 Introduction

History and geographical location of the unit UMR 987, entitled « Pathophysiology and Clinical Pharmacology of Pain », is a mixed Inserm/UVSQ single theme ('mono-thématique'), single team ('mono-équipe') research unit hosted by Assistance Publique Hôpitaux de Paris (AP-HP) at Ambroise Paré University Hospital in Boulogne-Billancourt (Paris Île-de-France West Medical Faculty). The research activities of this group are exclusively devoted to clinical research and include studies both in patients with acute (postoperative) or chronic pain syndromes and in healthy volunteers.

The Pathophysiology and Clinical Pharmacology of Pain laboratory was formed at the end of the 1990s by a small group of clinician researchers specialized in pain medicine, with a training in both clinical and basic research. The main objective of this group has been to develop research programs focused on patients, as such studies were largely lacking in France. The group, which has been located since its creation at the Pain Clinic of the Ambroise Paré Hospital in Boulogne-Billancourt, has rapidly expanded to become truly multidisciplinary, and the medical team has been reinforced by the addition of technicians, scientific officers ('ingénieurs') and students. The group was recognized and accredited as a mixed research unit ('UMR') by Inserm and Université Versailles Saint-Quentin-en-Yvelines (UVSQ) in 2002 (UMR 332), and was renewed in 2006 (as UMR 792). Following another AERES assessment in 2009, the group was again recognized as an UMR by Inserm and UVSQ in 2010 as UMR987.

Management team (tenured positions)

As tenured/permanent positions the unit includes 1 director of research (DR1 Inserm), 5 full professors (PUPH), 1 associate professor and 2 hospital doctors (PH). This multidisciplinary medical team (neurologists, anesthesiologists, rheumatologists, gastroenterologists) is assisted by 2 scientific officers ('ingénieurs'), 1 research technician and 1 secretary from Inserm. The unit director (DB) ensures the general coordination, overall goals and scientific objectives of the team. Each specific research topic is then under the coordination of one or two senior members, themselves responsibles for the supervision of juniors and PhDs. 2  General assessment of the unit

AERES nomenclature:

SVE1-LS4

Unit workforce

Unit workforce

The unit « Pathophysiology and Clinical Pharmacology of Pain » conducts a highly original work, rooted in excellent basic science translated to clinical pain conditions of significance relevance. The quality and impact of the work are strong. In the 10 past years, the team has demonstrated rapid translation of research into clinical output, with excellent and integrated clinical links and collaborations. This has allowed them to launch an epidemiological line of research on chronic pain that was previously lacking in France.

The unit shows an excellent track-record of high quality, high impact studies; it has published 86 peer-reviewed papers in the past 5 years in Pain, Brain, Ann Neurol., Anesthesiology, J Neurol Neurosurg Psychiatry, Gut, etc, with average IF=5. From 2000 to this date, 15 of their papers have been cited more than 100 times, reflecting the value the community places on their work. More than 120 invitations to lecture have been honoured at international meetings during 2008-2013.

Quality and stability of partnerships are excellent, particularly the clinical collaborations with an impressive numbers of hospitals. One specific feature of the team is indeed to function rather as a network than a 'unit', in the sense that most of the research work is distributed among a number of university hospitals within the Paris area. This is related to their transverse approach involving several medical disciplines and the lack of on-site research facilities (e.g. neuroimaging, neurophysiology). This cannot be seen as a drawback, as it has fostered the development of a large network of collaborations in response to specific needs (e.g. fMRI, evoked potentials recordings, skin biopsies). The good synergy between members working in different hospitals provides a unique opportunity for rapid translation of research into clinically relevant data.

The capacity to raise funds is very high, and more than 70 % of total funding comes from external sources, including 1 national PHRC, and grants from public organisms (Ministry of Health) and private research foundations (APICIL, CNP, UPSA, Fondation de France).

Institutional support is also very strong from both the Inserm and the university. Translational pain research is indeed detected as a leading theme by the Inserm, and is part of its strategic plan for the following years. University backing is very sound, and the university policy plans in following years will stress the fields of epidemiology and 'handicap', the team being a prominent example of both. Even if the functioning mode of the unit privileges networking to local functioning, stronger local support from the Ambroise Paré hospital would be expected given the quality of the work being done, the unit focus on clinical research and the involvement of several members in the hospital pain clinic. Nine (9) PhD theses have been started during the past 5 years, and the laboratory is recognised by the PhD students as an excellent training environment. One foreign PhD prepared and defended his thesis in the lab; most ongoing PhDs are medical doctors with a parallel hospital career. Apparently no postdocs have been received in the last term. International presence of post-docs and students is very limited despite the potential attractiveness of the group. Increasing recruitment from abroad should be encouraged.

In summary, this is a highly dynamic team with very strong leadership and management. There is a clear strategy with identifiable goals, and nice cohesion between members despite geographical dispersion. Long-term security for this team and area of research seems guaranteed both by intrinsic quality of the work and institutional support. The experts committee recommends increasing the number of junior permanent members with skills in the methodological/analysis domains, as there is a need to complement the work of MDs and provide support to them.

The project proposed is innovative, ambitious and likely to produce original results of considerable potential impact. The experts committee detects a possible dispersion of objectives to the next 5-year term, and suggests focusing on those with maximal translational potential and impact in the pain community. Privileging projects with strong transversal interactions and pathophysiological insights over those essentially correlational in nature, or with only tiny relations with the main objectives, may be the price to ensure a convergent and in-depth analysis of the multiple research lines proposed.

