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Emplois - Post-Doc

Offre d’emploi de la société Biomaneo pour un poste de Développeur informatique.

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3-year postdoctoral position on Phage encoded activators of Xer

Project:Bacterial chromosomes are generally circular. DNA circularity can result in the formation of chromosome dimers, which physically impede the segregation of genetic information at cell division. Bacteria have evolved a highly conserved chromosomally encoded recombination (Xer) machinery to resolve chromosome dimers by the addition of crossovers at a specific unique site of their circular chromosomes, dif.

Numerous mobile elements exploit Xer to integrate into the dif site of one of their host chromosomes. Integrative Mobile Elements exploiting Xer (IMEX) are often associated to pathogenicity. A salient example is provided by the evolutionary history of the agent of the cholera, Vibrio cholerae. The diarrhoea that is responsible for the epidemic propagation and high death rate associated with cholera is encoded in the genome of an IMEX, the cholera toxin phage (CTXf) 1,2. Interactions between CTXf and several other IMEX participate in the constant and rapid emergence of new cholera epidemic strains 3,4. Foremost among those is the toxin-linked cryptic satellite phage, TLCf, whose integration seems to be a prerequisite for CTXf integration 5.

The Xer machinery belongs to the family of tyrosine recombinases. It is very similar to Cre, the resolvase of phage P1, whose action mechanism has been thoroughly characterised at the atomic resolution. However, several features of the Xer machinery differentiate it from Cre and most other tyrosine recombinases. In particular, it is under the control of a large integral membrane cell division protein, FtsK. IMEX have evolved different mechanisms to escape the FtsK control 4,6,7.

We recently identified a Xer activation factor in the genome of TLCf, XafT. XafT is a small cytoplasmic protein with no sequence or structural similarities to FtsK. It contains a domain of unknown function that is encoded in many other IMEX. We have been able to reconstitute a full Xer recombination reaction in vitro using purified XafT. The aim of the postdoctoral work is to provide a detailed mechanistic understanding of XafT-mediated Xer recombination. In parallel, the postdoctoral fellow will screen for chemical compounds that can promote or inhibit Xer recombination reactions in vivo and characterise their mode of action. A related task will be to study how the different IMEX of V. cholerae interact with each other and how their interactions contribute to the dissemination of the cholera toxin genes in the environment.

Qualification:The ideal candidateshould have a solid experience of biochemistryand a good knowledge of molecular genetics. He will join a consortium of 4 teams with complementary expertise in bacterial genetics and biochemistry, structural biology, biophysics and chemistry.

Location:The teams are housedin the genome biology department of the Institute for Integrative Biology of the Cell (I2BC), which provides a very stimulating research environment. The institute is situated in Gif sur Yvette, a pleasant village in the southern outskirts of Paris.

Starting date: January 2017

Funding: French National Research Agency (ANR)

How to apply: candidates should send a letter, a CV and recommendation letters form three references francois-xavier.barre@i2bc.paris-saclay.fr

 

1.   Val, M.-E. et al. Mol. Cell 19, 559–566 (2005).

2.   Das, B. et al. PNAS 107, 4377–4382 (2010).

3.   Das, B. et al. PNAS. 108, 2516–2521 (2011).

4.   Midonet, C. et al. PNAS. 111, 16848–53 (2014).

5.   Hassan, F. et al. Nature 467, 982–5 (2010).

6.   Bischerour, J. et al. EMBO J. 31, 3757–3767 (2012).

7.   Barre, F.-X. & Midonet, C. PNAS (2016). doi:10.1073/pnas.1608539113

 

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Postdoctoral Research Fellow position

INSERM UMR1064 Center for Research in Transplantation and Immunology, France

 

Title: Antigen-specific Tregs in transplantation

 

The laboratory: The Center for Research in Transplantation and Immunology (CRTI) is a research unit (UMR 1064) dedicated to transplantation science and immunology since 1993 in Nantes. The CRTI (3,000 m2 of laboratory surface area and two animal facilities) currently comprises 179 people and is part of the “Institute of Transplantation-Urology-Nephrology (ITUN)” at Nantes University Hospital (CHU Nantes). Our main research areas are immunology, transplantation, Immune Mediated Inflammatory Disorders (IMIDs), regenerative medicine and genetics. Everyone in the lab speaks English and we hold our lab meetings in English.

