Role of metalloproteases in the CD95 signaling pathways

CD95L (also known as FasL or CD178) is a member of the tumor necrosis family (TNF) superfamily. Although this transmembrane ligand has been mainly considered as a potent apoptotic inducer in CD95 (Fas)-expressing cells, more recent studies pointed out its role in the implementation of non-apoptotic signals. Accordingly, this ligand has been associated with the aggravation of inflammation in different auto-immune disorders and in the metastatic occurrence in different cancers. Although it remains to decipher all key factors involved in the ambivalent role of this ligand, accumulating clues suggest that while the membrane bound CD95L triggers apoptosis, its soluble counterpart generated by metalloprotease-driven cleavage is responsible for its non-apoptotic functions. Nonetheless, the metalloproteases (MMPs and ADAMs) involved in the CD95L shedding, the cleavage sites and the different stoichiometries and functions of the soluble CD95L remain to be elucidated. To better understand how soluble CD95L triggers signaling pathways from apoptosis to inflammation or cell migration, we propose herein to summarize the different metalloproteases that have been described to be able to shed CD95L, their cleavage sites and the biological functions associated with the released ligands. Based on these new findings, the development of CD95/CD95L-targeting therapeutics is also discussed

Biodistribution of Nanostructured Lipid Carriers in Mice Atherosclerotic Model

Atherosclerosis is a major cardiovascular disease worldwide, that could benefit from innovative nanomedicine imaging tools and treatments. In this perspective, we here studied, by fluorescence imaging in ApoE-/- mice, the biodistribution of non-functionalized and RXP470.1-targeted nanostructured lipid carriers (NLC) loaded with DiD dye. RXP470.1 specifically binds to MMP12, a metalloprotease that is over-expressed by macrophages residing in atherosclerotic plaques. Physico-chemical characterizations showed that RXP-NLC (about 105 RXP470.1 moieties/particle) displayed similar features as non-functionalized NLC in terms of particle diameter (about 60-65 nm), surface charge (about −5 — −10 mV), and colloidal stability. In vitro inhibition assays demonstrated that RXP-NLC conserved a selectivity and affinity profile, which favored MMP-12. In vivo data indicated that NLC and RXP-NLC presented prolonged blood circulation and accumulation in atherosclerotic lesions in a few hours. Twenty-four hours after injection, particle uptake in atherosclerotic plaques of the brachiocephalic artery was similar for both nanoparticles, as assessed by ex vivo imaging. This suggests that the RXP470.1 coating did not significantly induce an active targeting of the nanoparticles within the plaques. Overall, NLCs appeared to be very promising nanovectors to efficiently and specifically deliver imaging agents or drugs in atherosclerotic lesions, opening avenues for new nanomedicine strategies for cardiovascular diseases

Analytical Methods for the Detection and Quantification of ADCs in Biological Matrices

International audienceUnderstanding pharmacokinetics and biodistribution of antibody-drug conjugates (ADCs) is a one of the critical steps enabling their successful development and optimization. Their complex structure combining large and small molecule characteristics brought out multiple bioanalytical methods to decipher the behavior and fate of both components in vivo. In this respect, these methods must provide insights into different key elements including half-life and blood stability of the construct, premature release of the drug, whole-body biodistribution, and amount of the drug accumulated within the targeted pathological tissues, all of them being directly related to efficacy and safety of the ADC. In this review, we will focus on the main strategies enabling to quantify and characterize ADCs in biological matrices and discuss their associated technical challenges and current limitations

Late-Stage Diversification of Phosphinic Dehydroalanine Pseudopeptides Based on a Giese-Type Radical C-Alkylation Strategy

A straightforward, late-stage diversification strategy for the installation of side chains on readily accessible unsaturated phosphinopeptidic scaffolds based on a Giese-type addition of alkyl radicals has been investigated. Among different alternatives, the preferred methodology is operationally simple as it can be carried out in an open flask with no need for protection of acidic moieties. Direct application to the synthesis of SPPS-compatible building blocks or to longer peptides is also reported

Computation of flexoelectric coefficients of a MoS2 monolayer with a model of self-consistently distributed effective charges and dipoles

International audienceFlexoelectricity is an electromechanical coupling phenomenon thatcan generate noticeable electric polarization in dielectricmaterials for nanoscale strain gradients. It is gaining increasingattention because of its potential applications and the fact thatexperimental results were initially an order of magnitude higherthan initial theoretical predictions. This stimulated intenseexperimental and theoretical research to investigate flexoelectriccoefficients in dielectric materials such as two-dimensionalmaterials. In this study, we concentrate on the calculation of theflexoelectric coefficients of 2D-MoS2 due to a model usingself-consistently determined charges and dipoles on the atoms. Morespecifically, we study the importance of two contributions thatwere neglected/omitted in previous papers using this model, namely,the charge term in the total polarization and the conservation ofelectric charge through a Lagrange multiplier. Our calculationsdemonstrate that the results for flexoelectric coefficientscomputed with this improved definition of polarization agree betterwith experimental measurements, provided that consistentdefinitions for signs are used. Additionally, we show how twophysical contributions with opposite signs compete to give netvalues of flexoelectric coefficients that can be either positive ornegative depending on their relative importance and give net valuesfor the case of MoS2

