Activities : submission deadlines

If you wish to have your submission evaluated by the next Scientific Concil, please note the following submissions dealines :

– Residential studies: 01/05/2015 (for a stay in 2015 or 2016)
– Authors’ residency prize : for a residency in 2016, applications are accepted until January 31, 2015

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Posted in News

A tribute to Anne Gruner Schlumberger
from Professor Fotis C. Kafatos

It is difficult to speak or write about your spiritual mother. Silence seems most appropriate, especially about someone who always avoided public recognition and adulation. But I need to say goodbye to the most remarkable human being who blessed me with her friendship. And I need to express the gratitude of myself and of the many others who, as youngsters, benefited by her generosity, of all the people that she helped educate, and of the countless children who were enriched by her libraries, in Greece and in France.

I met Annette in 1956, when I was 16, and she changed my life. Continue reading

Posted in History and life of the Foundation

Lauréats 2014 du Prix de la Résidence pour la photographie

PrixPhoto2014Le jury du Prix de la RĂ©sidence de la photographie de la Fondation des Treilles (composĂ© de Madame Laura Serani, prĂ©sidente, Hassan EzzaĂŻm, Charles-Henri Filippi, Costa Gavras, Macha Makeieff et Sarah Moon) vient de dĂ©signer, pour la session 2014, trois laurĂ©ats qui seront accueillis Ă  la Fondation des Treilles durant l’annĂ©e 2015 : Continue reading

Réexaminer le rÎle de la plasticité phénotypique dans le processus évolutif

Liste des participants :

Erik Andersen, Charles F. (Charlie) Baer, Christian Braendle (organisateur), Ivo Chelo, Asher Cutter, Marie Delattre, Ronald E. (Ron) Ellis, Marie-Anne FĂ©lix, Eric Haag, Simon C. Harvey, Karin C. Kiontke, Patrick McGrath, Stephen (Steve) Proulx, Scott Rifkin, Mattew (Matt) Rockman, Henrique TeotĂłnio, Mark Viney

Braendle_Teotonio_Group_2014

Compte rendu

Plasticité phénotypique et évolution chez les nématodes Caenorhabditis
par Christian Braendle et Henrique Teotonio
25 – 30 aoĂ»t 2014

Résumé

L’un des dĂ©fis majeurs de la biologie actuelle est de comprendre comment les variations de l’environnement interagissent avec le gĂ©nome et les processus de dĂ©veloppement pour produire de la diversitĂ© phĂ©notypique, et de comprendre Ă©galement comment ces interactions Ă©voluent. Notre but est de mieux dĂ©finir ces problĂšmes et de considĂ©rer les diffĂ©rentes approches permettant de les rĂ©soudre, en nous consacrant Ă  la biologie de Caenorhabditis elegans et d’autres espĂšces voisines. RĂ©cemment, C. elegans est devenu un organisme modĂšle de choix pour la gĂ©nomique comparative des populations et l’évolution expĂ©rimentale. Ces Ă©tudes, associĂ©es Ă  l’utilisation des outils classiques de biologie cellulaire et du dĂ©veloppement disponibles pour ce nĂ©matode, font de cet organisme l’un des mieux adaptĂ©s Ă  l’étude de la plasticitĂ© phĂ©notypique. Ainsi, des processus cellulaires et dĂ©veloppementaux bien caractĂ©risĂ©s peuvent ĂȘtre soumis Ă  des variations de l’environnement ou Ă  des manipulations gĂ©nĂ©tiques, tandis que des protocoles d’évolution expĂ©rimentale Ă  long terme, Ă  partir de variation naturelle existante ou de mutation, peuvent ĂȘtre couplĂ©s Ă  la cartographie Ă  haute rĂ©solution de phĂ©notypes complexes. Les rĂ©seaux de gĂšnes et leur dynamique temporelle peuvent ĂȘtre Ă©tudiĂ©s par la crĂ©ation de modĂšles informatiques. Cette confĂ©rence aux Treilles a rassemblĂ© des spĂ©cialistes reconnus de la plasticitĂ© phĂ©notypique, de l’évolution des rĂ©seaux de gĂšnes, de la structure des gĂ©nomes, de la gĂ©nĂ©tique des populations, de la cartographie QTL et GWAS, de l’expression gĂ©nique, de la dĂ©termination du sexe et du dĂ©veloppement de la lignĂ©e germinale, mais aussi du comportement et de l’écologie. Des intervenants venant de diffĂ©rents pays d’Europe ou des Etats-Unis, avec une expertise Ă  la fois thĂ©orique et pratique Ă©taient prĂ©sents. Parmi eux se trouvaient de nombreux jeunes chercheurs ayant rĂ©cemment crĂ©Ă© leurs groupes indĂ©pendants.

Mots clés

Variance phénotypique, plasticité phénotypique, interactions gÚnes-environnement, carte génotype-phénotype, nématodes Caenorhabditis, évolution.

Télécharger le compte rendu Revisiting the role of phenotypic plasticity in evolution

 

 

 

Asher Cutter Mark Viney Christian Braendle Ivo Chelo Marie-Anne FĂ©lix Stephen (Steve) Proulx Ronald E. (Ron) Ellis Henrique TeotĂłnio Marie Delattre Karin C. Kiontke Erik Andersen Matthew (Matt) Rockman Charles F. (Charlie) Baer Eric Haag Simon C. Harvey Patrick McGrath Scott Rifkin Revisiting the role of phenoplasticity in evolution using Caenorhabditis nematodes as model organisms - Fondation des Treilles, August 2014

Ségrégation des chromosomes : mécanismes et circuits de régulation

Liste des participants :

Anna Castro, Silke Hauf, Timothy (Tim) Hunt, Daisuke Izawa, Jean-Paul Javerzat, Geert Kops, Christian Lehner, Thierry Lorca, Marcos Malumbres, Adele Marston, Thomas U. Mayer (organisateur), Bela Novak, Terry Orr-Weaver, Olaf Stemmann, Kikuë Tachibana-Konwalski, Tomoyuki (Tomo) Tanaka, Katja Wassmann (organisateur), John Weir, Wolfgang Zachariae

Wassmann_Mayer_Group_2014

Compte rendu

Ségrégation des chromosomes : mécanismes et circuits de régulation / Mechanisms and Regulatory Circuits Mediating Chromosome Segregation in Meiosis and Mitosis
by Katja Wassmann
6 – 11 octobre 2014

Summary

The segregation of chromosomes is one of the most fundamental processes in biology. Despite the fact that mitosis and meiosis fascinate scientists since its first description more than 100 years ago, the underlying mechanisms and regulatory circuits are still poorly understood. Therefore, we decided to bring together experts which all share a vital interest in cell cycle research, yet have distinct complementary scientific expertise. This seminar gathered cell cycle specialists working on various model systems ranging from yeast and drosophila to Xenous oocytes and mouse models, structural biologists, and specialists in mathematical modeling. A third of the participants were young researchers who are going to or have recently set up their independent research group. The unique setup of the Fondation des Treilles meetings provided an ideal platform for mutually illuminating discussions where key questions in future cell cycle research were defined and multidisciplinary strategies to address these open questions were revealed. We are convinced that this meeting served as a nucleation center for future interdisciplinary research efforts in the field of cell cycle research.

Key words

Cell division, Chromosome segregation, Mitosis, Meiosis, Oocytes, Cohesin

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The Seminar

Participants were selected for their common interest in understanding mitotic and meiotic chromosome segregation. Usually we had three presentations in the morning, and four presentations in the afternoon. The seminar was started with a keynote lecture by the Nobel Prize laureate Tim Hunt. He gave an introduction on the key questions that have been studied in the field and the recent shift in interest from the regulation of kinases (which phosphorylate their substrates) to phosphatase, which counteract the very same kinases. He presented also the most recent work from his laboratory on the identification of Ensa, an inhibitor of the phosphatase PP2A-B55. Thomas U. Mayer gave the following talk on entry into the first meiotic division in Xenopus laevis oocytes. He presented recent, unpublished work showing that the E3 ubiquitin ligase APC/C is not required for maintaining oocytes arrested before entry into meiosis I, but on the contrary, for entry into meiotic M-phase. It is attractive to speculate that the mechanisms for meiotic entry he discovered in X. laevis oocytes apply also to mammalian oocytes. His presentation was followed by the talk of Anna Castro. Her group has discovered Arpp19, a close homologue of Ensa, as being required for counteracting PP2A-B55 for proper cell cycle progression. Arpp19 and Ensa are both phosphorylated and thereby activated by a kinase named Greatwall (Gwl). In her talk she showed that Gwl overexpression promotes cell transformation and increases tumor growth in mice, and in her talk she presented data on the question of whether this was dependent on Arpp19 and Ensa. In the afternoon, Marcos Malumbres then talked about how mammalian cells can die in mitosis which is an important issue to understand how tumor cells respond to drugs targeting mitotic kinases. Christian Lehner‘s talk on drosophila male meiosis brought important insights into the mechanisms of chromosome segregation in a chiasmata-independent manner. Using the budding yeast S. cerevisiae as a model system, AdĂšle Marston asked how kinetochores in meiosis I are attached to the bipolar spindle and whether they are stronger than in mitosis. John R. Weir, currently a postdoc in the lab of A. Musacchio, presented his data on the very ambitious goal of reconstituting and characterizing a human kinetochore, a multiprotein complex connecting chromosomes to the mitotic spindle.

