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  • 1.
    Cinege, Gyöngyi
    et al.
    Innate Immunity Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary.
    Fodor, Kinga
    Innate Immunity Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary.
    Magyar, Lilla B.
    Innate Immunity Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary; Doctoral School of Biology, University of Szeged, Szeged, Hungary.
    Lipinszki, Zoltán
    MTA SZBK Lendület Laboratory of Cell Cycle Regulation, Institute of Biochemistry, HUN-REN Biological Research Centre, Szeged, Hungary; National Laboratory for Biotechnology, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary.
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andó, István
    Innate Immunity Group, Institute of Genetics, HUN-REN Biological Research Centre, Szeged, Hungary.
    Cellular immunity of Drosophila willistoni reveals novel complexity in insect anti-parasitoid defense2024In: Cells, E-ISSN 2073-4409, Vol. 13, no 7, article id 593Article in journal (Refereed)
    Abstract [en]

    Coevolution of hosts and their parasites has shaped heterogeneity of effector hemocyte types, providing immune defense reactions with variable effectiveness. In this work, we characterize hemocytes of Drosophila willistoni, a species that has evolved a cellular immune system with extensive variation and a high degree of plasticity. Monoclonal antibodies were raised and used in indirect immunofluorescence experiments to characterize hemocyte subpopulations, follow their functional features and differentiation. Pagocytosis and parasitization assays were used to determine the functional characteristics of hemocyte types. Samples were visualized using confocal and epifluorescence microscopy. We identified a new multinucleated giant hemocyte (MGH) type, which differentiates in the course of the cellular immune response to parasitoids. These cells differentiate in the circulation through nuclear division and cell fusion, and can also be derived from the central hematopoietic organ, the lymph gland. They have a binary function as they take up bacteria by phagocytosis and are involved in the encapsulation and elimination of the parasitoid. Here, we show that, in response to large foreign particles, such as parasitoids, MGHs differentiate, have a binary function and contribute to a highly effective cellular immune response, similar to the foreign body giant cells of vertebrates.

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  • 2.
    Ebrahimi, Mahsa
    et al.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, 106 91, Sweden.
    Habernig, Lukas
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, 106 91, Sweden.
    Broeskamp, Filomena
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, 106 91, Sweden.
    Aufschnaiter, Andreas
    Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden.
    Diessl, Jutta
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, 106 91, Sweden.
    Atienza, Isabel
    Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), University of Cadiz, 11001 Cadiz, Spain.
    Matz, Steffen
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden.
    Ruiz, Felix A.
    Instituto de Investigación e Innovación Biomédica de Cádiz (INIBICA), University of Cadiz, 11001 Cadiz, Spain.
    Büttner, Sabrina
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
    Phosphate Restriction Promotes Longevity via Activation of Autophagy and the Multivesicular Body Pathway2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 11, article id 3161Article in journal (Refereed)
    Abstract [en]

    Nutrient limitation results in an activation of autophagy in organisms ranging from yeast, nematodes and flies to mammals. Several evolutionary conserved nutrient-sensing kinases are critical for efficient adaptation of yeast cells to glucose, nitrogen or phosphate depletion, subsequent cell-cycle exit and the regulation of autophagy. Here, we demonstrate that phosphate restriction results in a prominent extension of yeast lifespan that requires the coordinated activity of autophagy and the multivesicular body pathway, enabling efficient turnover of cytoplasmic and plasma membrane cargo. While the multivesicular body pathway was essential during the early days of aging, autophagy contributed to long-term survival at later days. The cyclin-dependent kinase Pho85 was critical for phosphate restriction-induced autophagy and full lifespan extension. In contrast, when cell-cycle exit was triggered by exhaustion of glucose instead of phosphate, Pho85 and its cyclin, Pho80, functioned as negative regulators of autophagy and lifespan. The storage of phosphate in form of polyphosphate was completely dispensable to in sustaining viability under phosphate restriction. Collectively, our results identify the multifunctional, nutrient-sensing kinase Pho85 as critical modulator of longevity that differentially coordinates the autophagic response to distinct kinds of starvation.

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  • 3.
    Ekhteraei-Tousi, Samaneh
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Lewerentz, Jacob
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Larsson, Jan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Painting of Fourth and the X-Linked 1.688 Satellite in D. melanogaster is Involved in Chromosome-Wide Gene Regulation2020In: Cells, E-ISSN 2073-4409, Vol. 9, no 2, article id 323Article in journal (Refereed)
    Abstract [en]

    Chromosome-specific regulatory mechanisms provide a model to understand the coordinated regulation of genes on entire chromosomes or on larger genomic regions. In fruit flies, two chromosome-wide systems have been characterized: The male-specific lethal (MSL) complex, which mediates dosage compensation and primarily acts on the male X-chromosome, and Painting of fourth (POF), which governs chromosome-specific regulation of genes located on the 4th chromosome. How targeting of one specific chromosome evolves is still not understood; but repeated sequences, in forms of satellites and transposable elements, are thought to facilitate the evolution of chromosome-specific targeting. The highly repetitive 1.688 satellite has been functionally connected to both these systems. Considering the rapid evolution and the necessarily constant adaptation of regulatory mechanisms, such as dosage compensation, we hypothesised that POF and/or 1.688 may still show traces of dosage-compensation functions. Here, we test this hypothesis by transcriptome analysis. We show that loss of Pof decreases not only chromosome 4 expression but also reduces the X-chromosome expression in males. The 1.688 repeat deletion, Zhr1(Zygotic hybrid rescue), does not affect male dosage compensation detectably; however, Zhr1 in females causes a stimulatory effect on X-linked genes with a strong binding affinity to the MSL complex (genes close to high-affinity sites). Lack of pericentromeric 1.688 also affected 1.688 expression in trans and was linked to the differential expression of genes involved in eggshell formation. We discuss our results with reference to the connections between POF, the 1.688 satellite and dosage compensation, and the role of the 1.688 satellite in hybrid lethality.

