Suppression of IL-12/IL-23 p40 subunit in the skin and blood of psoriasis patients by Tofacitinib is dependent on active interferon-γ signaling in dendritic cells: implications for the treatment of psoriasis and interferon-driven diseases

Interleukin (IL)-12 and IL-23 are pro-inflammatory cytokines produced by dendritic cells (DCs) and associated with Psoriasis (Pso) and Psoriatic Arthritis (PsA) pathogenesis. Tofacitinib, a Janus kinase inhibitor, effectively suppresses inflammatory cascades downstream the IL-12/IL-23 axis in Pso and PsA patients. Here we investigated whether Tofacitinib directly regulates IL-12/IL-23 production in DCs, and how this regulation reflects responses to Tofacitinib in Pso patients. We treated monocyte-derived dendritic cells and myeloid dendritic cells with Tofacitinib and stimulated cells with either lipopolysaccharide (LPS) or a combination of LPS and IFN-γ. We assessed gene expression by qPCR, obtained skin microarray and blood Olink data and clinical parameters of Pso patients treated with Tofacitinib from public datasets. Our results indicate that in DCs co-stimulated with LPS and IFN-γ, but not with LPS alone, Tofacitinib leads to the decreased expression of IL-23/IL-12 shared subunit IL12B (p40). In Tofacitinib-treated Pso patients, IL-12 expression and psoriasis area and severity index (PASI) are significantly reduced in patients with higher IFN-γ at baseline. These findings demonstrate for the first time that Tofacitinib suppresses IL-23/IL-12 shared subunit IL12B in DCs upon active IFN-γ signaling, and that Pso patients with higher IFN-γ baseline levels display improved clinical response after Tofacitinib treatment

Quality assurance and quality control of the 26 m2 SiPM production for the DarkSide-20k dark matter experiment

DarkSide-20k is a novel liquid argon dark matter detector currently under construction at the Laboratori Nazionali del Gran Sasso (LNGS) of the Istituto Nazionale di Fisica Nucleare (INFN) that will push the sensitivity for Weakly Interacting Massive Particle (WIMP) detection into the neutrino fog. The core of the apparatus is a dual-phase Time Projection Chamber (TPC), filled with 50 tonnes of low radioactivity underground argon (UAr) acting as the WIMP target. NUV-HD-cryo Silicon Photomultipliers (SiPM)s designed by Fondazione Bruno Kessler (FBK) (Trento, Italy) were selected as the photon sensors covering two Optical Planes, one at each end of the TPC, and a total of photosensitive surface for the liquid argon veto detectors. This paper describes the Quality Assurance and Quality Control (QA/QC) plan and procedures accompanying the production of FBK NUV-HD-cryo SiPM wafers manufactured by LFoundry s.r.l. (Avezzano, AQ, Italy). SiPM characteristics are measured at 77 K at the wafer level with a custom-designed probe station. As of March 2025, 1314 of the 1400 production wafers (94% of the total) for DarkSide-20k were tested. The wafer yield is 93.2 +- 2.5%, which exceeds the 80% specification defined in the original DarkSide-20k production plan

DarkSide-20k sensitivity to light dark matter particles

The dual-phase liquid argon time projection chamber is presently one of the leading technologies to search for dark matter particles with masses below 10 GeV c−2. This was demonstrated by the DarkSide-50 experiment with approximately 50 kg of low-radioactivity liquid argon as target material. The next generation experiment DarkSide-20k, currently under construction, will use 1,000 times more argon and is expected to start operation in 2027. Based on the DarkSide-50 experience, here we assess the DarkSide-20k sensitivity to models predicting light dark matter particles, including Weakly Interacting Massive Particles (WIMPs) and sub-GeV c−2 particles interacting with electrons in argon atoms. With one year of data, a sensitivity improvement to dark matter interaction cross-sections by at least one order of magnitude with respect to DarkSide-50 is expected for all these models. A sensitivity to WIMP–nucleon interaction cross-sections below 1 × 10−42 cm2 is achievable for WIMP masses above 800 MeV c−2. With 10 years exposure, the neutrino fog can be reached for WIMP masses around 5 GeV c−2

THU0461 Class I and Class II Hdacs Make Distinct Contributions to the Inflammatory Activation of Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Background: HDAC inhibitors (HDACi) display anti-inflammatory properties in animal and in vitro models of rheumatoid arthritis (RA), as well as initial safety and efficacy in the treatment of systemic onset juvenile idiopathic arthritis1,2. However, most currently available HDACi display relatively little selectivity for class I (HDAC 1-3, 8) and class II (HDAC 4-7, 9, 10) HDACs. Objectives: The present study aims to better characterize the different contribu-tions of HDAC family members to the inflammatory activation of RA fibroblast-like synoviocytes (FLS). Methods: HDAC mRNA expression in RA FLS was measured by quantitative PCR, and the activity of class I, IIa and IIb HDACs was assessed by enzymatic assays. The effects of pan-specific HDACi and selective HDAC1/2, HDAC3/6 and HDAC8 inhibitors on RA FLS gene expression was analyzed by ELISA and customized qPCR arrays. FLS were either transduced with adenoviral GFP-HDAC5 or transfected with HDAC5 siRNA, and gene expression was analyzed by qPCR array, while chemokine production was measured by ELISA. Analysis o

Structural performance of unreinforced full-scale façade concrete beam-column joint under cyclic load

Post-earthquake observations have shown that poorly reinforced concrete (RC) beam-column joints in existing structures determine premature brittle failures during seismic action. Failure of these critical parts, which transfer stresses and moments between beams and columns, resulted in the catastrophic collapse of structures in low to moderate seismic risk zones. Exterior (i.e. corner or facade) beam-column joints of buildings constructed without or with insufficient transverse reinforcements are commonly involved in the failure. The purpose of this study was to investigate the effective vulnerability of two full-scale exterior facade beam-column joints under transverse cyclic loading. Both the specimen design strategy and the test setup were conceived to emphasize the vulnerability of the joints and, therefore, to achieve shear failure in the joint panel prior to yielding both beam and column reinforcements under the simulated seismic action. In particular: (i) joint was characterized by the absence of any capacity design principle (i.e. total lack of stirrups in the joint panel) to highlight structural deficiencies typical of the 1960s-70s Italian construction practice; (ii) beams and columns were adequately designed to remain in the elastic field during the tests; (iii) the specimen was evaluated in the absence of axial load. In this work, the experimental seismic performance is compared to the one predicted by code/literature models. The test is then simulated using a numerical three-dimensional model for modelling crack propagation and fracture in concrete using the smeared crack technique. The model also allowed for a more comprehensive examination of the effects of certain assumptions on the mechanical performance of the RC joint during the experiment. (c) 2023 The Authors. Published by Elsevier B.V