The next morning was started by a talk from Olaf Stemmann on the role of the peptidyl-prolyl-isomerase Pin1 for regulating Securin-dependent inhibition of Separase, during mammalian mitosis. Using the fission yeast S. pombe as a model system, Jean-Paul Javerzat presented his recent results on the regulatory circuits for DNA release from Cohesin. Kikuë Tachibana Konwalski addressed whether reloading of Cohesin occurs during the extended prophase I arrest before entry into the meiotic divisions, in mouse oocytes by using genetically modified mice. In the afternoon, Katja Wassmann showed that the spindle assembly checkpoint protein BubR1 is absolutely essential for correct chromosome segregation in mouse oocyte meiosis. Tomoyuki U. Tanaka talked about the role of the kinase Aurora B in correcting faulty microtubule kinetochore attachments in the context of kinetochore attachments to the microtubule lateral side, and to the microtubule end. He also discussed the transition from a low- to a high- mechanical tension state of kinetochores. Daisuke Izawa, a postdoc from the lab of J. Pines, showed data on the in vitro reconstitution of the mitotic checkpoint complex, which is required for metaphase arrest upon spindle checkpoint activation. The last talk of the day by Geert J.P.L. Kops also dealt with spindle assembly checkpoint control. He discussed the inactivation of the checkpoint once all kinetochores are correctly attached through opposing phosphatases.

The following third day of the seminar we had presentations only in the morning to leave time in the afternoon for visiting the surroundings of the Domaine de Treilles in small groups. The session was started by Wolfgang Zachariae, who presented recent data on progression through the meiotic divisions, and how meiosis is linked to the differentiation program for spore formation, in budding yeast. Thierry Lorca talked about the kinase Greatwall and its role in the establishment of CSF arrest in Xenopus oocytes. Again, the role of Arpp19 for inhibition of PP2A was discussed, but this time in the context of maintaining oocytes arrested in metaphase of meiosis II for fertilization to occur. Terry Orr-Weaver discussed translational changes and regulated proteolysis that take place at the oocyte to embryo transition, in drosophila.

On the last day of our seminar we started with a presentation from Bela Novak. He gave a talk on the mathematical modeling of the regulation of the G2/M transition through nutritional modulation and relative to cell size. The final talk by Silke Hauf was focused on the balance of Cyclin B and Securin degradation relative to each other as fission yeast cells exit mitosis, to understand how the order of events is implemented in anaphase. The seminar was concluded by a final discussion, animated by Tim Hunt. All participants agreed that the seminar was extremely useful because of the relaxed setting and the small number of participants, allowing for in-depth discussions. The mix of young researchers at the postdoctoral stage, young group leaders, and experienced, senior researchers, combined with the interdisciplinarity of the seminar is expected to be very helpful for future projects of the participants. All participants agreed that a similar seminar should be organized in a couple of years, to further foster interactions and common projects in the long term.

Mécanismes et circuits de régulation permettant la ségrégation des chromosomes - Mechanisms and regulatory circuits mediating chromosome segregation in meiosis and mitosis - Fondation des Treilles - 2014 Anna Castro Silke Hauf Tim Hunt Daisuke Izawa Jean-Paul Javerzat Geert Kops Thierry Lorca Christian Lehner Marcos Malumbres Adele Marston Thomas Mayer Bela Novak Terry Orr-Weaver Olaf Stemmann Kikuë Tachibana-Konwalski Tomoyuki (Tomo) Tanaka Katja Wassmann John Weir Wolfgang Zachariae

Surmonter la résistance thérapeutique pour vaincre le cancer

Liste des participants

Julien Ablain, Laura Attardi, Alberto Bardelli, Glenn Dranoff, Mikala Egeblad, Jeffrey A. (Jeff) Engelman, Gerard Evan, Shridar Ganesan, Joseph (Jos) Jonkers, Anthony (Tony) Letai, Richard Marais, Frank McCormick, Benjamin (Ben) Neel, Scott Powers, Neal Rosen (organisateur), Louis M. Staudt, Hugues de Thé, David Tuveson (organisateur), Matthew G. (Matt) Vander Heiden, Valerie (Val) Weaver.

Tuveson_Rosen_Group2014

Compte rendu

Surmonter la résistance thérapeutique pour vaincre le cancer
par David Tuveson
27 juin – 2 juillet 2014

Keywords: Cancer drug resistance, adaptive resistance, immune therapies, cancer cell death, synthetic lethality, organoids, mitochondrial priming, cancer metabolism, Myc, Ras, P53, phosphatases, tumor tensile forces, drug delivery, cancer dormancy, clonal heterogeneity and evolution.

Overview: 

The 20 participants represented expertise in clinical oncology, genetics, drug development, biochemistry, cancer modeling, and immunology. The participants engaged in animated, unrestrained conversations on the mysteries and controversies in our field. Collaborations were formed, and unsupported areas were discarded.

Anthony Letai proposed that the response of patients to therapy reflected the apoptotic threshold of their cancer cells. Furthermore, that this can be measured as a fundamental property of the mitochondria contained in their cancer cells. Accordingly, Tony developed BH3 profiling for the neoplastic cell mitochondria, a technique that measures the ability of BH3 pro-death peptides to induce mitochondrial outer membrane permeabilization. BH3 profiling revealed that patients who respond to chemotherapy had highly primed mitochondria prior to treatment, as patients who responded poorly had poorly primed mitochondria. Most normal primary human cells were not primed, while bone marrow-derived cells were, perhaps explaining the special sensitivity of the bone marrow to cytotoxic therapy. Tony is now applying this technique to short term drug treatments of primary neoplastic cells harvested from patients, and finds that he can predict active drugs using “Dynamic BH3 Profiling. Dr. Letai posed the following questions that need to be addressed: “For which drugs will Dynamic BH3 profiling be most predicitive of clinical response?  For which tumors? Also, will there be a limit to the number of treatments that can be simultaneously tested?”

David Tuveson discussed pancreatic cancer, a lethal malignancy due to its late diagnosis and limited response to treatment. Pancreatic cancer is predicted to become the second most common cause of cancer death in the USA within a decade. Therefore, tractable methods that enable the development of new diagnostic and therapeutic approaches for pancreatic cancer patients was developed by Dave in collaboration with Hans Clevers (Utrecht, NE). Robust organoid models were prepared from normal and neoplastic adult murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from small amounts of tissue, proliferate indefinitely with ductal characteristics when passaged in semisolid media, survive freezing and thawing, and maintain a stable genome. Following orthotopic transplantation, the neoplastic organoids recapitulate the postulated stages of tumor development by forming intraepithelial and cystic neoplasms prior to progressing to invasive carcinomas. In culture, the organoids correctly predicted the resistance of Kras mutant cells to combined MEK and AKT inhibitors. Also, they suggested that combinations with pan-Her inhibitors would circumvent this adaptive resistance. Pancreatic organoids provide new molecular and cellular insights into cancer pathogenesis, and enable translational approaches that may reasonably accelerate the care of pancreatic cancer patients. Dr. Tuveson posed two challenges based upon this work: “Will organoid models of cancer accelerate individualized approaches to cancer genetics and cancer therapy?” Also, will the organoid approaches be useful methods to model adaptive resistance to therapies?”

Ben Neel discussed new insights into the role of PTP1B in breast cancer. Previous studies by his group and that of Michel Tremblay had found that PTP1B-deleted mice are resistant to HER2+ breast cancer. In addition, the Tremblay group had shown that mammary specific over-expression of PTP1B alone could be oncogenic.  Neel’s group tested the effects of PTP1B depletion (by shRNA) in a set of HER2+ human breast cancer cell lines. Surprisingly, there was no effect on proliferation of this lines in normal 2D culture, in low serum, at low density or in low glutamine or glucose. Likewise, colony formation in soft agare or Matrigel was unaffected. When these lines were injected into nude mice, however, tumorigenicity was impaired. Inducible depletion of PTP1B also arrested tumor growth. Remarkably, in both settings, PTP1B depletion resulted in marked hypoxia and necrosis.  Furtheremore, the PTP depleted lines also were much more sensitive to hypoxia in vitro. Reconstitution and inhibitor studies showed that these effects were PTP1B-specific and required PTP1B activity.  Subsequent investigations showed that none of the known hypoxia pathways were abberant in PTP1B-deficient cells. Instead, PTP1B appears to regulate a large (600kd) protein, RNF213, recently implicated in Moyamoya disease. RNF213, in turn, controls the activity of one or more a-ketoglutarate dependent dioxygenase enzymes, as the death of PTP1B-deficient cells can be rescued by specific oxygenase inhibitors. Dr. Neel feels that future studies need to be aimed at elucidating the details of this novel PTP1B/RNF213/a-kg dioxygenase pathway, and defining its roles in other malignancies.