Conclusion

An excellent group performing innovative top-level research.

 Strengths and opportunities:

High-quality work spanning from pathophysiology to epidemiological studies and clinical trials. Undisputable reputation of team members fostering international contacts and external funding. Past track of most relevant results and influential publications.

 Weaknesses and threats:

Possible excessive dispersion of new projects, threatening in-depth analysis and transversality.

 Recommendations:

Continue doing top-quality work. Focus research to ensure in-depth analysis of projects and privilege pathophysiologically-oriented over correlational studies. Increase effort to transmit results through generalistic neuroscience journals. Increase number of foreign PhD or post-doc.

 Detailed assessments Assessment of scientific quality and outputs

The scientific quality of past work and project is excellent to outstanding. The two leader senior members are present in the "top scientists" Web-of-Science report, with high citation (H) indexes of 43 and 39. The scientific output in terms of international publications is impressive: 86 peer-reviewed papers were produced in the last 5 years, with average IF= 5.009, of which 69 % were lead by members of the team as first or last authors. Clinical trials and epidemiological tools developed by the unit have had significant impact to orient clinical practice in France and abroad, and two screening questionnaires validated by the unit (DN4 and NPSI) have been translated to more than 50 languages. Most of the team's scientific output is published in good international journals with emphasis of pain (50 % of the production goes to pain-related journals). Although pain journals are a logical output for the team's work, the overall quality of the studies would deserve effort to publish in generalistic neuroscience journals, the presence of which in the list is relatively limited.

Assessment of the unit's academic reputation and appeal

The unit has a high academic reputation. The senior members of the team are regularly invited to lecture at international meetings and conferences, and sum up more than 120 oral presentations as invited speakers in the last 5 years. In parallel, a number of members participate to national and international teaching courses, symposia and/or workshops, and have organized/chaired personally such events in several occasions. Members have been appointed to the boards of international journals (Pain, European Journal of Pain), participate in ongoing European networks (PainOut, NeuroPain, euCPSP) and collaborate or coordinate international guidelines/recommendations for the assessment and therapy of pain (NeupSIG and EFNS Guidelines for neuropathic pain assessment, QST use and pharmacological therapy). The head of the unit is president-elect of the French Society for pain research (SFETD). Ability to rise external, competitive funding (independent from recurrent institutional support) is high, with more than 70% of funding coming from external sources. Despite the scientific appeal of the group, international presence of post-docs and students is limited, and increasing recruitment from abroad should be encouraged. One high-standard researcher working in US is planning to join the group during the next term.

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

The interactions with the economic and social environment are excellent. Partnerships are multiple and stable. Industrial collaboration is outstanding, with more than 15 contracts with private partners, and steady consultancy of senior members with pharmaceutical companies for the development of new drugs. Major interactions with patients' organizations (syringomyelia, fibromyalgia, glossodynia, irritable bowel syndrome) which in turn support the unit's multiple clinical trials and epidemiological studies. Senior members regularly participate in general audience-oriented activities via general press or television programs, and the unit is present in public awareness campaigns such as the "semaine du cerveau", "Universcience" or "Bar des Sciences" organized by CNRS and INSERM.

Assessment of the unit's organisation and life

There is a strong coherence of the group, based on a network-oriented organisation. Studying pain of multiple clinical origins has prompted a transverse approach with members working in different hospitals and disciplines. Despite the spatial segregation and different workplaces within Paris, the team exhibits a very neat integration, with fortnightly meetings gathering seniors and juniors, where students are asked to present their ongoing projects, and weekly smaller meetings to discuss specific points. Being active in several hospitals fosters the possibility of recruiting large patients' samples. Three members of the unit have been recently appointed professors or associate professors, and two new doctors have joined the staff (two others are joining the group during the next term). Polyvalent training of research technicians enable them to work with different members of the team, thus enhancing the structure solidity. The discussion of the experts committee with students and technicians at the end of the visit confirmed the above impression of coherence and commitment.

Assessment of the unit's involvement in training through research

The unit has extensive participation in training, both academic and through research. Since its creation, it has been affiliated to the Doctoral School "ED 158 cerveau-cognition-comportement" in Université Paris 6, and within this frame 9 students have prepared their PhD (5 of them already defended). Senior members participate in different pain medicine university courses, and have organised numerous international seminars in France ("cours supérieurs" of French Pain Society, Master of pain medicine) and abroad (European Federation of Neurological Societies (EFNS), European federation of pain chapters (EFIC), International Association for the Study of Pain (IASP), European League Against Rheumatism (EULAR). Different members of the team participate, organise or coordinate a number of university diplomas from 3 Paris universities on acute and chronic pain, pharmacological therapy, anaesthesiology and gastroenterology. The academic commitments and multiple competences of the team members (neurology, anaesthesiology, gastroenterology, internal medicine) obviously favours the involvement of the unit in teaching activities, which is outstanding.

Assessment of the strategy and the five-year plan

The research project follows the transversal strategy and is rooted on the dynamics established during the past years. The project is presented in 5 axes, namely: a) mechanisms and factors predicting hyperalgesia, itself containing 3 sub-axes: postoperative hperalgesia after autograft iliac crest bone harvest, diffuse hyperalgesia after aromatase inibitor treatment, and role of gut microbiota in intestinal hyperalgesia; b) new treatment strategies (repetitive cortical stimulation and botulinum toxin); c) cognitive functions and chronic pain; d) application of network meta-analysis to clinical trials. The oral presentation included a further axis; e) based on the application of the 'thermal grill hyperalgesia' to patients with either neuropathic or dysfunctional pain.

