Magnar Bjørås

• Vikedal, Krister; Jimenez, Natalia Berges; Riisnæs, Ida Mathilde Marstein; Ræder, Synnøve Brandt; Bjørnholt, Jørgen Vildershøj & Bjørås, Magnar [Vis alle 9 forfattere av denne artikkelen] (2026). Exploring the genetic landscape of ciprofloxacin-induced DNA supercompaction in Escherichia coli. Nucleic Acids Research (NAR). ISSN 0305-1048. 54(12). doi: 10.1093/nar/gkag573. Fulltekst i vitenarkiv
• Yang, Mingyi; Wang, Wei; Quilez, Maria Camara; Farsund, Borghild Hvesser; Andersen, Niklas Nonboe & Garten, Karin [Vis alle 13 forfattere av denne artikkelen] (2026). Modeling CLN3 Batten disease in astrocytes reveals alterations in mitochondria homeostasis, fatty acid metabolism and oxidative stress response. Journal of Biomedical Science. ISSN 1021-7770. 33(1). doi: 10.1186/s12929-026-01253-y. Fulltekst i vitenarkiv
• Dyhr, Emma; Pinedo, Lucía Cañete de; Frederiksen, Nicki; Bojer, Martin Saxtorph; Ingmer, Hanne & Sæbø, Ingvill Pedersen [Vis alle 11 forfattere av denne artikkelen] (2026). Antibacterial peptidomimetics via fragment display on small-molecule scaffolds. RSC Medicinal Chemistry. ISSN 2632-8682. 17(4), s. 1989–2001. doi: 10.1039/d5md00916b. Fulltekst i vitenarkiv
• Dyhr, Emma; Sæbø, Ingvill Pedersen; Riisnæs, Ida Mathilde Marstein; Bjørås, Magnar; Helgesen, Emily & Booth, James Alexander [Vis alle 7 forfattere av denne artikkelen] (2026). Antimicrobial Peptides Based on the TisB Toxin: Toward Enhanced Activity and Synergy with Antibiotics. ACS Omega. 11(26), s. 38837–38847. doi: 10.1021/acsomega.6c02137. Fulltekst i vitenarkiv
• Doncel, Beatriz Escobar; Zhang, Xiaoyi; Ljøstad, Åsne; Puebla, Mario Fernández de la; Shreyas, Rao & Fjeldstad, Synnøve Algrøy [Vis alle 11 forfattere av denne artikkelen] (2026). Two-photon in vivo imaging reveals cell type-specific mitophagy dynamic changes in mouse somatosensory cortex during aging. npj Aging. 12. doi: 10.1038/s41514-026-00414-5. Fulltekst i vitenarkiv Vis sammendrag

  Mitochondrial homeostasis is majorly maintained through mitochondrial autophagy (mitophagy). Recent research highlights the region- and cell type-specific nature of mitophagy during brain aging; however, these dynamics have largely remained unexplored in living brains. To address this gap, we conducted two-photon mt-Keima imaging in somatosensory cortical neurons and astrocytes in behaving male mice across two age groups, including 2–3-month-old (early-aged) and 18–20-month-old (old-aged) mice. We show reduced mitophagy in both cell types during aging, and we consistently found a higher level of mitophagy in astrocytes compared to neurons at the same age, in both age groups. Pharmacological augmentation of NAD+, a pivotal metabolite that induces mitophagy but normally declines in the aging brain, increased cellular mitophagy in both neurons and astrocytes in old-aged male mice at the dose and method of administration tested. Collectively, our data support an age-dependent reduction of mitophagy in neurons and astrocytes, at least in mouse somatosensory cortex, while NAD+ repletion offsets such reduction.

• Nothnagel, Patrizia Maria Christiane; Meslin, Paul-Arthur Richard; Wik, Jonas Aakre; Dufour, Damien; Strøm, Yunna Erika & Bjørås, Magnar [Vis alle 11 forfattere av denne artikkelen] (2026). Transient SUMOylation inhibition in human pre-adipocytes stably imprints a transcriptional beiging fate. Nucleic Acids Research (NAR). ISSN 0305-1048. 54(6), s. 1–22. doi: 10.1093/nar/gkag232. Fulltekst i vitenarkiv Vis sammendrag

  SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how perturbation of the SUMOylation pathway impacts adipocyte plasticity remains unclear. Here, we show that brief pharmacologic inhibition of SUMOylation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure produces changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and RNA-sequencing revealed immediate chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements at thermogenic enhancers, and increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling and stabilization of beiging transcription activators. We propose that transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity.

• Myhre, Vegard; Kaarbø, Mari; Yang, Mingyi; Fevang, Børre; Sousa, Mirta Mittelstedt Leal de & Reims, Henrik Mikael [Vis alle 11 forfattere av denne artikkelen] (2026). Altered duodenal N6-methyladenosine levels in common variable immunodeficiency associate with duodenal microbiota. Frontiers in Immunology. 17. doi: 10.3389/fimmu.2026.1875823. Fulltekst i vitenarkiv
• Yang, Mingyi; Liu, Gege; Bjørås, Magnar & Wang, Junbai (2026). Protocol for identifying functional regulatory mutation blocks by integrating genome sequencing and transcriptome data. STAR Protocols. 7(3), s. 104642–104642. doi: 10.1016/j.xpro.2026.104642. Fulltekst i vitenarkiv
• Belhaj, Imen; Åmellem, Ingrid; Tartanoglu, Can H.; Weidemann, Hanne Margrete; Vallenari, Evan Michael & Yang, Mingyi [Vis alle 10 forfattere av denne artikkelen] (2026). Lactate treatment improves brain biochemistry and cognitive function in transgenic Alzheimer’s and wild-type mice. Scientific Reports. 16(1). doi: 10.1038/s41598-026-48154-6. Fulltekst i vitenarkiv Vis sammendrag

  Lactate, a well-known metabolite and signalling molecule, holds therapeutic potential for neurodegenerative diseases. Here, we investigated the effects of chronic lactate treatment on cognition and molecular biomarkers in the 5XFAD mouse model of Alzheimer’s disease (AD) and in wild-type (WT) controls using behavioural testing alongside proteomic and transcriptomic analyses. Mice received lactate or vehicle injections 4 days per week for 11 weeks, with behavioural testing before and after the treatment period. Lactate improved working memory in late-treated AD mice, without eliciting anxiety-like behaviour. At the molecular level, lactate reduced Il1b expression, and in a sex-dependent manner, normalised NEFL, and enhanced synaptic integrity proteins (OPCML, PPFIA2, STXBP3, SYT1, VGLUT2, VSNL1) in AD mice, while also augmenting mitochondrial regulators (ATP5G2, GRPEL1, SLC25A23) across genotypes. Notably, lactate upregulated low-abundance ionotropic glutamate receptor mRNAs (Grik3, Grin2c, Grid2ip) in female AD mice, indicating enhanced glutamatergic signalling. In WT mice, lactate increased expression of neurotrophic factors (Bdnf, Igf1, Vegfa), anti-inflammatory cytokines (Il4 and Il13), and the neuronal lactate transporter Mct2, suggesting promoted neuronal resilience. Together, these findings indicate that lactate treatment can mitigate cognitive decline and enhance molecular pathways of resilience in AD, warranting larger, age-stratified studies to validate its therapeutic potential and elucidate underlying mechanisms.

• Myhre, Anders Eivind; Meyer-Myklestad, Malin Holm; Gullaksen, Hanne Hestdal; Søgaard, Ole S.; Tolstrup, Martin & Salgado, Maria [Vis alle 51 forfattere av denne artikkelen] (2026). Long-term HIV-1 remission achieved through allogeneic haematopoietic stem cell transplant from a CCR5Δ32/Δ32 sibling donor. Nature Microbiology. 11, s. 1374–1386. doi: 10.1038/s41564-026-02304-8. Fulltekst i vitenarkiv Vis sammendrag

  Only few cases of human immunodeficiency virus (HIV) remission have been reported after allogeneic haematopoietic stem cell transplantation (HSCT), mostly involving stem cell donors with the homozygous CCR5Δ32 (CCR5Δ32/Δ32) mutation, which confers resistance to CCR5-tropic HIV-1. Here we report the case of a 63-year-old man in off-treatment HIV remission, 5 years after HSCT with a CCR5Δ32/Δ32 sibling donor for myelodysplastic syndrome. In-depth clinical characterization including virological and immunological analyses of peripheral blood, gut and bone marrow samples revealed that full donor chimerism was achieved. Antiretroviral therapy was discontinued after 24 months, and 48 months after HSCT, no intact HIV DNA was detected in blood or gut biopsies. Replication-competent virus and HIV-specific T cell responses were absent, and HIV antibody responses showed a gradual decline. Full donor chimerism in the gut, which is the primary viral reservoir, underscores the likelihood of a cure.

• Zhou, Wenjing; Martinez-Garcia, Elena; Sarnow, Katharina; Kanli, Georgia; Nazarov, Petr V & Li, Yaquan [Vis alle 37 forfattere av denne artikkelen] (2025). Development of a highly differentiated rat brain organoid model for exploring glioblastoma invasion dynamics and therapy. Neuro-Oncology. ISSN 1522-8517. doi: 10.1093/neuonc/noaf271. Fulltekst i vitenarkiv Vis sammendrag

  Background: Human brain organoids (BOs) are important models for studying early brain development and neurological disorders. While techniques for creating BOs are advancing, they remain developmental structures. Therefore, when human BOs are used to studying glioma–host interactions, the tumor behavior may be influenced by the BO-developmental microenvironment. Here, we describe the maturation of rat brain organoids (rBOs) into fully differentiated BOs and demonstrate their value as a model for studying glioblastoma (GB)–host interactions and their use in testing therapeutic interventions. Materials and Methods: rBOs were obtained from fetal cortical brains on the 18th day of gestation. Transcriptomic, proteomic, and metabolomic analyses determined their differentiation into maturity. Their developmental trajectory was compared to human BOs derived from induced pluripotent stem cells as well as to rat brain development. Tumor–rBO interactions, including invasion parameters and therapeutic interactions, were studied using 5 human GB models. Results: The rBOs develop into organized structures with myelinated neurons, oligodendrocytes, synapses, and glial cells, mirroring the rat brain development. GB invasion in rBOs matched those observed in orthotopic xenografts, enabling real-time assessment of invasion metrics: cellular heterogeneity, single-cell invasion speed, and tumor progression. The BOs had a strong impact on GB transcriptional activity and can be used to study therapeutic interventions. The rBO differentiation status influenced GB invasion capacity. Conclusions: The rBOs serve as an effective target brain structure for studying GB invasion parameters and for evaluating therapeutic interventions. Their rapid development into mature brain tissue makes rBOs a valuable brain avatar system for studying tumor–host interactions.

• Kamyshnyi, Oleksandr; Kamyshna, Iryna; Petakh, Pavlo; Halabitska, Iryna; Bjørås, Magnar & Oksenych, Valentyn [Vis alle 8 forfattere av denne artikkelen] (2025). Towards molecular diagnostics of parental alienation. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 82(1). doi: 10.1007/s00018-025-05895-3. Fulltekst i vitenarkiv Vis sammendrag

  High-conflict parental divorce can result in parental alienation (PA), leading to chronic psychological stress in children that adversely affects their mental and physical health. This stress may manifest as anxiety, depression, eating disorders, immune dysfunction, and cardiovascular, neurological, endocrine, or gastrointestinal issues. The inconsistent legal recognition of PA highlights the need for objective diagnostic tools to inform judicial decisions. We propose a panel of molecular biomarkers, derived from well-established indicators of chronic stress, to address the limited data specific to PA. This panel targets hypothalamic-pituitary-adrenal (HPA) axis activation, neurotransmitter dysregulation, inflammation, oxidative stress, epigenetic modifications, and gut microbiota dysbiosis. Interdisciplinary collaboration among researchers, general practitioners, and legal professionals is crucial to validate and implement this panel, ultimately enhancing child welfare through early intervention.

• Kumari, Shrishti; Ravlo, Erlend; Jayaraman, Guhan; Sai, VV Raghavendra; Bjørås, Magnar & Madaboosi, Narayanan [Vis alle 7 forfattere av denne artikkelen] (2025). Silica coating of thermal decomposition-based hydrophilic and hydrophobic magnetic nanoparticles for nucleic acid extraction. Colloids and Surfaces A: Physicochemical and Engineering Aspects. ISSN 0927-7757. 725. doi: 10.1016/j.colsurfa.2025.137663. Fulltekst i vitenarkiv
• Ravlo, Erlend; Ianevski, Aleksandr; Wolska, Waleria; Schjølberg, Jørn-Ove; Quilez, Maria Camara & Nordli, Ine Emilie Olsen [Vis alle 23 forfattere av denne artikkelen] (2025). Combination of vemurafenib, pleconaril, and AG7404 attenuates enterovirus replication in vitro and in vivo. NAR Molecular Medicine. 3(1). doi: 10.1093/narmme/ugaf046. Fulltekst i vitenarkiv Vis sammendrag

  Enteroviruses infect multiple human tissues and cause diseases including meningitis, the common cold, myocarditis, pancreatitis, hepatitis, poliomyelitis, sepsis, type 1 diabetes, hand, foot, and mouth disease. Despite this burden, no antiviral therapy has been approved to date. Progress has been limited by the structural and topical diversity of enteroviruses because many variants are intrinsically insensitive to candidate agents and sensitive strains develop resistance rapidly. Here, we report that the approved anticancer drug vemurafenib inhibited replication of some tested enteroviruses in cell cultures. Passage of echovirus EV1 and coxsackievirus CVB5 for six cycles in cell culture yielded vemurafenib-resistant virus variants harboring mainly missense mutations in the viral 3A and VP1 proteins, underscoring the need for combination therapy. We therefore evaluated cocktails, combining vemurafenib with the VP1 inhibitor pleconaril and the 3C protease inhibitor AG7404. In cell culture, the cocktails suppressed replication of all seven tested enteroviruses. The combination was also effective in human pancreatic, retinal, and brain organoids. In infected mice, the triple regimen reduced viral titers in the pancreas. These findings support multi-stage targeting of the enterovirus life cycle as a promising path toward broadly active therapeutic cocktails.

• Kaarbø, Mari; Yang, Mingyi; Meyer-Myklestad, Malin Holm; Sundaram, Arvind; Sousa, Mirta & Sharma, Animesh [Vis alle 13 forfattere av denne artikkelen] (2025). Transcriptomic and proteomic profiling reveal immune and metabolic dysregulation in the colonic mucosa of people living with HIV with incomplete immune recovery. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1635523. Fulltekst i vitenarkiv Vis sammendrag

  Background People living with HIV are called immunological non-responders (INR) when their CD4+ T cell count is not restored to immunocompetent levels, despite successful viral suppression. INR have increased risk of progression to AIDS, non-AIDS related morbidity, and death. Impaired mucosal barrier function is a prevailing hypothesis for why INR among people with HIV (PWH) have persistently low CD4+ T cell counts. Objective To understand the molecular mechanisms behind incomplete immune recovery in INR, we analyzed gene regulation and protein expression in gut tissues from INR, immunological responders (IR) and healthy controls (HC). Methods The transcriptome was assessed by RNA-sequencing (RNA-seq) and the proteome was examined using shotgun proteomic mass spectrometry in mucosal biopsies from the sigmoid colon and terminal ileum. Results In INR compared to IR, we identified 3326 differentially expressed genes (DEGs) in the colon while no DEGs were observed in the ileum. Gene ontology (GO) analyses revealed that the DEGs in colon of INR, compared to IR, predominantly involved pathways related to immune response, metabolism, and cellular processes. Notably, GO analysis highlighted downregulation of genes associated with B cell-mediated immunity and adaptive responses in INR. Deconvolution analysis indicated that these transcriptomic changes were not solely due to shifts in immune cell composition. Proteomic analysis supported these findings, showing more differential protein composition between INR and IR in colon than ileum. These proteins are associated with the regulation of adaptive immune signaling and essential cellular processes, including cell signaling, tissue repair, and growth, all of which are characteristic features of inflammatory bowel disease (IBD). Conclusion Our findings suggest that incomplete immune recovery during anti-retroviral therapy in PWH is associated with specific dysregulations in the molecular environment of the sigmoid colon, which may share mechanisms with IBD. The identified macromolecules may serve as potential targets for adjuvant treatment to improve the prognosis for INR.

