Grading

Once the visits for the 2012-2013 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams). This score (A+, A, B, C) concerned each of the six criteria defined by the AERES. NN (not-scored) attached to a criteria indicate that this one was not applicable to the particular case of this research unit or this team. Criterion 1 -C1 : Scientific outputs and quality ; Criterion 2 -C2 : Academic reputation and appeal ; Criterion 3 -C3 : Interactions with the social, economic and cultural environment ; Criterion 4 -C4 : Organisation and life of the institution (or of the team) ; Criterion 5 -C5 : Involvement in training through research ; Criterion 6 -C6 : Strategy and five-year plan.

With respect to this score, the research unit concerned by this report and, its in-house teams received the following grades:

table of the unit: Dynamique Nucléaire C1 C2 C3 C4 C5 C6

This evaluation marks the 12th year of the leadership of the director as the head of the unit with a continued activity at Curie Research Center, Paris. During the considered period (2007)(2008)(2009)(2010)(2011)(2012), two junior teams left the unit and were replaced by two young teams ; one ATIP in 2009 and one ATIP/AVENIR in 2010. The PI of one junior team (N°3) established in 2007 (ERC 2009), was proposed for promotion which has been granted very recently by the International Research Council of the Center.

Management team:

The director of the unit (53), is helped by two administrative managers (100% and 80% respectively). The director is also supported by the board of group leaders, each of them taking specific responsibilities. The leader of team 3 has recently taken an even more active part in the managerial activities of the unit.

AERES

Doctoral students 10

Theses defended (from Janv 2007 to June 2012) 9

Postdoctoral students having spent at least 12 months in the unit* 12

Number of Research Supervisor Qualifications (HDR) taken 3

Qualified research supervisors (with an HDR) or similar positions 5 5

2  Assessment of the unit Strengths and opportunities:

The director of the unit is among the top world-class scientists and one of the most active among European and French researchers in the field of chromatin and epigenetics. As a consequence, her position as the unit director has brought high visibility to the unit and opened numerous opportunities for the unit's team leaders.

Additionally, the director has proven to be an outstanding manager, who not only is ensuring an excellent optimal organization of her unit, but also and additionally, is having an important impact on the organization of Science in Europe and the promotion of epigenetics at an international level. This internationally prominent position of the director and her involvement in many central "decisional nodes" is also clearly helping to establish thoughtful strategies and minimizing the adverse effects of the intense international competition in the areas covered by the unit's teams.

The unit had also been the cradle for the rise and development of several prestigious French teams: two of the past juniors unit's teams are now successful scientists directing their own groups elsewhere. A third one is now establishing her group in an Epigenetic Paris 7 University/CNRS Institute. In this respect, it is of note that the present very successful director of the Genetics and Developmental Biology unit (Institut Curie), started as a junior group leader in this unit. Today the unit is hosting equally promising group leaders and the committee foresees successful dissemination of these groups in the French science landscape in the future and hence the strengthening of this country's place in the field of epigenetics.

The unit has therefore served as a relay and enhancer of excellence and is hence playing a pivotal role in stimulating research in chromatin and genome biology, worldwide.

The other strength of the unit is the thoughtful and strategic development of research programs and core facilities, which have been put in place to increase the synergy between the units projects. A particularly remarkable example is the newly established Synthetic Genetic Array (SGA) in development under the responsibility of team 5, which will also have a high impact on the projects not only of teams 3 and 4, using yeast as a model, but also on the two other groups, studying non-yeast model systems.

In addition, the imaging facility provides training, helps design the experiments, choose the best reagents, choose the best system on the imaging facility, provides expertise for imaging analysis and treatment. The contribution of the facility to several projects is attested by the authorship of the manager of several publications and by numerous acknowledgements. The facility also develops its own image treatment tools. The number of users is between 30 and 40 using the facility for an average of 3000 hours of occupied systems per year.

The outstanding strategic scientific governance can also be illustrated by the development in the unit of transversal themes tackling different model systems to uncover the role of a particular mechanism, i. e., chromatin assembly, in different settings, or tackling a common model, i. e. yeast, to converge different concepts, i. e., meiotic double-strand break and nuclear compartmentalization.

In conclusion, the research programs and the accompanying appropriate actions are tremendously increasing the coherence of the whole and greatly strengthening the unit as a whole.

Weaknesses and threats:

The director of the unit has been very recently nominated as the director of "Curie Research Center". This is an important new responsibility that adds to her already heavy tasks.

Although the accumulation of responsibilities could at first be seen as a threat, taking into account the outstanding capabilities of the director of the unit in terms of administrative and scientific management, the committee feels this new appointment could rather be taken as an opportunity for the unit. In fact this will give rise to emerging possibilities for one of the newly appointed senior PIs and will ensure a smooth transfer of the leadership from the present director, who has been in charge of the unit for 12 years, to the head of the new senior group.

The director has proven in the past that she could efficiently conduct her unit and act at the same time as a coordinator of several European and National networks. During the same period, she has been the organizer of a significant number of high-profile prestigious international meetings. All these actions, among others, testify to the extraordinary working capabilities of the director and guaranty the success of the new configuration.

Additionally, the director is proposing specific actions to be undertaken at the level of the unit as well as that of her team to face her new additional responsibility as a Curie Research Center Director.

The first proposition is to promote team 3 leader as the unit deputy director. The second action aims at securing the team management by promoting a senior researcher of the team to the deputy team director position.

The committee has therefore paid a special attention to these propositions. Detailed subsequent discussions revealed here again a thoughtful strategic plan that convinced the committee of its validity and viability, without any major foreseeable pitfall. The actions proposed in the frame of this plan should reasonably compensate for the increased responsibility of the unit director and maintain the excellence of the unit. The plan however implies additional supports from the institutions (please see below).

Recommendations:

The director of the unit has now been nominated the director of "Curie Research Center". She wishes to keep her responsibility as the director of the unit with a progressive transfer of this leadership to the deputy director, which would fully take over after a defined period of time. The leader of team 3 has been recently promoted as a senior team leader by "Institut Curie Research Center" after the recommendation of the International Scientific Council. This PI has been already significantly involved in the management of the unit at different levels and gives all the signs of a capable unit leader. Discussions with both the director and the future deputy-director clarified the way the responsibilities will be shared and how the transfer will progressively occur.

Taking into account all the above-mentioned parameters, the committee approves and supports the proposed unit management plan, which appeared thoughtful and credible to the committee.

To support this decision, the committee recommends a series of actions, some already proposed by the director herself.

Accordingly, it appears critical that a full-time technical staff (engineer) is recruited and affected to team 3. This should help this team to stabilize its position as a senior group and also help its team leader to better ensure her increasing responsibilities.

Additional points

Discussions with technical staff, researchers, post-docs and students also revealed some important points that the committee has considered as serious issues that need urgent consideration. However, the committee also realizes that actions to face these problems sometimes exceed the responsibility of the unit and could engage the Curie Research Center.

1 -Space constraints appear as an acute issue, limiting an optimal accomplishment of the research programs in a safe environment. Indeed, this "space problem" is clearly creating a number of security issues. An example is the impossibility for the unit to respect the new European law regarding autoclaving of laboratory wastes containing GMOs. Respecting the law would require setting up an additional autoclave, which is presently impossible due to the acute space problem.

2 -The discussion with students and post-docs also revealed a need to undertake an action to support the administrative requirements for them, specifically foreigners, which are of significant numbers, to obtain housing.

3 -The third issue more specifically concerns the unit administrative management. Indeed, presently the unit has the benefit of two administrative managers (100% and 80% time, respectively). All five teams of the unit have many national and European grants with very complex management rules, which come in addition to the core funding as well as to the requirement to face specific units actions, i. e., teaching, AERES visit, etc. Discussions with corresponding staff members revealed a subsequent and unusually heavy workload and hence appeals for corrective actions.

 Detailed assessments

Assessment of scientific quality and outputs:

The published achievements of the unit are outstanding. All the team leaders published articles as senior author in journals of high visibility and impact. All the teams including the two junior groups that left during the considered period, have published 96 papers between 2007-2012 with an average impact factor of 10.634 (15 papers with an impact > 20 and 39 with an IF > 10).

The research programs of the five teams of the unit cover mostly the chromosome structure/dynamics, regulation of chromosome stability and gene expression. Interestingly an exquisite balance of model systems are in use hence ensuring a comprehensive approach to the issues considered. The examinations of the projects and discussions with the team leaders revealed the specific place of each model system and their complementary contribution to the unit research program as a whole. Model organisms encompassing yeast, Drosophila, Xenopus and mouse nicely complement efforts undertaken on human cell lines and cancer samples. A wide range of investigations specifically considering the mechanisms of chromatin assembly/disassembly, genome stability, nuclear organization, in specific settings such as early embryonic development and sexual differentiation uncover concepts that are readily applicable to disease-oriented issues, mainly cancer. The strong Curie environment in oncology has been taken as a ground for applications of the teams' discoveries in the pathological setting of cancer.

In conclusion, the unit is clearly one of the prime leaders in the wide field of chromatin dynamics worldwide.

Assessment of the unit's academic reputation and appeal:

Through exceptional achievements and leadership in international and European actions the unit has influenced the entire field of epigenetics and chromatin, making the unit highly attractive to young and older scientists from allover the world.