Each of these research areas are intrinsically interesting, and served by competent researchers; in each of them a senior and a junior ensure the coordination. There appears to be a thematic dispersion as compared with previous activities of the team; while some projects remain strongly interconnected, and rooted in pathophysiological hypothesis testing, others may lack strong transversal interactions (e.g. the study of gut microbiota) or are more correlational than pathophysiological (e.g. cognitive function correlates of chronic pain). Although each project has its intrinsic qualities, one may wonder whether such thematic dispersion might be detrimental to a convergent and indepth analysis of multiple and somewhat unconnected results.

Number as at 30/06/2013 Number as at 01/01/2015

	N1: Permanent professors (PUPH) and similar positions (PH)	6	6
	N2: Permanent researchers from Institutions and similar positions	1	1
	N3: Other permanent staff (without research duties)	6	8
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)		1
	N6: Other contractual staff (without research duties)	1	1
	TOTAL

N1 to N6 14 Unit workforce Number as at 30/06/2013 Number as at 01/01/2015

	Doctoral students	4
	Theses defended	5
	Postdoctoral students having spent at least 12 months in the unit*
	Number of Research Supervisor Qualifications (HDR) taken	1
	Qualified research supervisors (with an HDR) or similar positions	7


Patrick Le Quéré

DIRECTION DE L'ENSEIGNEMENT ET DE LA RECHECHE

 Introduction History and geographical location of the unit

The research unit "Laboratoire d'optique en biosciences" (LOB) has been created in 2001 by Mr Jean-Louis MARTIN with the aim to create an interdisciplinary laboratory at the interface between Physics (optics and spectroscopy) and Biology. The laboratory is organized in teams assembled on the basis of specific research axes. Each team can comprise more than a principal investigator. The same researcher can belong to different teams. The laboratory is located at École Polytechnique (Palaiseau) and administratively depends on the École Polytechnique, the INSERM and the CNRS.

Management team

The laboratory has been directed since its creation by Mr Jean-Louis MARTIN. Mr François HACHE has been elected as the director for the next 5-year contract. The management activity of the director is supported by a "Collège de direction" (CODIR) which is composed of all the researchers of the laboratory. Besides the CODIR, members of the laboratory also have regular discussions in the framework of the 'Conseil de laboratoire' and, once per year, at the "Assemblée générale".

AERES nomenclature

The laboratory is an interdiscplinary unit and falls under two AERES domains, namely the ST (Physics) and SDVE (Biology and Medicine) domains. 2  Overall assessment of the interdisciplinary unit

Unit workforce

The LOB is an interdisciplinar laboratory is comprised of a staff of 30 people including researchers, engineers post docs and students. The research activity of the laboratory, organized in thematic teams, can count on a very broad range of complementary expertise including, nonlinear optics, optical microscopy, ultrafast spectroscopy, nanoscience, microbiology and protein dynamics. This rich and unique scientific environment has permitted to realize ambitious research projects at the interface between physics and biology. The success of the laboratory is demonstrated by a very good scientific production and the generation of several patents.

Strengths and opportunities related to the context

This research unit has reported scientific results of an excellent quality in physics, biology and at the interface between the two disciplines.

At the occasion of the visit, the experts committee could appreciate the extremely positive feedback on the working conditions within the unit given by all the unit members (researchers, technical staff, postdocs and students).

Also remarkable is the effort that the unit has demonstrated in the technological transfer of the achieved results as demonstrated by an significant generation of patents.

The Equipex project "Morphoscope2" and the new X-Bio institute represent two important opportunities for the next contract that should stimulate new important collaborations and permit increased visibility.

Weaknesses and threats related to the context

No serious threats or weaknesses have been identified. The EQUIPEX coordinated by the team is undoubtedly an opportunity to create a state of the art platform for light microscopy and to initiate new collaborations. However care must be taken to support this operation with human resources to ensure that this development does not come at the expense of creativity and innovation of the team.

Recommendations

Altough the unit has a good visibility at national and international levels, a stronger visibility at international/european level could be reached for example toward applications for ERC grants.

Care should be taken that the promotion of new technologies to a broad community of biologists will not disperse the resources of the unit in too many collaborations and/or research domains.

 Detailed assessments

Assessment of scientific quality and outputs

Over the past 4 years the research unit has obtained key results in a broad range of research fields. This include, for example, the screening for inhibitors of the ThyX protein with a potential as novel therapeutic agents for the treatment of Helicobacter pylorii infections or tuberculosis. The development of an impressive technical platform for ultrafast spectroscopy and its application to the investigation of ultrafast phenomena regulating protein dynamics. The synthesis on nanoscale particles for e.g. monitoring the dynamics and spatial organization of H 2 O 2 signalling. The development of new microscopy configurations that will have a tremendous impact in the community of biologists. This includes an innovative multimodal (SHG-THG) microscopy technique which led to the first visualization and quantification of the early stages development of a zebrafish embryo, new optical schemes for fast and precise multicolour imaging and a robust optical system for SHG microscopy. Overall the scientific production of the laboratory has been excellent and has generated more than 130 articles on highly recognized international journals, comprising (7 biophys J, 2 PNAS , 2 Nature Methods, 1 Physical review letters, 1 Science, EMBO J).

Assessment of the unit's academic reputation and appeal

The 4 teams have a good visibility both at the national and international level. The results obtained from the thematic team 3, which place this group among the most worldwide recognized group in nonlinear microscopy, have generated about 50 invited talks in prestigious specialized conferences.

