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Editorial

By RALF JOCKERS, director of GDR 3545 CNRS « RCPG-Physio-Med » Dear GDR members,

Here we are for the 5 th edition of the NEWSLETTER of our GDR with all the essential information on G protein-coupled receptors gathered by our fantastic editorial team composed of Julie, Véronique, Angélique and Florence. I am happy to announce that we recently established a partnership with the British Society of Pharmacology that will be expended soon by exchanging young scientist speaking at our corresponding annual congresses. I am also happy to announce the 3 rd edition of the joint Hybrigenics-GDR-3545 call for a free Two-Hybrid Screen, exclusively reserved to GDR members (please check our web site). I am very much looking forward to see you all soon at our annual meeting in Montpellier, a privileged moment to talk about science with our academic and industrial partners. We have once again more than 200 participants and over 80 posters, which is an exceptional score! Ralf

Newsletter... number 5!

This is the fifth issue of the GDR 3545 Newsletter. This will provide you the last information of the GDR before the third annual meeting in Montpellier from October 20th to 22nd 2014 and the 2nd workshop, October 22 nd -23rd. We would like to take this opportunity to remind you the establishment of tool databases that would be beneficial for all GDR community. Do not hesitate to contact the indicated persons for your contribution. For this issue, we have decided to interview a young scientist, Guillaume Lebon, in the "A minute with…". We would also like to remind you that we are willing to take into account any comment or suggestion regarding the newsletter sections, to accept contributions from everybody and to hear any criticisms you might have to improve the quality of the newsletter. Furthermore, anyone from each of the participating teams of the GDR is more than welcome to contribute by using the address newsletter@gdr3545.com.

Florence, Angélique, Véronique et Julie

Who has initiated you to GPCRs' world?

Dr Ed Hulme, who is an expert of M1 muscarinic receptor. During my first post-doctoral position with Ed, we identified the binding site for the selective agonists of muscarinic M1 receptor and described their binding mode. This was for me the starting point of a fascinating research adventure to understand the ligand binding mode and activation mechanism of G protein-coupled receptor.

You have been doing your postdocs in UK, can you tell us about that period? What are the similarities and differences between British and French systems? I had the chance to work for two high-standard units of Medical research Council in UK, the MRC-National Institute for Medical Research in London and the MRC-Laboratory of Molecular Biology in Cambridge. In France, I worked for the university during my PhD and the CNRS since I joined the IGF in Montpellier. They all have advantages. It is difficult to compare the two systems in a few lines but the most striking difference is probably the time dedicated to administrative work in France. In UK, at the MRC, I had only science to focus on.

What is the composition of your group?

We are 5 at the moment, 1 Inserm researcher, Gaetan Bellot, 2 post-doctoral scientists, Chady Nasrallah and Harshesh Bhatt, 1 research assistant (ingénieur d'étude) Karine Rottier and myself.

What were the challenges and difficulties that you encountered to establish your group?

The first challenge is of course to be successful with grant application, and we all know the science funding situation at the moment, which makes it not that easy. It is then important to keep doing experimental work whilst establishing the lab, hiring and integrating new young scientists to the group. All this requires lots of time and energy. Finally, to be fully established as a scientific group the challenge is to publish the results of your research activities and to stay active in your scientific community.

Was there a specific person in your experience that gave you advices to build your scientific career?

We can probably call them mentors. I mean by mentor, people who give you advices in order for you to successfully build your scientific career. Scientific career is difficult; the experience of a mentor is highly valuable. I had the chance to cross the road of absolutely excellent scientists but also very good mentor, Ed Hulme when I was in London, Chris Tate and Richard Henderson when I was in Cambridge.

Tell us about the ATIP-AVENIR program, what does it implies? Can you tell us about your own experience in applying to this program?

The program ATIP-AVENIR gives the opportunity to young scientists to create and lead a team within an established laboratory in France and this is under a partnership between INSERM and CNRS. In my case, when I joined the IGF in September 2011, I applied to the ATIP-AVENIR call, my application was accepted and I was invited for an interview. I defended my proposal in front of a panel of international experts and it was actually a very challenging and scientifically stimulating interview. In July 2012, I got the final and positive answer front the ATIP-AVENIR program. I started the lab in January 2013 by receiving the first part of the funding money allocated to ATIP-AVENIR laureate. This program represents the first step to establish, independently, your own research program but also gives a reference to apply for other grants.

You are one of the few persons who have solved the structure of a GPCR, what kind of future to you envision of structural biology in this field? More and more high-resolution structures of course!, high-resolution structure of receptors but also of signalling complexes. We also need to have a more dynamic view of this highly flexible membrane protein receptor family. Again, I really hope that all this structural information will also help to design and discover new therapeutic molecules.

Your post doctoral period is not so far, which advises or hopes could you give to a PhD student or post doctoral fellow? As you said I was still a post-doc a few years ago, so I'm not sure if I am the best person to give advice to post-docs and PhD students. A scientific career is long and difficult and it is important for sure to be passionate and to be ready to spend lots of time in the lab.

And to finish, some short questions: Beer or wine? Well, both! Fish'n chips or tielle à la sétoise ? Fish'n chips with mushy peas Rugby or football? Rowing. Rugby only on TV See or Mountain? both

GDR information Annual meeting 2014

The 3rd annual meeting of the CNRS GDR-3545 G Protein-coupled Receptors: from Physiology to Drugs (RCPG-Physio-Med) will be held in Montpellier at the Corum from October 20 th to 22 nd 2014.

Workshop 2014

A workshop will be held in Montpellier, October 22 nd -23 th 2014 following the annual meeting. Like last year, this workshop is aimed to inform GDR members on techniques available within the network.

Tool databases to be found on your "Member space"

As previously mentioned, a part of the GDR website is a private space open only to GDR members. This space is dedicated to upload validated tools and protocols to establish databases on viral vectors, antibodies, transgenic mouse lines and GPCR structures and ligands. A temporary password has been sent by administrationweb@gdr3545.com. Be aware that only the webmaster can create a new account. Newcomers and departure must be informed using the address newsletter@gdr3545.com. This will help us both to create and maintain the members account and to keep our member list and email address.