Assessment of the unit's interaction with the social, economic and cultural environment:

To illustrate the outstanding contribution of the unit only several examples are presented below.

The involvement with the NOEs 'The Epigenome' and 'EpigeneSys', the unit has been able to engage in a number of highly visible outreach activities, involving artists, moviemakers and journalists. Not only the unit director but all the team leaders have been involved in various actions to disseminate knowledge and educate the public.

The unit is also very actively pursuing links to cancer research. The unit has been involved with several networks at the national level (SIRIC and PACRI) and participates in European networks that address the cancer epigenome. Several patents have been applied for with the potential to translate some of the fundamental findings of the unit into clinical practice.

Of particular interest is the organization of the course on Epigenetics. Each year the unit organizes a course with positions for students from European, National and Parisian Universities. In 2012 the 8th course was held.

Overall, the unit activity directly impacts the society through education and medicine.

Assessment of the unit's organisation and life:

The governance, communication and infrastructure are exemplary. The decision making within the unit is transparent, the level of infrastructure coordination is very high and the level of mentoring very good. Due to their successful expansion the unit currently suffers from space limitations and technical support (see above). The existence of unit retreats, a scientific advisory board and formalised procedures for promotions etc. testifies the excellent "lab culture". The unit provides services outside teams through the Imaging Facility and the robotic "Synthetic Genetic Array" platform.

Assessment of the unit's involvement in training through research:

The unit has been the training ground through research for an important number of students and post-docs. All PhD students enjoy PhD committees and proper mentoring. Additionally, following their PhD defense they are supported in their search for post-doctoral positions and above all, a significant number of post-docs has obtained a permanent position in France and abroad following their work in the unit. The training through research has therefore been a relay and enhancer of excellence in numerous cases.

Assessment of the five-year plan and strategy:

For all the teams, the five-year plan follows the excellent achievements during the reporting period. With promotion of team 3 as a senior group, the unit will be composed of three senior groups and two junior teams. One of these groups will shortly reach the end of the 5-year period and hence would need to consider its evolution outside the unit. The director has however mentioned to the committee that, following discussions at the Curie Research Center, this period could be extended to 7 years. This would allow this team to pursue its outstanding research in the unit. Overall, the level of established methodology and development of novel approaches is balanced, and, as could be judged from the preliminary data that have already been obtained, all the proposed programs are feasible. The projects are ambitious and will certainly ensure continued leadership of the unit in the field.

4  Team-by-team analysis Assessment of scientific quality and outputs:

The 5-year reporting period must be considered one of the most productive phases in PI's lifetime research to date, both with respect to quantity, quality and originality. Her published achievements are outstanding, with senior author papers in journals of high visibility and impact. Importantly, her trajectory appears to be still on the rise. Starting from her specialization in chromatin assembly during replication she expanded her interest to cover the dynamics of all major variants of histone H3, which are deposited outside of S-phase. The discovery of specialised chaperones and histone "assembly" lines during interphase has led to a number of novel and original models that inspire the entire field. The novel concepts that revolve around histone level homeostasis and its regulation by synthesis, degradation and a network of specialised chaperones has opened an entirely new field of study.

Their in-depth analysis of heterochromatin formation led them to consider factors "on top of" the nucleosome infrastructure. The discovery, that HP1 sumoylation and binding of non-coding satellite-derived RNA is required for heterochromatin formation must be considered seminal. The realisation that DNA replication and the repair of DNA damage -the two main processes that rely on chromatin assembly -are functionally compromised in cancer cell led the team to search for cancer-related phenotypes involving chromatin assembly factors (4 patents were filed). The team covers a broad range of methods from basic biochemistry to advanced microscopy and molecular biology. High level collaborations pave the way to organisms studies.

During the reporting period a number of methodological achievements have been instrumental, among them use of SNAP-tags to follow histone dynamics, the combination of stable cell lines expressing tagged histones for sensitive identification of chaperone complexes. The PI and her team not only generated an enormous amount of highly novel and interesting data, but they also cover the conceptual background in a series of highly authoritative review articles. The PI has become one of the prime leaders in the wide field of chromatin assembly and dynamics worldwide.

Assessment of the team's academic reputation and appeal:

A direct consequence of the PI's research achievements is her reputation in the field. She is one of the most popular faces of the "Chromatin and Epigenetics" community in Europe. Her standing is documented by the "FEBS/EMBO women in Science" award, which honoured her life-time achievements. Among the competitive grants she has obtained, the ERC advanced grant stands out, which characterises her as one of the most successful researchers in Europe. Her standing in the field is documented by more than 80 invitations as a speaker during the last 5 years, by her contribution to a large number of national and international advisory panels (most prominently the EMBO council). Through her unmatched engagement in the European Scene, notably as coordinator and inspiration of the NOE "EpigeneSys", she has influenced the entire research landscape in Europe. She serves as a role model not only for all women in science but for any ambitious, hardworking group leader in the Life Sciences. Her group is highly attractive to young scientists from all-over the world. The team is highly qualified, highly motivated and highly successful.

Assessment of the team's interaction with the social, economic and cultural environment:

Through her involvement with the NOEs 'The Epigenome' and 'EpigeneSys', the PI has been able to engage in a number of highly visible outreach activities, involving artists, moviemakers and journalists. She is one of the articulate "faces" of the Epigenetics community that takes every opportunity to propagate her enthusiasm and to educate the public.

Realising that chromatin assembly is a limiting process during all proliferation, and may be compromised in cancer cells that loose the integrity of their genomes, the team has very actively pursued links to cancer research. It coordinates several networks at the local and national level and participates in European networks that address the cancer epigenome. Four patents were filed that illustrate her ambition to translate some of her fundamental findings into the clinical realm of cancer prognosis and eventually treatment.

The unlimited willingness of the Pi to share her experience and give advice is illustrated by her involvement in SABs for several research institutes. The benefits for society through (1) shaping the research landscape at the local, national and European level, (2) translating her research into clinically relevant areas and (3) disseminating and educating the uninitiated cannot be overestimated.

Assessment of the team's organisation and life:

The PI not only leads a very productive team, but she also heads the entire unit. The documentation provided on governance, communication, infrastructure is exemplary. The decision making within the unit is transparent, the level of infrastructure coordination very high and the level of mentoring very good. Due to their successful expansion the unit currently suffers from space limitations and technical support. The existence of unit retreats, a scientific advisory board and formalised procedures for promotions etc. testify to an excellent lab culture. The unit provides services outside teams through the Imaging Facility and the robotic "Synthetic Genetic Array" platform. Bioinformatics support will continue to be very important in the near future, particularly since global analyses are likely to increase.

Assessment of the team's involvement in training through research:

Formal teaching commitments are very low. Yet the team leader has engaged in a number of teaching activities at the local and international level. Since 2009 she is deputy director of the Institute Curie-Research Center Educational Programme. All staff is encouraged and has the opportunity to participate in training courses (language skills, technical tutorials). The unit runs a highly successful "Course of Epigenetics" already in it's eight year and popular with PhD students from across Europe.

PhD students enjoy PhD committees and proper mentoring. The number of PhD students being promoted under the PI's direction is rather low. The main body of the work is carried out by post-doctoral fellows. Nevertheless, the PI participated in some 30 thesis committees during the reporting period.

Assessment of the five-year plan and strategy:

The five-year plan builds firmly on the achievements during the reporting period. The level of established methodology and development of novel approaches is balanced, and, judged by the preliminary data that have already been obtained, is feasible. The programme is ambitious in the sense that the aims are chosen such that the successful research will assure continued leadership.

Conclusion:

 Strengths and opportunities:

The leader and her team continue to work at the forefront of competitive, cutting-edge research at an international level. Their overall achievements are outstanding.

 Weaknesses and threats:

None.

 Recommendations:

The generation of knock-in / knockout mice is being outsourced. Once these mice have been generated histological analysis of these animals will require new collaborations.

Given the enormous number of tasks and responsibilities, undertaken by the PI herself the promotion of a senior team member to deputy Team Leader is highly appropriate.

The bioinformatic support needs to be accessible to the team's projects. This is why it is highly appropriate to embed informaticians in the unit / team, provided that they network with the general bioinformatic unit of I Curie. The space constraints are clearly limiting future development. The team leader is challenged with many administrative tasks. Some of this burden could be eased by hiring further personnel, but she also may have to learn to say "no" once in a while. Throughout, the team has done an excellent job in exploiting the unique advantages of the chosen model system, Drosophila, to address important biological questions. This is exemplified by the work on CAF-1, where genetics has been used to dissect its role in endocycling cells, meiotic cells and cells undergoing asymmetric division, three important contexts for a developing embryo for which there are no tissue culture models.

New technologies have also been used in innovative ways by applying them to answer still open questions in the field. For example, the work on the Bicoid gradient is very original, taking a different methodological approach (FCS vs. FRAP) thereby leading to very different measurements of the establishment of the Bicoid gradient compared to previous studies. This work has directly challenged many assumptions in the field and contradicts a number of models of the early gap network. The team's work measuring the dynamics of the Bicoid gradient may lead to a paradigm shift in our understanding of how early patterning by the segmentation network is thought to occur. For over two decades, it has been hotly debated if a morphogen gradient is sufficient to provide the robustness required to form the precise borders of gap gene expression. The teams' Development paper, which lead to the measurement of a much faster diffusion coefficient for Bicoid than previously observed, challenged the current dogma in the field.