• Dyhr, Emma; Sæbø, Ingvill Pedersen; Riisnæs, Ida Mathilde Marstein; Bjørås, Magnar; Helgesen, Emily & Booth, James Alexander [Vis alle 7 forfattere av denne artikkelen] (2025). Rational Design of Antimicrobial Peptides Based on Bacterial Type-I Toxins AapA1, IbsC, and Fst1. ACS Omega. 10(24), s. 25790–25800. doi: 10.1021/acsomega.5c01863. Fulltekst i vitenarkiv
• Starheim, Eirin Johannessen; Manaf, Adeel; Hashim, Adnan; Andersen, Niklas Nonboe; Ravlo, Erlend & Wang, Wei [Vis alle 12 forfattere av denne artikkelen] (2025). Rapid DNA and RNA isolation from few or single cells using low-cost NAxtra magnetic nanoparticles. Scientific Reports. 15(1). doi: 10.1038/s41598-025-05770-y. Fulltekst i vitenarkiv
• Dahl, Tuva Børresdatter; Jimenez, Ana Maria Teresa Quiles; Broch, Kaspar; Anstensrud, Anne Kristine; Gullestad, Lars & Andersen, Geir Øystein [Vis alle 16 forfattere av denne artikkelen] (2025). The N-6 methyladenosine dynamics in STEMI and the effect of IL-6 inhibition - a hypothesis generating sub-study of the ASSAIL-MI trial. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1532325. Fulltekst i vitenarkiv Vis sammendrag

  Background: Epitranscriptomics, with m6A as the most prevalent in mammals, is a novel treatment target for inflammatory diseases, including cardiovascular diseases. However, little is known about m6A RNA-regulation during myocardial infarction (MI). Methods: In this explorative sub-study of the ASSAIL-MI trial, we used whole blood samples from patients with acute ST-elevation MI (STEMI) (n=6) at admission and after 3–7 days, and from healthy control subjects (n=3). RNA was isolated, and m6A sites were analyzed using human m6A single nucleotide resolution microarray analysis. mRNA levels were analyzed using RNA sequencing analysis. Results: Compared with controls, patients with STEMI had a strikingly different pattern of m6A deposition. In total, 845 m6A methylation sites in whole blood RNA were hypomethylated and 36 were hypermethylated compared with controls. Of the hypomethylated transcripts, 194 transcripts were lower expressed, while 197 transcripts were higher expressed. The m6A pattern changed from an overall hypomethylation at admission to an overall hypermethylation 3–7 day after admission. Anti-inflammatory treatment with tocilizumab further altered the m6A deposition. Conclusions: In this hypothesis generating study, m6A deposition differs STEMI patients and healthy controls. The m6A pattern changes over the course of 3–7 days. This response is, at least to some degree, is modulated by blocking the IL-6 receptor. Our data may suggest that this post-transcriptional regulation of RNA is involved in the immune response during STEMI, highlighting its potential as a target for therapy in MI.

• Berg, Sigrid Ravn; Brambilla, Alessandro; Hagen, Lars; Sharma, Animesh; Vågbø, Cathrine Broberg & Liabakk, Nina-Beate [Vis alle 11 forfattere av denne artikkelen] (2025). Proteomic Analysis Uncovers Enhanced Inflammatory Phenotype and Distinct Metabolic Changes in IDH1 Mutant Glioma Cells. International Journal of Molecular Sciences. ISSN 1661-6596. 26(18). doi: 10.3390/ijms26189075. Fulltekst i vitenarkiv Vis sammendrag

  Isocitrate dehydrogenase 1 (IDH1) mutations are key drivers of glioma biology, influencing tumor aggressiveness and treatment response. To elucidate their molecular impact, we performed proteome analysis on patient-derived (PD) and U87MG glioma cell models with either mutant or wild-type IDH1. We quantified over 6000 protein groups per model, identifying 1594 differentially expressed proteins in PD-AS (IDH1MUT) vs. PD-GB (IDH1WT) and 904 in U87MUT vs. U87WT. Both IDH1MUT models exhibited enhanced MHC antigen presentation and interferon signaling, indicative of an altered immune microenvironment. However, metabolic alterations were model-dependent: PD-AS cells shifted toward glycolysis and purine salvage, while U87MUT cells retained oxidative phosphorylation, potentially due to D2-hydroxyglutarate (2OHG)-mediated HIF1A stabilization. We also observed a predominance of downregulated DNA repair proteins in IDH1MUT models, particularly those involved in homologous recombination. In contrast, RB1 and ASMTL were strongly upregulated in both IDH1MUT models, implicating them in DNA repair and cellular stress responses. We also found distinct expression patterns of proteins regulating histone methylation in IDH1MUT cells, favoring increased methylation of H3K4, H3K9, and H3K36. A key driver of this may be the upregulation of SETD2 in PD-AS, an H3K4 and H3K36 trimethyltransferase linked to the recruitment of HIF1A as well as DNA mismatch repair proteins. This study uncovers candidate biomarkers and pathways relevant to glioma progression and therapeutic targeting, but also underscores the complexity of predicting glioma pathogenesis and treatment responses based on IDH1 mutation status. While proteome profiling provides valuable insights, a comprehensive understanding of IDH1MUT gliomas will likely require integrative multi-omics approaches, including DNA/RNA methylation profiling, histone and protein post-translational modification analyses, and targeted DNA damage and repair assays.

• Nothnagel, Patrizia Maria Christiane; Meslin, Paul-Arthur Richard; Wik, Jonas Aakre; Strøm, Yunna Erika; Bjørås, Magnar & Enserink, Jorrit [Vis alle 10 forfattere av denne artikkelen] (2025). Transient SUMOylation Inhibition In Human Pre-adipocytes Stably Imprints a Transcriptional Beiging Fate. bioRxiv (preprint article). 54(6). doi: 10.1101/2025.03.07.642034. Fulltekst i vitenarkiv Vis sammendrag

  Abstract SUMOylation regulates chromatin states and transcriptional programs that preserve cellular identity, yet how transient perturbation of the SUMO pathway impacts adipocyte plasticity remains unclear. Here we show that brief pharmacologic inhibition of SUMO conjugation in human pre-adipocytes using TAK-981 primes stable de novo beige differentiation in the presence of the PPARG agonist rosiglitazone. Transient TAK-981 exposure before adipogenic induction produces long-lasting changes in the transcriptome and metabolism of mature adipocytes, including robust induction of canonical beiging markers like UCP1 and increased mitochondrial respiration. Mechanistically, ATAC-seq and transcription factor footprinting revealed immediate and durable chromatin remodeling and early mobilization of CEBP family members, followed by stable activation of CEBPA and PPARG regulatory networks. ChIP experiments demonstrated loss of H3K27me3 and gain of H3K27ac at PPAR response elements within key thermogenic enhancers, with increased PPARG occupancy across the UCP1 regulatory unit. This mechanism is enforced by enhanced cAMP-PKA-p38 signaling, and stabilization of beiging transcriptional activators. Our data support a model in which transient relief of SUMO-mediated repression unlocks dominant regulatory units, notably the UCP1 enhancer cluster, producing a monomorphic, cell type specific reprogramming toward adaptive thermogenesis. These findings identify SUMOylation as a reversible epigenetic barrier to adipocyte beiging and suggest that temporally controlled SUMO pathway inhibition combined with PPARG activation could be exploited to modulate adipose tissue thermogenic capacity. Graphical abstract SUMOylation restricts de novo differentiation of pre-adipocytes into beige adipocytes by repressing cAMP signaling and preventing epigenetic and transcriptional reprogramming of white adipocytes.

• Puebla, Mario Fernández de la; Zhang, Xiaoyi; Nagelhus, Erlend Arnulf; Bjørås, Magnar & Tang, Wannan (2025). IP3R2-Mediated Astrocytic Ca2+Transients Are Critical to Sustain Modulatory Effects of Locomotion on Neurons in Mouse Somatosensory Cortex. Cells. 14(14). doi: 10.3390/cells14141103. Fulltekst i vitenarkiv
• Berrocal, Marion Silvana Fernández; Døskeland, Dagny Sanden; Saasen, Vidar Langseth; Bugaj, Anna Maria; Kunath, Nicolas & Heggedal, Mina [Vis alle 12 forfattere av denne artikkelen] (2025). NEIL3 shapes hippocampal network dynamics and fear memory through modulation of PV+ interneurons. Progress in Neurobiology. ISSN 0301-0082. 253. doi: 10.1016/j.pneurobio.2025.102832. Fulltekst i vitenarkiv Vis sammendrag

  The dynamic balance between excitatory and inhibitory (E/I) signaling is critical for hippocampal network function and memory processing. Here, we uncover a novel role for the DNA glycosylase Endonuclease VIII-like 3 (NEIL3) in maintaining this E/I balance through its impact on parvalbumin-positive (PV⁺) GABAergic interneurons. NEIL3 deficiency leads to a selective reduction in PV⁺ interneurons and impaired perineuronal net (PNN) integrity, likely contributing to further PV⁺ neuron dysfunction. These changes result in altered hippocampal oscillatory dynamics, including increased beta and low gamma power, and reduced high gamma and ripple activity. These network alterations are accompanied by distinct effects on fear memory, as demonstrated using contextual and trace fear conditioning paradigms. NEIL3-deficient mice exhibited enhanced extinction of contextual fear memory but impaired extinction of trace fear memory. These findings suggest that the integrity of inhibitory networks plays differential roles in the spatial versus temporal aspects of fear memory extinction. Transcriptomic analysis further reveals dysregulation of genes involved in glutamatergic and GABAergic signaling. Among these, Gabra2 showed a marked downregulation, potentially driven by changes in promoter DNA methylation. This work identifies NEIL3 as an important regulator of the hippocampal inhibitory network, linking PV+ interneuron integrity and oscillatory coordination to distinct memory outcomes, and offers potential mechanistic insight into processes that may contribute to cognitive deficits in disorders characterized by E/I imbalance.

• Fosslie, Madeleine Lystad; Ilaslan, Erkut; Skuland, Trine; Choudalakis, Michel; Søegaard, Mirra Louise Cicilie & Halliwell, Jason Alexander [Vis alle 23 forfattere av denne artikkelen] (2025). Major waves of H2A.Z incorporation during mouse oogenesis and preimplantation embryo development. Nature Communications. 17(1). doi: 10.1038/s41467-025-66919-x. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Epigenomes of mammalian oocytes and embryos undergo major transitions essential for successful development. Here, we provide genome-wide maps of histone variant H2A.Z during twelve stages of mouse oogenesis and preimplantation embryo development and relate it to histone marks and genomic features. This revealed that major waves of H2A.Z incorporation occur early in growing oocytes, forming distinct patterns of maternal, embryonic, and persistent H2A.Z enrichment. Late maternal enrichment is inherited by the zygote and precedes reduced formation of lamina associated domains and early replication in the maternal genome of 2-cell embryos. Persistent H2A.Z enrichment is strongly associated with CpG islands and H3K4me3 near transcription start sites of active genes, but thousands of maternal and embryonic H2A.Z incorporation sites exist elsewhere, frequently at transposable elements. The persisting H2A.Z enrichments across related developmental stages enable preservation of epigenetic information despite major concurrent changes in H3K4me3, H3K27me3, and DNA methylation. Altogether, this advances our understanding of how histone variants contribute to epigenetic reprogramming during mammalian oogenesis and early development.

• Kissova, Miroslava; Segarra, Judit Martinez; Iveland, Tobias Solli; Vestvik, Marthe; Ravlo, Erlend & Wang, Wei [Vis alle 17 forfattere av denne artikkelen] (2025). RNaseH2 inhibition potentiates temozolomide response in patient derived glioblastoma cells. Scientific Reports. 15, s. 1–12. doi: 10.1038/s41598-025-25298-5. Fulltekst i vitenarkiv Vis sammendrag

  Glioblastoma (GBM) is the most common and lethal form of primary brain tumor, characterized by poor prognosis and limited treatment options, with a median survival of only 12 to 15 months post-diagnosis. Despite standard therapeutic protocols involving temozolomide (TMZ) and radiotherapy, effective treatment is challenging, underscoring the need to explore alternative therapeutic strategies. One promising approach is the inhibition of DNA damage response (DDR) pathways. RNaseH2, a key enzyme involved in ribonucleotide excision repair (RER), plays a critical role in maintaining genomic stability by removing ribonucleotides misincorporated into DNA. Thus, inhibition of RNaseH2 may enhance tumor mutational burden (TMB) and potentially transform immunogenically “cold” tumors into immunogenically “hot” tumors. In this study, a high-throughput screening (HTS) assay resulted in the identification of 52 potential RNaseH2 inhibitors from a library of 71227 compounds. We selected six of these inhibitors for further investigation, evaluating their effects both alone and in combination with TMZ in commercially available U87 MG wild-type and IDH1 mutant (IDH1 WT and MUT) glioma cells and patient-derived cells established from glioma organoids (GBO-PDC). This study highlights the therapeutic potential of RNaseH2 inhibition in combination with TMZ for GBM therapy, validated in patient-derived model, offering a promising avenue for treating this highly aggressive and yet uncurable cancer.

• Luan, Yan; Zhang, Hanyue; Liu, Yingfei; Zhou, Jing; Li, Wen & Ma, Kaige [Vis alle 14 forfattere av denne artikkelen] (2025). Inverse and dynamic levels of H3K4me3 and H3K27me3 regulate mouse postnatal dental gyrus development. Cell Death and Differentiation. ISSN 1350-9047. 33, s. 219–235. doi: 10.1038/s41418-025-01563-y. Fulltekst i vitenarkiv Vis sammendrag

  The dentate gyrus (DG), a crucial region of the hippocampus responsible for learning, spatial encoding, and memory formation, undergoes its main development and maturation after birth. Despite its importance, the regulatory mechanisms underlying postnatal DG development remain poorly understood. Thi …

• Bordin, Diana Lilian; Lefol, Yohan Pierre; Lagartos, Maria Jose Donate; Montaldo, Nicola Pietro; Rolseth, Veslemøy & Tekin, Nuriye Basdag [Vis alle 18 forfattere av denne artikkelen] (2025). SMUG1 DNA glycosylase modulates reward behaviour through regulation of olfactory receptor gene expression. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(14). doi: 10.1093/nar/gkaf722. Fulltekst i vitenarkiv
• Vikedal, Krister; Ræder, Synnøve Brandt; Riisnæs, Ida Mathilde Marstein; Bjørås, Magnar; Booth, James Alexander & Skarstad, Kirsten [Vis alle 7 forfattere av denne artikkelen] (2025). RecN and RecA orchestrate an ordered DNA supercompaction response following ciprofloxacin-induced DNA damage in Escherichia coli. Nucleic Acids Research (NAR). ISSN 0305-1048. 53(10). doi: 10.1093/nar/gkaf437. Fulltekst i vitenarkiv Vis sammendrag

  Fluoroquinolones induce double-strand breaks in bacterial DNA, triggering the SOS response, a major DNA damage response that ensures the expression of repair proteins but also promotes the emergence and spread of antibiotic resistance. Fluoroquinolone resistance, particularly in Escherichia coli, is a growing global health concern. Understanding bacterial responses to these antibiotics is critical for developing preventive strategies and novel treatments to combat resistance development. This study investigates DNA morphology in E. coli following exposure to ciprofloxacin (CIP), a fluoroquinolone antibiotic. We show that CIP induces a stepwise DNA reorganization, culminating in a highly dense nucleoid structure at midcell—a process we term DNA supercompaction. This phenomenon occurred also with other genotoxic agents. Live-cell imaging revealed that RecN, a structural maintenance of chromosomes (SMC)-like protein, is required for DNA supercompaction, and that RecN’s dynamics and activity in this response depend on RecA. Additionally, RecN and RecA frequently colocalized at nucleoid-associated positions. We suggest that RecN and RecA play active roles in DNA supercompaction following severe DNA damage, that their interplay is part of a prompt universal survival response to DNA double-strand breaks in E. coli, and that the extent of the compaction response depends on the DNA damage severity.

• Sæbø, Ingvill Pedersen; Dyhr, Emma; Riisnæs, Ida Mathilde Marstein; Franzyk, Henrik; Bjørås, Magnar & Booth, James Alexander [Vis alle 7 forfattere av denne artikkelen] (2025). Rational design of synthetic antimicrobial peptides based on the Escherichia coli ShoB toxin. Scientific Reports. 15(1). doi: 10.1038/s41598-025-98330-3. Fulltekst i vitenarkiv Vis sammendrag

  Antibiotic resistance is an escalating global concern, necessitating the development of novel antibiotics with unique mechanisms of action, and preferably also with a lowered propensity for resistance development. Type-I Toxin-Antitoxin (TA) systems that are ubiquitous in bacterial genomes consist of a genetic toxin element encoding a hydrophobic peptide and an antitoxin element producing an sRNA that inhibits the toxin translation. Although the biological roles of these membrane-associated toxins remain incompletely understood, their inherent lethality upon overexpression suggests a potential as antimicrobial agents. In this study, we explore the ShoB toxin from the shoB-ohsC TA system in Escherichia coli (E. coli) as a basis for designing synthetic antimicrobial peptides for exogenous delivery. We demonstrate that ShoB-derived peptides can retain antimicrobial efficacy when modified into shorter, cationic analogs with enhanced solubility. Our most promising hits exhibit rapid bactericidal action and frequency of resistance within E. coli cultures indicate a limited tendency for resistance development. These findings highlight that type-I TA systems constitute a novel source of potential peptide-based antibiotics, thereby offering an alternative largely unexplored strategy to combat antibiotic-resistant bacterial infections.

