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International audience; Given their potential in a better characterization and diagnosis of major pathologies like cancer or chronic inflammation, redox-activated Magnetic Resonance Imaging (MRI) probes have recently attracted much interest from chemists. Such redox responsive probes are capable of reporting on specific biomarkers that are related to tissue redox potential disruption or hypoxia. Lately, this research area has experienced remarkable development, including redox-responsive metal complexes and nanoparticles. Here we critically review the progress with a specific focus on metal-based probes and some nanoparticle examples. We demonstrate, via representative cases, the different molecular mechanisms that can generate a redox-modulated MRI response. They can be based on the redox activity of either the ligand or the metal center, provided the different oxidation states of the metal ion are endowed with different magnetic properties. A particular emphasis is given to recent advances and to the imaging probes that have attained in vivo validation. In overall, we aim to provide the reader with a comprehensive view of how intracellular or extracellular redox buffer systems can be assessed by using MRI contrast agents based on lanthanide or transition metal ions using T1-weighted, T2-weighted, paraCEST 1H or 19F MRI.

New information on the lethal and sublethal effects of neonicotinoids and fipronil on organisms is presented in this review, complementing the previous WIA in 2015. The high toxicity of these systemic insecticides to invertebrates has been confirmed and expanded to include more species and compounds. Most of the recent research has focused on bees and the sublethal and ecological impacts these insecticides have on pollinators. Toxic effects on other invertebrate taxa also covered predatory and parasitoid natural enemies and aquatic arthropods. Little, while not much new information has been gathered on soil organisms. The impact on marine coastal ecosystems is still largely uncharted. The chronic lethality of neonicotinoids to insects and crustaceans, and the strengthened evidence that these chemicals also impair the immune system and reproduction, highlights the dangers of this particular insecticidal classneonicotinoids and fipronil. , withContinued large scale – mostly prophylactic – use of these persistent organochlorine pesticides has the potential to greatly decreasecompletely eliminate populations of arthropods in both terrestrial and aquatic environments. Sublethal effects on fish, reptiles, frogs, birds and mammals are also reported, showing a better understanding of the mechanisms of toxicity of these insecticides in vertebrates, and their deleterious impacts on growth, reproduction and neurobehaviour of most of the species tested. This review concludes with a summary of impacts on the ecosystem services and functioning, particularly on pollination, soil biota and aquatic invertebrate communities, thus reinforcing the previous WIA conclusions (van der Sluijs et al. 2015).

International audience; A molecular theranostic agent designed for photodynamic therapy (PDT) treatment in the near-infrared and for imaging tissue tumors with magnetic resonance imaging (MRI) is reported. It consists of a linear pi-conjugated Zn(II) porphyrin dimer linked at each extremity to a GdDOTA-type complex. This agent has shown very promising potential for PDT applications with good singlet oxygen generation in DMSO and high linear absorption in the near- infrared (lambda(max) = 746 nm, epsilon approximate to 10(5) M-1 cm(-1)). Moreover, this molecule has a propensity for two-photon excited PDT with high two-photon cross sections (similar to 8000 GM in 880-930 nm range), which should allow for deeper tumor treatments and higher spatial precision as compared to conventional one-photon PDT. Regarding the MRI contrast agent properties, the molecule has shown superior relaxivity (14.4 mM(-1) s(-1) at 40 MHz, 298 K) in comparison to clinical contrast agents and the ability to be internalized in cells, thanks to its amphiphilic character. Irradiation of HeLa cells using either one-photon (740 nm) or two-photon excitation (910 nm) has led in both cases to important cell death.

International audience; Aggregation of misfolded proteins and progressive polymerization of otherwise soluble proteins is a common hallmark of a wide range of highly debilitating and increasingly prevalent diseases, including amyotrophic lateral sclerosis, cerebral amyloid angiopathy, type II diabetes and Parkinson's, Huntington's and Alzheimer's diseases. There is a growing interest in creating imaging agents to detect such aggregates in various imaging modalities, including PET, SPECT and MRI. We present here an overview of recent efforts from the perspective of early diagnosis of amyloid diseases, with a major focus on Aβ detection and metal complexes bearing PiB units.

The antimetastatic ruthenium(III) complex (H2Im)[trans-RuCl4(HIm)(DMSO)] (NAMI-A) as well as its two analogues (H2Ind)[trans-RuCl4(HInd)(DMSO)] (Ru-Ind) and (HIsq)[trans-RuCl4(Isq)(DMSO)] (Ru-Isq) (HIm–imidazole, HInd–indazole, Isq–isoquinoline, DMSO–dimethyl sulfoxide) were tested for their effect on endothelial cell functions in vitro on human skin microvascular endothelial cells (HSkMEC) and human endothelial progenitor cells (HPEC-CB.2) under normoxic (21 % O2) and hypoxic (1 % O2) conditions. All studied complexes showed very low cytotoxicity profiles towards both mature microvascular and precursor endothelial cells (ECs), independently of oxygen concentration. Among tested compounds Ru-Ind exhibited the highest cytotoxicity. The antiangiogenic activity of ruthenium complexes was evaluated for their influence on pseudo-vessels formation by microvascular endothelial cells (HSkMEC) because of their involvement in melanoma progression. Our studies indicated that Ru-Ind and Ru-Isq exhibited hypoxia- and dose-dependent-inhibition of angiogenesis on Matrigel™. Significant hypoxia-selective downregulation of pseudo-vessels formation by Ru-Isq correlates with efficient inhibition of cell motility. Interestingly, in the applied concentration doses migration of endothelial cells was also inhibited by NAMI-A, but the pseudo-vessels formation on Matrigel™ was unaffected. Angiogenesis-related genes expression profile for both mature and precursor ECs indicated that inhibition of angiogenesis, mainly due to Ru-Isq, as compared to NAMI-A and Ru-Ind correlated with downregulation of CD31 and CD144 expression and upregulation of NOTCH4 expression in mature ECs, which is essential for endothelial cell motility and stalk cells organization control. The hypoxia-selective antiangiogenic activity of Ru-Ind and Ru-Isq, NAMI-A analogues makes them potent antimetastatic therapeutics for their selective action in hypoxia which controls tumor pathologic angiogenesis. Electronic supplementary material The online version of this article (doi:10.1007/s10534-016-9974-9) contains supplementary material, which is available to authorized users.