Assessment of the team's academic reputation and appeal:

The team's work on the Bicoid gradient has been widely recognized. The latest papers have directly challenged the conclusions and hypothesis of many of the 'big players' in the field. This has lead to international recognition.

Assessment of the team's interaction with the social, economic and cultural environment:

Although this is a very small team, with a high teaching load, the team leader has participated in the Paris Science Festival for several years.

Assessment of the team's organisation and life:

From discussing with the students and post-doctoral fellows, the team leader is very supportive of her group and participates in organizing and managing the unit. She clearly manages the team with a coherent and logical scientific objective in mind. Given the small group size (only 4 people), the team is very productive, indicating that the work of all team members is coordinated and maximized to make a very efficient group. The convergence of the 'big questions' of chromatin reassembly, and thereby transcriptional regulation after nuclear division is a very productive way to get the most out of the group's expertise and resources.

Assessment of the team's involvement in training through research:

The team leader has made an outstanding contribution to training and teaching. She has taught at the Polytechnic Ecole for 12 years. She takes this role very seriously, spending a lot of time in preparation. Her excellence in teaching is emphasized by the fact that the University has made her a permanent Professor.

Assessment of the five-year plan and strategy:

The five-year proposal is both very feasible and very original. For the CAF project, the team will take advantage of utilizing genetics, which the team has strong expertise in. For the Bicoid project, the proposal plan is very innovative and exciting. The team leader already has established strong collaborations with physicists, which is crucial to the success of the project. Given her expertise, this exciting question and her established collaborations, this project will produce very exciting and timely results that will have a big impact on our understanding of how morphogen gradients function. The team has developed original and innovative research projects based on the use of budding yeast to uncover the functional impact of the special organization of the genome.

Within the considered period, the Pi has been able to set up a highly efficient research team, giving rise to important conceptual advances in the field by producing results published in two high profile journals (J. Cell Biol. & Genes & Dev.), both under her direct leadership. The group showed that tight DNA protein complexes cause replication fork stalling and in turn, localized heterochromatin formation. The group also identified a way to separate telomere clustering from the nuclear periphery, providing both mechanistic information and tools for understanding the consequences of altering telomere localization under various environmental conditions.

Assessment of the team's academic reputation and appeal:

During the past 5 years the team has been involved in a number of important national and European networks, such as INCa, ANR, LABEX, as well as Marie Curie Actions. It is of note that the PI has been also the laureate of an ERC Grant starting in 2009.

The team started in 2006/7 as a junior group with a post-doc and within the considered period, thanks to various funding sources, a true team with additional post-docs, PhD students and technical staff has been established. In addition the PI has also able attract a professor on sabbatical leave to the team.

Finally, the PI was invited to 8 international and prestigious meetings as a speaker, attesting her international visibility.

Assessment of the team's interaction with the social, economic and cultural environment:

The PI has actively contributed to the dissemination of knowledge by participating in public lectures and as well as science festivals and by being a board member of two different societies/foundations. She also contributes to the teaching of epigenetics at various levels.

Assessment of the team's organisation and life:

The success of the team in terms of scientific achievements testifies the capacity of the PI to efficiently and creatively manage the team. Additionally, the committee would like to highlight here the important involvement of the PI in the management of the unit revealing her remarkable managerial talent.

Assessment of the team's involvement in training through research:

During the considered period, 3 PhD and 4 master students have been supervised. Additionally, the Pi has been a member of the jury for Ph D theses (7) and of thesis committees (30). Students have authorship on the major publications led by the PI.

Assessment of the five-year plan and strategy:

In the coming years, the team will be developing various aspects of its main research theme: the functional impact of the spatial organization of the genome. The research programs are guided by questions regarding: i) the mechanisms directing the establishment and maintenance of nuclear compartments, as well as the functional importance of this compartmentalization, and ii) the relationship between active and repressive nuclear compartments.

Additionally, these projects have direct implications in the other teams' programs such as the role of nuclear organization in the control of meiotic recombination, which is the central subject of team N°4.

It is of note that the team is also developing the interface between its research and mathematics and modeling by establishing appropriate and fruitful collaborations (a manuscript is already submitted).

Overall, the team is leading original and promising research programs with foreseeable success in the coming years.

 Detailed assessments

Assessment of scientific quality and outputs:

Despite being established as an independent laboratory for only 3 years, the PI and her team have already made very significant findings that shed new light on the mechanisms controlling meiotic recombination. The team work is original, both in its conception and execution, and is of the very highest intellectual and technical standard. It is an outstanding example of how the intelligent use of yeast molecular genetics can be used to provide deep mechanistic insight into fundamental biological processes. This is coupled with the team's specialized technical expertise in mapping the precise sites of double-strand breaks (DSBs) across the genome.

The finding that, in yeast, the PHD protein Spp1 promotes DSBs through association with both the chromosomal axis and with chromatin marks on chromosomal loops, has provided the basis for a new model of meiotic recombination initiation that will likely be applicable to a wide range of eukaryotes, including mammals. This may yield new insights into the origin of defects of meiotic chromosome segregation in humans (aneuploidy).

This team was only established in 2009, so there has not been much time for the PI to publish senior author papers from her own group. The team should therefore be congratulated on the very nice paper, which was just published in Molecular Cell (2013) -one of the very best journals in molecular biology. A second paper is close to acceptance in another high impact journal. This is exceptional output for a small junior group.

Assessment of the team's academic reputation and appeal:

The team leader is rapidly gaining a strong international academic reputation as evidenced by invitations to speak at major meetings (Two Gordon conferences, and an EMBO meeting). With the recent and forthcoming publication of the new papers, it seems clear that the PI's academic reputation will continue to grow rapidly. The quality of the team's PhD students and postdocs is very high which reflects the appeal of the team to young researchers.

The PI has also organized meetings on a national level and she serves on the board of the French Genetics Society. She is to be commended on this level of engagement and commitment.

Assessment of the team's interaction with the social, economic and cultural environment:

The team leader has contributed to the Paris Science Festival and has an industrial partnership with EDF, which represents a good contribution to the dissemination of science to the wider cultural and economic environment. This is an appropriate level of engagement for a junior group.

Assessment of the team's organisation and life:

The team is well run, with the students and postdocs well supervised, engaged and productive. They play a full and active role in unit activities -journal clubs, seminars and meetings. The team leader serves on a large number of thesis committees.

Assessment of the team's involvement in training through research:

Students in the team are very well supervised and guided. The team leader also plays an active role in the International Epigenetics course run at the Institut Curie.

Assessment of the five-year plan and strategy:

By addressing chromatin events both upstream and downstream of DSBs during meiotic recombination, the team occupies a very good niche in a competitive field. The scientific questions are original and appropriately focused for a small team. Future plans combine the continued use of exquisite yeast genetics, in which the team has already demonstrated their excellence, with some bold aims. In particular, the aim to produce and compare the first genomewide maps of DSBs and meiotic cross-overs is a big one and will have a major impact. There is a high likelihood that they will be successful in this achieving this.

The team has presented an appropriate SWOT analysis. There are constraints placed on the team and its future development by space limitations within the unit. In particular, the current placement of the SGA platform for highthroughput yeast genetics at a site some kilometers away from the PI's main laboratory is a significant barrier to the most effective use of this facility and the opportunity it should provide. The future aims to assess affects on meiotic recombination in yeast mutants genome-wide will require good bioinformatics input into data analysis and interpretation. The team would therefore benefit from enhanced bioinformatics support at unit level.

Conclusion:

 Strengths and opportunities:

The strengths of the team are the quality of their scientific approach and outputs, combined with the precise mechanistic questions that they are asking of fundamental biological processes in a tractable genetic system. The expertise of the team gives them the opportunity to make a major scientific impact and for the team leader to become a highly respected international figure in the area of chromosome biology and meiosis. All measures indicate that this team leader is on an exponential upwards curve for both her scientific output and international recognition. The excellent mentoring provided within the unit will expedite this.

 Weaknesses and threats: None identified. This junior team program aims to understand the relationship between chromatin state and DNA damage repair (DDR) processes -how do histone modifications and variants impinge upon the DDR and how does the DDR alter the histone modification state? The PI has an impressive and innovative foothold into this field stemming both from postdoctoral work (which appeared recently in very high profile journals including Cell, Nature Struct Mol Biol, etc) and the feats accomplished by the PI's own 2.5-year-old lab.

A major springboard is the identification of a role for the conserved Ino80 chromatin remodelling complex in controlling levels of the histone variant H2AZ in chromatin. The team is using rigorous biochemical approaches, molecular genetics and high-throughput screening techniques to define the relevant pathways and mechanisms and their functional importance.

The team has performed SILAC experiments to identify proteins that interact with Ino80 specifically in response to DNA damage. This approach revealed DDR-dependent interactions between Ino80 and the ATPase Cdc48, a component that has been shown to degrade RNA polymerase II in response to DNA damage; genetic analysis also shows that Ino80 becomes essential for the DDR when the Cdc48 pathway is compromised. A major (and important) current goal is the dissection of the roles and interplay between these two complexes. The team is also exploring the role of H2AZ modifications (which are clearly important for genome maintenance, in thus far poorly understood capacities).