• Yao, Zhihao; Fang, Kun; Liu, Gege; Bjørås, Magnar; Jin, Victor X. & Wang, Junbai (2025). Integrated analysis of differential intra-chromosomal community interactions: A study of breast cancer. Artificial Intelligence in Medicine. ISSN 0933-3657. 167. doi: 10.1016/j.artmed.2025.103180. Fulltekst i vitenarkiv Vis sammendrag

  It is challenging to analyze the dynamics of intra-chromosomal interactions when considering multiple high-dimensional epigenetic datasets. A computational approach, differential network analysis in intra-chromosomal community interaction (DNAICI), was proposed here to elucidate these dynamics by integrating Hi-C data with other epigenetic data. DNAICI utilized a novel hyperparameter tuning method, for optimizing the network clustering, to identify valid intra-chromosomal community interactions at different resolutions. The approach was first trained on Hi-C data and other epigenetic data in an untreated and one hour estrogen (E2)-treated breast cancer cell line, MCF7, and uncovered two major types of valid intra-chromosomal community interactions (active/repressive) that resembles the properties of A/B compartments (or open/closed chromatin domains). It was further tested on the breast cancer cell line MCF7 and its corresponding tamoxifen-resistant (TR) derivative, MCF7TR, and identified 515 differentially interacting and expressed genes (DIEGs) within intra-chromosomal community interactions. In silico analysis of these DIEGs revealed that endocrine resistance is among the top biological pathways, suggesting an interacting/looping-mediated mechanism in regulating breast cancer tamoxifen resistance. This novel integrated network analysis approach offers a broad application in diverse biological systems for identifying a biological-context-specific differential community interaction.

• Dufour, Damien; Zhao, Xu; Chaleil, Florian; Nothnagel, Patrizia Maria Christiane; Bjørås, Magnar & Lefrançois-Martinez, Anne-Marie [Vis alle 8 forfattere av denne artikkelen] (2025). Pharmacological inhibition of SUMOylation with TAK-981 mimics genetic HypoSUMOylation in murine perigonadal white adipose tissue. Adipocyte. ISSN 2162-3945. 14(1). doi: 10.1080/21623945.2025.2474107. Fulltekst i vitenarkiv Vis sammendrag

  Post-translational modification by the small ubiquitin-like modifier (SUMO) is essential for cellular differentiation and homeostasis. Here, we investigate the role of SUMOylation in adipose tissue development using TAK-981, a pharmacological inhibitor of SUMOylation. Administration of TAK-981 to mice resulted in significant defect in weight gain and adipocyte atrophy in perigonadal white adipose tissue (gWAT) depots. Gene expression analyses revealed a marked downregulation of adipogenic genes, including Pparg, Cebpa, and Fasn. Our data thus indicate that TAK-981 treatment impaired adipogenesis in gWAT, consistent with prior findings that SUMOylation supports transcriptional regulation of adipogenesis and lipid metabolism. We also found significant infiltration of immune cells and efferocytosis in gWAT. Our results thus indicate that SUMOylation inhibition using a small molecule phenocopies genetic hypoSUMOylation models, highlighting its critical role in maintaining adipocyte functionality and immune environment. These findings provide evidence that SUMOylation is essential for fat accumulation in vivo. Furthermore, given that TAK-981 is currently under clinical evaluation for the treatment of solid tumors, our results underscore the importance of considering the potential unintended effects of SUMOylation inhibition on adipose tissue in patients.

• Abentung, Andreas; Sakshaug, Teri; Dumaru, Rabina; Liabakk, Nina-Beate; Yang, Mingyi & Wang, Junbai [Vis alle 8 forfattere av denne artikkelen] (2025). DNA glycosylases Ogg1 and Mutyh influence gene expression of PRC2 targets associated with cognition. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 82. doi: 10.1007/s00018-025-05730-9. Fulltekst i vitenarkiv Vis sammendrag

  Base excision repair, initiated by DNA glycosylases, preserves genomic integrity by removing damaged bases. DNA glycosylases Ogg1 and Mutyh were shown to alter the hippocampal transcriptome independently of DNA damage repair. However, the role of DNA glycosylases as transcriptional regulators and their involvement in cognition remain unclear. Here, we combine transcriptomic and epigenomic analyses of the hippocampus in mice deficient in DNA glycosylases. We report that the combined deficiency of Ogg1 and Mutyh impairs spatial long-term memory. Mechanistically, Ogg1 and Mutyh modulate DNA methylation of polycomb repressive complex 2 (PRC2) target genes. PRC2 occupancy and associated histone post-translational modifications depend on Ogg1 and Mutyh in neurons and glia. These epigenetic changes correlate with cell-type specific differences in gene expression of PRC2 targets. Finally, human genetic data link DNA glycosylase-regulated genes to cognitive function, highlighting a novel role for Ogg1 and Mutyh in modulating the epigenome to control transcriptional responses relevant for brain-related diseases.

• Lobie, Tekle Airgecho; Krog, Charlotte Solum; Skarstad, Kirsten; Bjørås, Magnar & Booth, James Alexander (2025). Escherichia coli type I toxin TisB exclusively controls proton depolarization following antibiotic induced DNA damage. Scientific Reports. 15(1). doi: 10.1038/s41598-025-96136-x. Fulltekst i vitenarkiv Vis sammendrag

  Bacterial toxin-antitoxin (TA) systems are genetic loci where the antitoxin gene product helps to control the expression or activity of the toxin gene product. Type I TA systems typically produce hydrophobic peptides that often localize to the inner membrane of bacteria. These amphipathic peptides can then potentially affect ion flows across the inner membrane. Here, we show that several type I toxins from Escherichia coli can affect depolarization, whereas tisB exclusively controls the depolarization of the proton gradient. tisB has been linked to persister cell formation following treatment with the antibiotic ciprofloxacin and tisB-istR has been implicated in the control of proton depolarization following treatment with ofloxacin. These results suggest that tisB could initiate the formation of persister cells by fully dissipating the proton gradient and that most of the electrical gradient greatly limiting ATP production following antibiotic-induced DNA damage.

• Yildirim, Zuleyha; Noll, Aurélia; Martin-Hernandez, Kathline; Amé, Jean-Christophe; Hanini, Najat & Messaddeq, Nadia [Vis alle 11 forfattere av denne artikkelen] (2025). Parp3 assists muscle function and skeletal muscle differentiation by selectively adjusting H3K27me3 enrichment. iScience. 28(4). doi: 10.1016/j.isci.2025.112267. Fulltekst i vitenarkiv Vis sammendrag

  Poly(ADP-ribose) polymerase 3 (Parp3) is known for its role in DNA repair, mitotic division, and cancer aggressiveness. Still, its physiological roles have yet to be defined. Here, we combined in vivo studies using Parp3-deficient mice with in cellulo studies to explore the involvement of Parp3 in skeletal muscle function and muscle differentiation. We show that Parp3 contributes to skeletal muscle integrity and promotes myogenic differentiation. Mechanistically, we show that Parp3 promotes the enrichment of the repressive histone mark H3K27me3 onto a panel of selected genes. For some genes, Parp3 also helps the binding of Ezh2, the histone methyltransferase that catalyzes H3K27me3. Moreover, Parp3 ADP-ribosylates Ezh2 in vitro. Altogether, these findings unveil Parp3 as a driver of efficient murine skeletal myogenesis in vitro and muscle function in young adults, and highlight an epigenetic control of gene expression.

• Li, Yanjiao; Wang, Yunhao; Cengiz, Aylin; Jin, Kangxuan; castroviejo, Blanca Corral & Lin, Xiaolin [Vis alle 19 forfattere av denne artikkelen] (2025). The RNA m6A landscape during human oocyte-to-embryo transition. EMBO Journal. ISSN 0261-4189. 44(14), s. 4150–4180. doi: 10.1038/s44318-025-00474-5. Fulltekst i vitenarkiv Vis sammendrag

  RNA N6-methyladenosine (m6A, m6A) modification is a critical regulator for a range of physiological processes. However, the dynamic m6A profiles within human preimplantation embryos remain uncharacterized. Here, we present the first RNA m6A landscape of single human oocytes and early embryos. Comparative analyses with mouse data reveal an intriguing divergence during the window of zygotic genome activation. m6A-modified genes are involved in regulation of gene transcription, while unmodified genes are mainly associated with basic metabolic processes. Maternal decay mRNAs exhibit a propensity for m6A modifications, and these genes are targeted by miRNAs. m6A modified genes that are constantly expressed across all stages demonstrate higher translation efficiency. Moreover, we observe frequent m6A enrichment on stage-specifically expressed retrotransposons, particularly within young subfamilies. m6A inhibitor leads to m6A erasure on massive retrotransposons. In summary, this study provides a resource to broaden our understanding about the regulatory roles of m6A during early human embryo development.

• Ianevski, Aleksandr; Quilez, Maria Camara; Wang, Wei; Suganthan, Rajikala; Hildrestrand, Gunn Annette & Grini, Jonas Viken [Vis alle 9 forfattere av denne artikkelen] (2025). Early transcriptional responses reveal cell type-specific vulnerability and neuroprotective mechanisms in the neonatal ischemic hippocampus. Acta neuropathologica communications. 13(1). doi: 10.1186/s40478-025-02062-4. Fulltekst i vitenarkiv Vis sammendrag

  Neonatal hypoxic-ischemic (H-I) brain injury, a leading cause of neurodevelopmental disabilities, severely affects the metabolically active and neurogenic hippocampus. To investigate its acute effects and identify drug targets for early therapeutic windows, we applied single-nucleus RNA sequencing on postnatal day 8 (P8) mouse hippocampi under sham, hypoxic, and hypoxic-ischemic conditions. We constructed a comprehensive hippocampal cell atlas and developed a machine-learning classifier for precise cell type identification. Our analysis reveals early vulnerabilities in mature neurons and notable resilience in immature DG, GABAergic, and Cajal-Retzius cells following H-I. Gene regulatory network analysis identified key transcription factors associated with neuronal vulnerability, along with upregulated ribosome biogenesis and dysregulated calcium homeostasis pathways. We observed rapid activation of astrocytes and microglia, with Runx1 identified as a potential key transcription factor associated with early microglia immune responses. Endothelial cells displayed complex transcriptional changes and predicted intercellular signaling patterns that may influence vascular repair and recovery. Our study advances the understanding of immediate cellular and transcriptional responses to neonatal H-I injury, providing new insights into hippocampal cell heterogeneity and pathophysiology. The integrated hippocampal atlas, post-H-I atlas, and machine learning classifier are available at https://hippo-seq.org.

• Ravlo, Erlend; Ianevski, Aleksandr; Skipperstøen, Marius Nårstad; Lysvand, Hilde; Schjølberg, Jørn-Ove & Solheim, Ole Skeidsvoll [Vis alle 20 forfattere av denne artikkelen] (2025). JAK inhibitors remove innate immune barriers facilitating viral propagation. NAR Molecular Medicine. 2(2). doi: 10.1093/narmme/ugaf017. Fulltekst i vitenarkiv
• Chen, Xiufei; Cheng, Jingfei; Kong, Linzhen; Shu, Xiao; Xu, Haiqi & Inoue, Masato [Vis alle 13 forfattere av denne artikkelen] (2025). Direct and bisulfite-free 5-methylcytosine and 5-hydroxymethylcytosine sequencing at single-cell resolution with scTAPS and scCAPS + . Genome Biology. ISSN 1465-6906. 26(1). doi: 10.1186/s13059-025-03708-1. Fulltekst i vitenarkiv
• Ravlo, Erlend; Ianevski, Aleksandr; Schjølberg, Jørn-Ove; Solvang, Vanessa; Dumaru, Rabina & Lysvand, Hilde [Vis alle 31 forfattere av denne artikkelen] (2025). Synergistic combination of orally available safe-in-man pleconaril, AG7404, and mindeudesivir inhibits enterovirus infections in human cell and organoid cultures. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 82. doi: 10.1007/s00018-025-05581-4. Fulltekst i vitenarkiv Vis sammendrag

  Enteroviruses can infect various human organs, causing diseases such as meningitis, the common cold, hand-foot-and-mouth disease, myocarditis, pancreatitis, hepatitis, poliomyelitis, sepsis, and type 1 diabetes. Currently, there are no approved treatments for enterovirus infections. In this study, we identified a synergistic combination of orally available, safe-in-man pleconaril, AG7404, and mindeudesivir, that at non-toxic concentrations effectively inhibited enterovirus replication in human cell and organoid cultures. Importantly, the cocktail did not alter glucose and insulin levels in the culture medium of pancreatic β-cells and preserved the contraction rhythm of infected heart organoids. These findings highlight a promising drug cocktail for further preclinical studies and clinical trials targeting a broad range of enterovirus-mediated diseases.

• Berrocal, Marion Silvana Fernández; Reis, Amilcar; Rolseth, Veslemøy; Suganthan, Rajikala; Kusnierczyk, Anna & França, Arthur [Vis alle 15 forfattere av denne artikkelen] (2025). NEIL3 influences adult neurogenesis and behavioral pattern separation via WNT signaling. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 82(1). doi: 10.1007/s00018-025-05629-5. Fulltekst i vitenarkiv Vis sammendrag

  Adult neurogenesis in the hippocampus, involving the generation and integration of new neurons, is essential for behavioral pattern separation, which supports accurate memory recall and cognitive plasticity. Here, we explore the role of the DNA repair protein NEIL3 in adult hippocampal neurogenesis and behavioral pattern separation. NEIL3 is required for efficient proliferation and neuronal differentiation of neonatal NSPCs and adult-born NPCs in the hippocampus following a behavioral pattern separation task. NEIL3-depleted mice exhibited a reduced preference for the novel object location, indicating a deficit in pattern separation. NEIL3-deficient adult-born neurons exhibited a significant reduction in mature-like membrane properties, indicating impaired functional maturation. Interestingly, these impairments were not associated with the decreased genomic integrity but with the altered transcriptional regulation of the Wnt signaling pathway. Given the importance of adult neurogenesis in cognitive function, targeting NEIL3 could offer therapeutic potential for addressing age-related hippocampal dysfunction and cognitive decline.

• Bai, Xiangning; Rayner, Simon; Skuggen, Linda Ellevog; Engseth, Kine; Bjørnstad, Pål Marius & Dalland, Marianne [Vis alle 9 forfattere av denne artikkelen] (2025). A preliminary evaluation of a fast, low-cost, and high-throughput nucleic acid extraction method for bacterial microbiota profiling in low-microbial biomass samples. Scientific Reports. 15(1). doi: 10.1038/s41598-024-84682-9. Fulltekst i vitenarkiv Vis sammendrag

  The respiratory tract is colonized with low-density microbial communities, which have been shown to impact human respiratory health through microbiota–host interactions. However, a lack of fast and cost-effective nucleic acid extraction method for low-microbial biomass samples hinders investigation of respiratory microbiota. Here, we performed a pilot study to assess the suitability of the NAxtra nucleic acid extraction protocol for profiling bacterial microbiota in respiratory samples. A small number of nasopharyngeal aspirate (n = 8), nasal swab (n = 8), and saliva samples (n = 8) were collected, nucleic acids were isolated using the NAxtra protocol, and 16 S rRNA gene sequencing was performed to characterize bacterial microbiota, which were compared to the same sample types from previous studies using other protocols. The bacterial composition in nasal and saliva samples were consistent with previous reports. Saliva microbiota was significantly richer than nasal microbiota and varied less among individual samples than nasal microbiota. Bacterial composition in nasal samples was distinct from nasopharyngeal aspirates, but closer to saliva samples. A sequencing depth of 50,000 reads/sample was sufficient for microbiota profiling in low biomass respiratory samples. Our pilot study indicates the potential of the NAxtra protocol for bacterial microbiota characterization of low-microbial biomass samples and supports a more comprehensive study to fully evaluate the value of the NAxtra protocol in microbiota research and clinical diagnostics of respiratory pathogens.