International audience; In an effort to explore novel ligand scaffolds for stable and inert lanthanide complexation in magnetic resonance imaging contrast agent research, three chiral ligands containing a highly rigid (1S,2S)-1,2-cyclobutanediamine spacer and different number of acetate and picolinate groups were efficiently synthesized. Potentiometric studies show comparable thermodynamic stability for the Gd3+ complexes formed with either the octadentate (L3)4– bearing two acetate or two picolinate groups or the heptadentate (L2)4– analogue bearing one picolinate and three acetate groups (log KGdL = 17.41 and 18.00 for [Gd(L2)]− and [Gd(L3)]−, respectively). In contrast, their dissociation kinetics is revealed to be very different: the monohydrated [Gd(L3)]− is considerably more labile, as a result of the significant kinetic activity of the protonated picolinate function, as compared to the bishydrated [Gd(L2)]−. This constitutes an uncommon example in which lowering ligand denticity results in a remarkable increase in kinetic inertness. Another interesting observation is that the rigid ligand backbone induces an unusually strong contribution of the spontaneous dissociation to the overall decomplexation process. Thanks to the presence of two inner-sphere water molecules, [Gd(L2)]− is endowed with high relaxivity (r1 = 7.9 mM–1 s–1 at 20 MHz, 25 °C), which is retained in the presence of large excess of endogenous anions, excluding ternary complex formation. The water exchange rate is similar for [Gd(L3)]− and [Gd(L2)]−, while it is 1 order of magnitude higher for the trishydrated tetraacetate analogue [Gd(L1)]− (kex298 = 8.1, 10, and 127 × 106 s–1, respectively). A structural analysis via density functional theory calculations suggests that the large bite angle imposed by the rigid (1S,2S)-1,2-cyclobutanediamine spacer could allow the design of ligands based on this scaffold with suitable properties for the coordination of larger metal ions with biomedical applications.

Antibiotic resistance is a growing public health concern. Because only a few novel classes of antibiotics have been developed in the last 40 years, such as the class of oxazolidinones, new antibacterial strategies are urgently needed [1]. Nucleic acid-based antibiotics are a new type of antimicrobials. However, free nucleic acids cannot spontaneously cross the bacterial cell wall and membrane, consequently, their intracellular delivery into bacteria needs to be assisted. Here, we introduce an original lipopolyplex system named liposome polymer nucleic acid (LPN), capable of versatile nucleic acid delivery into bacteria. We characterized LPN formed with significant therapeutic nucleic acids: 11 nt antisense single-stranded (ss) DNA and double-stranded (ds) DNA of 15 and 95 base pairs (bp), 9 kbp plasmid DNA (pDNA), and 1,000 nt ssRNA. All these complexes were efficiently internalized by two different bacterial species, i.e., Escherichia coli and Pseudomonas aeruginosa, as shown by flow cytometry. Consistent with intracellular delivery, LPN prepared with an antisense oligonucleotide and directed against an essential gene, induced specific and important bacterial growth inhibition likely leading to a bactericidal effect. Our findings indicate that LPN is a versatile platform for efficient delivery of diverse nucleic acids into Gram-negative bacteria.

At present, there is a lack of well-validated protocols that allow for the analysis of the mechanical properties of muscle and tendon tissues. Further, there are no reports regarding characterization of mouse skeletal muscle and tendon mechanical properties in vivo using elastography thereby limiting the ability to monitor changes in these tissues during disease progression or response to therapy. Therefore, we sought to develop novel protocols for the characterization of mechanical properties in musculotendinous tissues using atomic force microscopy (AFM) and ultrasound elastography. Given that TIEG1 knockout (KO) mice exhibit well characterized defects in the mechanical properties of skeletal muscle and tendon tissue, we have chosen to use this model system in the present study. Using TIEG1 knockout and wild-type mice, we have devised an AFM protocol that does not rely on the use of glue or chemical agents for muscle and tendon fiber immobilization during acquisition of transversal cartographies of elasticity and topography. Additionally, since AFM cannot be employed on live animals, we have also developed an ultrasound elastography protocol using a new linear transducer, SLH20-6 (resolution: 38 µm, footprint: 2.38 cm), to characterize the musculotendinous system in vivo. This protocol allows for the identification of changes in muscle and tendon elasticities. Such innovative technological approaches have no equivalent to date, promise to accelerate our understanding of musculotendinous mechanical properties and have numerous research and clinical applications.

International audience; In temperate regions goat's reproduction is seasonal. To obtain year-round breeding, hormonal treatments are currently applied. These treatments usually combine a progesterone analog with the pregnant mare serum gonadotropin (PMSG). However, their use has significant ethical and environmental drawbacks. Therefore, alternative methods to manage reproduction are needed. The discovery that in mammals the neuropeptide kisspeptin is a major positive regulator of hypothalamo-pituitary gonadal axis offered an attractive alternative strategy to control reproduction. We have previously designed a kisspeptin analog, called C6, which offers pharmacological advantages over endogenous kisspeptin. These include a longer lasting effect and enhanced activity following intramuscular injection. In the present work, we evaluated C6 effect on LH and FSH plasma concentrations in the Alpine goat breed and tested whether C6 could replace PMSG to trigger ovulation. An intramuscular injection of C6 (15 nmol/doe) given 24 hours after the end of progestogen treatment induced a surge-like peak of both LH and FSH. This was followed by an increase of progesterone, a hallmark of ovulation induction and corpus luteus formation. These results were obtained at three different time of the year: during the breeding season, the non-breeding season and at the onset of the breeding season. Furthermore, we compared the efficacy of C6 and PMSG to induce fertile ovulations when these treatments are given at the onset of the breeding season and are followed by artificial insemination. The results of this first attempt were extremely promising with gestation rates of 45% and 64% for C6 and PMSG respectively. Pending optimization of the treatment procedure in order to improve efficacy, kisspeptin analogs could be the long sought-after alternative to PMSG.

International audience; In the perfect world—an ideal laboratory grown vascular graft must be composed of viable tissue elements with potentials for repair and regeneration, an acceptable range of resistance to thrombosis—infections, sensitivity to vasoactive mediators, secretory and contractile properties, mimicking natural blood vessels. Three key components of generating such custom-made vessels are biocompatible polymer of natural structural proteins for building a scaffold, healthy primary vascular cells grown in the scaffold maintaining close anatomical and functional integrity, and provision for a microenvironment for providing balanced metabolic support. In addition, maintenance of a pulsatile flow of nutrients and polarization of cellular components in the synthetic vessels are also important. Obtaining decellularized vascular grafts from cadaveric donors or xenografts, populating with recipient’s primary vascular cells, and maintaining them in bioreactors or recipients own body tissue are other potential alternative approaches. Here, we will discuss some central aspects and updated information on authentic artificial blood vessel.

