (Refereed)
    Abstract [en]

    Purpose of Review A pressure difference between the intraocular and intracranial compartments at the site of the lamina cribrosa has been hypothesized to have a pathophysiological role in several optic nerve head diseases. This paper reviews the current literature on the translamina cribrosa pressure difference (TLCPD), the associated pressure gradient, and its potential pathophysiological role, as well as the methodology to assess TLCPD. Recent Findings For normal-tension glaucoma (NTG), initial studies indicated low intracranial pressure (ICP) while recent findings indicate that a reduced ICP is not mandatory. Summary Data from studies on the elevated TLCPD as a pathophysiological factor of NTG are equivocal. From the identification of potential postural effects on the cerebrospinal fluid (CSF) communication between the intracranial and retrolaminar space, we hypothesize that the missing link could be a dysfunction of an occlusion mechanism of the optic nerve sheath around the optic nerve. In upright posture, this could cause an elevated TLCPD even with normal ICP and we suggest that this should be investigated as a pathophysiological component in NTG patients.

  • 17. Lasswitz, Lisa
    et al.
    Chandra, Naresh
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Arnberg, Niklas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Glycomics and Proteomics Approaches to Investigate Early Adenovirus-Host Cell Interactions2018In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 430, no 13, p. 1863-1882Article in journal (Refereed)
    Abstract [en]

    Adenoviruses as most viruses rely on glycan and protein interactions to attach to and enter susceptible host cells. The Adenoviridae family comprises more than 80 human types and they differ in their attachment factor and receptor usage, which likely contributes to the diverse tropism of the different types. In the past years, methods to systematically identify glycan and protein interactions have advanced. In particular sensitivity, speed and coverage of mass spectrometric analyses allow for high-throughput identification of glycans and peptides separated by liquid chromatography. Also, developments in glycan microarray technologies have led to targeted, high-throughput screening and identification of glycan-based receptors. The mapping of cell surface interactions of the diverse adenovirus types has implications for cell, tissue, and species tropism as well as drug development. Here we review known adenovirus interactions with glycan- and protein-based receptors, as well as glycomics and proteomics strategies to identify yet elusive virus receptors and attachment factors. We finally discuss challenges, bottlenecks, and future research directions in the field of non-enveloped virus entry into host cells.

  • 18.
    Linden, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Heijl, Anders
    Jóhannesson, Gauti
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Aspberg, Johan
    Andersson Geimer, Sabina
    Bengtsson, Boel
    Initial intraocular pressure reduction by mono‐ versus multi‐therapy in patients with open‐angle glaucoma: results from the Glaucoma Intensive Treatment Study2018In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 96, no 6, p. 567-572Article in journal (Refereed)
    Abstract [en]

    Purpose: To study newly diagnosed glaucoma patients given mono‐ or multi‐therapy regarding differences in initial intraocular pressure (IOP) reduction, target IOP levels reached and influence of untreated baseline IOP on IOP reduction.

    Methods: Patients newly diagnosed with manifest primary open‐angle glaucoma and included in the Glaucoma Intensive Treatment Study (GITS) were randomized to immediate intensive treatment with any of three different IOP‐lowering substances supplied in two bottles plus 360° laser trabeculoplasty or to conventional stepwise treatment starting with a single‐drug. Intraocular pressure reduction was analysed 1 month after initiation of treatment.

    Results: One hundred eighteen patients (143 eyes) received mono‐therapy and 122 patients (152 eyes) multi‐therapy. Median baseline IOP was 24.0 (min: 9.7, max: 56.0) mmHg in mono‐therapy eyes and 24.0 (min: 12.3, max: 48.5) mmHg in multi‐therapy eyes (p = 0.56). After 1 month in the two groups, respectively, values for median IOP reduction were 6.3 (range: −5.3–31.0) and 11.0 (range: 0.7–34.5) mmHg, and for mean relative decline 26.8 (range: −32.0–55.4) and 46.0 (range: 4.6–81.6) % (p = 0.000). A larger proportion of the multi‐therapy patients reached each target IOP level (p = 0.000). The higher the baseline IOP, the larger the observed pressure reduction, considering both absolute and relative figures. The effect was more pronounced in eyes with multi‐therapy than in those with mono‐therapy (p = 0.000). For every mmHg higher IOP at baseline, the IOP was reduced by an additional 0.56 (mono‐therapy) or 0.84 (multi‐therapy) mmHg.

