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  • 1.
    Chotiwan, Nunya
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Willekens, Stefanie M. A.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Schexnaydre, Erin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lindquist, Richard
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Hahn, Max
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mihai, Ionut Sebastian
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Zhang, Jianguo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ebel, Gregory D.
    Department of Microbiology, Immunology and Pathology, Colorado State University, CO, Fort Collins, United States.
    Carlson, Lars-Anders
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Marcellino, Daniel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Type I interferon shapes brain distribution and tropism of tick-borne flavivirus2023In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 2007Article in journal (Refereed)
    Abstract [en]

    Viral tropism within the brain and the role(s) of vertebrate immune response to neurotropic flaviviruses infection is largely understudied. We combine multimodal imaging (cm-nm scale) with single nuclei RNA-sequencing to study Langat virus in wildtype and interferon alpha/beta receptor knockout (Ifnar-/-) mice to visualize viral pathogenesis and define molecular mechanisms. Whole brain viral infection is imaged by Optical Projection Tomography coregistered to ex vivo MRI. Infection is limited to grey matter of sensory systems in wildtype mice, but extends into white matter, meninges and choroid plexus in Ifnar-/- mice. Cells in wildtype display strong type I and II IFN responses, likely due to Ifnb expressing astrocytes, infiltration of macrophages and Ifng-expressing CD8+ NK cells, whereas in Ifnar-/-, the absence of this response contributes to a shift in cellular tropism towards non-activated resident microglia. Multimodal imaging-transcriptomics exemplifies a powerful way to characterize mechanisms of viral pathogenesis and tropism.

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  • 2.
    Mihai, Ionut Sebastian
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Chafle, Sarang
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Representing and extracting knowledge from single-cell data2023In: Biophysical Reviews, ISSN 1867-2450Article, review/survey (Refereed)
    Abstract [en]

    Single-cell analysis is currently one of the most high-resolution techniques to study biology. The large complex datasets that have been generated have spurred numerous developments in computational biology, in particular the use of advanced statistics and machine learning. This review attempts to explain the deeper theoretical concepts that underpin current state-of-the-art analysis methods. Single-cell analysis is covered from cell, through instruments, to current and upcoming models. The aim of this review is to spread concepts which are not yet in common use, especially from topology and generative processes, and how new statistical models can be developed to capture more of biology. This opens epistemological questions regarding our ontology and models, and some pointers will be given to how natural language processing (NLP) may help overcome our cognitive limitations for understanding single-cell data.

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  • 3.
    Mihai, Ionut Sebastian
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Das, Debojyoti
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Maršalkaite, Gabija
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Meta-analysis of gene popularity: Less than half of gene citations stem from gene regulatory networks2021In: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 12, no 2, p. 1-13, article id 319Article in journal (Refereed)
    Abstract [en]

    The reasons for selecting a gene for further study might vary from historical momentum to funding availability, thus leading to unequal attention distribution among all genes. However, certain biological features tend to be overlooked in evaluating a gene’s popularity. Here we present a meta-analysis of the reasons why different genes have been studied and to what extent, with a focus on the gene-specific biological features. From unbiased datasets we can define biological properties of genes that reasonably may affect their perceived importance. We make use of both linear and nonlinear computational approaches for estimating gene popularity to then compare their relative importance. We find that roughly 25% of the studies are the result of a historical positive feedback, which we may think of as social reinforcement. Of the remaining features, gene family membership is the most indicative followed by disease relevance and finally regulatory pathway association. Disease relevance has been an important driver until the 1990s, after which the focus shifted to exploring every single gene. We also present a resource that allows one to study the impact of reinforcement, which may guide our research toward genes that have not yet received proportional attention.

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  • 4.
    Rosendal, Ebba
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Mihai, Ionut Sebastian
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). National Clinical Research School in Chronic Inflammatory Diseases (NCRSCID), Karolinska Institutet, Solna, Sweden.
    Becker, Miriam
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. 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, 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.
    Das, Debojyoti
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Frängsmyr, Lars
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Persson, B. David
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Swedish National Veterinary Institute (SVA), Uppsala, Sweden.
    Rankin, Gregory
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
    Gröning, Remigius
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Corporate Research, Umeå, Sweden.
    Forsell, Mattias
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Ankarklev, Johan
    Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Microbial Single Cell Genomics Facility, SciLifeLab, Biomedical Center (BMC) Uppsala University, Uppsala, Sweden.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Henriksson, Johan
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections2022In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 13, no 3, article id e00892-22Article in journal (Refereed)
    Abstract [en]

    The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal outcome. Individual factors such as age, sex, and comorbidities increase the risk for severe infections, but other aspects, such as genetic variations, are also likely to affect the susceptibility to SARS-CoV-2 infection and disease severity. Here, we used a human 3D lung cell model based on primary cells derived from multiple donors to identity host factors that regulate SARS-CoV-2 infection. With a transcriptomics-based approach, we found that less susceptible donors show a higher expression level of serine protease inhibitors SERPINA1, SERPINE1, and SERPINE2, identifying variation in cellular serpin levels as restricting host factors for SARS-CoV-2 infection. We pinpoint their antiviral mechanism of action to inhibition of the cellular serine protease, TMPRSS2, thereby preventing cleavage of the viral spike protein and TMPRSS2-mediated entry into the target cells. By means of single-cell RNA sequencing, we further locate the expression of the individual serpins to basal, ciliated, club, and goblet cells. Our results add to the importance of genetic variations as determinants for SARS-CoV-2 susceptibility and suggest that genetic deficiencies of cellular serpins might represent risk factors for severe COVID-19. Our study further highlights TMPRSS2 as a promising target for antiviral intervention and opens the door for the usage of locally administered serpins as a treatment against COVID-19.

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1 - 4 of 4
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