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The controlled release of mitochondrial content into the cytosol has emerged as one of the key steps in mitochondrial signaling. In particular, the release of mitochondrial DNA (mtDNA) into the cytosol has been shown to activate interferon beta (IFN-β) gene expression to execute the innate immune response. In this report, we show that human adenovirus type 5 (HAdV-C5) infection induces the release of mtDNA into the cytosol. The release of mtDNA is mediated by the viral minor capsid protein VI (pVI), which localizes to mitochondria. The presence of the mitochondrial membrane proteins Bak and Bax are needed for the mtDNA release, whereas the viral E1B-19K protein blocked pVI-mediated mtDNA release. Surprisingly, the pVI-mediated mtDNA release did not increase but inhibited the IFN-β gene expression. Notably, the pVI expression caused mitochondrial leakage of the HSP60 protein. The latter prevented specific phosphorylation of the interferon regulatory factor 3 (IRF3) needed for IFN-β gene expression. Overall, we assign a new mitochondria and IFN-β signaling-modulating function to the HAdV-C5 minor capsid protein VI., Importance: Human adenoviruses (HAdVs) are common pathogens causing various self-limiting diseases, including conjunctivitis and the common cold. HAdVs need to interfere with multiple cellular signaling pathways during the infection to gain control over the host cell. In this study, we identified human adenovirus type 5 (HAdV-C5) minor capsid protein VI as a factor modulating mitochondrial membrane integrity and mitochondrial signaling. We show that pVI-altered mitochondrial signaling impedes the cell's innate immune response, which may benefit HAdV growth. Overall, our study provides new detailed insights into the HAdV-mitochondria interactions and signaling. This knowledge is helpful when developing new anti-viral treatments against pathogenic HAdV infections and improving HAdV-based therapeutics., Competing Interests: The authors declare no conflict of interest.

Objective: The objective of this study was 2-fold: first, to evaluate whether superb microvascular imaging (SMI) could be used to visualize neovascularization in temporal arteries, and, second, to evaluate the diagnostic performance of high frequency ultrasound with SMI using an extended protocol in patients with suspected giant cell arteritis (GCA)., Methods: This retrospective study comprised 120 patients consecutively examined with an extended CDU protocol (temporal, facial, axillary, subclavian, brachiocephalic, and carotid arteries) between 2020 and 2022. Of all patients, 107 had no previous GCA diagnosis and 13 had a previous GCA diagnosis. SMI was used to evaluate neovascularization in the temporal arteries. Arteritis were characterized as low- or medium-echogenic, homogeneous wall thickening, with or without a positive compression sign in the temporal arteries. The Halo count, i.e., the number of temporal and axillary artery segments with signs of arteritis, was evaluated. The reference was clinically diagnosed GCA confirmed after ≥6-month follow-up., Results: Of the eligible 107 patients with new suspected GCA, 33 (31%) received a clinical GCA diagnosis. Neovascularization was detected in 14 patients (43%). Patients with neovascularization displayed a higher halo count [median 6 (25th-75th percentile 4.75-7) vs. 3 (2-4-4), p = 0.005]. CDU of only the temporal arteries showed sensitivity and specificity (95% confidence intervals) of 94% (80-100%) and 100% (95-100%), respectively. The addition of extra-cranial arteries increased the sensitivity to 100%. Of the 13 patients investigated for suspected relapse, three had a clinically confirmed relapse. One of them displayed neovascularization together with other signs of inflammation., Conclusions: We show for the first time that inflammatory neovascularization of the temporal arteries can be detected by SMI. Neovascularization is associated with a more-widespread cranial disease. The value of neovascularization should be further investigated, especially for the detection of GCA relapse., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Skoog, Svensson, Eriksson, Sjöwall and Zachrisson.)

Polycystic ovary syndrome (PCOS) is associated with a low-grade inflammation, but it is unknown how hyperandrogenism, the hallmark of PCOS, affects the immune system. Using a PCOS-like mouse model, it is demonstrated that hyperandrogenism affects immune cell populations in reproductive, metabolic, and immunological tissues differently in a site-specific manner. Co-treatment with an androgen receptor antagonist prevents most of these alterations, demonstrating that these effects are mediated through androgen receptor activation. Dihydrotestosterone (DHT)-exposed mice displayed a drastically reduced eosinophil population in the uterus and visceral adipose tissue (VAT). A higher frequency of natural killer (NK) cells and elevated levels of IFN-γ and TNF-α are seen in uteri of androgen-exposed mice, while NK cells in VAT and spleen displayed a higher expression level of CD69, a marker of activation or tissue residency. Distinct alterations of macrophages in the uterus, ovaries, and VAT are also found in DHT-exposed mice and can potentially be linked to PCOS-like traits of the model. Indeed, androgen-exposed mice are insulin-resistant, albeit unaltered fat mass. Collectively, it is demonstrated that hyperandrogenism causes tissue-specific alterations of immune cells in reproductive organs and VAT, which can have considerable implications on tissue function and contribute to the reduced fertility and metabolic comorbidities associated with PCOS., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Transgenic mice expressing human major histocompatibility complex class II (MHCII) risk alleles are widely used in autoimmune disease research, but limitations arise due to non-physiologic expression. To address this, physiologically relevant mouse models are established via knock-in technology to explore the role of MHCII in diseases like rheumatoid arthritis. The gene sequences encoding the ectodomains are replaced with the human DRB1*04:01 and 04:02 alleles, DRA, and CD74 (invariant chain) in C57BL/6N mice. The collagen type II (Col2a1) gene is modified to mimic human COL2. Importantly, DRB1*04:01 knock-in mice display physiologic expression of human MHCII also on thymic epithelial cells, in contrast to DRB1*04:01 transgenic mice. Humanization of the invariant chain enhances MHCII expression on thymic epithelial cells, increases mature B cell numbers in spleen, and improves antigen presentation. To validate its functionality, the collagen-induced arthritis (CIA) model is used, where DRB1*04:01 expression led to a higher susceptibility to arthritis, as compared with mice expressing DRB1*04:02. In addition, the humanized T cell epitope on COL2 allows autoreactive T cell-mediated arthritis development. In conclusion, the humanized knock-in mouse faithfully expresses MHCII, confirming the DRB1*04:01 alleles role in rheumatoid arthritis and being also useful for studying MHCII-associated diseases., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

RNA-based medicines have potential to treat a large variety of diseases, and research in the field is very dynamic. Proactively, The European Medicines Agency (EMA) organized a virtual conference on February 2, 2023 to promote the development of RNA-based medicines. The initiative addresses the goal of the EMA Regulatory Science Strategy to 2025 to "catalyse the integration of science and technology in medicines development." The conference focused on RNA technologies (excluding RNA vaccines) and involved different stakeholders, including representatives from academia, industry, regulatory authorities, and patient organizations. The conference comprised presentations and discussion sessions conducted by panels of subject matter experts. In this meeting report, we summarize the presentations and recap the main themes of the panel discussions.