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Muon colliders offer enormous potential for the exploration of the particle physics frontier but are challenging to realize. A new international collaboration is forming to make such a muon collider a reality.

The presence of circulating rheumatoid factor (RF) and the formation of ectopic lymphoid structures (ELS) in labial salivary glands (SG) of patients with Sjögren's Syndrome (SS) have been reported as independent risk factors associated with the development of SG B-cell MALT lymphoma (MALT-L). Neoplastic MALT-L B-cells express highly hypermutated B-cell receptors bearing RF immunoreactivity in up to 50% of the cases, but whether their maturation and proliferation is dependent on ELS or is also induced by extrafollicular responses in the SG is currently unclear. The definition of ELS and their association with circulating autoantibodies has so far relied on SG histopathology which bears significant limitations. Conversely, molecular pathology analysis through whole-tissue RNA Sequencing (RNASeq) has allowed a better definition of disease heterogeneity and disease taxonomy. To perform transcriptomic profiling of SS minor SG tissue characterised by different degrees of inflammatory aggregate organization and to identify transcriptomic clusters and gene signatures associated with peripheral and histological biomarkers of disease. Labial SG were obtained from 99 patients including SS with and without ELS (respectively ELS+ and ELS-, as assessed by immunohistochemistry) and non-specific chronic sialadenitis (Sicca). Total RNA was extracted, complementary DNA libraries were prepared and sequenced. Differentially expressed genes (DEG), deconvolution and pathway analysis were performed. Unsupervised gene clustering by differential expression between sicca and SS confirmed a clear transcriptome segregation between the two diagnoses. As expected, in SS SG expression of genes associated with inflammation and adaptive immune responses was upregulated (e.g. CCR7, CD19, CR2, CXCL13, CXCL9, CXCR5, FCRL3, FCRL4, IL21R, MS4A1, PAX5, SLAMF6, TLR10) (Figure A). Bulk RNAseq cell deconvolution confirmed immune cell enrichment (Th, B and plasma cells) in SS SG, especially those ELS+. A three-way comparison among sicca, ELS+ and ELS- SG, showed only a few genes specifically associated to ELS- and sicca, whereas most of the DEGs were either ELS+ specific or common to all SS (Figure B). Results of pathway analysis on ELS+ and SS-associated DEGs showed very similar profiles characterised by adaptive and interferon-associated pathway activation. Weighted Gene Co-Expression Network analysis showed higher activation of anti-viral pathways in ELS- SG, where ELS+ SG were enriched in adaptive immune pathways. Principal component analysis on SS SG mRNA showed that a significant proportion of variability was associated with the presence of RF in the serum of patients independently of the presence of ELS. Surprisingly, transcriptome clustering was closer between ELS+/RF+ and ELS-/RF+ SG than the clustering of ELS+/RF- with ELS-/RF- SG. Accordingly, SG of RF+ patients showed significant upregulation of B cell-associated genes (e.g. CXCL13, MS4A1). However, while SG transcriptomes of ELS+/RF+ were characterised by genes associated with germinal centre formation (e.g IL21, AICDA, LTB), transcriptomes from ELS-/RF+ SG displayed a unique set of DEGs such as BCL2, TRIM22, XAF1, DDX58, DDX60 and IFIT1. Conversely, a similar analysis performed based on anti-Ro/SSA and/or anti-La/SSB did not yield any significant differences in gene expression. A comprehensive bulk RNA sequencing analysis of SS and sicca patients SG showed that higher tissue inflammation with features of functional germinal centres is associated to the presence of both RF and ELS, rather than ELS alone. Furthermore, the existence of a RF-driven SG transcriptome independent of the presence of ELS suggest that both follicular and extra-follicular responses support the selection of B-cells with RF immunoreactivity within the SG of SS patients and could be involved in B-cell lymphomagenesis. [Display omitted] NIL. NIL. Elena Pontarini: None declared, Davide Lucchesi: None declared, Katriona Goldmann: None declared, Myles Lewis: None declared, Qingxuan Song Employee of: Janssen Pharmaceuticals, Inc., Spring House, PA, USA, Elizabeth Thomas Employee of: Janssen Pharmaceuticals, Inc., Spring House, PA, USA, Ling-Yang Hao Employee of: Janssen Pharmaceuticals, Inc., Spring House, PA, USA, Kathy Sivils Employee of: Janssen Pharmaceuticals, Inc., Spring House, PA, USA, Costantino Pitzalis: None declared, Michele Bombardieri Speakers bureau: UCB, Janssen, Consultant of: GSK, Janssen, MedImmune, Grant/research support from: Janssen, MedImmune.

