Ageing in the 21st century in Europe: social challenges and innovation opportunities to support elderly independency and wellbeing.

This chapter describes the vision of the EMPATHIC project of social challenges and innovation opportunities to support elderly independency and well- being. Asanintroduction,wefirstidentifythemainchallengesthatresultfromthe current demographic status in Europe. Then, we show the vision and approach pro- posed by the EMPATHIC project to deal with some of these challenges. Next sec- tion develops the main concepts, goals and outcomes of the EMPATHIC project. The following section reports the impact of the project and the final section de- scribes the exploitation of the results as well as the concluding remarksThe research leading to the results in this paper has been conducted in the project EMPATHIC (Grant N: 769872) that received funding from the European Union’s Horizon 2020 research and innovation programme

Prolyl oligopeptidase is inhibited in relapsing-remitting multiple sclerosis

Peer reviewe

Ageing in the 21st century in Europe: social challenges and innovation opportunities to support elderly independency and wellbeing.

This chapter describes the vision of the EMPATHIC project of social challenges and innovation opportunities to support elderly independency and well- being. Asanintroduction,wefirstidentifythemainchallengesthatresultfromthe current demographic status in Europe. Then, we show the vision and approach pro- posed by the EMPATHIC project to deal with some of these challenges. Next sec- tion develops the main concepts, goals and outcomes of the EMPATHIC project. The following section reports the impact of the project and the final section de- scribes the exploitation of the results as well as the concluding remarksThe research leading to the results in this paper has been conducted in the project EMPATHIC (Grant N: 769872) that received funding from the European Union’s Horizon 2020 research and innovation programme

The expression levels of prolyl oligopeptidase responds not only to neuroinflammation but also to systemic inflammation upon liver failure in rat models and cirrhotic patients

Abstract Background Liver failure in experimental animals or in human cirrhosis elicits neuroinflammation. Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory events in neurodegenerative diseases: PREP protein levels are increased in brain glial cells upon neuroinflammatory insults, but the circulating PREP activity levels are decreased in multiple sclerosis patients in a process probably mediated by bioactive peptides. In this work, we studied the variation of PREP levels upon liver failure and correlated it with several inflammatory markers to conclude on the relation of PREP with systemic and/or neuroinflammation. Methods PREP enzymatic activity and protein levels measured with immunological techniques were determined in the brain and plasma of rats with portacaval shunt (PCS) and after treatment with ibuprofen. Those results were compared with the levels of PREP measured in plasma from cirrhotic patients with or without minimal hepatic encephalopathy (MHE). Levels of several pro-inflammatory cytokines and those of NO/cGMP homeostasis metabolites were measured in PCS rats and cirrhotic patients to conclude on the role of PREP in inflammation. Results In PCA rats, we found that PREP levels are significantly increased in the hippocampus, striatum and cerebellum, that in the cerebellum the PREP increase was significantly found in the extracellular space and that the levels were restored to those measured in control rats after administration of an anti-inflammatory agent, ibuprofen. In cirrhotic patients, circulatory PREP activity was found to correlate to systemic and neuroinflammatory markers and had a negative correlation with the severity of the disease, although no clear relation to MHE. Conclusions These results support the idea that PREP levels could be used as indicators of cirrhosis severity in humans, and using other markers, it might contribute to assessing the level of neuroinflammation in those patients. This work reports, for the first time, that PREP is secreted to the extracellular space in the cerebellum most probably due to glial activation and supports the role of the peptidase in the inflammatory response

Analysis of the interaction between elderly people and a simulated virtual coach

The EMPATHIC project develops and validates new interaction paradigms for personalized virtual coaches (VC) to promote healthy and independent aging. To this end, the work presented in this paper is aimed to analyze the interaction between the EMPATHIC-VC and the users. One of the goals of the project is to ensure an end-user driven design, involving senior users from the beginning and during each phase of the project. Thus, the paper focuses on some sessions where the seniors carried out interactions with a Wizard of Oz driven, simulated system. A coaching strategy based on the GROW model was used throughout these sessions so as to guide interactions and engage the elderly with the goals of the project. In this interaction framework, both the human and the system behavior were analyzed. The way the wizard implements the GROW coaching strategy is a key aspect of the system behavior during the interaction. The language used by the virtual agent as well as his or her physical aspect are also important cues that were analyzed. Regarding the user behavior, the vocal communication provides information about the speaker's emotional status, that is closely related to human behavior and which can be extracted from the speech and language analysis. In the same way, the analysis of the facial expression, gazes and gestures can provide information on the non verbal human communication even when the user is not talking. In addition, in order to engage senior users, their preferences and likes had to be considered. To this end, the effect of the VC on the users was gathered by means of direct questionnaires. These analyses have shown a positive and calm behavior of users when interacting with the simulated virtual coach as well as some difficulties of the system to develop the proposed coaching strategy.The research presented in this paper is conducted as part of the project EMPATHIC that has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement no 769872

Structural Analysis of Prolyl Oligopeptidases Using Molecular Docking and Dynamics: Insights into Conformational Changes and Ligand Binding

Prolyl oligopeptidase (POP) is considered as an important pharmaceutical target for the treatment of numerous diseases. Despite enormous studies on various aspects of POPs structure and function still some of the questions are intriguing like conformational dynamics of the protein and interplay between ligand entry/egress. Here, we have used molecular modeling and docking based approaches to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana). Despite high sequence and structural similarity, they possess different affinities for the ligands. Interestingly, human POP was found to be more specific, selective and incapable of binding to a few planar ligands which showed extrapolation of porcine POP in human context is more complicated. Possible routes for substrate entry and product egress were also investigated by detailed analyses of molecular dynamics (MD) simulations for the three proteins. Trajectory analysis of bound and unbound forms of three species showed differences in conformational dynamics, especially variations in β-propeller pore size, which was found to be hidden by five lysine residues present on blades one and seven. During simulation, β-propeller pore size was increased by ∼2 Å in porcine ligand-bound form which might act as a passage for smaller product movement as free energy barrier was reduced, while there were no significant changes in human and A. thaliana POPs. We also suggest that these differences in pore size could lead to fundamental differences in mode of product egress among three species. This analysis also showed some functionally important residues which can be used further for in vitro mutagenesis and inhibitor design. This study can help us in better understanding of the etiology of POPs in several neurodegenerative diseases

FoxO1, A2M, and TGF-beta 1 : three novel genes predicting depression in gene X environment interactions are identified using cross-species and cross-tissues transcriptomic and miRNomic analyses

To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues "omics" approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-beta 1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-beta 1 showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful 'hypothesis-free' approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.Peer reviewe