• Obermann, Tobias; Sakshaug, Teri Shearer; Kanagaraj, Vishnu Vignesh; Abentung, Andreas; Sousa, Mirta Mittelstedt Leal de & Hagen, Lars [Vis alle 9 forfattere av denne artikkelen] (2024). Genomic 8-oxoguanine modulates gene transcription independent of its repair by DNA glycosylases OGG1 and MUTYH. Redox Biology. 79, s. 1–11. doi: 10.1016/j.redox.2024.103461. Fulltekst i vitenarkiv Vis sammendrag

  8-oxo-7,8-dihydroguanine (OG) is one of the most abundant oxidative lesions in the genome and is associated with genome instability. Its mutagenic potential is counteracted by a concerted action of 8-oxoguanine DNA glycosylase (OGG1) and mutY homolog DNA glycosylase (MUTYH). It has been suggested that OG and its repair has epigenetic-like properties and mediates transcription, but genome-wide evidence of this interdependence is lacking. Here, we applied an improved OG-sequencing approach reducing artificial background oxidation and RNA-sequencing to correlate genome-wide distribution of OG with gene transcription in OGG1 and/or MUTYH-deficient cells. Our data identified moderate enrichment of OG in the genome that is mainly dependent on the genomic context and not affected by DNA glycosylase-initiated repair. Interestingly, no association was found between genomic OG deposition and gene expression changes upon loss of OGG1 and MUTYH. Regardless of DNA glycosylase activity, OG in promoter regions correlated with expression of genes related to metabolic processes and damage response pathways indicating that OG functions as a cellular stress sensor to regulate transcription. Our work provides novel insights into the mechanism underlying transcriptional regulation by OG and DNA glycosylases OGG1 and MUTYH and suggests that oxidative DNA damage accumulation and its repair utilize different pathways.

• Wang, Junbai; Yang, Mingyi; Ali, Omer; Dragland, Jenny Sofie; Bjørås, Magnar & Farkas, Lorant (2024). Predicting regulatory mutations and their target genes by new computational integrative analysis: A study of follicular lymphoma. Computers in Biology and Medicine. ISSN 0010-4825. 178, s. 1–15. doi: 10.1016/j.compbiomed.2024.108787. Fulltekst i vitenarkiv Vis sammendrag

  Mutations in DNA regulatory regions are increasingly being recognized as important drivers of cancer and other complex diseases. These mutations can regulate gene expression by affecting DNA-protein binding and epigenetic profiles, such as DNA methylation in genome regulatory elements. However, identifying mutation hotspots associated with expression regulation and disease progression in non-coding DNA remains a challenge. Unlike most existing approaches that assign a mutation score to individual single nucleotide polymorphisms (SNP), a mutation block (MB)-based approach was introduced in this study to assess the collective impact of a cluster of SNPs on transcription factor-DNA binding affinity, differential gene expression (DEG), and nearby DNA methylation. Moreover, the long-distance target genes of functional MBs were identified using a new permutation-based algorithm that assessed the significance of correlations between DNA methylation at regulatory regions and target gene expression. Two new Python packages were developed. The Differential Methylation Region (DMR-analysis) analysis tool was used to detect DMR and map them to regulatory elements. The second tool, an integrated DMR, DEG, and SNP analysis tool (DDS-analysis), was used to combine the omics data to identify functional MBs and long-distance target genes. Both tools were validated in follicular lymphoma (FL) cohorts, where not only known functional MBs and their target genes (BCL2 and BCL6) were recovered, but also novel genes were found, including CDCA4 and JAG2, which may be associated with FL development. These genes are linked to target gene expression and are significantly correlated with the methylation of nearby DNA sequences in FL. The proposed computational integrative analysis of multiomics data holds promise for identifying regulatory mutations in cancer and other complex diseases.

• Ianevski, Aleksandr; Frøysa, Irene Trøen; Lysvand, Hilde; Calitz, Carlemi; Smura, Teemu & Nilsen, Hans-Johnny [Vis alle 18 forfattere av denne artikkelen] (2024). The combination of pleconaril, rupintrivir, and remdesivir efficiently inhibits enterovirus infections in vitro, delaying the development of drug-resistant virus variants. Antiviral Research. ISSN 0166-3542. 224, s. 1–8. doi: 10.1016/j.antiviral.2024.105842. Fulltekst i vitenarkiv Vis sammendrag

  Enteroviruses are a significant global health concern, causing a spectrum of diseases from the common cold to more severe conditions like hand-foot-and-mouth disease, meningitis, myocarditis, pancreatitis, and poliomyelitis. Current treatment options for these infections are limited, underscoring the urgent need for effective therapeutic strategies. To find better treatment option we analyzed toxicity and efficacy of 12 known broad-spectrum anti-enterovirals both individually and in combinations against different enteroviruses in vitro. We identified several novel, synergistic two-drug and three-drug combinations that demonstrated significant inhibition of enterovirus infections in vitro. Specifically, the triple-drug combination of pleconaril, rupintrivir, and remdesivir exhibited remarkable efficacy against echovirus (EV) 1, EV6, EV11, and coxsackievirus (CV) B5, in human lung epithelial A549 cells. This combination surpassed the effectiveness of single-agent or dual-drug treatments, as evidenced by its ability to protect A549 cells from EV1-induced cytotoxicity across seven passages. Additionally, this triple-drug cocktail showed potent antiviral activity against EV-A71 in human intestinal organoids. Thus, our findings highlight the therapeutic potential of the pleconaril-rupintrivir-remdesivir combination as a broad-spectrum treatment option against a range of enterovirus infections. The study also paves the way towards development of strategic antiviral drug combinations with virus family coverage and high-resistance barriers.

• Bordin, Diana Lilian; Grooms, Kayla Mae; Montaldo, Nicola Pietro; Martin, Sarah Louise Fordyce; Sætrom, Pål & Samson, Leona D. [Vis alle 8 forfattere av denne artikkelen] (2024). Loss of alkyladenine DNA glycosylase alters gene expression in the developing mouse brain and leads to reduced anxiety and improved memory. DNA Repair. ISSN 1568-7864. 135, s. 1–10. doi: 10.1016/j.dnarep.2024.103632. Fulltekst i vitenarkiv Vis sammendrag

  Neurodevelopment is a tightly coordinated process, during which the genome is exposed to spectra of endogenous agents at different stages of differentiation. Emerging evidence indicates that DNA damage is an important feature of developing brain, tightly linked to gene expression and neuronal activity. Some of the most frequent DNA damage includes changes to DNA bases, which are recognized by DNA glycosylases and repaired through base excision repair (BER) pathway. The only mammalian DNA glycosylase able to remove frequent alkylated DNA based is alkyladenine DNA glycosylase (Aag, aka Mpg). We recently demonstrated that, besides its role in DNA repair, AAG affects expression of neurodevelopmental genes in human cells. Aag was further proposed to act as reader of epigenetic marks, including 5-hydroxymethylcytosine (5hmC), in the mouse brain. Despite the potential Aag involvement in the key brain processes, the impact of Aag loss on developing brain remains unknown. Here, by using Aag knockout (Aag-/-) mice, we show that Aag absence leads to reduced DNA break levels, evident in lowered number of γH2AX foci in postnatal day 5 (P5) hippocampi. This is accompanied by changes in 5hmC signal intensity in different hippocampal regions. Transcriptome analysis of hippocampi and prefrontal cortex, at different developmental stages, indicates that lack of Aag alters gene expression, primarily of genes involved in regulation of response to stress. Across all developmental stages tested aldehyde dehydrogenase 2 (Aldh2) emerged as one of the most prominent genes deregulated in Aag-dependent manner. In line with the changes in hippocampal DNA damage levels and the gene expression, adult Aag-/- mice exhibit altered behavior, evident in decreased anxiety levels determined in the Elevated Zero Maze and increased alternations in the Elevated T Maze tests. Taken together these results suggests that Aag has functions in modulation of genome dynamics during brain development, important for animal behavior.

• Bugaj, Anna Maria; Kunath, Nicolas; Saasen, Vidar Langseth; Berrocal, Marion Silvana Fernández; Vankova, Ana & Sætrom, Pål [Vis alle 8 forfattere av denne artikkelen] (2024). Dissecting gene expression networks in the developing hippocampus through the lens of NEIL3 depletion. Progress in Neurobiology. ISSN 0301-0082. 235:102599, s. 1–14. doi: 10.1016/j.pneurobio.2024.102599. Fulltekst i vitenarkiv Vis sammendrag

  Gene regulation in the hippocampus is fundamental for its development, synaptic plasticity, memory formation, and adaptability. Comparisons of gene expression among different developmental stages, distinct cell types, and specific experimental conditions have identified differentially expressed genes contributing to the organization and functionality of hippocampal circuits. The NEIL3 DNA glycosylase, one of the DNA repair enzymes, plays an important role in hippocampal maturation and neuron functionality by shaping transcription. While differential gene expression (DGE) analysis has identified key genes involved, broader gene expression patterns crucial for high-order hippocampal functions remain uncharted. By utilizing the weighted gene co-expression network analysis (WGCNA), we mapped gene expression networks in immature (p8-neonatal) and mature (3 m-adult) hippocampal circuits in wild-type and NEIL3-deficient mice. Our study unveiled intricate gene network structures underlying hippocampal maturation, delineated modules of co-expressed genes, and pinpointed highly interconnected hub genes specific to the maturity of hippocampal subregions. We investigated variations within distinct gene network modules following NEIL3 depletion, uncovering NEIL3-targeted hub genes that influence module connectivity and specificity. By integrating WGCNA with DGE, we delve deeper into the NEIL3-dependent molecular intricacies of hippocampal maturation. This study provides a comprehensive systems-level analysis for assessing the potential correlation between gene connectivity and functional connectivity within the hippocampal network, thus shaping hippocampal function throughout development.

• Yang, Mingyi; Kaarbø, Mari; Myhre, Vegard; Reims, Henrik Mikael; Karlsen, Tom Hemming & Wang, Junbai [Vis alle 13 forfattere av denne artikkelen] (2024). Altered Genome-Wide DNA Methylation in the Duodenum of Common Variable Immunodeficiency Patients. Journal of Clinical Immunology. ISSN 0271-9142. 44(6), s. 1–16. doi: 10.1007/s10875-024-01726-5. Fulltekst i vitenarkiv Vis sammendrag

  Purpose A large proportion of Common variable immunodeficiency (CVID) patients has duodenal inflammation with increased intraepithelial lymphocytes (IEL) of unknown aetiology. The histologic similarities to celiac disease, lead to confusion regarding treatment (gluten-free diet) of these patients. We aimed to elucidate the role of epigenetic DNA methylation in the aetiology of duodenal inflammation in CVID and differentiate it from true celiac disease. Methods DNA was isolated from snap-frozen pieces of duodenal biopsies and analysed for differences in genome-wide epigenetic DNA methylation between CVID patients with increased IEL (CVID_IEL; n = 5) without IEL (CVID_N; n = 3), celiac disease (n = 3) and healthy controls (n = 3). Results The DNA methylation data of 5-methylcytosine in CpG sites separated CVID and celiac diseases from healthy controls. Differential methylation in promoters of genes were identified as potential novel mediators in CVID and celiac disease. There was limited overlap of methylation associated genes between CVID_IEL and Celiac disease. High frequency of differentially methylated CpG sites was detected in over 100 genes nearby transcription start site (TSS) in both CVID_IEL and celiac disease, compared to healthy controls. Differential methylation of genes involved in regulation of TNF/cytokine production were enriched in CVID_IEL, compared to healthy controls. Conclusion This is the first study to reveal a role of epigenetic DNA methylation in the etiology of duodenal inflammation of CVID patients, distinguishing CVID_IEL from celiac disease. We identified potential biomarkers and therapeutic targets within gene promotors and in high-frequency differentially methylated CpG regions proximal to TSS in both CVID_IEL and celiac disease.

• Neurauter, Christine Gran; Pannone, Marco; Sousa, Mirta; Wang, Wei; Kusnierczyk, Anna & Luna, Luisa [Vis alle 9 forfattere av denne artikkelen] (2024). Enhanced glutathione levels confer resistance to apoptotic and ferroptotic programmed cell death in NEIL DNA glycosylase deficient HAP1 cells. Free Radical Biology & Medicine. ISSN 0891-5849. 213, s. 470–487. doi: 10.1016/j.freeradbiomed.2024.01.037. Fulltekst i vitenarkiv Vis sammendrag

  The NTHL1 and NEIL1-3 DNA glycosylases are major enzymes in the removal of oxidative DNA base lesions, via the base excision repair (BER) pathway. It is expected that lack of these DNA glycosylases activities would render cells vulnerable to oxidative stress, promoting cell death. Intriguingly, we found that single, double, triple, and quadruple DNA glycosylase knockout HAP1 cells are, however, more resistant to oxidative stress caused by genotoxic agents than wild type cells. Furthermore, glutathione depletion in NEIL deficient cells further enhances resistance to cell death induced via apoptosis and ferroptosis. Finally, we observed higher basal level of glutathione and differential expression of NRF2-regulated genes associated with glutathione homeostasis in the NEIL triple KO cells. We propose that lack of NEIL DNA glycosylases causes aberrant transcription and subsequent errors in protein synthesis. This leads to increased endoplasmic reticulum stress and proteotoxic stress. To counteract the elevated intracellular stress, an adaptive response mediated by increased glutathione basal levels, rises in these cells. This study reveals an unforeseen role of NEIL glycosylases in regulation of resistance to oxidative stress, suggesting that modulation of NEIL glycosylase activities is a potential approach to improve the efficacy of e.g. anti-inflammatory therapies.

• Alonso, Lucia Ramos; Holland, Petter; Gras, Stéphanie Le; Zhao, Xu; Jost, Bernard & Bjørås, Magnar [Vis alle 9 forfattere av denne artikkelen] (2023). Mitotic chromosome condensation resets chromatin to safeguard transcriptional homeostasis during interphase. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 120(4). doi: 10.1073/pnas.2210593120. Fulltekst i vitenarkiv Vis sammendrag

  Mitotic entry correlates with the condensation of the chromosomes, changes in histone modifications, exclusion of transcription factors from DNA, and the broad downregulation of transcription. However, whether mitotic condensation influences transcription in the subsequent interphase is unknown. Here, we show that preventing one chromosome to condense during mitosis causes it to fail resetting of transcription. Rather, in the following interphase, the affected chromosome contains unusually high levels of the transcription machinery, resulting in abnormally high expression levels of genes in cis, including various transcription factors. This subsequently causes the activation of inducible transcriptional programs in trans, such as the GAL genes, even in the absence of the relevant stimuli. Thus, mitotic chromosome condensation exerts stringent control on interphase gene expression to ensure the maintenance of basic cellular functions and cell identity across cell divisions. Together, our study identifies the maintenance of transcriptional homeostasis during interphase as an unexpected function of mitosis and mitotic chromosome condensation.

• Starheim, Eirin Johannessen; Ravlo, Erlend; Schjølberg, Jørn-Ove; Solvang, Vanessa; Wang, Wei & Scrimgeour, Nathan Robert [Vis alle 12 forfattere av denne artikkelen] (2023). NAxtra magnetic nanoparticles for low-cost, efficient isolation of mammalian DNA and RNA. Scientific Reports. 13(1), s. 1–13. doi: 10.1038/s41598-023-46868-5. Fulltekst i vitenarkiv Vis sammendrag

  A cost-effective, viral nucleic acid (NA) isolation kit based on NAxtra magnetic nanoparticles was developed at the Norwegian University of Science and Technology in response to the shortage of commercial kits for isolation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA during the coronavirus disease 2019 (COVID-19) pandemic. This method showed comparable sensitivity to available kits at significantly reduced cost, making its application for other biological sources an intriguing prospect. Thus, based on this low-cost nucleic acid extraction technology, we developed a simple, low- and high-throughput, efficient method for isolation of high-integrity total NA, DNA and RNA from mammalian cell lines (monolayer) and organoids (3D-cultures). The extracted NA are compatible with downstream applications including (RT-)qPCR and next-generation sequencing. When automated, NA isolation can be performed in 14 min for up to 96 samples, yielding similar quantities to available kits.

• Sæbø, Ingvill Pedersen; Bjørås, Magnar; Franzyk, Henrik; Helgesen, Emily & Booth, James Alexander (2023). Optimization of the Hemolysis Assay for the Assessment of Cytotoxicity. International Journal of Molecular Sciences. ISSN 1661-6596. 24(3), s. 1–20. doi: 10.3390/ijms24032914. Fulltekst i vitenarkiv Vis sammendrag

  In vitro determination of hemolytic properties is a common and important method for preliminary evaluation of cytotoxicity of chemicals, drugs, or any blood-contacting medical device or material. The method itself is relatively straightforward, however, protocols used in the literature vary substantially. This leads to significant difficulties both in interpreting and in comparing the obtained values. Here, we examine how the different variables used under different experimental setups may affect the outcome of this assay. We find that certain key parameters affect the hemolysis measurements in a critical manner. The hemolytic effect of compounds tested here varied up to fourfold depending on the species of the blood source. The use of different types of detergents used for generating positive control samples (i.e., 100% hemolysis) produced up to 2.7-fold differences in the calculated hemolysis ratios. Furthermore, we find an expected, but substantial, increase in the number of hemolyzed erythrocytes with increasing erythrocyte concentration and with prolonged incubation time, which in turn affects the calculated hemolysis ratios. Based on our findings we propose an optimized protocol in an attempt to standardize future hemolysis studies.

