Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting.

Background and objective S ystemic sclerosis (SSc) is a severe autoimmune disease, in which the pathogenesis is dependent on both genetic and epigenetic factors. Altered gene expression in SSc monocytes, particularly of interferon (IFN)-responsive genes, suggests their involvement in SSc development. We investigated the correlation between epigenetic histone marks and gene expression in SSc monocytes. Methods C hromatin immunoprecipitation followed by sequencing (ChIPseq) for histone marks H3K4me3 and H3K27ac was performed on monocytes of nine healthy controls and 14 patients with SSc. RNA sequencing was performed in parallel to identify aberrantly expressed genes and their correlation with the levels of H3K4me3 and H3K27ac located nearby their transcription start sites. ChIP-qPCR assays were used to verify the role of bromodomain proteins, H3K27ac and STATs on IFNresponsive gene expression. Results 1046 and 534 genomic loci showed aberrant H3K4me3 and H3K27ac marks, respectively, in SSc monocytes. The expression of 381 genes was directly and significantly proportional to the levels of such chromatin marks present near their transcription start site. Genes correlated to altered histone marks were enriched for immune, IFN and antiviral pathways and presented with recurrent binding sites for IRF and STAT transcription factors at their promoters. IFN\u3b1 induced the binding of STAT1 and STAT2 at the promoter of two of these genes, while blocking acetylation readers using the bromodomain BET family inhibitor JQ1 suppressed their expression. Conclusion SS c monocytes have altered chromatin marks correlating with their IFN signature. Enzymes modulating these reversible marks may provide interesting therapeutic targets to restore monocyte homeostasis to treat or even prevent SSc

Fragility curves of masonry buildings in aggregate accounting for local mechanisms and site effects

The seismic evaluation of masonry buildings in aggregate, largely diffused within the existing Italian and European building stock, represents a difficult and open task that has not been exhaustively investigated so far. The study proposes a procedure aimed at evaluating the potential impact of the combination of local mechanisms and site-amplification in terms of fragility curves on an existing unreinforced masonry (URM) aggregate which is made of five adjacent structural units mutually interacting with each other during seismic sequences. The case study is inspired by built heritage of the historic centre of Visso struck by the Central Italy 2016/2017 earthquakes. The in-plane (IP) response of URM buildings was simulated through nonlinear dynamic analyses performed on a 3D equivalent frame model of the structure, whereas out-of-plane (OOP) mechanisms were analysed by adopting the rigid-block assumption but assuming, as seismic input, the floor accelerations derived from the post-processing of data derived from the global 3D model. An innovative procedure considering the pounding effect to the global response of the building is also presented. Two soil conditions were assumed with (freefield) and without (bedrock) site amplification. The results showed that site effects strongly affected the seismic vulnerability of the aggregate, also altering the combination between IP and OOP mechanisms. In fact, for bedrock condition, especially for medium-high damage levels, local mechanisms were prevailing with respect to the IP response. Conversely, for freefield condition, IP mainly governed the overall behaviour for all the damage levels, consistently with the field evidence

Performance of Fiber Reinforced Mortar coating for irregular stone masonry: Experimental and analytical investigations

Nowadays, the application of Fiber Reinforced Mortar (FRM) is widely used for the consolidation and rehabilitation of masonry structures because represents an effective solution in terms of reversibility and applicability. The paper illustrates the results of cyclic diagonal compression tests performed in situ on stone masonry specimens isolated from the walls of a historic building of L'Aquila (Italy). The tested stone masonry is representative of existing structures of the territories of the central Apennines in Italy. Only two of four panels were strengthened by FRM to provide also the reference value of the unreinforced masonry. The FRM comprised a glass-fiber grid embedded in a natural hydraulic lime (NHL)-based mortar applied as a coating to the masonry surfaces as well as carbon shear connectors. The tests were analyzed to derive the shear strength and the shear modulus of the masonry, as well as their evolution during the tests. Moreover, these tests were compared and integrated with a consistent number of experimental data collected in the current literature aiming to validate a new analytical equation for the estimation of the shear strength of the reinforced masonry, merely based on the properties of the unreinforced masonry and the FRM mortar

Modelling and Seismic Response Analysis of Existing URM Structures. Part 1: Archetypes of Italian Modern Buildings

Five existing unreinforced masonry buildings, built in different Italian cities in a relatively recent time frame, were selected to study the seismic behaviour of modern existing structures, not designed to withstand seismic actions. The buildings were modelled using an equivalent-frame approach, adopting, and comparing two nonlinear constitutive laws and introducing specific modelling strategies to represent the distinctive features of modern existing URM structures. Nonlinear static analyses were performed to determine capacity and multi-stripe time history analyses to evaluate displacement demand at increasing return periods. Although non-exhaustive, the results show a trend of generally decreasing seismic vulnerability for more recent buildings