    Conclusion: Intensive treatment led to considerably greater IOP reduction than mono‐therapy. Among patients with IOP ≥30 mmHg at diagnosis an IOP of <16 was reached in 2/3 of those with multi‐therapy but in none with mono‐therapy. The IOP reduction was highly dependent on the untreated IOP level.

  • 19.
    Malla, Sandhya
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Melguizo-Sanchis, Dario
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Steering pluripotency and differentiation with N6-methyladenosine RNA modification2019In: Biochimica et Biophysica Acta. Gene Regulatory Mechanisms, ISSN 1874-9399, E-ISSN 1876-4320, Vol. 1862, no 3, p. 394-402Article in journal (Refereed)
    Abstract [en]

    Chemical modifications of RNA provide a direct and rapid way to modulate the existing transcriptome, allowing the cells to adapt rapidly to the changing environment. Among these modifications, N6-methyladenosine (m6A) has recently emerged as a widely prevalent mark of messenger RNA in eukaryotes, linking external stimuli to an intricate network of transcriptional, post-transcriptional and translational processes. m6A modification modulates a broad spectrum of biochemical processes, including mRNA decay, translation and splicing. Both m6A modification and the enzymes that control m6A metabolism are essential for normal development. In this review, we summarized the most recent findings on the role of m6A modification in maintenance of the pluripotency of embryonic stem cells (ESCs), cell fate specification, the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), and differentiation of stem and progenitor cells.

  • 20.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden..
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 2, p. 327-337Article in journal (Refereed)
    Abstract [en]

    Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population-based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow-up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all pheterogeneity > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.

  • 21.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sundkvist, Anneli
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Circulating levels of inflammatory markers and DNA methylation, an analysis of repeated samples from a population based cohort2019In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 14, no 7, p. 649-659Article in journal (Refereed)
    Abstract [en]

    DNA methylation in blood may adapt to conditions affecting our health, such as inflammation, and multiple studies have identified differential DNA methylation related to smoking, obesity and various diseases. The purpose of this study was to evaluate previously reported, and explore possible new, associations between levels of inflammatory markers and DNA methylation in blood. We used a well-characterized study population consisting of 127 individuals, all of whom were participants in the population-based Vasterbotten Intervention Programme cohort and had provided two blood samples, ten years apart. Levels of CRP and 160 other proteins were measured in plasma, and DNA methylation levels (assessed using the 850K Illumina Infinium MethylationEPIC BeadChip) were measured in white blood cell DNA. Associations between CpG methylation and protein levels were estimated using linear mixed models. In the study we were able to confirm the direction for 85 of 102 previously reported protein-methylation associations. Depicting associations in a network allowed us to identify CpG sites with associations to multiple proteins, and ten CpG sites were each associated with three or more inflammatory markers. Furthermore, two genetic regions included nine additional unreported CpG sites that may represent trans-acting methylation sites. Our study supports a complex interaction between DNA methylation and circulating proteins involved in the inflammatory response. The notion of trans-acting methylation sites affecting, or being affected by, the expression of genes on completely different chromosomes should be taken into account when interpreting results from epigenome-wide association studies.

  • 22.
    Nilsson, Lena Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Winkvist, Anna
    Esberg, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Dairy Products and Cancer Risk in a Northern Sweden Population2019In: Nutrition and Cancer, ISSN 0163-5581, E-ISSN 1532-7914Article in journal (Refereed)
    Abstract [en]