Background:In Sjögren Disease (SD) salivary gland epithelial cells (SGEC) sustain inflammation due to their acquired capacity to express/secrete adhesion/pro-inflammatory molecules. However, the mechanisms responsible for SGECs activation remain undetermined. The link between immune cells’ function and cells’ metabolic reprogramming is known under the term “immunometabolism” and has become one of the most exciting areas of investigation in the field of immuno-rheumatology, despite its relevance in SD has not been investigated as yet.We hypothesize that the altered cell energy metabolism of SGECs is a central driver of SG inflammation in SD and one that is targetable for the development of innovative therapies.Objectives:I–To determine (in vivo) in a viral-induced model of experimental sialoadenitis the relationship between SG inflammation and cell metabolic reprogramming;II–To identify ex vivo the main metabolic pathways differing between SD and sicca (control) SGECs;III–To assess ex vivo and in vitro the expression of glycolysis in SGECs and to investigate its contribution to SGECs activation.Methods:Aim I- SD mouse models were produced. After culling at different time points [day_0 (non-cannulated), day_5-12-19 (cannulated)], SG bulk RNA-seq analysis focused on metabolic pathways was conducted. Aim II- The metabolic profile of cultured SGECs from SD and sicca patients was analysed (mass spectrometry). Aim III- The expression of the glycolysis marker GLUT-1, along with lymphocytes (CD45+) and epithelial cells (PanCK+, CK7+, CK14+) markers, was determined (IFI) on paraffin-embedded sections of SD and sicca minor SG. SGECs cultures were treated as follows: 1) fluorescent glucose (6-NBDG), to assess glucose up-take; 2) 2-deoxy-glucose (2DG), to evaluate the effect of glycolysis inhibition on SGECs activation [ICAM-1 expression (IFI) and IL-6/type-I IFN production (Elisa and IFNα/β reporter cells)]; treatment conditions are in Figure 1d.Results:Aim-I: Following the inflammatory insult, bulk RNA-seq analysis in AdV-induced sialoadenitis, demonstrated changes in the SG metabolic profile. Down-regulation of specific pathways (i.e. oxidative phosphorylation and pyruvate metabolism), occurred up to day 12 post-cannulation (Figure 1a).Aim-II: A metabolic difference between SGECs from SD and sicca patients was revealed (i.e. glycolysis and TCA cycles) (Figure 1b).Aim III: As glycolysis turned out to be one of the most expressed pathways in SD, we further investigated its expression in SGECs. The expression of the glucose transporter GLUT-1 was highly detected in SD SG tissue by SGECs wile no expression was detected in sicca. Such GLUT-1 expression was mainly localized in ducts, especialy in ductal luminal cytokeratin-7 positive (CK7+) cells (Figure 1c). In vitro treatment of SGECs with fluorescent glucose demonstrated an higher glucose uptake in SD SGECs (representative example-Figure 1c). In primary SGECs culture, following stimulation with Poly(I:C), which mimics viral sensing by SGEC, an increase in IL-6, type-I IFN and the adhesion molecule ICAM-1 was observed. SGECs treatment with the glycolisis-inhibitor 2DG prevented [if Poly(I:C) and 2DG were administered concomitantly] or reduced [if 2DG was added following 12h stimulation with Poly(I:C)] the expression of adhesion/pro-inflammatory molecules (Figure 1d).Conclusion:In vivo experiments confirm that inflammation is intimately linked with metabolic changes occurring in SD SG. After induction of inflammation, we observed a down-regulation of oxidative phosphorylation and changes in glucose metabolism. Mass spectometry analysis confirmed the higher expression of specific metabolic pathways in SD SGECs, such as glycolysis. The increased expression of GLUT-1 in SD CK7+ ductal epithelial cells and the higher glucose up-take in SD cultured SGECs confirm such a shift towards glycolysis. Remarkably, glycolysis inhibition affects SGECs activation, indicating that metabolic reprogramming is likely responsible for their pathogenic behaviour. In vivo investigations on the potential utility of drugs targeting glycolysis in SD are currently ongoing.REFERENCES:NIL.Figure 1.Acknowledgements:The presenting author of this abstract (SC) is recipient of a “Career Research Grant” funded by FOREUM – Foundation for Research in Rheumatology.Disclosure of Interests:None declared.

