president  Mr Didier Houssin

Pierre

The Unit is located on the campus of the University Hospital of Lille, within the Pole Research of the Faculty of Medicine (3rd floor), where it occupies premises of about 1100 m2.

Management team

The direction committee of the UMR includes the two team managers and the head of the production platform of pancreatic islets, assisted by the administrative officer and two members of the UMR. 2  Overall assessment of the interdisciplinary unit

The laboratory "Translational Research in Diabetes" is a continuation of the laboratory "Biotherapy of diabetes" (headed by Mr François PATTOU), established in January 2010 and strengthened by the arrival in 2012 of the "Experimental Diabetes" team, led by Amar Abderrahmani, who holds an ANR Chair of Excellence. The laboratory is internationally recognized for its contribution to the development and validation of islet transplantation in patients with type 1 diabetes. Publications are globally of very good level (with some excellent recent productions : NEJM, Gastroenterology, and Nature and J Clin Invest in collaboration). The overall project of the Unit aims to improve the care of diabetic patients with a clear objective of clinical translation, based on experimental research. Strengthening complementarity and interaction between these two components of the laboratory will undoubtedly allow the realisation of the projects. The research Unit is in a very favorable environment with the recent creation of the EGID federation.

Strengths and opportunities related to the context

Well recognized laboratory with world class expertise clearly identified in the field of islet transplantation.

Charisma and strong reputation of the director.

Recent arrival of a new team focused on more fundamental research on beta cell survival.

Creation of the Laboratory of Excellence EGID gathering 3 laboratories in Lille and construction of a building to allow development in the same geographic site.

Strong support from local institutions.

Weaknesses and threats related to the context

Laboratory mainly based on university-professors (mainly clinicians) who can not devote full-time to research.

Risk of dispersion if the interactions between the "historical" members of the laboratory and the newly arrived team are not put more into perspective, with common goals.

Recommendations

Recruitment of full-time researchers and international postdocs is important to stabilize the activity of the laboratory.

Given the current strengths, particular attention should be paid to better ensure consistency between the various projects proposed for the next five-year to avoid the risk of dispersion. The laboratory is internationally recognized for its long-term contributions to the development and validation of pancreatic islet transplantation in type 1 diabetic patients (Mr François PATTOU, MC VANTYGHEM). An important commitment from the Hospital allowed the setting of a "cell therapy laboratory" for islet preparation with international standards (J. KERR-CONTE). This expertise, rather unique in France, gives to the team of Mr François PATTOU a leader position in the field. The publications resulting from this activity are excellent (NEJM, JCEM, Gastroenterology, Diabetes Care, Am J Transplant).

In the context of bariatric surgery (also calleds "metabolic " surgery), used as therapeutic approach in type 2 diabetes, the team of Mr François PATTOU is developing an extremely original tissue bank (ABOS collection with biopsies of liver, adipose tissue and muscle) with samples obtained before and after surgery as well as at 1, 5 and 10 years of follow-up. Over 900 patients (1000 planned) have been collected so far. The access of this tissue bank to industrial, academic and international partners allowed important collaborations and co-publications in highly visible journals (Nature, J Clin Invest). The use of the bank in internal research programs should be develop in the coming years.

The main experimental research lines are: the study of beta cell survival using the biological material that cannot be used for graft (J. KERR-CONTE) and the study of molecular mechanisms controlling apoptosis in models of cultured beta cells (A. ABDERRAHMANI). Significant results were 1) the demonstration of the possibility of proliferation of adult human beta cells in a model of islet transplantation under the renal capsule in mice (Diabetologia and 2) the characterization of signalling pathways (ICER, JNK3) involved in the protection of beta cells against "diabetogenic" stress (Diabetes, Diabetologia).

The experimental part of the unit was strengthened by the recent arrival of team 2, which aims at addressing the molecular mechanisms involved in the survival of beta cells. This arrival also fulfills the requirement made by AERES in 2009 to further develop the experimental component of the laboratory. Attention still needs to be paid to the integration of this new team in the unit, especially to put it in coherence with the global research objective of the laboratory.

Overall, the research output of the laboratory during the last 5 years is qualified as excellent by the committee. The importance of the clinical research and the transfer to clinical practice has provided an international recognition of the group of Mr François PATTOU. The arrival of a more experimental component is appreciated. The type and number of publications, industrial contracts, patents, invitations is at the level that can be expected from a team of this size, working at the front of the research in the field of diabetes .