After login to the member's space, you can consult and complete the GPCRs, antibodies and mice lines databases.

PhD defenses

Amandine Dupuis has defended her phD thesis prepared under the direction of Christine Rausch at the University of Auvergne on September 19th 2014 and entitled "Le récepteur de la sérotonine 5-HT2A: une nouvelle cible thérapeutique pour le traitement de la douleur neuropathique. Approche physiopathologique et pharmacologique chez le rat neuropathique". Read the summary here : http://www.gdr3545.com/index.php/news/thesesabstracts/116-the-serotonin-receptor-5-ht2a-a-newtarget-to-manage-neuropathic-pain-pathophysiologicaland-pharmacological-approaches-in-neuropathic-rat Ivan Gushchin has defended his phD thesis prepared under the direction of Valentin Gordeliy at the University of Grenoble on September 5th 2014 and entitled: Structural studies of microbial rhodopsins and other membrane proteins by means of X-ray crystallography and computer modeling. Read the summary here : http://www.gdr3545.com/index.php/news/thesesabstracts/115-etudes-structurales-des-rhodopsinesmicrobiennes-et-des-autres-proteines-membranaires-aumoyen-de-la-cristallographie-aux-rayons-x-et-de-lamodelisation-informatique Alexandre Bignon has defended his phD thesis prepared under the direction of Karl Balabanian at the University Paris Sud on September 30th 2014 and entitled: "Dérégulation des récepteurs de chimiokine CCR1 et CXCR4 dans le lupus érythémateux disséminé et la lymphopénie T CD4+ idiopathique". Read the summary here : http://www.gdr3545.com/index.php/news/thesesabstracts/114-deregulation-des-recepteurs-dechimiokine-ccr1-et-cxcr4-dans-le-lupus-erythemateuxdissemine-et-la-lymphopenie-t-cd4-idiopathique

Press review

A 'switchable' molecule to specifically detect G protein-coupled receptors; D Bonnet and AS Klymchenko. Researchers from the 'Laboratoire d'innovation thérapeutique' (CNRS / Université de Strasbourg) and the 'Laboratoire de biophotonique et pharmacologie' (CNRS / Université de Strasbourg) have set up an innovative method using fluorescent to visualize and quantify G protein-coupled receptors at the cell surface and more particularly the oxytocin receptor. This work has been published in ChemBioChem. See also En direct des laboratoires de l'institut de Chimie, 2014: http://www.cnrs.fr/inc/communication/direct_labos.ht m. A subtle relationship between cell proliferation and G protein-coupled receptors. Sandra Lecat and her coworkers from the 'laboratoire biotechnologie et signalisation cellulaire' (CNRS / Université de Strasbourg) showed that GPCRs are involved in regulating the activation of the mTORC1 complex, a central regulator of cell proliferation, by a new mechanism based on a modification of the intracellular localization of REDD1. This work has been published in Journal of Cell Science. See also En direct des laboratoires de l'institut de des Sciences Biologiques, 2014: http://www.cnrs.fr/insb/recherche/parutions/articles20 14/s-lecat.html.

Fernando Arenzana-Seisdedos leader of the Viral Pathogenesis Unit at Pasteur institute (Inserm U1108) was awarded the George Jacques and Elias Canetti prize 2014 for his research on AIDS. http://www.pasteur.fr/fr/institutpasteur/presse/documents-presse/pierre-arditi-remetfernando-arenzana-l-institut-pasteur-le-prix-georgesjacques-et-elias-canetti-2014-pour-ses-recherches-sur-lesida

Publications

Gangarossa G, Ceolin L, Paucard

  CR2) -ATIP-AVENIR team leader. He is the group leader of the "Structural biology of G protein coupled receptors: a focus on class C" team in the "Institut de Génomique Fonctionnelle" (IGF) at Montpellier. After a postdoctoral experience in UK where he solved the structure of A2A receptor by X raycrystallography, he has established his own group thanks to the ATIP-AVENIR CNRS and INSERM program with the aim to determine highresolution structure of G protein-coupled receptors (GPCRs) bound to their ligands and to their signaling complexes. http://www.igf.cnrs.fr/en/research/transverseaxis/gpcr-signaling What are your research interests? My research interest is focused on understanding the structure-function relationship of the large family of highly medically relevant membrane proteins: the G Protein-Coupled Receptors. GPCRs are fascinating cellular machinery that receive a message and transmit this signal to the intracellular compartment of the cell, to finally activate intracellular signaling machineries, such as the trimeric G protein or arrestin. In the lab, we combine molecular pharmacology and biophysical techniques such as X-ray crystallography to decipher at the molecular level how the ligands bind to the receptor and induce conformational changes to activate the intracellular G protein. Finally, GPCRs are important and validated drug target and I like to think that the results of our academic research may help to develop or discover new medicine related to GPCRs. What is your background? I completed a Phd in biochemistry and Molecular biology in Nantes University, with Professor Vehary Sakanyan (2003-2006), working on the characterisation of RNA polymerase subunit for the conception of transcription inhibitor. In december 2006, I joined the Lab of Dr Ed Hulme, NIMR London, UK, in collaboration with GSK. There, I learned molecular pharmacology techniques for studying G protein-coupled receptors. In december 2007, I moved to the Laboratory of Molecular Biology (LMB), Cambridge, to join Chris Tate and Richard Henderson for a second post-doctoral experience in collaboration with Heptares Therapeutic. During this work, I learned protein crystallisation and X-ray structure determination and solved the 3D structure of the A2A receptor-bound to its N°5 -October 2014 natural agonist adenosine. In September 2011, I joined the lab of J.P. Pin and L. Prézeau to start a program on structural studies of class C GPCRs and I was awarded of an ATIP-AVENIR Grant.

