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De la révolution photonique Ou comment l’optique non-linéaire crée de nouvelles approches en imagerie cellulaire et tissulaire

Didier Marguet and Thierry Galli

Les cellules souches embryonnaires humaines au secours des hépatites fulminantes

Yves-Edouard Herpe, Michelle Hadchouel, Anne Weber, Jean-Paul Thiéry and Yacine Laâbi

Une bactérie au pays des biopuces : étude du transcriptome de Salmonella dans des macrophages infectés

Sébastien P. Faucher, Steffen Porwollik, Charles M. Dozois, Michael McClelland and France Daigle

Immunothérapie anti-cancer sans dommages collatéraux

Marie-Christine Meunier, Jean-Sébastien Delisle, Chantal Baron and Claude Perreault

Des Casques Bleus chez les plantes : un microARN, miR164, stabilise les frontières dans le méristème

Alexis Peaucelle and Patrick Laufs

Un nouveau concept explicatif de la pharmaco-dépendance : le découplage des neurones sérotoninergiques et noradrénergiques

Jean-Pol Tassin, Christophe Lanteri and Lucas Salomon

Dissection fonctionnelle d’un nouveau régulateur de l’initiation de la réplication du chromosome bactérien

Marie-Françoise Noirot-Gros

Aide-toi et le ciel t’aidera ! De l’importance du rayonnement thermique chez l’oiseau en vol migratoire

Jacques Larochelle and Jérôme Léger

NEDD1 et les complexes de nucléation des microtubules : recruter pour mieux organiser

Laurence Haren Ingrid Bazin and Marie-Hélène Rémy

Le chien et son génome

Francis Galibert and Catherine André

Un neuropeptide à l’origine du vieillissement testiculaire ?

Arnaud Lacombe, Vincent Lelièvre, Charles E. Roselli, Wael Salameh, Yan-He Lue, Gregory Lawson, Jean-Marc Muller, James A. Waschek and Éric Vilain

Des senseurs pour contrôler le style de vie bactérien : le choix entre infection chronique ou aiguë

Alain Filloux and Isabelle Ventre

La modélisation comme outil d’analyse pour la biologie du développement

Christophe Godin, Jan Traas, Isabelle Bohn-Courseau and Pierre Barbier de Reuille

La diversité des interactions plantes-pollinisateurs : un pré-requis indispensable à la stabilité des écosystèmes

Colin Fontaine, Jacques Meriguet, Michel Loreau and Isabelle Dajoz

Nouvelle approche des fibroses par microscopie multiphotonique avec génération de second harmonique

Monica Hernest, Ana-Maria Pena, Mathias Strupler, Emmanuel Beaurepaire, Jean-Louis Martin, Marie-Claire Schanne-Klein and Pierre-Louis Tharaux

Les cellules souches de la moelle osseuse au secours de la maladie d’Alzheimer

Alain R. Simard and Serge Rivest

Propriétés inattendues de l’échangeur anionique du globule rouge : la leçon des poissons

Hélène Guizouarn, Sonia Martial and Franck Borgese

Connexines, rénine et hypertension

Jacques-Antoine Haefliger and Paolo Meda

La fée Nanog ou le retour dans les limbes

Laure Coulombel

Brèves

Jean-Claude Ameisen, Raymond Ardaillou, Armand Bensussan, Christian Schmitt, Marie-Christine Bohler, Pascale Borensztein, Alexandre Bouron, Hervé Chneiweiss, Dominique Costagliola, Laure Coulombel, Alain Ehrenberg, Jacques Epelbaum, Évelyne Ferrary, Pascal Ferré, Gérard Friedlander, Thierry Galli, Hélène Gilgenkrantz, Simone Gilgenkrantz, Richard Hamelin, Stéphane Hatem, Dominique Labie, Olivier Lortholary, Anne-Marie Moulin, Lucie Parent and José Sahel

Microscopie à deux photons pour l’imagerie cellulaire fonctionnelle : avantages et enjeux : ou Un photon c’est bien… mais deux c’est mieux !

Pascal Dufour, Suzie Dufour, Annie Castonguay, Nathalie McCarthy and Yves De Koninck
SummaryOne of the main challenges of modern biochemistry and cell biology is to be able to observe molecular dynamics in their functional context, i.e. in live cells in situ. Thus, being able to track ongoing molecular events with maximal spatial and temporal resolution (within subcellular compartments), while minimizing interference with tissue biology, is key to future developments for in situ imaging. The recent use of non-linear optics approaches in tissue microscopy, made possible in large part by the availability of femtosecond pulse lasers, has allowed major advances on this front that would not have been possible with conventional linear microscopy techniques. Of these approaches, the one that has generated most advances to date is two-photon laser scanning fluorescence microscopy. While this approach does not really provide improved resolution over linear microscopy in non absorbing media, it allows us to exploit a window of low absorbance in live tissue in the near infrared range. The end result is much improved tissue penetration, minimizing unwanted excitation outside the focal area, which yields an effective improvement in resolution and sensitivity. The optical system is also simplified and, more importantly, phototoxicity is reduced. These advantages are at the source of the success of two-photon microscopy for functional cellular imaging in situ. Yet, we still face further challenges, reaching the limits of resolution that conventional optics can offer. Here we review some recent advances in optics/photonics approaches that hold promises to improve our ability to probe the tissue in finer areas, at faster speed, and deeper into the tissue. These include super-resolution techniques, introduction of non paraxial optics in microscopy and use of amplified femtosecond lasers, yielding enhanced spatial and temporal resolution as well as tissue penetration.

