Power laws in microrheology experiments on living cells: comparative analysis and modelling

We compare and synthesize the results of two microrheological experiments on the cytoskeleton of single cells. In the first one, the creep function J(t) of a cell stretched between two glass plates is measured after applying a constant force step. In the second one, a micrometric bead specifically bound to transmembrane receptors is driven by an oscillating optical trap, and the viscoelastic coefficient $G_e(\omega)$ is retrieved. Both $J(t)$ and $G_e(\omega)$ exhibit power law behavior: $J(t)= A(t/t_0)^\alpha$ and $\bar G_e(\omega)\bar = G_0 (\omega/\omega_0)^\alpha$, with the same exponent $\alpha\approx 0.2$. This power law behavior is very robust ; $\alpha$ is distributed over a narrow range, and shows almost no dependance on the cell type, on the nature of the protein complex which transmits the mechanical stress, nor on the typical length scale of the experiment. On the contrary, the prefactors $A_0$ and $G_0$appear very sensitive to these parameters. Whereas the exponents $\alpha$ are normally distributed over the cell population, the prefactors $A_0$ and $G_0$ follow a log-normal repartition. These results are compared with other data published in the litterature. We propose a global interpretation, based on a semi-phenomenological model, which involves a broad distribution of relaxation times in the system. The model predicts the power law behavior and the statistical repartition of the mechanical parameters, as experimentally observed for the cells. Moreover, it leads to an estimate of the largest response time in the cytoskeletal network: $\tau_m \approx 1000$ s.Comment: 47 pages, 14 figures // v2: PDF file is now Acrobat Reader 4 (and up) compatible // v3: Minor typos corrected - The presentation of the model have been substantially rewritten (p. 17-18), in order to give more details - Enhanced description of protocols // v4: Minor corrections in the text : the immersion angles are estimated and not measured // v5: Minor typos corrected. Two references were clarifie

L'APPLICATION DU PRINCIPE DE LAÏCITE A LA JUSTICE

Ce rapport sur « l’application de la laïcité à la justice » est le fruit d’un travail collectif mené sur deux années par une équipe d’enseignants-chercheurs (juristes et sociologues) avec le soutien de la mission de recherche « Droit et Justice ».Le sujet est d’autant plus intéressant que la justice n’est sans doute pas un service public comme les autres. Outre une laïcisation plus lente, la justice se distingue également des autres services publics par la diversité des acteurs qui s’y croisent : tous ne sont pas des professionnels (les jurés notamment) et parmi les professionnels, tous ne sont pas des agents publics. Toutes ces personnes ne sont donc pas soumises aux mêmes règles.L’essentiel de la recherche a consisté à voir si le droit positif mettait à la charge de tous les acteurs de la justice une obligation de laïcité et de neutralité religieuse, et le cas échéant selon la même intensité. Parmi ceux-ci, certains acteurs sont par ailleurs amenés à trancher des questions d’ordre religieux susceptibles de les placer sur un terrain qui ne leur est pas familier.Ils ne peuvent pas s’abriter derrière leur neutralité pour ne pas répondre à la question soulevée par ces litiges. La recherche s’est donc portée également sur la manière dont les juges mettenten œuvre leur neutralité dans leur compréhension et leur traitement ou leur qualification du fait religieux.Pour répondre à ces questions, une étude du droit positif complétée par des entretiens auprès des professionnels concernés a été privilégiée

Le dédale de la non-discrimination religieuse

International audienc

Exiger l'exécution de la prestation de travail est-il discriminer ?

International audienceLa perversion de la notion de discriminatio

Interest of multi-modal imaging in bilateral lesions of basal ganglia: A case report of a post-anoxic dystonia

International audienceObjectives: We report the case of a 16-year-old patient with progressive generalized choreo-dystonia that appeared two months after a suicide attempt by hanging associated with a cardiorespiratory arrest. An initial magnetic resonance imaging (MRI) brain scan was judged normal by radiologists. Discordance between clinical presentation and morphological imaging led to the hypothesis of a psychogenic dystonia but striatal lesions were suspected by neurologists.Methods: A second MRI high field was performed and the patient also underwent 123I-fluopane single photon emission computed tomography (SPECT). MRI and SPECT fusion images were analysed.Results: The second MRI failed to reveal any lesions involving the basal ganglia. 123I-fluopane-SPECT, however, highlighted bilateral posterior putaminal presynaptic dopaminergic denervation. Post hoc analysis of MRI and SPECT fusion images confirmed bilateral posterior putamen lesions, with low signal intensity on DWI, confirming the diagnosis of postanoxic generalized dystonia.Conclusions: We report this case to highlight the utility of multimodal imaging in diagnosis of bilateral lesions in difficult neurologic disorders where there is discordance between the clinical presentation and morphological brain imaging

Lipoic acid decreases breast cancer cell proliferation by inhibiting IGF-1R via furin downregulation