Glenn Dranoff presented evidence that the NKG2D pathway may be involved in the therapeutic effects of cancer vaccines and immune checkpoint blockade. NKG2D is an activating receptor expressed on NK cells and CD8+ cytotoxic T lymphocytes, which contributes to immune mediated tumor control. Although NKG2D ligands show minimal expression in healthy tissues, oncogenic stress triggers upregulation of these ligands on the surface of cancer cells. Tumors escape from NKG2D mediated cytotoxicity, however, through shedding surface ligands, particularly MICA, which leads to NKG2D downregulation and dysfunction. Some patients who respond to immunotherapy generate antibody responses to MICA that overcome this immune escape through binding shed MICA and promoting MICA specific cytotoxicity. In collaboration with Kai Wucherpfennig, fully human anti-MICA monoclonal antibodies have been isolated from responding cancer patients, and these enhance NK and CD8+ T cell function through several MICA-specific mechanisms. The anti-MICA monoclonal antibodies as well as a novel NKG2D-Fc fusion protein that targets all NKG2D ligands might prove useful in cancer immunotherapy. Dr. Dranoff challenged the community to determine whether restoration of NKG2D function will be sufficient to promote immune mediated tumor destruction in cancer patients.

Frank McCormick presented a cell system of Ras-less MEFs as a platform to investigate the specific effects of Ras oncogenes. K-Ras plays a direct causal role in many human cancers, most notably in pancreatic cancers, which are almost always driven by K-Ras mutations. We have discovered that K-Ras, initiates a stem-like program that increases drug resistance, enables K-Ras cancer cells to initiate tumors and metastasize efficiently and produce the cytokine LIF that maintains cells in a stem-like state. Blocking LIF with neutralizing antibodies could represent a new therapeutic strategy for K-Ras cancers.  The stem-like program that K-Ras initiates is mediated by direct binding to Calmodulin, resulting in loss of CaM kinase and inhibition of non-canonical wnt signaling. We have been able to disrupt K-Ras/Calmodulin binding by activating PKC, using an orally available natural compound related to phorbol esters.  This compound prevents tumor formation in mouse models of pancreatic cancer.

Laura Attardi discovered that P53 tumor suppressor mechanisms are separable from the canonical acute DNA damage induced cell cycle arrest and cell death pathways. By leveraging a p53 knock-in mouse strain expressing a transcriptional activation domain mutant that activates only a subset of p53 target genes yet is completely active in tumor suppression in a variety of different tumor types, she has been able to discover a set of novel p53 tumor suppression-associated target genes, which she is currently analyzing. She discussed the approaches she is taking to functionally identify the key targets mediating p53 tumor suppression.

Gerard Evan discussed the importance of considering nodes of tumor cells as opposed to isolated oncogenes, including the Mitogen kinase/Ras cloud, the Myc cloud, and the E2F cloud. Gerard also discussed cooperation of the Myc and Ras oncogenes in mouse models of lung and pancreatic cancer. He demonstrated that Myc/Ras oncogenic cooperation, known for some 30 years but without an underlying mechanism, is very multifaceted and includes both tumor cell intrinsic and extrinsic (microenvironmental) processes. For example, he demonstrated how acute activation of Myc can rapidly convert indolent PanIN lesions to PDAC, together with the dramatic signature desmoplasia that characterizes this particular cancer: subsequent de-activation of Myc triggers rapid regression back to a PanIN state, accompanied by regression of desmoplasia. These studies reveal the complex way that nodal oncogenes cooperate with each other to drive and maintain cancers,

Matt Vander Heiden argued that metabolic changes in the tumor can be predictive of therapeutic response, and might be targets for therapies, but success in both areas will require a better understanding of tumor metabolism. He presented data to suggest that the metabolism of tumors in mice is not the same as the metabolism of cell lines in culture. Lung and pancreatic tumors oxidize more glucose than cell lines derived from those tumors grown in culture, and also use amino acids as a nutrient source. At least some of the amino acids tumors use can be derived from the breakdown of normal tissue proteins. The increased turnover of tissue proteins in pancreatic cancer results in an increased in branch chain amino acids in both human patients and in mouse models of pancreatic cancer. One explanation for the differences in metabolism between tumors and cultured cells is that tumors are comprised primarily of non-proliferating cells and thus are likely to dominate the metabolic signal measured in the tumor. Cell culture is a reasonable model of proliferative cancer cell metabolism, and data was also presented to suggest that regulation of glucose metabolism is important in part to supply the nucleotides for DNA replication. Serine synthesis and metabolism via the mitochondria to generate folates for nucleotide synthesis are important for this process as well.

Neal Rosen discussed the mechanisms of drug response to targeted therapies, and resistance in human tumors. Neal discussed the pathway modulation that occurs in cancer cells when treated with therapies that target oncogene dependent targets, including oncogenic BRAF in melanoma and Her2 in TNBC. Neal coined this process “adaptive resistance”, and it appears to be a general phenomenon in neoplastic cells, including ER and AR blockade in breast and prostate cancer, respectively. To circumvent adaptive resistance, the pathway of resistance must be elaborated such that suitable additional antagonists are employed. Dr. Rosen hypothesized that strong blockage of cancer cell dependencies would leave less opportunity for adaptive resistance to occur in the first place.

Mikala Egeblad has devised intravital microscopy methods to visualize drug penetration, cancer cell death, and stromal responses in tumors after administration of cytotoxic chemotherapy. She has observed that heterogeneity in drug penetration into tumors can be a barrier against tumor response to therapy. She has also documented an influx of inflammatory cells into tumors after cytotoxic therapy, and she and many other groups have found that this influx of reactive inflammatory cell reduces the response to therapy. Currently, Mikala Egeblad’s group is studying whether regional variation in the microenvironment influence cancer cells ability to acquire genomic changes conferring resistance. They have also started to implement imaging in lungs during dissemination of cancer cells and found that neutrophils promote cancer cell invasion and metastatic seeding. Major unanswered questions from this work are 1) how do inflammatory cells alter cancer cells to reduce therapy responses? And 2) to what extent do inflammatory cells contribute to drug resistance of metastatic cancer?

Julien Ablain discussed a new zebrafish system of cancer modeling. He adapted the CRISPR/cas9 technology of genome editing to develop a vector system for tissue-specific gene inactivation in zebrafish. This tool allows cell type-restricted, high-throughput loss-of-function studies. Knock-out of p53 specifically in melanocytes of melanoma-prone fish expressing mutant Braf resulted in rapid tumor formation, thus providing a proof of principle for an in vivo screen of candidate melanoma-suppressor genes. Dr. Ablain proposed that this zebrafish system will allow the identification of novel tumor-suppressor genes (other than cdkn2a, pten and p53) that cooperate with activated Braf to drive melanomagenesis.

Lou Staudt discussed the development of rational drug combinations to improve the therapy of the most aggressive subtype of diffuse large B cell lymphoma (DLBCL), termed activated B cell-like DLBCL. The B cell receptor (BCR) signaling pathway is key to the pathogenesis of ABC DLBCL, which turns on multiple downstream survival pathways, including NF-B and PI(3) kinase.   This “chronic active” BCR signaling can be targeted by the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which has produced a high response rate in ABC DLBCL in early phase clinical trials. While some patients have prolonged remissions, the majority eventually relapse, necessitating the development of combination therapies. Ibrutinib synergizes well with drugs targeting the other major survival mechanisms in ABC DLBLC including the PI(3) kinase pathway and BCL2. The drug lenalidomide inhibits IRF4, the master transcription factor for ABC DLBCL, and synergizes strongly with ibrutinib in killing ABC DLBCL cells. It is evident that there are too many combinations of drugs to be tested sequentially in clinical trials. Therefore, it will be imperative to derive rational combinations of 3 or more drugs that inhibit all parallel survival mechanisms as well as common resistance mechanisms to achieve a high rate of long-lasting remissions.

Valerie Weaver emphasized the importance of biophysical and biochemical properties of the tissue microenvironment in regulating cancer progression and treatment. She discussed the role of biophysical properties of the cells and the extracellular matrix microenvironment and presented data to illustrate how tissue mechanics is able to disrupt normal tissue homeostasis and contribute to the malignant behavior of cells and tissues. In her presentation she stressed that all tumors are mechanically corrupted and she presented evidence to demonstrate how high tissue levels force, derived from elevated cell contractility (intrinsic force), and the stiffness of the extracellular matrix (extrinsic force), collaborate to stimulate tumor cell growth, survival and motility/invasion in culture and in vivo. Her findings indicate that many oncogenes could promote the malignant behavior of tissues because they alter cell contractility and induce tissue fibrosis. Mechanistically her data argue that at the cellular level high force promotes integrin adhesions to alter growth factor receptor signaling and at the tissue level high force alters the vasculature to promote hypoxia and impede drug delivery and stimulates chemokine expression to modify the immune response. In support of this hypothesis she presented work relating to pancreatic fibrosis and a JAK-Stat3-integrin-tissue tension circuit that fosters pancreatic tumor progression/aggression. Understanding how intrinsic and extrinsic force regulates tumor behavior and treatment response may reveal novel targetable pathways towards which new therapies can be developed. Dr. Weaver’s work will address the fundamental issues of how abnormal cell and tissue mechanics of tumors contribute to treatment resistance, and the role of oncogenes in this process.