The visibility of the unit is also demonstrated by the capability of attracting foreign PhD students and outstanding visiting professors.

The research projects are all regularly financed through different funding programs mostly at national level (ANR, Région idF, RTRA triangle de la physique, CNRS). Team 3 has been recently granted with an Equipex "Morphoscope2" to set up a multiscale imaging facility at École Polytechnique that will increase the visibility of the research unit even further.

Different members of the laboratory are implicated in the coordinatiotn of scientific networks such as the axis Nanobioscience, C'nano d'Ile de France, and the axis New-contrast and in depth imaging in the framework of France Bio Imaging.

The excellent scientific carrier of the incoming director of the unit has been awarded in 2011 by the prize « Médaille d'argent du CNRS ».

Assessment of the unit's organisation and life

The laboratory is organized in thematic teams assembled on the basis of specific research axes and not on around the personnality of a scientist. This assures for each team a good critical mass and visibility, however it could also have a cost in visibility for the senior researchers (principal investigators). This is especially true in an international context where the function of team leader is having more and more a central role.

In the occasion of the different meetings organized during the visit, the experts committee could appreciate the extremely positive feedback on the working condition within the unit given by all the unit members (students, researchers, technical staff). The researchers highlighted the excellent atmosphere in the lab and feel very involved with the direction in consultations for decision-making and arbitration. The technical staff (ITA) is very well integrated in the research activity of the unit, they participate actively in the design of the experiments and share the authorship on the publications.The students and post docs have reported very good working conditions and seem well integrated in the scientific and social life of the unit. They also gave the idea of a dynamic and strongly welded group. Although the different teams have full autonomy in the organization of the internal scientific life, a significant effort is done in maintaining transversal research projects as it is demonstrated by several common publications.

Assessment of the unit's involvement in training through research

The unit members are all strongly involved in the teaching activity, mostly in M1, M2 and Erasmus courses. The incoming director is currently implicated in the creation of an interdisciplinar doctoral school in collaboration with the Université Versailles Saint-Quentin. During the 2008-2013 period, 20 students have defended their PhD.

Assessment of the strategy and the five-year plan

The 4 teams have presented research projects in line with their past activity and demonstrated that they have the financial support, man power and scientific expertise to carry out the different projects with success.

Two major events will have a major impact on the unit's life in the next five year, the Equipex project "Morphoscope2" and the new X-Bio institute.

The "Morphoscope2" project represents a unique opportunity for the thematic team "Advanced microscopy and tissue physiology" to explore new optical schemes for microscopy; it will also permit to increase the visibility of the whole unit and stimulate new collaborations. The new X-bio institute will attract new research teams and will considerably strengthen the interdisciplinarity of the LOB if the expertise of the new groups will be chosen to be in synergy with those existing at the LOB. These two events could help guiding the instrumental development made at the LOB toward well-defined biological questions.

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

Team 1, "Molecular mechanism of microbial adaptation", is composed of 2 research directors, 2 assistant professors, 2 assistant engineers and 4 temporary staff (doctoral students and post-docs). The members of the team work principally on three different biological systems: thymidilate synthase X, DNA repair in Archaea and Heme based gas sensor proteins. These topics derive from the specificities and strengths of this team which are historically the genetic manipulation of Archae (very few teams in the world are able to make mutations and express proteins heterogolously in Archae), and the fine molecular characterization of heme based sensors. These two aspects converge with the subject of thymidilate synthase X, originally derived from Archae but also present in some Eubacteria, where the team has managed to make considerable progress in describing the fine details of substrate binding and action. A more recent development of the project is the screening for inhibitors of the ThyX protein, and the application of these inhibitors as potential novel therapeutic agents for the treatment of Helicobacter pylorii infections or tuberculosis.

The project of this team has advanced very well over the evaluation period with the publication of 28 articles of which a dozen are in collaboration with team 2. Notable aspects include an investigation of ThyX structure and function with an aim to find specific inhibitors (7 articles including 2 PNAS) and a series of excellent articles on heme based gas sensor proteins (6 articles in collaboration with team 2). To these major streams are added a smaller collection of articles concerning DNA repair in Archaea and some more peripheral topics.

The project has a history of using an interdisciplinary approach, in particular a long and productive close collaboration between team 1 and team 2 on heme containing proteins. This interdisciplinarity has been and continues to be very important for the progress of the project. The production is steady and of excellent quality resulting in an international reputation for the research directors associated with the team.

Assessment of the unit's academic reputation and appeal

The team is involved in many projects, both national and european. Members of the team participate in international meetings and are visible at the international level (12 invited talks in the period 2008-2013). In particular the team has an international grant from New-Zealand as evidence of high international visibility, as well collaboration with Uganda concerning tuberculosis. Involvement in networks perhaps needs developing, especially in view of the international/european composition of the team. Contacts have however been established with the MM4TB (More medecines for Tuberculosis) consortium and this is to be encouraged.

Both research directors in the team are highly visible on the international stage and have an excellent international reputation for their associated research specificities, this is for example visible in the visits made to the team by foreign students.

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

The team has published one patent, and is involved with industrial partners for the development of inhibitors for ThyX, this would seem a reasonable track record for a fundamental science team with some projects of medical interest. The writing of an article for a general public should also be underlined as an important contribution to public awareness of biotechnology and the use of microbes.

Assessment of the unit's organisation and life

The team has many shared resources and these seem to be well used by the different members of the team. They currently have excellent accessibility to core facilities, though this will need to be maintained with the development of X-Bio.