The Crilin calorimeter is a semi-homogeneous calorimetric system that uses Lead Fluoride (PbF 2 ) crystals with UV-extended Silicon Photomultipliers (SiPMs). Proposed for the Muon Collider, it requires high granularity to distinguish signal particles and address substructures for jet identification. Anticipating substantial occupancy due to beam-induced backgrounds, simulations indicate a photon flux with an average energy of 1.7 MeV and approximately 4.5 MHz/cm 2 fluence rate. Prioritizing time-of-arrival measurements within the calorimeter is crucial for associating clusters with interaction vertices. The calorimeter’s energy resolution is vital for determining jet kinematics. Extensive radiation hardness studies confirm the system’s effectiveness when operating in a challenging radiation environment, with exposure up to 10 kGy/year total ionizing dose (TID) and a neutron fluence equivalent to 10 14 neutrons 1 MeV/cm 2 /year. Prototype (Proto-1), with two layers of 3×3 PbF 2 crystals, achieved a timing resolution below 50 ps for energy deposits exceeding 1 GeV during 2023 tests. A comprehensive overview, including mechanics, electronics, and test beam outcomes, is presented. Construction is underway for a larger 9 9 crystal matrix prototype with 5 layers, to be completed in 2024. Testing is scheduled for the summer of 2025.

Aims/hypothesis Endothelium-derived factors are thought to be physiological modulators of large artery stiffness. The aim of the study was to investigate whether endothelial function could be a determinant of arterial stiffness in essential hypertensive patients, in relation with the concomitant presence of type 2 diabetes mellitus. Methods The study included 341 participants (84 hypertensive patients with and 175 without type 2 diabetes mellitus, 82 matched controls). Brachial artery endothelium-dependent flow-mediated dilation (FMD) was determined by high-resolution ultrasound and computerised edge detection system. Applanation tonometry was used to measure carotid–femoral pulse wave velocity (PWV). Results Hypertensive patients with diabetes had higher PWV (10.1 ± 2.3 m/s vs 8.6 ± 1.4 m/s, p  < 0.001) and lower FMD (3.51 ± 2.07 vs 5.16 ± 2.96%, p  < 0.001) than non-diabetic hypertensive patients, who showed impaired vascular function when compared with healthy participants (7.9 ± 1.6 m/s and 6.68 ± 3.67%). FMD was significantly and negatively correlated to PWV only in hypertensive diabetic patients ( r  = −0.456, p  < 0.001), but not in hypertensive normoglycaemic patients ( r  = −0.088, p  = 0.248) or in healthy participants ( r  = 0.008, p  = 0.946). Multivariate analysis demonstrated that, in the diabetic group, FMD remained an independent predictor of PWV after adjustment for confounders ( r 2  = 0.083, p  = 0.003). Subgroup analysis performed in non-diabetic hypertensive patients revealed that neither obesity nor the metabolic syndrome affected the relationship between FMD and PWV. Conclusions/interpretation Endothelial dysfunction is a determinant of aortic stiffness in hypertensive diabetic patients but not in hypertensive patients without diabetes. These results suggest that type 2 diabetes mellitus on top of hypertension might worsen arterial compliance by endothelium-related mechanisms.

In modern experiment, a high granularity is required in order to distinguish signal particles from background and to solve the substructures necessary for jet identification. Time of arrival measurements in the calorimeter could play an important role in HL-LHC, since a high number of pile-up collisions is expected, and the timing could be used to assign clusters to the corresponding interaction vertex. In a Muon Collider, the timing could be used to remove signals produced by beam-induced background, asynchronous with respect to the bunch crossing. The calorimeter energy resolution is also fundamental to measure the kinematic properties of jets: a finely segmented calorimeter design should be favored in order to solve the jet substructure. However, this contrasts with the requirement for high timing resolution even for signal events involving low energy deposits, such as in the case of high impulse muons. Our proposed design, the Crilin calorimeter, is a semi-homogeneous calorimeter based on Lead Fluoride (PbF 2 ) Crystals readout by surface-mount UV-extended Silicon Photomultipliers (SiPMs). In this paper, the development of a small prototype consisting of 2 layers of 3 × 3 crystals each is reported along with the relative results.

