Laboratoire de Mécanique et d’Acoustique

With more than 20 molecules in clinical use, monoclonal antibodies have finally come of age as therapeutics, generating a market value of $11 billion in 2004, expected to reach $26 billion by 2010. While delivering interesting results in the treatment of several major diseases including autoimmune, cardiovascular and infectious diseases, cancer and inflammation, clinical trials and research are generating a wealth of useful information, for instance about associations of clinical responses with Fc receptor polymorphisms and the infiltration and recruitment of effector cells into targeted tissues. Some functional limitations of therapeutic antibodies have come to light such as inadequate pharmacokinetics and tissue accessibility as well as impaired interactions with the immune system, and these deficiencies point to areas where additional research is needed. This review aims at giving an overview of the current state of the art and describes the most promising avenues that are being followed to create the next generation of antibody‐based therapeutic agents. This article is part of a themed section on Vector Design and Drug Delivery. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009

A study of strain localization in triaxial tests on sand, using computed tomography is reported. The inception and the development of the localization are detected and described, both qualitatively and quantitatively. The complex geometrical structures involved in the localization patterns are described and the local void ratio evolution in the localization zone(s) is determined. Dense and loose Hostun RF sand specimens were tested under a confining pressure of 60 kPa. It is shown that strain localization can occur in different localization patterns depending on test conditions; a mechanism involving, simultaneously, a central cone and a set of planes in pairs was found for many of the specimens tested. The comparison of the local void ratio evolution in the shear zones with the global void ratio measurement supports the important conclusion that a limit void ratio is reached in the shear zones. This ratio is significantly different from the final void ratio defined from the global measurements; the lack of physical relevance of the latter is established. Cet article présente les résultats dune étude consacrée à la localisation de la deformation dans Pessai triaxial sur sable, utilisant la tomographie numérisée. On pent ainsi détecter et décrire la naissance de la localisation, depuis ses premières manifestations jusquà la rupture. La description obtenue est à la fois qualitative et quantitative: les structures géométriques complexes qui apparaissent sont caractérisées, et évolution locale de Pindice des vides pent ôtre mesurée. Des échantillons denses et l&cric;ches de sable dHostun RF ont é testés sous une contrainte de confinement de 60 kPa. On montre que la localisation pent sorganiser de fagon assez varée du point de vue géométrique, suivant les conditions dessai; cependant on a observé dans plusieurs cas un mécanisme similaire, qui comprend un c&cric;ne central associé à des paires de plans se coupant suivant une arête située dans le plan dune des extrémités de échantillon. éode de la variation de Pindice des vides dans les zones de cisaillement met en évidence une limite atteinte dans ces zones; par comparaison avec Pindice des vides moyen dans échantillon, on constate que cette limite est sensiblement différente de celle quon pourrait déduire des mesures globales, si Pon ignorait Pexistence de déformations localisées dans échantillon. Ainsi on doit conclure que les mesures globales sont généralement insuffisantes pour caractériser Pindice des vides en grandes déformation dans les échantillons triaxiaux sur les mat6riaux denses.

This paper starts with a brief discussion of so-called wavelet transforms, i.e., decompositions of arbitrary signals into localized contributions labelled by a scale parameter. The main features of the method are first illustrated through simple mathematical examples. Then we present the first applications of the method to the recognition and visualisation of characteristic features of speech and of musical sounds.

This chapter elaborates some closely related methods developed to estimate the effective behavior of nonlinear composites with random microstructures. The constitutive behavior of the individual constituents of the composite is assumed to be governed by a potential, or strain-energy function, in such a way that the strain and stress fields are related by the constitutive relation. The response of the phases is assumed to be linear for purely hydrostatic loadings and nonlinear in shear. The extension of the Hashin–Shtrikman variational principles, which can be used to obtain improved bounds (depending on up to two-point statistical information) for nonlinear composites, is presented. It is possible to obtain nontrivial lower bounds for the effective stress potential by an analogous development taking the polarization field to be piecewise constant. The variational principles are used to generate a general class of bounds for nonlinear composites, by making suitable approximations in the set of admissible linear comparison composites. Various interpretations of the variational procedures are developed, including an interpretation of the resulting bounds in terms of secant moduli. The variational principles for materials with a certain concavity hypothesis are also elaborated.