Assessment of the team's academic reputation and appeal

The PI has an impressive set of distinctions including the FSER Prize for young group leaders, first place rankings in both CNRS and INSERM first class competitions, and five grant awards. The PI has been selected as a speaker for at least 7 international meetings and invited for seminars. Therefore, his status as a young investigator is clearly high and most likely on an upward trajectory.

In this 2.5-year period, the PI has clearly assembled a committed and effective team -we are particularly impressed by the recruitment of 3 postdocs from around the world. He has also set up the SGA platform for the Institute.

Assessment of the team's interaction with the social, economic and cultural environment:

N/A
Assessment of the team's organisation and life:

Given the space allocated to the team, we are particularly impressed that they could have produced such high quality results; this is a testament to the PI's effectiveness. Moreover, the SGA platform is located 3 km from the unit, a suboptimal situation that presents extra challenges for the PI and his team members.

Assessment of the team's involvement in training through research:

While it is too early to comment extensively on this, the assembly of a productive team suggests the PI has already been and will continue to be highly successful in training through research.

Assessment of the five-year plan and strategy:

The centerpiece of the proposal is to extract and pursue meaningful mechanistic information from genomewide data sets (most prominently synthetic genetic analysis, SGA). The plan is bold in tackling the large amount of data likely to be generated from several SGA screens. The PI's expertise in the fields of chromatin composition and regulation as well as DNA repair gives him a unique and promising perspective. Given this and the PI's experience with the suggested approaches, along with his plan to strategically screen mutations about which he has an extensive and unique scientific understanding, we find the plan credible and feasible. The growing expertise in SGA approaches is also of great value for the entire unit and promising collaborations with other teams (Teams 3 and 4) are already arising.

*

  This person has changed from DR to PR but was present on June 30, 2012 and will be still present in 2014

  Permanent professors and similar positions N2: Permanent EPST or EPIC researchers and similar positions 1

  Permanent professors and similar positions N2: Permanent EPST or EPIC researchers and similar positions 1

  talk + 20' discussion/questions + 05' private discussion with AERES committee) Ms Valérie BORDE (junior group) pathways to genome integrity (20' talk + 20' discussion/questions + 05' private discussion with AERES committee) Mr Manolis PAPAMICHOS-CHRONAKIS (junior group) Discussion with Ms Geneviève ALMOUZNI : head of the unit (30 min /1h) 10:00 Private deliberation of the visiting committee (in presence of the AERES scientific advisor) 14:00 End of the visit 6  Statistics by field: SVE on 10/06/2013



  Grading table of the team: Chromosome Dynamics and Recombination

	1  Introduction
	C1	C2	C3	C4	C5	C6
	A+	A	NN	A+	A	A+
	
	 Grading table of the team: Chromatin Pathways to Genome Integrity
	C1	C2	C3	C4	C5	C6
	NN	NN	NN	NN	NN	A+

History and geographical location of the unit:

Unit workforce Number as at 30/06/2012 Number as at 01/01/2014

	nomenclature:
	SVE1_LS2
	Unit workforce:
	Unit workforce	Number as at 30/06/2012	Number as at 01/01/2014	2014-2018 Number of project producers
	N1: Permanent professors and similar positions		1	1*
	N2: Permanent researchers from Institutions and similar positions	9	8	7
	N3: Other permanent staff (without research duties)	10,8	10,8	10,8
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral researchers, students, visitors, etc.)	28	21	17
	N6: Other contractual staff (without research duties)	4	4	4
	TOTAL N1 to N6	51,8	44,8	39,8
	Percentage of producers		100 %

Team 1 :

	Chromatin Dynamics
	Name of team leader: Ms Genevieve ALMOUZNI
	Workforce
	Team workforce	Number as at 30/06/2012	Number as at 01/01/2014	2014-2018 Number of project producers
	N1: Permanent professors and similar positions
	N2: Permanent EPST or EPIC researchers and similar positions	5	4	4
	N3: Other permanent staff (without research duties)	3	3	3
	N4: Other professors (PREM, ECC, etc.)
	N5: Other EPST or EPIC researchers (DREM, Postdoctoral researchers, students, visitors, etc.)	17	12	10
	N6: Other contractual staff (without research duties)	2	2	2
	TOTAL N1 to N6	27	21	19
	Team workforce	Number as at 30/06/2012	Number as at 01/01/2014
	Doctoral students	5
	Theses defended (from Janv 2007 to June 2012)	4
	Postdoctoral students having spent at least 12 months in the unit	8
	Number of Research Supervisor Qualifications (HDR) taken	1
	Qualified research supervisors (with an HDR) or similar positions	2	2

 Detailed assessments

Grades Critères C1 Qualité scientifique et production C2 Rayonnement et attractivité académiques C3 Relations avec l'environnement social, économique et culturel C4 Organisation et vie de l'entité C5 Implication dans la formation par la recherche C6 Stratégie et projet à cinq ans

	A+	67	62	52	73	65	60
	A	57	67	71	45	65	63
	B	12	7	4	7	6	14
	C	0	0	0	3	0	1
	Non Noté	3	3	12	11	3	1
	Percentages
	Critères	C1 Qualité scientifique et production	C2 Rayonnement et attractivité académiques	C3 Relations avec l'environnement social, économique et culturel	C4 Organisation et vie de l'entité	C5 Implication dans la formation par la recherche	C6 Stratégie et projet à cinq ans
	A+	48%	45%	37%	53%	47%	43%
	A	41%	48%	51%	32%	47%	45%
	B	9%	5%	3%	5%	4%	10%
	C	0%	0%	0%	2%	0%	1%
	Non Noté	2%	2%	9%	8%	2%	1%
	Histogram

 Supervising bodies' general comments

Conclusion:

 Strengths and opportunities:

The clear strength of proposal comes from the convergence of expertise in the team, in both chromatin assembly in newly replicated nuclei and in transcriptional regulation in the early Drosophila embryo, which are both essential to tackle the very interesting question of how transcriptional memory is maintained during cell division. There is currently very little known about this process, and the tools and expertise developed in the team provide a great opportunity to tackle it.

 Weaknesses and threats:

The small size of the group will limit their ability to be competitive. They need to expand, but given the lack of space for the unit, this is currently very difficult.

 Recommendations:

No specific recommendations.

Conclusion:

 Strengths and opportunities:

The ability of the PI to lead her projects has been clearly demonstrated in the past 5 years, as can be judged by the excellent science produced and ongoing, and by her ability to secure the corresponding funding and attract people. She already occupies within the unit a very strong position, attested by her promotion to senior group leader position by the Research Center. This promotion is not only promising the development of increasing ground-breaking research programs, but also allows the team leader to upgrade her managerial responsibilities. This latter point corresponds in fact to her proposed promotion to become deputy director of the unit. The committee considers this situation as an excellent opportunity for the personal evolution of the PI, which has shown her managerial talents, as well as for increasing the attractiveness of the team and hence stimulating its development.

 Weaknesses and threats:

The committee could not identify any clear threats but has recommendations to strengthen the team, which, if not satisfied in a short term, could become threats.

Conclusion:

 Strengths and opportunities:

The work is uniformly well-done and constitutes a significant and potentially ground-breaking set of contributions to a highly important and competitive field whose fruits are likely to include not only a basic understanding of how genetic information is maintained, but also cancer treatments (given the extensive array of relationships between altered epigenetic regulation and cancer).

 Weaknesses and threats: None (see below).

 Recommendations:

The space issues mentioned above and the large distance between the PI's laboratory and the distant SGA platform are weaknesses that should be addressed as soon as this is possible.

Conduct or programme of visit:

The visit was well prepared and perfectly organized, with a detailed high-quality documents provided two months in advance. It included presentations by the director of Curie Research Center, the director of the unit and by the group leaders and with ample time for discussions with the director, group leaders, technical and administrative staff, students and postdocs.

High quality posters were set-up covering almost all the ongoing team projects. All the unit members responsible for the posters including mostly students and post-doc presented their posters to the committee members. The committee had sufficient time, albeit in a very tight schedule, to discuss various issues and meet with all the representatives of CNRS, Curie, UPMC. The visit was executed smoothly and without any problems. A visit of the labs had also been organized at the end of the first day.


Ms Catherine Chiron

Fernando Mr

D A Lopes

Silva

Massimo Mr

Avoli

Ms Catherine Barthelemy

Ms Séverine Samson

Yves Mr

Trotter

Ms Anne Flury-Herard

Cea Ms

Chantal Lasserre

Grading

Once the visits for the 2012-2013 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams). This score (A+, A, B, C) concerned each of the six criteria defined by the AERES. NN (not-scored) attached to a criteria indicate that this one was not applicable to the particular case of this research unit or this team. Criterion 1 -C1: Scientific outputs and quality; Criterion 2 -C2: Academic reputation and appeal; Criterion 3 -C3: Interactions with the social, economic and cultural environment; Criterion 4 -C4: Organisation and life of the institution (or of the team); Criterion 5 -C5: Involvement in training through research; Criterion 6 -C6: Strategy and five-year plan.

 Introduction

History and geographical location of the unit:

The UMR 663 was created in January 2005 and reconducted in January 2009 (evaluated A by AERES).

