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Biogenesis of peptide signals - ER 3

Bioactive peptides (neuropeptides, hormones, immunomodulatory peptides, etc.) are involved in many physiological processes, including osteoporosis, cardiovascular diseases, obesity, cancers and Altzheimer’s disease. The research project of the team is designed to extend the known repertoire of signal peptides and cellular targets using: (1) Exploitation of the remarkable properties of the amphibian skin to secrete enormous quantities of neuropeptides, hormones, growth factors and antimicrobial peptides that are identical or very similar to those produced by the mammalian brain and intestine, (2) Characterization, in terms of peptide targets and enzymes, of the impact of still poorly documented post-translational modifications that broaden the information encoded in the gene sequence (i) the secondary proteolytic processing during which a mature bioactive peptide is cleaved to generate a second peptide with a different function; (ii) post-translational isomerisation of an amino acid within a mature bioactive peptide, which modifies its biological activity.

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Biochemistry, molecular biology, bioactive peptides, anti-microbial peptides, proteolytic processing enzymes, secondary proteolytic processing, post-translational isomerisation

Teams and research themes

Each newly discovered bioactive peptide adds to our knowledge of how these peptides are manufactured, how they are recognized by their intra- or extra-cellular targets, and their signals transduced under normal and pathological conditions. This body of information may be used to develop pharmacological tools, identify appropriate targets, or design biomarkers and medication when a malfunctioning peptide is associated with pathological processes. The use of peptides as therapeutic agents has long been limited by the cost of their production, their inability to cross physiological barriers and their rapid destruction by proteases. The expansion of techniques for bulk production by chemical synthesis or the synthesis of recombinant proteins, together with the advances in drug delivery techniques and structure-based drug design have stimulated renewed interest in the development of peptide medication. Several peptide drugs (natural molecules or derivatives of natural molecules) are presently on the market or in phase III clinical trials, e.g. calcitonin (osteoporosis), somatostatin analogues (endocrine tumors, acromegaly), hirudin (venous thrombosis) CGRP antagonists (migrains), insulin and glucagon (diabetes), GnRH analogues (prostate cancer, sterility) and antimicrobial peptide derivatives like protegrin (pneumonia) and indolicin (acne). However, we undoubtedly know very little about the immense variety of bioactive peptides produced by the living world. Peptidomics is still growing field of research, although not very well explored. Fewer than one hundred human bioactive peptides have been characterised, while 100–150 protein G receptors encoded by the human genome remain orphans. And blood plasma contains at least 5000 peptides, most of which has still to be identified. The detection, identification and purification of small-sized peptides produced in small quantities by most tissues, like the central nervous system (less than 0.1% of total protein content) is a barrier that is difficult to overcome. Thus, considerable advances in methodology and instrumentation will be required in order to unravel the secrets of the peptidomes. And sequencing genomes does not necessarily lead to the identification of these peptides, because of the small size of their open reading frames, the editing of some mRNAs, the tissue specificity of the cleavage of their precursor molecules and post-translational modifications that distort the reading of the genetic message. Peptides are a paramount example of how one single gene can release multiple functionalities.

The research project of ER3 is designed to extend the known repertoire of signal peptides and cellular targets using unconventional complementary approaches. The search for new biologically active peptides, together with their structural and functional characterization is in the center of the concerns of the team, but will not constitute the single object of study. Efforts will also be devoted to the characterization of the biosynthetic pathways of these peptides including the identification of the implied enzymes. The objective is to develop inhibitors when a functional disordered state is associated with pathogenic processes.

Identification and characterization of new bioactive peptides in the skin of amphibians

    The amphibian skin is a remarkable reservoir of bioactive peptides. Over 500.000 peptides – hormones, neuropeptides, growth factors, antimicrobial peptides are produced by the approximately 5000 species of anurans. These peptides are invariably identical or very similar to those produced by the brain and intestine of mammals (the concept of the skin-brain-intestine triangle). They are produced in enormous quantities (up to several hundred thousand times those produced by mammalian brain) and many of them have a much greater biological activity than their mammalian counterparts. The peptide-rich secretion of the skin of frogs and toads is thus a natural chemical library that may be readily exploited to discover new bioactive peptides and then to look for their mammalian orthologues by molecular cloning and computer-based analysis. The degree of polymorphism is remarkable - two closely related species of frogs have different repertoires of peptides, and each species may produce a series of 10–20 analogues of each generic peptide. Hence analysis of their structure-function relationships will lead to an understanding of the phenomenal diversity of these molecules and how they may be used to design or optimize new active agents. The projects aligned with this theme are designed to use the richness and diversity of the peptidome of the amphibian skin to discover new bioactive peptides.