International audience; Computers are the only research tools that by design exhibit chaotic behavior: a minimal change in the input to a computation can change its output in any imaginable way. Developers and users of scientific software should be aware of this feature and set up safety nets for protecting themselves against bad surprises.

International audience; Technical debt is a useful metaphor for understanding the long-term impact of technical choices. The analysis of technical debt has found its place in the software industry, with results that are applicable to scientific software as well. But technical debt is also a useful concept to look at how we use computers in doing scientific research.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by brain accumulation oftoxic protein aggregates, including extracellular amyloid beta (Aβ) plaques, inflammation, neuronaldeath and progressive cognitive dysfunction. Current diagnostic modalities, based on cognitive tests,fail to detect early AD onset, thus emphasising the need to develop improved methods forpre-symptomatic disease detection.Building on the properties of the Pittsburgh Compound B (PiB), an Aβ-binding molecule suitable touse as positron emission tomography (PET) imaging agent, and aiming at using a more clinically available modality (like magnetic ressonance imaging, MRI), PiB derivatives have been conjugated to the macrocyclic chelator 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO3A) monoamide. However, these derivatives do not readily cross the highly selective blood-brainbarrier (BBB). Taking advantage of the capacity of functionalised carbon nanotubes (f-CNTs) to cross biological barriers, including the BBB, this manuscript reports on the conjugation of two PiB derivative Gd3+ complexes – Gd(L2) and Gd(L3) – to multi-walled f-CNTs (f-MWNTs) and assessment of their in vivo biodistribution and brain uptake. It is shown that Gd(L2) and Gd(L3) can be efficiently loaded onto different f-MWNTs, with significant improvement in brain accumulation of the conjugates compared to the free metal complexes.Overall, this study demonstrates that f-MWNTs have potential to be used as carriers in theranostic applications involving brain delivery of BBB impermeable compounds

International audience; Idiopathic pulmonary fibrosis is a progressive, devastating, and yet untreatable fibrotic disease of unknown origin. Interleukin-33 (IL-33), an IL-1 family member acts as an alarmin with pro-inflammatory properties when released after stress or cell death. Here, we investigated the role of IL-33 in the bleomycin (BLM)-induced inflammation and fibrosis model using mice IL-33 receptor [chain suppression of tumorigenicity 2 (ST2)] mice compared with C57BL/6 wild-type mice. Unexpectedly, 24 h post-BLM treatment ST2-deficient mice displayed augmented inflammatory cell recruitment, in particular by neutrophils, together with enhanced levels of chemokines and remodeling factors in the bronchoalveolar space and/or the lungs. At 11 days, lung remodeling and fibrosis were decreased with reduced M2 macrophages in the lung associated with M2-like cytokine profile in ST2-deficient mice, while lung cellular inflammation was decreased but with fluid retention (edema) increased. In vivo magnetic resonance imaging (MRI) analysis demonstrates a rapid development of edema detectable at day 7, which was increased in the absence of ST2. Our results demonstrate that acute neutrophilic pulmonary inflammation leads to the development of an IL-33/ST2-dependent lung fibrosis associated with the production of M2-like polarization. In addition, non-invasive MRI revealed enhanced inflammation with lung edema during the development of pulmonary inflammation and fibrosis in absence of ST2.

The limits of life of aerobic microorganisms are well understood, but the responses of anaerobic microorganisms to individual and combined extreme stressors are less well known. Motivated by an interest in understanding the survivability of anaerobic microorganisms under Martian conditions, we investigated the responses of a new isolate, Yersinia intermedia MASE-LG-1 to individual and combined stresses associated with the Martian surface. This organism belongs to an adaptable and persistent genus of anaerobic microorganisms found in many environments worldwide. The effects of desiccation, low pressure, ionizing radiation, varying temperature, osmotic pressure, and oxidizing chemical compounds were investigated. The strain showed a high tolerance to desiccation, with a decline of survivability by four orders of magnitude during a storage time of 85 days. Exposure to X-rays resulted in dose-dependent inactivation for exposure up to 600 Gy while applied doses above 750 Gy led to complete inactivation. The effects of the combination of desiccation and irradiation were additive and the survivability was influenced by the order in which they were imposed. Ionizing irradiation and subsequent desiccation was more deleterious than vice versa. By contrast, the presence of perchlorates was not found to significantly affect the survival of the Yersinia strain after ionizing radiation. These data show that the organism has the capacity to survive and grow in physical and chemical stresses, imposed individually or in combination that are associated with Martian environment. Eventually it lost its viability showing that many of the most adaptable anaerobic organisms on Earth would be killed on Mars today., MASE is supported by European Community's Seventh Framework Program (FP7/2007-2013) under Grant Agreement no 607297.

International audience; The green microalgae Dunaliella genus is known for the production of high added value molecules. In this study, strain AL-1 was isolated from the Sebkha of Sidi El Hani (Sousse, Tunisia). This isolate was identified both morphologically and genetically via 18S rRNA gene sequence as a member of the genus Dunaliella. Strain AL-1 was found to be closely related to Dunaliella salina, Dunaliella quartolecta and Dunaliella polymorpha with more than 97% similarity. Response surface methodology was used to maximize carotenoid production by strain AL-1 by optimizing its growth conditions. The highest carotenoid content was obtained at salinity: 51, light intensity: 189.89 μmol photons·m−2·s−1, and nitrogen: 60 mg·L−1. Proteomic profiling, using two-dimensional gel electrophoresis, was performed from standard and optimized cultures. We detected 127 protein spots which were significantly differentially expressed between standard and optimized cultures. Among them 16 protein spots were identified with mass spectrometry and grouped into different functional categories using KEGG (Kyoto Encyclopedia of Genes and Genomes) such as photosynthetic Calvin cycle, regulation/defense, energy metabolism, glycolysis, and cellular processes. The current study could be of great interest in providing information on the effect of stressful conditions in microalgae carotenoid production.

International audience; A novel dual-imaging cisplatin-carrying molecular cargo capable of performing simultaneous optical and MR imaging is reported herein. This long-lasting MRI contrast agent (r1 relaxivity of 23.4 mM-1s-1 at 3T, 25 oC) is a photo-activated cisplatin prodrug (PtGdL) which enables real-time monitoring of anti-cancer efficacy. PtGdL is a model for monitoring the drug delivery and anti-cancer efficacy by MRI with a much longer retention time (24 hours) in several organs such as renal cortex and spleen than GdDOTA and its motif control GdL. Upon complete release of cisplatin, all PtGdL is converted to GdL enabling subsequent MRI analyses of therapy efficacy within its reasonably short clearance time of 4 hours. There is also responsive fluorescence enhancement for monitoring by photon-excitation.