It is located in Hôpital Necker-Enfants Malades (Paris) and also benefit from hosting resources at CEA (Neurospin and SHFJ, Orsay), at Institut de Psychology (Boulogne), and at the Centre de Psychiatrie et Neurosciences (Hôpital Sainte Anne).

Management team:

Director of the unit: Ms Catherine CHIRON AERES nomenclature:

SVE1_LS5

Unit workforce: The unit constitutes a multi-disciplinary research group with a well-defined area: Pediatric Epilepsy;

• Within this area, the field "Encephalopatic Epilepsies" constitutes the core of the unit's research;

• The unit occupies a world leading position in this field;

• The unit publishes in the best journals in the field, and it has a strong international profile;

• The unit receives substantial additional funds from ANR (Agence Nationale de la Recherche), diverse Foundations/Associations, Industry, European (FP7) and other sources;

• The unit attracts foreign visitors and PhD students;

• The translational character of the unit's research is an asset;

•

The assurance that Catherine Chiron can continue the leadership for the coming 5 years.

Weaknesses and threats:

• The lack of manpower specifically with respect to the following functions: research engineer for the development of advanced tools for imaging processing, senior researcher with tenure for the basic experimental program; administrative assistant with tenure;

• The forthcoming retirement of the leader of the Pharmacology team;

• The spread among separated sites;

•

The very modest funding from the University;

• Few junior group members.

Recommendations:

• Better use of management tools to increase the efficiency of unit's governance;

• Carry out an active search for the manpower indicated above by using the national INSERM competition calls;

• Reduce the number of groups to 4, by fusing the groups Nosology & Genetics with the group Basic Epileptology, while keeping the other 3 (Imaging, Neuropsychology and Pharmacology) as they are;

• Try to find a young clinical pharmacologist interested in pediatrics to help to carry on the project of the Pharmacology team;

• Active recruitment of excellent junior researchers or PhD-MDs.

 Detailed assessments

Assessment of scientific quality and outputs:

The unit constitutes a multi-disciplinary research group clearly dedicated to the theme "Pediatric Epilepsy" in its various facets, extending to relevant aspects of human brain plasticity. The whole consortium constitutes a harmoniously entity where multiple synergies operate. The unit is unique since it has the core focus on Encephalopatic Epilepsies ranging from the neonate to the school-going child. The unit encloses a number of disciplines, ranging from genetics, pathophysiology, pharmacology, neuropsychology, clinical nosology with very strong links to brain imaging, both morphologic and functional. The unit publishes in the best journals in the field (Nature Genetics, Lancet Neurol, Nat review Neurol, Neuron, Neuroimage, Cortex, …) , and it has a strong international profile. Substantial funding, additional to INSERM and a small donation of the University, is obtained from European sources and from Industrial partners.

Assessment of the unit's academic reputation and appeal:

Members of the unit are regularly invited to attend important international meetings. In the field of Pediatric Epilepsies, the unit can be considered one of the world leaders. Unit members participate in and organize advanced courses not only in France but also internationally. The unit attracts foreign visitors and students as indicated below (criterion 5).

Assessment of the unit's interaction with the social, economic and cultural environment:

Several research findings that emerged from the unit have been already incorporated in clinical practice, particularly in the diagnostic of children epilepsies using brain imaging methodologies, and in the field of antiepileptic drugs, where contracts with pharmaceutical enterprises were established and specific funds were obtained.

Assessment of the unit's organisation and life:

The unit's organization is rather informal and it appears to run smoothly, notwithstanding the rather complicated structure with groups spread over different sites. The communication between these groups internally and also externally is very satisfactory. Although the governance is recognized as efficient and collegial by the staff, management tools are minimally utilized.

Assessment of the unit's involvement in training through research:

Unit's members participate in several courses both at the undergraduate and at the graduate levels. In the last years, the unit has increased appreciably the number of PhD students: in 2012 there were 24. Some of these come from foreign countries: Czech Republic, Belgium, Italy, Russia, Portugal. All students have a supervisor, and some also a co-supervisor; the students rate the coaching they obtain in the unit as very positive. There is a good supply of courses. The students appear well integrated in the various research projects notwithstanding their diverse backgrounds and seem to be systematically involved in publications. There are regular seminars for the whole unit where students take also an active part.

Assessment of the five-year plan and strategy:

The unit is regarded as having a very good research program and high-standard goals for the coming years. It should be able to reinforce its unique position in Pediatric Epilepsy at the forefront of the international field, with important scientific contributions. A strong multidisciplinary approach focusing on clearly defined objectives constitutes an important asset. In addition the translational character of the research with multiple cross-links between basic research and clinical practice, in both directions, is highly valuable. Specific points to be mentioned:

The visit was well organized and the Agenda was fulfilled satisfactorily.

  de Sèvres, 75015 Paris Conduct or programme of visit: 8h30 -9h00 Huis clos -Présentation de l'AERES au comité par le Délégué 9h00 -9h15 Devant l'unité, présentation du Comité de visite et Présentation de l'AERES par le Délégué 9h15-10h Présentation de l'unité, bilan et projet (Ms Catherine CHIRON) AUDITION DES GROUPES (30 mn chacun dont la moitié du temps pour la discussion, et 5 mn en tête à tête avec le chef de groupe, si demandé par le président ou les chefs de groupes) 10h00-10h30 Bilan et projet groupe Neuropsychologie (Ms Isabelle JAMBAQUE / Ms Nathalie ANGEARD) 10h30-11h00 Bilan et projet groupe Imagerie (Ms Lucie HERTZ-PANNIER / Ms Anna KAMINSKA) groupe Phénotype/Génotype/Epileptologie fondamentale (Ms Rima NABBOUT-TARANTINO / Mr. Jacques LASCHET) 11h45-12h15 Bilan et projet groupe Pharmacologie (Mr. Gérard PONS / Mr. Vincent JULLIEN) 12h45-14h Déjeuner de travail SESSION RENCONTRE AVEC LE PERSONNEL PERMANENT ET NON PERMANENT Le comité se répartit en trois sous-groupes (Amphithéâtre et Mezzanine) 14h -14h45 Rencontre avec les ITA titulaires, CDD Auditoire : membres du Comité, Délégué AERES, représentant tutelle ITA, sans la Direction Rencontre avec les doctorants et post-doctorants et/ou CDD « chercheurs » Auditoire : membres du Comité, Délégué AERES, sans la Direction Rencontre avec les chercheurs et enseignants chercheurs titulaires Auditoire : membres du Comité, Délégué AERES, sans la Direction 14h45-15h Pause 15h-15h45 Rencontre avec les représentants de la Tutelle: Auditoire : membres du Comité, Délégué AERES 15h45-16h15 Rencontre avec la direction de l'unité Auditoire : membres du Comité, Délégué AERES 16h30-18h30 Réunion du comité à huis clos Présence : membres du Comité, délégué AERES

Unit workforce Number as at 30/06/2012 Number as at 01/01/2014

				2014-2018
				Number of
				project
				producers
	N1: Permanent professors and similar positions (PR, PUPH, DR)	4 (2.5 FTE)	4 (2.5)	4
	N2: Permanent researchers from Institutions and similar positions (MCF, MCUPH, CEA)	8 (3.35)	7 (3.25)	7
	N3: Other permanent staff (without research duties) (PH)	7 (1.3)	6 (1)	6
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)
	N5: Other researchers from Institutions (Emeritus DR, Post-Doc, Interface Clinician, Contractual Researchers) (Emeritus Research Director, Postdoctoral students, visitors, etc.)	4 (3)	6 (4.5)	4
	N6: Other contractual staff (without research duties) (TECH, Secretary, Vacations)	5 (4.25)	5 (4)
	TOTAL N1 to N6	28 (14.1)	28 (15.25)	21

Unit workforce Number as at 30/06/2012 Number as at 01/01/2014

	Doctoral students Theses defended Postdoctoral students having spent at least 12 months in the unit* Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 2	24 11 2 3

 Assessment of the unit Strengths and opportunities:

2013 Grades Critères C1 Qualité scientifique et production C2 Rayonnement et attractivité académiques C3 Relations avec l'environnement social, économique et culturel C4 Organisation et vie de l'entité C5 Implication dans la formation par la recherche C6 Stratégie et projet à cinq ans

	A+	67	62	52	73	65	60
	A	57	67	71	45	65	63
	B	12	7	4	7	6	14
	C	0	0	0	3	0	1
	Non Noté	3	3	12	11	3	1
	Percentages
	Critères	C1 Qualité scientifique et production	C2 Rayonnement et attractivité académiques	C3 Relations avec l'environnement social, économique et culturel	C4 Organisation et vie de l'entité	C5 Implication dans la formation par la recherche	C6 Stratégie et projet à cinq ans
	A+	48%	45%	37%	53%	47%	43%
	A	41%	48%	51%	32%	47%	45%
	B	9%	5%	3%	5%	4%	10%
	C	0%	0%	0%	2%	0%	1%
	Non Noté	2%	2%	9%	8%	2%	1%
	Histogram

5  Statistics by field: SVE on 10/06/

We are very grateful to the visiting committee for his helpful report and recommendations that we will seriously take into consideration. In addition, we would like to make three specific comments.