Microscopies multi-harmoniques pour l’imagerie structurale de tissus intacts

Delphine Débarre, Ana-Maria Pena, Willy Supatto, Thierry Boulesteix, Mathias Strupler, Martin-Pierre Sauviat, Jean-Louis Martin, Marie-Claire Schanne-Klein and Emmanuel Beaurepaire
SummaryOne principal advantage of multiphoton excitation microscopy is that it preserves its three-dimensional micrometer resolution when imaging inside light-scattering samples. For that reason two-photon-excited fluorescence microscopy has become an invaluable tool for cellular imaging in intact tissue, with applications in many fields of physiology. This success has driven increasing interest in other forms of nonlinear microscopy that can provide additional information on cells and tissues, such as second- (SHG) and third- (THG) harmonic generation microscopies. In recent years, significant progress has been made in understanding the contrast mechanisms of these recent methodologies, and high-resolution imaging based on intrinsic sources of signal has been demonstrated in cells and tissues. Harmonic generation exhibits structural rather than chemical specificity and can be obtained from a variety of non-fluorescent samples. SHG is observed specifically in dense, non-centrosymmetric arrangements of polarizable molecules, such as collagen fibrils, myofilaments, and polarized microtubule bundles. SHG imaging is therefore emerging as a novel approach for studying processes such as the physiopathological remodelling of the collagen matrix and myofibrillogenesis in intact tissue. THG does not require a non-centrosymmetric system ; however no signal can be obtained from a homogeneous medium. THG imaging therefore provides maps of sub-micrometer heterogeneities (interfaces, inclusions) in unstained samples, and can be used as a general purpose structural imaging tool. Recent studies showed that this technique can be used to image embryo development in small organisms and to characterize the accumulation of large lipid bodies in specialized cells. SHG and THG microscopy both rely on femtosecond laser technology and are easily combined with two-photon microscopy.

Microscopie Raman stimulée (CARS) : principes et applications

Nadia Djaker, Didier Marguet and Hervé Rigneault
SummaryA new technique in microscopy is now available which permits to image specific molecular bonds of chemical species present in cells and tissues. The so called Coherent Anti-Stokes Raman Scattering (CARS) approach aims at maximazing the light matter interaction between two laser pulses and an intrinsic molecular vibrationnal level. This is possible through a non linear process which gives rise to a coherent radiation that is greatly enhanced when the frequency difference between the two laser pulses equals the Raman frequency of the aimed molecular bond. Similar to confocal microscopy, the technique permits to build an image of a molecular density within the sample but doesn’t require any labelling or staining since the contrast uses the intrinsic vibrationnal levels present in the sample. Images of lipides in membranes and tissues have been reported together with their spectral analysis. In the case of very congested media, it is also possible to use a non invasive labelling such as deuterium which shifts the molecular vibration of the C-H bond down to the C-D bond range which falls in a silent region of the cell and tissue vibrational spectra. Such an approach has been used to study lipid phase in artificial membranes. Although the technique is still under development, CARS has now reach a maturity which will permit to bring the technology at a commercial stage in the near futur. The last remaining bottleneck is the laser system which needs to be simplified but solutions are now under evaluation. When combined with others more conventionnel techniques, CARS should give its full potential in imaging unstained samples and like two photons techniques has the potential of performing deep tissues imaging.

L’OCT plein champ

Arnaud Dubois and Claude Boccara
SummaryOptical coherence tomography (OCT) is an emerging technique for imaging of biological media with micrometer-scale resolution, whose most significant impact concerns ophthalmology. Since its introduction in the early 1990’s, OCT has known a lot of improvements and sophistications. Full-field OCT is our original approach of OCT, based on white-light interference microscopy. Tomographic images are obtained by combination of interferometric images recorded in parallel by a detector array such as a CCD camera. Whereas conventional OCT produces B-mode (axially-oriented) images like ultrasound imaging, full-field OCT acquires tomographic images in the en face (transverse) orientation. Full-field OCT is an alternative method to conventional OCT to provide ultrahigh resolution images (~ 1 µm), using a simple halogen lamp instead of a complex laser-based source. Various studies have been carried, demonstrating the performances of this technology for three-dimensional imaging of ex vivo specimens. Full-field OCT can be used for non-invasive histological studies without sample preparation. In vivo imaging is still difficult because of the object motions. A lot of efforts are currently devoted to overcome this limitation. Ultra-fast full-field OCT was recently demonstrated with unprecedented image acquisition speed, but the detection sensitivity has still to be improved. Other research directions include the increase of the imaging penetration depth in highly scattering biological tissues such as skin, and the exploitation of new contrasts such as optical birefringence to provide additional information on the tissue morphology and composition.