The pathogenic role of B-cells in primary Sjögren's Syndrome (pSS) is well established and B cell abnormalities. Because of the substantial role of B-cells, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, has been considered as a potential biologic disease modifying drug to reduce disease activity in pSS. To date, the TRial for Anti-B-Cell Therapy In patients with pSS (TRACTISS) is the largest multi-centre, placebo-controlled trial with RTX. Despite the unmet primary endpoints (30% reduction in fatigue or oral dryness, measured by visual analogue scale), RTX treated patients showed an improvement in unstimulated whole salivary flow (Bowman et al. Arthritis Rheumatol 2017;69:1440–1450). To provide the first longitudinal transcriptomic and histological analysis at 3 time points over 48 weeks of labial SGs of pSS patients treated with RTX, in comparison to placebo, from the TRACTISS cohort. 26 pSS patients randomised to RTX or placebo arm consented for labial SG biopsies at baseline, weeks 16 and 48. Patients received two 1000mg cycles of RTX or placebo at baseline and week 24. SG focus score, inflammatory aggregate area fraction, B-cells (CD20+), T-cells (CD3+), follicular dendritic cells (FDCs) (CD21+) and plasma cells (CD138+) density were assessed by H&E and immunofluorescence staining. The histological analysis was performed by digital imaging using QuPath software. RNA was extracted from matched labial SG lobules and sequenced with Illumina platform. A Principal Component Analysis (PCA) and features driving the PCA were investigated along with the most influential gene loadings. The limma-voom R pipeline was used to extract Differential Expressed Genes (DEGs) between placebo and RTX group at week 48, and gene ontology (GO) enrichment analysis performed through EnrichR to derive GO terms and pathways associated with DEGs. Placebo-treated labial SGs showed a worsening of inflammation highlighted by the increment of B-cell density, development of new FDC networks, and a higher ectopic GC prevalence at week 48, compared to RTX-treated patients. No difference in total T-cells and plasma cell infiltration was observed. RTX downregulated genes involved in immune cell recruitment and inflammatory aggregate organisation (e.g. CCR7, CCL19, CD52, and PDCD1) and gene signature-based analysis of 64 immune cell types highlighted how RTX preferentially blocked class-switched- and memory-B-cells infiltration in SGs at week 48. Pathway analyses confirmed the downregulation of leukocyte migration, MHC class II antigen presentation, and T-cell co-stimulation immunological pathways, such as the CD40 receptor complex pathway. The analysis of placebo SGs transcriptomic at week 48 showed a higher expression of genes linked to ectopic GC organisation, such as CXCL13, CCL19, LTβ, in female compared to male subjects. Gender was confirmed as a key co-variate responsible for most of the variation in the PCA, together with the SG focus score and the foci area fraction. Treatment with RTX showed beneficial effects on labial SG inflammatory infiltration in pSS, by downregulating genes involved in immune cell recruitment, activation and organisation in ectopic GCs. Class-switched-B-cells, memory-B-cells and FDC network development were primarily affected appearing to be responsible for the lack of progression in SG B cell infiltration in the RTX compared to the placebo arm in which clear worsening of SG immunopathology over 48 weeks was detected in female patients. Although a clear association with the clinical improvement in unstimulated salivary flow observed at week 48 in RTX-treated patients could not be established given the low number of patients consenting to 3 longitudinal biopsies it is conceivable that RTX is responsible for preserving exocrine function. SJB receives a salary contribution from the NIHR Birmingham Biomedical Research Centre. Elena Pontarini: None declared, Farzana Chowdhury: None declared, Elisabetta Sciacca: None declared, Sofia Grigoriadou: None declared, Felice Rivellese: None declared, Davide Lucchesi: None declared, Katriona Goldmann: None declared, Liliane Fossati-Jimack: None declared, Paul Emery: None declared, Wan Fai Ng: None declared, Nurhan Sutcliffe: None declared, Colin Everett: None declared, Catherine Fernandez: None declared, Anwar Tappuni: None declared, Myles Lewis: None declared, Costantino Pitzalis: None declared, Simon J. Bowman Consultant of: SJB In 2020 I have received consultancy fees from Novartis, Abbvie and Galapagos., Michele Bombardieri: None declared