The first comment regards "the lack of senior researcher with tenure for the basic experimental program". We just finalized the process to recruit a senior MCU-PH on this program who has a recognized high-quality expertise on basic epileptology (H index 10). He will join the unit in January 2014.

The second comment regards "the forthcoming retirement of the leader of the Pharmacology team". We did anticipate this retirement (planned for 2016) in order to avoid any weakness for the team: Vincent Jullien (MCU-PH 1 st class, HDR authorized to be defended in 2013) is already currently co-head of the Pharmacology team (see Organigram in Results p27 and Project p16). In addition, V.Jullien's leadership in PK/PD and modeling will be reinforced by C.Chiron's expertise in clinical trials (DR1, 0.5 FTE for Pharmacology).

The third comment regards the recommendation to "fusing the groups Nosology and Genetics with the group Basic Epileptology". In practice, this process is already on going: both groups share the same tenure researchers, the same translational projects, and they gave a common presentation to the visiting committee.

Catherine CHIRON Director UMR 663


Grading

Once the visits for the 2012-2013 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams). This score (A+, A, B, C) concerned each of the six criteria defined by the AERES. NN (not-scored) attached to a criteria indicate that this one was not applicable to the particular case of this research unit or this team. Criterion 1 -C1 : Scientific outputs and quality ; Criterion 2 -C2 : Academic reputation and appeal ; Criterion 3 -C3 : Interactions with the social, economic and cultural environment ; Criterion 4 -C4 : Organisation and life of the institution (or of the team) ; Criterion 5 -C5 : Involvement in training through research ; Criterion 6 -C6 : Strategy and five-year plan.

 Introduction History and geographical location of the unit

The team was set up in the faculty of pharmacy between 1996 and 1999 and was first evaluated by the French ministry of research in 2006 and the unit was renewed in 2010 as EA4065 at Paris 5.

Management team:

The unit, EA4065, is directed by Professor Marie-José BUTEL and co-directed by Professor Jean-Louis PONS and comprises seven permanent professors and assistant professors with teaching duties, three of whom also have hospital positions.

AERES nomenclature

SVE1, LS6

Unit workforce: Qualified research supervisors (with an HDR) or similar positions 5

 Assessment of the unit

The unit is well integrated into the scientific policy of the Faculty of Pharmacy department "Perinatality, Microbiology, Drug" which encompasses the Inserm unit U767 "Normal and pathologic pregnancy" and the UMR 216 IRD "Mother and child faced tropical infections" and the Hospital University Department (DHU) "Risk and Pregnancy". The Faculty of Pharmacy has proven to be supportive for the unit as shown by the appointment of a professor (PU-PH) and of an assistant professor with hospital position (MCU-PH) recruited in 2013. For the next five year contract period, a research group comprising a professor, a research engineer and an assistant-engineer from the Conservatoire National des Arts et métiers will join the unit.

Strengths and opportunities:

The research focus of the unit, EA4065, is on intestinal microbiota in preterm infants. This focus was considered to be an under studied niche and the association of clinicians and basic researchers promises a high probability of success. The Unit provided a research plan for the forthcoming 5 year period (2014)(2015)(2016)(2017)(2018) and has made key strategic decisions and alliances that should enable them to start to ramp up their research and make a significant impact in the area of neonatal gut microbiology. The location of the unit at the Faculty of Pharmacy Paris 5, is near other eminent research centres including the Necker, The Pasteur Institute, Paris XI, and Micalis at Jouy en Josas, whose proximity will facilitate collaborations with eminent collegues in the field at Micalis, at Necker or at Pasteur Institute. These collaborative links will increase opportunities to the Unit to become a global force in neonatal gut microbiology and make a significant impact in this field. Considering its size and composition, the team has been dynamic and successful in obtaining grants from public sources, such as with the highly competitive funding agency ANR, and from private organisations, such as Danone or Nestlé. The Unit has shown a good track record of publications (42 rank A publications) considering the level of manpower in the Unit and the heavy teaching load.

Weaknesses and threats:

The Unit has certain weaknesses, already identified by the research unit itself or highlighted by the expert panel:

-The publication record, in terms of the numbers of primary publications is good when compared to their peers and taking into account the relatively low number of fulltime researchers. However, the impact and H index are lower than those of other colleagues working in the field, probably due to the heavy teaching duties of the members of the unit, the absence of permanent researchers, and the number of projects being currently run in the Unit simultaneously. Due to the limited size of the unit, some of the results are often descriptive rather than mechanistic.

-The Unit has been slow in adopting Next Generation Sequencing approaches and this has recently led to the establishment of a strategic alliance with INRA at Jouy-en-Josas. However, the expert panel identified the need to clarify who will take the lead in any high impact publications originating from this collaboration.

-There is currently a lack of PhD students and researchers with postdoctoral position in the unit, despite the level of funding and the number of researchers with HDR. Of note, two researchers were recently awarded HDR status. The unit should benefit from the connection with the "Conservatoire National des Arts et Métiers" in their recruitment of good students and engineers.

Recommendations:

There is currently not enough in-depth research focusing on several high-impact topics. The unit is advised to strategically choose several interesting research questions/hypotheses in order, according to the small size of the unit, to undertake a much more in-depth research program to gain more mechanistic insights. In agreement with the proposal of the unit itself, the expert panel strongly encourages the researchers to rapidly embed genomic approaches (high throughput sequencing and concomitant bioinformatics) in their research, This focus will allow the unit to develop their own global approaches for a better understanding of the infant gut microbiota, to become a leader in the field of neonatal gut microbiota, increase their visibility in future papers and become much more attractive to facilitate the recruitment of PhD and post doctoral scientists of high quality.

 Detailed assessments

Assessment of scientific quality and outputs:

The main theme of the unit is the ecology of the GI tract of neonates, ranging from establishment of the microbiota of preterm infants, to its role in enteropathies and immunostimulation/allergies. The quality of the research performed, in the context of the intestinal microbiota establishment in preterm neonates and the relationship in health and diseases, is considered to be quite good/satisfactory and they have developed a significant presence in this field of research, with a central position within a department that offers all the facilities to perform clinical trials and to have access to infant cohorts. The experimental approaches are good. The Unit has integrated animal models in their research to validate their observations and evaluate the role of the microbiota and probiotics. The science that has been undertaken is deemed to be of a robust nature and of good quality. The output is good, with a total from 2006 to 2012 of 38 original articles in good international journals (like Anaerobe, Applied and Environmental microbiology) with mean impact factor 3.6; 27 of them directly originated from the research done in the unit and 10 generated from collaborations. The unit also gave 22 oral and poster presentations at national and international meetings and 12 invited talks mostly at the national level. The group has several collaborations with national partners. The quality and quantity of the external funding is good.

Assessment of the unit's academic reputation and appeal:

The research projects of the unit are concerned with a medically important field, and the number of research units developing projects in this area is limited worldwide. The unit has a good national visibility through collaborations with neonatal hospital units leading to ANR funded prjects "Premaflora" and "Epiflore" and involvment in the national network "Probiotics", is well-known for its expertise in gut microbiology of neonates and in the field of Bifidobacteria. The unit has many collaborations, mostly at the national level. There is evidence that the unit is capable of acquiring significant research funds from national academic funding organisations and from globally recognized international companies. The unit is involved in several national networks related to different aspects of their work. It has a good reputation at the national level as evidenced from publications and ongoing collaborations.

Assessment of the unit's interaction with the social, economic and cultural environment

The unit is well integrated into the scientific policy of the Faculty of Pharmacy Department of "Perinatality, Microbiology, Drug" encompassing the Inserm unit U767 "Normal and pathologic pregnancy" and the UMR 216 IRD "Mother and child faced tropical infections" and the Hospital University Department (DHU) "Risk and Pregnancy". The main interactions appear to be with clinical units, especially neonatal and maternity units. There is a good backup to the clinic units with dissemination of information to health staff. Evidence was provided of good relationships with industry, mostly with manufacturers of infant formulas and probiotics. The senior staff regularly provides lectures to outside groups. Popular public via popular public scientific publications and press conference provide evidence for the unit effort to disseminate their results to the lay community.

Assessment of the unit's organisation and life:

Despite the fact that the unit is located at two different sites, this is a small collegiate unit with regular formal meetings. All the staff attends 3 meetings per month during which scientific results and operational aspects of the team are discussed. One researcher takes care of health and safety issues and measures are taken that the projects are done in accordance with ethical regulations. Three researchers are authorized to conduct animal experiments. New knowledge and new skills are entering this Unit. Members of the lab are very supportive of the leader of the unit.

The projects are divided in 3 axes, two concerning the microbiota in neonates (establishment and maturation) and the third one aims to evaluate the role of the cell wall in bifidobacteria and clostridia. The latest project is linked to the expertise of a scientist who joined the team very recently. Interestingly, there is no close separation between the different axes since researchers contribute to the different axis.

Assessment of the unit's involvement in training through research

Members are deeply involved in teaching at different levels of school of Pharmacy and in Master degree. The unit welcomes a significant proportion of Master students, mainly at the M1 level. There are only a few PhD students but their number will probably increase in the next contract with the increased number of HDR recently defended.

Assessment of the five-year plan and strategy

The planned future research is a logical step forward from previous findings. The research is organized as three axes.