International audience

International audience; In July 2009, a group of entomologists and ornithologists met at Notre-Dame-de-Londres, as a result of an international enquiry amongst entomologists on the catastrophic decline of insects all over Europe. On the basis of numerous observations in the field as well as overwhelming circumstantial evidence, they came to the hypothesis that the new generation of pesticides, the persistent, systemic, and neurotoxic neonicotinoids and fipronil, introduced in the early 1990s, is likely to be responsible at least in part for these declines. In response to the Appeal of Notre-Dame-de-Londres, the Task Force on Systemic Pesticides (TFSP), which conducted the Worldwide Integrated Assessment (WIA) of systemic pesticides, was established. In undertaking the WIA over the course of five years, the TFSP has examined over 1,100 scientific peer-reviewed papers published over the last two decades. This book contains the main findings of the WIA, which includes translations into Filipino and Spanish.

International audience; Genomic plasticity mediated by transposable elements can have a dramatic impact on genome integrity. To minimize its genotoxic effects, it is tightly regulated either by intrinsic mechanisms (linked to the element itself) or by host-mediated mechanisms. Using mass spectrometry, we show here for the first time that MOS1, the transposase driving the mobility of the mariner Mos1 element, is phosphorylated. We also show that the transposition activity of MOS1 is downregulated by protein kinase AMP cyclic-dependent phosphorylation at S170, which renders the transposase unable to promote Mos1 transposition. One step in the transposition cycle, the assembly of the paired-end complex, is specifically inhibited. At the cellular level, we provide evidence that phosphorylation at S170 prevents the active transport of the transposase into the nucleus. Our data suggest that protein kinase AMP cyclic-dependent phosphorylation may play a double role in the early stages of genome invasion by mariner elements.

We investigated the effects of betaine, C-phycocyanin (C-PC), and their combined use on the growth of A549 lung cancer bothin vitroandin vivo.When cells were coincubated with betaine and C-PC, an up to 60% decrease in viability was observed which is significant compared to betaine (50%) or C-PC treatment alone (no decrease). Combined treatment reduced the stimulation of NF-κB expression by TNF-αand increased the amount of the proapoptotic p38 MAPK. Interestingly, combined treatment induced a cell cycle arrest in G2/M phase for ~60% of cells.In vivostudies were performed in pathogen-free male nude rats injected with A549 cells in their right flank. Their daily food was supplemented with either betaine, C-PC, both, or neither. Compared to the control group, tumour weights and volumes were significantly reduced in either betaine- or C-PC-treated groups and no additional decrease was obtained with the combined treatment. This data indicates that C-PC and betaine alone may efficiently inhibit tumour growth in rats. The synergistic activity of betaine and C-PC on A549 cells growth observedin vitroremains to be further confirmedin vivo.The reason behind the nature of their interaction is yet to be sought.

International audience; Most of today’s scientific research relies on computers and software for processing scientific information. Examples of such computer-aided research are the analysis of experimental data or the simulation of phenomena based on theoretical models. With the rapid increase of computational power, scientific software has integrated more and more complex scientific knowledge in a black-box fashion. As a consequence, its users do not know, and do not even have a chance of finding out, which assumptions and approximations their computations are based on. This black-box nature of scientific software has made the verification of much computer-aided research close to impossible. The present work starts with an analysis of this situation from the point of view of human-computer interaction in scientific research. It identifies the key role of digital scientific notations at the human-computer interface, reviews the most popular ones in use today, and describes a proof-of-concept implementation of Leibniz, a language designed as a verifiable digital scientific notation for models formulated as mathematical equations.

International audience; This work intends to investigate samarium and holmium complexes with a set of H4dota-analogues bearing methylphosphonate/methylphosphinic acid pendant arms (H5do3ap, H5do3apPrA and H4do3apABn) as new bifunctional ligands for radiolanthanide targeted therapy. Radiolanthanide complexes of these ligands were prepared and evaluated and thermodynamic solution studies were also performed to get a better insight on the radiochemical results. The radiocomplexes were quantitatively prepared, are hydrophilic and negatively charged. They present a high in vitro and in vivo stability, a low plasma protein binding and a rapid clearance from the main organs with a high rate of whole body radioactivity excretion. Stability constants with Sm(III) and Ho(III) were determined by potentiometry and the values found are very high for all the ligands. Actually, they are similar to those of H4dota for the phosphinate analogues and even higher for the phosphonate ligand, being the constants similar to those with other lanthanide(III) ions. The effect of methylphosphorus acid pendant arms functionalization and the use of these ligands as bifunctional chelate agents are discussed. Copyright © 2009 John Wiley & Sons, Ltd.

Molecular compositions, nanoparticle compositions, and pharmaceutical compositions of the invention provide for the delivery of a polynucleotide to a hypoxic cell or tissue. The compositions can also be used for the delivery a hydrophobic pharmaceutical agent, either alone or in combination with a polynucleotide, to a hypoxic cell or tissue. Methods of making such compositions and methods of using such composition to treat a condition associated with a hypoxic cell or tissue are provided as well. Also provideded are kits for use in treating a condition associated with a hypoxic cell or tissue., Les compositions moléculaires, les compositions nano-particulaires et les compositions pharmaceutiques de l'invention permettent l'administration d'un polynucléotide en direction d'une cellule ou d'un tissu hypoxique. Ces compositions peuvent également être utilisées en vue de l'administration d'un agent pharmaceutique hydrophobe, soit seul, soit en combinaison avec un polynucléotide, en direction d'une cellule ou d'un tissu hypoxique. L'invention concerne également des procédés de fabrication desdites compositions et leurs procédés d'utilisation pour traiter une pathologie associée à une cellule ou à un tissu hypoxique. L'invention concerne encore des nécessaires utilisables dans le cadre du traitement d'une pathologie associée à une cellule ou à un tissu hypoxique.