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  • 4.
    Ghannoum, Salim
    et al.
    Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
    Antos, Kamil
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Leoncio Netto, Waldir
    Oslo Centre for Biostatistics and Epidemiology, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Gomes, Cecil
    University of Arizona Cancer Center, University of Arizona, Tucson, United States.
    Köhn-Luque, Alvaro
    Oslo Centre for Biostatistics and Epidemiology, Faculty of Medicine, University of Oslo, Oslo, Norway.
    Farhan, Hesso
    Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Institute of Pathophysiology, Medical University of Innsbruck, Innsbruck, Austria.
    CellMAPtracer: A User-Friendly Tracking Tool for Long-Term Migratory and Proliferating Cells Associated with FUCCI Systems2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 2, article id 469Article in journal (Refereed)
    Abstract [en]

    Cell migration is a fundamental biological process of key importance in health and disease. Advances in imaging techniques have paved the way to monitor cell motility. An ever-growing collection of computational tools to track cells has improved our ability to analyze moving cells. One renowned goal in the field is to provide tools that track cell movement as comprehensively and automatically as possible. However, fully automated tracking over long intervals of time is challenged by dividing cells, thus calling for a combination of automated and supervised tracking. Furthermore, after the emergence of various experimental tools to monitor cell-cycle phases, it is of relevance to integrate the monitoring of cell-cycle phases and motility. We developed CellMAPtracer, a multiplatform tracking system that achieves that goal. It can be operated as a conventional, automated tracking tool of single cells in numerous imaging applications. However, CellMAPtracer also allows adjusting tracked cells in a semiautomated supervised fashion, thereby improving the accuracy and facilitating the long-term tracking of migratory and dividing cells. CellMAPtracer is available with a user-friendly graphical interface and does not require any coding or programming skills. CellMAPtracer is compatible with two- and three-color fluorescent ubiquitination-based cell-cycle indicator (FUCCI) systems and allows the user to accurately monitor various migration parameters throughout the cell cycle, thus having great potential to facilitate new discoveries in cell biology.

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  • 5.
    Günther, René
    et al.
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Dresden, Germany.
    Pal, Arun
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Dresden High Magnetic Field Laboratory (HLD), Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
    Williams, Chloe
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Zimyanin, Vitaly L.
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Department of Molecular Physiology and Biological Physics, University of Virginia, VA, Charlottesville, United States.
    Liehr, Maria
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.
    von Neubeck, Cläre
    German Cancer Consortium(DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay—National Center for Radiation Research in Oncology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Clinic for Particle Therapy, West German Proton Therapy Centre Essen (WPE) gGmbH, University Medical Centre of Essen, Essen, Germany.
    Krause, Mechthild
    German Cancer Consortium(DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany; OncoRay—National Center for Radiation Research in Oncology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden—Rossendorf, Institute of Radiooncology—OncoRay, Dresden, Germany; Department of Radiotherapy and Radiation Oncology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.
    Parab, Mrudula G.
    Department of Neurology, University Hospital Carl Gustav Carus Dresden, Technical University Dresden, Dresden, Germany.
    Petri, Susanne
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Kalmbach, Norman
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Sterneckert, Jared
    Center for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Wegner, Florian
    Department of Neurology, Hannover Medical School, Hannover, Germany.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Hermann, Andreas
    Translational Neurodegeneration Section, Albrecht-Kossel, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, Rostock, Germany.
    Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 7, article id 1246Article in journal (Refereed)
    Abstract [en]

    Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated SOD1 mutations (D90Ahom, R115Ghet or A4Vhet) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90Ahom MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115Ghet and A4Vhet mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS.

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  • 6.
    Han, Jing
    et al.
    Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
    Deng, Huan
    Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
    Lyu, Yizhen
    Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
    Xiao, Xiang
    Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
    Zhao, Yan
    Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
    Liu, Jiaxin
    Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
    Guo, Ziwei
    Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
    Liu, Xuan
    Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
    Qiao, Lichun
    Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Key Laboratory of Environment and Genes Related to Diseases, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
    Gao, Hang
    Laboratory of Resource Biology and Biotechnology in Western China (Ministry of Education), Provincial Key Laboratory of Biotechnology, College of Life Sciences, Northwest University, Xi'an 710069, China.
    Lammi, Mikko
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Department of Occupational and Environmental Health, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China.
    Identification of N-glycoproteins of knee cartilage from adult osteoarthritis and Kashin-Beck disease based on quantitative glycoproteomics, compared with normal control cartilage2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 16, p. 2513-2513, article id 36010590Article in journal (Refereed)
    Abstract [en]

    Glycoproteins are involved in the development of many diseases, while the type and content of N-glycoproteins in the cartilage of osteoarthritis (OA) and Kashin-Beck disease (KBD) are still unclear. This research aims to identify N-glycoproteins in knee cartilage patients with OA and KBD compared with normal control (N) adults. The cartilage samples were collected from gender- and age-matched OA (n = 9), KBD (n = 9) patients, and N (n = 9) adults. Glycoproteomics and label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) obtained N-glycoproteins of KBD and OA. A total of 594 N-glycoproteins and 1146 N-glycosylation peptides were identified. The identified data were further compared and analyzed with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interactions (PPI). Pairwise comparison of the glycoproteins detected in the three groups showed that integrin beta-1 (ITGB1), collagen alpha-1 (II) chain (COL2A1), collagen alpha-1 (VII) chain (COL7A1), carbohydrate sulfotransferase 3 (CHST-3), carbohydrate sulfotransferase 4 (CHST-4), thrombospondin 2 (THBS2), bone morphogenetic protein 8A (BMP8A), tenascin-C (TNC), lysosome-associated membrane protein (LAMP2), and beta-glucuronidase (GUSB) were significantly differentially expressed. GO results suggested N-glycoproteins mainly belonged to protein metabolic process, single-multicellular and multicellular organism process, cell adhesion, biological adhesion, and multicellular organism development. KEGG and PPI results revealed that key N-glycoproteins were closely related to pathways for OA and KBD, such as phagosome, ECM-receptor interaction, lysosome, focal adhesion, protein digestion, and absorption. These results reflected glycoprotein expression for OA and KBD in the process of ECM degradation, material transport, cell-cell or cell-ECM interaction, and information transduction. These key significantly differentially expressed N-glycoproteins and pathways lead to the degeneration and degradation of the cartilage of OA and KBD mainly by disrupting the synthesis and catabolism of basic components of ECM and chondrocytes and interfering with the transfer of material or information. The key N-glycoproteins or pathways in this research are potential targets for pathological mechanisms and therapies of OA and KBD.