    The role of dairy products in cancer is unclear. We assessed consumption of fermented milk, non-fermented milk, cheese, and butter, estimated from semi-quantitative food frequency questionnaires, in relation to prospective risk of breast, prostate, colorectal, smoking-, and obesity-related cancers in 101,235 subjects, including 12,552 cancer cases, in the population-based Northern Sweden Health and Disease Study. Most analyses (n = 20) rendered null results. In men, we observed an increased prostate cancer risk among high-consumers of cheese (hazard ratio (HR) for highest vs. lowest quintile (Q5-Q1), 1.11; 95% CI, 0.97-1.27; Ptrend = 0.013). In women, high-consumers of cheese had a decreased risk of overall cancer (HR Q5-Q1, 0.95; 95% CI, 0.88-1.04; Ptrend = 0.039), smoking-related (HR Q5-Q1, 0.84; 95% CI, 0.72-0.97; Ptrend ≤ 0.001), and colorectal cancers (HR Q5-Q1, 0.82; 95% CI, 0.63-1.07; Ptrend = 0.048). Butter yielded a weak decreased obesity-related cancer risk in women (HR Q5-Q1, 0.91; 95% CI, 0.81-1.02; Ptrend = 0.049). Fermented milk yielded HRs below zero in women, but with no clear linear associations. In conclusion, this study does not support any major adverse or beneficial effects of fermented milk, non-fermented milk, cheese, and butter in the diet from a cancer risk perspective.

  • 23.
    Nyrén, Rakel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Makoveichuk, Elena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Malla, Sandhya
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Kersten, Sander
    Nilsson, Stefan K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Ericsson, Madelene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Lipoprotein lipase in mouse kidney: effects of nutritional status and high-fat diet2019In: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, no 3, p. F558-F571Article in journal (Refereed)
    Abstract [en]

    Activity of lipoprotein lipase (LPL) is high in mouse kidney, but the reason is poorly understood. The aim was to characterize localization, regulation, and function of LPL in kidney of C57BL/6J mice. We found LPL mainly in proximal tubules, localized inside the tubular epithelial cells, under all conditions studied. In fed mice, some LPL, colocalized with the endothelial markers CD31 and GPIHBP1 and could be removed by perfusion with heparin. indicating a vascular location. The role of angiopoietin-like protein 4 (ANGPTL4) for nutritional modulation of LPL activity was studied in wild-type and Angptl4(-/-) mice. In Angptl4(-/-) mice, kidney LPL activity remained high in fasted animals, indicating that ANGPTL4 is involved in suppression of LPL activity on fasting, like in adipose tissue. The amount of ANGPTL4 protein in kidney was low, and the protein appeared smaller in size, compared with ANGPTL4 in heart and adipose tissue. To study the influence of obesity, mice were challenged with high-fat diet for 22 wk, and LPL was studied after an overnight fast compared with fasted mice given food for 3 h. High-fat diet caused blunting of the normal adaptation of LPL activity to feeding/fasting in adipose tissue, but in kidneys this adaptation was lost only in male mice. LPL activity increases to high levels in mouse kidney after feeding, but as no difference in uptake of chylomicron triglycerides in kidneys is found between fasted and fed states, our data confinn that LPL appears to have a minor role for lipid uptake in this organ.

  • 24. Peerboom, Nadia
    et al.
    Schmidt, Eneas
    Trybala, Edward
    Block, Stephan
    Bergström, Tomas
    Pace, Hudson P.
    Bally, Marta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Cell Membrane Derived Platform To Study Virus Binding Kinetics and Diffusion with Single Particle Sensitivity2018In: Acs Infectious Diseases, ISSN 2373-8227, Vol. 4, no 6, p. 944-953Article in journal (Refereed)
    Abstract [en]

    Discovery and development of new antiviral therapies essentially rely on two key factors: an in-depth understanding of the mechanisms involved in viral infection and the development of fast and versatile drug screening platforms. To meet those demands, we present a biosensing platform to probe virus-cell membrane interactions on a single particle level. Our method is based on the formation of supported lipid bilayers from cell membrane material. Using total internal reflection fluorescence microscopy, we report the contribution of viral and cellular components to the interaction kinetics of herpes simplex virus type 1 with the cell membrane. Deletion of glycoprotein C (gC), the main viral attachment glycoprotein, or deletion of heparan sulfate, an attachment factor on the cell membrane, leads to an overall decrease in association of virions to the membrane and faster dissociation from the membrane. In addition to this, we perform binding inhibition studies using the antiviral compound heparin to estimate its IC50 value. Finally, single particle tracking is used to characterize the diffusive behavior of the virus particles on the supported lipid bilayers. Altogether, our results promote this platform as a complement to existing bioanalytical assays, being at the interface between simplified artificial membrane models and live cell experiments.

