FRCM-to-masonry bonding behaviour in the case of curved surfaces: Experimental investigation

Fabric-reinforced cementitious matrix (FRCM) are composite materials more and more used for the reinforcement of masonry structures. The combination of high tensile strength fabrics (or meshes) with cementitious matrices, having good thixotropic capabilities and vapour permeability, makes such composites suitable for reinforcing a large number of masonry structures, including the one belonging to the historic heritage. FRCMs are bonded to the outer surfaces of structural masonry elements and, thanks to their adhesive capacity, bear much of the tensile stresses that unreinforced masonry cannot withstand. The effectiveness of such reinforcements, which is highly dependent on their ability to adhere to the masonry substrate, is generally investigated throughout specific experimental investigations (shear tests). Almost all the papers in the literature devoted to bond-slip analysis refer to the case of flat bonding surfaces, although these reinforcements are also widely used on curved structural elements such as arches and vaults. Therefore, this paper reports and examines the results of an extensive experimental program concerning the behavior of FRCM systems applied on curved masonry specimens. The results point out the influence of both curvature and reinforcement position (intrados or extrados) on the response of specimens in terms of bearing capacity, failure mode and post-peak response

Characterization of the pathophysiological role of CD47 in uveal melanoma

Uveal melanoma (UM) represents the most frequent primary intraocular tumor, however, limited therapeutic options are still available. We have previously shown that cluster of differentiation 47 (CD47) is significantly upregulated in UM cells following inflammatory stimuli and that it represents a predictor of disease progression. Here, we aimed to better characterize the pathophysiological role of CD47 in UM. We show that CD47 is not modulated at different cancer stages, although patients with the lowest expression of CD47 show significant better progression-free survival, after correcting for the presence of BAP1, GNAQ, and GNA11 mutations. By stratifying patients based on the expression of CD47 in the tumor, we observed that patients with high levels of CD47 have a significant increase in immune score as compared to patients with low levels of CD47. In particular, deconvolution analysis of infiltrating immune cell populations revealed that a significantly higher number of CD4+ and CD8+ T cells can be found in patients with high CD47 levels, with the most enriched populations being the Th2, Treg, and CD8+ Tcm cells. We also show that a large number of transcripts are significantly modulated between the groups of patients with high and low levels of CD47, with a significant enrichment of interferon IFN-alpha regulated genes. The results from this study may propel the development of anti-CD47 therapies for UM patients

Inhibition of PI3K Prevents the Proliferation and Differentiation of Human Lung Fibroblasts into Myofibroblasts: The Role of Class I P110 Isoforms

Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease characterized by an accumulation of fibroblasts and myofibroblasts in the alveolar wall. Even though the pathogenesis of this fatal disorder remains unclear, transforming growth factor-β (TGF-β)-induced differentiation and proliferation of myofibroblasts is recognized as a primary event. The molecular pathways involved in TGF-β signalling are generally Smad-dependent yet Smad-independent pathways, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), have been recently proposed. In this research we established ex-vivo cultures of human lung fibroblasts and we investigated the role of the PI3K/Akt pathway in two critical stages of the fibrotic process induced by TGF-β: fibroblast proliferation and differentiation into myofibroblasts. Here we show that the pan-inhibitor of PI3Ks LY294002 is able to abrogate the TGF-β-induced increase in cell proliferation, in α- smooth muscle actin expression and in collagen production besides inhibiting Akt phosphorylation, thus demonstrating the centrality of the PI3K/Akt pathway in lung fibroblast proliferation and differentiation. Moreover, for the first time we show that PI3K p110δ and p110γ are functionally expressed in human lung fibroblasts, in addition to the ubiquitously expressed p110α and β. Finally, results obtained with both selective inhibitors and gene knocking-down experiments demonstrate a major role of p110γ and p110α in both TGF-β-induced fibroblast proliferation and differentiation. This finding suggests that specific PI3K isoforms can be pharmacological targets in IPF

The yeast P5 type ATPase, Spf1, regulates manganese transport into the endoplasmic reticulum

The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn2+ homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn2+ in ∆spf1 cells and an increase following it’s overexpression. In agreement with the observed loss of luminal Mn2+ we could observe concurrent reduction in many Mn2+-related process in the ER lumen. Conversely, cytosolic Mn2+-dependent processes were increased. Together, these data support a role for Spf1p in Mn2+ transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn2+-dependent neurological disorders

A DNA Vaccine against Chikungunya Virus Is Protective in Mice and Induces Neutralizing Antibodies in Mice and Nonhuman Primates

Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus indigenous to tropical Africa and Asia. Acute illness is characterized by fever, arthralgias, conjunctivitis, rash, and sometimes arthritis. Relatively little is known about the antigenic targets for immunity, and no licensed vaccines or therapeutics are currently available for the pathogen. While the Aedes aegypti mosquito is its primary vector, recent evidence suggests that other carriers can transmit CHIKV thus raising concerns about its spread outside of natural endemic areas to new countries including the U.S. and Europe. Considering the potential for pandemic spread, understanding the development of immunity is paramount to the development of effective counter measures against CHIKV. In this study, we isolated a new CHIKV virus from an acutely infected human patient and developed a defined viral challenge stock in mice that allowed us to study viral pathogenesis and develop a viral neutralization assay. We then constructed a synthetic DNA vaccine delivered by in vivo electroporation (EP) that expresses a component of the CHIKV envelope glycoprotein and used this model to evaluate its efficacy. Vaccination induced robust antigen-specific cellular and humoral immune responses, which individually were capable of providing protection against CHIKV challenge in mice. Furthermore, vaccine studies in rhesus macaques demonstrated induction of nAb responses, which mimicked those induced in convalescent human patient sera. These data suggest a protective role for nAb against CHIKV disease and support further study of envelope-based CHIKV DNA vaccines

Origin and development of oligoadenylate synthetase immune system

Abstract Background Oligoadenylate synthetases (OASs) are widely distributed in Metazoa including sponges, fish, reptiles, birds and mammals and show large variation, with one to twelve members in any given species. Upon double-stranded RNA (dsRNA) binding, avian and mammalian OASs generate the second messenger 2'-5'-linked oligoadenylate (2-5A), which activates ribonuclease L (RNaseL) and blocks viral replication. However, how Metazoa shape their OAS repertoires to keep evolutionary balance to virus infection is largely unknown. We performed comprehensive phylogenetic and functional analyses of OAS genes from evolutionarily lower to higher Metazoa to demonstrate how the OAS repertoires have developed anti-viral activity and diversified their functions. Results Ancient Metazoa harbor OAS genes, but lack both upstream and downstream genes of the OAS-related pathways, indicating that ancient OASs are not interferon-induced genes involved in the innate immune system. Compared to OASs of ancient Metazoa (i.e. sponge), the corresponding ones of higher Metazoa present an increasing number of basic residues on the OAS/dsRNA interaction interface. Such an increase of basic residues might improve their binding affinity to dsRNA. Moreover, mutations of functional residues in the active pocket might lead to the fact that higher Metazoan OASs lose the ability to produce 3'-5'-linked oligoadenylate (3-5A) and turn into specific 2-5A synthetases. In addition, we found that multiple rounds of gene duplication and domain coupling events occurred in the OAS family and mutations at functionally critical sites were observed in most new OAS members. Conclusions We propose a model for the expansion of OAS members and provide comprehensive evidence of subsequent neo-functionalization and sub-functionalization. Our observations lay the foundation for interrogating the evolutionary transition of ancient OAS genes to host defense genes and provide important information for exploring the unknown function of the OAS gene family

Modeling of the Tensile Behavior FRCM Systems for Repair and Strengthening Interventions of Masonry Structures

Fiber Reinforced Cementitious Matrix (FRCM) systems are an innovative solution for strengthening interventions of existing masonry and concrete constructions. The current literature provides interesting experimental and numerical studies which underline the potentialities of FRCMs and their specific features. Direct tensile tests are generally used for characterizing the behavior of FRCM strengthening systems. These tests particularly underline the occurrence of both matrix cracking and debonding of the reinforcement from the matrix, phenomena which particularly influence the performance of FRCM systems. The present paper aims at numerically analyzing the response of FRCM strengthening systems during tensile tests carried out throughout different setup configurations. To this end, a simple model carried out from literature and opportunely modified is presented in the paper and validated with reference to experimental case studies. Moreover, the obtained results are critically examined to emphasize the role of the proposed model for the interpretation of the results carried out from standard tensile tests

Modeling of shear-lap tests of flat and curved masonry specimens strengthened by FRCM

Nowadays Fiber Reinforced Cementitious Matrix (FRCM) systems play a relevant role in the context of innovative interventions for the seismic rehabilitation of masonry structures. Their capacity in improving the strength of masonry components is comparable with the one observed in case of Fiber Reinforce Polymer (FRP) systems, but with additional advantages (lower costs, environmental compatibility, removability, etc.). Nevertheless, although a relevant number of applications concerns curved structures (arches, vaults, domes, etc.), the majority of studies available in literature provide a contribution mainly concerning the specific case of applications on flat masonry substrates. The present paper is part of a research activity carried out by the Authors with the main goal to provide a contribution toward the study of the bond behavior of FRCM systems externally applied to curved masonry elements. In particular, the results of numerical analyses carried out by means of a simple modeling approach proposed by the Authors are here carried out by considering as case studies specimens object of a recent experimental investigation. Specific aspects influencing the local bond behavior of FRCM systems applied on curved masonry substrates are then analyzed by opportunely introducing them into the numerical model. The obtained results allow for understanding the effect of important features, experimentally observed in terms of global response, and here assessed in terms of local bond behavior, by particularly emphasizing the role of the curvature and the strengthening position