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  • 7. Humphreys, Daniel
    et al.
    ElGhazaly, Mohamed
    Frisan, Teresa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Senescence and Host-Pathogen Interactions2020In: Cells, E-ISSN 2073-4409, Vol. 9, no 7, article id 1747Article, review/survey (Refereed)
    Abstract [en]

    Damage to our genomes triggers cellular senescence characterised by stable cell cycle arrest and a pro-inflammatory secretome that prevents the unrestricted growth of cells with pathological potential. In this way, senescence can be considered a powerful innate defence against cancer and viral infection. However, damage accumulated during ageing increases the number of senescent cells and this contributes to the chronic inflammation and deregulation of the immune function, which increases susceptibility to infectious disease in ageing organisms. Bacterial and viral pathogens are masters of exploiting weak points to establish infection and cause devastating diseases. This review considers the emerging importance of senescence in the host-pathogen interaction: we discuss the pathogen exploitation of ageing cells and senescence as a novel hijack target of bacterial pathogens that deploys senescence-inducing toxins to promote infection. The persistent induction of senescence by pathogens, mediated directly through virulence determinants or indirectly through inflammation and chronic infection, also contributes to age-related pathologies such as cancer. This review highlights the dichotomous role of senescence in infection: an innate defence that is exploited by pathogens to cause disease.

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  • 8.
    Hörnblad, Andreas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Remeseiro, Silvia
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Epigenetics, Enhancer Function and 3D Chromatin Organization in Reprogramming to Pluripotency2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 9, article id 1404Article, review/survey (Refereed)
    Abstract [en]

    Genome architecture, epigenetics and enhancer function control the fate and identity of cells. Reprogramming to induced pluripotent stem cells (iPSCs) changes the transcriptional profile and chromatin landscape of the starting somatic cell to that of the pluripotent cell in a stepwise manner. Changes in the regulatory networks are tightly regulated during normal embryonic development to determine cell fate, and similarly need to function in cell fate control during reprogramming. Switching off the somatic program and turning on the pluripotent program involves a dynamic reorganization of the epigenetic landscape, enhancer function, chromatin accessibility and 3D chromatin topology. Within this context, we will review here the current knowledge on the processes that control the establishment and maintenance of pluripotency during somatic cell reprogramming.

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  • 9.
    Jamshidi, Esmail
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Boström, Adrian Desai E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Wilczek, Alexander
    Department of Clinical Sciences, Karolinska Institutet at Danderyd Hospital, Stockholm, Sweden.
    Nilsonne, Åsa
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Åsberg, Marie
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Increased methylation of brain-derived neurotrophic factor (BDNF) is related to emotionally unstable personality disorder and severity of suicide attempt in women2023In: Cells, E-ISSN 2073-4409, Vol. 12, no 3, article id 350Article in journal (Refereed)
    Abstract [en]

    Brain-derived neurotrophic factor (BDNF) has previously been associated with the pathogenesis of both emotionally unstable personality disorder (EUPD) and suicidal behavior. No study has yet investigated BDNF-associated epigenetic alterations in a group of severely impaired EUPD and suicidal patients. The discovery cohort consisted of 97 women with emotionally unstable personality disorder (EUPD) with at least two serious suicide attempts (SAs) and 32 healthy female controls. The genome-wide methylation pattern was measured by the Illumina EPIC BeadChip and analyzed by robust linear regression models to investigate mean BDNF methylation levels in a targeted analysis conditioned upon severity of suicide attempt. The validation cohort encompassed 60 female suicide attempters, stratified into low- (n = 45) and high-risk groups (n = 15) based on degree of intent-to-die and lethality of SA method, and occurrence of death-by-suicide at follow-up. Mean BDNF methylation levels exhibited increased methylation in relation to EUPD (p = 0.0159, percentage mean group difference ~3.8%). Similarly, this locus was confirmed as higher-methylated in an independent cohort of females with severe suicidal behavior (p = 0.0300). Results were independent of age and BMI. This is the first study to reveal emerging evidence of epigenetic dysregulation of BDNF with dependence on features known to confer increased risk of suicide deaths (lethality of suicide-attempt method and presence of EUPD diagnosis with history of recent SAs). Further studies investigating epigenetic and genetic effects of BDNF on severe suicidal behavior and EUPD are needed to further elucidate the role of epigenetic regulatory mechanisms and neurotrophic factors in relation to suicide and EUPD, and hold potential to result in novel treatment methods.

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  • 10.
    Johansson, Emil
    et al.
    Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Kerkman, Priscilla
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands.
    Scharf, Lydia
    Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
    Lindman, Jacob
    Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
    Szojka, Zsófia I.
    Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Månsson, Fredrik
    Department of Translational Medicine, Lund University, Malmö, Sweden.
    Biague, Antonio
    National Laboratory for Public Health, Bissau, Guinea-Bissau.
    Medstrand, Patrik
    Department of Translational Medicine, Lund University, Malmö, Sweden.
    Norrgren, Hans
    Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
    Buggert, Marcus
    Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Karlsson, Annika C.
    Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
    Forsell, Mattias N. E.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Esbjörnsson, Joakim
    Department of Translational Medicine, Lund University, Malmö, Sweden; Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
    Jansson, Marianne
    Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Hierarchical Clustering and Trajectory Analyses Reveal Viremia-Independent B-Cell Perturbations in HIV-2 Infection2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 19, article id 3142Article in journal (Refereed)
    Abstract [en]

    Time to AIDS in HIV-2 infection is approximately twice as long compared to in HIV-1 infection. Despite reduced viremia, HIV-2-infected individuals display signs of chronic immune activation. In HIV-1-infected individuals, B-cell hyperactivation is driven by continuous antigen exposure. However, the contribution of viremia to B-cell perturbations in HIV-2-infected individuals remains largely unexplored. Here, we used polychromatic flow cytometry, consensus hierarchical clustering and pseudotime trajectory inference to characterize B-cells in HIV-1- or HIV-2-infected and in HIV seronegative individuals. We observed increased frequencies of clusters containing hyperactivated T-bethighCD95highCD27int and proliferating T-bet+CD95highCD27+CD71+ memory B-cells in viremic HIV-1 (p < 0.001 and p < 0.001, respectively), viremic HIV-2 (p < 0.001 and p = 0.014, respectively) and in treatment-naïve aviremic HIV-2 (p = 0.004 and p = 0.020, respectively)-infected individuals, compared to seronegative individuals. In contrast, these expansions were not observed in successfully treated HIV-1-infected individuals. Finally, pseudotime trajectory inference showed that T-bet-expressing hyperactivated and proliferating memory B-cell populations were located at the terminal end of two trajectories, in both HIV-1 and HIV-2 infections. As the treatment-naïve aviremic HIV-2-infected individuals, but not the successfully ART-treated HIV-1-infected individuals, showed B-cell perturbations, our data suggest that aviremic HIV-2-infected individuals would also benefit from antiretroviral treatment.