BackgroundDysregulation of Natural Killer (NK) cells has been shown to influence the development of autoimmune diseases1, but their role in Sjögren's syndrome (SS) remain unclear.ObjectivesThe main goal of our study was to investigate the recruitment and functional relevance of NK cells in the early phases of salivary gland (SG) inflammation in an inducible murine model of SS.MethodsSialoadenitis was induced in WT-C57BL/6 mice via SG retro-cannulation of 108 pfu/gland of luciferase-encoding adenovirus-5 (AdV). FACS analysis of NK cells (CD45pos/NK1.1pos/CD3neg) was performed in digested SG, while snap-frozen SG tissues were stained for either cytotoxic NK cells (NK1.1pos/CD3neg/Granzyme Bpos) or B (B220pos) and T cells (CD3pos). Negatively selected CFSEpos NK cells from WT-C57BL/6 mice spleens were adoptively transferred in AdV-infected mice to evaluate NK cell recruitment and proliferation in the SG. Virus infected cell clearance by NK cells was assessed with luciferase activity quantification in SG. To achieve NK cell depletion, 200μg of anti-NK1.1 antibody were administered via intraperitoneal injection every 48h. Anti-nuclear antibodies were assessed on Hep-2-coated microscope slides, and anti-AdV antibodies with ELISA assay.ResultsAdV infection in SG induced an early NK cell recruitment peaking at 4 days post-cannulation (dpc). This is due to an active NK cell migration to the SG at 1dpc followed by their intra-SG proliferation at 3-5dpc, as shown by cell transfer experiments. NK cells preferentially accumulate before B/T cell aggregates formation. Activating markers NKp46 and CD69 were up regulated from 5dpc onwards when an increased degranulation potential was observed. Accordingly, NK cells, rather then cytotoxic T cells, mainly mediated cytotoxic activity, as measured by granzyme B expression, at 4/5dpc. NK depletion impaired viral control at 3dpc but not at later time-points. Conversely, NK depletion did not affect the formation of SS-like inflammatory foci or lymphoid chemokine expression. Moreover, NK cells did not influence the production of ANA or anti-AdV antibodies.ConclusionsHere we show that NK cells are actively recruited to the inflammatory site of the SG and are critically involved in the early immune control of AdV infection in this organ but are dispensable for the development of SS-like inflammatory foci and autoimmunity.ReferencesSchleinitz N1, Vély F, Harlé JR, Vivier E. Natural killer cells in human autoimmune diseases. Immunology. 2010 Dec;131(4):451-8.Disclosure of InterestNone declared

The measurement of physics processes at new energy frontier experiments requires excellent spatial, time, and energy resolutions to resolve the structure of collimated high-energy jets. Calorimeters, as other detectors, must face this increasing performance demand. In a future TeV-scale Muon Collider, the beam-induced background (BIB) represents the main challenge in the design of the detectors and of the event reconstruction algorithms and can pose serious limitations to the physics performance. However, it is possible to reduce the BIB impact on the Muon Collider calorimeter by exploiting some of its characteristics and by ensuring high granularity, excellent timing, longitudinal segmentation and good energy resolution. The proposed R&D is an innovative semi-homogeneous electromagnetic calorimeter based on stackable modules of lead fluoride crystals (PbF 2 ) readout by surface-mount UV-extended Silicon Photomultipliers (SiPMs): the Crilin calorimeter (CRystal calorImeter with Longitudinal INformation). The calorimeter should operate in a very harsh radiation environment, withstanding yearly a neutron flux of 10 14 n1MeV /cm 2 and a dose of 100 krad. In this paper, the radiation tolerance measured in several irradiation campaigns and the timing performances evaluated during a test beam at CERN-H2 with 120-GeV electron are discussed. A description of the latest prototype Proto-1, that will be shortly tested, is also provided.

In view of Run3 (2020) the LHCb experiment is planning a major upgrade to fully readout events at 40 MHz collision rate. This in order to highly increase the statistic of the collected samples and go further in precision beyond Run2. An unprecedented amount of data will be produced, which will be fully reconstructed real-time to perform fast selection and categorization of interesting events. The collaboration has decided to go for a fully software trigger which will have a total time budget of 13 ms to take a decision. This calls for faster hardware and software. In this talk we will present our efforts on the application of new technologies, such as GPU cards, for the future LHCb trigger system. During Run2 a node equipped with a GPU has been inserted in the LHCb online monitoring system; during normal data taking, a subset of real events is sent to the node and processed in parallel by GPU-based and CPU-based track reconstruction algorithms. This gives us the unique opportunity to test the new hardware and the new algorithms in a realistic environment. We will present the setup of the testbed, the algorithms developed for parallel architectures and discuss the performance compared to the current LHCb track reconstruction algorithms.