  C (2014) In vivo properties of KNT-127, a novel delta opioid agonist: receptor internalisation, antihyperalgesia and antidepressant effects in mice. Br J Pharmacol. (In Press).Carayon K, Moulédous L, CombedazouA, Mazères S, Haanappel E, Salomé L, Mollereau C (2014) Heterologous Regulation of mu-opioid (MOP) Receptor Mobility in the Membrane of SH-SY5Y Cells. J Biol Chem. (In press). Baillie GS, Marullo S, Scott MG (2014) A biosensor to monitor dynamic regulation and function of tumour suppressor PTEN in living cells Nat Commun. 5:4431. Rogee S, Hartley O, Randriamampita C, Scott MG, Marullo S, Sauvonnet N, Arenzana-Seisdedos F, Lagane B, Brelot A (2014) Targeting Spare CC Chemokine Receptor 5 (CCR5) as a Principle to Inhibit HIV-1 Entry J Biol Chem 289:19042-19052.

Biologie et Bioinformatique des Sytèmes de Signalisation" of

  the "Physiologie de la Reproduction et des Comportements" laboratory at INRA Val de Loire center, as part of the ARD2020 "Biomédicaments" project sponsorized by Région Centre. Mohammed Akli Ayoub is the recipient of LE

	The persons responsible for the different tool lists are: Transgenic mouse lines: Dominique Massotte
	GPCR amino acid sequences with TM, ICL and ECL annotations: Didier Rognan Antibodies against GPCRs, ligands and signaling proteins:
	Véronique Gigoux
	Recruitment
	Mohammed Akli Ayoub has been recruited in the group "

STUDIUM® RESEARCH FELLOWSHIP -SMART LOIRE VALLEY and is the laureate of the international mobility program Agreenskills +.

	See	more	information	at	http://www.val-de-
	loire.inra.fr/Toutes-les-actualites/Agreenskills-Inra-Val-de-Loire-un-chercheur-laureat

Marion Espéli has been recruited in the group "Chemokine SDF-1/CXCL12 and its receptors » lead

  by Karl Balabanian at INSERM U996 Clamart. Marion is the laureate of the "Junior Team Leader starting package" awarded by the LabEx Lermit. http://www.labexlermit.fr/fr/component/content/article/30-presentationappels-a-projets/77-laureat-junior-team-2013

	New group
	A new group named DRuGS

"Déficit de Récompense, GPCR et Sociabilité" lead by Jérôme Becker and Julie Le Merrer has

  been created in the "Physiologie de la Reproduction et des Comportements" laboratory of the INRA Val de Loire Center.

Xue L, Rovira X, Scholler P, Zhao H, Liu J, Pin J-P Rondard

  (2014) Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy. Nat Commun. In Press.

		Bjordal M, Arquier N, Kniazeff J, Pin J-P Léopold P (2014) Amino acids sensing in a brain dopaminergic
		circuitry controls feeding behavior in Drosophila. Cell 156: 510-21.
		Polovinkin V, Balandin T, Volkov O, Round E, Borshchevskiy V, Utrobin P, von Stetten D, Royant A,
		Willbold D, Arzumanyan G, Chupin V, Popot JL, Gordeliy V (2014) Nanoparticle Surface-Enhanced
	A, Lerner-Natoli Valjent E (2014) Repeated stimulation of dopamine D1-like receptor and M, Perroy J, Fagni L, hyperactivation of mTOR signaling lead to generalized seizures, altered dentate gyrus plasticity, and memory deficits. Hippocampus. In Press. Moutin E, Compan V, Raynaud F, Clerté C, Bouquier N, Labesse G, Ferguson ML, Fagni L, Royer CA, Perroy J (2014) The stoichiometry of scaffold complexes in living neurons -DLC2 functions as a dimerization engine for GKAP. J Cell Sci. 127:3451-62.	Raman Scattering of Bacteriorhodopsin Stabilized by Amphipol A8-35. J Membr Biol. In Press. Polovinkin V, Gushchin I, Sintsov M, Round E, Balandin T, Chervakov P, Schevchenko V, Utrobin P, Popov A, Borshchevskiy V, Mishin A, Kuklin A, Willbold D, Chupin V, Popot JL, Gordeliy V (2014) High-Resolution Structure of a Membrane Protein Transferred from Amphipol to a Lipidic Mesophase. J Membr Biol. (In Press) Dalonneau F, Liu XQ, Sadir R, Almodovar J, Mertani HC, Bruckert F, Albiges-Rizo C, Weidenhaupt M, Lortat-Jacob H, Picart C (2014) The effect of delivering the
		chemokine SDF-1α in a matrix-bound manner on myogenesis. Biomaterials. 35:4525-35.
		Sapay N, Estrada-Mondragon A, Moreau C, Vivaudou M,
		Crouzy S (2014) Rebuilding a macromolecular membrane complex at the atomic scale: Case of the Kir6.2 potassium channel coupled to the muscarinic
		acetylcholine receptor M2. Proteins. 82:1694-707.
	Duhr F, Déléris P, Raynaud F, Séveno M, Morisset-Lopez S, Mannoury la Cour C, Millan MJ, Bockaert J, Marin P, Chaumont-Dubel S (2014) Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth. Nat Chem Biol. 10:590-7. News & Views: Seo and Nat Chem Biol 10, 488-489. Tsai Neuronal differentiation: 5-HT6R can do it alone.	Picciocchi A, Siaučiūnaiteė-Gaubard L, Petit-Hartlein I, Sadir R, Revilloud J, Caro L, Vivaudou M, Fieschi F, Moreau C, Vivès C (2014) C-terminal engineering of CXCL12 and CCL5 chemokines: functional characterization by electrophysiological recordings. PLoS One. 9:e87394.
	Sbai O, Monnier C, Dodé C, Pin J-P, Hardelin J-P Rondard P (2014) Biased signalling through G protein-coupled
	PROKR2 receptors harboring missense mutations. FASEB journal : 28: 3734-44.
	Rovira X, Malhaire F, Scholler P, Rodrigo de Losada J, Gonzalez-Bulnes P, Llebaria A, Pin J-P, Giraldo J
	Goudet C (2014) Overlapping binding sites drive allosteric agonism and positive cooperativity in type 4
	metabotropic glutamate receptors. FASEB journal In Press.
	Pittolo S, Gómez-Santacana X, Eckelt K, Rovira X,

Lecoutey C, Hedou D, Freret T, Giannoni P, Gaven F, Since M, Bouet V, Ballandonne C, Corvaisier S, Malzert Fréon A, Mignani S, Cresteil