Because it drives the compromise between resolution and penetration, the diffraction limit has long represented an unreachable summit to conquer in ultrasound imaging. Within a few years after the introduction of optical localization microscopy, we proposed its acoustic alter ego that exploits the micrometric localization of microbubble contrast agents to reconstruct the finest vessels in the body in-depth. Various groups now working on the subject are optimizing the localization precision, microbubble separation, acquisition time, tracking, and velocimetry to improve the capacity of ultrasound localization microscopy (ULM) to detect and distinguish vessels much smaller than the wavelength. It has since been used in vivo in the brain, the kidney, and tumors. In the clinic, ULM is bound to improve drastically our vision of the microvasculature, which could revolutionize the diagnosis of cancer, arteriosclerosis, stroke, and diabetes.

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Rickettsia conorii is an obligate intracellular bacterium that causes Mediterranean spotted fever in humans. We determined the 1,268,755-nucleotide complete genome sequence of R. conorii, containing 1374 open reading frames. This genome exhibits 804 of the 834 genes of the previously determined R. prowazekii genome plus 552 supplementary open reading frames and a 10-fold increase in the number of repetitive elements. Despite these differences, the two genomes exhibit a nearly perfect colinearity that allowed the clear identification of different stages of gene alterations with gene remnants and 37 genes split in 105 fragments, of which 59 are transcribed. A 38-kilobase sequence inversion was dated shortly after the divergence of the genus.

By the end of 2018, 42 years after the landing of the two Viking seismometers on Mars, InSight will deploy onto Mars' surface the SEIS (Seismic Experiment for Internal Structure) instrument; a six-axes seismometer equipped with both a long-period three-axes Very Broad Band (VBB) instrument and a three-axes short-period (SP) instrument. These six sensors will cover a broad range of the seismic bandwidth, from 0.01 Hz to 50 Hz, with possible extension to longer periods. Data will be transmitted in the form of three continuous VBB components at 2 sample per second (sps), an estimation of the short period energy content from the SP at 1 sps and a continuous compound VBB/SP vertical axis at 10 sps. The continuous streams will be augmented by requested event data with sample rates from 20 to 100 sps. SEIS will improve upon the existing resolution of Viking's Mars seismic monitoring by a factor of 2500 at 1 Hz and 200 000 at 0.1 Hz. An additional major improvement is that, contrary to Viking, the seismometers will be deployed via a robotic arm directly onto Mars' surface and will be protected against temperature and wind by highly efficient thermal and wind shielding. Based on existing knowledge of Mars, it is reasonable to infer a moment magnitude detection threshold of M w 3 at 40 epicentral distance and a potential to detect several tens of quakes and about five impacts per year. In this paper, we first describe the science goals of the experiment and the rationale used to define its requirements. We then provide a detailed description of the hardware, from the sensors to the deployment system and associated performance, including transfer functions of the seismic sensors and temperature sensors. We conclude by describing the experiment ground segment, including data processing services, outreach and education networks and provide a description of the format to be used for future data distribution.

The complete assembly of the entire human genome sequence by Venter et al. confirms recent estimates that the total number of human protein coding genes might be less than 30,000--a mere one-third increase over the nematode Caenorhabditis elegans. Such a low gene number constitutes a paradigm change, which could drastically modify our understanding of organism complexity and evolution, as well as our current interpretation of transcriptome analyses. It may also have severe consequences on the long-term sustainability of the biomedical industry in the postgenomic era.

