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Nguyen P.,University Pierre and Marie Curie | Derreumaux P.,University Pierre and Marie Curie | Derreumaux P.,Institut Universitaire de France
Accounts of Chemical Research | Year: 2014

Evolution has fine-tuned proteins to accomplish a variety of tasks. Yet, with aging, some proteins assemble into harmful amyloid aggregates associated with neurodegenerative diseases, such as Alzheimer's disease (AD), which presents a complex and costly challenge to our society. Thus, far, drug after drug has failed to slow the progression of AD, characterized by the self-assembly of the 39-43 amino acid β-amyloid (Aβ) protein into extracellular senile plaques that form a cross-β structure. While there is experimental evidence that the Aβ small oligomers are the primary toxic species, standard tools of biology have failed to provide structures of these transient, inhomogeneous assemblies. Despite extensive experimental studies, researchers have not successfully characterized the nucleus ensemble, the starting point for rapid fibril formation. Similarly scientists do not have atomic data to show how the compounds that reduce both fibril formation and toxicity in cells bind to Aβ42 oligomers. In this context, computer simulations are important tools for gaining insights into the self-assembly of amyloid peptides and the molecular mechanism of inhibitors.This Account reviews what analytical models and simulations at different time and length scales tell us about the dynamics, kinetics, and thermodynamics of amyloid fibril formation and, notably, the nucleation process. Though coarse-grained and mesoscopic protein models approximate atomistic details by averaging out unimportant degrees of freedom, they provide generic features of amyloid formation and insights into mechanistic details of the self-assembly process. The thermodynamics and kinetics vary from linear peptides adopting straight β-strands in fibrils to longer peptides adopting in parallel U shaped conformations in fibrils. In addition, these properties change with the balance between electrostatic and hydrophobic interactions and the intrinsic disorder of the system. However, simulations suggest that the critical nucleus size might be on the order of 20 chains under physiological conditions. The transition state might be characterized by a simultaneous change from mixed antiparallel/parallel β-strands with random side-chain packing to the final antiparallel or parallel states with the steric zipper packing of the side chains.Second, we review our current computer-based knowledge of the 3D structures of inhibitors with Aβ42 monomer and oligomers, a prerequisite for developing new drugs against AD. Recent extensive all-atom simulations of Aβ42 dimers with known inhibitors such as the green tea compound epigallocatechin-3-gallate and 1,4-naphthoquinon-2-yl-l-tryptophan provide a spectrum of initial Aβ42/inhibitor structures useful for screening and drug design. We conclude by discussing future directions that may offer opportunities to fully understand nucleation and further AD drug development. © 2013 American Chemical Society.


Adamo C.,Chimie Paristech | Adamo C.,Institut Universitaire de France | Jacquemin D.,Institut Universitaire de France | Jacquemin D.,University of Nantes
Chemical Society Reviews | Year: 2013

In this tutorial review, we show how Time-Dependent Density Functional Theory (TD-DFT) has become a popular tool for computing the signatures of electronically excited states, and more specifically, the properties directly related to the optical (absorption and emission) spectra of molecules. We discuss the properties that can be obtained with widely available programs as well as how to account for the environmental effects (solvent and surfaces) and present recent applications in these fields. We next expose the transformation of the TD-DFT results into chemically intuitive parameters (colours as well as charge-transfer distances). Eventually, the non-specialised reader will find a series of advices and warnings necessary to perform her/his first TD-DFT calculations. © 2013 The Royal Society of Chemistry.


Alix-Panabieres C.,Montpellier University Hospital Center | Alix-Panabieres C.,Institut Universitaire de France | Pantel K.,University of Hamburg
Nature Reviews Cancer | Year: 2014

During the past ten years, circulating tumour cells (CTCs) have received enormous attention as new biomarkers and the subject of basic research. Although CTCs are already used in numerous clinical trials, their clinical utility is still under investigation. Many issues regarding the detection and characterization of CTCs remain unknown. In this Opinion article, we propose a conceptual framework of CTC assays and point out current challenges of CTC research, which might structure this dynamic field of translational cancer research. © 2014 Macmillan Publishers Limited.