T, Boulouard M, Claeysen S, Rochais C, Dallemagne P (2014) Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment. Proc Natl Acad Sci U S A. 111:E3825-30. P (2014) Major ligand-induced rearrangement of the heptahelical domain interface in a G proteincoupled receptor dimer. Nat Chem Biol. In Press. Dalton J, Goudet C, Pin J-P, Llobet A, Giraldo J, Llebaria A Gorostiza P (2014) A photochromic allosteric modulator to control endogenous G protein-coupled receptor signalling in vivo. Nat Chem Biol. In Press. Olofsson L, Felekyan S, Doumazane E, Scholler P, Fabre L, Zwier JM, Rondard P, Seidel CAM, Pin J-P Margeat E

Niescierowicz K, Caro L, Cherezov V, Vivaudou M, Moreau CJ

	(2014) Functional assay for T4 lysozyme-
	engineered G Protein-Coupled Receptors with an ion channel reporter. Structure. 22:149-55.

Karaki S, Becamel C, Murat S, Mannoury la Cour C, Millan MJ, Prézeau L, Bockaert J, Marin P,

  Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities. J Vis Exp. (89).

	Brulé C, Perzo N, Joubert JE$, Sainsilly X, Leduc R, Castel H, Prézeau L (2014) Biased signaling regulates the	pharmacology similar to that in mammalian cell membranes. PLoS One. 9:e100616.
	pleiotropic effects of the urotensin II receptor to modulate its cellular behaviors. FASEB J. (In Press). Tritschler L, Felice D, Colle R, Guilloux JP, Corruble E, Gardier AM, David DJ (2014) Vortioxetine for the treatment of major depressive disorder. Expert Rev Clin Pharmacol: 1-15. Hache G, Guiard BP, Nguyen TH, Quesseveur G, Gardier AM, Peters D, Munro G, Coudore F (2014) Antinociceptive activity of the new triple reuptake inhibitor NS18283 in a mouse model of chemotherapy-induced neuropathic pain. Eur J Pain. (In Press). Le Dantec Y, Hache G, Guilloux JP, Guiard BP, David DJ, Adrien J, Escourrou P (2014) NREM sleep hypersomnia and reduced sleep/wake continuity in a neuroendocrine mouse model of anxiety/depression based on chronic corticosterone administration. Neuroscience (In Press).	Freitas C, Desnoyer A, Meuris F, Bachelerie F, Balabanian K, Machelon V (2014) The relevance of the chemokine receptor ACKR3/CXCR7 on CXCL12-mediated effects in cancers with a focus on virus-related cancers. Cytokine Growth Factor Rev. (In Press) Bignon A, Gaudin F, Hémon P, Tharinger H, Mayol K, Walzer T, Loetscher P, Peuchmaur M, Berrebi D, Balabanian K (2014) CCR1 inhibition ameliorates the progression of lupus nephritis in NZB/W mice. J Immunol. 1;192(3):886-96. Boujedidi H, Robert O, Bignon A, Cassard-Doulcier AM, Renoud ML, Gary-Gouy H, Hemon P, Tharinger H, Prévot S, Bachelerie F, Naveau S, Emilie D, Balabanian K, Perlemuter G (2014) CXCR4 dysfunction in non-alcoholic steatohepatitis in mice and patients.. Clin Sci (Lond). (In Press)
	Darcet F, Mendez-David I, Tritschler L, Gardier AM, Guilloux JP David DJ (2014) Learning and memory	Elhabazi K, Ayachi S, Ilien B, Simonin F (2014)
	impairments in a neuroendocrine mouse model of anxiety/depression. Front Behav Neurosci 8: 136.
	Tran-Dinh A, Levoye A, Louedec L, Lambert G, Meilhac O, Amarenco P. (2014) Very low levels of LDL-
	cholesterol associated with PCSK9 inhibition do not increase the risk of hemorrhagic transformation after
	cerebral ischemia/reperfusion. Stroke. (In Press)
	Petit AC, Quesseveur G, Gressier F, Colle R, David DJ, Gardier AM, Ferreri F, Lepine JP, Falissard B, Verstuyft C, Guiard BP Corruble E (2014) Converging
	translational evidence for the involvement of the serotonin 2A receptor gene in major depressive
	disorder. Prog Neuropsychopharmacol Biol Psychiatry. (In Press).
	Samuels B, David I, David DJ, Gardier AM, Hen R (2014) Role of hippocampal neurogenesis in the mechanism of
	action of antidepressant/anxiolytic drugs in animal model of depression and anxiety. Neurobiology of mood
	disorders. B. P. Guiard and E. Dremencov, Bentham Science Publishers: 210-233.
	Quesseveur G, Guiard BP (2014) New Strategies for the Treatment of Mood Disorders: The Triple Reuptake
	Inhibitors. Neurobiology of mood disorders. B. P. Guiard and E. Dremencov, Bentham Science Publishers: 234-	Vandermoere phosphoproteomics unravels biased phosphorylation of F (2014) Quantitative
	253. Gardier AM (2014). Intracerebral in vivo microdialysis in knockout mice: advantages and drawbacks.	serotonin 2A receptor at Ser280 by hallucinogenic versus non-hallucinogenic agonists. Mol Cell Proteomics. 13: 1273-85.
	Neurobiology of mood disorders. B. P. Guiard and E. Dremencov, Bentham Science Publishers: 3-22. Margathe JF, Iturrioz X, Alvear-Perez R, Marsol C, Riché S, Chabane H, Tounsi N, Kuhry M, Heissler D, Hibert M, Llorens-Cortes C, Bonnet D (2014) Structure-Activity Relationship Studies toward the Discovery of Selective	Armando S, Quoyer J, Lukashova V, Maiga A, Percherancier Y, Heveker N, Pin JP, Prézeau L, and Bouvier M (2014) The chemokine CXC4 and CC2 receptors form homo-and heterooligomers that can engage their signaling G-protein effectors and βarrestin. FASEB J. (In Press).
	Apelin Receptor Agonists. J. Med. Chem. 7, 2908-19.	Techlovská S, Chambers JN, Dvořáková M, Petralia RS, Blahos J (2014) Metabotropic Glutamate Receptor 1 Wang YX, Hájková A, Nová A, Franková D, Prezeau L,
	melatonin receptor MT1 isolated in mixed detergents shows	Splice Variants mGluR1a and mGluR1b Combine in mGluR1a/b Dimers in vivo. Neuropharm. (In Press).