In the local environment, the space available for the team seems adequate, though perhaps not optimal. The independence of the younger permanent members of the team needs to be encouraged, and reinforced. The team has a major role in the interdisciplinary nature of the unit, being the team with the most solid biological background. Communication with the other teams is excellent.

Assessment of the unit's involvement in training through research

The team is clearly very strongly involved in the teaching of students at the universities Paris 6 and 11, and the training of students at the lab bench. Training has been given both to students from the LOB but also visiting students from other institutes and laboratories, including foreign laboratories.

Assessment of the strategy and the five-year plan

The major thrust of the project is a continuation of the excellent research on the different proteins of interest in complete coherence with the last years. The most original, ambitious and exciting part of the project concerns the examination of NucS and DNA metabolism in living cells using a variety of microscopic techniques, though of course this comes with associated risks; however the team is ideally placed to profit from the expertise of the laboratory in advanced microscopy techniques and build on the teams expertise in the manipulation of archae. The project thus remains largely based on the competences present in the laboratory and is not over ambitious in attacking problems for which the members are not prepared.

The strategy of drug development and testing for new inhibitors of ThyX is perhaps more risky. It is not clear that the team has the experience and means necessary to be competitive in this project alone. It is thus important that they find the right partners (public and/or private) able to help the team bring lead compounds up to and through pre-clinical trials. This difficulty is of course compensated by the considerable interest that such novel antibiotics could offer to the modern pharmacopaea.

Conclusion

This team has produced excellent results, a good international visibility and is strongly involved in the development of interdisciplinary research at the LOB.

 Strengths and opportunities:

The strengths of the team lie in their mastery of the historical subjects, DNA replication in the Archae and Haem based gas sensors. Over recent years the team has developed considerable expertise in ThyX protein, which they discovered and this experience represents a considerable strength. The integration of a team of biologists in a laboratory dedicated to interdisciplinarity, developing new and exciting methods to attack biological questions is evidently an exceptional opportunity provided by the environment that the team has experience exploiting.

In the prospective the development of the X-Bio project represents both a considerable threat and magnificent opportunity. This arrival of new teams with the development of X-Bio could put strain on infrastructure used by the team, or alternatively expand access to important infrastructures. The team must assure that the latter occurs. Equally the arrival of new biologists as part of this program will provide the opportunity for new collaborations.

Beyond the local X-Bio project, the Paris-Saclay project clearly provides a wonderful opportunity for the different scientists associated with this development, and can only increase the international visibility and attractivity (already very good) of the team.

 Weaknesses and threats:

The weaknesses of the team are few and hard to identify, perhaps an over self-reliance that is exemplified by an absence from pertinent european projects, but the senior researchers of the team are aware of this and are actively seeking to fix this. Beyond the potential threat to the local environment provided by X-bio, mentioned above, no serious external threats were identified.

 Recommendations:

Engage actively in the X-Bio program to ensure that the arrival of new biological teams does not reduce access to core infrastructures currently not shared with other teams (cell culture, centrifuges, sequencing, etc.).

Encourage young researchers to develop and lead projects in synergy with current projects as a step to gaining scientific independence.

Find appropriate partners to help develop the ThyX inhibitor project. The team 2 "Internal dynamic of protein" is composed by 4 research directors, 1 researcher (CR1) 5 technical engineers and 5 temporary staff (doctoral students and post doc).

The team aims to analyse protein dynamics in different biological processes (enzymatic activity, protein folding). The team has developed and uses powerful tools to study different types of biological processes. The scientific positioning of the team is the development of high quality scientific instruments, coupled with simulations of protein dynamics in the context of biology. The team has developed many collaborations with biologists within the LOB and in external laboratories, which attest of both the quality and consistency of the team scientific instrumentation and scientific recognition. The team clearly develops an interdisciplinary activity at the interface between physics and biology, but consistency between different biological problematics could be addressed more clearly.

The team developed a platform for femto and picosecond laser sources for the study of ultrafast phenomena in biomolecules such as functional processes in proteins on time scales of the order of internal displacement in the proteins. The strength of this platform for spectroscopy lies in its numerous possibilities (Raman, absorption, fluorescence, etc.) and in particular in its ability to explore the physical phenomena on time scales covering almost 10 orders of magnitude: from femtoseconds to milliseconds. For these typical time scale, transport at the cell scale can be studied The activity around the circular time solved dichroism is unique internationally. It will allow to observe changes in protein conformation. This powerful and highly original device has already been used to study the protein folding in water. It will take its full extent in the context of future collaborations with biologists who may use this original technique for answering questions remaining open using standard methods

The activity around the infrared spectroscopy in the femtosecond scale is at the highest international level. The team has developed new techniques for pulse shaping, frequency conversion, both powerful and original, allowing to perform the control coherent and coherent spectroscopy of proteins in the femtosecond scale. An elegant and original pump probe spectroscopy method is used to synchronize two femtosecond pulses with characteristic times ranging from the picosecond to the millisecond. This work has been the subject of several patents and industrial collaborations are underway.

Assessment of the unit's academic reputation and appeal

The team is involved in many national and international collaborations, especially with teams of biologists. The team has first-class optical instrumentation that allows to establish fruitful cooperation on various aspects of protein dynamics. Because the team is composed of physicists developing high level instrumentation and using it to solve biological problems in collaboration with several groups of biologists, it is difficult to pinpoint a specific biological focus.

The team coordinated the French network femtosecond technologies, and participated in three international programs, which demonstrates its good visibility. The director of the unit who is a team member got the silver medal of the CNRS in 2011. The team has a good international visibility as evidenced by the numerous conferences to which its members were invited and publications in international peer-reviewed journals with good level in the areas of physical chemistry, biophysics and the optics.