Antimicrobial peptides: new structures, new mechanisms.

The need to discover new antibiotics to combat the growing number of pathogens that are resistant to one or more conventional antibiotics has led to the present interest in membranotropic antimicrobial peptides. We do not presently know enough about the relationship between the structure, mechanism of action and range of activities of these molecules for us to rationally optimize their antibiotic properties. Peptides with similar structures have, in certain cases, different target spectra, while peptides with quite different structures sometimes have overlapping target spectra. That is due to 2 facts: (1) a restricted sample of peptides that does not allow establishing rigorous structure-function relationships; (2) the activity of natural peptides is not an intrinsic property but depends on the nature of the membrane of the target micro-organisms. The researches that we perform aims at (1) increasing our level of knowledge of the structure/activity relationships by widening the available panel of antimicrobial peptides, (2) to understand the mode of action of these molecules since the initial step of recognition of the microbial target until the final stage of cellular death. The proposed approach will succeed because, in addition to the many cationic membranotropic peptides with amphipathic helices already identified, two new types of peptide with broad activity spectra have just been isolated from amphibian skin. One is dermaseptin S9, which has an alpha helix with a hydrophobic core and cationic ends; the others are plasticins, which are antimicrobial peptides with glycine zipper motifs GXXXG, which forms oligomers in aqueous solutions. Several biophysical approaches will be used to elucidate their mechanisms of action and to shed light on the exact roles of various parameters, such as charge, degree of helical structure, amphipathy and flexibility, on the ability of helical peptides to bind to and disrupt bacterial membranes.

Secondary proteolytic maturation: enzymes and target peptides

Limited proteolysis of polypeptide precursors is one of the main post-translational modifications that take place during intracellular transport or outside the cell. The position and number of progenitor sequences of bioactive peptides vary greatly. A single precursor may be cleaved to give different peptides, depending on the tissue specificity. Some bioactive peptides produced by an initial maturation may themselves be a precursor of a second peptide having a different action. Secondary proteolytic processing regulates not just the activity of a peptide, but may also be a source of structural and functional diversity. The nature and function of many bioactive peptides produced by this process in mammals remains to be determined. We need to identify these molecules and to determine how the enzymes involved in maturation act, and then design specific inhibitors. Analysis of the peptides in cell lines in the presence and absence of these inhibitors will enable us to identify the precursors of selected peptide targets.

Aminopeptidase B (Ap-B ; EC is ubiquitous in mammals and is also present in the secretions produced by amphibian skins. Ap-B is a bifunctional enzyme in vitro, it has an aminopeptidase activity that is specific for basic amino acids and also leucotriene A4 hydrolase (LTA4H) activity, that allows it to hydrolyse the epoxide function of leucotriene A4 to give leucotriene B4, a powerful lipid mediator of inflammation. Thus Ap-B may be implicated in the activation or breakdown of peptides or lipid messengers in processes like inflammation and proliferative disorders, or in type II diabetes. Ap-B acts in synergy with other exo- and endopeptidases in the secondary proteolytic processing of several neuropeptides and hormones (miniglucagon; CCK8) by a novel mechanism. The target peptide is cleaved by an endoprotease like NRD convertase or cathepsin L on the N-terminal side of single or pairs of basic amino acids; the basic residues are then removed by Ap-B. This process is different from the proteolytic maturation of the precursors of hormones and neuropeptides that involves the cleavage of proforms on the C-terminal side of a dibasic site (prohormone convertases, furine) followed by removal of basic residues by carboxypeptidase B.

This segment of the research project is designed to use several complementary approaches to extend the known panel of neuropeptide and hormone targets of Ap-B, together with all the specific physiological actions that remain to be identified.

• The 3D structure will be determined in presence or in absence of substrate analogues and directed mutagenesis will be used to identify the amino acids involved in substrate recognition and catalysis.