Logez C, Berger S, Legros C, Banères

JL, Cohen W, Delagrange P, Nosjean O, Boutin JA, Ferry G, Simonin F, Wagner R (2014) Recombinant human Romain B, Hachet-Haas M, Rohr S, Brigand C, Galzi JL, Gaub MP, Pencreach E, Guenot D (2014) Hypoxia differentially regulated CXCR4 and CXCR7 signaling in colon cancer. Mol Cancer. 14: 13:58.

Reviews

Job offers

Browse all job offers on the GDR web (http://gdr3545.com/index.php/news/job-offers).

To add your job offer, contact Ralf Jockers (ralf.jockers@inserm.fr )

Local contacts

Important information? New publications? Recruitment of new persons? ... Local contacts are here to gather your communications.

Clamart campus: Christelle Freitas (christelle.freitas@upsud.fr); Clermont-Ferrand campus: Jérôme Busserolles (jerome.busserolles@udamail.fr); Grenoble campus: Christophe Moreau (christophe.moreau@ibs.fr); Illkirch ESBS campus: Sandra Lecat (lecat@unistra.fr); Montpellier campus: Julie Kniazeff (julie.kniazeff@igf.cnrs.fr); Paris campus: Angélique Levoye (Angelique.levoye@inserm.fr) et Florence Gbahou (florence.gbahou@inserm.fr ); Paris Sud campus : Jean-Philippe Guilloux (jean-philippe.guilloux@u-psud.fr); Toulouse campus: Véronique Gigoux (veronique.gigoux@inserm.fr) et Lionel Moulédous (lionel.mouledous@ipbs.fr); Tours campus: Nathalie Langonne (Nathalie.Langonne@tours.inra.fr); Lyon campus: Anass Jawhari (ajawhari@calixar.com) We are still looking for some volunteers for the unrepresented campus (Lille, Illkirch Pharma…).

Industrial partners corner

, an industrial partner of the GDR-3545, has the pleasure to offer 1 full yeast twohybrid screen per year (10 000€) to GDR members. Submission deadline for the next call is 8 th December 2014. More information on selection process and time table at: http://www.gdr3545.com/index.php/news/partnersannouncements/108-call-for-yeast-two-hybrid-screen-2014 "Illuminations:

A Cell Notes Publication", provides the latest more powerful and sensitive bioluminescent kits for cellular analysis: cell signaling, metabolism, kinase profiling, ... and drugs development. To get your "Illuminations" copy and read an article about the new GloSensor technology, please follow this link : http://www.gdr3545.com/index.php/news/partnersannouncements/111-illuminations-a-cell-notespublication presents the Methoxy e-Coelenterazine a substrate for Renilla luciferase (Rluc) with 13-fold higher luminescence than Coelenterazine 400a for Luminescent Detection. Interested in this product? More information on it and others popular coelenterazines here : http://www.gdr3545.com/index.php/news/partnersannouncements/109-methoxy-e-coelenterazineluminescent-detection-by-interchim Tecan's washers and plate readers offer the perfect combination to yield a high cell number during assay preparation and to maintain a perfect environment for long-term experiments. For more information go to: http://www.gdr3545.com/index.php/news/partnersannouncements/112-worried-about-consistent-resultsfrom-your-cell-assay , company specialized in the native isolation of integral membrane protein targets, announced today the issue of a new generation of compounds able to extract and stabilize complex pharmaceutical targets. For more information : http://www.gdr3545.com/index.php/news/partnersannouncements/107-calixar-to-extend-its-portfolio-ofstrategic-compounds-for-complex-pharmaceutical-targetisolation and visit www.calixar.com or contact Dr Martine MOULY, Chief Communication Officer, mmouly@calixar.com presents EnSightTM his new multimodal microplate reader. In addition to the conventional technologies (Absorbance, Fluorescence, Luminescence, Alpha, TRF / TR-FRET) this modular and scalable microplate reader can be equipped with the Label-free and a cellular imaging system. To discover more about this new reader, follow this link : http://www.gdr3545.com/index.php/news/partnersannouncements/110-ensighttm-nouveau-lecteur-demicroplaques-multimodal-perkinelmer

What's up in GPCR world ?