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

The technology transfer activity of the team is good. This transfer concerns mainly the activity of pump probe spectroscopy using shaped femtosecond pulse, which has led to the development of innovative techniques. First patent shall be transferred to the company Fast Lite. A CIFRE grant was signed. A second patent is being filed and technology transfer is underway.

Assessment of the unit's organisation and life

The team has a cooperative management that helps maintaining the coherence of the instrumentation developed between the different activities. It is strength of the team. Complementary skills (experimental / theoretical physicists and biologists) contribute to interdisciplinary and collaboration between the teams. The team fits into the interdisciplinary context of the laboratory. Several team members are heavily involved in the establishment and management of the whole laboratory (direction of the laboratory, department of physics at the École Polytechnique).

Assessment of the unit's involvement in training through research

Several team members are heavily involved in teaching courses at École Polytechnique in Master 1 and Master 2 as part of the Université Paris Saclay and in international courses (Physics for optics and NanoSciences). The team leader is currently developing an interdisciplinary graduate school "interfaces" in partnership with UVSQ.

Assessment of the strategy and the five-year plan

The team has a set of top level scientific instruments that will allow remarkable results to be gained on the dynamics of proteins. The team now plans to exploit this powerful and almost unique instrumentation to study photoinduced effects in proteins. The team is very well positioned in the interdisciplinary context of the laboratory, the École Polytechnique and Université Paris Saclay. It has developed many collaborations with biologists that have relevance both in the instrumentation developed and the biological problems studied. Interdisciplinary should be further strengthened while preserving the team potential in innovative instrumentation, and trying wherever possible to address more precisely a given biological issue.

Conclusion  Strengths and opportunities:

The team has developed an original high-performance scientific instrumentation, with a strong coherence. These achievements put the team in an excellent position to strengthen interdisciplinary cooperation with biologists. The creation of X-bio is an interesting opportunity for the team for future collaboration.

 Weaknesses and threats:

It is important to keep the balance between excellence in scientific instrumentation and a strong opening to the biology as well as the coherence between the different activities.

The nomination of a senior member of the team as laboratory director must not destabilize the activity around the circular dichroism.

 Recommendations:

Continue to develop excellence in instrumentation, in the context of biological studies, in collaboration with teams of biologists. The activity of this team concerns the development of various multimodal-imaging techniques based on the use of several nonlinear optical contrasts. The team explores applications of these techniques in biology and biomedical domains.

During the last 5 years the team has realized many important innovative experimental developments, which allowed it to obtain important results. Among them, the elaboration of an innovative multimodal (SHG-THG) microscopy technique led to the first visualization and quantification of the early stages of development of the zebrafish embryo. This constitutes a major breakthrough, which brought key information on the first cell divisions in living vertebrate embryos. The experts committee emphasizes the quality and originality of the innovative instruments conceived by the team which are based on the spectral and spatial control of the optical excitation in nonlinear microscopy. The experts committee was particularly impressed by the results obtained on tissue imaging in multiple species (such as in "Brainbow"-labelled tissues) using two-photon microscopy by wavelength mixing.

The team has shown that SHG microscopy is a valuable tool for probing collagen in biological tissues. The experts committee noted the substantive work done by the team on the understanding of the microscopic origin of the nonlinear signal in collagen structures, an important step for the quantification of collagen content in tissues. The experts committee found very interesting the introduction of the polarimetric techniques for the determination of the collagen fibrils orientation and their application to cornea imaging, opening the way to medical diagnosis. The academic production of the team is major, with 48 invited conference talks and 45 original papers published between 2008 and 2013. These article were published both in specialized and general science journals. Among the publications with the highest impact factor, one article was published in Nature Methods in 2012, 1 in Nature Methods in 2011, 1 article in Science in 2010. In the vast majority of these articles, the researchers of this team were the last and/or first authors of the paper Concerning the THz imaging and spectroscopy, the experts committee noted the progress made towards the control of THz radiation polarization and focusing. The experts committee found interesting the result concerning the development of an attenuated total internal reflection (ATR) geometry, which leads to subwavelength axial resolution for THz micro-spectroscopy.

Assessment of the unit's academic reputation and appeal

This team has an excellent scientific production as evidenced by the number and quality of its publications as well as the number of its patents. It is internationally recognized for its expertise in nonlinear microscopy and its renown is reflected by the number of invitations to the best international conferences. It has a dense and growing collaborative network and attracts talented post-docs and young researchers, as well as visiting professors. The team is very successful in financing its activity as shown by the large number of grants obtained from public and private institutions. The expertise of the team in tissue microscopy has been recognized through the grant of an Equipex project Morphoscope2 whose aim is to set up a multiscale imaging facility at École Polytechnique. This major equipment grant will foster the development of innovative microscope techniques and offer a state of the art imaging platform for the community.

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

The integration of the team in the environment is good. Close collaboration has been developed with l'Oreal in the field of collagen imaging. These developments in understanding and imaging the structure of collagen have potentially wide applications for the cosmetic industry, and led to significant financing by l'Oreal. The investigators involved work also closely with the "Banque Française des Yeux" and the "Institut de la Vision" to apply these advanced microscopy technique in ophthalmology, both to study the structure of cornea (for grafting and to understand lesions in diabetic patients) and the structure of the retina. These projects show both the quality of the collaboration between the 2 sub units and a good understanding of the potential applications of the methods they are developing.