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  • 11. Kamran, Muhammad
    et al.
    Imran, Qari Muhammad
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Laboratory of Plant Molecular Pathology and Functional Genomics, Division of Plant Biosciences, College of Agriculture and Life Science, Kyungpook National University, Daegu, South Korea.
    Ahmed, Muhammad Bilal
    Falak, Noreen
    Khatoon, Amna
    Yun, Byung-Wook
    Endophyte-mediated stress tolerance in plants: a sustainable strategy to enhance resilience and assist crop improvement2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 20, article id 3292Article, review/survey (Refereed)
    Abstract [en]

    Biotic and abiotic stresses severely affect agriculture by affecting crop productivity, soil fertility, and health. These stresses may have significant financial repercussions, necessitating a practical, cost-effective, and ecologically friendly approach to lessen their negative impacts on plants. Several agrochemicals, such as fertilizers, pesticides, and insecticides, are used to improve plant health and protection; however, these chemical supplements have serious implications for human health. Plants being sessile cannot move or escape to avoid stress. Therefore, they have evolved to develop highly beneficial interactions with endophytes. The targeted use of beneficial plant endophytes and their role in combating biotic and abiotic stresses are gaining attention. Therefore, it is important to experimentally validate these interactions and determine how they affect plant fitness. This review highlights research that sheds light on how endophytes help plants tolerate biotic and abiotic stresses through plant–symbiont and plant–microbiota interactions. There is a great need to focus research efforts on this vital area to achieve a system-level understanding of plant–microbe interactions that occur naturally.

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  • 12. Kirui, Jared
    et al.
    Abidine, Yara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Centre for Experimental and Clinical Infection Research, TWINCORE, Institute for Experimental Virology, a Joint Venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany.
    Islam, Md. Koushikul
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Yong-Dae, Gwon
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lasswitz, Lisa
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    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).
    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. Centre for Experimental and Clinical Infection Research, TWINCORE, Institute for Experimental Virology, a Joint Venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 7, article id 1828Article in journal (Refereed)
    Abstract [en]

    Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood. The phosphatidylserine-dependent receptors, T-cell immunoglobulin and mucin domain 1 (TIM-1) and Axl receptor tyrosine kinase (Axl), are transmembrane proteins that can serve as entry factors for enveloped viruses. Previous studies used pseudoviruses to delineate the role of TIM-1 and Axl in CHIKV entry. Conversely, here, we use the authentic CHIKV and cells ectopically expressing TIM-1 or Axl and demonstrate a role for TIM-1 in CHIKV infection. To further characterize TIM-1-dependent CHIKV infection, we generated cells expressing domain mutants of TIM-1. We show that point mutations in the phosphatidylserine binding site of TIM-1 lead to reduced cell binding, entry, and infection of CHIKV. Ectopic expression of TIM-1 renders immortalized keratinocytes permissive to CHIKV, whereas silencing of endogenously expressed TIM-1 in human hepatoma cells reduces CHIKV infection. Altogether, our findings indicate that, unlike Axl, TIM-1 readily promotes the productive entry of authentic CHIKV into target cells.

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  • 13.
    Kohler, Verena
    et al.
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
    Kohler, Andreas
    Büttner, Sabrina
    Closing the gap: membrane contact sites in the regulation of autophagy2020In: Cells, E-ISSN 2073-4409, Vol. 9, no 5, p. 1184-1184Article, review/survey (Refereed)
    Abstract [en]

    In all eukaryotic cells, intracellular organization and spatial separation of incompatible biochemical processes is established by individual cellular subcompartments in form of membrane-bound organelles. Virtually all of these organelles are physically connected via membrane contact sites (MCS), allowing interorganellar communication and a functional integration of cellular processes. These MCS coordinate the exchange of diverse metabolites and serve as hubs for lipid synthesis and trafficking. While this of course indirectly impacts on a plethora of biological functions, including autophagy, accumulating evidence shows that MCS can also directly regulate autophagic processes. Here, we focus on the nexus between interorganellar contacts and autophagy in yeast and mammalian cells, highlighting similarities and differences. We discuss MCS connecting the ER to mitochondria or the plasma membrane, crucial for early steps of both selective and non-selective autophagy, the yeast-specific nuclear–vacuolar tethering system and its role in microautophagy, the emerging function of distinct autophagy-related proteins in organellar tethering as well as novel MCS transiently emanating from the growing phagophore and mature autophagosome.

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  • 14. Kowald, Saskia
    et al.
    Huge, Ylva
    Tandiono, Decky
    Ali, Zaheer
    Vazquez-Rodriguez, Gabriela
    Erkstam, Anna
    Fahlgren, Anna
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Biomedical and Clinical Sciences, Division of Urology, Linköping University, Linköping, Sweden.
    Cao, Yihai
    Jensen, Lasse D.
    Novel zebrafish patient-derived tumor xenograft methodology for evaluating efficacy of immune-stimulating bcg therapy in urinary bladder cancer2023In: Cells, E-ISSN 2073-4409, Vol. 12, no 3, article id 508Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bacillus Calmette-Guérin (BCG) immunotherapy is the standard-of-care adjuvant therapy for non-muscle-invasive bladder cancer in patients at considerable risk of disease recurrence. Although its exact mechanism of action is unknown, BCG significantly reduces this risk in responding patients but is mainly associated with toxic side-effects in those facing treatment resistance. Methods that allow the identification of BCG responders are, therefore, urgently needed.

    METHODS: Fluorescently labelled UM-UC-3 cells and dissociated patient tumor samples were used to establish zebrafish tumor xenograft (ZTX) models. Changes in the relative primary tumor size and cell dissemination to the tail were evaluated via fluorescence microscopy at three days post-implantation. The data were compared to the treatment outcomes of the corresponding patients. Toxicity was evaluated based on gross morphological evaluation of the treated zebrafish larvae.

    RESULTS: BCG-induced toxicity was avoided by removing the water-soluble fraction of the BCG formulation prior to use. BCG treatment via co-injection with the tumor cells resulted in significant and dose-dependent primary tumor size regression. Heat-inactivation of BCG decreased this effect, while intravenous BCG injections were ineffective. ZTX models were successfully established for six of six patients based on TUR-B biopsies. In two of these models, significant tumor regression was observed, which, in both cases, corresponded to the treatment response in the patients.