Assessment of the unit's academic reputation and appeal

The laboratory is a component of the EGID research Federation, granted Laboratory of Excellence in 2012, which demonstrates the importance and the quality of the research in the field of diabetes in Lille.

One of the team is involved in several European networks supported in the framework of the FP7. Although the laboratory is not coordinating these programs, participation in networks of high levels demonstrates the visibility and recognition of the team.

A. Abderrahmani got a (CNRS-Université Lille). The arrival from Lausanne of a recently appointed full-time professor position at the Université Lille with a "Chair of Excellence" from ANR clearly shows the attractiveness and recognition of the laboratory and of the EGID Federation.

Access to human pancreatic islets of high quality and the ABOS collection give a very strong appeal to the laboratory, opening the possibility to numerous collaborations. The establishment of a "Summer course" in diabetology with EGID should also allow greater attractiveness of international students and postdocs in the coming years.

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

The laboratory has developed methodologies and innovative approaches for islet transplantation in type 1 diabetic patients. These include the upstream aspects (preparation of islets from donor pancreas), the transplant procedures (optimization of preservation solutions, evaluation of immunosuppressive procedures) as well as the surgery by itself (search for alternative graft sites, such as muscle). These are recognized innovations with patents and industrial collaborations, leading among others to the development of an integrated culture system for human islets (called PRISM, in partnership with the MacoPharma company).

Team 2 is also interacting with industrial partners within the scope of his project on the use of peptides to modulate signaling pathways involved in survival/apoptosis of pancreatic beta cells. These approaches would benefit from being developed in a more concerted manner with the other projects of the research Unit.

The implementation and coordination by the Unit of the "cell therapy laboratory", highly functional and certified for the preparation of biological materials for therapeutic, must also be emphasized in the socio -economic impact of the laboratory. The quality process and ISO certification of this structure should serve as a basis for improving the procedures and operation of the rest of the unit.

Assessment of the unit's organisation and life

The laboratory is rather small in size and based on 8 university-teachers, including 6 clinicians, some students and a significant number of technical staff (most of them with a CDD). A significant effort was made in recent years with the university and the hospital to provide long-term support to several contracts under the form of CDI, and a position for a technician (university) will be open in 2014. This organization was operational in the context of a clinical research laboratory. With the development of more mechanistic research axes, it will be important to better define a policy aiming at recruiting full-time researchers.

Organization and life of the laboratory (seminars, meetings, management) seems operational given the size and location of the teams in the vicinity of the Surgery departement and the Laboratory of Cellular Therapy. A specific problem in the organization of the gestion/administration has been corrected recently with the support of EGID and INSERM. The current premises are compatible with laboratory activity and the construction of new laboratories dedicated to the EGID federation will open opportunities for growth if necessary. It will be important to accelerate the dessimination of a Quality Assurance Procedure to the whole unit. The constraint of night (or weekend) work for some of the staff (for the preparation of islets according to the arrival of the pancreas) is generally well managed (with the CHU), but a better organization of work outside office hours for other staff of the Unit is required (statement for isolated workers, risk assessment in DUER, implementation of individual sheets of exposure for all stafff).

Assessment of the unit's involvement in training through research

The laboratory is rather small in size (6 HDR). The doctoral training activity remains limited, but of excellent quality with training doctors for research, allowing them to integrate a university hospital career (2 recruited over the last 4 years). The creation of a new teaching in the Master 2R and the organization with EGID, a "Summer Course" of diabetes have been noticed. No difficulty with the Doctoral School has been noted during the discussion with the director.

Assessment of the strategy and the five-year plan

The research program of the laboratory, in the continuity of its past activities, is perfectly logical and appropriate. The integration of a more mechanistic research line on the survival of beta cells is certainly a very positive point for better positioning the unit among the leading research laboratories in Europe. It will be important, however, to ensure consistency and synergies between this new team and the experimental approaches of the laboratory which aims at improving the therapy of diabetes.

The involvement of the laboratory in EGID is a major issue , allowing functional and very high level intractions with the laboratories of B. STAELS and Ph. FROGUEL. Theses collaborations must be maintained and expanded. Participation in European networks, already effective, is to continue through H2020. However, attention must be paid to a real initiator and coordinator of scientific programs likely to attract postdocs and researchers.