The team published numerous vulgarization articles and gave multiple interviews (Biofutur, Le Monde, La Recherche, pour La Science).

Assessment of the unit's organisation and life

The team is subdivided into 3 subgroups:

-technological development of third harmonic generation and non linear microscopy, under the direction of the team leader is focused mainly on the development of these technologies; -physics and application of second harmonic generation, supervised by a senior scientist. This group is more focused on the practical application of non-linear microscopy for the imaging of collagen tissues, especially tendons and cornea; -terahertz imaging and spectroscopy, under the direction of another senior scientist. This group is doing the most fundamental work of the 3, studying the fundamentals of the nearly unexplored field of imaging using terahertz waves.

Interactions between these 3 subgroups are unequal. Significant collaboration is present between the first two groups, particularly on the topic of corneal imaging. Collaboration between the groups of the team leader and anohter team member on technological optical developments is noticeable. However the integration of the activities of one team member is less advanced, essentially due to the very upstream character of his developments.

Assessment of the unit's involvement in training through research

The group leaders are involved in the structuration of the upcoming Université Paris Saclay. They participate in many teaching courses (mostly in M2 courses and at the École Polytechnique). During the 2008-2013 period, 10 PhDs and 8 post doctoral fellows were trained in this team, for a total of 13 PhDs and 11 post doctorants.

Assessment of the strategy and the five-year plan

In line with their achievements, the members of the team plan to explore new methodological and technological developments in nonlinear microscopy. These developments will benefit from the Equipex project "Morphoscope2" which aims at setting up state-of-the-art multiscale imaging facilities at École Polytechnique. The expertise of the team in "advanced microscopies" is the cornerstone of the project. The facility will be opened to the new biology groups joining the campus (in the X-Bio institute) and therefore will certainly result in new collaborations and synergies.

The team will continue to develop innovative multimodal nonlinear techniques and will explore the possibility to perform correlative microscopy between different modalities. The team will also use these optical techniques to tackle, in collaboration with biologists, very fundamental biological problems such as the study of the roles of fluid flows during embryonic development or the study of the differentiation and clonal structure of the developing nervous system.

Concerning THz imaging, the experts committee finds interesting the application of the attenuated total reflection imaging to study cell membrane electro-permeabilization. The experts committee also suggests that the team explores applications where THz lateral resolution does not set a severe limitation. An imaging contrast obtained under a combined THz and Optical excitations is worth exploring to be able to achieve micrometer spatial resolution of a THz spectral signature.

Conclusion  Strengths and opportunities:

This team is internationally recognized for its expertise in nonlinear microscopy and has established very fruitful national and international collaborations. The excellence and international outreach of the team is reflected in its attractiveness for young talented researchers. The Equipex project constitutes an excellent opportunity for the development of a state-of-the-art imaging facility and to trigger new collaborations.

 Weaknesses and threats:

The team has to ensure that the many requests for collaboration do not lead to a wide dispersion of its research activities. The EQUIPEX coordinated by the team is undoubtedly an opportunity to create state-of-the-art platform for light microscopy and to initiate new collaborations. However care must be taken to support this operation in human resources to ensure that this development does not come at the expense of creativity and innovation of the team.

 Recommendations:

The team would gain by better integrating the THz activities.

The activity on adaptive optics should not be lost after the departure of a permanent staff scientist. The team Nano imaging and cell dynamic is composed of one Research director, one maitre de conference, one assistant engineer and 3 PhDs.

The team studies the problems of cellular dynamics and visualizes the phenomena by using rare-earth doped nano-particles. These nano-particles are designed in collaboration with chemists of the Laboratoire de Physique de la Matière Condensée from the École polytechnique. These particles have a great interest since they are photostable and have long life duration. The team has an important experience in single molecules tracking and has developed several outstanding tools used in numerous applications such as proteins-DNA interactions, tracking and localization of toxin receptors in clostridium, detection of ROS in vascular smooth muscles and in tumors. The ROS detection was possible since the nano-particles doped with europium have a powerful property of oxido-reduction. These particles are very sensitive tools and have been used to follow dynamics and spatial organization of H 2 O 2 signalling. In addition the team has developed a system of microfluidic channels to study red blood cells diseases.

The team has published 18 articles in journals of high quality such as Nature Nanotech, Phys Rev Lett., Biophys., J. Langmuir. The work is performed in collaboration with LOB and École polytechnique teams or laboratories of Ile de France. Above the 12 mentioned collaborations 6 have given rise to articles and 3 to a financial support.

The team Nano-imaging and cell dynamic carries out a interdisciplinary research.

Assessment of the unit's academic reputation and appeal

The team is present in 15 national projects, in addition the team leader coordinates the axis Nanobioscience d'Ile de France and is a member of the network France Bio-imaging (call investments for the future/ infrastructure for research in biology and health coordinated by ANR). During the examined period the team has recruited one École Polytechnique Maître de Conference with an INSERM chair, one assistant engineer and has organized 3 international meetings and 3 national symposia.

Assessment of the unit's interaction with the social, economic and cultural environment Four patents were issued from the team's research including 2 during the examined period. A patent is in discussion with the firm Horiba Jobin Yvon concerning the amplification by nano-particles of the hydrodynamic force that acts on receptors.

One important aspect whose development is in progress concerns nano-particles with the replacement of Y 3+ by gadolinium. This allows simultaneous measurement of ROS and high contrast in MRI imaging in small animals. The team's results have been presented in 10 invited talks. The team is implicated in scientific animations for the general public.