Bacteria respond to nutritional stresses by producing an intracellular alarmone, guanosine 5'-(tri)diphosphate, 3'-diphosphate [(p)ppGpp], which triggers the stringent response resulting in growth arrest and expression of resistance genes. In Escherichia coli, upon fatty acid or carbon starvation, SpoT enzyme activity switches from (p)ppGpp degradation to (p)ppGpp synthesis, but the signal and mechanism for this response remain totally unknown. Here, we characterize for the first time a physical interaction between SpoT and acyl carrier protein (ACP) using affinity co-purifications and two-hybrid in E. coli. ACP, as a central cofactor in fatty acid synthesis, may be an ideal candidate as a mediator signalling starvation to SpoT. Accordingly, we show that the ACP/SpoT interaction is specific of SpoT and ACP functions because ACP does not interact with the homologous RelA protein and because SpoT does not interact with a non-functional ACP. Using truncated SpoT fusion proteins, we demonstrate further that ACP binds the central TGS domain of SpoT, consistent with a role in regulation. The behaviours of SpoT point mutants that do not interact with ACP reveal modifications of the balance between the two opposite SpoT catalytic activities thereby changing (p)ppGpp levels. More importantly, these mutants fail to trigger (p)ppGpp accumulation in response to fatty acid synthesis inhibition, supporting the hypothesis that the ACP/SpoT interaction may be involved in SpoT-dependent stress response. This leads us to propose a model in which ACP carries information describing the status of cellular fatty acid metabolism, which in turn can trigger the conformational switch in SpoT leading to (p)ppGpp accumulation.

FusionDB (http://igs-server.cnrs-mrs.fr/FusionDB/) constitutes a resource dedicated to in-depth analysis of bacterial and archaeal gene fusion events. Such events can provide the 'Rosetta stone' in the search for potential protein-protein interactions, as well as metabolic and regulatory networks. However, the false positive rate of this approach may be quite high, prompting a detailed scrutiny of putative gene fusion events. FusionDB readily provides much of the information required for that task. Moreover, FusionDB extends the notion of gene fusion from that of a single gene to that of a family of genes by assembling pairs of genes from different genomes that belong to the same Cluster of Orthogonal Groups (COG). Multiple sequence alignments and phylogenetic tree reconstruction for the N- and C-terminal parts of these 'COG fusion' events are provided to distinguish single and multiple fusion events from cases of gene fission, pseudogenes and other false positives. Finally, gene fusion events with matches to known structures of heterodimers in the Protein Data Bank (PDB) are identified and may be visualized. FusionDB is fully searchable with access to sequence and alignment data at all levels. A number of different scores are provided to easily differentiate 'real' from 'questionable' cases, especially when larger database searches are performed. FusionDB is cross-linked with the 'Phylogenomic Display of Bacterial Genes' (PhydBac) online web server. Together, these servers provide the complete set of information required for in-depth analysis of non-homology-based gene function attribution.

Biofilm formation by the opportunistic pathogen Pseudomonas aeruginosa requires the expression of a number of surface adhesive components. The expression of surface organelles facilitating biofilm formation is controlled by environmental signals acting through transcriptional regulatory networks. We analysed the expression of a family of P. aeruginosa adhesins encoded by three distinct fimbrial gene clusters (cupA, cupB and cupC). Using transposon mutagenesis, we have identified several regulatory loci that upregulated cupB and cupC transcription. One such locus contains three components, RocS1, RocR and RocA1, which represent a variant of a classical two-component signal transduction pathway. RocS1 is a sensor kinase, RocA1 is a DNA binding response regulator that activates cup genes, and RocR is an antagonist of RocA1 activity. Using a two-hybrid assay, we have shown that RocS1 interacts with receiver domains of both RocA1 and RocR. Expression of the Cup system in response to environmental stimuli is accomplished by a novel mechanism in which the sensor kinase activates its cognate response regulator through a phosphorelay pathway, while an additional repressor protein modulates this interaction.

We present a general method for estimating the location of small, well-separated scatterers in a randomly inhomogeneous environment using an active sensor array. The main features of this method are (i) an arrival time analysis (ATA) of the echo received from the scatterers, (ii) a singular value decomposition of the array response matrix in the frequency domain, and (iii) the construction of an objective function in the time domain that is statistically stable and peaks on the scatterers. By statistically stable we mean here that the objective function is self-averaging over individual realizations of the medium. This is a new approach to array imaging that is motivated by time reversal in random media, analysed in detail previously. It combines features from seismic imaging, like ATA, with frequency-domain signal subspace methodology like multiple signal classification. We illustrate the theory with numerical simulations for ultrasound.