A 2-year post-doctoral position (with possibility of extending this period) is open in the team 2 “Gene and cell engineering in tolerance and regenerative medicine” under the supervision of Dr. Carole Guillonneau, for a highly motivated and talented post-doctoral fellow.

The city of Nantes offers a culturally active, young and dynamic environment. Nantes has an international airport, is conveniently located within 45 min drive from some beautiful sea resorts located on the French Atlantic coast and 2 hours high-speed train from Paris. The organization “Chercheurs Etrangers à Nantes” can help you with all administrative paperwork regarding visas, residence/work permits, social security, accommodation, French courses… Please go and visit their website for foreign researchers settling in Nantes: www.nantes-chercheur.org/en/

The context: Regulatory T cells (Tregs) have been described as being capable of inducing tolerance to allogeneic organs, however, CD8+ Treg, while demonstrated as crucial in some diseases, have been put aside and their role and potential in tolerance remain unclear. We investigate both in rodent and human antigen-specific regulatory CD8+ T lymphocytes, their biology at a cellular and molecular level, their generation upon encounter with an antigen and their role in transplantation tolerance and autoimmunity. These aspects are particularly important in current transplantation since new immunosuppressive strategies are based on the generation of a donor-specific tolerance.
The objectives of this project are to use human donor-derived antigen to expand human CD8+ Tregs and generate tolerogenic human antigen-specific T cells, to characterize the cell product and to provide the proof of concept for clinical application using transplanted humanized NSG mice in comparison to polyclonal CD8+ Tregs. The second objective of this project will be to determine the potential of TCR-engineered CD8+ T cells for transplantation tolerance using the rat cardiac transplantation model and already available “tolerogenic” TCRs (Tol-TCRs).
With this project, we expect to develop new strategies of tolerance induction using CD8+ Tregs and to further determine the role of the TCR and MHC/peptide interaction in this process.

- Candidate’s profile:
The applicant should hold a PhD in immunology with good skills in molecular biology, cell culture and flow cytometry. In vivo experience with rodent models will be appreciated. Technological facilities are available for graft surgery in rat and in humanized NSG mice, rat transgenesis-platform, tetramer production and purification, mRNA sequencing. INSERM1064 has shared equipment and instrumentation: tissue culture rooms: FACS for analysis and sorting; QPCR machines…
Competitive salary and excellent work environment are offered. Please send CV, a cover letter and names of three references to: carole.guillonneau@univ-nantes.fr

- Relevant publications:
    1.    Bézie S., Picarda E., Ossart J., Martinet B., Anegon I. and Guillonneau C. Compensatory regulatory networks between CD8 T, B and myeloid cells in organ transplantation tolerance. J. Immunol. 2015 Nov 9. pii: 1500473.
    2.    Bézie S., Picarda E., Ossart J., Tesson L., Usal C., Renaudin K., Anegon I. and Guillonneau C. Interleukin-34, a new Treg-specific cytokine mediator of transplant tolerance. J. Clin Invest. 2015, Oct 1;125(10):3952-64.
    3.    Picarda E., Bézie S., Venturi V., Echasserieau K., Meriau E., Renaudin K., Delhumeau A., Brouard S., Bernardeau K., Anegon I. and Guillonneau C.. MHC class II allo-peptide activates TCR-biased-CD8+ Tregs and suppresses organ rejection. J. Clin Invest., 2014. Jun 2;124(6):2497-512.
    4.    LI X.-L., Menoret S., Bezie S., Caron L., Chabannes D., Hill M., Halary F., Angin M., Heslan M., Usal C., Liang L., Guillonneau C., Le Mauff B., Cuturi M.-C., Josien R. and Anegon I. Mechanism and localization of CD8 regulatory T cells in a heart transplant model of tolerance. J. Immunol.,          2010. 185(2):823-33.
    5.    Guillonneau C., Marcelo H., Hubert F.X., Chiffoleau E., Hervé C., Li X.-L., Heslan M., Usal C., Tesson L., Menoret S., Saoudi A., Le Mauff B., Josien R., Cuturi M.C. and Anegon I. CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine         2,3-dioxygenase. J. Clin. Invest. 2007. 117(4):1096-106.

 

 

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