  • 25. Rengasamy, Madhumitha
    et al.
    Zhang, Fan
    Vashisht, Ajay
    Song, Won-Min
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Sun, Yifei
    Li, SiDe
    Zhang, Weijia
    Zhang, Bin
    Wohlschlegel, James A.
    Walsh, Martin J.
    The PRMT5/WDR77 complex regulates alternative splicing through ZNF326 in breast cancer2017In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 45, no 19, p. 11106-11120Article in journal (Refereed)
    Abstract [en]

    We observed overexpression and increased intranuclear accumulation of the PRMT5/WDR77 in breast cancer cell lines relative to immortalized breast epithelial cells. Utilizing mass spectrometry and biochemistry approaches we identified the Zn-finger protein ZNF326, as a novel interaction partner and substrate of the nuclear PRMT5/WDR77 complex. ZNF326 is symmetrically dimethylated at arginine 175 (R175) and this modification is lost in a PRMT5 and WDR77-dependent manner. Loss of PRMT5 or WDR77 in MDA-MB-231 cells leads to defects in alternative splicing, including inclusion of A-T rich exons in target genes, a phenomenon that has previously been observed upon loss of ZNF326. We observed that the alternatively spliced transcripts of a subset of these genes, involved in proliferation and tumor cell migration like REPIN1/AP4, ST3GAL6, TRNAU1AP and PFKM are degraded upon loss of PRMT5. In summary, we have identified a novel mechanism through which the PRMT5/WDR77 complex maintains the balance between splicing and mRNA stability through methylation of ZNF326.

  • 26.
    Rutegård, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Haapamäki, Markku M
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Multicentre, randomised trial comparing acellular porcine collagen implant versus gluteus maximus myocutaneous flap for reconstruction of the pelvic floor after extended abdominoperineal excision of rectum: study protocol for the Nordic Extended Abdominoperineal Excision (NEAPE) study2019In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 9, no 5, article id e027255Article in journal (Refereed)
    Abstract [en]

    Introduction: Different surgical techniques are used to cover the defect in the floor of the lesser pelvis after an ‘extralevator’ or ‘extended’ abdominoperineal excision for advanced rectal cancer. However, these operations are potentially mutilating, and the reconstruction method of the pelvic floor has been studied only sparsely. We aim to study whether a porcine-collagen implant is superior or equally beneficial to a gluteus maximus myocutaneous flap as a reconstruction method.

    Methods and analysis: This is a multicentre non-blinded randomised controlled trial with the experimental arm using a porcine-collagen implant and the control arm using a gluteus maximus muscle and skin rotation flap. Considered for inclusion are patients with rectal cancer, who are operated on with a wide abdominoperineal rectal excision including most of the levator muscles and where the muscle remnants cannot be closed in the midline with sutures. Patients with a primary or recurrent rectal cancer with an estimated survival of more than a year are eligible. The randomisation is computer generated with a concealed sequence and stratified by participating hospital and preoperative radiotherapy regimen. The main outcome is physical performance 6 months after surgery measured with the timed-stands test. Secondary outcomes are perineal wound healing, surgical complications, quality of life, ability to sit and other outcomes measured at 3, 6 and 12 months after surgery. To be able to state experimental arm non-inferiority with a 10% margin of the primary outcome with 90% statistical power and assuming 10% attrition, we aim to enrol 85 patients from May 2011 onwards.

    Ethics and dissemination: The study has been approved by the Regional Ethical Review board at Umeå University (protocol no: NEAPE-2010-335-31M). The results will be disseminated through patient associations and conventional scientific channels.