While most organisms grow at temperatures ranging between 20 and 50 degrees C, many archaea and a few bacteria have been found capable of withstanding temperatures close to 100 degrees C, or beyond, such as Pyrococcus or Aquifex. Here we report the results of two independent large scale unbiased approaches to identify global protein properties correlating with an extreme thermophile lifestyle. First, we performed a comparative proteome analyses using 30 complete genome sequences from the three kingdoms. A large difference between the proportions of charged versus polar (noncharged) amino acids was found to be a signature of all hyperthermophilic organisms. Second, we analyzed the water accessible surfaces of 189 protein structures belonging to mesophiles or hyperthermophiles. We found that the surfaces of hyperthermophilic proteins exhibited the shift already observed at the genomic level, i.e. a proportion of solvent accessible charged residues strongly increased at the expense of polar residues. The biophysical requirements for the presence of charged residues at the protein surface, allowing protein stabilization through ion bonds, is therefore clearly imprinted and detectable in all genome sequences available to date.

From a set of experimental studies showing how intersegmental coordination develops during childhood in various posturokinetic tasks, we have established a repertoire of equilibrium strategies in the course of ontogenesis. The experimental data demonstrate that the first reference frame used for the organization of balance control during locomotion is the pelvis, especially in young children. Head stabilization during posturokinetic activities, particularly locomotion, constitutes a complex motor skill requiring a long time to develop during childhood. When studying the emergence of postural strategies, it is essential to distinguish between results that can be explained by biomechanical reasons strictly and those reflecting the maturation of the central nervous system (CNS). To address this problem, we have studied our young subjects in situations requiring various types of adaptation. The studies dealing with adaptation of postural strategies aimed at testing short and long-term adaptation capacity of the CNS during imposed transient external biomechanical constraints in healthy children, and during chronic internal constraints in children with skeletal pathologies. In addition to maintenance of balance, another function of posture is to ensure the orientation of a body segment. It appears that the control of orientation and the control of balance both require the trunk as an initial reference frame involving a development from egocentric to exocentric postural control. It is concluded that the first step for children consists in building a repertoire of postural strategies, and the second step consists in learning to select the most appropriate postural strategy, depending on the ability to anticipate the consequence of the movement in order to maintain balance control and the efficiency of the task.

This paper presents Tcoffee@igs, a new server provided to the community by Hewlet Packard computers and the Centre National de la Recherche Scientifique. This server is a web-based tool dedicated to the computation, the evaluation and the combination of multiple sequence alignments. It uses the latest version of the T-Coffee package. Given a set of unaligned sequences, the server returns an evaluated multiple sequence alignment and the associated phylogenetic tree. This server also makes it possible to evaluate the local reliability of an existing alignment and to combine several alternative multiple alignments into a single new one. Tcoffee@igs can be used for aligning protein, RNA or DNA sequences. Datasets of up to 100 sequences (2000 residues long) can be processed. The server and its documentation are available from: http://igs-server.cnrs-mrs.fr/Tcoffee/.

The phylogenetic diversity of prokaryotic communities exposed to arid conditions in the hot desert of Tataouine (south Tunisia) was estimated with a combination of a culture and - molecular-based analysis. Thirty-one isolates, representative of each dominant morphotypes, were affiliated to Actinobacteria, Firmicutes, Proteobacteria and the CFB group while none related to Archaea. Analysis of 16S rRNA gene libraries revealed the presence of species related to Bacteria and Archaea. Sequences related to Archaea were all affiliated to the non-thermophilic Crenarchaeota subgroup. Bacterial sequences were dominated by Proteobacteria, Actinobacteria and Acidobacteria; a few sequences were distributed among eight others phyla, including Thermus/Deinococcus relatives. A correlation between tolerance to desiccation and to radiation has been demonstrated for the radiotolerant bacteria Deinococcus radiodurans. Because bacteria living in the hot desert of Tataouine are one way or another tolerant to desiccation, we investigate whether they could also be tolerant to radiation. Exposition of soil samples to intense gamma radiation yields Bacillus, Thermus/Deinococcus and alpha-Proteobacteria relatives. Four of these strains correspond to radiotolerant species as revealed by evaluation of the resistance levels of the individual cultures. A detailed analysis of the resistance levels for two Thermus/Deinococcus and two alpha-Proteobacteria relatives revealed that they correspond to new radiotolerant species.

