Mantra 2.0: An online collaborative resource for drug mode of action and repurposing by network analysis

Elucidation of molecular targets of a compound (mode of action, MoA) and of its off-targets is a crucial step in drug development. We developed an online collaborative resource (MANTRA 2.0) that supports this process by exploiting similarities between drug-induced transcriptional profiles. Drugs are organised in a network of nodes (drugs) and edges (similarities) highlighting “communities” of drugs sharing a similar MoA. A user can upload gene expression profiles (GEPs) before and after drug treatment in one or multiple cell types. An automated processing pipeline transforms the GEPs into a unique drug ”node” embedded in the drug-network. Visual inspection of the neighbouring drugs and communities helps in revealing its MoA, and to suggest new applications of known drugs (drug repurposing). MANTRA 2.0 allows storing and sharing user-generated network nodes, thus making MANTRA 2.0 a collaborative ever-growing resource

Implementation of fatigue model for unidirectional laminate based on finite element analysis : theory and practice

The aim of this study is to deal with the simulation of intra-laminar fatigue damage in unidirectional composite under multi-axial and variable amplitude loadings. The variable amplitude and multi-axial loading is accounted for by using the damage hysteresis operator based on Brokate method [6]. The proposed damage model for fatigue is based on stiffness degradation laws from Van Paepegem combined with the 'damage' cycle jump approach extended to deal with unidirectional carbon fibres. The parameter identification method is here presented and parameter sensitivities are discussed. The initial static damage of the material is accounted for by using the LadevSze damage model and the permanent shear strain accumulation based on Van Paepegem's formulation. This approach is implemented into commercial software (Siemens PLM). The validation case is run on a bending test coupon (with arbitrary stacking sequence and load level) in order to minimise the risk of inter-laminar damages. This intra-laminar fatigue damage model combined efficient methods with a low number of tests to identify the parameters of the stiffness degradation law, this overall procedure for fatigue life prediction is demonstrated to be cost efficient at industrial level. This work concludes on the next challenges to be addressed (validation tests, multiple-loadings validation, failure criteria, inter-laminar damages...)

Enhancement of wave damping within metamaterials having embedded negative stiffness inclusions

The wave dissipation properties of layered periodic structures are modelled by FE as well as analytical approaches. A linear oscillator incorporating a negative stiffness element and having exceptional energy dissipation properties is exhibited and incorporated within the modelled structures. The structural dynamic stability of both the oscillator and the modelled waveguides is discussed and ensured. The numerical results provide evidence of a drastic increase of several orders of magnitude for the damping ratio of the flexural waves propagating within the structures

Genetic and pharmacological regulation of the endocannabinoid CB1 receptor in Duchenne muscular dystrophy

The endocannabinoid system refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. However, the potential role of endocannabinoids in skeletal muscle disorders remains unknown. Here we report the role of the endocannabinoid CB1 receptors in Duchenne's muscular dystrophy. In murine and human models, CB1 transcripts show the highest degree of expression at disease onset, and then decline overtime. Similar changes are observed for PAX7, a key regulator of muscle stem cells. Bioinformatics and biochemical analysis reveal that PAX7 binds and upregulates the CB1 gene in dystrophic more than in healthy muscles. Rimonabant, an antagonist of CB1, promotes human satellite cell differentiation in vitro, increases the number of regenerated myofibers, and prevents locomotor impairment in dystrophic mice. In conclusion, our study uncovers a PAX7-CB1 cross talk potentially exacerbating DMD and highlights the role of CB1 receptors as target for potential therapies

A progessive damage fatigue model for unidirectional laminated composites based on finite element analysis: theory and practice

The simulation of the fatigue damage of laminated composites under multi-axial and variable amplitude loadings has to deal with several new challenges and several methods of damage modelling. In this paper we present how to account for the complex loading by using the damage hysteresis operator approach for fatigue. It is applied to a fatigue model for intra-laminar damage based on stiffness degradation laws from Van Paepegem and has been extended to deal with unidirectional carbon fibres. The parameter identification method is presented here and parameter sensitivities are discussed. The initial static damage of the material is accounted for by using the Ladevèze damage model and the permanent shear strain accumulation based on Van Paepegem’s formulation. This approach has been implemented into commercial software. The intra-laminar fatigue damage model combines efficient methods with a low number of tests to identify the parameters of the stiffness degradation law, this overall procedure for fatigue life prediction is demonstrated to be cost efficient at industrial level

A progessive damage fatigue model for unidirectional laminated composites based on finite element analysis: theory and practice

The simulation of the fatigue damage of laminated composites under multi-axial and variable amplitude loadings has to deal with several new challenges and several methods of damage modelling. In this paper we present how to account for the complex loading by using the damage hysteresis operator approach for fatigue. It is applied to a fatigue model for intra-laminar damage based on stiffness degradation laws from Van Paepegem and has been extended to deal with unidirectional carbon fibres. The parameter identification method is presented here and parameter sensitivities are discussed. The initial static damage of the material is accounted for by using the Ladevèze damage model and the permanent shear strain accumulation based on Van Paepegem’s formulation. This approach has been implemented into commercial software. The intra-laminar fatigue damage model combines efficient methods with a low number of tests to identify the parameters of the stiffness degradation law, this overall procedure for fatigue life prediction is demonstrated to be cost efficient at industrial level

An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of α-synuclein

Neuropathological and experimental evidence suggests that the cell-to-cell transfer of α-synuclein has an important role in the pathogenesis of Parkinson's disease (PD). However, the mechanism underlying this phenomenon is not fully understood. We undertook a small interfering RNA (siRNA), genome-wide screen to identify genes regulating the cell-to-cell transfer of α-synuclein. A genetically encoded reporter, GFP-2A-αSynuclein-RFP, suitable for separating donor and recipient cells, was transiently transfected into HEK cells stably overexpressing α-synuclein. We find that 38 genes regulate the transfer of α-synuclein-RFP, one of which is ITGA8, a candidate gene identified through a recent PD genome-wide association study (GWAS). Weighted gene co-expression network analysis (WGCNA) and weighted protein-protein network interaction analysis (WPPNIA) show that those hits cluster in networks that include known PD genes more frequently than expected by random chance. The findings expand our understanding of the mechanism of α-synuclein spread