• The Ap-B from amphibian skin will be purified and its enzymatic nature characterized;  target peptides in the serous glands will also be identified.

Post-translational isomerisation: mechanisms and new targets

One novel post-translational modification that broadens the one-dimensional information encoded in the genetic sequence is the L-D isomerisation of an amino acid within a peptide chain. This isomerisation alters the 3D structure of target peptides and proteins, and thus their biological activity. Little is known about most of the peptides involved in this modification, mainly because these alterations are not detect by the methods usually used for structural analysis or in in silico studies. The list of peptide targets for isomerisation is thus probably far from exhaustive, particularly in mammals, where only two example of a D amino acid-containing peptides are known.

The laboratory has two powerful model systems that will be used to carry out this work. One is the crustacean peduncular endocrine system, in which a small number of cells produce two stereoisomers of neurohormones (e.g. CHH, an hyperglycemic hormone); and the other is the holocrine glands of amphibian skin, which elaborate enormous quantities of D amino acid opioid peptides (dermorphins and deltorphins).

Several complementary approaches will be used to (1) identify new target peptides and (2) understand more clearly the modalities and mechanisms involved. The first point requires the development of routine techniques for detecting D amino acids in a peptide chain. In particular classical methods of chiral analysis must be optimized to increase their sensitivity, which is presently too low for analyzing small quantities of peptide. Alternative methods, such as mass spectrometry are developed. The peptides identified in amphibians will be characterized [activities; structure (CD, FTIR, NMR)]. The information obtained will be compared with data on the CHH structure (with and without isomerization) that is in progress in the laboratory.

The combined application of biochemical and molecular biology approaches to study on these two model systems should enable us to characterize the L-D isomerase(s) and their range of expression and also to demonstrate more of the sequences of peptides and proteins containing D amino acids, particularly in mammals.


The outcomes of the entire project should significantly enrich the arsenal of bioactive peptides that could serve as a starting point for the development of new pharmacological tools or therapeutic agents. Potential candidates will be optimized (pharmacophore search; stiffening of skeletal and / or side chains, incorporation of synthons; stabilization by incorporation of pseudopeptide links ...) to generate more active and stable analogues.

Scientific advances, significant results

Our studies have enabled us to:

(1) characterize potent peptide antagonists from frog skin that selectively target CGRP (calcitonin gene-related peptide, a highly potent vasodilatory and cardiotonic endogenous peptide implied in several pathologies, like the cerebral vasospasm, angina, migraine, and Raynaud’s disease) receptors in the central and peripheral nervous systems of mammals [1-2];

(2) demonstrate that, in amphibians, the effect of TRH (Thyrotropin-releasing hormone) on alpha-MSH secretion is mediated in the intermediate lobe of the pituitary through the novel receptor subtype xTRHR3, which plays a major role in the neuroendocrine regulation of skin-colour adaptation [3];

(3) identify new alpha-helical antimicrobial peptides with a hydrophobic core and cationic termini whose sequence resemble that of channel-forming proteins, and microbicidal peptides with glycine-zipper motifs which form oligomeric pores in the membrane [4].

(4) carry out structural and ultrastructural studies on the architecture of the neuroendocrine system where isomerisation occurs, to elucidate the dynamics of this modification and to establish that this modification occurs in several peptides [5-7];

(5) reconstruct the evolution of the CHH family of hormones in the arthropods [8] and of the genes encoding the dermaseptin super family of proteins. These latter genes are highly conserved and have a hypervariable region that encode peptides whose nature, function and origin are most diverse (antimicrobial peptides, neuropeptides, and hormones) [9-10];

(6) characterize the crustacean ACE and show that there are several isoforms [11];

(7) demonstrate that Ap-B is involved in a new mechanism for maturing hormones and neuropeptides and identify its first physiological substrate in mammals, glucagon, which is transformed to miniglucagon by the synergistic actions of NRD convertase and Ap-B; these findings indicate that it may be involved in the physiology of glucose homeostasis [12];

(8) construct the molecular tools (prokaryote and eukaryote expression systems and 3D structural models) needed to study the structure and function of Ap-B and to design specific inhibitors for use in demonstrating the physiological substrates of the enzyme and identifying the disorders in which the enzyme or its substrates may be implicated [13];

(9) identify evolutionary divergence within the M1 family of metalloproteases to which Ap-B belongs [13].