International audienceAbstract Background Breast cancer is the second most common cancer in the world. Despite advances in therapies, the mechanisms of resistance remain the underlying cause of morbidity and mortality. Lipoic acid (LA) is an antioxidant and essential cofactor in oxidative metabolism. Its potential therapeutic effects have been well documented, but its mechanisms of action (MOA) are not fully understood. Methods The aim of this study is to validate the inhibitory LA effect on the proliferation of various breast cancer cell lines and to investigate the MOA that may be involved in this process. We tested LA effects by ex vivo studies on fresh human mammary tumour samples. Results We demonstrate that LA inhibits the proliferation and Akt and ERK signalling pathways of several breast cancer cells. While searching for upstream dysregulations, we discovered the loss of expression of IGF-1R upon exposure to LA. This decrease is due to the downregulation of the convertase, furin, which is implicated in the maturation of IGF-1R. Moreover, ex vivo studies on human tumour samples showed that LA significantly decreases the expression of the proliferation marker Ki67. Conclusion LA exerts its anti-proliferative effect by inhibiting the maturation of IGF-1R via the downregulation of furin

Cisplatin increases PD-L1 expression and optimizes immune check-point blockade in non-small cell lung cancer

International audienceThe number of clinical protocols testing combined therapies including immune check-point inhibitors and platinum salts is currently increasing in lung cancer treatment, however preclinical studies and rationale are often lacking. Here, we evaluated the impact of cisplatin treatment on PD-L1 expression analyzing the clinicopathological characteristics of patients who received cisplatin-based neoadjuvant chemotherapy followed by surgery and showed that cisplatin-based induction treatment significantly increased PD-L1 staining in both tumor and immune cells from the microenvironment. Twenty-two patients exhibited positive PD-L1 staining variation after neoadjuvant chemotherapy; including 9 (23.1%) patients switching from <50% to ≥50% of stained tumor-cells. We also confirmed the up-regulation of PD-L1 by cisplatin, at both RNA and protein levels, in nude and immunocompetent mice bearing tumors grafted with A549, LNM-R, or LLC1 lung cancer cell lines. The combined administration of anti-PD-L1 antibodies (3 mg/kg) and cisplatin (1 mg/kg) to mice harboring lung carcinoma significantly reduced tumor growth compared to single agent treatments and controls. Overall, these results suggest that cisplatin treatment could synergize with PD-1/PD-L1 blockade to increase the clinical response, in particular through early and sustainable enhancement of PD-L1 expression

Personalized Dosimetry with Intensification Using 90Y-Loaded Glass Microsphere Radioembolization Induces Prolonged Overall Survival in Hepatocellular Carcinoma Patients with Portal Vein Thrombosis.

International audienceThe objective of this study was to evaluate the response rate and survival of hepatocellular carcinoma portal vein thrombosis (PVT) patients treated with (90)Y-loaded glass microspheres using a personalized dosimetry and intensification concept. The microspheres were administered to 41 hepatocellular carcinoma PVT patients (main = 12; lobar/segmental = 29). (99m)Tc-macroaggregated albumin SPECT/CT quantitative analysis was used to calculate the tumor dose (TD), healthy injected liver dose (HILD), and injected liver dose (ILD). Response was evaluated at 3 mo using the criteria of the European Association for the Study of the Liver, with CT follow-up lasting until disease progression or death. Survival was assessed using the Kaplan-Meier method. The mean injected activity was 3.1 ± 1.5 GBq, and mean ILD was 143 ± 49 Gy. When a TD threshold of 205 Gy was applied, (99m)Tc-macroaggregated albumin SPECT/CT achieved a 100% sensitivity and 90% overall accuracy (0 false-negatives; 4 false-positives) in response prediction. On the basis of TD and HILD values, 37% of patients received an intensification of the treatment (increased injected activity with the aim of achieving a TD ≥ 205 Gy and HILD 150 Gy). This intensification resulted in a high response rate (85%) without increased liver toxicity of grade 3 or higher (6% vs. 12% in the patients who did not receive treatment intensification; not statistically significant). For the total 41 patients, median overall survival (OS) was 18 mo (95% confidence interval, 11-25 mo). For patients with a TD of less than 205 Gy, median OS was 4.3 mo (3.7-5 mo), versus 18.2 mo (8.5-28.7 mo) for those with a TD of 205 Gy or more (P = 0.005). Median OS was 20.9 mo for patients with a TD of 205 Gy or more and good PVT targeting (n = 36). OS was 12 mo (3 mo to ∞) for patients with main PVT, versus 21.5 mo (12-28.7 mo) for those with segmental or lobar PVT (not statistically significant). For the 5 patients with complete portal vein revascularization who underwent lobar hepatectomy, median OS was not reached yet exceeded 24.5 mo and was significantly higher than that of other patients (P = 0.0493). Using a (99m)Tc-macroaggregated albumin SPECT/CT personalized dosimetry and intensification concept with (90)Y-loaded glass microspheres induced prolonged OS for PVT patients as compared with the standard of care (sorafenib), without increasing liver toxicity. Prospective randomized studies are therefore warranted

Cell Stiffening in Response to External Stress is Correlated to Actin Recruitment

We designed a micromanipulation device that allows the local application of a constant force on living cells, and the measurement of their stiffness. The force is applied through an Arg-Gly-Asp-coated bead adhering on the cell and trapped in optical tweezers controlled by a feedback loop. Epifluorescence observations of green fluorescent protein-actin in the cells are made during force application. We observe a stiffening of cells submitted to a constant force within a few minutes, coupled to actin recruitment both at the bead-cell contact and up to several micrometers from the stress application zone. Moreover, kinetics of stiffening and actin recruitment exhibit a strong correlation. This work presents the first quantification of the dynamics of cell mechanical reinforcement under stress, which is a novel insight into the elucidation of the more general phenomenon of cell adaptation to stress