Analysis of strengths and weaknesses made by the laboratory is highly relevant and clearly shows the very limportant opportunities in Lille at the moment (ELabEx EGID, regional dynamics and strong support from local institutions, importance of the topic, tools and original apporches).

conclusion • Strengths and Opportunities :

Laboratory with well recognized international expertise clearly identified in the field of islet transplantation. Charismatic director with strong reputation. More fundamental ongoing research lines on beta cell survival with the arrival of the new team 2. Creation of the Laboratory of Excellence EGID gathering 3 laboratories, and construction of a building to allow its development in the same geographic area. Strong support from local institutions (university, hospital and INSERM)

• Weaknesses and Threats:

Laboratory based solely on university professors (mainly clinicians) who can devote only part of their time to research. There is a risk of dispersion if the interactions between the "historical" members of the laboratory and the newly arrived team are not put in a better perspective with a common goal and real synergy.

• Recommendations:

The recruitment in the near future of full-time researchers and international postdocs is important to stabilize the laboratory. Given the current strengths, particular attention should be paid to better ensure consistency between the various projects proposed for the next five-years and to avoid the risk of dispersion. The research projects conducted by team 1 are highly original and have led to several landmark studies in the field. This is particularly obvious for the clinical studies investigating new sites of implantation (e.g. muscles) for islets grafts in type 1 diabetic patients, as well as those investigating the effects of bariatric surgery on patients with type 2 diabetes.

Overall, the novelty and quality of the work performed by this team and its scientific productivity is excellent with some clear outstanding contributions (NEJM, Gastroenterology,…). Some of their contributions are pioneering studies with trend-setting implications and even practice-changing impact for diabetic patients. The fact that this team is routinely and consistently publishing in relevant journals of this speciality represents strong evidence of the innovative and importance of their work, carried-out despite many of the researchers having important clinical and administrative responsibilities.

Together, researchers of team 1 have produced 92 publications including 50 original articles/reviews as first or last authors. The productivity is however variable among the PIs of the team. A significant number of co-authored publications are collaborations with reputed French or international research groups for whom the laboratory has provided human materials. Although this collaborative research is not a direct contribution of the team, providing other research groups with exclusive and high quality human material (in particular Langerhans islets) is a very important and crucial contribution to the scientific community for the advancement of the research on diabetes. In this regard, the current constitution of another biobank including tissues coming from obese/diabetic patients well characterized at the clinical level (cohort ABOS), will be also of a very high interest not only for this team but also for the whole scientific community working on metabolic disorders associated with obesity.

Finally, the arrival of a new team (team 2) with clear and demonstrated expertise in the cell biology of beta cells should nicely complement the clinical work already on-going and further promote the translational research aspects characterizing this laboratory.

Assessment of the team's academic reputation and appeal

Team 1 has undoubtedly acquired over the last years, a recognized international reputation as a leading group in pancreatic islet allo-transplantation. Their capacity to provide human islets of quality to other national/international teams has further established and reinforced their scientific reputation of excellence in this field of research. The completion of the ABOS cohort is also likely to further promote their international visibility and to expand their network of collaborators worldwide.

The team has received several grants from local, national and international agencies. In addition, the team is involved in several European and international consortia (FP7 Beta cell therapy, IMI direct, European consortium for islet transplantation, Collaborative Islet transplant registry). The capacity of the team to raise funds dedicated to its research and clinical trials not only reflect the dynamism of the group leader but also their national/international recognition by funding agencies and their peers. Finally, this team is part of the EGID (European Genomic Institute for Diabetes) which was recently accredited LABEX in 2012.

The work of this team is very much seen as trend-setting with clear potential benefits for patient populations. The numerous invitations to present their work at national and international meetings confirm the high visibility and recognition of the team members as well as their capacity to provide innovative research in the field of diabetes management.

In summary, team 1 benefits of an excellent national and international visibility, appeal and reputation.

Assessment of the team's interaction with the social, economic and cultural environment Team 1 has performed very well in producing research that can be translated into clinical applications. The work of the team has resulted in particular into two filed patents related to the isolation and preservation of human Langerhans islets, as well as two industrial contracts (Macopharma for the development of a performing system to culture human Langerhans islets, PRISM; and Cousin Biotech for the development of a medical device used in miniinvasive treatment of diabetes).