    CONCLUSIONS: The observed BCG-related anti-tumor effect indicates that ZTX models might predict the BCG response and thereby improve treatment planning. More experiments and clinical studies are needed, however, to elucidate the BCG mechanism and estimate the predictive value.

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  • 15.
    Kurek, Magdalena
    et al.
    NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, 171 64 Solna, Sweden.
    Åkesson, Elisabet
    Division of Neurogeriatrics, Department of Neurobiology Care Sciences & Society, Karolinska Institutet, Huddinge, Sweden; R & D Unit, Stockholms Sjukhem, 112 19 Stockholm, Sweden.
    Yoshihara, Masahito
    Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
    Oliver, Elizabeth
    NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, 171 64 Solna, Sweden.
    Cui, Yanhua
    NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, 171 64 Solna, Sweden.
    Becker, Martin
    Center of Neurodevelopmental Disorders (KIND), Department of Women's and Children's Health, Karolinska Institutet, Centre for Psychiatry Research, Region Stockholm and Astrid Lindgren Children's Hospital, Karolinska University Hospital, 171 64 Solna, Sweden.
    Alves-Lopes, João Pedro
    NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, 171 64 Solna, Sweden.
    Bjarnason, Ragnar
    Children's Medical Center, Landspítali University Hospital, Reykjavik, Iceland; Department of Paediatrics Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
    Romerius, Patrik
    Department of Paediatric Oncology and Haematology, Clinical Sciences, Lund University, Skånes Universitetssjukhus, Lund, Sweden.
    Sundin, Mikael
    Division of Paediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Sweden; Pediatric Blood Disorders, Immunodeficiency and Stem Cell Transplantation Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Huddinge, Sweden.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Langenskiöld, Cecilia
    Department of Paediatric Oncology, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Vogt, Hartmut
    Crown Princess Victoria's Child and Youth Hospital, Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden.
    Henningsohn, Lars
    Division of Urology, Institution for Clinical Science Intervention and Technology, Karolinska Institutet, Huddinge, Sweden.
    Petersen, Cecilia
    NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, 171 64 Solna, Sweden.
    Söder, Olle
    NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, 171 64 Solna, Sweden.
    Guo, Jingtao
    Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, United States.
    Mitchell, Rod T.
    MRC Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; Edinburgh Royal Hospital for Sick Children, Edinburgh, United Kingdom.
    Jahnukainen, Kirsi
    NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, 171 64 Solna, Sweden; Division of Haematology-Oncology and Stem Cell Transplantation, Children's Hospital, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
    Stukenborg, Jan-Bernd
    NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, 171 64 Solna, Sweden.
    Spermatogonia Loss Correlates with LAMA 1 Expression in Human Prepubertal Testes Stored for Fertility Preservation2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 2Article in journal (Refereed)
    Abstract [en]

    Fertility preservation for male childhood cancer survivors not yet capable of producing mature spermatozoa, relies on experimental approaches such as testicular explant culture. Although the first steps in somatic maturation can be observed in human testicular explant cultures, germ cell depletion is a common obstacle. Hence, understanding the spermatogonial stem cell (SSC) niche environment and in particular, specific components such as the seminiferous basement membrane (BM) will allow progression of testicular explant cultures. Here, we revealed that the seminiferous BM is established from 6 weeks post conception with the expression of laminin alpha 1 (LAMA 1) and type IV collagen, which persist as key components throughout development. With prepubertal testicular explant culture we found that seminiferous LAMA 1 expression is disrupted and depleted with culture time correlating with germ cell loss. These findings highlight the importance of LAMA 1 for the human SSC niche and its sensitivity to culture conditions.

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  • 16.
    Lorén, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Dahl, Christen P.
    Do, Lan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Almaas, Vibeke M.
    Geiran, Odd R.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Low Molecular Mass Myocardial Hyaluronan in Human Hypertrophic Cardiomyopathy2019In: Cells, E-ISSN 2073-4409, Vol. 8, no 2, article id 97Article in journal (Refereed)
    Abstract [en]

    During the development of hypertrophic cardiomyopathy, the heart returns to fetal energy metabolism where cells utilize more glucose instead of fatty acids as a source of energy. Metabolism of glucose can increase synthesis of the extracellular glycosaminoglycan hyaluronan, which has been shown to be involved in the development of cardiac hypertrophy and fibrosis. The aim of this study was to investigate hyaluronan metabolism in cardiac tissue from patients with hypertrophic cardiomyopathy in relation to cardiac growth. NMR and qRT-PCR analysis of human cardiac tissue from hypertrophic cardiomyopathy patients and healthy control hearts showed dysregulated glucose and hyaluronan metabolism in the patients. Gas phase electrophoresis revealed a higher amount of low molecular mass hyaluronan and larger cardiomyocytes in cardiac tissue from patients with hypertrophic cardiomyopathy. Histochemistry showed high concentrations of hyaluronan around individual cardiomyocytes in hearts from hypertrophic cardiomyopathy patients. Experimentally, we could also observe accumulation of low molecular mass hyaluronan in cardiac hypertrophy in a rat model. In conclusion, the development of hypertrophic cardiomyopathy with increased glucose metabolism affected both hyaluronan molecular mass and amount. The process of regulating cardiomyocyte size seems to involve fragmentation of hyaluronan.

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  • 17.
    Martinez-Gamero, Carlos
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Malla, Sandhya
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Aguilo, Francesca
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    LSD1: Expanding functions in stem cells and differentiation2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 11, article id 3252Article, review/survey (Refereed)
    Abstract [en]

    Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSC) provide a powerful model system to uncover fundamental mechanisms that control cellular identity during mammalian development. Histone methylation governs gene expression programs that play a key role in the regulation of the balance between self-renewal and differentiation of ESCs. Lysine-specific deme-thylase 1 (LSD1, also known as KDM1A), the first identified histone lysine demethylase, demethyl-ates H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner. Moreover, it has also been shown to demethylate non-histone substrates playing a central role in the regulation of nu-merous cellular processes. In this review, we summarize current knowledge about LSD1 and the molecular mechanism by which LSD1 influences the stem cells state, including the regulatory cir-cuitry underlying self-renewal and pluripotency.

