Immunotherapy with tolerogenic apolipoprotein B-100–loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice

BACKGROUND: Atherosclerosis is a chronic inflammatory disease characterized by a massive intimal accumulation of low-density lipoprotein that triggers chronic vascular inflammation with an autoimmune response to low-density lipoprotein components. METHODS AND RESULTS: To dampen the inflammatory component of atherosclerosis, we injected hypercholesterolemic huB100(tg) × Ldlr(-/-) mice (mice transgenic for human apolipoprotein B100 [ApoB100] and deficient for the low-density lipoprotein receptor) intravenously with dendritic cells (DCs) that had been pulsed with the low-density lipoprotein protein ApoB100 in combination with the immunosuppressive cytokine interleukin-10. DCs treated with ApoB100 and interleukin-10 reduced proliferation of effector T cells, inhibited production of interferon-γ, and increased de novo generation of regulatory T cells in vitro. Spleen cells from mice treated with DCs plus ApoB100 plus interleukin-10 showed diminished proliferative responses to ApoB100 and significantly dampened T-helper 1 and 2 immunity to ApoB100. Spleen CD4(+) T cells from these mice suppressed activation of ApoB100-reactive T cells in a manner characteristic of regulatory T cells, and mRNA analysis of lymphoid organs showed induction of transcripts characteristic of these cells. Treatment of huB100(tg) × Ldlr(-/-) mice with ApoB100-pulsed tolerogenic DCs led to a significant (70%) reduction of atherosclerotic lesions in the aorta, with decreased CD4(+) T-cell infiltration and signs of reduced systemic inflammation. CONCLUSIONS: Tolerogenic DCs pulsed with ApoB100 reduced the autoimmune response against low-density lipoprotein and may represent a novel possibility for treatment or prevention of atherosclerosis.Swedish Research CouncilFoundation for Strategic ResearchVinnovaSwedish Heart-Lung FoundationEuropean Union (AtheroRemo integrated project)Stockholm County CouncilPublishe

Isospin-breaking corrections to light leptonic decays in lattice QCD+QED at the physical point

We report on the physical-point RBC/UKQCD calculation of the leading isospin-breaking corrections to light-meson leptonic decays. This is highly relevant for future precision tests in the flavour physics sector, in particular the first-row unitarity of the Cabibbo-Kobayashi-Maskawa matrix containing the elements $V_{us}$ and $V_{ud}$. The simulations were performed using Domain-Wall fermions for $2+1$ flavours, and with isospin-breaking effects included perturbatively in the path integral through order $\alpha$ and $(m_u - m_d)/\Lambda _{\mathrm{QCD}}$. We use QED$_{\mathrm{L}}$ for the inclusion of electromagnetism, and discuss here the non-locality of this prescription which has significant impact on the infinite-volume extrapolation.Comment: Proceedings for The 39th International Symposium on Lattice Field Theory, 8th-13th August, 2022, Rheinische Friedrich-Wilhelms-Universit\"at Bonn, Bonn, German

High-pressure phase of brucite stable at Earth's mantle transition zone and lower mantle conditions

We investigate the high-pressure phase diagram of the hydrous mineral brucite, Mg(OH)(2), using structure search algorithms and ab initio simulations. We predict a high-pressure phase stable at pressure and temperature conditions found in cold subducting slabs in Earth’s mantle transition zone and lower mantle. This prediction implies that brucite can play a much more important role in water transport and storage in Earth’s interior than hitherto thought. The predicted high-pressure phase, stable in calculations between 20 and 35 GPa and up to 800 K, features MgO(6) octahedral units arranged in the anatase–TiO(2) structure. Our findings suggest that brucite will transform from a layered to a compact 3D network structure before eventual decomposition into periclase and ice. We show that the high-pressure phase has unique spectroscopic fingerprints that should allow for straightforward detection in experiments. The phase also has distinct elastic properties that might make its direct detection in the deep Earth possible with geophysical methods

Inhibition of T cell response to native low-density lipoprotein reduces atherosclerosis

Immune responses to oxidized low-density lipoprotein (oxLDL) are proposed to be important in atherosclerosis. To identify the mechanisms of recognition that govern T cell responses to LDL particles, we generated T cell hybridomas from human ApoB100 transgenic (huB100tg) mice that were immunized with human oxLDL. Surprisingly, none of the hybridomas responded to oxidized LDL, only to native LDL and the purified LDL apolipoprotein ApoB100. However, sera from immunized mice contained IgG antibodies to oxLDL, suggesting that T cell responses to native ApoB100 help B cells making antibodies to oxLDL. ApoB100 responding CD4+ T cell hybridomas were MHC class II–restricted and expressed a single T cell receptor (TCR) variable (V) β chain, TRBV31, with different Vα chains. Immunization of huB100tgxLdlr−/− mice with a TRBV31-derived peptide induced anti-TRBV31 antibodies that blocked T cell recognition of ApoB100. This treatment significantly reduced atherosclerosis by 65%, with a concomitant reduction of macrophage infiltration and MHC class II expression in lesions. In conclusion, CD4+ T cells recognize epitopes on native ApoB100 protein, this response is associated with a limited set of clonotypic TCRs, and blocking TCR-dependent antigen recognition by these T cells protects against atherosclerosis