Lecuit T.,Institut Universitaire de France | Lenne P.-F.,Institut Universitaire de France | Munro E.,University of Chicago
Annual Review of Cell and Developmental Biology | Year: 2011

Cell shape changes underlie a large set of biological processes ranging from cell division to cell motility. Stereotyped patterns of cell shape changes also determine tissue remodeling events such as extension or invagination. In vitro and cell culture systems have been essential to understanding the fundamental physical principles of subcellular mechanics. These are now complemented by studies in developing organisms that emphasize how cell and tissue morphogenesis emerge from the interplay between force-generating machines, such as actomyosin networks, and adhesive clusters that transmit tensile forces at the cell cortex and stabilize cell-cell and cell-substrate interfaces. Both force production and transmission are self-organizing phenomena whose adaptive features are essential during tissue morphogenesis. A new era is opening that emphasizes the similarities of and allows comparisons between distant dynamic biological phenomena because they rely on core machineries that control universal features of cytomechanics. © 2011 by Annual Reviews. All rights reserved.


Indirect nuclear spin-spin coupling involving very commonly encountered nuclei such as 1H, 13C, 19F, or 31P provides definitive data for characterization of molecules in solution. Nonbonded spin coupling characterized by high magnitude values have been repeatedly authenticated for a range of compounds such as functionalized cyclophanes, naphthalenes, coordination complexes of polyphosphines, as well as fluorinated arene complexes. The range of applications in chemistry and structural biology involving a 19F NMR probe proves that TS spin coupling with this nucleus can be a valuable additional tool in pursuing structural questions. Analysis of TS 19F coupling in fluorinated organic molecules, but also in amino acids, proteins, nucleic acids, and nucleic acid-protein complexes can inform us regarding the differentiation of rotamers and diastereoisomers, estimation of internuclear distances, computation of tertiary and quaternary structures, as well as understanding of dynamic processes involved in solution.


Romero N.B.,Institut Universitaire de France
Acta neuropathologica communications | Year: 2014

Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We undertook a detailed muscle morphological analysis of 14 NEB-mutated NM patients with different clinical forms to define muscle pathological patterns and correlate them with clinical course and genotype. Three groups were identified according to clinical severity. Group 1 (n = 5) comprises severe/lethal NM and biopsy in the first days of life. Group 2 (n = 4) includes intermediate NM and biopsy in infancy. Group 3 (n = 5) comprises typical/mild NM and biopsy in childhood or early adult life. Biopsies underwent histoenzymological, immunohistochemical and ultrastructural analysis. Fibre type distribution patterns, rod characteristics, distribution and localization were investigated. Contractile performance was studied in muscle fibre preparations isolated from seven muscle biopsies from each of the three groups. G1 showed significant myofibrillar dissociation and smallness with scattered globular rods in one third of fibres; there was no type 1 predominance. G2 presented milder sarcomeric dissociation, dispersed or clustered nemaline bodies, and type 1 predominance/uniformity. In contrast, G3 had well-delimited clusters of subsarcolemmal elongated rods and type 1 uniformity without sarcomeric alterations. In accordance with the clinical and morphological data, functional studies revealed markedly low forces in muscle bundles from G1 and a better contractile performance in muscle bundles from biopsies of patients from G2, and G3.In conclusion NEB-mutated NM patients present a wide spectrum of morphological features. It is difficult to establish firm genotype phenotype correlation. Interestingly, there was a correlation between clinical severity on the one hand and the degree of sarcomeric dissociation and contractility efficiency on the other. By contrast the percentage of fibres occupied by rods, as well as the quantity and the sub sarcolemmal position of rods, appears to inversely correlate with severity. Based on our observations, we propose myofibrillar dissociation and changes in contractility as an important cause of muscle weakness in NEB-mutated NM patients.


Gallay T.,Institut Universitaire de France
Archive for Rational Mechanics and Analysis | Year: 2011

We consider the inviscid limit for the two-dimensional incompressible Navier-Stokes equation in the particular case where the initial flow is a finite collection of point vortices. We suppose that the initial positions and the circulations of the vortices do not depend on the viscosity parameter ν, and we choose a time T > 0 such that the Helmholtz-Kirchhoff point vortex system is well-posed on the interval [0, T]. Under these assumptions, we prove that the solution of the Navier-Stokes equation converges, as ν → 0, to a superposition of Lamb-Oseen vortices whose centers evolve according to a viscous regularization of the point vortex system. Convergence holds uniformly in time, in a strong topology which allows us to give an accurate description of the asymptotic profile of each individual vortex. In particular, we compute to leading order the deformations of the vortices due to mutual interactions. This makes it possible to estimate the self-interactions, which play an important role in the convergence proof. © 2010 Springer-Verlag.