Scott Powers proposed a more focused approach to developing therapeutic strategies from the extensive genomic characterizations of DNA copy number alterations across many tumor types. Most copy number alterations are large and likely involve the action of tens perhaps hundreds of dosage-sensitive oncogenic drivers and tumor suppressors. In contrast, the number of focal amplicons like HER2 that can be considered as a distinct genetic event, independent of other nearby changes, is limited. Based on analysis of expression and protein data in TCGA, showed that our current understanding of how the HER2 amplicon works is backed by human data but that our current understanding of how the CCND1 amplicon works is not supported at all. Scott proposed that new genetic tools and models will be needed to develop a better understanding of recurrent focal amplicons and hopefully lead to new targeted therapeutic strategies.

Jeff Engelman described the response of lung cancer patients to drugs targeting EGFR or ALK. Transient responses are usually followed by resistance in most patients, and re-biopsy of the lung lesions revealed that on-target gatekeeper mutations occurs in many cases, whereas parallel pathways are activated in others. The parallel pathways include amplification of c-MET, and therefore strategies that include chemical kinase inhibitors that resist gatekeeper mutations, and those that also target c-MET and other bypass kinases, are under way. Finally, the surprising observation that adenocarcinoma cells display altered differentiation to neuroendocrine cancers resembling small cell carcinoma has been made in a minority of patients. These neuroendocrine-like cells still harbor the mutant EGFR alleles, and respond to classical SCLC regimens such as etoposide and cisplatin. Dr. Engelman hypothesized that altered cellular differentiation states may be another important resistance mechanism for human cancer, as appears to be the case in prostate cancer following blockade with new AR antagonists.

Alberto Bardelli presented models of colorectal cancer progression based on genetic and pharmacological data. He proposed that CRC develops in at least three major subtypes all of which start by acquiring an APC/beta cat mutation. At this stage all 3 subtypes are highly dependent on EGFR GFs provided by the environment. Upon selective forces imposed by yet unknown pressures the first groups survives by mutational activation of KRAS/NRAS and BRAF. The second subtype evolves through acquisition of deregulated RTKs (HER2, ALK, NTRK, IGFR1). The third subgroup progresses by overcoming the selective pressure through increased production of EGFR ligands (autocrine loop). Dr Bardelli also showed that EGFR blockade with the monoclonal antibodies cetuximab and panitumumab is effective in cells ad patients only in the third subgroup. Dr Bardelli went on to identify the mechanisms of acquired resistance to EGFR blockade and described an approach based on individual cell barcoding to visualize clonal evolution under drug selection. Using this approach he argued that in addition to the major clones that emerge during drug selection a large number of minority populations also survive indicating the presence of additional mechanisms of resistance or persistence in the population. The polyclonal nature of therapeutic resistance can also be observed in patients by measuring the concomitant emergence of multiple mutations in KRAS, NRAS and BRAF in the blood of individual treated with anti EGFR antibodies. Finally he presented data suggesting that the concomitant blockade of EGFR and MEK intercepts multiple mechanisms of acquired resistance to EGFR blockade. These findings represent the basis for clinical trials that are ongoing in Dr Bardelli’s institution.

Richard Marais showed that ultraviolet (UV) light accelerates BRAF-driven melanoma by targeting TP53. Sunscreen slows the development of melanoma, but offers incomplete protection, so it should be used in conjunction with other strategies to protect the skin from the damaging effects of UV light. He described the induction of paradoxical activation of ERK signaling by BRAF inhibitors in tumors when RAS is active in cells. He described use of biochemical and genomic approaches to identify mechanisms of resistance to BRAF inhibitors in BRAF mutant melanoma patients and commented that many mechanisms of resistance exist, although not all mechanisms have been validated in patients. Paradox breaking inhibitors appear to be active in resistant tumors. He also showed that reactivation of the ERK pathway in resistant cells drives invasion and metastasis through upregulation of IL8 and expression of extracellular proteases. Thus, resistance may be accompanied by increased metastasis in the presence of the drug. Also, he described that resistant cells appear to switch from glucose to glutamine as a major carbon source and this appears to contribute to the resistant phenotype. He concluded that it is important to develop precision medicine approaches to improve outcomes for melanoma patients who have developed resistance to targeted therapies.

Hugues de The discussed how his laboratory has been interested in the molecular basis for therapy response in the field of cancer. I first presented data on breast cancer linking P53 status to initial response to dose-dense chemotherapy. In the neo-adjuvant setting, we demonstrated that pathologically complete remissions in P53-mutant tumours were followed by long-term survival, likely pointing to the cure of the majority of these patients. Thus, P53-mutant breast cancers are exquisitely sensitive to dose-dense alkylation. I then presented data on the acute promyelocytic leukemia, a disease that is exquisitely sensitive to retinoic acid and arsenic. We showed evidence that differentiation is not the primary basis for APL cure. Animal models argue that PML/RARA degradation by these two drugs is the basis for irreversible loss of leukemia self-renewal. Loss of the driving oncogene triggers a PML/P53 senescence program that is ultimately responsible for APL eradication. Mutations that abolish degradation by arsenic or retinoic acid were associated to therapy resistance. Resistance to arsenic maps to the PML part of PML/RARA, while resistance to retinoic acid is due to mutations in the RARA part. Other models were presented in which therapy-triggered degradation of the driving oncogene is associated to remission.

Jos Jonkers discussed mouse models of TNBC, and therapeutic approaches using GEMMS and PDX models. Dr. Jonkers demonstrated that strong alkylating agents could cure mouse models of Brca1/Brca2/p53 mutant TNBC, and old clinical data support the use of these agents. Furthermore, mechanisms of escape for PARP inhibitors and Adriamycin could also be demonstrated using these TNBC allograft models, including drug efflux pumps. Dr. Jonkers suggests that methods to cure people of TNBC can be developed by combining cytotoxic drugs, targeted drugs, drugs that block resistance mechanisms, and immunotherapies.

Shridar Ganesan analyzed published clinical data to develop a model of how adjuvant chemotherapy works to prevent breast cancer recurrence. In this model a stochastic transition of disseminated metastatic cells from a dormant/G0 state to active growth is postulated to drive recurrence. Different breast cancer classes are characterized by different transition rates, that leads to different dynamics of relapse. Analysis data from adjuvant treatment trials suggest that adjuvant therapies can only eliminate metastatic foci that are in active growth during the time in which adjuvant therapy is delivered. One implication is that we need to reconsider how to optimize scheduling and dosing of chemotherapy to improve outcomes in early stage breast cancer. This work poses the following clinically relevant question. First, what is the optimal dosing schedule of chemotherapy to deliver maximum efficacy and minimal toxicity? Second, is maximizing time of exposure to minimum effective dose more important than achieving maximum tolerated dose? Finally, how can non-cycle/G0 cancer cells best be killed?

Glenn Dranoff Frank McCormick Richard Marais Val Weaver Dave Tuveson Scott Powers Jos Jonkers Hugues de Thé Alberto Bardelli Matthew Vander Heiden Benjamin (Ben) Neel Julien Ablain Gerard Evan Shridar Ganesan Jeffrey (Jeff) Engleman Anthony (Tony) Letai Laura Attardi Mikala Egeblad Louis Staudt Neal Rosen Overcoming therapeutic resistance to defeat cancer - Fondation des Treilles

Quelle(s) valeur(s) pour la biodiversité ?

Liste des participants :

Gilles Boeuf, Charles-Hubert Born, Mathilde Hautereau-Boutonnet (organisatrice), Vincent Devictor, Isabelle Doussan, JérÎme Dubois, Jérome Dupras, Laurent Fonbaustier, Sophie Gambardella, Julien Hay, Sophie Lavallée, Sandrine Maljean-Dubois, Mustapha Mekki, Alain Papaux, Emmanuel Putman, Jean-Michel Salles, Eve Truilhé-Marengo (organisatrice), Alexandre Zabalza

Biodiversite2014_Groupe

Compte rendu

Quelle(s) valeur(s) pour la biodiversité ?
par Mathilde Hautereau-Boutonnet et Eve Truilhé-Marengo
8 – 13 septembre 2014

Résumé

Durant la semaine du 8 septembre 2014, la Fondation des Treilles a accueilli un sĂ©minaire s’intitulant « Quelle(s) valeur(s) pour la biodiversité ? ». Aujourd’hui, la biodiversitĂ© ne cesse de se dĂ©grader. La question est alors de savoir si accorder une valeur Ă  la biodiversitĂ© peut conduire Ă  une amĂ©lioration de sa protection. Ce sĂ©minaire rĂ©unissait 18 chercheurs dont deux juniors provenant des disciplines scientifiques, Ă©conomiques, philosophiques et juridiques. Au cours de ce sĂ©minaire, les diffĂ©rentes interventions et Ă©changes sur ce sujet ont permis de mettre en Ă©vidence la relativitĂ© de la notion de « valeur » selon les disciplines et d’éprouver Ă  la fois le potentiel et les limites d’une protection de la biodiversitĂ© par le biais des valeurs. Au terme de ce sĂ©jour, on peut en retenir que c’est finalement en recourant Ă  une prise en compte multidisciplinaire des critĂšres de valeur(s) que la biodiversitĂ© pourrait ĂȘtre davantage protĂ©gĂ©e.