Imidacloprid, a new systemic insecticide used as seed-dressing, has been widely used in France since 1994. Its application mode and its efficiency allow a significant reduction in comparison with the usual quantity of chemicals used during pulverising treatment. But the insecticide imidacloprid is suspected to have harmful effects on the pollinators as many bees have died since its introduction. Recent studies have shown that imidacloprid has chronic and sub-lethal toxicities at levels of μg/kg or less. It was therefore necessary to detect imidacloprid at these levels in soils, plants, flowers, and pollens. With this aim, we characterised the bio-availability of imidacloprid in the environment using a new quantitative analytical method, as a basis for the evaluation of the risk for bees., Un nouveau type d’insecticide systémique, l’imidaclopride, est largement utilisé depuis 1994 en enrobage de semences. En effet, son mode d’application et son efficacité ont permis de réduire de manière très significative les quantités habituellement utilisées par pulvérisation. Néanmoins, suite à de fortes dépopulations de ruchers, l’insecticide imidaclopride est suspecté d’avoir des effets délétères sur les insectes pollinisateurs. De récentes études ont montré que cet insecticide présente une toxicité chronique et sublétale pour des doses de l’ordre de la partie par milliard (µg/kg), ou moins, puisqu’on on observe un taux de 50 % de mortalité chez l’abeille en dix jours pour une concentration de 0,1 µg/kg d’imidaclopride dans une nourriture contaminée. Il s’est donc avéré nécessaire de pouvoir détecter de telles quantités d’imidaclopride dans les sols, les plantes, les fleurs et les pollens. Par de nouvelles méthodes analytiques, nous avons mis en évidence la bio-disponibilité de l’imidaclopride dans l’environnement et permis d’appréhender les risques encourus par les abeilles.

International audience; Using autoregressive modeling of discrete signals, we investigate the influence of mass and size on the memory function of a tracer particle immersed in a Lennard-Jones liquid. We find that the memory function of the tracer particle scales with the inverse reduced mass of the simulated system. Increasing the particle's mass leads rapidly to a slow exponential decay of the velocity autocorrelation function, whereas the memory function changes just its amplitude. This effect is the more pronounced the smaller and the heavier the tracer particle is. (C) 2003 American Institute of Physics.

International audience; The formamidopyrimidine-DNA glycosylase (Fpg, MutM) is a bifunctional base excision repair enzyme (DNA glycosylase/AP lyase) that removes a wide range of oxidized purines, such as 8-oxoguanine and imidazole ring-opened purines, from oxidatively damaged DNA. The structure of a non-covalent complex between the Lactoccocus lactis Fpg and a 1,3-propanediol (Pr) abasic site analogue-containing DNA has been solved. Through an asymmetric interaction along the damaged strand and the intercalation of the triad (M75/R109/F111), Fpg pushes out the Pr site from the DNA double helix, recognizing the cytosine opposite the lesion and inducing a 60 degrees bend of the DNA. The specific recognition of this cytosine provides some structural basis for understanding the divergence between Fpg and its structural homologue endo nuclease VIII towards their substrate specificities. In addition, the modelling of the 8-oxoguanine residue allows us to define an enzyme pocket that may accommodate the extrahelical oxidized base.

International audience; For protein-DNA complex crystallization, the choice of the DNA fragment is crucial. With the aim of crystallizing the 31 kDa Fpg DNA-repair enzyme bound to DNA, oligonucleotide duplexes varying in length, sequence, end type and nature of the specific DNA target site were used. Crystals of several protein-DNA combinations grew from solutions containing both polyethylene glycol and salt. This systematic crystallization screening followed by optimization of the crystallization conditions by microseeding led to crystals of Fpg bound to a 13 base-pair duplex DNA carrying the 1,3-propanediol abasic site analogue which are suitable for crystallographic analysis. Complete native data sets have been collected to 2.1 A resolution.

Provided is a co-polymer of formula A-B-C or a pharmaceutically acceptable salt thereof, where A comprises a water soluble polymer; B comprises a matrix metalloprotease (MMP)-cleavable polypeptide; C is a chemotherapeutic drug or a derivative thereof; and A is connected to B at a first end through a first covalent bond or a first linking moiety and B is connected to C at a second end through a second covalent bond or a second linking moiety, where the co-polymer is not cross-linked., Cette invention concerne un copolymère de formule A-B-C ou un sel pharmaceutiquement acceptable de celui-ci, où A représente un polymère hydrosoluble ; B représente un polypeptide clivable par une métalloprotéase matricielle (MMP) ; C est un médicament chimiothérapique ou un dérivé de celui-ci ; et A est lié à B à une première extrémité par une première liaison covalente ou un premier fragment de liaison et B est lié à C à une seconde extrémité par une seconde liaison covalente ou un second fragment de liaison, le copolymère n'étant pas réticulé.

The present invention relates to particles, useful for drug release detection, comprising: at least one luminescent metal complex of formula [Ln].[L], wherein: Ln is a lanthanide ion, L is an organic ligand comprising a hydrophilic unit with at least 6 chelating groups chosen from the group consisting of hydroxyl, carboxyl, optionally in the carboxylate form, carbonyl, ether, phosphonate, phosphinate, thiolate, amino and imino functions, and - at least one drug comprising a conjugated aromatic system, wherein said drug is not covalently bonded to the metal complex, said particle having a size comprised from 3 nm to 2 000 nm, and wherein the distribution of the metal complex and the drug within the particle is such that the mean distance between a drug molecule and a metal complex is less than 15 nm., L'invention concerne des particules utilisées pour détecter la libération d'un médicament et comprenant au moins un complexe métallique luminescent de formule [Ln].[L], où: Ln est un ion lanthanide, L un ligand organique comprenant une unité hydrophile contenant au moins 6 groupes de chélation choisis dans le groupe comprenant l'hydroxyle, le carboxyle, éventuellement sous forme de carboxylate, le carbonyle, l'éther, le phosphonate, le phosphinate, le thiolate, les fonctions amine et imine, et - au moins un médicament comprenant un système aromatique conjugué, ledit médicament n'étant pas lié par covalence au complexe métallique, ladite particule ayant une dimension comprise entre 3 nm et 2 000 nm, la répartition du complexe métallique et du médicament au sein des particules étant telle que la distance moyenne séparant une molécule de médicament et un complexe métallique soit inférieure à 15 nm.

International audience; Radiation damage in DNA is caused mainly by hydroxyl radicals which are generated by ionizing radiation in water and removing hydrogen atoms from the DNA chain. This damage affects certain nucleotide sequences more than others due to differences in the local structure of the DNA chains. This sequence dependence has been analyzed experimentally and calculated theoretically for a rigid DNA model. In this paper we take into account the flexibility of the DNA chain and show how it modifies the strand breakage probabilities. We use a simple harmonic model for DNA flexibility which permits the study of a long (68 base pair) fragment with modest computational effort. The essential influence of flexibility is an increased breakage probability towards the ends of the fragment, which can also be identified in the experimental data.