Computation of flexoelectric coefficients of a MoS2 monolayer with a model of self-consistently distributed effective charges and dipoles

International audienceFlexoelectricity is an electromechanical coupling phenomenon that can generate noticeable electric polarization in dielectric materials for nanoscale strain gradients. It is gaining increasing attention because of its potential applications and the fact that experimental results were initially an order of magnitude higher than initial theoretical predictions. This stimulated intense experimental and theoretical research to investigate flexoelectric coefficients in dielectric materials such as two-dimensional materials. In this study, we concentrate on the calculation of the flexoelectric coefficients of 2D-MoS 2 due to a model using self-consistently determined charges and dipoles on the atoms. More specifically, we study the importance of two contributions that were neglected/omitted in previous papers using this model, namely, the charge term in the total polarization and the conservation of electric charge through a Lagrange multiplier. Our calculations demonstrate that the results for flexoelectric coefficients computed with this improved definition of polarization agree better with experimental measurements, provided that consistent definitions for signs are used. Additionally, we show how two physical contributions with opposite signs compete to give net values of flexoelectric coefficients that can be either positive or negative depending on their relative importance and give net values for the case of MoS 2

Principle of virtual power applied to deformable semiconductors with strain, polarization, and magnetization gradients

International audienceThe aim of this article is to generalize previous works in order to provide a systematic method to derive the equilibrium equations and the constitutive ones for deformable semiconductors accounting for first-order strain, polarization, and magnetization gradients. This is done by use of the “principle of virtual power” subject to the objectivity requirement (i.e., translational and rotational invariances) to which we add the first and the second laws of thermodynamics associated with the conservation of energy and the entropy production. This leads to a generalized expression of the Clausius–Duhem inequality, from which constitutive equations are derived. The interactions of the electromagnetic fields with the deformable and the semiconducting continua appear naturally by generalized non-symmetric stress tensors and the body and surface forces of electromagnetic origin. A comparison with some previous works is made putting emphasis on flexoelectricity that will be dealt with in a future work. Finally, special attention is given to particular cases relative to dissipative phenomena associated with semiconducting properties. In order to be close to what is nowadays done by physicists, the SI units have replaced the Lorentz–Heaviside units often used in previous works

Preliminary results concerning the flexoelectricity of carbon nanotubes

International audienceUnlike piezoelectricity (proportionality between a uniform stress or strain and the electric polarization of a material), flexoelectricity (proportionality between stress or strain gradient and electric polarization of a material) is rarely considered for electromechanical transduction and energy harvesting at the sub-micron scale, though flexoelectricity does not require that the material unit cell be non-centrosymmetric (as volume piezoelectricity does). Indeed, the challenge is to find a material with flexoelectric effects strong enough to be interesting for applications. One strategy could be to use the increase of the deformation gradient for a reduction of scale and the corresponding transition from bulk effects to surface effects to allow for new ways to select materials at the nanoscale and get an interesting conversion ratio between electric and mechanical energies. In order to study these phenomena, we have improved on previous molecular dynamics simulations of the bending of various carbon single-wall nanotubes by non-longitudinal static electric fields [1,2] and compared the results with the previsions of a continuum mechanics model for the bending of a flexoelectric beam by an external electric field [3], in order to extract the relevant flexoelectric tensor components from a fit. Preliminary results will be given

Qualitative evidence of the flexoelectric effect in a single multi-wall carbon nanotube by nanorobotic manipulation

International audienceThe flexoelectric effect corresponds to the linear variation of the electric polarization of a<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtmaterial subjected to a strain gradient (i.e. during its mechanical bending). Unlike</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtpiezoelectricity, it also exists in non-centrosymmetric materials. Furthermore, due to the</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtgradient term, its magnitude can increase as the size of the system decreases. Thanks to this</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gteffect, nanoscale systems could be used to harvest thermal vibration energy to power a</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtmicrodevice. These could be multi-wall carbon nanotubes since they are known to bend easily</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtin an elastic manner. However, it is very challenging to experimentally measure the</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtflexoelectric behavior of a single multi-wall carbon nanotube due to its small size (less than 50</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtnm in diameter), to the low level of induced charges and to the need to vary the imposed stress.</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtTo progress in this direction, a six-degree-of-freedom robot with a fiber tip is used inside a</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtdual-beam microscope to pick up a few single carbon nanotubes from a tangle and connect them</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtto the fiber tip. After ion-soldering the two tips, each carbon nanotube is dynamically bent</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtseveral times while monitoring the brightness of the bending area and its effective radius of</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtcurvature. This allowed us to demonstrate qualitatively the flexoelectric effect at the level of a</span&gt</font&gt</div&gt<div style=""&gt<font face="arial, helvetica"&gt<span style="font-size: 13px;"&gtsingle MWCNT.</span&gt</font&gt</div&g