The expertise and innovative therapies developed by this group have led also to several reports in the lay press and on national radio and television. The team obtained also financial support from private companies in particular for the constitution of the ABOS biobank.

Since obesity and diabetes have reached pandemic proportions worldwide and have become a major problem of public health, the socio-economic impact of the research and clinical trials performed by this team is likely to become very important in the proximal future.

Overall, interaction with social, economic and cultural environment is excellent.

Assessment of the team's organisation and life

The Team appears to be well organized into coherent subgroups and managed effectively despite having a varied composition made up of clinicians, university professors, trainees and a technical platform dedicated to the isolation and culture of Langerhans islets for allo-transplantation. In this context, the team leader demonstrates high leadership skills and exerts a clear positive influence, not only on the laboratory atmosphere but also in terms of guiding and coordinating effectively the work. This is highly valued in particular by the postdocs and PhD students. Team members meet on a regular basis to share results and participate to weekly meetings. There are no apparent interpersonal conflicts within the members of this team. One major concern of the leader is the urgent need for additional help with overwhelming administrative tasks in particular regarding the management of international/European grants and biobanks.

One can regret however that the staff of the technical platform isolating and evaluating the quality of human islet for allo-transplantation is not more deeply involved in basic/translational scientific projects. As well, whether efforts are promoted to train tomorrow's scientists and clinicians to ensure continuity of the research activity is unclear. The recruitment of full-time researchers should be considered to stabilize the team for the future.

Assessment of the team's involvement in training through research

A number of Ph.D students and postdocs are, or have been, associated with this team, few of which are not French nationals. Since 2006, 3 Ph.D thesis were awarded and 2 PHD students are currently trained. The postdocs and Ph.D students who graduated published at least a first-authored publication in journals of their specialities. The Team appears also sufficiently funded to allow trainees to travel to meetings when and where appropriate. Some of the projects in which postdocs or Ph.D student are involved are at high risk/high reward but apparently with no clear alternatives if unfruitful. It seems that the time the clinicians can dedicate to basic/translational research may to not be always adequate and sufficient to complete the rather ambitious team's projects. This could also have impact on the training of students. Stabilisation of positions within the team for postdocs/Ph.D students should be more clearly defined as a strategy for the future.

Finally, members of the team 1 are contributing teaching duties in 3 different master programs from University of Lille 2, Paris Sud and Créteil.

Assessment of the strategy and the five-year plan

The five-year strategic plan of team 1 is centered on three different axis coherent with the different expertise of the senior clinicians/scientists. These include principally clinical studies but also some aspects of fundamental research derived from the clinical activity of team 1. The plan is well prepared and thought out to build upon the recent advances obtained by the team, as well as the availability of human islets and of a biobank of tissues from the ABOS cohorts of patients under construction. The plan includes several specific and highly innovative projects, which should ensure that the Team remains a leading authority in this area gaining concomitantly further national and international recognition.

These axis focus in particular on the following themes:

1. The improvement of the isolation procedure and quality of human islets for allo-transplantation and basic research. The study of islets biology using mouse models, in particular the impact of obesity on islet dysfunctions. For these fundamental aspects, team 1 plans to tightly collaborate with team 2, in particular by providing team 2 with human material of quality.

2. Various clinical trials and follow up of islets-transplanted patients. The clinical evaluation of alternative sites of implantation for islets allo-grafts and the development of mini-pig animal models of islets transplantation.

3. The analysis of the efficiency of metabolic surgery (gastric bypass, GBP) for the treatment of type 2 diabetic patients, in particular the retrospective analysis of the ABOS cohort. The development of new surgical methods for GBP and alternative non-invasive methods to mimic the GBP using a mini-pig animal model.

In addition to the research described above, team 1 plans also to develop other projects complementary to their research to open new perspectives for the future. In particular, they envisage i) to start characterizing iPS cells from patients of the ABOS cohort for therapeutic purposes, ii) to develop a mini-pig animal model to investigate obesity-associated metabolic diseases, iii) to perform clinical studies aiming at understanding factors promoting diabetes in stress conditions, and iv) to investigate in a multi-disciplinary approach the impact of habitation architecture on the alimentary behaviour (ABOS cohort).