International audience; The equilibrium behaviour of the bovine phosphatidylethanolamine-binding protein (PEBP) has been studied under various conditions of pH, temperature and urea concentration. Far-UV and near-UV CD, fluorescence and Fourier transform infrared spectroscopies indicate that, in its native state, PEBP is mainly composed of beta-sheets, with Trp residues mostly localized in a hydrophobic environment; these results suggest that the conformation of PEBP in solution is similar to the three-dimensional structure determined by X-ray crystallography. The pH-induced conformational changes show a transition midpoint at pH 3.0, implying nine protons in the transition. At neutral pH, the thermal denaturation is irreversible due to protein precipitation, whereas at acidic pH values the protein exhibits a reversible denaturation. The thermal denaturation curves, as monitored by CD, fluorescence and differential scanning calorimetry, support a two-state model for the equilibrium and display coincident values with a melting temperature Tm = 54 degrees C, an enthalpy change DeltaH = 119 kcal.mol-1 and a free energy change DeltaG(H2O, 25 degrees C) = 5 kcal.mol-1. The urea-induced unfolding profiles of PEBP show a midpoint of the two-state unfolding transition at 4.8 M denaturant, and the stability of PEBP is 4.5 kcal.mol-1 at 25 degrees C. Moreover, the surface active properties indicate that PEBP is essentially a hydrophilic protein which progressively unfolds at the air/water interface over the course of time. Together, these results suggest that PEBP is well-structured in solution but that its conformation is weakly stable and sensitive to hydrophobic conditions: the PEBP structure seems to be flexible and adaptable to its environment.

International audience; Automated magnetic resonance imaging (MRI) texture analysis was compared with visual MRI analysis for the diagnosis of skeletal muscle dystrophy in 14 healthy and 17 diseased subjects. MRI texture analysis was performed on 8 muscle regions of interest (ROI) using four statistical methods (histogram, co-occurrence matrix, gradient matrix, runlength matrix) and one structural (mathematical morphology) method. Nine senior radiologists assessed full leg transverse slice images and proposed a diagnosis. The 59 extracted texture parameters for each ROI were statistically analyzed by Correspondence Factorial Analysis. Non-parametric tests were used to compare diagnoses based on automated texture analysis and visual analysis. Texture analysis methods discriminated between healthy volunteers and patients with a sensitivity of 70%, and a specificity of 86%. Comparison with visual analysis of MR images suggests that texture analysis can provide useful information contributing to the diagnosis of skeletal muscle disease.

International audience; The DNA duplex d(CTCTCG*AGTCTC)d(GAGACTC*GAGAG) containing a single trans-diammine-dichloroplatinum(ll) interstrand cross-link (where G* and C* represent the platinated bases) has been studied by two-dimensional NMR, All the exchangeable and non-exchangeable proton resonance lines were assigned (except H5'/H5 ") and the NOE intensities were transformed into distances via the RELAZ program. By combining the NOESY and COSY data (330 constraints) and NMR-constrained molecular mechanics using JUMNA, a solution structure of the cross-linked duplex has been determined. The duplex is distorted over two base pairs on each side of the interstrand cross-link and exhibits a slight bending of its axis (similar to 20 degrees) towards the minor groove. The platinated guanine G* adopts a syn conformation, The rotation results in a Hoogsteen-type pairing between the complementary G(6)* and C-19* residues which is mediated by the platinum moiety and is stabilized by a hydrogen bond between O6(G(6)*) and N4H(C-19*). The rise between the cross-linked residues and the adjacent residues is increased owing to the interaction between these adjacent residues and the ammine groups of the platinum moiety, These results are discussed in relation to the slow rate of closure of the monofunctional adducts into interstrand cross-links.

International audience; Little information is available correlating the structural properties of peptides with their immunogenicity in terms of responses via cytotoxic T lymphocytes (CTLs). The TT-NP6 chimeric peptide, consisting of two copies of a promiscuous T-helper epitope (T: residues 288-302 from the fusion protein of the measles virus) linked to the NP6 T-cytotoxic epitope (NP6: residues 52-60 from the nucleoprotein of measles virus) was able to induce virus-specific CTL responses in the absence of any adjuvant and hydrophobic component. The present work was undertaken to gain insight into structural features of the TT-NP6 peptide that may be important in optimizing the CTL immunogenicity of the peptide. Circular dichroism data, obtained in a buffer of physiological ionic strength and pH, strongly suggest a self-associated state for the peptide, which was confirmed by a sedimentation velocity experiment. However, helix association is accompanied by loss of overall helical content. Thermal-dependence studies show that the unfolding of self-associated alpha-helices is significantly more pronounced than the unfolding of isolated alpha-helices. Circular dichroism data, together with tryptic limited proteolysis, suggest the presence of a charged amino acid within the hydrophobic core. This study should provide a basis for engineering more effective immunogenic peptides against the measles virus by increasing the stability of the TT-NP6 peptide.

Background: The periplasmic protein TolB from Escherichia coli is part of the Tol–PAL (peptidoglycan-associated lipoprotein) multiprotein complex used by group A colicins to penetrate and kill cells. TolB homologues are found in many Gram-negative bacteria and the Tol–PAL system is thought to play a role in bacterial envelope integrity. TolB is required for lethal infection by Salmonella typhimurium in mice. Results: The crystal structure of the selenomethionine-substituted TolB protein from E. coli was solved using multiwavelength anomalous dispersion methods and refined to 1.95 A. TolB has a two-domain structure. The N-terminal domain consists of two α helices, a five-stranded β -sheet floor and a long loop at the back of this floor. The C-terminal domain is a six-bladed β propeller. The small, possibly mobile, contact area (430 A 2 ) between the two domains involves residues from the two helices and the first and sixth blades of the β propeller. All available genomic sequences were used to identify new TolB homologues in Gram-negative bacteria. The TolB structure was then interpreted using the observed conservation pattern. Conclusions: The TolB β -propeller C-terminal domain exhibits sequence similarities to numerous members of the prolyl oligopeptidase family and, to a lesser extent, to class B metallo- β -lactamases. The α / β N-terminal domain shares a structural similarity with the C-terminal domain of transfer RNA ligases. We suggest that the TolB protein might be part of a multiprotein complex involved in the recycling of peptidoglycan or in its covalent linking with lipoproteins.