Mots clés

BiodiversitĂ© – espĂšces – faunes – flores – valeur(s) – coĂ»t – valeur Ă©conomique – valeur philosophique – valeur juridique – valeur politique – valeur scientifique – patrimoine – bien – service Ă©cologique – service Ă©cosystĂ©mique – marchĂ© – propriĂ©tĂ© – droit – droit international – pĂȘche – terre –

Compte rendu

Le sĂ©minaire s’intitulant « Quelle(s) valeur(s) pour la biodiversité ? » rĂ©unissant des chercheurs provenant de multiples disciplines (sciences, Ă©conomie, droit, philosophie) a Ă©tĂ© accueilli Ă  la Fondation des Treilles durant la semaine du 8 septembre 2014.

L’idĂ©e de ce sĂ©minaire partait du constat suivant : l’instrument juridique joue un rĂŽle important dans la protection de la biodiversitĂ©. Aujourd’hui, coexistent et s’entremĂȘlent des rĂšgles de droit international, europĂ©en et national, porteuses de dispositifs relevant de ce qu’on appelle le droit spĂ©cial de l’environnement, parfois de type local, tournĂ©s vers la protection et rĂ©gulation des espĂšces protĂ©gĂ©s, menacĂ©es, nuisible, rares, remarquables, en voie de disparition, relevant de la flore et la faune ou autres populations, mais aussi de type global tendant Ă  apprĂ©hender les Ă©lĂ©ments de la biodiversitĂ© dans leur ensemble en saisissant leurs interactions, par le biais de Ă©cosystĂšmes, et plus particuliĂšrement des espaces protĂ©gĂ©s via les parc nationaux ou rĂ©serves naturelles. Plus particuliĂšrement, le droit international s’est emparĂ© de la protection de la biodiversitĂ© avec la Convention de Rio sur la diversitĂ© biologique en la dĂ©finissant comme la « variabilitĂ© des organismes vivants de toute origine y compris, entre autres, les Ă©cosystĂšmes terrestres, marins et autres Ă©cosystĂšmes aquatiques et les complexes Ă©cologiques dont ils font partie; cela comprend la diversitĂ© au sein des espĂšces et entre espĂšces ainsi que celle des Ă©cosystĂšmes ».

Pourtant, aujourd’hui, la biodiversitĂ© ne cesse de se dĂ©grader. Selon le Millenium Ecosystem Assessment, le taux d’extinction des espĂšces est de l’ordre de 1% tous les ans et plus de la moitiĂ© des Ă©cosystĂšmes de notre planĂšte est en danger. Pour en rendre compte, l’IUCN a crĂ©Ă© un indicateur Ă  partir de listes rouges. Cet indice montre que l’état de la biodiversitĂ© n’a cessĂ© de se dĂ©grader depuis les annĂ©es 50. Au total, 11 espĂšces sur les 119 recensĂ©es comme en voie d’extinction quitteraient prochainement le territoire français.

Face Ă  ce constat, ce sĂ©minaire entendait posait la question suivante : « aujourd’hui face aux faiblesses du droit, n’est-il pas temps de refonder, rĂ©viser, amĂ©liorer les techniques de protection de la biodiversitĂ© en s’intĂ©ressant Ă  ses valeurs ? »

Comme l’a montrĂ© le sĂ©minaire, ce sont avant tout les Ă©conomistes qui occupent le terrain de cette recherche sur les valeurs. En effet, depuis quelques annĂ©es, l’on assiste Ă  la multiplication d’études destinĂ©es Ă  mettre en avant l’évaluation de la biodiversitĂ© et des services liĂ©s aux Ă©cosystĂšmes pour mieux la protĂ©ger. Pourtant de l’aveu mĂȘme des Ă©conomistes prĂ©sents, ces thĂ©ories peuvent ĂȘtre critiquĂ©es ou relativisĂ©es. 

De ce fait, notre sĂ©minaire a voulu offrir une place importante aux autres disciplines : le droit, les sciences de l’écologie et la philosophie. Il est vrai que, Ă  bien y regarder, le discours sur la valeur n’est pas l’apanage des sciences Ă©conomiques. Il suffit pour s’en convaincre de jeter un coup d’Ɠil vers certains dictionnaires de langue française, notamment le dictionnaire Larousse qui fait rĂ©fĂ©rence Ă  pas moins de dix dĂ©finitions associĂ©es Ă  des exemples. La valeur est attachĂ©e Ă  ce que vaut un objet en argent ou en quantitĂ©, Ă  ce qui est digne de respect moral ou intellectuel, Ă  ce qui est considĂ©rĂ© comme personnellement un idĂ©al Ă  atteindre, ce Ă  quoi on tient, au jugement relatif Ă  ce qui est bien ou mal, important ou peu important, etc. On en retient une notion aux multiples dĂ©cors, passant du sens aux sens, Ă  cheval sur l’apprĂ©ciation objective et subjective, quantitative et qualitative, intuitive, personnelle et rationnelle. Peu Ă©tonnant alors que son champ d’étude dĂ©passe les sciences Ă©conomiques.

Le sĂ©minaire a alors permis, Ă  travers les diffĂ©rentes interventions des chercheurs rĂ©unis, de mettre en Ă©vidence la nĂ©cessitĂ© de prendre en compte une pluralitĂ© de valeurs. Alors que les juristes ont mis en Ă©vidence l’évolution du droit dans ce domaine, en particulier la place croissante de la dimension non instrumentale de la biodiversitĂ© dans les rĂšgles de droit, la rĂ©novation possible des catĂ©gories de biens et de la notion de propriĂ©tĂ©, ses Ă©volutions nĂ©cessaires au contact des instruments de marchĂ© et de l’avĂšnement des services Ă©cosystĂ©miques, les Ă©cologues ont insistĂ© sur la nĂ©cessaire prise en compte de la valeur scientifique de la biodiversitĂ© pour mieux « dĂ©cider » et les philosophes ont mis en Ă©vidence les doutes quant Ă  l’efficacitĂ© de l’action humaine dans ce domaine.

S’il est impossible, au terme de ce sĂ©minaire, de conclure que, accorder une valeur Ă  la biodiversitĂ©, c’est garantir sa protection, il est en revanche incontestable que le fait de rĂ©flĂ©chir et de mettre en Ă©vidence la pluralitĂ© de valeurs accordĂ©e Ă  la biodiversitĂ© devrait conduire Ă  l’avenir Ă  renforcer sa protection.

Isabelle Doussan Sophie Gambardella Alexandre Zabalza Alain Papaux Gilles Boeuf Mustapha Mekki JérÎme Dubois Eve Truilhé-Marengo Julien Hay Mathilde Boutonnet Sophie Lavallée Emmanuel Putman Sandrine Maljean-Dubois Jérome Dupras Laurent Fonbaustier Charles-Hubert Born Quelle(s) valeur(s) pour la biodiversité ? - Fondation des Treilles Absent sur la photo : Vincent Devictor Absent sur la photo : Jean-Michel Salles

Cycles et croissances Ă©conomiques / Business cycles and economic growth

Liste des participants :

Amanar Akhabbar, François Allisson, Richard Arena, Tiziana Assenza, Michael Assous, Roger Backhouse, Pascal Bridel (organisateur), Olivier Bruno, Katia Caldari, Matthieu Charpe, Muriel Dal-Pont Legrand (organisateur), Domenico Delli Gatti, Rodolphe Dos Santos Ferreira, Harald Hagemann, Maria Cristina Marcuzzo, Andreas Pyka, Alain Raybaut, Hans-Michael Trautwein, Amos Witztum.

Bridel_DalPont_group2014

Compte rendu :

Cycles et croissance Ă©conomique / Business cycles and economic growth
par Pascal Bridel et Muriel Dal-Pont Legrand
16 – 21 juin 2014

Résumé

Avant d’ĂȘtre considĂ©rĂ©s comme des champs de recherche indĂ©pendants, l’analyse des cycles et la thĂ©orie de la croissance de la productivitĂ© ont longtemps Ă©tĂ© considĂ©rĂ©es comme des dynamiques Ă©troitement reliĂ©es. Plus prĂ©cisĂ©ment, ce n’est qu’au lendemain de la rĂ©volution keynĂ©sienne que le dĂ©veloppement de la macroĂ©conomie s’est vĂ©ritablement structurĂ© autour de deux champs indĂ©pendants avec, d’une part, les thĂ©ories des cycles qui s’intĂ©ressent aux mouvements stochastiques et, d’autre part, la thĂ©orie de la croissance qui analyse les conditions d’existence, d’unicitĂ© et le comportement d’un Ă©quilibre stable de longue pĂ©riode. L’objectif principal de ce sĂ©minaire Ă©tait de rĂ©unir des historiens de la thĂ©orie Ă©conomique et des praticiens de la thĂ©orie moderne des cycles et de la croissance pour un Ă©change sur l’origine et l’évolution de la relation entre les cycles des affaires et la croissance Ă©conomique.