• Bali, Nesrine; Brennhaug, Svein Jonsson; Bjørås, Magnar; Bandyopadhyay, Sulalit & Manaf, Adeel (2023). Optimized synthesis of polyacrylic acid-coated magnetic nanoparticles for high-efficiency DNA isolation and size selection. RSC Advances. 13(42), s. 29109–29120. doi: 10.1039/d3ra04687g. Fulltekst i vitenarkiv Vis sammendrag

  Solid-phase reversible immobilization (SPRI) bead technology is widely used in molecular biology for convenient DNA manipulation. However, commercial SPRI bead kits lack cost advantages and flexibility. It is, therefore, necessary to develop new and alternative cost-effective methods of on-par or better quality. Herein, an easy and cost-effective method is proposed for synthesizing polyacrylic acid-coated iron oxide nanoparticles (PAA-IONPs) through in situ polymerization at lab scale for high-efficiency nucleic acid extraction and size selection. A design of experiment (DoE) approach was used to investigate the influence of iron oxide nanoparticles (IONPs), acrylic acid (AA) monomer, and sodium dodecyl sulfate (SDS) surfactant amounts on the sizes and carboxyl group densities of PAA-IONPs. Thorough characterization by thermogravimetric analysis (TGA), attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) and vibrating sample magnetometry (VSM) highlights the importance of a low starting pH achieved by a high ratio of AA/IONPs, to yield the largest sizes (554 nm) and highest carboxyl group densities (2.13 mmol g−1) obtained in this study. An efficient DNA purification strategy is then presented using homemade beads-suspension buffer and optimized bead concentrations (17% PEG 8000, 2.5 M NaCl, and 3 mg mL−1 PAA-IONPs). This method shows comparable performance to the control (AMPure XP beads) for DNA recovery. An adjustable PAA-IONPs DNA purification system was also developed to be used for DNA-size selection at low DNA amounts (50–100 ng) with a high degree of resolution and recovery. In conclusion, this work offers an optimized PAA-IONPs synthesis protocol and a flexible DNA purification approach that will enable researchers to manipulate DNA under various conditions, holding the significant potential to benefit future molecular biology research and diagnostics.

• Kaarbø, Mari; Yang, Mingyi; Hov, Johannes R.; Holm, Kristian; Sousa, Mirta Mittelstedt Leal de & Macpherson, Magnhild E [Vis alle 15 forfattere av denne artikkelen] (2023). Duodenal inflammation in common variable immunodeficiency has altered transcriptional response to viruses. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. doi: 10.1016/j.jaci.2022.09.029. Fulltekst i vitenarkiv
• Yang, Mingyi; Ali, Omer; Bjørås, Magnar & Wang, Junbai (2023). Identifying functional regulatory mutation blocks by integrating genome sequencing and transcriptome data. iScience. 26(8), s. 1–23. doi: 10.1016/j.isci.2023.107266. Fulltekst i vitenarkiv Vis sammendrag

  Millions of single nucleotide variants (SNVs) exist in the human genome; however, it remains challenging to identify functional SNVs associated with diseases. We propose a non-encoding SNVs analysis tool bpb3, BayesPI-BAR version 3, aiming to identify the functional mutation blocks (FMBs) by integrating genome sequencing and transcriptome data. The identified FMBs display high frequency SNVs, significant changes in transcription factors (TFs) binding affinity and are nearby the regulatory regions of differentially expressed genes. A two-level Bayesian approach with a biophysical model for protein-DNA interactions is implemented, to compute TF-DNA binding affinity changes based on clustered position weight matrices (PWMs) from over 1700 TF-motifs. The epigenetic data, such as the DNA methylome can also be integrated to scan FMBs. By testing the datasets from follicular lymphoma and melanoma, bpb3 automatically and robustly identifies FMBs, demonstrating that bpb3 can provide insight into patho-mechanisms, and therapeutic targets from transcriptomic and genomic data.

• Benjakul, Sopisa; Anthi, Aina Karen; Kolderup, Heidi Anette; Vaysburd, Marina; Lode, Heidrun Elisabeth & Mallery, D [Vis alle 20 forfattere av denne artikkelen] (2023). A pan-SARS-CoV-2-specific soluble angiotensin-converting enzyme 2-albumin fusion engineered for enhanced plasma half-life and needle-free mucosal delivery. PNAS Nexus. 2(12), s. 1–15. doi: 10.1093/pnasnexus/pgad403. Fulltekst i vitenarkiv Vis sammendrag

  Immunocompromised patients often fail to raise protective vaccine-induced immunity against the global emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Although monoclonal antibodies have been authorized for clinical use, most have lost their ability to potently neutralize the evolving Omicron subvariants. Thus, there is an urgent need for treatment strategies that can provide protection against these and emerging SARS-CoV-2 variants to prevent the development of severe coronavirus disease 2019. Here, we report on the design and characterization of a long-acting viral entry-blocking angiotensin-converting enzyme 2 (ACE2) dimeric fusion molecule. Specifically, a soluble truncated human dimeric ACE2 variant, engineered for improved binding to the receptor-binding domain of SARS-CoV-2, was fused with human albumin tailored for favorable engagement of the neonatal fragment crystallizable receptor (FcRn), which resulted in enhanced plasma half-life and allowed for needle-free transmucosal delivery upon nasal administration in human FcRn-expressing transgenic mice. Importantly, the dimeric ACE2-fused albumin demonstrated potent neutralization of SARS-CoV-2 immune escape variants.

• Ravlo, Erlend; Sousa, Mirta; Andresen, Lise Lima; Holberg-Petersen, Mona; Klundby, Ingvild & Aas, Per Arne [Vis alle 14 forfattere av denne artikkelen] (2023). A fast, low-cost, robust and high-throughput method for viral nucleic acid isolation based on NAxtra magnetic nanoparticles. Scientific Reports. 13(1), s. 1–7. doi: 10.1038/s41598-023-38743-0. Fulltekst i vitenarkiv Vis sammendrag

  The year of 2020 was profoundly marked by a global pandemic caused by a strain of coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19). To control disease spread, a key strategy adopted by many countries was the regular testing of individuals for infection. This led to the rapid development of diagnostic testing technologies. In Norway, within a week, our group developed a test kit to quickly isolate viral RNA and safely detect SARS-CoV-2 infection with sensitivity comparable to available kits. Herein, the procedure employed for the detection of SARS-CoV-2 in swab samples from patients using the NTNU-COVID-19 test kit is described in detail. This procedure, based on NAxtra magnetic nanoparticles and an optimized nucleic acid extraction procedure, is robust, reliable, and straightforward, providing high-quality nucleic acids within 14 min. The NAxtra protocol is adaptable and was further validated for extraction of DNA and RNA from other types of viruses. A comparison of the protocol on different liquid handling systems is also presented. Due to the simplicity and low cost of this method, implementation of this technology to diagnose virus infections on a clinical setting would benefit health care systems, promoting sustainability.

• Lin, Xiaolin; Wang, Wei; Yang, Mingyi; Damseh, Nadirah; Sousa, Mirta & Jacob, Fadi [Vis alle 29 forfattere av denne artikkelen] (2023). A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial–temporal regulation of histone arginine methylation in neurodevelopment. Genome Biology. ISSN 1465-6906. 24(1). doi: 10.1186/s13059-023-03037-1. Fulltekst i vitenarkiv Vis sammendrag

  Background Oxidation Resistance 1 (OXR1) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency. Results We report a novel loss-of-function mutation in the TLDc domain of the human OXR1 gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model the function of OXR1 in early human brain development using patient-derived brain organoids revealing that OXR1 contributes to the spatial–temporal regulation of histone arginine methylation in specific brain regions. Conclusions This study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.

• Olsen, Maria Belland; Sannes, Ann-Christin; Yang, Kuan; Nielsen, Morten Birkeland; Einarsen, Ståle Valvatne & Christensen, Jan Olav [Vis alle 9 forfattere av denne artikkelen] (2022). Mapping of pituitary stress-induced gene regulation connects Nrcam to negative emotions. iScience. 25(9). doi: 10.1016/j.isci.2022.104953. Fulltekst i vitenarkiv Vis sammendrag

  Environmental stressors such as repeated social defeat may initiate powerful activation of subconscious parts of the brain. Here, we examine the consequences of such stress (induced by resident-intruder paradigm) on the pituitary gland. In male stressed vs. control rats, by RNA- and bisulfite DNA sequencing, we found regulation of genes involved in neuron morphogenesis and communication. Among these, Neuronal cell adhesion molecule (Nrcam) showed reduced transcription and reduced DNA methylation in a region corresponding to intron 1 in human NRCAM. Also, genetic variability in this area was associated with altered stress response in male humans exposed to repeated social defeat in the form of abusive supervision. Thus, our data show that the pituitary gene expression may be affected by social stress and that genetic variability in NRCAM intron 1 region influences stress-induced negative emotions. We hope our shared datasets will facilitate further exploration of the motions triggered by social stressors.

• Ianevski, Aleksandr; Ahmad, Shahzaib; Anunnitipat, Kraipit; Oksenych, Valentyn; Zusinaite, Eva & Tenson, Tanel [Vis alle 8 forfattere av denne artikkelen] (2022). Seven classes of antiviral agents. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 79(12). doi: 10.1007/s00018-022-04635-1. Fulltekst i vitenarkiv Vis sammendrag

  The viral epidemics and pandemics have stimulated the development of known and the discovery of novel antiviral agents. About a hundred mono- and combination antiviral drugs have been already approved, whereas thousands are in development. Here, we briefly reviewed 7 classes of antiviral agents: neutralizing antibodies, neutralizing recombinant soluble human receptors, antiviral CRISPR/Cas systems, interferons, antiviral peptides, antiviral nucleic acid polymers, and antiviral small molecules. Interferons and some small molecules alone or in combinations possess broad-spectrum antiviral activity, which could be beneficial for treatment of emerging and re-emerging viral infections.

• Liu, Xin; Risbakk, Sanne; Carvalho, Patricia Almeida; Yang, Mingyi; Backe, Paul Hoff & Bjørås, Magnar [Vis alle 8 forfattere av denne artikkelen] (2022). Immobilization of FeFe-hydrogenase on black TiO2 nanotubes as biocathodes for the hydrogen evolution reaction. Electrochemistry communications. ISSN 1388-2481. 135. doi: 10.1016/j.elecom.2022.107221. Fulltekst i vitenarkiv Vis sammendrag

  Hydrogenases are attractive biocatalysts for utilization in electrochemical devices as potential replacement for Pt in hydrogen evolving electrodes. In this work, we investigate the immobilization of ferredoxin tagged FeFe-hydrogenase (Fd-HydA1) on black TiO2 nanotubes (bTNTs), with uniform nanotube opening diameters of 140 nm. By utilizing an immunogold labelling method, we show that the enzymes attach on the top surface of the bTNTs film rather than on the inner nanotube walls, reflecting the difficulty to insert enzymes into high aspect-ratio nanomaterials for O2-shielding. Nevertheless, cyclic voltammetry demonstrates direct electron transfer between Fd-HydA1 and bTNTs for the hydrogen evolution reaction (HER) in neutral media. This work provides new insight towards design of new nanostructured electrodes for enzyme immobilization.

• Ali, Omer; Farooq, Amna; Yang, Mingyi; Jin, Victor X.; Bjørås, Magnar & Wang, Junbai (2022). abc4pwm: affinity based clustering for position weight matrices in applications of DNA sequence analysis. BMC Bioinformatics. 23(1). doi: 10.1186/s12859-022-04615-z. Fulltekst i vitenarkiv Vis sammendrag

  Background Transcription factor (TF) binding motifs are identified by high throughput sequencing technologies as means to capture Protein-DNA interactions. These motifs are often represented by consensus sequences in form of position weight matrices (PWMs). With ever-increasing pool of TF binding motifs from multiple sources, redundancy issues are difficult to avoid, especially when every source maintains its own database for collection. One solution can be to cluster biologically relevant or similar PWMs, whether coming from experimental detection or in silico predictions. However, there is a lack of efficient tools to cluster PWMs. Assessing quality of PWM clusters is yet another challenge. Therefore, new methods and tools are required to efficiently cluster PWMs and assess quality of clusters. Results A new Python package Affinity Based Clustering for Position Weight Matrices (abc4pwm) was developed. It efficiently clustered PWMs from multiple sources with or without using DNA-Binding Domain (DBD) information, generated a representative motif for each cluster, evaluated the clustering quality automatically, and filtered out incorrectly clustered PWMs. Additionally, it was able to update human DBD family database automatically, classified known human TF PWMs to the respective DBD family, and performed TF motif searching and motif discovery by a new ensemble learning approach. Conclusion This work demonstrates applications of abc4pwm in the DNA sequence analysis for various high throughput sequencing data using ~ 1770 human TF PWMs. It recovered known TF motifs at gene promoters based on gene expression profiles (RNA-seq) and identified true TF binding targets for motifs predicted from ChIP-seq experiments. Abc4pwm is a useful tool for TF motif searching, clustering, quality assessment and integration in multiple types of sequence data analysis including RNA-seq, ChIP-seq and ATAC-seq.

• Ianevski, Aleksandr; Zusinaite, Eva; Tenson, Tanel; Oksenych, Valentyn; Wang, Wei & Afset, Jan Egil [Vis alle 8 forfattere av denne artikkelen] (2022). Novel Synergistic Anti-Enteroviral Drug Combinations. Viruses. 14(9). doi: 10.3390/v14091866. Fulltekst i vitenarkiv Vis sammendrag

  Background: Enterovirus infections affect people around the world, causing a range of illnesses, from mild fevers to severe, potentially fatal conditions. There are no approved treatments for enterovirus infections. Methods: We have tested our library of broad-spectrum antiviral agents (BSAs) against echovirus 1 (EV1) in human adenocarcinoma alveolar basal epithelial A549 cells. We also tested combinations of the most active compounds against EV1 in A549 and human immortalized retinal pigment epithelium RPE cells. Results: We confirmed anti-enteroviral activities of pleconaril, rupintrivir, cycloheximide, vemurafenib, remdesivir, emetine, and anisomycin and identified novel synergistic rupintrivir–vemurafenib, vemurafenib–pleconaril and rupintrivir–pleconaril combinations against EV1 infection. Conclusions: Because rupintrivir, vemurafenib, and pleconaril require lower concentrations to inhibit enterovirus replication in vitro when combined, their cocktails may have fewer side effects in vivo and, therefore, should be further explored in preclinical and clinical trials against EV1 and other enterovirus infections.

• Quiles-Jiménez, Ana M T; Dahl, Tuva Børresdatter; Bjørås, Magnar; Alseth, Ingrun; Halvorsen, Bente & Gregersen, Ida (2022). Epitranscriptome in Ischemic Cardiovascular Disease: Potential Target for Therapies. Stroke. ISSN 0039-2499. 53(6), s. 2114–2122. doi: 10.1161/STROKEAHA.121.037581. Fulltekst i vitenarkiv
• Egiazarian, Milena Armenovna; Strømstad, Silje; Sakshaug, Teri; Nescolarde, Ana Beatriz Núñez; Bethge, Nicole & Bjørås, Magnar [Vis alle 7 forfattere av denne artikkelen] (2022). Age- and sex-dependent effects of DNA glycosylase Neil3 on amyloid pathology, adult neurogenesis, and memory in a mouse model of Alzheimer's disease. Free Radical Biology & Medicine. ISSN 0891-5849. 193(Pt 2), s. 685–693. doi: 10.1016/j.freeradbiomed.2022.11.020. Fulltekst i vitenarkiv Vis sammendrag

  Oxidative stress generating DNA damage has been shown to be a key characteristic in Alzheimer's disease (AD). However, how it affects the pathogenesis of AD is not yet fully understood. Neil3 is a DNA glycosylase initiating repair of oxidative DNA base lesions and with a distinct expression pattern in proliferating cells. In brain, its function has been linked to hippocampal-dependent memory and to induction of neurogenesis after stroke and in prion disease. Here, we generated a novel AD mouse model deficient for Neil3 to study the impact of impaired oxidative base lesion repair on the pathogenesis of AD. Our results demonstrate an age-dependent decrease in amyloid-β (Aβ) plaque deposition in female Neil3-deficient AD mice, whereas no significant difference was observed in male mice. Furthermore, male but not female Neil3-deficient AD mice show reduced neural stem cell proliferation in the adult hippocampus and impaired working memory compared to controls. These effects seem to be independent of DNA repair as both sexes show increased level of oxidative base lesions in the hippocampus upon loss of Neil3. Thus, our findings suggest an age- and sex-dependent role of Neil3 in the progression of AD by altering cerebral Aβ accumulation and promoting adult hippocampal neurogenesis to maintain cognitive function.