Although these projects in their whole are coherent and complementary, they might be however a bit overambitious for the human resources currently available. In this regard, more detailed milestones and priorities on the developments of all these projects should be established. Also, most of the projects described are clearly clinical prospective or retrospective studies. More basic and translational aspects should be developed in the future through close interactions with the team 2 working on the Langerhans islet biology. In this respect, it is evident that team 1 will greatly help team 2 by providing human material of quality for their studies, however how team 1 will benefit from the work of team 2 is still quite unclear. Finally the development of the mini-pig animal model to investigate new surgical/nonsurgical methods for GBP and obesity-associated metabolic disease should be a priority to support the clinical activity of team 1 with more fundamental/translational research on type 2 diabetes also.

Conclusion

• Strengths and opportunities:

Strong leadership.

Important questions with real potential translational benefits. Projects are focusing on relevant public health priorities.

Innovative and competitive clinical research.

Very good track record.

Good prospects for continued and increased national and international funding.

Good prospects of strengthening industry links.

Strong position to strengthen national and international collaborations in particular by providing high and reliable quality human materials.

Excellent opportunities for interactions within team 2.

• Weaknesses and threats:

The limited size of the team compared with the large number of proposed projects.

The absence of full-time researchers and no well-established or apparent recruitment strategy of the next generation of leading researchers/clinicians.

Overwhelming administrative responsibilities.

Some of the research topics of postdocs/PhD students are at high risk.

Currently no translational research on type 2 diabetes to support clinical activities in metabolic surgery (GBP).

The development of new know-hows (e.g. iPS cells differentiation) is extremely time-and resourcesconsuming.

• Recommendations:

The team would undoubtedly benefit from:

-Developing more efforts to attract foreign clinicians, students and scientists, -Recruiting basic scientist working on T2D to further develop the mini-pig model of metabolic diseases (in addition to team 2 focusing on islets biology), -Improving the commitment of scientist/technicians of the "Plateforme de Biothérapie" in basic research, -Defining and allocating more carefully priorities and manpower for each axis of research, -Continuing its excellent work!  Detailed assessments

Assessment of scientific quality and outputs

The research program of team 2 is centered on the understanding of the cause of beta-cell dysfunction/apoptosis in the context of type 2 diabetes, with specific focus on deregulation of general transcription factors (ICER) and on the roles of jun kinase (JNK) isoforms. This research gradually evolved from characterization of the mechanism of control of JNK isoforms and their deregulation by metabolic stress to attempts to find ways to interfere with these processes in order to improve beta-cell survival under diabetic conditions. This line of research has recently benefited from new access of team 2 to human islets through its interactions with team1. The recent installation in Lille does not yet result in visible outputs.

The scientific output of this team over the last 5 years is considered as very good taking into consideration the small size of the team and the fact that the production inevitably suffered from the move from Lausanne to Lille in 2011/2012. The team leader published 5 papers as last author in very good journals in the field (N Engl J Med, Gastroenterol, J Hepatol, Diabetes, Diabetologia, J Clin Endocrinol Metab), and contributed to 15 papers in the like. He did not, however, publish his results in general audience journals, which would bring more visibility to his work. His work is regularly cited by his pairs. The yearly number of citations increased from ~80 in 2008 to ~130 in the last few years. He was not invited as a speaker in international conferences, but the work of his team has regularly been accepted for communications in such meetings.

Assessment of the team's academic reputation and appeal

The team was created in the frame the EGID consortium in Lille (recognized Labex in 2012). The complementarity of this team with the activities of Prof. Mr François PATTOU laboratory logically supports their association in a single research Unit. Team 2 leader obtained an important ANR grant ("Chaire d'excellence" from université de Lille ) to facilitate his installation in Lille. However, this grant is ending in a near future and the capacity of team 2 to attract PhD and postdocs and to develop its research plan will now depend on the ability to raise funds in the coming year.

Prof ABDERRAHMANI is editor for Plos One, a well-known Open Access journal covering all aspects of life sciences.

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

Because of the very recent installation of this group in Lille, the committee considered that it was not possible to correctly evaluate this item.

Assessment of the team's organisation and life

The global organization of team 2 seems adequate with respect to the size of the group and the type of research conducted. Two permanent positions (CDI) for technical staff have been allocated to the team by the research Unit and by EGID. Resources are accessible locally or through collaboration with team 1 and other members of the EGID consortium. Although a specific "welcome grant" form EGID was allocated to help the installation of the team, its ability to survive will depend on its capacity to raise new grants after the completion of the current ANR support. It should be noted, however, that this evaluation is considered premature in view of the fact that team 2 was created only recently.