Au lendemain de la crise de 2008 et dans le cadre d’une croissance Ă©conomique anĂ©mique, ce sĂ©minaire a permis un examen circonstanciĂ© de l’évolution de cette importante littĂ©rature et plus prĂ©cisĂ©ment des diffĂ©rentes tentatives menĂ©es par les Ă©conomistes afin de rĂ©concilier thĂ©ories des cycles d’équilibre (TCE) et thĂ©orie de la croissance. AprĂšs avoir identifiĂ© une sĂ©rie de tentatives destinĂ©es à  rĂ©concilier la dynamique des cycles avec celle de la croissance, ce sĂ©minaire a permis de clarifier les ruptures et les continuitĂ©s entre des prĂ©occupations thĂ©oriques anciennes et la modĂ©lisation rĂ©cente de cette problĂ©matique qui n’est toujours pas apprĂ©hendĂ©e d’une maniĂšre satisfaisante.

Mots clé : cycle, croissance, cycles réels

Keywords: cycle, growth, real business cycles

—–

Dans un premier groupe de communications, plusieurs historiens de la pensĂ©e Ă©conomique ont offert une analyse d’approches anciennes pour en tirer une inspiration et des parallĂšles avec la problĂ©matique contemporaine cycles-croissance. En discutant la contribution de D.H. Robertson (1915), Pascal Bridel montre la parentĂ© qui semble exister avec les chocs exogĂšnes de la thĂ©orie contemporaine des cycles rĂ©els : les agents rĂ©agissent d’une maniĂšre rationnelle aux chocs technologiques qui crĂ©ent Ă  la fois cycles et croissance. Amanar Akkhabar examine le modĂšle dynamique de LĂ©ontief pour illustrer la mĂ©thode originale que cet auteur applique Ă  son explication des cycles, de la croissance et des fluctuations. Dans le cadre d’un examen des Ă©conomises russes du tournant du 20Ăšme siĂšcle (Tugan-Baranovsky, Kondratriev et Boukharine notamment), François Allisson se demande quel rĂŽle jouent les schĂ©mas marxistes de reproduction dans leur analyse des cycles et de la croissance. Richard Arena se concentre sur la thĂ©orie des changements structuraux dans le court terme et le long terme ; il propose notamment une classification en trois classes des modĂšles en fonction de leurs capacitĂ©s Ă  relier cycles et changements structuraux (Pasinetti, Solow et croissance endogĂšne). Ces diffĂ©rences le mĂšnent Ă  distinguer trois types diffĂ©rents de changements structuraux. MichaĂ«l Assous propose une nouvelle formulation de la thĂ©orie des cycles de Kalecki. Il argumente en particulier que la dĂ©monstration de « self-sustaining cycles » dĂ©pend presque exclusivement de la valeur que Kalecki donne aux paramĂštres de son modĂšle (anticipations et progrĂšs technique notamment). Il examine Ă©galement les consĂ©quences d’une modification de la distribution du revenu sur la dynamique profit-investissement et donc de la croissance. Roger Backhouse offre une lecture extrĂȘmement intĂ©ressante de la disparition apparente de la thĂ©orie des cycles dans le programme de recherche des Ă©conomistes amĂ©ricains dans les deux dĂ©cennies suivant la publication de la ThĂ©orie gĂ©nĂ©rale. Utilisant les cas de Hansen et Samuelson, l’auteur dĂ©montre cependant que cette transition ne s’est pas faite au dĂ©triment total des thĂ©ories des cycles prĂ© keynĂ©siennes qui conservent un rĂŽle dans le cadre de la macroĂ©conomie naissante des annĂ©es 1940. Katia Caldari propose une analyse trĂšs dĂ©taillĂ©e de l’extrĂȘme difficultĂ© qu’ont les successeurs d’Alfred Marshall Ă  rĂ©concilier son analyse du long terme avec le court terme (et donc des cycles avec la question de la croissance). L’auteur considĂšre que cette difficultĂ© provient d’une incomprĂ©hension mĂ©thodologique Ă  saisir le rĂŽle jouĂ© par le temps dans la pensĂ©e marshallienne. Muriel Dalpont (et autres) rĂ©examinent l’ouvrage de Harrod (1936) largement Ă©clipsĂ© par la rĂ©volution keynĂ©sienne. Tout en se concentrant sur la contribution essentielle de Harrod (le lien entre concurrence imparfaite et cycles), les auteurs la mettent en rapport avec la dynamique du taux d’épargne dans le cadre du modĂšle dans lequel le taux de croissance effectif s’ajuste au taux de croissance d’équilibre. Dans le mĂȘme ordre d’idĂ©e, Rodolphe Dos Santos Ferreira rĂ©examine l’Essay in Dynamics Theory de Harrod. En particulier, il dĂ©veloppe l’intuition principale de l’auteur en modĂ©lisant l’interaction entre l’instabilitĂ© du sentier de croissance provoquĂ©e par les cycles. Il relie Ă©galement cette tentative prĂ©coce avec la dĂ©marche rĂ©cente de Woodford (1992). Harald Hageman (et autres) se sont, quant Ă  eux, intĂ©ressĂ©s aux parallĂšles entre les cycles de croissance de Schumpeter et Ă  leur rĂ©apparition contemporaine chez Aghion et Saint-Paul. Les auteurs se concentrent sur le concept de rĂ©cessions productives, une analyse proposĂ©e par Aghion et Saint Paul, qui se fonde sur un modĂšle de coĂ»t d’opportunitĂ© pour examiner les efforts de rĂ©allocation d’actifs effectuĂ©s par les entrepreneurs Ă  la suite d’une rĂ©cession, et qui se veut comme Ă©tant l’expression moderne de la pensĂ©e SchumpetĂ©rienne. C’est ce point qui est examinĂ© dans le papier. Christina Marcuzzo offre un survol analytique du dĂ©bat entre les Ă©conomistes de Cambridge Ă  propos des Ă©quilibres de courte et de longue pĂ©riode. La dispute entre nĂ©o-keynĂ©siens et nĂ©o-ricardiens est naturellement au centre de cette discussion thĂ©orique qui n’a jamais vraiment trouvĂ© de solution parmi la tradition cambridgienne. Hans-Michael Trautwein s’intĂ©resse quant Ă  lui aux contributions de Neisser et Haberler Ă  la transmission internationale des cycles. AprĂšs un examen dĂ©taillĂ©, ces deux approches sont comparĂ©es avec la macroĂ©conomie moderne des Ă©conomies ouvertes.

De leur cĂŽtĂ©, les thĂ©oriciens et les praticiens de la thĂ©orie moderne des cycles ont offert une sĂ©rie de survols liĂ©s Ă  l’origine de ces diffĂ©rents modĂšles. Dans le prolongement de la crise de 2008, Bruno Olivier s’intĂ©resse aux rapports entre les cycles de croissance et la distribution du revenu. L’auteur modĂ©lise la maniĂšre dont des variations de la distribution du revenu peuvent influencer le rythme de croissance tout en menant, paradoxalement, Ă  une situation de crise Ă©conomique. Mathieu Charpe rĂ©examine la question des fluctuations et de dependency ; l’auteur montre que le taux d’utilisation des ressources anticipĂ© dans le long terme ajuste l’output gap d’aujourd’hui. En utilisant la technique rĂ©cente des agent-based models, Domenico Delli Gatti propose de remĂ©dier Ă  l’une de leurs faiblesses en offrant une stratĂ©gie de formalisation qui rĂ©duit la ‘dimensionnalité’ de ces modĂšles en remplaçant la distribution de l’environnement financier des entreprises par les premier et second moments de la distribution elle-mĂȘme. Ces moments peuvent alors ĂȘtre utilisĂ©s comme des variables macroĂ©conomiques traditionnelles. ParallĂšlement, Tiziana Assenza propose un modĂšle qui illustre comment les ‘esprits animaux’ et des anticipations hĂ©tĂ©rogĂšnes amplifient les cycles et comment une coordination endogĂšne d’anticipations pessimistes renforce la crise et freine la reprise. Utilisant l’approche des chocs structurels, Andrea Pyka montre comment, dans le long terme, l’innovation et les changements structuraux ont influĂ© la croissance Ă©conomique depuis la rĂ©volution industrielle. L’auteur argumente en faveur d’un cercle vertueux entre capital humain, accroissement du revenu et hausse de la demande. De son cĂŽtĂ©, Alain Raybaut offre un survol dĂ©taillĂ© des discussions des trois derniĂšres dĂ©cennies sur la stabilitĂ©, les cycles dans une dynamique complexe dans des modĂšles de croissance avec monnaie. Finalement, dans un papier trĂšs novateur, et en faisant de nombreux aller-retour entre thĂ©orie classique et thĂ©orie moderne, Amos Witztum examine les rapports entre inĂ©galitĂ© et croissance. Sa contribution tente une synthĂšse entre la question des incitatifs, celle des abilities (capital humain) et l’idĂ©e trop souvent nĂ©gligĂ©e de l’utilitĂ© sociale de la croissance. En d’autres termes, l’auteur s’interroge avec pertinence sur l’acceptabilitĂ© sociale d’une croissance qui serait crĂ©atrice d’une plus grande inĂ©galitĂ© distributive.