• Kaarbø, Mari; Yang, Mingyi; Hov, Johannes Espolin Roksund; Holm, Kristian; Sousa, Mirta & Macpherson, Magnhild Eide [Vis alle 15 forfattere av denne artikkelen] (2022). Duodenal inflammation in common variable immunodeficiency has altered transcriptional response to viruses. Journal of Allergy and Clinical Immunology. ISSN 0091-6749. doi: 10.1016/j.jaci.2022.09.029. Fulltekst i vitenarkiv Vis sammendrag

  Background A substantial proportion of common variable immunodeficiency (CVID) patients has duodenal inflammation of largely unknown etiology. However, because of its histologic similarities with celiac disease, gluten sensitivity has been proposed as a potential mechanism. Objective We aimed to elucidate the role of the duodenal microenvironment in the pathogenesis of duodenal inflammation in CVID by investigating the transcriptional, proteomic, and microbial signatures of duodenal biopsy samples in CVID. Methods DNA, total RNA, and protein were isolated from snap-frozen pieces of duodenal biopsy samples from CVID (with and without duodenal inflammation), healthy controls, and patients with celiac disease (untreated). RNA sequencing, mass spectrometry–based proteomics, and 16S ribosomal DNA sequencing (bacteria) were then performed. Results CVID separated from controls in regulation of transcriptional response to lipopolysaccharide and cellular immune responses. These differences were independent of mucosal inflammation. Instead, CVID patients with duodenal inflammation displayed alterations in transcription of genes involved in response to viral infections. Four proteins were differently regulated between CVID patients and healthy controls—DBNL, TRMT11, GCHFR, and IGHA2—independent of duodenal inflammation. Despite similar histology, there were major differences in CVID with duodenal inflammation and celiac disease both at the RNA and protein level. No significant difference was observed in the bacterial gut microbial signature between CVID, celiac, and healthy controls. Conclusion Our findings suggest the existence of altered functions of the duodenal epithelium, particularly in response to lipopolysaccharide and viruses. The latter finding was related to duodenal inflammation, suggesting that viruses, not gluten sensitivity, could be related to duodenal inflammation in CVID. Key words CVID RNA sequencing proteomics microbiome gut microbiota microbiota gastrointestinal tract duodenum celiac disease Primary immunodeficiency IgA

• Pinto, Sneha M.; Subbannayya, Yashwanth; Kim, Hera; Hagen, Lars; Górna, Maria W & Nieminen, Anni I. [Vis alle 10 forfattere av denne artikkelen] (2022). Multi-OMICs landscape of SARS-CoV-2-induced host responses in human lung epithelial cells. iScience. 26(1), s. 1–33. doi: 10.1016/j.isci.2022.105895. Fulltekst i vitenarkiv Vis sammendrag

  COVID-19 pandemic continues to remain a global health concern owing to the emergence of newer variants. Several multi-Omics studies have produced extensive evidence on host-pathogen interactions and potential therapeutic targets. Nonetheless, an increased understanding of host signaling networks regulated by post-translational modifications and their ensuing effect on the cellular dynamics is critical to expanding the current knowledge on SARS-CoV-2 infections. Through an unbiased transcriptomics, proteomics, acetylomics, phosphoproteomics, and exometabolome analysis of a lung-derived human cell line, we show that SARS-CoV-2 Norway/Trondheim-S15 strain induces time-dependent alterations in the induction of type I IFN response, activation of DNA damage response, dysregulated Hippo signaling, among others. We identified interplay of phosphorylation and acetylation dynamics on host proteins and its effect on the altered release of metabolites, especially organic acids and ketone bodies. Together, our findings serve as a resource of potential targets that can aid in designing novel host-directed therapeutic strategies.

• Karlsen, Tom Rune; Olsen, Maria Belland; Kong, Xiang Yi; Yang, Kuan; Quiles-Jiménez, Ana M T & Kroustallaki, Pinelopi [Vis alle 15 forfattere av denne artikkelen] (2022). NEIL3-deficient bone marrow displays decreased hematopoietic capacity and reduced telomere length. Biochemistry and Biophysics Reports. 29. doi: 10.1016/j.bbrep.2022.101211. Fulltekst i vitenarkiv Vis sammendrag

  Deficiency of NEIL3, a DNA repair enzyme, has significant impact on mouse physiology, including vascular biology and gut health, processes related to aging. Leukocyte telomere length (LTL) is suggested as a marker of biological aging, and shortened LTL is associated with increased risk of cardiovascular disease. NEIL3 has been shown to repair DNA damage in telomere regions in vitro. Herein, we explored the role of NEIL3 in telomere maintenance in vivo by studying bone marrow cells from atherosclerosis-prone NEIL3-deficient mice. We found shortened telomeres and decreased activity of the telomerase enzyme in bone marrow cells derived from Apoe−/−Neil3−/− as compared to Apoe−/− mice. Furthermore, Apoe−/−Neil3−/− mice had decreased leukocyte levels as compared to Apoe−/− mice, both in bone marrow and in peripheral blood. Finally, RNA sequencing of bone marrow cells from Apoe−/−Neil3−/− and Apoe−/− mice revealed different expression levels of genes involved in cell cycle regulation, cellular senescence and telomere protection. This study points to NEIL3 as a telomere-protecting protein in murine bone marrow in vivo.

• Ianevski, Aleksandr; Simonsen, Ronja Meyer; Myhre, Vegard; Tenson, Tanel; Oksenych, Valentyn & Bjørås, Magnar [Vis alle 7 forfattere av denne artikkelen] (2022). DrugVirus.info 2.0: an integrative data portal for broad-spectrum antivirals (BSA) and BSA-containing drug combinations (BCCs). Nucleic Acids Research (NAR). ISSN 0305-1048. 50(W1), s. W272–W275. doi: 10.1093/nar/gkac348. Fulltekst i vitenarkiv Vis sammendrag

  Viruses can cross species barriers and cause unpredictable outbreaks in man with substantial economic and public health burdens. Broad-spectrum antivirals, (BSAs, compounds inhibiting several human viruses), and BSA-containing drug combinations (BCCs) are deemed as immediate therapeutic options that fill the void between virus identification and vaccine development. Here, we present DrugVirus.info 2.0 (https://drugvirus.info), an integrative interactive portal for exploration and analysis of BSAs and BCCs, that greatly expands the database and functionality of DrugVirus.info 1.0 webserver. Through the data portal that now expands the spectrum of BSAs and provides information on BCCs, we developed two modules for (i) interactive analysis of users’ own antiviral drug and combination screening data and their comparison with published datasets, and (ii) exploration of the structure–activity relationship between various BSAs. The updated portal provides an essential toolbox for antiviral drug development and repurposing applications aiming to identify existing and novel treatments of emerging and re-emerging viral threats.

• Olsen, Maria Belland; Huse, Camilla; Sousa, Mirta; Murphy, Sarah Louise Mikalsen; Sarno, Antonio & Obermann, Tobias Sebastian [Vis alle 20 forfattere av denne artikkelen] (2022). DNA Repair Mechanisms are Activated in Circulating Lymphocytes of Hospitalized Covid-19 Patients. Journal of Inflammation Research. 15, s. 6629–6644. doi: 10.2147/JIR.S379331. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: Reactive oxygen species (ROS) are an important part of the inflammatory response during infection but can also promote DNA damage. Due to the sustained inflammation in severe Covid-19, we hypothesized that hospitalized Covid-19 patients would be characterized by increased levels of oxidative DNA damage and dysregulation of the DNA repair machinery. Patients and Methods: Levels of the oxidative DNA lesion 8-oxoG and levels of base excision repair (BER) proteins were measured in peripheral blood mononuclear cells (PBMC) from patients (8-oxoG, n = 22; BER, n = 17) and healthy controls (n = 10) (Cohort 1). Gene expression related to DNA repair was investigated in two independent cohorts of hospitalized Covid-19 patients (Cohort 1; 15 patents and 5 controls, Cohort 2; 15 patients and 6 controls), and by publicly available datasets. Results: Patients and healthy controls showed comparable amounts of oxidative DNA damage as assessed by 8-oxoG while levels of several BER proteins were increased in Covid-19 patients, indicating enhanced DNA repair in acute Covid-19 disease. Furthermore, gene expression analysis demonstrated regulation of genes involved in BER and double strand break repair (DSBR) in PBMC of Covid-19 patients and expression level of several DSBR genes correlated with the degree of respiratory failure. Finally, by re-analyzing publicly available data, we found that the pathway Hallmark DNA repair was significantly more regulated in circulating immune cells during Covid-19 compared to influenza virus infection, bacterial pneumonia or acute respiratory infection due to seasonal coronavirus. Conclusion: Although beneficial by protecting against DNA damage, long-term activation of the DNA repair machinery could also contribute to persistent inflammation, potentially through mechanisms such as the induction of cellular senescence. However, further studies that also include measurements of additional markers of DNA damage are required to determine the role and precise molecular mechanisms for DNA repair in SARS-CoV-2 infection.

• Kennedy, Lauritz Hagen; Glesaaen, Emilie Rylund; Palibrk, Vuk; Pannone, Marco; Wang, Wei & Al-Jabri, Ali [Vis alle 13 forfattere av denne artikkelen] (2022). Lactate receptor HCAR1 regulates neurogenesis and microglia activation after neonatal hypoxia-ischemia. eLIFE. 11. doi: 10.7554/eLife.76451. Fulltekst i vitenarkiv Vis sammendrag

  Neonatal cerebral hypoxia-ischemia (HI) is the leading cause of death and disability in newborns with the only current treatment being hypothermia. An increased understanding of the pathways that facilitate tissue repair after HI may aid the development of better treatments. Here, we study the role of lactate receptor HCAR1 in tissue repair after neonatal HI in mice. We show that HCAR1 knockout mice have reduced tissue regeneration compared with wildtype mice. Furthermore, proliferation of neural progenitor cells and glial cells, as well as microglial activation was impaired. Transcriptome analysis showed a strong transcriptional response to HI in the subventricular zone of wildtype mice involving about 7300 genes. In contrast, the HCAR1 knockout mice showed a modest response, involving about 750 genes. Notably, fundamental processes in tissue repair such as cell cycle and innate immunity were dysregulated in HCAR1 knockout. Our data suggest that HCAR1 is a key transcriptional regulator of pathways that promote tissue regeneration after HI.

• Ianevski, Aleksandr; Yao, Rouan; Simonsen, Ronja Meyer; Myhre, Vegard; Ravlo, Erlend & Kaynova, Gerda D. [Vis alle 18 forfattere av denne artikkelen] (2022). Mono- and combinational drug therapies for global viral pandemic preparedness. iScience. 25(4). doi: 10.1016/j.isci.2022.104112. Fulltekst i vitenarkiv Vis sammendrag

  Broadly effective antiviral therapies must be developed to be ready for clinical trials, which should begin soon after the emergence of new life-threatening viruses. Here, we pave the way towards this goal by reviewing conserved druggable virus-host interactions, mechanisms of action, immunomodulatory properties of available broad-spectrum antivirals (BSAs), routes of BSA delivery, and interactions of BSAs with other antivirals. Based on the review, we concluded that the range of indications of BSAs can be expanded, and new pan- and cross-viral mono- and combinational therapies can be developed. We have also developed a new scoring algorithm that can help identify the most promising few of the thousands of potential BSAs and BSA-containing drug cocktails (BCCs) to prioritize their development during the critical period between the identification of a new virus and the development of virus-specific vaccines, drugs, and therapeutic antibodies.

• Ravlo, Erlend; Evensen, Lasse; Sanson, Gorm; Hildonen, Siri; Ianevski, Aleksandr & Skjervold, Per Olav [Vis alle 12 forfattere av denne artikkelen] (2022). Antiviral Immunoglobulins of Chicken Egg Yolk for Potential Prevention of SARS-CoV-2 Infection. Viruses. 14(10). doi: 10.3390/v14102121. Fulltekst i vitenarkiv Vis sammendrag

  Background: Some viruses cause outbreaks, which require immediate attention. Neutralizing antibodies could be developed for viral outbreak management. However, the development of monoclonal antibodies is often long, laborious, and unprofitable. Here, we report the development of chicken polyclonal neutralizing antibodies against SARS-CoV-2 infection. Methods: Layers were immunized twice with 14-day intervals using the purified receptor-binding domain (RBD) of the S protein of SARS-CoV-2/Wuhan or SARS-CoV-2/Omicron. Eggs were harvested 14 days after the second immunization. Polyclonal IgY antibodies were extracted. Binding of anti-RBD IgYs was analyzed by immunoblot and indirect ELISA. Furthermore, the neutralization capacity of anti-RBD IgYs was measured in Vero-E6 cells infected with SARS-CoV-2-mCherry/Wuhan and SARS-CoV-2/Omicron using fluorescence and/or cell viability assays. In addition, the effect of IgYs on the expression of SARS-CoV-2 and host cytokine genes in the lungs of Syrian Golden hamsters was examined using qRT-PCR. Results: Anti-RBD IgYs efficiently bound viral RBDs in situ, neutralized the virus variants in vitro, and lowered viral RNA amplification, with minimal alteration of virus-mediated immune gene expression in vivo. Conclusions: Altogether, our results indicate that chicken polyclonal IgYs can be attractive targets for further pre-clinical and clinical development for the rapid management of outbreaks of emerging and re-emerging viruses.

• Sousa, Mirta; Ye, Jing; Gomez, Luisa Fernanda Luna; Hildrestrand, Gunn Annette; Bjørås, Karine & Scheffler, Katja [Vis alle 7 forfattere av denne artikkelen] (2021). Impact of oxidative DNA damage and the role of DNA glycosylases in neurological dysfunction. International Journal of Molecular Sciences. ISSN 1661-6596. 22:12924(23), s. 1–22. doi: 10.3390/ijms222312924. Fulltekst i vitenarkiv Vis sammendrag

  The human brain requires a high rate of oxygen consumption to perform intense metabolic activities, accounting for 20% of total body oxygen consumption. This high oxygen uptake results in the generation of free radicals, including reactive oxygen species (ROS), which, at physiological levels, are beneficial to the proper functioning of fundamental cellular processes. At supraphysiological levels, however, ROS and associated lesions cause detrimental effects in brain cells, commonly observed in several neurodegenerative disorders. In this review, we focus on the impact of oxidative DNA base lesions and the role of DNA glycosylase enzymes repairing these lesions on brain function and disease. Furthermore, we discuss the role of DNA base oxidation as an epigenetic mechanism involved in brain diseases, as well as potential roles of DNA glycosylases in different epigenetic contexts. We provide a detailed overview of the impact of DNA glycosylases on brain metabolism, cognition, inflammation, tissue loss and regeneration, and age-related neurodegenerative diseases based on evidence collected from animal and human models lacking these enzymes, as well as post-mortem studies on patients with neurological disorders.

• Maddirevula, Sateesh; Alameer, Seham; Ewida, Nour; Sousa, Mirta; Bjørås, Magnar & Vågbø, Cathrine Broberg [Vis alle 7 forfattere av denne artikkelen] (2021). Insight into ALKBH8-related intellectual developmental disability based on the first pathogenic missense variant. Human Genetics. ISSN 0340-6717. 141, s. 209–215. doi: 10.1007/s00439-021-02391-z. Fulltekst i vitenarkiv Vis sammendrag

  ALKBH8 is a methyltransferase that modifies tRNAs by methylating the anticodon wobble uridine residue. The syndrome of ALKBH8-related intellectual developmental disability (MRT71) has thus far been reported solely in the context of homozygous truncating variants that cluster in the last exon. This raises interesting questions about the disease mechanism, because these variants are predicted to escape nonsense mediated decay and yet they appear to be loss of function. Furthermore, the limited class of reported variants complicates the future interpretation of missense variants in ALKBH8. Here, we report a consanguineous family in which two children with MRT71-compatible phenotype are homozygous for a novel missense variant in the methyltransferase domain. We confirm the pathogenicity of this variant by demonstrating complete absence of ALKBH8-dependent modifications in patient cells. Targeted proteomics analysis of ALKBH8 indicates that the variant does not lead to loss of ALKBH8 protein expression. This report adds to the clinical delineation of MRT71, confirms loss of function of ALKBH8 as the disease mechanism and expands the repertoire of its molecular lesions.