Gluckman E.,Institut Universitaire de France
Blood Reviews | Year: 2011

Since the first human cord blood transplant, performed in 1988, cord blood banks have been established worldwide for collection and cryopreservation of cord blood for allogeneic hematopoietic stem cell transplant. Umbilical cord blood (UCB) has now become one of the most commonly used source of hematopoietic stem cells for allogeneic transplantation. Today a global network of cord blood banks and transplant centers has been established for a common inventory with an estimated 600,000 UCB have been banked and more than 20,000 UCB units distributed worldwide for adults and children with severe hematological diseases. Several studies have shown that the number of cells is the most important factor for engraftment while some degree of HLA mismatches is acceptable. The absence of ethical concern, and the unlimited supply of cells explain the increasing interest of using cord blood for developing regenerative medicine. © 2011 Elsevier Ltd.


Kerneis M.,Institut Universitaire de France
JACC. Cardiovascular interventions | Year: 2013

This study sought to assess the consequences of switching prasugrel to clopidogrel on platelet inhibition and clinical outcomes after an acute coronary syndrome (ACS). Many ACS patients are switched from prasugrel to clopidogrel within the recommended 1-year duration of treatment. Platelet reactivity was measured with the VerifyNow P2Y(12) assay (Accumetrics, San Diego, California) in 300 ACS patients treated for 15 days with prasugrel 10 mg. Patients displaying low on-treatment platelet reactivity (LPR) and/or at high risk of bleeding were switched to clopidogrel 75 mg and tested again 15 days later. The rate of patients with high on-treatment platelet reactivity (HPR), P2Y(12) reaction units (PRU) >208, and LPR (PRU <0) were evaluated before and after the switch. Bleeding and ischemic events were also recorded. On a regimen of prasugrel 10 mg, the rate of patients with LPR was 45.6% (n = 137), whereas 4.3% (n = 13) had HPR. A group of 31 patients (10.3%) was switched to clopidogrel 75 mg, of whom 29 had LPR (93.5%) on a regimen of prasugrel. On-treatment platelet reactivity (PRU) increased from 14 ± 4 on a regimen of prasugrel to 155 ±15 on a regimen of clopidogrel (p = 0.0001), resulting in a much lower rate of patients with LPR (9.7%). The rate of patients with HPR increased from 0% with prasugrel to 29% (n = 9) with clopidogrel. The rate of minor bleeding decreased after the switch from 32.2% to 9.7%; p = 0.03. An LPR is frequent in patients treated with prasugrel 10 mg. Early switching from prasugrel 10 mg to clopidogrel 75 mg reduces the number of patients with LPR and minor bleeding events but unmasks a group of nonresponders to clopidogrel with unknown consequences on clinical outcomes. Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.


Tall A.R.,Columbia University | Yvan-Charvet L.,Institut Universitaire de France
Nature Reviews Immunology | Year: 2015

Hypercholesterolaemia leads to cholesterol accumulation in macrophages and other immune cells, which promotes inflammatory responses, including augmentation of Toll-like receptor (TLR) signalling, inflammasome activation, and the production of monocytes and neutrophils in the bone marrow and spleen. On a cellular level, activation of TLR signalling leads to decreased cholesterol efflux, which results in further cholesterol accumulation and the amplification of inflammatory responses. Although cholesterol accumulation through the promotion of inflammatory responses probably has beneficial effects in the response to infections, it worsens diseases that are associated with chronic metabolic inflammation, including atherosclerosis and obesity. Therapeutic interventions such as increased production or infusion of high-density lipoproteins may sever the links between cholesterol accumulation and inflammation, and have beneficial effects in patients with metabolic diseases. © 2015 Macmillan Publishers Limited. All rights reserved.

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