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  • 18.
    Moustogiannis, Athanasios
    et al.
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Micras Asias, Athens, Greece.
    Philippou, Anastassios
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Micras Asias, Athens, Greece.
    Zevolis, Evangelos
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Micras Asias, Athens, Greece.
    Taso, Orjona S.
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Micras Asias, Athens, Greece; School of Biological Sciences, Deanery of Biomedical Sciences, Centre for Discovery Brain Sciences, Edinburgh, United Kingdom.
    Giannopoulos, Antonios
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Chatzigeorgiou, Antonios
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Micras Asias, Athens, Greece.
    Koutsilieris, Michael
    Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Micras Asias, Athens, Greece.
    Effect of mechanical loading of senescent myoblasts on their myogenic lineage progression and survival2022In: Cells, E-ISSN 2073-4409, Vol. 11, no 24, article id 3979Article in journal (Refereed)
    Abstract [en]

    Background: During aging, muscle cell apoptosis increases and myogenesis gradually declines. The impaired myogenic and survival potential of the aged skeletal muscle can be ameliorated by its mechanical loading. However, the molecular responses of aged muscle cells to mechanical loading remain unclear. This study examined the effect of mechanical loading of aged, proliferating, and differentiated myoblasts on the gene expression and signaling responses associated with their myogenic lineage progression and survival. Methods: Control and aged C2C12 cells were cultured on elastic membranes and underwent passive stretching for 12 h at a low frequency (0.25 Hz) and different elongations, varying the strain on days 0 and 10 of myoblast differentiation. Activation of ERK1/2 and Akt, and the expression of focal adhesion kinase (FAK) and key myogenic regulatory factors (MRFs), MyoD and Myogenin, were determined by immunoblotting of the cell lysates derived from stretched and non-stretched myoblasts. Changes in the expression levels of the MRFs, muscle growth, atrophy, and pro-apoptotic factors in response to mechanical loading of the aged and control cells were quantified by real-time qRT-PCR. Results: Mechanical stretching applied on myoblasts resulted in the upregulation of FAK both in proliferating (day 0) and differentiated (day 10) cells, as well as in increased phosphorylation of ERK1/2 in both control and aged cells. Moreover, Akt activation and the expression of early differentiation factor MyoD increased significantly after stretching only in the control myoblasts, while the late differentiation factor Myogenin was upregulated in both the control and aged myoblasts. At the transcriptional level, mechanical loading of the proliferating myoblasts led to an increased expression of IGF-1 isoforms and MRFs, and to downregulation of muscle atrophy factors mainly in control cells, as well as in the upregulation of pro-apoptotic factors both in control and aged cells. In differentiated cells, mechanical loading resulted in an increased expression of the IGF-1Ea isoform and Myogenin, and in the downregulation of atrophy and pro-apoptotic factors in both the control and aged cells. Conclusions: This study revealed a diminished beneficial effect of mechanical loading on the myogenic and survival ability of the senescent muscle cells compared with the controls, with a low strain (2%) loading being most effective in upregulating myogenic/anabolic factors and downregulating atrophy and pro-apoptotic genes mainly in the aged myotubes.

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  • 19.
    Nicolay, Wiebke
    et al.
    TWINCORE—Centre for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Moeller, Rebecca
    TWINCORE—Centre for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany; Center for Emerging Infections and Zoonoses (RIZ), Institute of Biochemistry & Research, University of Veterinary Medicine Hannover, Hannover, Germany.
    Kahl, Sina
    TWINCORE—Centre for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Vondran, Florian W. R.
    Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany; German Centre for Infection Research (DZIF), Braunschweig, Germany.
    Pietschmann, Thomas
    TWINCORE—Centre for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany.
    Kunz, Stefan
    Institute of Microbiology, Lausanne University Hospital, Lausanne, Switzerland.
    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—Centre for Experimental and Clinical Infection Research, Institute for Experimental Virology, Hannover, Germany; Center for Emerging Infections and Zoonoses (RIZ), Institute of Biochemistry & Research, University of Veterinary Medicine Hannover, Hannover, Germany.
    Characterization of rna sensing pathways in hepatoma cell lines and primary human hepatocytes2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 11, article id 3019Article in journal (Refereed)
    Abstract [en]

    The liver is targeted by several human pathogenic RNA viruses for viral replication and dissemination; despite this, the extent of innate immune sensing of RNA viruses by human hepatocytes is insufficiently understood to date. In particular, for highly human tropic viruses such as hepatitis C virus, cell culture models are needed to study immune sensing. However, several human hepatoma cell lines have impaired RNA sensing pathways and fail to mimic innate immune responses in the human liver. Here we compare the RNA sensing properties of six human hepatoma cell lines, namely Huh-6, Huh-7, HepG2, HepG2-HFL, Hep3B, and HepaRG, with primary human hepatocytes. We show that primary liver cells sense RNA through retinoic acid-inducible gene I (RIG-I) like receptor (RLR) and Toll-like receptor 3 (TLR3) pathways. Of the tested cell lines, Hep3B cells most closely mimicked the RLR and TLR3 mediated sensing in primary hepatocytes. This was shown by the expression of RLRs and TLR3 as well as the expression and release of bioactive interferon in primary hepatocytes and Hep3B cells. Our work shows that Hep3B cells partially mimic RNA sensing in primary hepatocytes and thus can serve as in vitro model to study innate immunity to RNA viruses in hepatocytes.

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  • 20. Ouasti, Sihem
    et al.
    Faroni, Alessandro
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Blond McIndoe Laboratories, Division of Cell Matrix Biology and Regenerative Medicine, School ofBiological Sciences, Faculty of Biology Medicine and Health, University of Manchester, ManchesterAcademic Health Science Centre, Manchester, UK.
    Ghibaudi, Matilde
    Reid, Adam J.
    Tirelli, Nicola
    Hyaluronic Acid (HA) Receptors and the Motility of Schwann Cell(-Like) Phenotypes2020In: Cells, E-ISSN 2073-4409, Vol. 9, no 6, article id 1477Article in journal (Refereed)
    Abstract [en]

    The cluster of differentiation 44 (CD44) and the hyaluronan-mediated motility receptor (RHAMM), also known as CD168, are perhaps the most studied receptors for hyaluronic acid (HA); among their various functions, both are known to play a role in the motility of a number of cell types. In peripheral nerve regeneration, the stimulation of glial cell motility has potential to lead to better therapeutic outcomes, thus this study aimed to ascertain the presence of these receptors in Schwann cells (rat adult aSCs and neonatal nSCs) and to confirm their influence on motility. We included also a Schwann-like phenotype (dAD-MSCs) derived from adipose-derived mesenchymal stem cells (uAD-MSCs), as a possible basis for an autologous cell therapy. CD44 was expressed similarly in all cell types. Interestingly, uAD-MSCs were RHAMM(low), whereas both Schwann cells and dASCs turned out to be similarly RHAMM(high), and indeed antibody blockage of RHAMM effectively immobilized (in vitro scratch wound assay) all the RHAMM(high) Schwann(-like) types, but not the RHAMM(low) uAD-MSCs. Blocking CD44, on the other hand, affected considerably more uAD-MSCs than the Schwann(-like) cells, while the combined blockage of the two receptors immobilized all cells. The results therefore indicate that Schwann-like cells have a specifically RHAMM-sensitive motility, where the motility of precursor cells such as uAD-MSCs is CD44- but not RHAMM-sensitive; our data also suggest that CD44 and RHAMM may be using complementary motility-controlling circuits.