• Kong, Xiang Yi; Huse, Camilla; Yang, Kuan; Øgaard, Jonas; Jimenez, Natalia Berges & Vik, Erik Sebastian [Vis alle 24 forfattere av denne artikkelen] (2021). Endonuclease v regulates atherosclerosis through c-c motif chemokine ligand 2-mediated monocyte infiltration. Journal of the American Heart Association (JAHA). 10(14). doi: 10.1161/JAHA.120.020656. Fulltekst i vitenarkiv Vis sammendrag

  Background: In cardiovascular diseases, atherosclerotic disorder are the most frequent and important with respect to morbidity and mortality. Inflammation mediated by immune cells is central in all parts of the atherosclerotic progress, and further understanding of the underlying mechanisms is needed. Growing evidence suggests that deamination of adenosine‐to‐inosine in RNA is crucial for a correct immune response; nevertheless, the role of adenosine‐to‐inosine RNA editing in atherogenesis has barely been studied. Several proteins have affinity for inosines in RNA, one being ENDOV (endonuclease V), which binds and cleaves RNA at inosines. Data on ENDOV in atherosclerosis are lacking. Methods and Results: Quantitative polymerase chain reaction on ENDOV mRNA showed an increased level in human carotid atherosclerotic plaques compared with control veins. Inosine‐ribonuclease activity as measured by an enzyme activity assay is detected in immune cells relevant for the atherosclerotic process. Abolishing EndoV in atherogenic apolipoprotein E‐deficient (ApoE−/−) mice reduces the atherosclerotic plaque burden, both in size and lipid content. In addition, in a brain stroke model, mice without ENDOV suffer less damage than control mice. Finally, lack of EndoV reduces the recruitment of monocytes to atherosclerotic lesions in atherogenic ApoE−/− mice. Conclusions: ENDOV is upregulated in human atherosclerotic lesions, and data from mice suggest that ENDOV promotes atherogenesis by enhancing the monocyte recruitment into the atherosclerotic lesion, potentially by increasing the effect of CCL2 activation on these cells.

• Xu, Kaiqi; Chatzitakis, Athanasios Eleftherios; Backe, Paul Hoff; Ruan, Qiushi; Tang, Junwang & Rise, Frode [Vis alle 8 forfattere av denne artikkelen] (2021). In situ cofactor regeneration enables selective CO2 reduction in a stable and efficient enzymatic photoelectrochemical cell. Applied Catalysis B: Environmental. ISSN 0926-3373. 296. doi: 10.1016/j.apcatb.2021.120349. Fulltekst i vitenarkiv Vis sammendrag

  Mimicking natural photosynthesis by direct photoelectrochemical (PEC) reduction of CO2 to chemicals and fuels requires complex cell assemblies with limitations in selectivity, efficiency, cost, and stability. Here, we present a breakthrough cathode utilizing an oxygen tolerant formate dehydrogenase enzyme derived from clostridium carboxidivorans and coupled to a novel and efficient in situ nicotinamide adenine dinucleotide (NAD+/NADH) regeneration mechanism through interfacial electrochemistry on g-C3N4 films. We demonstrate stable (20 h) aerobic PEC CO2-to-formate reduction at close to 100 % faradaic efficiency and unit selectivity in a bio-hybrid PEC cell of minimal engineering with optimized Ta3N5 nanotube photoanode powered by simulated sunlight with a solar to fuel efficiency of 0.063 %, approaching that of natural photosynthesis.

• Ianevski, Aleksandr; Yao, Rouan; Zusinaite, Eva; Lello, Laura Sandra; Wang, Sainan & Jo, Eunji [Vis alle 28 forfattere av denne artikkelen] (2021). Synergistic interferon-alpha-based combinations for treatment of sars-cov-2 and other viral infections. Viruses. 13:2489(12), s. 1–18. doi: 10.3390/v13122489. Fulltekst i vitenarkiv Vis sammendrag

  Background: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. Methods: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. Results: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα–remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. Conclusions: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.

• Karlsen, Tom Rune; Kong, Xiang Yi; Holm, Sverre; Quiles-Jiménez, Ana M T; Dahl, Tuva Børresdatter & Yang, Kuan [Vis alle 17 forfattere av denne artikkelen] (2021). NEIL3-deficiency increases gut permeability and contributes to a pro-atherogenic metabolic phenotype. Scientific Reports. 11(1). doi: 10.1038/s41598-021-98820-0. Fulltekst i vitenarkiv Vis sammendrag

  Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe−/− mice. Herein, we identified a time point prior to quantifiable differences in atherosclerosis between Apoe−/−Neil3−/− mice and Apoe−/− mice. Mice at this age were selected to explore the metabolic and pathophysiological processes preceding extensive atherogenesis in NEIL3-deficient mice. Untargeted metabolomic analysis of young Apoe−/−Neil3−/− mice revealed significant metabolic disturbances as compared to mice expressing NEIL3, particularly in metabolites dependent on the gut microbiota. 16S rRNA gene sequencing of fecal bacterial DNA indeed confirmed that the NEIL3-deficient mice had altered gut microbiota, as well as increased circulating levels of the bacterially derived molecule LPS. The mice were challenged with a FITC-conjugated dextran to explore gut permeability, which was significantly increased in the NEIL3-deficient mice. Further, immunohistochemistry showed increased levels of the proliferation marker Ki67 in the colonic epithelium of NEIL3-deficient mice, suggesting increased proliferation of intestinal cells and gut leakage. We suggest that these metabolic alterations serve as drivers of atherosclerosis in NEIL3-deficient mice.

• Ladner, Jason T.; Henson, Sierra N.; Boyle, Annalee S.; Engelbrektson, Anna L.; Fink, Zane W. & Rahee, Fatima [Vis alle 22 forfattere av denne artikkelen] (2021). Epitope-resolved profiling of the SARS-CoV-2 antibody response identifies cross-reactivity with endemic human coronaviruses. Cell Reports Medicine. 2(1), s. 1–13. doi: 10.1016/j.xcrm.2020.100189. Fulltekst i vitenarkiv Vis sammendrag

  The SARS-CoV-2 proteome shares regions of conservation with endemic human coronaviruses (CoVs), but it remains unknown to what extent these may be cross-recognized by the antibody response. Here, we study cross-reactivity using a highly multiplexed peptide assay (PepSeq) to generate an epitope-resolved view of IgG reactivity across all human CoVs in both COVID-19 convalescent and negative donors. PepSeq resolves epitopes across the SARS-CoV-2 Spike and Nucleocapsid proteins that are commonly targeted in convalescent donors, including several sites also recognized in some uninfected controls. By comparing patterns of homologous reactivity between CoVs and using targeted antibody-depletion experiments, we demonstrate that SARS-CoV-2 elicits antibodies that cross-recognize pandemic and endemic CoV antigens at two Spike S2 subunit epitopes. We further show that these cross-reactive antibodies preferentially bind endemic homologs. Our findings highlight sites at which the SARS-CoV-2 response appears to be shaped by previous CoV exposures and which have the potential to raise broadly neutralizing responses.

• Kunath, Nicolas; Bugaj, Anna Maria; Bigonah, Pegah; Berrocal, Marion Silvana Fernandez; Bjørås, Magnar & Ye, Jing (2021). DNA repair enzyme NEIL3 enables a stable neural representation of space by shaping transcription in hippocampal neurons. iScience. 24(12). doi: 10.1016/j.isci.2021.103470. Fulltekst i vitenarkiv Vis sammendrag

  DNA repair enzymes are essential for the maintenance of the neuronal genome and thereby proper brain functions. Emerging evidence links DNA repair to epigenetic gene regulation; however, its contribution to different transcriptional programs required for neuronal functions remains elusive. In this study, we identified a role of the DNA repair enzyme NEIL3 in modulating the maturation and function of hippocampal CA1 neurons by shaping the CA1 transcriptome during postnatal development and in association with spatial behavior. We observed a delayed maturation in Neil3-/- CA1 and identified differentially regulated genes required for hippocampal development. We revealed impaired spatial stability in Neil3-/- CA1 place cells and found spatial experience-induced gene expression essential for synaptic plasticity. This is the first study that links molecular underpinnings of DNA repair to the neural basis of spatial cognition beyond animals' behavioral phenotypes, thus shedding light on the molecular determinants enabling a stable neural representation of space.

• Hildrestrand, Gunn Annette; Rolseth, Veslemøy; Kunath, Nicolas; Suganthan, Rajikala; Jensen, Vidar & Bugaj, Anna Maria [Vis alle 24 forfattere av denne artikkelen] (2021). NEIL1 and NEIL2 DNA glycosylases modulate anxiety and learning in a cooperative manner in mice. Communications Biology. 4. doi: 10.1038/s42003-021-02864-x. Fulltekst i vitenarkiv Vis sammendrag

  Oxidative DNA damage in the brain has been implicated in neurodegeneration and cognitive decline. DNA glycosylases initiate base excision repair (BER), the main pathway for oxidative DNA base lesion repair. NEIL1 and NEIL3 DNA glycosylases affect cognition in mice, while the role of NEIL2 remains unclear. Here, we investigate the impact of NEIL2 and its potential overlap with NEIL1 on behavior in knockout mouse models. Neil1−/−Neil2−/− mice display hyperactivity, reduced anxiety and improved learning. Hippocampal oxidative DNA base lesion levels are comparable between genotypes and no mutator phenotype is found. Thus, impaired canonical repair is not likely to explain the altered behavior. Electrophysiology suggests reduced axonal activation in the hippocampal CA1 region in Neil1−/−Neil2−/− mice and lack of NEIL1 and NEIL2 causes dysregulation of genes in CA1 relevant for synaptic function. We postulate a cooperative function of NEIL1 and NEIL2 in genome regulation, beyond canonical BER, modulating behavior in mice.

• Meehyun, Ko; Chang, Soo Young; Byun, Soo Young; Ianevski, Aleksandr; Choi, Inhee & Hung, Anne-Laure Pham [Vis alle 13 forfattere av denne artikkelen] (2021). Screening of FDA-Approved Drugs Using a MERS-CoV Clinical Isolate from South Korea Identifies Potential Therapeutic Options for COVID-19. Viruses. 13(4). doi: 10.3390/v13040651. Fulltekst i vitenarkiv Vis sammendrag

  Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI > 100), atovaquone, an anti-malarial (TI > 34), and ciclesonide, an inhalable corticosteroid (TI > 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.

Se alle arbeider i NVA

• Nyrnes, Siri Ann; Haug, Marte Gjøl; Sæther, Rakel Rian; Klocke, Vanessa Solvang & Bjørås, Magnar (2025). Innovative clinical treatment synergized with cardiac disease modeling in Noonan syndrome. doi: https:/www.wcpccs2025.org/en/. Fulltekst i vitenarkiv Vis sammendrag

  Background and aims: Noonan syndrome (1:1,000 – 2,500) requires personalized treatment. While targeted therapies exist, clinical trials are difficult due to the rarity of the condition. This project aimed to implement the novel MEK inhibitor trametinib in the clinic and model the disease in vitro. Materials and Methods: A girl with Noonan syndrome (RIT1 variant: c.244T>A, p.(F82I)) presented at birth with hypertrophic cardiomyopathy (HCM) and pulmonary stenosis (1). Initial management included betablockers and pulmonary balloon dilation followed by a septal myectomy at age nine. By age 15-16, she developed refractory chylothorax and abdominal chylous requiring repeated drainage and prolonged hospitalization. At 17, she was cachectic (42 kg). In June 2024, trametinib therapy inhibiting the overactive MAPK pathway was initiated (2). Cardiomyocytes from reprogrammed skin biopsies of the patient and her healthy mother were generated (4). Results: On trametinib (1.0 mg/day), chylous drainage was no longer required, and her well-being improved. She has attended school uninterruptedly since August 2024. The dose was reduced to 0.75 mg/day in November 2024 due to acne and hair loss, known side effects. By March 2025, MRI showed a ~20% reduction in cardiac wall thickness and echocardiography demonstrated improved cardiac function. All effusions resolved. At 16-month followup, her status remained stable, and NT-proBNP was normalized (1,3). Disease modeling demonstrated elevated RIT1 protein levels (6), and cardiac hypertrophy (7). Single-nucleus transcriptome analysis of patient-derived models revealed enhanced RAS/MAPK signaling, hypertrophy, oxidative stress, and myocyte disarray in cardiomyocytes (5). Trametinib reversed these disease characteristics in cardiomyocytes (8), and reversed fibrosis in cardiac fibroblasts (9). Conclusions: Trametinib effectively treated HCM and chylous effusions in Noonan syndrome. Disease modeling confirmed that trametinib reduced RIT1-related gene expression differences between patient and control.

• Bali, Nesrine; Kissova, Miroslava; Bjørås, Magnar & Bandyopadhyay, Sulalit (2024). Kinetically Controlled Loading of Hydrophilic Iron Oxide Nanoclusters in Hydrophobic Polymeric Nanoparticles through Flash Nanoprecipitation. Fulltekst i vitenarkiv
• Døskeland, Dagny Sanden; Saasen, Vidar Langseth; Grini, Jonas Viken; Ye, Jing & Bjørås, Magnar (2024). The Role of TDG-Mediated DNA Demethylation in Spatial Cognition. Fulltekst i vitenarkiv
• Otterlei, Marit; Haugan, Maria Schei; Bjørås, Magnar & Müller, Fredrik (2024). Hva bør Norge bidra med for å redusere antibiotikaresistens-krisen? Dagens medisin. ISSN 1501-4290. Fulltekst i vitenarkiv
• Bali, Nesrine; Kissova, Miroslava; Bjørås, Magnar & Bandyopadhyay, Sulalit (2024). Kinetically Controlled Loading of Hydrophilic Iron Oxide Nanoclusters in Hydrophobic Polymeric Nanoparticles through Flash Nanoprecipitation. Fulltekst i vitenarkiv
• Egiazarian, Milena Armenovna; Abentung, Andreas; Sakshaug, Teri; Karabeika, Emily; Hanumaihgari, Priyanka Reddy & Grøntvedt, Gøril Rolfseng [Vis alle 9 forfattere av denne artikkelen] (2024). The role of impaired oxidative base lesion repair in Alzheimer’s disease. Alzheimer's & Dementia. ISSN 1552-5260. 20(51). doi: 10.1002/alz.090686. Fulltekst i vitenarkiv
• Egiazarian, Milena Armenovna; Abentung, Andreas; Karabeika, Emily; Hanumaihgari, Priyanka; Schnur, Paulina & Hovland, Oline Øie [Vis alle 10 forfattere av denne artikkelen] (2024). The role of impaired oxidative base lesion repair in Alzheimer's disease. Fulltekst i vitenarkiv
• Ravlo, Erlend; Ianevski, Aleksandr; Starheim, Eirin Johannessen; Wang, Wei; Ji, Ping & Lysvand, Hilde [Vis alle 23 forfattere av denne artikkelen] (2023). Boosted production of antibodies that neutralized different SARS-CoV-2 variants in a COVID-19 convalescent following messenger RNA vaccination - a case study. International Journal of Infectious Diseases. ISSN 1201-9712. 137(Dec), s. 75–78. doi: 10.1016/j.ijid.2023.10.011. Fulltekst i vitenarkiv Vis sammendrag

  Vaccinated convalescents do not develop severe COVID-19 after infection with new SARS-CoV-2 variants. We questioned how messenger RNA (mRNA) vaccination of convalescents provides protection from emerging virus variants. From the cohort of 71 convalescent plasma donors, we identified a patient who developed immune response to infection with SARS-CoV-2 variant of 20A clade and who subsequently received mRNA vaccine encoding spike (S) protein of strain of 19A clade. We showed that vaccination increased the production of immune cells and anti-S antibodies in the serum. Serum antibodies neutralized not only 19A and 20A, but also 20B, 20H, 21J, and 21K virus variants. One of the serum antibodies (100F8) completely neutralized 20A, 21J, and partially 21K strains. 100F8 was structurally similar to published Ab188 antibody, which recognized non-conserved epitope on the S protein. We proposed that 100F8 and other serum antibodies of the patient which recognized non- and conserved epitopes of the S protein, could have additive or synergistic effects to neutralize various virus variants. Thus, mRNA vaccination could be beneficial for convalescents because it boosts production of neutralizing antibodies with broad-spectrum activity.

• Quiles-Jiménez, Ana M T; Sousa, Mirta; Huse, Camilla; Dyrhol-Riise, Anne Ma; Holter, Jan Cato & Christensen, Erik Egeland [Vis alle 12 forfattere av denne artikkelen] (2023). Severely ill COVID-19 patients have altered circulating levels of proteins controlling the epitranscriptome. Journal of Infection. ISSN 0163-4453. doi: 10.1016/j.jinf.2023.03.002. Fulltekst i vitenarkiv
• Bali, Nesrine; Brennhaug, Svein Jonsson; Bjørås, Magnar; Manaf, Adeel & Bandyopadhyay, Sulalit (2023). Design of Polymeric Magnetic Nanoparticles for Biomedical Applications. Fulltekst i vitenarkiv
• Schipmann, Stephanie; Sivakanesan, Sarankan; Rath, Daniel Stavne; Brandal, Petter; Vik-Mo, Einar Osland & Bjørås, Magnar [Vis alle 13 forfattere av denne artikkelen] (2023). Glioblastom hos voksne. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(2), s. 151–154. doi: 10.4045/tidsskr.22.0314. Fulltekst i vitenarkiv Vis sammendrag

  lioblastom er den vanligste formen for primær hjernekreft hos voksne, og sykdommen har en alvorlig prognose. Selv om det er gjort store fremskritt i molekylær karakteristikk, har det ikke vært større gjennombrudd i behandlingen på mange år. Vi presenterer her en klinisk oversikt over dagens diagnostikk og behandling samt hvilke utfordringer og muligheter som ligger i å utvikle bedre og mer persontilpasset behandling.