Parmi les 19 participants au sĂ©minaire, il est intĂ©ressant de relever, qu’au cĂŽtĂ© de chercheurs expĂ©rimentĂ©s, six relevaient de la catĂ©gorie « jeunes chercheurs » (entre deux Ă  sept ans de leur thĂšse de doctorat), soit environ 30% du total.

Télécharger les abstracts de tous les articles (fichier.pdf).

Andreas Pyka Michael Trautwein Tiziana Assenza Maria Cristina Marcuzzo Rodolphe Dos Santos Ferreira François Allisson Amanar Akhabbar Muriel Dal-Pont Legrand Olivier Bruno Harlad Hagemann Michael Assous Roger Backhouse Alain Raybaut Richard Arena Pascal Bridel Katia Caldari Amos Witztum Domenico Delli Gatti Matthieu Charpe Cycles et croissance économique - Business cycles and economic growth - Fondation des Treilles

ActivitĂ©s : dates d’Ă©chĂ©ance de dĂ©pĂŽt des dossiers

Pour examen lors de la prochaine rĂ©union des instances concernĂ©es, les dates d’Ă©chĂ©ance sont respectivement:

– Demandes de sĂ©jour d’Ă©tude : le 5 janvier 2015 (pour un sĂ©jour en 2015 ou 2016)
– Prix rĂ©sidence d’auteur : pour une rĂ©sidence en 2016, les candidatures seront reçues jusqu’au 31 janvier 2015

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Combiner les dimensions – L’imagerie des processus d’infections de l’Ă©chelle du nano Ă  celle du corps entier

Liste des participants

Rogerio Amino, Priscille Brodin, Rut Carballido-Lopez, Maria Teresa Catanese, Jost Enninga (organisateur), Friedrich Frischknecht (organisateur), Kay GrĂŒnewald, Volker Heussler, Frank Lafont, Emmanuel Lemichez, Musa Mhlanga, Serge Mostowy, Agneta Richter-Dahlfors, Kristine Schauer, Spencer Shorte, Bettina Stolp, Sven van Teeffelen, Ger van Zandbergen, Michael Way

Enninga_Frischknecht_group_2014

Compte rendu

Combiner les dimensions – L’imagerie des processus d’infections de l’Ă©chelle du nano Ă  celle du corps entier
by Jost Enninga
7 – 12 avril 2014


Summary:
Infectious disease is a major cause of morbidity and mortality in our increasingly connected world due to widespread antibiotic resistance and the lack of vaccines against a large number of microbes. Understanding the molecular and cellular events of infection and their effects on the whole body are highly relevant for the rational development of novel drugs, vaccines and identification of novel drug targets. Research on this led to a discipline named “cellular microbiology” that combines microbiology, cell biology and immunology. It has become clear that cellular microbiology requires more quantitative, mainly imaging-based approaches including expertise from physicists and computer scientists to meet its goals. With this seminar, leading specialists from the associated research fields have discussed these current challenges to bridge cellular microbiology with cutting-edge microscopy.

Key words: Host-pathogen interactions, Light microscopy, Electron microscopy, Cellular microbiology, Infection models

 

The conference started discussing novel paradigms how intracellular bacterial pathogens undermine host cell functions, and how this can be analyzed by cutting edge imaging techniques. Jost Enninga (Institut Pasteur, Paris) opened the first session presenting the imaging of host cell invasion by the bacterial pathogen Shigella flexneri.  He addressed cell attachment, uptake, vacuolar rupture and inter- as well as intra-cellular spread.  Thanks to single-cell fluorescence reporters it is possible to follow quantitatively the temporal order of both the bacterial behavior as well as the cytosolic immune response in a highly heterogeneous setting. Jost presented evidence that the infected host plays an important role in controlling both the maintenance and the rupture of the vacuole involving a network of RabGTPases. The molecular details could be monitored by large volume correlative light electron microscopy. Priscille Brodin (INSERM, Lille) portrayed the power of high-content screening using drug and siRNA libraries during macrophage infection with Mycobacterium tuberculosis. She tracked the growth of this pathogens within the immune cells as readout. Her work identified novel small molecules with an important antimicrobial activity carrying a huge pharmacological potential. During the second half of her talk, she explained how Mycobacterium ulcerans, the causative agent of Buruli ulcer, takes advantage of the secreted polyketide mycolactone, to induce analgesia during the infection. Intracellular pathogens often hijack the host cytoskeleton, and Serge Mostowy (Imperial College, London) outlined the biology of septins, which can be considered as the fourth component of the host cytoskeleton. Using multimodal imaging technologies, he revealed how septins control the entry and intracellular growth of bacterial pathogens, such as Shigella and Listeria. In addition, he established a novel zebrafish infection model that allows imaging from the subcellular to the full body level during bacterial challenge. With this model, he has been capable to study the interaction of intracellular pathogens with different host cell types including stem cells.

The afternoon session of our first day in Les Treilles focused on quantitative imaging approaches to study host responses to parasitic infections. Ger van Zandbergen (Paul-Ehrlich-Institute) discussed Leishmania major (L. major) infection of human immune cells. His research group has been conducting high-content screens in primary human macrophages. To study progression of infection and its modulation by the innate immune system, he used fluorescently labeled parasites that can be tracked by 3D live cell imaging correlated with high-pressure freezing and focused ion beam scanning electron microscopy (SEM). Their imaging data suggests that apoptotic parasites are the first to enter into host cells.  The induction of autophagy in cells infected by dead parasites deceives the immune system to turn off inflammatory responses. Rogerio Amino (Institut Pasteur) presented intravital imaging studies of Plasmodium sporozoite infection in rodents. His lab studies the mechanisms and functions of host cell traversal (CT) of the sporozoites leading to invasion of the liver. Using a fading assay that measures the reduction of cytoplasmic GFP signal upon membrane wounding, he observed locomotion of RFP+ parasites through both Kupffer cells and endothelial cells. Freddy Frischknecht (University of Heidelberg) described inter-disciplinary approaches to measure the motility of individual Plasmodium sporozoites. Building upon in vivo observations showing that malaria sporozoites display different motility patterns in different environments, he outlined the power of novel tools and biophysical assays to understand the link between the shape of the parasite, its adhesion properties and its motility. Using micropillars he demonstrated that the environment rather than chemotaxis drives migration patterns. Reflection interference contrast microscopy (RICM), traction force microscopy (TFM) and optical tweezers enabled his laboratory to measure intricate details of the parasite movements. Volker Heussler (University of Bern) discussed Plasmodium berghei interactions with primary hepatocytes. He investigates strategies of cytosolic immune response evasion induced during the proliferation of merozoites. Utilizing transgenic parasites and fluorescent markers of cellular organelles, he showed that the membranes forming the vesicles in which merozoites are packaged prior to secretion into the liver sinusoids are of cellular origin.

The second day started with presentations on novel technologies to investigate viral infections. To better understand the assembly of viral particles Kay Gruenewald (Oxford University) and Maria Teresa Catanese (King’s College, London) portrayed the importance of electron microscopy for viral cell biology. Kay explained cryo- tomography to resolve unprecedented details of the Herpex Simplex virus particle. Follow up investigations using integrated EM approaches revealed that the herpes virion reveals two functional ‘poles’ that seem to be related to cell entry and virus assembly at an intriguing compartment called the nucleoplasmic reticulum. He demonstrated new emerging possibilities to correlate light cell imaging based on fluorescent tags, including super resolution microscopy, with electron and X-ray cryo-microscopy. Maria Teresa outlined progress on our understanding of Hepatitis C virus cell biology using custom-made EM affinity grids. Preparing highly-purified virions for mass spectrometry, Maria Teresa identified novel players of virus assembly. The underlying principles of this process were investigated by cell-based fluorescent reporter systems for sensitive distinction of individual HCV-infected cells. The power of fluorescence microscopy for the study of viral cell biology was demonstrated by Michael Way (Cancer UK, London). In addition to the screening of his ‘best of’ shots of Vaccinia virus surfing on actin waves and microtubules, Michael showed recent work on vaccinia F11 and A36 proteins that interfere with RhoA signaling and N-WASP-Arp2/3-dependent actin polymerization, respectively. Together his work illustrates how studying viral infection can shed light on signaling, transport and cytoskeleton dynamics of the host cell. Bettina Stolp (University of Heidelberg) presented how an integrative imaging approach at different scales revealed an important HIV-1 immune evasion mechanism. She combined in vitro assays, such as migration in flow chambers and collagen gels, with approaches in vivo, including imaging in zebrafish and intravital multiphoton microscopy in mouse. Her elegant studies showed that the HIV protein Nef interferes with actin remodeling and impairs chemotaxis of primary human T lymphocytes, guided motility of zebrafish primordial germ cells and the homing of primary murine lymphocytes to peripheral lymph nodes.