Assessment of the unit's organization and life

With its expertise in tracking of single biomolecules, the team has collaborated with team 1 (Molecular mechanisms of microbial adaptation) to decipher the interaction of NucS and DNA in living cells. The team has also one common article with members of team 2 (Internal proteins dynamics).

Important collaborations exist with other laboratories of the École Polytechnique: Laboratoire de Physique de la matière condensée, Laboratoire de mécanique des solides, Laboratoire d'hydrodynamique. These collaborations have resulted in common publications and common financial supports. These collaborations play a great role in the interdisciplinary research done by the team.

Assessment of the unit's involvement in training through research

The team's members are involved in training M2, M2 Erasmus and at international level the team has hosted foreign students for the course "NSF undergraduate program".

Five students have defended their PhD and 2 post docs have participated to the projects.

Recently the team has given a scientific formation in the national workshop MiFoBio (Microscopie Fonctionnelle en Biologie).

Assessment of the strategy and the five-year plan

The team presents 6 projects which are in the continuity of previous work and based on the use of rare-earth doped nano-particles. The goal for the next five years is to increase the use of nano-particles in biology.

Various projects are listed: Study of the proteins-DNA interactions, organization of membrane dynamics, Toxin -cells interactions to understand how ingested botolinum toxin passes from the gut into the bloodstream, ROS tracking in tumor cells or in neurodegenerative diseases using Zebrafish, the investigation of sickle cell anemia and multimodal in vivo imaging. These projects will be performed either in collaboration with teams at the École Polytechnique or with laboratory in the region Ile de France. The link between the different projects is the use of the nano-particles, but the different projects have not the same pertinence and some choices have to be made to target the more important biological projects.

Conclusion  Strengths and opportunities:

The team has a strong expertise in doped rare-earth nano-particles with a solid collaboration with chemists of the "Laboratoire de Physique de la matière condensée". They are very competent in nano-particle imaging. Well-chosen collaborations have been fruitful to analyze some aspects of cellular dynamics.

The team has good publications and participates actively to the training of PhD students and post docs and has a good attractiveness for students. This team has an important activity of valorisation and is well supported financially.

 Weaknesses and threats:

Six different projects in collaboration are presented some with biomedical aspects. It seems that the team has no project on its own. Of course the heart of the research is the development and the exploration of the different functionalities of these nano-particles, but the different collaborations have not the same pertinence and more targeted collaborations will allow an important biomedical axis to be developed.

 Recommendations:

An aspect has to be encouraged, which is the optimisation of nano-particles to measure ROS with applications in some pathologies. The team have to concentrate the efforts on limited topics in order to work in depth on biological aspects. The creation of X-Bio at the École Polytechnique can provide the opportunity to recruit a collaborator more specialized in the domain of cell signalling.

N3:N4:

  Permanent researchers from Institutions and similar positions 12 12 Other permanent staff (without research duties) 13 12 Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.) 2 N6: Other contractual staff (without research duties)

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.) 1 N6: Other contractual staff (without research duties) microscopy and tissue physiology" is composed of 4 research directors, 2 researchers (CR1, CR2) 1 technical engineers and 7 temporary staff (doctoral students and post doc).

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.) N6: Other contractual staff (without research duties)

  12h00-12h30 Bilan et projet équipe 4 "Nanoimagerie et dynamique cellulaire" 12h45-14h00 Déjeuner de travail avec les représentants des tutelles Session rencontre avec le personnel permanent et non permanent Le comité d'experts se répartit en trois sous-groupes 14h00-14h45 Rencontre avec les ITA titulaires , CDD Auditoire : membres du comité d'experts et DS, sans les tutelles, ni la direction. Rencontre avec les doctorants et post-doctorants et/ou CDD « chercheurs », Ingénieurs Auditoire : membres du comité d'experts et DS, sans les tutelles, ni la direction. Rencontre avec les chercheurs et enseignants chercheurs titulaires. Auditoire : membres du comité d'experts et DS, sans les tutelles, ni la direction, ni les responsables d'équipes 14h45-15h15 Rencontre avec le directeur de l'école doctorale 15h15-15h45 Rencontre avec la direction de l'unité Auditoire : membres du comité d'experts et DS 15h45-16h15 Pause 16h15-18h00 Réunion du comité d'experts à huis clos Présence : membres du comité d'experts et DS

Team 1: Molecular mechanisms of microbial adaptation Name of team leader: Mr Hannu MYLLYKALLIO Workforce Team workforce Number as at 30/06/2013 Number as at 01/01/2015 N1: Permanent professors

	and similar positions	2	2
	N2: Permanent EPST or EPIC researchers and similar positions	2	2
	N3: Other permanent staff (without research duties)	3 (1.9FTE)	2 (0.9FTE)
	N4: Other professors (PREM, ECC, etc.)
	N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.)	1
	N6: Other contractual staff
	(without research duties)

TOTAL N1 to N6 8 6 Team workforce Number as at 30/06/2013 Number as at 01/01/2015

	Doctoral students	1
	Theses defended	2
	Postdoctoral students having spent at least 12 months in the unit	5
	Number of Research Supervisor Qualifications (HDR) taken
	Qualified research supervisors (with an HDR) or similar positions	3	3

 Detailed assessments

Specific premises visited:

The laboratory and the technological platforms have been visited. En vous souhaitant bonne réception de la présente, je vous prie de croire, Chère Madame, à l'assurance de mes meilleures salutations.

Conduct or programme of visit:

Patrick Le Quéré

Directeur adjoint de l'Enseignement et de la Recherche