  • 27.
    Salami, Alireza
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
    Avelar-Pereira, Barbara
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Garzon, Benjamin
    Sitnikov, Rouslan
    Kalpouzos, Gregoria
    Functional coherence of striatal resting-state networks is modulated by striatal iron content2018In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 183, p. 495-503Article in journal (Refereed)
    Abstract [en]

    Resting-state spontaneous fluctuations have revealed individual differences in the functional architecture of brain networks. Previous research indicates that the striatal network shows alterations in neurological conditions but also in normal aging. However, the neurobiological mechanisms underlying individual differences in striatal resting-state networks (RSNs) have been less explored. One candidate that may account for individual differences in striatal spontaneous activity is the level of local iron accumulation. Excessive iron in the striatum has been linked to a loss of structural integrity and reduced brain activity during task performance in aging. Using independent component analysis in a sample of 42 younger and older adults, we examined whether higher striatal iron content, quantified using relaxometry, underlies individual differences in spontaneous fluctuations of RSNs in general, and of the striatum in particular. Higher striatal iron content was linked to lower spontaneous coherence within both caudate and putamen RSNs regardless of age. No such links were observed for other RSNs. Moreover, the number of connections between the putamen and other RSNs was negatively associated with iron content, suggesting that iron modulated the degree of cross-talk between the striatum and cerebral cortex. Importantly, these associations were primarily driven by the older group. Finally, a positive association was found between coherence in the putamen and motor performance, suggesting that this spontaneous activity is behaviorally meaningful. A follow-up mediation analysis also indicated that functional connectivity may mediate the link between striatal iron and motor performance. Our preliminary findings suggest that striatal iron potentially accounts for individual differences in spontaneous striatal fluctuations, and might be used as a locus of intervention.

  • 28.
    Salami, Alireza
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Aging Research Center, Karolinska Institutet and Stockholm University, Sweden.
    Garrett, Douglas D.
    Wåhlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Rieckmann, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Papenberg, Goran
    Karalija, Nina
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany.
    Jonasson, Lars
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Andersson, Micael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Johansson, Jarkko
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Lövdén, Martin
    Lindenberger, Ulman
    Bäckman, Lars
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI).
    Dopamine D2/3 Binding Potential Modulates Neural Signatures of Working Memory in a Load-Dependent Fashion.2019In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 39, no 3, p. 537-547Article in journal (Refereed)
    Abstract [en]

    Dopamine (DA) modulates corticostriatal connections. Studies in which imaging of the DA system is integrated with functional imaging during cognitive performance have yielded mixed findings. Some work has shown a link between striatal DA (measured by PET) and fMRI activations, whereas others have failed to observe such a relationship. One possible reason for these discrepant findings is differences in task demands, such that a more demanding task with greater prefrontal activations may yield a stronger association with DA. Moreover, a potential DA–BOLD association may be modulated by task performance. We studied 155 (104 normal-performing and 51 low-performing) healthy older adults (43% females) who underwent fMRI scanning while performing a working memory (WM) n-back task along with DA D2/3 PET assessment using [11C]raclopride. Using multivariate partial-least-squares analysis, we observed a significant pattern revealing positive associations of striatal as well as extrastriatal DA D2/3 receptors to BOLD response in the thalamo–striatal–cortical circuit, which supports WM functioning. Critically, the DA–BOLD association in normal-performing, but not low-performing, individuals was expressed in a load-dependent fashion, with stronger associations during 3-back than 1-/2-back conditions. Moreover, normal-performing adults expressing upregulated BOLD in response to increasing task demands showed a stronger DA–BOLD association during 3-back, whereas low-performing individuals expressed a stronger association during 2-back conditions. This pattern suggests a nonlinear DA–BOLD performance association, with the strongest link at the maximum capacity level. Together, our results suggest that DA may have a stronger impact on functional brain responses during more demanding cognitive tasks.

  • 29. Schoneberg, Johannes
    et al.
    Pavlin, Mark Remec
    Yan, Shannon
    Righini, Maurizio
    Lee, Il-Hyung
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Bahrami, Amir Houshang
    Goldman, Daniel H.
    Ren, Xuefeng
    Hummer, Gerhard
    Bustamante, Carlos
    Hurley, James H.
    ATP-dependent force generation and membrane scission by ESCRT-III and Vps42018In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 362, no 6421, p. 1423-+Article in journal (Refereed)
    Abstract [en]