Seismic fragility assessment of existing masonry buildings in aggregate

The paper describes the derivation of fragility curves useful for the seismic risk analyses of existing unreinforced masonry buildings inserted in aggregate. The L-shaped examined aggregate consists of three adjacent structural units that may mutually interact during seismic events. The seismic assessment is focused on the corner unit. The effects of different connection types between the adjacent units on the structural response were investigated. The seismic vulnerability of the masonry aggregate was assessed through nonlinear dynamic analyses (NDA) performed according to the multi-stripes approach. Both the in-plane and out-of-plane mechanisms were analyzed. The in-plane response of the corner unit is assessed through a 3D equivalent frame model of the entire aggregate, while the evaluation of its out-of-plane response makes use of the rigid-block assumption. Although evaluated in a separate way, the NDAs performed on the latter are based on the time histories derived from the global 3D model. The results are then processed in order to derive fragility curves, firstly, of the single failure mechanisms and, then, of the overall combined behavior. To this aim, various performance conditions are examined. For the reference building, the damage limit state is mainly governed by the in-plane behavior, while the collapse limit state by out-of-plane mechanisms. Moreover, the higher the connection level between adjacent structural units, the higher the interaction between in-plane and out-of-plane mechanisms at the collapse limit state

Modelling and Seismic Response Analysis of Existing URM Structures. Part 2: Archetypes of Italian Historical Buildings

This work presents a comprehensive strategy for analysing the complex seismic response of five Italian historical URM buildings, corresponding to different periods until 1920s. One distinctive feature of historical buildings is the need for integrating global modelling and local response of structural portions, due to possible activation of local failure modes interacting with the overall dynamic building response. Global behaviour is analysed via pushover and dynamic analyses of 3D equivalent-frame models. An original approach is adopted for assessing local out-of-plane mechanisms, accounting for their dynamic response to input time histories, filtered by the global response of the 3D model

Modelling and Seismic Response Analysis of Existing URM Structures. Part 2: Archetypes of Italian Historical Buildings

This work presents a comprehensive strategy for analysing the complex seismic response of five Italian historical URM buildings, corresponding to different periods until 1920s. One distinctive feature of historical buildings is the need for integrating global modelling and local response of structural portions, due to possible activation of local failure modes interacting with the overall dynamic building response. Global behaviour is analysed via pushover and dynamic analyses of 3D equivalent-frame models. An original approach is adopted for assessing local out-of-plane mechanisms, accounting for their dynamic response to input time histories, filtered by the global response of the 3D model

Comparing the Observed and Numerically Simulated Seismic Damage: A Unified Procedure for Unreinforced Masonry and Reinforced Concrete Buildings

A unified procedure for assessing the effectiveness of modelling strategies for existing buildings is proposed. The procedure is applied to unreinforced masonry and cast-in-place and precast reinforced concrete real buildings struck by earthquakes. A cross-structural-typology Matching Index (MI) is proposed. It aims to synthetically compare numerical outcomes with the evidence of the damage experienced by the case-study buildings. Results confirmed a good reliability and effectiveness of the developed numerical models (mean MI value higher than 0.70 for all the investigated cases) and the capability of the models in reproducing the performance states occurred in the real cases

Comparing the Observed and Numerically Simulated Seismic Damage: A Unified Procedure for Unreinforced Masonry and Reinforced Concrete Buildings

A unified procedure for assessing the effectiveness of modelling strategies for existing buildings is proposed. The procedure is applied to unreinforced masonry and cast-in-place and precast reinforced concrete real buildings struck by earthquakes. A cross-structural-typology Matching Index (MI) is proposed. It aims to synthetically compare numerical outcomes with the evidence of the damage experienced by the case-study buildings. Results confirmed a good reliability and effectiveness of the developed numerical models (mean MI value higher than 0.70 for all the investigated cases) and the capability of the models in reproducing the performance states occurred in the real cases

JNK-dependent downregulation of FoxO1 is required to promote the survival of fibroblast-like synoviocytes in rheumatoid arthritis.

Forkhead box O (FoxO) transcription factors integrate environmental signals to modulate cell proliferation and survival, and alterations in FoxO function have been reported in rheumatoid arthritis (RA). To examine the relationship between inflammation and FoxO expression in RA, and to analyse the mechanisms and biological consequences of FoxO regulation in RA fibroblast-like synoviocytes (FLS). RNA was isolated from RA patient and healthy donor (HD) peripheral blood and RA synovial tissue. Expression of FoxO1, FoxO3a and FoxO4 was measured by quantitative PCR. FoxO1 DNA binding, expression and mRNA stability in RA FLS were measured by ELISA-based assays, immunoblotting and quantitative PCR. FLS were transduced with adenovirus encoding constitutively active FoxO1 (FoxO1ADA) or transfected with small interfering RNA targeting FoxO1 to examine the effects on cell viability and gene expression. FoxO1 mRNA levels were reduced in RA patient peripheral blood compared with HD blood, and RA synovial tissue FoxO1 expression correlated negatively with disease activity. RA FLS stimulation with interleukin 1β or tumour necrosis factor caused rapid downregulation of FoxO1. This effect was independent of protein kinase B (PKB), but dependent on c-Jun N-terminal kinase (JNK)-mediated acceleration of FoxO1 mRNA degradation. FoxO1ADA overexpression in RA FLS induced apoptosis associated with altered expression of genes regulating cell cycle and survival, including BIM, p27(Kip1) and Bcl-XL. Our findings identify JNK-dependent modulation of mRNA stability as an important PKB-independent mechanism underlying FoxO1 regulation by cytokines, and suggest that reduced FoxO1 expression is required to promote FLS survival in R