• Bali, Nesrine; Manaf, Adeel; Brennhaug, Svein Jonsson; Bjørås, Magnar & Bandyopadhyay, Sulalit (2022). Optimization of Carboxyl-Coated Magnetic Nanoparticles for DNA Size Selection. Fulltekst i vitenarkiv
• Ali, Zeeshan; Ravlo, Erlend; Aas, Per Arne; Hagen, Lars; Erlandsen, Sten Even & Ottesen, Vegar [Vis alle 9 forfattere av denne artikkelen] (2022). Scalable Production of Silica-coated Magnetic Nanobeads and their Applications in Viral Diagnostics. Fulltekst i vitenarkiv
• Ravlo, Erlend; Bjørås, Magnar & Kainov, Denis (2026). Antiviral Strategies: From Mono- to Combination-Therapy and Immunomodulation. Norges teknisk-naturvitenskapelige universitet. ISSN 9788235302762. Fulltekst i vitenarkiv Vis sammendrag

  I nyere tid har vi opplevd en økning i nye virus, samt en tilbakekomst av gamle kjenninger. Den største kilden til nye virus har vært fra dyreriket, og klimaendringene vil øke denne hyppigheten. Tiden det tar for den konvensjonelle medisinutviklingsprosessen å bekjempe virus holder ikke følge med denne økningen. COVID-19 pandemien gjorde dette ekstra merkbart og fremhevet et behov for nye metoder som kan raskt tilpasses, skaleres og forbli hardføre ovenfor virusets egen utvikling. I denne avhandlingen har vi prøvd å håndtere denne utfordringen ved å indentifisere, evaluere og optimalisere antivirale strategier mot oppståtte eller endemiske virus, med et hovedfokus på coronavirus og enterovirus. Arbeidet er delt inn i tre komplementære deler. Den første delen tok for seg raske immunplattformer. Disse utforsket vi ved å frembringe antistoffer fra høns, som ble høstet fra eggene deres. Disse antistoffene er målrettet mot SARS-CoV-2 sitt cellebindende protein, og antistoffet uskadeliggjorde viruset i forsøkene våre, samt reduserte målbart virus mRNA i hamstere som ble forebyggende behandlet med antistoffet. Vi undersøkte også hvordan mRNA vaksinering av en tidligere COVID-syk pasient førte til produksjon av antistoffer som var i stand til å håndtere et spektrum av SARS-CoV-2 varianter. Disse to studiene illustrerer samlet hvordan billig passiv immunrespons og tilpasningsdyktig aktiv immunrespons kan dekke tidsrommet mellom tiden der et virus oppstår og når oppdaterte vaksiner og antistoffer er tilgjengelige. Den andre delen fokuserte på gjenbruk av medisiner og en rasjonell kombinasjons tilnærming som en strategi for å sette fart på oppdagelsen av antivirale stoffer og begrense resistensutvikling. Et større panel bestående av FDA-godkjente medisinske stoffer ble testet mot MERS-CoV, og resultatet ble en arbeidsmåte som raskt kunne gå fra testing av store mengder stoffer til noen få gode, som kunne testet videre for klinisk bruk. Vi testet også bruken av et av kroppens egne signalstoffer, interferon-alfa, sammen med medisinske stoffer som direkte påvirker virusets forskjellige livsstadier. Dette ble gjort på flere virusfamilier, og vi så at effekt av kombinasjonene var større en enkeltbehandlingene. I den tredje delen var fokuset på mulig negative sider ved medisiner som påvirker vertens evne til å bekjempe viruset. Her undersøkte vi hvordan et stoff som bremser en del av betennelsesreaksjonen kan utfolde seg. Det vi fant var at selv om det kan være særdeles nyttig i tilfeller hvor kroppens betennelsesreaksjon utgjør en fare for seg selv, så kan den også medføre at kroppens egne signaler for tidlig smitte av virus blir sterkt begrenset. Dette medfører at viruset kan infiltrere flere celler. Som en helhet viste studien at bruken av slike medikamenter bør gjøres med god kunnskap om hvor i sykdomforløpet pasienten befinner seg. Samlet har vi i denne avhandlingen bidratt til utviklinger av mulige prosedyrer, og vist fram et konseptuelt rammeverk for hurtige svar på nye virus trusler. Arbeidet er gjort med bruk av cellelinjer, humane organoider, og dyremodeller. Hver av disse modellene har ulike grader av kompleksitet og effektivitet som til sammen styrker den overførbare verdien av forskingen til klinikken.

• Døskeland, Dagny Sanden; Ye, Jing & Bjørås, Magnar (2026). Neuroepigenetic Roles of the DNA Glycosylases TDG and NEIL3 in Hippocampal Plasticity and Memory. Norges teknisk-naturvitenskapelige universitet. ISSN 9788235300805. Fulltekst i vitenarkiv Vis sammendrag

  Epigenetic mechanisms provide neurons with a means to couple stable cellular identity to experience-dependent transcriptional plasticity, a balance that is essential for learning, memory, and cognitive flexibility. DNA glycosylases are classically studied for their roles in base excision repair, yet accumulating evidence suggests that select family members also contribute to transcriptional and epigenetic regulation. This thesis investigates the neuroepigenetic roles of the DNA glycosylases NEIL3 and TDG in hippocampal plasticity and memory. This work combines transgenic mouse models, behavioral assays of hippocampal-dependent learning, transcriptional profiling, histological and electrophysiological analyses, and targeted epigenetic measurements to investigate the roles of NEIL3 and TDG in learning and memory in the adult brain. NEIL3 function was examined using a global knockout mouse model, whereas TDG function was assessed using a newly established conditional knockout with restricted TDG depletion in adult forebrain excitatory neurons. Behaviorally, both NEIL3- and TDG-deficient mice show intact acquisition and retrieval of conditioned fear, indicating preserved associative learning. In contrast, both models exhibit altered fear extinction, consistent with impaired regulation or updating of established memory. NEIL3 deficiency selectively disrupts hippocampal inhibitory circuitry, characterized by reduced parvalbumin-positive interneuron integrity, loss of perineuronal nets, and altered oscillatory dynamics, accompanied by transcriptional changes and altered DNA methylation at inhibitory gene loci promoters, including Gabra2. Together, these alterations position NEIL3 as a modulator of inhibitory circuit integrity, suggesting that DNA repair–associated epigenetic mechanisms can influence network stability and, in turn, shape the capacity for adaptive memory updating. By comparison, conditional deletion of Tdg in adult excitatory neurons primarily affects transcriptional stability, producing an aberrantly elevated baseline transcriptional state followed by broad repression after extinction training. This pattern suggests that TDG is required to preserve an experience-sensitive transcriptional state in mature hippocampal neurons, such that established memories can be adaptively modified rather than rigidly maintained. These findings provide the first evidence that TDG contributes to transcriptional regulation and memory flexibility in the adult brain, consistent with its established role in active DNA demethylation. Although direct links to genome-wide methylation dynamics remain to be determined, these findings suggest that TDG helps maintain epigenetic and transcriptional balance and enables the reshaping of gene expression programs during behavioral adaptation. Together, these results highlight DNA glycosylase–dependent regulation as a contributor to hippocampal plasticity and cognitive flexibility.

• Starheim, Eirin Johannessen; Bjørås, Magnar; Aas, Per Arne; Erlandsen, Sten Even & Bandyopadhyay, Sulalit (2026). High sensitivity nanoparticle techniques for isolating mammalian DNA and RNA in molecular research and diagnostics. Norges teknisk-naturvitenskapelige universitet. ISSN 9788235300287. Fulltekst i vitenarkiv Vis sammendrag

  Nucleic acids, commonly known as DNA and RNA, are molecules that govern all life on Earth by encoding genetic information that instructs the functioning, development, growth, and reproduction of organisms. Studies of mammalian DNA and RNA are essential for progress in molecular research and diagnostics, as they provide insights into the genetic mechanisms underlying various biological processes and diseases. Generally, analysis of these biopolymers relies on their isolation from mammalian samples. Although a large variety of isolation procedures have been devised throughout history, these methods still represent bottlenecks in both research and clinical settings due to limitations in affordability, efficiency, and performance. In recent years, magnetic beads have emerged as a promising alternative to more traditional isolation techniques, displaying potential for rapid and automated processing of many samples simultaneously using magnet-based platforms. In this thesis, the bead-based NAxtra technology, created at the Norwegian University of Science and Technology, was used to develop low-cost, fast, and highly sensitive procedures for isolating mammalian nucleic acids from cell cultures of varying complexity (Paper I), limited cell quantities or single cells (Paper II), and blood plasma (Paper III). The respective papers indicate that these methods may rival the performance of alternative commercial kits, while also potentially offering considerable cost reductions or substantial improvements in processing speed for isolating cellular nucleic acids. To substantiate these indications, further validation across more compositionally challenging sample matrices and a broader spectrum of nucleic acid targets, together with a more comprehensive cost analysis, represents an important direction for future work. Overall, the toolkit comprising these three NAxtra-based procedures displays promising characteristics that may help facilitate future advances in molecular research and diagnostics, thereby potentially contributing to new scientific discoveries or improvements in patient care.

• Vikedal, Krister; Skarstad, Kirsten; Bjørås, Magnar; Helgesen, Emily & Booth, James Alexander (2026). DNASupercompaction: A Novel Orchestrated Response to Severe DNA Damage in Bacteria. Universitetet i Oslo. ISSN 9788234807695. Fulltekst i vitenarkiv Vis sammendrag

  Bacteria respond to antibacterial drug exposure by activating stress responses. These responses can promote survival and drive resistance development, thereby compromising antibacterial drug effectiveness. Studying bacterial stress responses is therefore essential for guiding measures that help ensure treatments remain effective. The aim of this thesis was to investigate how bacteria rearrange their chromosome when exposed to severe DNA damage caused by antibacterial drugs. Using Escherichia coli exposed to the antibacterial drug ciprofloxacin as a model system, live-cell microscopy revealed an ordered two-step nucleoid rearrangement that culminates in a dense and persistent midcell compaction. This response, termed DNA supercompaction, was also observed after exposure to other DNA-damaging agents and across bacterial species, including clinical isolates, underscoring its broader biological relevance. The genetic landscape of DNA supercompaction was explored through a genome-wide screening combined with machine learning-assisted analysis of compaction phenotypes. Key DNA repair proteins, RecA, RecBCD, and RecN, emerged as essential orchestrators of the response. Additionally, single-cell fluorescence imaging revealed a dynamic interplay between RecA and RecN at nucleoid-associated positions during DNA supercompaction. Overall, this work identifies DNA supercompaction as an important and conserved component of the bacterial DNA damage response and provides a framework for future studies of this newly recognized layer of bacterial stress adaptation, which may prove relevant for preserving antibacterial drug effectiveness.

• Berrocal, Marion Silvana Fernandez; Ye, Jing & Bjørås, Magnar (2025). From DNA repair to cognition: NEIL3 DNA glycosylase shapes hippocampal networks and memory. Norges teknisk-naturvitenskapelige universitet. ISSN 9788232694150. Fulltekst i vitenarkiv Vis sammendrag

  DNA-glykosylasen NEIL3, som er en del av base-ekskikjonreparasjon (BER) systemet, har hovedsakelig blitt undersøkt for sin rolle i genomisk vedlikehold. Nyere bevismateriale viser imidlertid at NEIL3 også har funksjoner knyttet til sentralnervesystemet, spesielt i hippocampus, som er essensiell for læring og hukommelse. Denne avhandlingen undersøker rollen til NEIL3 i i utviklingen av hippocampus, nevrogenese hos voksne hjernen, synaptisk plastisitet og kognisjon, a ved å andvende diverse metoder til å studere en Neil3 knockout musemodell. I tidlig utvikling fører mangel på NEIL3 til forsinket modning av nevroner i flere områder i hippocampus, (CA1, CA3, gyrus dentatus), som vist ved lavere nivåer av NeuN. Transkriptomiske analyser i den første artikkelen viser at NEIL3 koordinerer modning av hippocampus gjennom regulaering av gennettverk som er involvert i utvikling av nerver og synaptisk plastisitet. dette er effekter som varierer ved region og alder, spesielt hos nyfødte. Hos voksne fortsetter NEIL3 å påvirke hippocampal funksjon. Artikkel II viser hvordan høyt uttrykk av NEIL3 i gyrus dentatus bistår nevrogenese i voksne; mangel av NEIL3 reduserer proliferasjon i stamceller og forsinker differensieringen av nevroner. Atferdsmessige tester indikerer at “pattern separation” er nedsatt i Neil3 knockout mus, knyttet til reduksjoner i komponenter av WNT signalveien og “neurogenic factors” som NeuroD1 og Prox1. Elektrofysiologiske studier viser at DG-nevroner uten NEIL3 har umodne egenskaper og enklere dendritiske strukturer, noe som fremhever NEIL3s betydning for nevronal utvikling. NEIL3 påvirker i tillegg hippocampale kretser ved å modulere eksitatorisk/inhibitorisk balanse, gjennom påvirkning av PV+ internevroner. Artikkel III viser at mangel på NEIL3 forstyrrer PV+ internevroner og PNN, særlig i CA1 og gyrus dentatus. Dette fører til endrede hippocampale oscillasjoner, med økt beta- og lav-gamma-effekt, redusert høy-gamma og «ripples», noe som forstyrrer fasekoblingen i CA1 stedceller og hemmer ekstinksjonen av fryktminne. Mekanistisk sett fungerer NEIL3 som en epigenetisk regulator; fravær av NEIL3 forårsaker hypermetylering av Gabra2 promoteren, som reduserer Gabra2 genuttrykk. Dette er det første beviset som kobler NEIL3 til genregulering gjennom DNA metylering, som involverer TET enzymer og BER. Samlet sett kopler NEIL3 vedlikehold av genomet og nevral plastisitet gjennom DNA reparasjon, transkripsjon, nevrogenese, internevron funksjonalitet, og hukommelse, noe som gjør dette enzymet essensielt for hippocampal funksjonalitet. Disse funnene gir innsikt i det molekylære grunnlaget for kognisjon og kan informere videre forskning på nevro-utviklings- og nevro-degenerative lidelser som kjennetegnes av ubalanse mellom eksitatorisk og inhibitorisk aktivitet samt hukommelsesforstyrrelser.

• Døskeland, Dagny Sanden; Ye, Jing & Bjørås, Magnar (2022). Assessing the Role of TDG in the Hippocampus-dependent Memory using Transgenic Mouse Models and rAAV Viral Tools. Norges teknisk-naturvitenskapelige universitet. Fulltekst i vitenarkiv Vis sammendrag

  Tymin DNA-glykosylase (TDG) er et enzym med viktige roller i genomisk reperasjon og epigenetisk regulering. Tiltredende bevis indikerer en viktig rolle for TDG i aktiv DNA-demetylering. DNA-methylering har en regulerende funksjon i gentranskripsjon gjennom rekrutering av proteiner involvert i genundertrykkelse, eller gjennom å hemme binding av transkripsjonsfaktorer til DNA. DNA-metylering har blitt implisert som en nødvendig mekanisme for dannelse av langtidshukommelse grunnet sin rolle i transkripsjonregulering av gener som er assosiert med synaptisk plastisitet. TDG's rolle i demetylering implikerer en mulig rolle for TDG i dannelse av langtidshukommelse, siden denne typen hukommelse av avhengig av transkripsjonell regulering. Denne studien undersøker rollen til TDG-regulert DNA-demetylering i hippocampus-avhengig hukommelse. Mer spesifikt, om mangel av TDG i hippocampus fører til endring i adferd og kognisjon hos mus. Jeg optimaliserte en protokoll for fjerning av TDG i hippocampale nevroner ved å bruke virale mekanismer. Videre evaluerte jeg adfersel og hukommelse til LoxP-miniTdg-mus. Dette ble gjort gjennom å måle angst-lignende adferd i OFT og ved å teste romlig hukommelse i preferansetestene NOL og Y-maze. Til slutt etablerte jeg en ny musemodell med betinget fjerning av TDG i hjernen. Resultatene mine tyder på at: 1) en viral konsentrasjon på 1:20 er optimal for å fjerne TDG samtidig som man unngår Cre-indusert nevronisk død og skader i hippocampus. 2) Det er ikke klart om fjerning av TDG i hippocampale nevroner påvirker langsiktig romlig hukommelse, da det ble introdusert betydelige forskjeller innad i gruppene som ble analysert. 3) Etablering av en ny musemodell med betinget hjernespesifikk fjerning av TDG var vellykket. Dette ble bekreftet ved Immunohistokjemi (IHC) av grønt fluoriserende protein (GFP) som viser Cre-indusert GFP-uttrykk, og antagelig fjerning av Tdg i CA1, CA3 og DG. Denne dyremodellen kan brukes i fremtidige studier for å videre undersøke TDG's rolle i hippocampus-avhengig hukommelse.

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