Biosynthesis of iron-sulfur clusters (Fe-S) depends on multiprotein systems. Recently, we described the SUF system of Escherichia coli and Erwinia chrysanthemi as being important for Fe-S biogenesis under stressful conditions. The SUF system is made of six proteins: SufC is an atypical cytoplasmic ABC-ATPase, which forms a complex with SufB and SufD; SufA plays the role of a scaffold protein for assembly of iron-sulfur clusters and delivery to target proteins; SufS is a cysteine desulfurase which mobilizes the sulfur atom from cysteine and provides it to the cluster; SufE has no associated function yet. Here we demonstrate that: (i) SufE and SufS are both cystosolic as all members of the SUF system; (ii) SufE is a homodimeric protein; (iii) SufE forms a complex with SufS as shown by the yeast two-hybrid system and by affinity chromatography; (iv) binding of SufE to SufS is responsible for a 50-fold stimulation of the cysteine desulfurase activity of SufS. This is the first example of a two-component cysteine desulfurase enzyme.

Under nano- to femtosecond pulsed illumination at their plasmonic resonance wavelength, metal nanoparticles efficiently absorb the incident light energy that is subsequently converted into heat. In a liquid environment, with sufficiently high pulse fluences (light energy per unit area), this heat generation may result in the local formation of a transient nanobubble. This phenomenon has been the subject of a decade of investigations and is at the basis of numerous applications from cancer therapy to photoacoustic imaging. The aim of this article is to clarify the question of the fluence threshold required for bubble formation. Using a Runge-Kutta-4 numerical algorithm modeling the heat diffusion around a spherical gold nanoparticle, we numerically investigate the influence of the nanoparticle diameter, pulse duration (from the femto- to the nanosecond range), wavelength, and Kapitza resistivity in order to explain the observations reported in the literature.

The early light-induced proteins (ELIPs) belong to the multigenic family of pigment-binding light-harvesting complexes. ELIPs accumulate transiently and are believed to play a protective role in plants exposed to high levels of light. Constitutive expression of the ELIP2 gene in Arabidopsis resulted in a marked reduction of the pigment content of the chloroplasts, both in mature leaves and during greening of etiolated seedlings. The chlorophyll loss was associated with a decrease in the number of photosystems in the thylakoid membranes, but the photosystems present were fully assembled and functional. A detailed analysis of the chlorophyll-synthesizing pathway indicated that ELIP2 accumulation downregulated the level and activity of two important regulatory steps: 5-aminolevulinate synthesis and Mg-protoporphyrin IX (Mg-Proto IX) chelatase activity. The contents of glutamyl tRNA reductase and Mg chelatase subunits CHLH and CHLI were lowered in response to ELIP2 accumulation. In contrast, ferrochelatase activity was not affected and the inhibition of Heme synthesis was null or very moderate. As a result of reduced metabolic flow from 5-aminolevulinic acid, the steady state levels of various chlorophyll precursors (from protoporphyrin IX to protochlorophyllide) were strongly reduced in the ELIP2 overexpressors. Taken together, our results indicate that the physiological function of ELIPs could be related to the regulation of chlorophyll concentration in thylakoids. This seems to occur through an inhibition of the entire chlorophyll biosynthesis pathway from the initial precursor of tetrapyrroles, 5-aminolevulinic acid. We suggest that ELIPs work as chlorophyll sensors that modulate chlorophyll synthesis to prevent accumulation of free chlorophyll, and hence prevent photooxidative stress.