Cellular immune responses to low density lipoprotein in atherosclerosis

Atherosclerosis is an inflammatory disease of the medium and large sized arterial vessels. Low density lipoprotein (LDL) particles carrying cholesterol are trapped within the arterial intima and elicit both innate as well as adaptive immune responses. T cells are present in the atherosclerotic plaque and cellular immunity plays an important role in lesion development. Mouse models of atherosclerosis are efficient means of unraveling the inflammatory process in the intima. The studies in this thesis have used some of these models to investigate the impact of the adaptive immunity on atherosclerosis and how antigen specific immunity can be explored to create new therapeutic opportunities. Dendritic cells (DC) are potent inducers of T cells. To explore the effect of DC on atherosclerosis, in the context of an atherosclerosis-related antigen, we injected hypercholesterolemic Apoe-/- mice with malondialdehyde (MDA)-LDL pulsed DC. This cell transfer increased local inflammation in the vessel wall and accelerated plaque development. Importantly, the treatment also generated adaptive immune responses specific for components of LDL. This study suggests that DC can be used to influence atherogenic immunity. The use of the hypercholesterolemic huB100tg x Ldlr-/- mouse model permitted us to study human LDL-derived epitopes to dissect the cellular autoimmune response in atherosclerosis. We demonstrated that CD4+ T cells, expressing T cell receptors (TCRs) with the variable beta domain TRBV31, recognize apolipoprotein B100 (ApoB100) of LDL and are needed for the development of advanced atherosclerosis. This illustrates the importance of ApoB100-specific T cell immunity in the atherogenic process. Furthermore, we employed a strategy for immunoprotection of atherosclerosis by nasally administrating an ApoB100-derived peptide fused to the B-subunit of cholera toxin. This treatment targeted the mucosal immunity which led to an induction of antigen-specific regulatory T cells and significantly reduced atherosclerosis in Apoe-/- mice. Finally, to make use of DC as a treatment modality for atherosclerotic disease, we injected huB100tg x Ldlr-/- mice with DC that had been made tolerogenic by treatment with IL-10 and ApoB100. This led to a very significant reduction of atherosclerotic lesions in the aorta with decreased CD4+ T cell infiltrates and dampened systemic inflammation. The tolerogenic DC therapy diminished the autoreactive T cell response to ApoB100, showing the relevance of antigen-specific immunity in atherosclerosis and treatments thereof. In conclusion, we have studied the adaptive immunity to ApoB100 of LDL in mouse models. This has led to the identification of novel therapeutic targets for cardiovascular disease. We found that pro-atherosclerotic T cells can recognize ApoB100 and that DC can present epitopes of LDL and activate pro-inflammatory T cells. When manipulating DC to induce T cell tolerance to ApoB100, immunoprotection is established with reduced atherosclerosis as a consequence. Finally, by using derivatives of ApoB100 for mucosal vaccination we could also target atherosclerosis development

Simulation of line fault locator on HVDC Light electrode line

In this bachelor thesis, cable fault locators are studied for use on the overhead electrode lines in the HVDC (High Voltage Direct Current) Light project Caprivi Link. The cable fault locators studied operates with the principle of travelling waves, where a pulse is sent in the tested conductor. The time difference is measured from the injection moment to the reflection is received. If the propagation speed of the pulse is known the distance to the fault can be calculated. This type of unit is typically referred to as a TDR (Time Domain Reflectometer). The study is performed as a computer simulation where a simplified model of a TDR unit is created and applied to an electrode line model by using PSCAD/EMTDC. Staged faults of open circuit and ground fault types are placed at three distances on the electrode line model, different parameters of the TDR units such as pulse width and pulse amplitude along with its connection to the electrode line are then studied and evaluated. The results of the simulations show that it is possible to detect faults of both open circuit and ground fault types with a suitable TDR unit. Ground faults with high resistance occurring at long distances can be hard to detect due to low reflection amplitudes from the injections. This problem can somewhat be resolved with a function that lets the user compare an old trace of a “healthy” line with the new trace. The study shows that most of the faults can be detected and a distance to the fault can be calculated within an accuracy of ± 250 m. The pulse width of the TDR needs to be at least 10 μs, preferable 20 μs to deliver high enough energy to the fault to create a detectable reflection. The pulse amplitude seams to be of less significance in this simulation, although higher pulse amplitude is likely to be more suitable in a real measurement due to the higher energy delivered to the fault. The Hipotronics TDR 1150 is a unit that fulfil these requirements and should therefore be able to work as a line fault locator on the electrode line

Investigating the usefulness of a generative AI when designing user interfaces

Generative AI is a hot topic as of 2023, with huge financial investments in the industry. The areas of use for it are rapidly expanding. One potential benefit of generative AI could be in the field of UX design.For this master's thesis, a Stable Diffusion model has been fine-tuned to create pictures of login screens based on text prompts written by a user. A set of these pictures have been used in a prototype and the concept has been evaluated through user tests. The prototype and the concept of using generative AI in UX design received a positive reception from testers. It was established that further work on the fine-tuned model and how to use it as a tool is required for it to be effectively integrated into the design process of user interfaces