    The endosomal sorting complexes required for transport (ESCRTs) catalyze reverse topology scission from the inner face of membrane necks in HIV budding, multivesicular endosome biogenesis, cytokinesis, and other pathways. We encapsulated ESCRT-III subunits Snf7, Vps24. and Vps2 and the AAA+ ATPase (adenosine triphosphatase) Vps4 in giant vesicles from which membrane nanotubes reflecting the correct topology of scission could be pulled. Upon ATP release by photo-uncaging, this system generated forces within the nanotubes that led to membrane scission in a manner dependent upon Vps4 catalytic activity and Vps4 coupling to the ESCRT-III proteins. Imaging of scission revealed Snf7 and Vps4 puncta within nanotubes whose presence followed ATP release, correlated with force generation and nanotube constriction, and preceded scission. These observations directly verify long-standing predictions that ATP-hydrolyzing assemblies of ESCRT-Ill and Vps4 sever membranes.

  • 30.
    Stomby, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Region Jönköping County, Jönköping, Sweden.
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Dahlqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Evang, Johan Arild
    Ryberg, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Bollerslev, Jens
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johannsson, Gudmundur
    Ragnarsson, Oskar
    Elevated resting-state connectivity in the medial temporal lobe and the prefrontal cortex among patients with Cushing's syndrome in remission2019In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 180, no 5, p. 329-338Article in journal (Refereed)
    Abstract [en]

    Objective: Cushing's syndrome is associated with long-term cognitive deficits and affective symptoms such as depression and anxiety. The alterations in brain function under lying these deficits after Cushing's syndrome are unclear and therefore we aimed to explore alterations in resting-state functional connectivity in patients with Cushing's syndrome in remission. Design: Cross-sectional case-control study. Methods: Nineteen women with Cushing's syndrome in remission for a median time of 7 years (IQR: 6-10) and a mean age of 45 years were included at three university clinics. These patients and 38 age-matched female controls underwent brain imaging at a single center. The main outcome measure was functional connectivity at rest, measured with functional magnetic resonance imaging. Results: The medial temporal lobe (MTL) and prefrontal cortex networks, exhibited elevated functional connectivity among patients compared to controls. The degree of elevated functional connectivity in the MTL was negatively associated with time in remission. Conclusions: Resting-state functional connectivity within glucocorticoid receptor-rich regions, particularly the MTL and medial prefrontal cortex, was increased in patients. These differences in connectivity may provide a neural basis for the cognitive deficits and affective symptoms commonly experienced by patients with Cushing's syndrome in remission.

  • 31. Zapatero-Belinchon, Francisco J.
    et al.
    Dietzel, Erik
    Dolnik, Olga
    Doehner, Katinka
    Costa, Rui
    Hertel, Barbara
    Veselkova, Barbora
    Kirui, Jared
    Klintworth, Anneke
    Manns, Michael P.
    Poehlmann, Stefan
    Pietschmann, Thomas
    Krey, Thomas
    Ciesek, Sandra
    Gerold, Gisa
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Sodeik, Beate
    Becker, Stephan
    von Hahn, Thomas
    Characterization of the Filovirus-Resistant Cell Line SH-SY5Y Reveals Redundant Role of Cell Surface Entry Factors2019In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 11, no 3, article id 275Article in journal (Refereed)
    Abstract [en]

    Filoviruses infect a wide range of cell types with the exception of lymphocytes. The intracellular proteins cathepsin B and L, two-pore channel 1 and 2, and bona fide receptor Niemann-Pick Disease C1 (NPC1) are essential for the endosomal phase of cell entry. However, earlier steps of filoviral infection remain poorly characterized. Numerous plasma membrane proteins have been implicated in attachment but it is still unclear which ones are sufficient for productive entry. To define a minimal set of host factors required for filoviral glycoprotein-driven cell entry, we screened twelve cell lines and identified the nonlymphocytic cell line SH-SY5Y to be specifically resistant to filovirus infection. Heterokaryons of SH-SY5Y cells fused to susceptible cells were susceptible to filoviruses, indicating that SH-SY5Y cells do not express a restriction factor but lack an enabling factor critical for filovirus entry. However, all tested cell lines expressed functional intracellular factors. Global gene expression profiling of known cell surface entry factors and protein expression levels of analyzed attachment factors did not reveal any correlation between susceptibility and expression of a specific host factor. Using binding assays with recombinant filovirus glycoprotein, we identified cell attachment as the step impaired in filovirus entry in SH-SY5Y cells. Individual overexpression of attachment factors T-cell immunoglobulin and mucin domain 1 (TIM-1), Axl, Mer, or dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) rendered SH-SY5Y cells susceptible to filovirus glycoprotein-driven transduction. Our study reveals that a lack of attachment factors limits filovirus entry and provides direct experimental support for a model of filoviral cell attachment where host factor usage at the cell surface is highly promiscuous.