1. Séon A., Pierre T.N., Redeker V., Lacombe C., Delfour A., Nicolas P. and Amiche M. Isolation, structure, synthesis and activity of a new member of calcitonin gene-related peptide from frog skin and molecular cloning of its precursor. J. Biol. Chem. 2000, 275, 5934-40.

2. Ladram A, Besné I, Breton L, de Lacharrière O, Nicolas P, Amiche M. Pharmacological study of C-terminal fragments of frog skin calcitonin gene-related peptide. Peptides 2008, 7, 1150-1156.

3. Bidaud I., Galas L., Bulant M., Jenks B.G., Ouwens D.T., Jegou S., Ladram A., Roubos E.W., Tonon M.C., Nicolas P. and Vaudry H. Distribution of the mRNAs encoding the thyrotropin-releasing hormone (TRH) precursor and three TRH receptors in the brain and pituitary of Xenopus laevis: effect of background color adaptation on TRH and TRH receptor gene expression. J. Comp. Neurol. 2000, 477, 11-28.

4. Nicolas P. and Amiche M. The dermaseptins. « Handbook of Biologically Active Peptides » 2006, chap. 45, pp 295-304 (Kastin A., ed., Acad. press).

5. Soyez D, Toullec JY, Ollivaux C, Géraud G. L- to D-amino-acid isomerization in a peptide hormone is a late post-translational event occurring in specialized neurosecretory cells. J. Biol. Chem. 2000, 275, 37870-5.

6. Ollivaux C, Soyez D. Dynamics of biosynthesis and release of crustacean hyperglycemic hormone isoforms in the X-organ-sinus gland complex of the crayfish Orconectes limosus. Eur J Biochem. 2000,  267, 5106-14.

7. Ollivaux C, Vinh J, Soyez D, Toullec J-Y. Crustacean Hyperglycaemic and Vitellogenesis Inhibiting Hormones in the lobster Homarus gammarus: implication for structural and functional evolution of a neuropeptide family. FEBS J. 2006, 273, 2151-60.

8. Montagné N, Soyez D, Gallois D, Ollivaux C, Toullec JY. New insights into evolution of crustacean hyperglycaemic hormone in decapods : first characterization in Anomura. FEBS J. 2008, 275, 1039-1052.

9. Amiche M., Séon A., Pierre T.N. and Nicolas P. The dermaseptin precursors: a protein family with a common preproregion and a variable C-terminal antimicrobial domain. FEBS Lett. 1999, 456, 352-6.
10. Vanhoye D, Bruston F, Nicolas P, Amiche M. Antimicrobial peptides from Hylid and Ranid frogs originated from a 150 my old ancestral precursor with a conserved signal peptide but a hypermutable antimicrobial domain. Eur J Biochem. 2003, 270: 2068-81. 

11. Kamech N, Simunic J, Franklin JS, Francis S, Tabitsika M, Soyez D. Evidence for an angiotensin-converting enzyme polymorphism in the crayfish Astacus leptodactylus. Peptides 2007, 28 (7), 1368-74.

12. Fontes G, Lajoix AD, Bergeron F, Cadel S, Prat A, Foulon T, Gross R, Dalle S, Le-Nguyen D, Tribillac F, Bataille D. Miniglucagon-generating endopeptidase, which processes glucagon into miniglucagon, is composed of NRD convertase and aminopeptidase B. Endocrinology 2005, 146, 702-712. 

13. Pham V-L, Cadel S, Gouzy-Darmon C, Hanquez C, Beinfeld MC, Nicolas P, Etchebest C, Foulon T. Aminopeptidase B, a glucagon-processing enzyme: site directed mutagenesis of the Zn2+-binding motif and molecular modelling. BMC Biochem. 2007, 31, 8-21.