Based on the previous observation that RANTES mediates the cytotoxic activity of human HIV-specific CD8+ T cells via the chemokine receptor CCR3, we studied the effect of this chemokine on different effector CD8+ cytolytic cells requiring Fas/Fas ligand (FasL) or perforin-dependent pathway. In CTLs derived from PBMCs of HIV-infected patients, both the spontaneous and the RANTES-induced cytotoxicity were inhibited by anti-FasL neutralizing Abs. In contrast, allogeneic CTLs or NK cells killing through perforin were not affected by RANTES and anti-FasL Ab. Accordingly, RANTES enhanced the expression of FasL in a concentration- and time-dependent manner in HIV-specific CTLs, whereas anti-RANTES Ab decreased markedly FasL expression. Finally, cell surface expression of FasL protein in HIV-specific CTLs was also up-regulated by eotaxin, a selective ligand for CCR3. Our observations show that the action of RANTES via CCR3 is necessary to regulate FasL expression on HIV-specific CD8+ T cells that kill through the Fas/FasL pathway.

International audience; Glycofection (transfection by using sugar-substituted polylysine) was assessed in order to provide an alternative to viral vectors for the transfer of genes into vascular smooth muscle cells. A rabbit vascular smooth muscle cell line (Rb-1 cells) was selectively transfected by using glycoplexes (glycosylated polylysine/pSV2LUC complexes) in the presence of 10 mu M of the fusogenic peptide GALA. A sugar-specific transfection was obtained when the glycofection was conducted for 1 h with glycoplexes containing either alpha Gal, alpha -Glc, alpha -GalNAc, beta -GlcNAc, or beta -GalNAc residues. The gene expression was high after transfection, with glycoplexes bearing alpha Gal, alpha -GalNAc, or beta -GalNAc residues that were weakly internalized, and low with glycoplexes carrying Lact or Rha residues that were well taken up by cells. These results suggest that 1) glycofection can be a good approach for a selective transfer of genes intovascular smooth muscle cells, 2) an efficient uptake of the glycoplexes is not the unique limiting step for an efficient transfection, and 3) the sugar-dependent trafficking of the glycoplexes inside the cells may account for the transfection efficiency.

International audience; Thanatin is the first inducible insect peptide that has been found to have, at physiological concentrations, a broad range of activity against bacteria and fungi. Thanatin contains 21 amino acids including two cysteine residues that form a disulfide bridge. Two-dimensional (2D) 1H-NMR spectroscopy and molecular modelling have been used to determine its three-dimensional (3D) structure in water. Thanatin adopts a well-defined anti-parallel beta-sheet structure from residue 8 to the C-terminus, including the disulfide bridge. In spite of the presence of two proline residues, there is a large degree of structural variability in the N-terminal segment. The structure of thanatin is quite different from the known structures of other insect defence peptides, such as antibacterial defensin and antifungal drosomycin. It has more similarities with the structures of various peptides from different origins, such as brevinins, protegrins and tachyplesins, which have a two-stranded beta-sheet stabilized by one or two disulfide bridges. Combined with activity test experiments on several truncated isoforms of thanatin, carried out by Fehlbaum et al. [Fehlbaum, P., Bulet, P., Chernysh, S., Briand, J. P., Roussel, J. P., Letellier, L., Hétru, C. & Hoffmann, J. (1996) Proc. Natl Acad. Sci. USA 93, 1221-1225], our structural study evidences the importance of the beta-sheet structure and also suggests that anti-Gram-negative activity involves a site formed by the Arg20 side-chain embedded in a hydrophobic cluster.

International audience; Lectins are present on the surface of many cells. Many lectins actively recycle from membrane to endosomes and efficiently take up glycoconjugates in a sugar-dependent manner. On this basis, glycoconjugates, specially those obtained by chemical means, are good candidates as carriers of drugs, oligonucleotides or genes. In this paper, we present a panel of methods suitable to transform unprotected reducing oligosaccharides into glycosynthons designed to be easily linked to therapeutic agents. All the glycosynthons presented here are glycosylamines or derivatives, mainly glyco-amino acids or glycopeptides. Glycosylamines are easy to obtain, but they are very labile in slightly acidic or neutral medium; they must be stabilized, by acylation for instance. The coupling efficiency of a reducing sugar with ammonia as well as an alkylamine or an arylamine is higher at high temperature, however, because of the Amadori rearrangement, special conditions have to be selected to prepare the expected glycosylamine derivative with a high yield. Glycosylamines are easily acylated by N-protected amino acids, or by halogeno acids which can then be transformed into amino acids. Alternatively, unprotected reducing oligosaccharides may very efficiently be transformed into N-glycosyl-amino acids and then protected by N-acylation. With a glutamyl derivative having both the alpha-amino and the gamma-carboxylic groups free, the coupling and the acylation, which is intramolecular, are roughly quantitative. N-oligosaccharyl-amino acid derivatives are interesting glycosynthons, because their sugar moiety bears the specificity towards membrane lectins while the amino acid part has the capacity to easily substitute a therapeutic agent.

International audience

International audience; Dimerization models of c-erbB2 transmembrane domains (Leu651-Ile675) are studied by molecular mechanics and molecular dynamics simulations. Both wild and Glu mutated transmembrane helices exhibit the same relative orientation for favorable associations and dimerize preferentially in left-handed coiled-coil structures. The mutation point 659 belongs to the interfacing residues, and in the transforming domain, symmetric hydrogen bonds between Glu carboxylic groups stabilize the dimeric structure. The same helix packing found for the wild dimers, except side-chain-side-chain hydrogen bonds, suggests that the transmembrane domains dimerize according to similar process. Structural and energetical characterization of the models are presented.

International audience; Colicins use two envelope multiprotein systems to reach their cellular target in susceptible cells of Escherichia coli: the Tol system for group A colicins and the TonB system for group B colicins. The N-terminal domain of colicins is involved in the translocation step. To determine whether it interacts in vivo with proteins of the translocation system, constructs were designed to produce and export to the cell periplasm the N-terminal domains of colicin E3 (group A) and colicin B (group B). Producing cells became specifically tolerant to entire extracellular colicins of the same group. The periplasmic N-terminal domains therefore compete with entire colicins for proteins of the translocation system and thus interact in situ with these proteins on the inner side of the outer membrane. In vivo cross-linking and co-immunoprecipitation experiments in cells producing the colicin E3 N-terminal domain demonstrated the existence of a 120 kDa complex containing the colicin domain and TolB. After in vitro cross-linking experiments with these two purified proteins, a 120 kDa complex was also obtained. This suggests that the complex obtained in vivo contains exclusively TolB and the colicin E3 domain. The N-terminal domain of a translocation-defective colicin E3 mutant was found to no longer interact with TolB. Hence, this interaction must play an important role in colicin E3 translocation.