After introducing the different microbes, the conference switched to a broad analysis of emerging quantitative imaging. Spencer Shorte (Imagopole, Institut Pasteur) is dedicated to enable numerous of mainly biology-trained users the access to cutting edge scientific imaging technologies while developing and improving existing imaging systems. One current focus of his research is phototoxicity that can be especially observed during high-speed, multi-dimensional and super-resolution imaging. A second technique, micro-mirror enhanced microscopic imaging (MEMI-OP), allows the bleaching of a defined 3 dimensional area, using ultrafast micro-mirrors to allow high-speed, multi-dimensional, spatial and angular light control for FRAP and optogenetic experiments. Spencer concluded underlining “Get more out of your photons and be kinder to your biology”. Subsequently, Sven van Teffelen introduced Escherichia coli cell growth and the shape-determining peptidoglycan cell wall. With computational simulations Sven modelled the bacterial cell wall as a network of springs under tension that twist upon shrinkage. The mathematical model could show that chiral proteoglycan orientation was dictated by motion of the bacterial protein MreB, leading to the conclusion that the physical coupling between MreB and the cell-wall synthesis results in the uniform bacterial growth.

Switching from pathogens to bacterial toxins, Emmanuel Lemichez (INSERM, Unviersité de Nice) gave an overview how they catalyze post-translational modifications of host cell substrates. His team has established that a group of toxins induces the opening of large transcellular tunnels in endothelial cells (TEMs), through the direct inhibition of RhoA (Staphylococcus aureus EDIN toxin) or by raising the flux of cyclic-AMP in the absence of RhoA inhibition (adenylate cyclases of Bacillus anthracis or B. pertussis). Rut Carballido-Lopez (INRA, Jouy-en-Josas) compared the bacterial counterparts of eukaryotic actin and tubulin, and employed these cytoskeletal elements to perform many functions, including cell morphogenesis. Experiments using total internal reflection fluorescence microscopy (TIRF) have recently shown a dynamic relation between the bacterial protein MreB and cell wall synthesis. Work using highly inclined laminated optical sheet (HILO) microscopy revealed that YkuR, an essential enzyme of the peptidoglycan precursor biosynthetic pathway, forms diffraction-limited cytoplasmic foci that require MreB. Studying nuclear architecture and spatial organization of chromosomes is important for understanding the regulation of gene expression in human health and disease. Musa Mhlanga (CSIR, South Africa) presented new work illustrating a fundamental role for loop-mediated chromatin contact on the transcription of co-regulated genes in a multigene complex. In this case, genome-editing tools were applied to disrupt contacts between gene loops in a well-characterized multigene complex. In addition, the Mhlanga laboratory has recently performed a high content genome wide screen searching for miRNAs involved in the host response to HIV infection discovering a novel viral apoptosis evasion mechanism.

The conference concluded with the presentation of promising imaging approaches that have a high potential to analyze host-pathogen interactions in an integrated way.  Frank Lafont (Institut Pasteur, Lille) showed how to combine the use of atomic force microscopy (AFM), fluorescence and transmission electron microscopy to investigate host-pathogen interactions. Using this approach, he showed the recruitment of membrane and cytoplasmic proteins to the site of adhesion, and in the case of actin with nanoscale resolution. Frank developed this further using AFM to probe the interior of the cell by measuring relative stiffness with a deep probe. He was able to image a stiffer Golgi and showed, for the first time, images of mitochondria in live cells using AFM. Kristine Schauer (Institut Curie, Paris) discussed the generation of normalized cells to study trafficking, signaling and host-pathogen interactions through micropatterning. She could not observe a preferential site of focal invasion by Salmonella, however bacteria moved to the bottom of the cell after internalization. She went on outlining how to use micropatterned cells in high-throughput screenings taking advantage of the possibility to apply statistical analysis to compare subtle differences. Agneta Richter-Dahlfors (Karolinska Institutet, Stockholm) addressed combined transcriptomic analysis, nanotechnology and multimodal imaging to investigate the local and the systemic environment during kidney infection by uropathogenic Escherichia coli. She stressed the importance of in vivo systems to study the interplay of cells and tissues, but also the need to improve in vitro systems that closely mimic the complexity of live animals. Agneta is also developing nanoprobes capable of sensing pH, oxygen, C-reactive protein to be used as real time sensors for local imaging at the site of infection and for monitoring inflammatory systemic responses. She finished her presentation bridging science and art and closed an exciting week about cutting edge microscopy for the study of microbial pathogenesis.

Sven van Teeffelen Serge Mostowy Frank Lafont Emmanuel Lemichez Friedrich Frischknecht Priscille Brodin Rogerio Amino Betty Stolp Rut Carballedo-Lopez Ger van Zandbergen Michael Way Spencer Shorte Kristine Schauer Agneta Richter-Dahlfors Kay GrĂŒnewald Maria Teresa Catanese Volker Heussler Musa Mhlanga Jost Enninga Combiner les dimensions - L'imagerie des processus d'infections de l'Ă©chelle du nano Ă  celle du corps entier

Entretiens sur la MĂ©lancolie

Liste des participants :

Laura Bossi, Jean-Louis CabanÚs, Daniel Couty, Patrick Dandrey, Yves Hersant (organisateur), Jacques Jouanna, Robert Kopp (organisateur), Thoma Llorens Serra, Dominique Païni, Jackie Pigeaud, HélÚne Prigent, Gérard Régnier dit Jean Clair (organisateur), Catriona Seth, Daniel Widlöcher.

Les actes de cette rencontre ont Ă©tĂ© rĂ©unis dans un ouvrage intitulĂ© “De la MĂ©lancolie”, publiĂ© chez Gallimard en mai 2007 dans la sĂ©rie “Les entretiens de la Fondation des Treilles” de la collection “Les cahiers de la NRF”.

Extrait de la quatriĂšme de couverture :

Dans la mĂ©decine grecque, la mĂ©lancolie, la bile noire, est d’abord un liquide organique, au mĂȘme titre que le flegme, la bile jaune et le sange. De l’Ă©quilibre de ces humeurs ou de leur dĂ©sĂ©quilibre dĂ©pend la santĂ© ou la maladie des individus. Elles dĂ©terminent surtout le tempĂ©rament de ces derniers, l’esprit et le corps Ă©tant indissociables.

Le tempĂ©rament du mĂ©lancolique a prĂ©occupĂ©, bien plus que les autres, non seulement les mĂ©decins, mais aussi les philosophes et les poĂštes, les peintres et les musiciens, car, depuis l’AntiquitĂ© Ă©galement, il est le signe distinctif de l’homme d’exception, du gĂ©nie. C’est ce qu’a mis en Ă©vidence, pour la premiĂšre fois dans la longue durĂ©e, l’exposition de Jean Clair “MĂ©lancolie. GĂ©nie et folie en Occident”. Elle avait rĂ©uni par centaines des Ɠuvres plastiques, des observations scientifiques, des documents imprimĂ©s, afin d’illustrer, l’histoire mouvementĂ©e et les multiples facettes de ce sentiment -le seul qui pense- qui ne se confond ni avec la simple tristesse ni avec notre moderne dĂ©pression dont elle participe pourtant. Toutes les Ă©poques de la civilisation europĂ©enne -et d’elle seule, semble-t-il- ont connu cette affection du corps et de l’Ăąme, cette fureur du crĂ©ateur, ce dĂ©sespoir de penser. Elles lui ont donnĂ© diffĂ©rents noms : taedium vitae, acedia, spleen, mal de siĂšcle, lypĂ©manie, nĂ©vrose maniaco-dĂ©pressive.

C’est Ă  la suite de cette exposition, et pour en discuter une nouvelle fois les tenants et les aboutissants, que des mĂ©decins et des psychiatres, des historiens de la pensĂ©e grecque, des historiens et des critiques d’art, des historiens de la littĂ©rature se sont rĂ©unis Ă  la Fondation des Treilles. Dans un esprit transdisciplinaire, ils reviennent ici sur les aspects les plus importants de la mĂ©lancolie antique, de l’acĂ©die mĂ©diĂ©vale, des diffĂ©rentes formes de la mĂ©lancolie Ă  la Renaissance et Ă  l’Ăąge classique, du mal du siĂšcle romantique, du spleen baudelairien, des nĂ©vroses contemporaines. Ces entretiens mettent en lumiĂšre la profonde unitĂ© de la mĂ©lancolie, d’Hippocrate Ă  Freud, d’Aristote Ă  Levinas, de Michel-Ange Ă  Giacometti, des PĂšres de l’Eglise aux cliniciens d’aujourd’hui.