In the first axis, they plan to continue to study the microbiota composition of neonates. They will have access to a French multicentric cohort of infants that will be followed up for 12 years (EPIFLORE) allowing evaluation of the relationship between the microbiota establishment in neonates, the early perinatal factors and the diseases occuring during childhood. As part of this axis, the Unit plans to specifically evaluate the genotypic diversity of bifidobacteria and clostridia, in samples collected from the cohort previously set up (PREMAFLORA). The aim is of considerable scientific interest, but the readouts and deliverables are not clearly defined. Finally, they plan to investigate the microbiota composition of infants suffering from necrotizing enterocolitis NEC and to evaluate the involvement of bacteria in this disease. In that context, they will also focus on the role of clostridia in NEC by studying the effect of a specific strain and mutants in an animal model. They have also selected a bifidobacterial strain with potential probiotic characteristics, as it is able to protect against NEC in an animal model. They plan to study the effect of this strain in neonates in collaboration with an industrial partner and a pediatrician at the Necker-Enfants Malades hospital. In light of preliminary positive results, this should pave the way for interesting commercial benefits, but also for fundamental research to better understand the mechanism(s) of action.

In the second axis, they aim to decipher the impact of the microbiota on the development of the intestinal immune system. They notably focused their study on allergic diseases. They plan first to first evaluate the impact of microbiota from allergic infants in a gnotobiotic model of allergy to cow milk (β lactoglobulin). Using such a model, they also plan to evaluate the effect of selected probiotics to attenuate the impact of the allergen. This part is interesting since it will allow more mechanistic studies to be performed, but should require a full-time researcher (work intensive model). It also requires good expertise in immunology, notably to evaluate the local immune responses (purification of cells from lamina propria, cytometry, etc...). They also plan to evaluate the faecal eosinophil-derived neurotoxin (EDN) as a potential biomarker of food allergy using a large cohort of infants. This is a small study that could, however, lead to interesting outcomes. The impact of the microbiota will also be evaluated in respiratory allergy in a large scale epidemiological study (from a cohort in Paris).

The third axis aims to evaluate the dynamics of the cell wall in bifidobacteria and clostridia. This is a new research theme linked to the expertise of a researcher (PU-PH) joining the unit. Through the construction of mutants, they plan to evaluate the role of cell wall components in the pro-inflammatory and virulence activities of clostridial strains. The role of cell wall components of bifidobacteria will be also evaluated using in vitro models, in collaboration with a group at INRA. The research program for the next five-year plan is a wide-ranging and time consuming project considering the size of the unit. To be competitive and to deliver important novel findings, this unit deserves immunologist skills and manpower working on axis 2 of the project.

  Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.) spent at least 12 months in the unit* 1 Number of Research Supervisor Qualifications (HDR) taken 2

5

  Statistics by field: SVE on 10/06

 Conduct of the visit

The visit had taken place the 17th December 2012, at the Faculty of Pharmacy, rue de l'Observatoire, Paris Descartes University. After a short closed meeting between the experts and the AERES scientific deputy, the on site evaluation has started at 9:00 and pursued as mentioned in the joined schedule to finish at 16:45. The visit had been carefully prepared and members of the committee appreciated the scientific quality of the oral presentation. During the visit, the informations essential for the understanding of the life of the unit were provided to the panel of experts. The relative contributions of the director, co-director, and of the other members of the team to the oral presentation and to the answers to the questions of the committee were carefully and appropriately planned.


Grading

Once the visits for the 2012-2013 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams). This score (A+, A, B, C) concerned each of the six criteria defined by the AERES. NN (not-scored) attached to a criteria indicate that this one was not applicable to the particular case of this research unit or this team.

Criterion 1 -C1: Scientific outputs and quality; Criterion 2 -C2: Academic reputation and appeal; Criterion 3 -C3:

Interactions with the social, economic and cultural environment; Criterion 4 -C4:

Organisation and life of the institution (or of the team); Criterion 5 -C5:

Involvement in training through research; Criterion 6 -C6:

Strategy and five-year plan.

With respect to this score, the research unit concerned by this report and its in-house teams the following grades:

 Grading table of the unit: Neuroplasticité et thérapies des addictions This new unit will move from the Pharmacy Faculty to the Biomedical Faculty rue des Saints Pères (another location of the Paris 5 University) where it plans to establish collaborations with chemists and where technical platforms will be available for further developments.

C1 C2 C3 C4 C5 C6 A A A A A A
The general theme of the former team/future unit to be reviewed was linked to the research topic of addiction with preclinical and clinical approaches. It involves presently 9 permanent positions, 1 PhD student and 2 ERASMUS students (Italy, UK). For the next period (2014)(2015)(2016)(2017)(2018), four permanent members of the present team will leave.

Management team

As a reminder, in the former unit, the team is headed by Ms Florence NOBLE , who will be the director of the future unit. Specifically regarding this team, the management appears to be fine as 6 PhD theses and one HDR were defended in the 2010-2013 contract and financial ressources were found (an ANR is starting in 2013, several contracts with industrial partners are reported). 2. The potential of the research conducted is very timely and might provide new therapeutic strategies.

AERES nomenclature

SVE1_LS5

Unit workforce

Unit workforce

3. The unit has strong support from the CNRS, and from the Biomedical Faculty (rue des Saints-Pères location) and the Paris Descartes University, who all confirm the moving to the Saints-Pères location of the Paris Descartes University with the advantages of getting help of different technical platforms of the two SFR (structure fédérative de recherche) in Chemistry, Toxicology, Cell Signalisation, Therapeutic Targeting (C2T2S), and in Neurosciences and Pharmacology of the Biomedical Faculty.

4. More space in the Saints-Pères location (180 m 2 for the new unit) should allow recruitment of researchers and post docs.

Weaknesses and threats

1. In terms of human resources, the project involves very few people for very time-consuming and diverse subprojects raising questions about the feasibility of the whole proposal. The number of HDR should be increased to welcome more students (one researcher of the team should get his HDR as soon as possible). The number of post-docs from abroad should also be increased. A clearer identification of who is responsible of the different sub-projects will be welcome.

2. In terms of scientific project, the unit should focus more on some original and timely aspects of the project for which they have already gathered data and find their own "niche" in the context of the large number of highly competitive teams working already in the field of addiction in France and abroad, which have already investigated the issue of vulnerability and variability in drug addiction. This very competitive field needs highly innovative concepts and techniques to make a breakthrough. Hence, again regarding the small number of people, the team should find a way to make each sub-project more in coherence and potentiate one to another instead of being completeley independent as they have been presented in the document and during the visit.

3. Regarding the technological feasability of the project, the Saints-Pères location will provide access to the new technologies that are going to be developed in the future project. Therefore, the moving to the Biomedical Faculty appears a crucial step (and therefore a threat if not fulfilled) for the feasability of the project. 4. Regarding the potential therapeutic outcomes of the project, the loss of the clinical surrounding provided by the present UMR is detrimental.

Recommendations

Due to the very small size of the unit, the project should be more focused. Based on the grounds of previously acquired data, the member of the unit should put their forces and competences together to study in depth the questions raised by previously acquired data. The unit should be more involved in international networks, which regarding the project should be of interest for most of these networks.

 Detailed assessments Assessment of scientific quality and outputs

The main objectives of the team since 2010 were aimed at (1) increasing the knowledge on the neuropathological mechanisms of addiction focusing mainly on psychostimulants (MDMA and cocain) and opiates, and (2) optimizing the existing treatments and developing new therapeutic strategies. The scientific production over the last 4 years (2007-2012) is presented over 4 themes Polyconsommation, Substitution treatment, Mechanisms of action of opioids, Psychostimulants.

The general impression is a dispersion of projects according to the low number of researchers involved, with difficulties to dress a leading link between these different sets of data. Four themes are investigated in the team with no evident link betweem them though that there are all related to addiction. It is therefore quite difficult to envisage which one among these results can be efficiently pursued for therapeutic applications.

Despite this remark, the overall level of scientific publication of the permanent members of the former team is good both qualitatively and quantitatively, with a mean of 2.24 publications per person per year, 35 international peer-reviewed publications since 2007 (among which 4 review articles), and 4 book chapters. Out of the 35 articles, 63% of the production results from a major contribution of the team/unit. Most of the papers were published in good or even leading journals in their specific research fields, such as 1 Translational Psychiatry, 1 Plos One, 2 Addiction Biology, 1 Journal of Neuroscience, 3 Psychopharmacology, 1 Pain, 2 Neuropharmacology, 1 Neuropsychopharmacology and others with a large part of them having an impact factor (IF) between 4 and 8, but none above an IF of 9. Of the 35 articles, 91% of them have an IF superior to 2, 57% with an IF>4, 5.7% with an 7<IF<9 and 0% with an IF>9. The head of the team demonstrates a high number of invitations in national and international conferences (26/27 in total with 5 international and 21 national). Collaborations are active and productive as evidenced by many papers (10 of 35) based on collaborative work. Of the 3 future permanent lab members, all are producers.