  • 32. Zheng, Jiaojiao
    et al.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Santoni, Giola
    Wallner, Bengt
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Xie, Shao-Hua
    Lagergren, Jesper
    Prediabetes and diabetes in relation to risk of gastric adenocarcinoma2019In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 120, no 12, p. 1147-1152Article in journal (Refereed)
    Abstract [en]

    Background: Whether prediabetes or diabetes increases the risk of gastric adenocarcinoma is not clear.

    Methods: This cohort study included 111,198 participants in the Northern Swedish Health and Disease Study. The participants were followed up from November 1985 to April 2017. The exposure to prediabetes or diabetes was assessed by oral glucose tolerance tests and self-reports. The incidence of the outcome gastric adenocarcinoma was identified from the Swedish Cancer Registry. Multivariable Cox regressions were used to analyse the associations between prediabetes or diabetes and the risk of gastric adenocarcinoma, providing hazard ratios (HR) with 95% confidence intervals (CI), with adjustment for sex, age, calendar year, body mass index, tobacco smoking and education level.

    Results: Compared with normoglycaemic participants, the risk of gastric adenocarcinoma was not increased among participants with prediabetes (HR 1.07, 95% CI 0.79–1.44), diabetes (HR 0.77, 95% CI 0.46–1.29) or any of these exposures (HR 0.96, 95% CI 0.73–1.27). No associations were identified between prediabetes or diabetes and the risk of gastric adenocarcinoma in stratified analyses or in analyses separating cardia and non-cardia gastric adenocarcinoma.

    Conclusions: This study does not support the hypothesis that prediabetes or diabetes increases the risk of gastric adenocarcinoma.

  • 33. Zuo, Nianming
    et al.
    Salami, Alireza
    Umeå University, Faculty of Medicine, Umeå Centre for Functional Brain Imaging (UFBI). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Aging Research Center, Karolinska Institute and Stockholm University, Stockholm, Sweden.
    Yang, Yihong
    Yang, Zhengyi
    Sui, Jing
    Jian, Tianzi
    Activation-based association profiles differentiate network roles across cognitive loads2019In: Human Brain Mapping, ISSN 1065-9471, E-ISSN 1097-0193, Vol. 40, no 9, p. 2800-2812Article in journal (Refereed)
    Abstract [en]

    Working memory (WM) is a complex and pivotal cognitive system underlying the performance of many cognitive behaviors. Although individual differences in WM performance have previously been linked to the blood oxygenation level-dependent (BOLD) response across several large-scale brain networks, the unique and shared contributions of each large-scale brain network to efficient WM processes across different cognitive loads remain elusive. Using a WM paradigm and functional magnetic resonance imaging (fMRI) from the Human Connectome Project, we proposed a framework to assess the association and shared-association strength between imaging biomarkers and behavioral scales. Association strength is the capability of individual brain regions to modulate WM performance and shared-association strength measures how different regions share the capability of modulating performance. Under higher cognitive load (2-back), the frontoparietal executive control network (FPN), dorsal attention network (DAN), and salience network showed significant positive activation and positive associations, whereas the default mode network (DMN) showed the opposite pattern, namely, significant deactivation and negative associations. Comparing the different cognitive loads, the DMN and FPN showed predominant associations and globally shared-associations. When investigating the differences in association from lower to higher cognitive loads, the DAN demonstrated enhanced association strength and globally shared-associations, which were significantly greater than those of the other networks. This study characterized how brain regions individually and collaboratively support different cognitive loads.

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