The article of the month « Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist». Celine Valant, Lauren T May, Luigi Aurelio, Chung Hui Chuo, Paul J White, Jo-Anne Baltos, Patrick M. Sexton, Peter J. Scammells, and Arthur Christopoulos Proc. Nat. Acad. Sci. USA 111, 4614-19 (2014) In this article, the authors aimed at rationally design a novel ligand targeting the Adenosine 1 receptor (A1AR) with improved pharmacology to potentially opening new avenues for cardioprotection treatment. While classical orthosteric agonists of A1AR have limited beneficial effect for this application because they also induce major adverse effects like bradycardia, the rationally designed compound is aimed at promoting the known therapeutic effect of A1AR agonists, and simultaneously at silencing the adverse effects. To achieve that goal, the authors take advantage of the high dynamics of G protein-coupled receptors (GPCRs). Indeed, these proteins are fluctuating between different conformations, which are promoting a specific cellular response. When interacting with the receptor, ligands stabilize one of the receptor conformations which in turn model the cellular response. This phenomenon is often referred to as biased agonism. Although none of the orthosteric ligands of A1AR have been reported to be biased, the allosteric modulator VCP171 promotes bias in the prototypical R-PIA orthosteric agonist signaling. On this basis, the authors designed a so called bitopic ligand containing both the orthosteric moiety, adenosine, to confer high efficacy and the allosteric moiety, VCP171, to induce bias signaling, the two moieties being fused by linkers of different size. These ligands are thought to bind both to the orthosteric and allosteric sites of A1AR and to have a combined pharmacological profile as seen in Figure 1. If such ligand binds both to the orthosteric and allosteric binding sites, it would in turn display both competitive and noncompetitive antagonism relative to the concentration of orthosteric ligand used. The authors processed in analyzing the pharmacological and signaling properties of these ligands. First, all bitopic ligands were found to displace [3H]-DPCPX orthosteric antagonist in a binding assay with the compound VCP746 showing the highest affinity (Ki~60 nM -about 100-fold higher than adenosine itself). In [35S]-GTPγS binding assay, all the whole series of ligands was found to be full agonists but with different potencies. In this assay, VCP746 was also the more potent. In a second step, the authors validated the bitopic binding of VCP746 by analyzing its functional interaction with DPCPX in an ERK1/2 phosphorylation assay. By comparing the experimental data obtained with those predicted by the theoretical model, VCP746 was confirmed to interact with A1AR in bitopic manner. In addition of synthesizing a bitopic ligand, this study aims at identifying a biased agonist. Accordingly, modulation of forskolin-induced cAMP accumulation was measured for both classical and bitopic agonists and compared to ERK1/2 signaling. The first assay was chosen because it represents the canonical A1AR-Gi/oadenylyl cylase pathway while the later constitutes a downstream convergent pathway activated both in a G protein-dependent and -independent manner. Compared to prototypical orthosteric agonists, VCP746 showed a preferential coupling to cAMP pathway (about 30-fold preference). At last, the authors tested the physiological relevance of VCP746. By using rat embryonic cardiomyoblasts (H9c2(2-1)) under ischemic conditions, VCP746 was more efficient in reducing cell death than other A1AR agonists (e.g. CPA). The effect of VCP746 was also assessed on rat atrial rate. Compared to orthosteric agonists, who dramatically reduced heart rate at high concentration, VCP746 did not have substantial effect even at concentration that showed maximal cardioprotective effect (Figure 2). Altogether, these data indicate that the bitopic VCP746 is a biased agonist of A1AR therapeutically relevant. This study shows that the rational design of bitopic ligand at GPCR may constitute an interesting alternative to classical agonists or allosteric modulator to promote biased agonism and decrease adverse effects linked with more classical ligands.

Very Important Publications

Reviews:

Vilardaga JP1, Jean-Alphonse FG1, Gardella

Book:

Current Opinion in cell Bilogy, 2014, Vol 27 : special issue on GPCR (dimerization, signaling, endosome, arrestin, biased ligands, ubiquitination, trafficking...)

Conferences

GTBio2014 will be held from October 7th to 10th 2014 in Grenoble, France. This meeting is organized be the 'Institut de Biologie Structurale' together with ESRF and the French Crystallography Association. http://gtbio2014.ibs.fr A symposium on "Biomembranes and membrane proteins" will be held from November 14th in Grenoble, France.

This symposium aims at sharing information regarding scientific projects, methods and instruments developped for membrane proteins and membranes. PSBWorkshop2014@ibs.fr

Molecular


Do we observe positive effects of diversity in all ecosystems? carbon and water cycles …and for all ecosystem functions?

Regions submitted every year to dry periods:

Material & Methods

Quercus faginea Pinus nigra Pinus sylvestris

3 local tree species competing for resources:

Tree Transpiration

Material & Methods

For each species, selection of trees in 3 different "neighborhoods":

-

Resistance to drought

Material & Methods

Resistance to drought b c

Plot level a a δ 13 C a (‰)

δ 13 C c (‰) δ 13 C b (‰) c c δ 13 C plot (‰) = Ʃ (δ 13 C i × BA i ) Ʃ (BA i )

Material & Methods

Calculation of plot-level δ 13 C

Take Home

Higher stability of productivity in mixed stands (5 out of 6) related to:

• Faster rates of wood production (i.e. over-yielding) in mixed stands

• Decreased year-to-year variation in productivity through asynchronous responses of species to climate

• Greater temporal stability in the growth rates of individual tree species

Productivity

Conclusions

(2) Water availability plays an important role in shaping tree species and ecosystem response to diversity (4) Favoring mixed forest ecosystems could be preferred in certain regions, not only to preserve biodiversity, but also to reduce the risk or delay the negative effect of drought

53

(1) Tree species diversity can influence the functioning of tree species forest ecosystems in terms of water and carbon acquisition and use

(3) More diverse forests can be more resistant to drought, but not necessarily!

•

  Negative impact of Qp on Qc when these species compete for water resources• Managing for mixed stands in the Mediterranean region might, in some cases, increase the detrimental effect of drought on species functioning

•

  Measurements conducted for 3-5 days during 5 periods along the summer 2013 Community assembly in Mediterranean forest ecosystems strongly affects water use during drought, • but to different extends among species, • and potentially with contrasting effects o Positive effects for some species o Negative effects for some other Several underlying mechanisms (e.g. stratification of canopy) could explain the positive and negative effects of species interactions but were not tested here diverse forest stands are less exposed to drought than less diverse stands Causes : Niche complementarity and Facilitation processes ? to 42 stands (30×30m) varying in species richness in each studied region: The variations in other confounding factors (soil, topography, land-use history,…) were kept at a minimum. Selection of a subsample of dominant and co-dominant trees of each species in each stand Extraction of wood cores at breast height 36 Grossiord C. Grossiord C.

  Selection of years with contrasting climatic conditions (dry vs. wet)

  If difference in δ 13 C is high, low resistance If difference in δ 13 C is low, high resistance

1. Tree Transpirationwww.wikipedia.com www.wikipedia.com www.wikipedia.com

Sapflow sensors (Granier et al. 1987)Material & Methods Italy24

regions across North -South gradient in Europe to cover the major forest types

FunDivEUROPE exploratory platform3. Productivity Material & Methods


Carine Le Bourvellec

Dimitra Chormova

Catherine M G C Renard

Dimitra Chromova

Roe D J Guillen-Rodriguez

Covalent interactions between dietary fiber and condensed tannins: fiber structure defines the binding

Keywords: Cell wall, procyanidins, irreversible, binding References :