Régulation de p16INK4a, sénescence et oncogenèse

Wei Wen Chien and Martine Ffrench
SummaryThe transcriptional regulation of p16INK4a is essential for cellular aging and oncogenic stress response. This regulation involves p16INK4a transcriptional activators such as proteins Ets1 and 2 or E47. The binding of these proteins to INK4a promoter can be inhibited by proteins Id-1 or -4 after heterodimer formation. The transcriptional inhibition of p16INK4a includes also the transcriptional repression by Bmi-1, and an epigenetic regulation which appears complex and remains incompletely understood. Actually, INK4a promoter and exon1 present a CpG island which can be methylated on cytosines by DNA methyltransferases. This DNA methylation is preceded by the lysine 9 histone H3 methylation and by the deacetylation of histone H4 both involved in gene silencing. Indeed, RNA Helicase A might protect INK4a against methylation of CpG island. Furthermore, chromatin remodelling involving SWI/SNF complex, antagonist to Bmi-1, might activate INK4a expression. The analysis of INK4a regulation mechanisms and the comprehension of the epigenetic modulation of its expression may allow us to develop a rational use of new anti-neoplastic agents.

La PI3-kinase : de la synapse immunologique au contrôle de la prolifération T

Stéphanie Fabre, Valérie Lang and Georges Bismuth
SummaryT cell clonal expansion contributing to host defense against pathogens is a tightly controlled process to maintain the homeostasis of the immune system. Our understanding of how T cell growth and proliferation are controlled following antigenic stimulation is therefore a major challenge. Antigen recognition occurs when a naive T lymphocyte contacts an antigen-presenting cell. A specialized junction enriched in T-cell receptors, costimulation molecules and signaling adaptors, called the immunological synapse, is then created for several hours between the two cell types. Recent discoveries now clarify the molecular mechanisms used by this organization to control T cell growth and proliferation. It has been established that the immunological synapse functions in fact as an integrative platform where class Ia phosphoinositide-3-kinases (PI3Ks) are recruited and activated to continuously produce high levels of 3’-phosphoinositides. These lipids regulate the localization and the activation of a wide range of PH-domain containing proteins, among which the serine-threonine kinase Akt, a downstream effector of PI3Ks, appears to be a key player. FoxO (Forkhead subgroup O) family members control in various cell systems genes implicated in apoptosis, stress resistance and cell cycle arrest, thereby contributing to maintain quiescence in unstimulated cells. In naïve T cells contacting antigen-presenting cells a rapid but also very prolonged nuclear exclusion of these transcription factors is observed downstream of Akt. Mainly, this compartmentalization process is mandatory to induce T cell growth triggered by the T cell/antigen-presenting cell interaction. These findings demonstrate that to initiate cell cycle progression the formation of the immunological synapse is an undemanding tactic used by primary T cells to securely maintain the 3’-phosphoinositide-dependent mitotic switch governed by the spatial control of FoxO transcription factors.

Tuberculose et VIH : drame de l’Afrique

Dominique Labie

Différences et similitudes des promotions industrielles et des promotions institutionnelles

Joël Ménard and Véronique Daurat
SummaryThe Délégation à la Recherche Clinique d’Ile-de-France et de l’Assistance Publique/Hôpitaux de Paris (AP-HP) has elaborated a pragmatic approach for the monitoring of institutionally sponsored clinical studies. The mandatory practices aiming at preventing enrolled volunteers from risks and results from fraud and poor quality have been reviewed and a four-stage graduate monitoring has been defined, which is applied since 2002. This system needs to be scientifically assessed and adapted to the permanent evolution of national and international regulations.

Cibles des médicaments antithrombotiques

Ludovic Drouet and Laurent Ripoll
SummaryNew antithrombotic agents are being developed not only to improve efficacy, but also to increase safety in comparison with widely used conventional agents such as the oral anticoagulants. New anticoagulant, antiplatelet, and profibrinolytic compounds are currently under study in drug development programs, and most of those in phase II or III of development are derived from the observation of natural phenomena and merely mimic processes developed by mammalians, including humans, to avoid thrombosis, or by blood-sucking insects or animals to prevent coagulation of the blood their are feeding on. By contrast, drug candidates identified by means of rigorous research and designed to target new pathways and achieve direct and specific inhibition of factors that are presumed to play an important role in thrombogenesis have generally failed to show any benefit and sometimes even induce deleterious effects. The clinical development of new drugs, even those mimicking natural phenomena, improves our knowledge of the pathogenesis of thrombosis and sheds light, retrospectively, on previous conceptual errors. The improvement in our basic knowledge and the development of new types of drugs suggest that, in contrast to the current antithrombotic compounds that are used in a broad range of clinical settings, use of new drugs should be restricted to specific situations in which their mechanisms of action are predicted to deliver the highest medical benefit. A major obstacle resides in the fact that current drug development programs are still required to comply with long obsolete guidelines based on the characteristics of first-generation antithrombotic agents, and that do not take into account the specific mechanisms of action of new drugs. This situation should change, however, and new antithrombotic drugs should soon be able to benefit from adapted development programs that will make it possible to determine their optimal risk-benefit ratio.