International audience; AIMS:Heme oxygenase-1 (HO-1, HMOX1) can prevent tumor initiation; while in various tumors, it has been demonstrated to promote growth, angiogenesis, and metastasis. Here, we investigated whether HMOX1 can modulate microRNAs (miRNAs) and regulate human non-small cell lung carcinoma (NSCLC) development.RESULTS:Stable HMOX1 overexpression in NSCLC NCI-H292 cells up-regulated tumor-suppressive miRNAs, whereas it significantly diminished the expression of oncomirs and angiomirs. The most potently down-regulated was miR-378. HMOX1 also up-regulated p53, down-regulated angiopoietin-1 (Ang-1) and mucin-5AC (MUC5AC), reduced proliferation, migration, and diminished angiogenic potential. Carbon monoxide was a mediator of HMOX1 effects on proliferation, migration, and miR-378 expression. In contrast, stable miR-378 overexpression decreased HMOX1 and p53; while enhanced expression of MUC5AC, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and Ang-1, and consequently increased proliferation, migration, and stimulation of endothelial cells. Adenoviral delivery of HMOX1 reversed miR-378 effect on the proliferation and migration of cancer cells. In vivo, HMOX1 overexpressing tumors were smaller, less vascularized and oxygenated, and less metastatic. Overexpression of miR-378 exerted opposite effects. Accordingly, in patients with NSCLC, HMOX1 expression was lower in metastases to lymph nodes than in primary tumors.INNOVATION AND CONCLUSION:In vitro and in vivo data indicate that the interplay between HMOX1 and miR-378 significantly modulates NSCLC progression and angiogenesis, suggesting miR-378 as a new therapeutic target. REBOUND TRACK: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16, 293-296, 2012) with the following serving as open reviewers: James F. George, Mahin D. Maines, Justin C. Mason, and Yasufumi Sato.

International audience; Diethylenetriaminepentaacetic acid (DTPA)–bisamide derivatives functionalized with p‐toluidine, 6‐aminocoumarin, 1‐naphthalene methylamine and 4‐ethynylaniline were synthesized and fully characterized by mass spectrometry, NMR spectroscopy, FTIR spectroscopy and elemental analysis. LnIII complexes (Ln = Gd, Eu, Tb, Y) of the ligands DTPA–bis‐p‐toluidineamide (DTPA–BTolA), DTPA–bis‐6‐coumarinamide (DTPA–BCoumA), DTPA–bis‐1‐naphthylmethylamide (DTPA–BNaphA) and DTPA–bis‐4‐ethynylphenylamide (DTPA–BEthA) were prepared and studied for their bimodal magnetic resonance imaging/optical properties. EuIII and TbIII derivatives in aqueous solutions exhibit characteristic red and green emission, respectively, with quantum yields of 0.73 % for EuIII–DTPA–BNaphA and 2.5 % for TbIII–DTPA–BEthA. Ligand‐centred photophysical properties of the GdIII complexes were investigated to gain insight into energy‐transfer processes that take place in these systems. The GdIII complexes were also analyzed by nuclear magnetic relaxation dispersion (NMRD) techniques. The relaxivity (r1) at 20 MHz and 310 K equals 4.1 s–1 mM–1 for Gd–DTPA–BTolA, 5.1 s–1 mM–1 for Gd–DTPA–BCoumA, 6.4 s–1 mM–1 for Gd–DTPA–BNaphA and 5.7 s–1 mM–1 for Gd–DTPA–BEthA. These values are higher than the value of 3.8 s–1 mM–1 for Gd–DTPA (Magnevist). The improved relaxivity is due to the increase in the rotational tumbling time τR with a factor of 1.6 for Gd–DTPA–BTolA, 2.1 for Gd–DTPA–BCoumA, 3.1 for Gd–DTPA–BNaphA and 6.5 for Gd–DTPA–BEthA. In a 4 % human serum albumin solution, the apparent relaxivity at 20 MHz increases to values of 13.9 and 19.1 s–1 mM–1 for Gd–DTPA–BNaphA and Gd–DTPA–BEthA, respectively. All these features assist the search for optimal bimodal optical and magnetic resonance imaging probes.

International audience; Among endothelial cells (ECs), subpopulations are mainly distinguished in terms of maturation, tissue specialization and functions. Heterogeneity is an important characteristic of endothelial cells responsible for organ-specific cell and molecule delivery. Endothelial cell heterogeneity is a key to embryonic development as well as cell recruitment in adult organism during the immune response; it determines also the pathologic spreading of diseases, such as cancer invasion and infectious disease progression among species. Heterogeneity is also a feature of intra-organ specialization of endothelial cells. ECs are highly reactive to the microenvironment and their condition reflects healthy vs. diseased states. They respond to tissue hypoxia which brings a new parameter to endothelial heterogeneity. Hypoxia changes the phenotype and biology of ECs by turning on angiogenesis to restore physioxia. Highly responsive to hypoxia are the endothelial precursor cells (EPCs) and the selected cancer stem cell (CSC) populations, the most aggressive dedifferentiated tumor cells. They cooperate with one another and contribute to the vascular mimicry process of angiogenesis. This has a most effective impact on tumor cells escape and spreading.

This chapter provides a conceptual overview of basic multicomponent self‐assembly principles and related problems of helicates. It explains the physico‐chemical concepts of fundamental processes dealing with the formation of metal‐ligand bonds and their supramolecular counterparts for mononuclear coordination compounds. These principles are then transposed to supramolecular helicates, highlighting the specific features accompanying this extension, especially the consideration of intramolecular interactions. Then, the chapter focuses on the description and assessment of cooperative interactions that play an important role in the stabilization of self‐assembled edifices. Kinetic factors are discussed in relation to the self‐assembly mechanisms of dinuclear helicates. The chapter also presents an overview of tools for assessing cooperativity in helicates. It describes the development and applications of thermodynamic modelling in detail. Finally, the chapter provides qualitative discussion on possible secondary interactions that control the structure of metallohelicates (helical conformational folding). Tutorial examples of helical assemblies are given across the whole chapter.

International audience

International audience; We have used chemical probes and UV light to perform a high resolution mapping of an Escherichia coli transcription elongation complex that was arrested in vivo by a protein readblock at a position distal to the promoter. The in situ probing data provide a precise picture of a constrained ternary complex in which the front edge of the polymerase is located at