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  • 21.
    Seyfferth, Carolin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Wessels, Bernard
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Vahala, Jorma
    Kangasjärvi, Jaakko
    Delhomme, Nicolas
    Hvidsten, Torgeir R.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway.
    Tuominen, Hannele
    Lundberg-Felten, Judith
    PopulusPtERF85 Balances Xylem Cell Expansion and Secondary Cell Wall Formation in Hybrid Aspen2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 8, article id 1971Article in journal (Refereed)
    Abstract [en]

    Secondary growth relies on precise and specialized transcriptional networks that determine cell division, differentiation, and maturation of xylem cells. We identified a novel role for the ethylene-induced Populus Ethylene Response Factor PtERF85 (Potri.015G023200) in balancing xylem cell expansion and secondary cell wall (SCW) formation in hybrid aspen (Populus tremula x tremuloides). Expression of PtERF85 is high in phloem and cambium cells and during the expansion of xylem cells, while it is low in maturing xylem tissue. Extending PtERF85 expression into SCW forming zones of woody tissues through ectopic expression reduced wood density and SCW thickness of xylem fibers but increased fiber diameter. Xylem transcriptomes from the transgenic trees revealed transcriptional induction of genes involved in cell expansion, translation, and growth. The expression of genes associated with plant vascular development and the biosynthesis of SCW chemical components such as xylan and lignin, was down-regulated in the transgenic trees. Our results suggest that PtERF85 activates genes related to xylem cell expansion, while preventing transcriptional activation of genes related to SCW formation. The importance of precise spatial expression of PtERF85 during wood development together with the observed phenotypes in response to ectopic PtERF85 expression suggests that PtERF85 contributes to the transition of fiber cells from elongation to secondary cell wall deposition.

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  • 22.
    Sharafutdinov, Irshad
    et al.
    Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, Erlangen, Germany.
    Tegtmeyer, Nicole
    Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, Erlangen, Germany.
    Rohde, Manfred
    Central Facility for Microscopy, Helmholtz Centre for Infection Research, Inhoffenstraße 7, Braunschweig, Germany.
    Olofsson, Annelie
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ur Rehman, Zia
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Arnqvist, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Backert, Steffen
    Department of Biology, Division of Microbiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Staudtstr. 5, Erlangen, Germany.
    Campylobacter jejuni surface-bound protease HtrA, but not the secreted protease nor protease in shed membrane vesicles, disrupts epithelial cell-to-cell junctions2024In: Cells, E-ISSN 2073-4409, Vol. 13, no 3, article id 224Article in journal (Refereed)
    Abstract [en]

    Fundamental functions of the intestinal epithelium include the digestion of food, absorption of nutrients, and its ability to act as the first barrier against intruding microbes. Campylobacter jejuni is a major zoonotic pathogen accounting for a substantial portion of bacterial foodborne illnesses. The germ colonizes the intestines of birds and is mainly transmitted to humans through the consumption of contaminated poultry meat. In the human gastrointestinal tract, the bacterium triggers campylobacteriosis that can progress to serious secondary disorders, including reactive arthritis, inflammatory bowel disease and Guillain–Barré syndrome. We recently discovered that C. jejuni serine protease HtrA disrupts intestinal epithelial barrier functions via cleavage of the tight and adherens junction components occludin, claudin-8 and E-cadherin. However, it is unknown whether epithelial damage is mediated by the secreted soluble enzyme, by HtrA contained in shed outer-membrane vesicles (OMVs) or by another mechanism that has yet to be identified. In the present study, we investigated whether soluble recombinant HtrA and/or purified OMVs induce junctional damage to polarized intestinal epithelial cells compared to live C. jejuni bacteria. By using electron and confocal immunofluorescence microscopy, we show that HtrA-expressing C. jejuni bacteria trigger efficient junctional cell damage, but not soluble purified HtrA or HtrA-containing OMVs, not even at high concentrations far exceeding physiological levels. Instead, we found that only bacteria with active protein biosynthesis effectively cleave junctional proteins, which is followed by paracellular transmigration of C. jejuni through the epithelial cell layer. These findings shed new light on the pathogenic activities of HtrA and virulence strategies of C. jejuni.

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  • 23.
    Song, Inseon
    et al.
    Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
    Kuznetsova, Tatiana
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Baidoe-Ansah, David
    Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
    Mirzapourdelavar, Hadi
    Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
    Senkov, Oleg
    Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
    Hayani, Hussam
    Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
    Mironov, Andrey
    Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
    Kaushik, Rahul
    Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
    Druzin, Michael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Johansson, Staffan
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Dityatev, Alexander
    Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany; Medizinische Fakultät, Otto-von-Güricke-Universität Magdeburg, Magdeburg, Germany; Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany.
    Heparan sulfates regulate axonal excitability and context generalization through CA2+/Calmodulin-dependent protein kinase II2023In: Cells, E-ISSN 2073-4409, Vol. 12, no 5, article id 744Article in journal (Refereed)
    Abstract [en]

    Our previous studies demonstrated that enzymatic removal of highly sulfated heparan sulfates with heparinase 1 impaired axonal excitability and reduced expression of ankyrin G at the axon initial segments in the CA1 region of the hippocampus ex vivo, impaired context discrimination in vivo, and increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity in vitro. Here, we show that in vivo delivery of heparinase 1 in the CA1 region of the hippocampus elevated autophosphorylation of CaMKII 24 h after injection in mice. Patch clamp recording in CA1 neurons revealed no significant heparinase effects on the amplitude or frequency of miniature excitatory and inhibitory postsynaptic currents, while the threshold for action potential generation was increased and fewer spikes were generated in response to current injection. Delivery of heparinase on the next day after contextual fear conditioning induced context overgeneralization 24 h after injection. Co-administration of heparinase with the CaMKII inhibitor (autocamtide-2-related inhibitory peptide) rescued neuronal excitability and expression of ankyrin G at the axon initial segment. It also restored context discrimination, suggesting the key role of CaMKII in neuronal signaling downstream of heparan sulfate proteoglycans and highlighting a link between impaired CA1 pyramidal cell excitability and context generalization during recall of contextual memories.