Dietary fiber has been traditionally considered as a good health promoting agent and its anticancer properties have been extensively reported, though there is still no consensus about a direct relationship between higher fiber consumption and low cancer risk (Alberts et al., 2000; Barnard et al., 2004). That is why phytochemicals, specifically polyphenols, associated to dietary fiber could have an added value for gastrointestinal health and maybe anticancer properties. Polyphenols and cell-wall are strictly compartmentalized in the plant. However, once fruit are harvested, processed and eaten, these vacuolar polyphenols, most specifically procyanidins, have an opportunity to interact non-covalently with cell-walls whenever they are released from the cell (Renard et al., 2001). After heat treatment (cooking, pasteurization) procyanidins cell-wall complexes could become irreversible due to formation of covalent bonds (Le Bourvellec et al., 2013). These interactions may play an important role in controlling the release of polyphenols from food matrices for absorption in the gastrointestinal tract and in the matrix fermentation by microbiota. The main objectives of this work were to investigate covalent interactions between cell-walls (from pear) and procyanidins and to evaluate the consequences of these interactions on cell-wall composition. Cell-walls were extracted from pear parenchyma either directly or after separation of stone cells and parenchymatous cells. We artificially created complexes of the different cell-walls and procyanidins (DPn 9) at 25 °C and 95 °C. The complexes were analysed for polyphenols (HPLC-DAD) and polysaccharides (GC and colorimetry). The different cell-walls were also characterized after incubation at 95 °C with and without procyanidins. The nature of interaction was investigated by ITC. Procyanidins bound to the various cell-walls, at 25°C and 95°C, indicating complex formation. More procyanidins were bound to parenchymatous cell-walls (parenchymatous cells > stone + parenchymatous > stone cells) and after treatment at 95 °C. Undisrupted cell walls that contained a balanced ratio of the various polymers retained procyanidins with higher DPn. Neutral sugars contents decreased significantly for all the different cell-wall types after contact with procyanidin solutions, especially for the cell-wall coming from parenchymatous cells. Arabinose was highly decreased followed by fucose and galactose. ITC assays at 25 °C revealed hydrophobic interactions. At 45 °C very high association constants and positive enthalpy and entropy were observed.

Acknowledgments :

We gratefully thank PACA (regional), Agropolis Foundation and Toupargel for funding the project and Line Tichit for technical support.


domain: sdv sde

text:
How overyielding occurs in continuous processes?

In continuous processes, density-dependence (actually ratio-dependence) + varying inputs may lead to the appearance of overyielding!

Hypotheses : role of other phenomena?

• Variable yields • Recycling matter (mortality)

• Maintenance • Higher the diversity, higher the probability of having microorganisms able to pre-treat a number of non biodegradable molecules (that are then avaialable for others)… • Higher the diversity, higher the probability of having predators (for example viruses) that make a part of the biomass available as substrates… • …

Explanation

In the presence of mortality, the biomass concentration will decay and tends towards zero. In such a case, it can be shown that there necessarily will remain some substrate for arbitrarily large T. Thus, in the presence of several species, the remaining substrate can be used by a species having a lower decay rate than those who have « disappeared already », improving then the total biogas production… Hypotheses Simulations -Blue species the best « Y.r »… -…but a higher mortality than the green species; -Thus, some substrate remains after its death,…

Explanations

-…substrate that can then be used by the green species which is still alive!

Conclusions and perspectives

_03

Overyielding P 1

 1 to P 3 𝑃 4 to 𝑃 6If there exists 𝑃 𝑖 𝑖=4..6 > max(𝑃 𝑖 𝑖=4..6 ), then there is overyielding and it is said to be => max(biogaz(T)) obtained in pure culture; 2. The simple competition model cannot explain overyielding but MORE IMPORTANTLY,… …RESULTS DO NOT DEPEND ON m i (.)! Indeed they remain true for the system : Modeling : competition for a limiting substrate 3. Results remain valid for any biotic interactions modeled into kinetics functions (density-dependence, Generalized Lotka-Volterra…)! In fact, for any process engineer it is obvious! If the yield is constant, the quantity of biogaz to be produced over a period of time does only depend on the quantity of resource and not on the kinetics at which it is produced! Searching for non modeled phenomena _02 Jérôme HARMAND / 4th French-Chilean workshop on Bioprocess Modeling, Santiago de Chile / 20-22 September 2016

Jérôme HARMAND / 4th French-Chilean workshop on Bioprocess Modeling, Santiago de Chile / 20-22 September 2016

Jérôme HARMAND / 4th French-Chilean workshop on Bioprocess Modeling, Santiago de Chile / 20-22 September 2016Under H1, the biogas produced from 0 to T is :Modeling : competition for a limiting substrate

Jérôme HARMAND / 4th French-Chilean workshop on Bioprocess Modeling, Santiago de Chile / 20-22 September 2016Overyielding : non modeled phenomena?Other interactions than those modeled into kinetics! Which phenomena could be in play?

Jérôme HARMAND / 4th French-Chilean workshop on Bioprocess Modeling, Santiago de Chile / 20-22 September 2016 Simulation results

Jérôme HARMAND / 4th French-Chilean workshop on Bioprocess Modeling, Santiago de Chile / 20-22 September 2016 Thank you for your attention!

Consider :

Then :

If S(T) is negligible compared to S(0) (hypothesis H1), then :

If then

Modeling : competition for a limiting substrate

A question…

What may significantly differ a batch from a continuous process ?

 Mortality ?  Indeed, because of the presence of a dilution rate, the mortality can sometimes be neglected in continuous processes while it cannot in batch processes…

A new model for batch process

Including mortality in the batch model

Overyielding can now occur!

Conclusions and perspectives

• Over yielding in batch cannot be explained by classical models of N species in competition on a limiting substrate; • If mortality is included, overyielding may appear;

• « Engine of overyielding » are of different nature in batch and in continuous bioreactors… • We must now inventory i) possible (candidates) phenomena to be studied to allow overyielding and ii) identify possible experiments to sort out the most probable phenomena in play in real ecosystems.


Jérôme Mariette

Héléne Chiapello

Nathalie Villa-Vialaneix

Integrating Tara Oceans data sets using a multiple kernel approach

Introduction

The Tara Oceans expedition [Sunagawa et al., 2015] facilitated the study of plankton communities by providing the scientists an ocean metagenomic data set combined with environmental measures. During the expedition, 243 seawater samples were collected from 68 locations representing all main oceanic regions from three depth layers : the surface (SRF), the deep chlorophyll maximum (DCM) layer and the mesopelagic (MES) zone.