Assessment of the unit's academic reputation and appeal

The academic reputation is very good in regards to the number of collaborative projects (2 national with one ANR whose coordinator is the PI of the team and 2 international Erasmus projects (with Italy/Bologne and USA/Baltimore), the participation to a GDR network, the implication in a Labex (resistance to medicine and toxicity. The team has also organized some colloques and symposia among which 6 were abroad. The PI is a member of the editorial board of the Journal of Addiction and of the committee of "Le Courrier des Addictions". The team has collected prizes such as the « Coup d'Elan pour la Recherche française (250 000 euros) and some travel grants and poster prizes. The team was a member of the IFR 71 "Institut Médicament, Toxicologie, Chimie, Environnement" and will join the new SF C2T2S at the Biomedical Faculty of the Paris Descartes University.

In terms of attractiveness, the team has welcomed 2 post-docs in the past 5 years and will welcome a new post-doc on an ANR project in the next three years. One of these former two post-docs was recruited (as professor) in 2010.

Assessment of the unit's interaction with the social, economic and cultural environment

The team interactions with the social, economic and cultural environment are excellent. The team has indeed been implicated 1. in articles published in professional journals such as Le Flyer (Bulletin de Liaison des Centres de Soins Spécialisés pour Toxicomanes et Médecins Relais, Réseaux de Soins, Pharmaciens d'Officine, ECIMUD et structures de soins auprès des usagers de drogues) 2. in several expertises (Ministère de la Santé, INSERM, SFN) 3. has participated to numerous debates organized for professionnals 4. has obtained many contracts with industrial companies and academic agencies (MILDT, ANR) Furthermore, the PI was nomitated as Directeur-adjoint scientifique at the INSB of the CNRS.

Assessment of the unit's organisation and life

The organisation and life in the team/unit is very good. The UMR to which belongs the present team organizes 2 or 3 "conseils de laboratoire" per year. The team has further organized monthly meetings as well as specific meetings to discuss data and projects. Its members have several responsabilities (Web master for instance and others). They look in good harmony with the team leader and report to appreciate the team's organization and to attend conferences on a regular basis. The PI confirms that the two technical persons belonging to INSERM will stay in the team and these two confirm that they want to stay in the team.

Assessment of the unit's involvement in training through research

The team provides very good PhD training (7 theses between 2006 and 2012, which were all affiliated to the Ecole doctorale ED 436 "Médicament Toxicologie, Chimie, Environnement » from the Paris Descartes and Paris Diderot Universities) and a good follow-up of PhD students for their post-doc and a good level of scientific production per student (despite the fact that the team has only 1 HDR). There were 4 thesis defended by pharmacy students who all got the "Médaille de l'Internat" to be 100% in research for one year and then 50% of their time in the lab. They have all published articles from their PhD works. Importantly, there is a training programme for PhD supervisors in the university. Nine master 1 and master 2 students have been trained in the lab and 2 Erasmus students have been working in the lab.

The MCU in the team (MCU since 2010) has several responsibilities in the M1 Santé and L2 Pharmacy. There is a lack of involvement in teaching units related to addiction research. Researchers of the team are involved at the M2 level in Pharmacology (a few hours/year). The PI of the team has been a member of various PhD (17) and HDR (5) defences mostly in neuroscience. In conclusion, the training through research is fine though the teaching aspect could have been better developped.

Assessment of the five-year plan and strategy

At a scientific level, for the next 5 years (2014)(2015)(2016)(2017)(2018), the team proposed to develop a project with 3 independent aims of research:

Aim 1: (financed by ANR (2012ANR ( -2016))) "longitudinal study in rats of vulnerability and variability in the different stages of drug self-administration and in the response to pharmacological treatment". This new project is aimed at characterising behaviourally animals on anxiety, hedonia, stress response before, during and after selfadministration of drugs inducing different level of drug dependence and see whether correlations can be found between these behavioural markers and response to substitutive treatments during abstinence. Hence a very ambitious transcriptomic, (including miRNA) and biochemical analyses will be implemented to find both peripheral markers and new candidates for therapeutic approaches. This transcriptomic study will be out sourced to a specialized company.

Aim 2 : "Neurochemical memory : what are the cellular and molecular mechanisms involved?". This theme is in line with previous data obtained and is aimed at determining whether the increase in dopamine, enkephalin and BDNF observed in the nucleus accumbens is specific to drugs, dependent on Rack1 and dopamine D1 receptors for BDNF, and involved in the vulnerability to relapse. Aim 3 : "mGluR7 and addiction : regulation of receptor and fonction ?". This new theme aimed at deciphering the role of mGluR7 in heroin and cocaine behavioural responses will be using new selective molecules designed in collaboration with the chemical group located at the Biomedical Faculty of the Paris Descartes University.

Aim 1, which is already financed by ANR, is going to be tremendously time and energy consuming and very risky as it is. The team has to think very carefully which strategy will be followed once hundred of genes will be fished. Nevertheless this project was selected by ANR and the financial support given by ANR will allow paying the transcriptomic analysis and hiring a new post-doc, giving the opportunity to increase the forces of the team. Aim 2 is the project which is more in line with previous team researches and requires technologies that the team has already used (intra cerebral dialysis).

Aim 3 is a completely new one and aims at showing that mGLUR7 receptor is a good candidate for drug addiction therapeutic. It is again a very ambitious and risky project since everything has to be done from start and no preliminary data are presented demonstrating the opportunity to follow such a project.

Each of these projects in itself is interesting but does not synergize with the others. Hence, these projects are quite risky, time and energy consuming and regarding the small size of the unit (4 persons), one can question whether the team will be competitive.

In conclusion, the committee is questioning the adequacy between large, very ambitious, time-consuming and diverse projects with the very small size of the unit.

  location of the unit The new project unit "Neuroplasticité et Traitements des Addictions » to be reviewed is presently the preclinical team named "Neurochimie et Neurobiologie des Addictions », nowadays part of the unit "Neuropsychopharmacologie des addictions", which is directed by Mr Jean Michel SCHERRMANN and labelised both by the CNRS (UMR8206) and INSERM (U705) within the Paris 5 René Descartes and Paris 7 Denis Diderot Universities in the 2010-2013 contract. The future principal investigator (PI) of this future unit is Ms Florence NOBLE, who is currently the deputy director of the UMR and the responsible for team "Neurochimie et Neurobiologie des Addictions ".

Number as at 30/06/2012 Number as at 01/01/2014 2014-2018 Number of project producers N1: Permanent professors and similar

	positions	2	1	1
	N2: Permanent researchers from Institutions and similar positions	3	2	2
	N3: Other permanent staff (without research duties)	4	2
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)		1	1
	N6: Other contractual staff (without research duties)
	TOTAL N1 to N6	9	6	4
	Percentage of producers

Unit workforce Number as at 30/06/2012 Number as at 01/01/2014

  The unit has a good level of funding both from academic and private sources.

	Doctoral students Theses defended Postdoctoral students having spent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) taken Strengths and opportunities Qualified research supervisors (with an HDR) or similar positions 2  Assessment of the unit 1.

5 

 5 Statistics by field: SVE on 10/06/2013

	Grades

Critères C1 Qualité scientifique et production C2 Rayonnement et attractivité académiques C3 Relations avec l'environnement social, économique et culturel C4 Organisation et vie de l'entité C5 Implication dans la formation par la recherche C6 Stratégie et projet à cinq ans

	A+	67	62	52	73	65	60
	A	57	67	71	45	65	63
	B	12	7	4	7	6	14
	C	0	0	0	3	0	1
	Non Noté	3	3	12	11	3	1
	Percentages
	Critères	C1 Qualité scientifique et production	C2 Rayonnement et attractivité académiques	C3 Relations avec l'environnement social, économique et culturel	C4 Organisation et vie de l'entité	C5 Implication dans la formation par la recherche	C6 Stratégie et projet à cinq ans
	A+	48%	45%	37%	53%	47%	43%
	A	41%	48%	51%	32%	47%	45%
	B	9%	5%	3%	5%	4%	10%
	C	0%	0%	0%	2%	0%	1%
	Non Noté	2%	2%	9%	8%	2%	1%
	Histogram

Le rapport mentionne que la perte de l'équipe Clinique pour ce nouveau contrat est préjudiciable. Le rattachement des cliniciens dans l'Unité pourrait effectivement paraitre plus rationnel vu les thématiques que nous développons. Néanmoins comme nous l'avons mentionné, nous avons établi depuis de nombreuses années des contacts forts avec plusieurs cliniciens dans plusieurs régions françaises et avec lesquels nous sommes très régulièrement en contact. La présence à l'organigramme de cliniciens ne nous semble donc pas être essentielle, les contacts étant déjà très fortement ancrés.

Le comité de visite souligne dans son rapport des projets trop larges et dispersés au regard de la composition de l'Unité. Dans le projet présenté pour les 5 prochaines années, nous avons effectivement 3 axes de recherche, qui peuvent paraitre indépendants, mais qui sont tous les trois tournés vers la pharmacologie des addictions, et les traitements, qui sont des axes de recherche originaux par rapport aux autres laboratoires français et étrangers travaillant dans le champ des addictions. Les projets ayant été réfléchis sur plusieurs années, ils apparaissent à l'écriture obligatoirement large, mais naturellement en fonction des données que nous obtiendrons, peu à peu ils se focaliseront sur les résultats les plus pertinents, et tout naturellement seront en interconnexions les uns avec les autres, tournés vers les pharmacothérapies. De plus nous avons déjà été contactés par des Chercheurs et Ingénieurs-Techniciens qui souhaiteraient pouvoir rejoindre l'Unité après sa création.