Graduate Schools
Scientific partnerships

IFR 83 – Biologie Intégrative


  • Temporin-Sha analogs and uses. Introduced at the National Institute of Industrial Property (INPI) by the Cabinet Becker and Associates commissioned by the Sorbonne Université, March 19, 2009 (Sorbonne Université, IRD, CNRS). Abbassi FAmiche MLadram ANicolas P, Oury B, Sereno D.
  • Dermaseptin B2 as inhibitor of tumor growth. Introduced by the Cabinet Lavoix mandated by the CNRS, on 01/07/2009 under No. 09P0227 BFF (CNRS, Sorbonne Université, Paris 12). Delbé J, Amiche M, Courty J, Hamma Kourbali Y, Ladram A, Nicolas P, Van Zoggel H, Galanth C.
Main equipment

Production of recombinant proteins (baculovirus); purification of proteins and peptides (FPLC, HPLC) ; protein sequencing by Edman chemistry ; immunochemical characterization of proteins and peptides (ELISA) ; fluorescence microscopy ; optical spectroscopy (UV absorption - visible, fluorescence); isolated organs assays.

Main publications
  • Piesse C, Cadel S, Gouzy-Darmon C, Jeanny J-C, Carrière V, Goidin D, Jonet L, Gourdji D, Cohen P, Foulon T. Expression of ami-nopeptidase B in the developing and adult rat retina. Exp. Eye Res. 2004, 79, 639-648.
  • Foulon T, Cadel S, Piesse C and Cohen P. Aminopeptidase B. Handbook of Proteolytic Enzymes 2nd Ed., Londres, 2004, Ed. A.J. Barrett, N.D. Rawlings and J.F. Woesner, Academic Press, Chapter 90.
  • Toullec, J-Y, Serrano L, Lopez P, Soyez D,  Spanings-Pierrot C. The crustacean hyperglycemic hormones from an euryhaline crab Pa-chygrapsus marmoratus and a fresh water crab Potamon ibericum: eyestalk and pericardial isoforms. Peptides 2005, 27, 1269-1280.
  • Fontes G, Lajoix AD, Bergeron F, Cadel S, Prat A, Foulon T, Gross R, Dalle S, Le-Nguyen D, Tribillac F, Bataille D. Miniglucagon-generating endopeptidase, which processes glucagon into miniglucagon, is composed of NRD convertase and aminopeptidase B. Endocrinology 2005, 146, 702-712.
  • El Amri C, Lacombe C, Zimmerman K, Ladram A, Amiche M, Nicolas P, Bruston F. The plasticins: membrane adsorption, lipid di-sorders, and biological activity. Biochemistry 2006, 45, 14285-14297.
  • Soyez D. Cellular approach of the biogenesis of D-amino acid containing peptides in Eukaryotes: the crustacean model. in “D-Amino Acids: A New Frontier in Amino Acid and Protein Research – Practical methods and protocols.” H. Bruckner, A. D'Aniello, G. Fisher, N. Fujii, H. Homma and R. Konno, eds, Nova Science Publishers, Hauppauge, New York, USA. 2006, pp 431-440.
  • Lequin O, Ladram A, Chabbert L, Bruston F, Convert O, Vanhoye D, Chassaing G, Nicolas P, Amiche M. Dermaseptin S9, an alpha-helical antimicrobial peptide with a hydrophobic core and cationic termini. Biochemistry 2006, 45, 468-480.
  • Ollivaux C, Vinh J, Soyez D, Toullec J-Y. Crustacean Hyperglycaemic and Vitellogenesis Inhibiting Hormones in the lobster Homarus gammarus: implication for structural and functional evolution of a neuropeptide family. FEBS J. 2006, 273, 2151-2160.
  • Hwang S-R, O’Neill A, Bark S, Foulon T, Hook V. Secretory vesicle aminopeptidase B related to neuropeptide processing : molecular identification and subcellular localization to enkephalin- and NPY-containing chromaffin granules. J. Neurochem. 2007, 100, 1340-1350.
  • Kamech N, Simunic J, Franklin JS, Francis S, Tabitsika M, Soyez D. Evidence for an angiotensin-converting enzyme (ACE) polymorphism in the crayfish Astacus leptodactylus. Peptides 2007, 28, 1368-1374.
  • Pham VL, Cadel MS, Gouzy-Darmon C, Hanquez C, Beinfeld MC, Nicolas P, Etchebest C, Foulon T. Aminopeptidase B, a gluca-gon-processing enzyme: site directed mutagenesis of the Zn2+-binding motif and molecular modelling. BMC Biochem. 2007, 31, 8-21.