In [Sunagawa et al., 2015], several approaches have been used to show a vertical stratification of the ocean microbial composition mainly driven by temperature. In the presented work, we propose to take advantage of kernel methods to integrate taxonomic and functional community composition with environmental factors of 139 ocean samples in a single exploratory analysis.

Method

Integrating multiple data sets

In the following, we consider M sets of input data, (x m i ) i=1,...,N,m=1,...,M all measured on the same observations (1, . . . , N ) which take values in an arbitrary space (X m ) m . X m is equipped with a kernel K m : X m × X m → R that provides pairwise similarity between the observations,

K m ij := K m (x i , x j ). K m is assumed symmetric (K m ij = K m ji ) and positive (∀ N ∈ N, ∀ (α i ) i=1,...,N ⊂ R, ∀ (x i ) i=1,...,N ⊂ X m , i,i α i α i K m ii ≥ 0
). The M kernels can be combined into a single one K * , defined as a convex combination as following :

K * ij = M m=1 α m K m ij (1)
where α m ≥ 0 and M m=1 α m = 1. In this first version of the work, α m are chosen such that all kernels have the same weight : α m = 1 M . Kernel methods allow to implement different versions of any algorithm which can be expressed in terms of dot products. This is the case of the kernel PCA, a PCA analysis performed in the feature space (H, ., . ) induced by the kernel. The kernel PCA was first introduced in [Schölkopf et al., 1998] and suppose that the kernel K * is centered. Then, the following eigenvalue problem is solved : K * α = λα. The eigenvectors (α) k=1,...,n ∈ R n and the corresponding eigenvalues (λ k ) k=1,...,n are obtained from the centered matrix.

Data sets and kernels

The present section is dedicated to describe the data sets and the kernels used. Three data sets provided by the Tara Oceans companion website 1 are used to evaluate the proposed method :

1. http ://ocean-microbiome.embl.de/companion.html -the environmental dataset which contains 22 numeric features (i.e., temperature, salinity, . . . ).

Similarity between ocean samples are computed using the linear kernel, given by K(x i , x j ) =< x i , x j >. -the taxonomic community composition that contains more than 35,000 species. The operational taxonomic units (OTUs) provided, allow to compute both compositional and phylogenetic dissimilarities. The first one is obtained using the Bray-Curtis distance given by

d BC = s |n A s -n B s | s n A s + n B s , (2)
where (n A s ) s=1,...,S and (n B s ) s=1,...,S respectively represent the count of species s in community A and B. The phylogenetic dissimilarities requires first to build the phylogenetic trees using fasttree [Morgan N. [START_REF] Price | [END_REF] with the OTUs sequences as inputs. The weighted Unifrac distance is then applied. This one is given by

d wU F = e l e |p e -q e | e p e + q e
, where for each branch e, l e represent its length and p e (respectively q e ) the fraction of community A (respectively community B) below branch e. Kernels can then be obtained from these two dissimilarities using

K ij = - 1 2 d ij - 1 N N k=1 (d ik + d kj ) + 1 N 2 N k, k =1 d kk ,
as suggested in [START_REF] Lee | Nonlinear Dimensionality Reduction. Information Science and Statistics[END_REF], where d can either be d BC or d wU F . -the functional community composition which contains more than 63,000 KEGG orthologous groups.

To obtain a functional composition kernel, the Bray-Curtis dissimilarity (Equation ( 2)) is used.

Results and discussion

The results obtained confirm those exposed in [Sunagawa et al., 2015]. Samples are not clearly grouped by their ocean regions but are separated by their depth layer of origin.

Figure 1 presents the kernel PCA results performed on the combined kernel K * . The histogram (left) presents the entropy supported by the first 15 axes of the kernel PCA and shows that the first two axes are enough to provide relevant information on the data. Figure 1 (right) displays the projections of the ocean samples on the first two principal component. The first axis represents 18.08% of the total entropy and opposes samples from the mesopelagic (MES) zone and the epipelagic layers (SRF and DCM).

To conclude, integrating taxonomic and functional community composition with environmental factors allows to have a fast insight of the different data sets within a single analysis. Future work should investigate multiple kernel learning (MKL) in order to learn kernels weights, α m , defined in Equation 1 as proposed in [Speicher and Pfeifer, 2015]. MKL would allow to have a better insight on the different data sets by sorting the kernels considering their weight and thus their significance. Also, the self-organizing map algorithm [Kohonen, 2001] and its extension to data described by a kernel will be investigated to classify the different ocean samples.

Figure 1 -

 1 Figure 1 -Kernel PCA Entropy preserved by the 15 first axes on the left and projection of the observations on the first two principal components on the right. Colors represent the oceanic regions and shapes the depth layers.

[

  Speicher and Pfeifer, 2015] Speicher,N. and Pfeifer, N. (2015). Integrating different data types by regularized unsupervised multiple kernel learning with application to cancer subtype discovery. Bioinformatics, 12(31) :i268-i275.[Sunagawa et al., 2015] Sunagawa, S., Coelho, L. P., Chaffron, S., Kultima, J. R., Labadie, K., Salazar, G., Djahanschiri, B., Zeller, G., Mende, D. R., Alberti, A., Cornejo-Castillo, F. M., Costea, P. I., Cruaud, C., d'Ovidio, F., Engelen, S., Ferrera, I., Gasol, J. M., Guidi, L., Hildebrand, F., Kokoszka, F., Lepoivre, C., Lima-Mendez, G., Poulain, J., Poulos, B. T., Royo-Llonch, M., Sarmento, H., Vieira-Silva, S., Dimier, C., Picheral, M., Searson, S., Kandels-Lewis, S., , Bowler, C., de Vargas, C., Gorsky, G., Grimsley, N., Hingamp, P., Iudicone, D., Jaillon, O., Not, F., Ogata, H., Pesant, S., Speich, S., Stemmann, L., Sullivan, M. B., Weissenbach, J., Wincker, P., Karsenti, E., Raes, J., Acinas, S. G., and Bork, P. (2015). Structure and function of the global ocean microbiome. Science, 348(6237).