| 1. |
- Bergero, Roberta, et al.
(författare)
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Meiosis and beyond - understanding the mechanistic and evolutionary processes shaping the germline genome
- 2021
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Ingår i: Biological Reviews. - : John Wiley & Sons. - 1464-7931 .- 1469-185X. ; 96:3, s. 822-841
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Forskningsöversikt (refereegranskat)abstract
- The separation of germ cell populations from the soma is part of the evolutionary transition to multicellularity. Only genetic information present in the germ cells will be inherited by future generations, and any molecular processes affecting the germline genome are therefore likely to be passed on. Despite its prevalence across taxonomic kingdoms, we are only starting to understand details of the underlying micro-evolutionary processes occurring at the germline genome level. These include segregation, recombination, mutation and selection and can occur at any stage during germline differentiation and mitotic germline proliferation to meiosis and post-meiotic gamete maturation. Selection acting on germ cells at any stage from the diploid germ cell to the haploid gametes may cause significant deviations from Mendelian inheritance and may be more widespread than previously assumed. The mechanisms that affect and potentially alter the genomic sequence and allele frequencies in the germline are pivotal to our understanding of heritability. With the rise of new sequencing technologies, we are now able to address some of these unanswered questions. In this review, we comment on the most recent developments in this field and identify current gaps in our knowledge.
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| 2. |
- Büscher, Monika, et al.
(författare)
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Ways of grounding imagination
- 2004
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Ingår i: PDC 04: Proceedings of the eighth conference on Participatory design: Artful integration: interweaving media, materials and practices - Volume 1. - New York, New York, USA : ACM Publications. - 9781581138511 ; , s. 193-203
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Konferensbidrag (refereegranskat)abstract
- This paper discusses and evaluates use of different participatory design methods in relation to addressing the challenge of grounding imagination. It presents reflections on the use of three participatory design methods, deployed in the WorkSpace project: future laboratories, in-situ prototyping experiments and bricolage. The analysis examines how the methods differ, and how they complement one another, in relation to supporting the process of grounding imagination. The paper introduces 'future laboratories' as a participatory design method, specifically aiming at promoting interdisciplinary collaboration and grounded imagination.
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| 3. |
- Reinert, Line S, et al.
(författare)
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Brain immune cells undergo cGAS-STING-dependent apoptosis during herpes simplex virus type 1 infection.
- 2020
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Ingår i: The Journal of clinical investigation. - 1558-8238. ; 131:1
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Tidskriftsartikel (refereegranskat)abstract
- Protection of the brain from viral infections involves the type I interferon (IFN-I) system, defects in which renders humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels leads to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we here show that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, while lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices, or mice treated with caspase inhibitor, exhibited lower viral load and improved outcome of infection. Collectively, we identify an activation-induced apoptosis program in brain immune cells which down-modulates local immune responses.
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| 4. |
- Reyahi, Azadeh, et al.
(författare)
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An IKBKE variant conferring functional cGAS/STING pathway deficiency and susceptibility to recurrent HSV-2 meningitis.
- 2023
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Ingår i: JCI insight. - 2379-3708. ; 8:21
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms underlying susceptibility to recurrent herpes simplex virus type 2 (HSV-2) meningitis remain incompletely understood. In a patient experiencing multiple episodes of HSV-2 meningitis, we identified a monoallelic variant in the IKBKE gene, which encodes the IKKε kinase involved in induction of antiviral IFN genes. Patient cells displayed impaired induction of IFN-β1 (IFNB1) expression upon infection with HSV-2 or stimulation with double-stranded DNA (dsDNA) and failed to induce phosphorylation of STING, an activation marker of the DNA-sensing cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway. The patient allele encoded a truncated IKKε protein with loss of kinase activity and also capable of exerting dominant-negative activity. In stem cell-derived microglia, HSV-2-induced expression of IFNB1 was dependent on cGAS, TANK binding kinase 1 (TBK1), and IKBKE, but not TLR3, and supernatants from HSV-2-treated microglia exerted IKBKE-dependent type I IFN-mediated antiviral activity upon neurons. Reintroducing wild-type IKBKE into patient cells rescued IFNB1 induction following treatment with HSV-2 or dsDNA and restored antiviral activity. Collectively, we identify IKKε to be important for protection against HSV-2 meningitis and suggest a nonredundant role for the cGAS/STING pathway in human antiviral immunity.
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