  • Abbassi F, Oury B, Blasco T, Sereno D, Bolbach G, Nicolas P, Hani K, Amiche A, Ladram A. Isolation, characterization and molecu-lar cloning of new temporins from the skin of the North African ranid Pelophylax saharica. Peptides 2008, 29, 1526-1533.
  • Montagné N, Soyez D, Gallois D, Ollivaux C, Toullec JY. New insights into evolution of crustacean hyperglycaemic hormone in decapods-first characterization in Anomura. FEBS J. 2008, 275, 1039-1052.
  • Amiche M, Ladram A, Nicolas P. A consistent nomenclature of antimicrobial peptides isolated from the subfamily Phyllomedusinae. Peptides 2008, Peptides, 11, 2074-2082.
  • Abbassi F, Galanth C, Amiche M, Saito K, Piesse C, Zargarian L, Hani K, Nicolas P, Lequin O, Ladram A (2008) Solution Structure and Model Membrane Interactions of Temporins-SH, Antimicrobial Peptides from Amphibian Skin. A NMR Spectroscopy and Diffe-rential Scanning Calorimetry Study. Biochemistry 2008, 47, 10513-10525.
  • Beinfeld MC, Funkelstein L, Foulon T,  Cadel S, Kitagawa K, Toneff T, Reinheckel T, Peters C, Hook V. Cathepsin L Plays a Major Role in Cholecystokinin Production in Mouse Brain Cortex and in Pituitary AtT-20 Cells:  Protease Gene Knockout and Inhibitor Studies. Peptides, 2009, 30, 1882-1891.
  • Sachon E, Clodic G, Galanth C, Amiche M, Olli­vaux C, Soyez D, Bolbach G. D-Amino Acid Detec­tion in Peptides by MALDI-TOF-TOF. Anal. Chem. 2009, 81, 4389-4396.
  • Auvynet C, Joanne P, Bourdais J, Nicolas P, Lacombe C, Rosenstein Y. Dermaseptin DRS-DA4, although closely related to dermaseptin B2, presents chemotactic and gram-negative selective bactericidal activities. FEBS J 2009, 276, 6773-6786.
  • Galanth C, Abbassi F, Lequin O, Ayala-Sanmar­tin J, Ladram A., Nicolas P, Amiche A. Mechanism of antibacterial action of dermaseptin B2 : interplay between hélix-hinge-helix structure and membrane curvature strain. Biochemistry 2009, 48, 313-327.
  • Simunic J, Soyez D, Kamech N. Characterization of a membrane-bound angiotensin-converting enzyme isoform in crayfish testis and evidence for its release into the seminal fluid. FEBS J. 2009, 276, 4727–4738
  • Ollivaux C, Gallois D, Amiche M, Boscameric M, Soyez D. Molecular and cellular specificity of post-translational aminoacyl isomerization in the crustacean hyperglycaemic hormone family. FEBS J. 2009, 276, 4790–4802
  • Joanne P, Galanth C, Goasdoué N, Nicolas P, Sagan S, Lavielle S, Chassaing G, El Amri C, Alves I. Lipid reorganization induced by membrane active peptides probed using differential scanning calorime­try. Biochim. Biophys. Acta. 2009, 1788, 1772-1781.
  • Montagné N., Desdevises Y., Soyez D. and Toullec J.Y. Molecular evolution of the Crustacean Hyperglycemic Hormone family in ecdysozoans. BMC Evolutionary Biology, 2010, 10:62
  • Feten Abbassi, Olivier Lequin, Christophe Piesse, Nicole Goasdoué, Thierry Foulon, Pierre Nicolas, and Ali Ladram. Temporin-SHf, a new type of phe-rich and hydrophobic ultrashort antimicrobial peptide. J. Biol. Chem, 2010, 285, 16880-16892.
Main guardianship

Sorbonne Université

Contact Informations
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FOULON Thierry
+33 (0)1 44 27 36 98
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Site Jussieu,
Bâtiment A,
5ème étage,pièce 514A,
7, Quai Saint Bernard,
75005 Paris

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Sorbonne Université, Bâtiment A,
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Faculty Members :
8 (dont 1 PR émérite)

Researchers :
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