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  • 24.
    Zapatero-Belinchón, Francisco J.
    et al.
    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. Centre for Experimental and Clinical Infection Research, Institute for Experimental Virology, TWINCORE, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Institute of Molecular Biology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Braunschweig, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Ötjengerdes, Rina
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Institute of Molecular Biology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig site, Braunschweig, Germany.
    Sheldon, Julie
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.
    Schulte, Benjamin
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig site, Braunschweig, Germany.
    Carriquí-Madroñal, Belén
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Brogden, Graham
    Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Arroyo-Fernández, Laura M.
    Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Vondran, Florian W. R.
    German Center for Infection Research (DZIF), Hannover-Braunschweig site, Braunschweig, Germany; Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
    Maasoumy, Benjamin
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig site, Braunschweig, Germany.
    von Hahn, Thomas
    Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Department of Gastroenterology, Hepatology and Interventional Endoscopy, Asklepios Hospital Barmbek, Semmelweis University, Campus Hamburg, Hamburg, Germany.
    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. Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany; Department of Biochemistry & Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
    Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 7Article in journal (Refereed)
    Abstract [en]

    The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very‑low-density lipoprotein (VLDL) secretory pathway. Hence, medications that interfere with the lipid metabolism of the cell, such as statins, may affect HCV infection. Here, we study the interplay between lipoprotein receptors, lipid homeostasis, and HCV infection by genetic and pharmacological interventions. We found that individual ablation of the lipoprotein receptors SR‑B1 and LDLr did not drastically affect HCV entry, replication, or infection, but double lipoprotein receptor knock-outs significantly reduced HCV infection. Furthermore, we could show that this effect was neither due to altered expression of additional HCV entry factors nor caused by changes in cellular cholesterol content. Strikingly, whereas lipid‑lowering drugs such as simvastatin or fenofibrate did not affect HCV entry or infection of immortalized hepatoma cells expressing SR-B1 and/or LDLr or primary human hepatocytes, ablation of these receptors rendered cells more susceptible to these drugs. Finally, we observed no significant differences between statin users and control groups with regards to HCV viral load in a cohort of HCV infected patients before and during HCV antiviral treatment. Interestingly, statin treatment, which blocks the mevalonate pathway leading to decreased cholesterol levels, was associated with mild but appreciable lower levels of liver damage markers before HCV therapy. Overall, our findings confirm the role of lipid homeostasis in HCV infection and highlight the importance of the mevalonate pathway in the HCV replication cycle.

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  • 25.
    Zimyanin, Vitaly L.
    et al.
    Department of Molecular Physiology and Biological Physics, School of Medicine, University of Virginia, VA, Charlottesville, United States; Center for Membrane and Cell Physiology, School of Medicine, University of Virginia, VA, Charlottesville, United States; Department of Neurology, Technische Universität Dresden, Dresden, Germany.
    Pielka, Anna-Maria
    Translational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.
    Glaß, Hannes
    Translational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.
    Japtok, Julia
    Department of Neurology, Technische Universität Dresden, Dresden, Germany.
    Großmann, Dajana
    Translational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.
    Martin, Melanie
    Institute of Physiology, Technische Universität Dresden, Dresden, Germany.
    Deussen, Andreas
    Institute of Physiology, Technische Universität Dresden, Dresden, Germany.
    Szewczyk, Barbara
    Translational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany.
    Deppmann, Chris
    Department of Biology, Graduate School of Arts and Sciences, University of Virginia, VA, Charlottesville, United States.
    Zunder, Eli
    Department of Biomedical Engineering, School of Medicine, University of Virginia, VA, Charlottesville, United States.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.
    Boeckers, Tobias M.
    Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ulm Site, Ulm, Germany; Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.
    Sterneckert, Jared
    Centre for Regenerative Therapie, Technische Universität Dresden, Dresden, Germany; Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
    Redemann, Stefanie
    Department of Molecular Physiology and Biological Physics, School of Medicine, University of Virginia, VA, Charlottesville, United States; Center for Membrane and Cell Physiology, School of Medicine, University of Virginia, VA, Charlottesville, United States; Department of Cell Biology, School of Medicine, University of Virginia, VA, Charlottesville, United States.
    Storch, Alexander
    Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Centre, University of Rostock, Rostock, Germany; Department of Neurology, University of Rostock, Rostock, Germany.
    Hermann, Andreas
    Translational Neurodegeneration Section, “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, University of Rostock, Rostock, Germany; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) Rostock/Greifswald, Rostock, Germany; Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Centre, University of Rostock, Rostock, Germany.
    Live cell imaging of ATP levels reveals metabolic compartmentalization within motoneurons and early metabolic changes in FUS ALS motoneurons2023In: Cells, E-ISSN 2073-4409, Vol. 12, no 10, article id 1352Article in journal (Refereed)
    Abstract [en]

    Motoneurons are one of the most energy-demanding cell types and a primary target in Amyotrophic lateral sclerosis (ALS), a debilitating and lethal neurodegenerative disorder without currently available effective treatments. Disruption of mitochondrial ultrastructure, transport, and metabolism is a commonly reported phenotype in ALS models and can critically affect survival and the proper function of motor neurons. However, how changes in metabolic rates contribute to ALS progression is not fully understood yet. Here, we utilize hiPCS-derived motoneuron cultures and live imaging quantitative techniques to evaluate metabolic rates in fused in sarcoma (FUS)-ALS model cells. We show that differentiation and maturation of motoneurons are accompanied by an overall upregulation of mitochondrial components and a significant increase in metabolic rates that correspond to their high energy-demanding state. Detailed compartment-specific live measurements using a fluorescent ATP sensor and FLIM imaging show significantly lower levels of ATP in the somas of cells carrying FUS-ALS mutations. These changes lead to the increased vulnerability of diseased motoneurons to further metabolic challenges with mitochondrial inhibitors and could be due to the disruption of mitochondrial inner membrane integrity and an increase in its proton leakage. Furthermore, our measurements demonstrate heterogeneity between axonal and somatic compartments, with lower relative levels of ATP in axons. Our observations strongly support the hypothesis that mutated FUS impacts the metabolic states of motoneurons and makes them more susceptible to further neurodegenerative mechanisms.

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