Assessment of the unit's involvement in training through research

The involvement of team 2 to training through research is judged adequate based on interview of PhD and postdoc fellows from the lab and from the history of the team leader before his move to Lille.

Team 2 leader has created a new UE for the Master recherche Biologie-Santé and a new international summer research school starting from July 2014. Again, team 2 is too young to assess this point correctly.

Assessment of the strategy and the five-year plan

In the continuity of the work done during the past years, the research program of team 2 is centred on the understanding of the cause of beta-cell dysfunction/apoptosis, with a specific focus on the roles of the JNK isoforms. The proposed project comprises careful dissection of the mechanism of control of JNK3 by IB1 (a scaffold protein highly expressed in beta-cells) and upstream kinases such as DLK1 (also highly expressed in beta-cells). The objective is to understand whether a down-regulation of this pathway by metabolic stress in patients with T2D contributes to beta-cell demise. A complementary aim is to develop pharmacological approach to improve beta-cell survival by using peptides that mimic the beneficial effect of DLK1 and IB1-mediated activation of JNK3. The work will be performed initially in cell lines, but this research will strongly benefit from the access of team 2 to human islets through its interactions with team1. However, the molecular toolkit to study this pathway in human cells is incomplete and needs to be developed.

Although this project is original and could lead to new developments to fight T2D, a solid proof of concept of the importance of the DLK1-IB1-JNK3 pathway to beta-cell survival in the context of metabolic stress is needed. Only few preliminary (yet encouraging) results about the effect of JNK3 manipulation in vivo (transgenic mice) were available. Team 2 is therefore encouraged to further build on this type of study before going for a peptide strategy to interact with the pathway. This pharmacological approach may also not be the best, as peptides are not easily delivered at the right site of action. An alternative approach might be developed with non-academic partners when the target will be further validated in human islets. There are also some questions about the feasibility of this approach. Nevertheless, the committee thinks that it is worth giving the time to team 2 to test this hypothesis thoroughly. They should however try to develop this project in closer integration with team 1, with a global objective of the laboratory to improve the success rate of islet transplantation.

Conclusion

• Strengths and opportunities:

The research program of team 2 is well focused, original and has the potential to lead to better understanding of protective mechanisms of beta cell survival, which should ultimately be important for the improvement in the success rate of islet transplantation in T1D and for the development of new treatment for T2D. The easy access to human islets and to ABOS collection, thanks to its interactions with team 1, should provide an advantage to team 2 in comparison with other research groups in the field.

• Weaknesses and threats:

Attention should be paid to the stability of the group in the medium/long term. Regarding the project, it relies on detailed analyses of one pathway that will be targeted by a single risky pharmacological approach based on inhibitory peptides. No alternative program is proposed.

• Recommendations:

The main recommendation of the committee is to further develop the interaction with team 1 in order to validate the role and importance of the JNK3 pathway in human islet with the aim of improving beta cell survival and function in the context of T1D (e.g. islet transplantation) and T2D. The group is still fragile and should be rapidly consolidated to ensure the sustainability of the proposed team.

  location of the unit The Research Unit "Biotherapies of Diabetes" is a Bipartite unit of the Université Lille 2 -INSERM. After being a University team (EA 1044), the unit was labeled by INSERM as ERIT-M in 2000, before becoming UNIT-M in 2005 and UMR 859 in 2009. Since 2011, the UMR 859 is also one of the three components of the Research Federation EGID, that got a LABEX under the Investment for the Future Programme.

  Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.

3

   Detailed assessments Assessment of scientific quality and outputs The Laboratory " Translational Research in Diabetes " (UMR 856 INSERM-University -CHU Lille Lille 2 , directed by Mr François PATTOU) is the direct continuation of the Laboratory "Biotherapie du Diabetes" (Director Mr François PATTOU), established in January 2010 and strengthened by the arrival in 2011 of the team "Diabète Experimental", led by A. Abderrahmani who holds a Chair of Excellence ANR (2010-2014) and is appointed Professor at the Université Lille 2.

  Permanent EPST or EPIC researchers and similar positions 1 N3: Other permanent staff (without research duties) 8 11 N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.

  voie ville) : 1 Place de Verdun, 59045 Lille Cedex Déroulement ou programme de visite : 09h30 -09h45 Accueil des participants (Salle du conseil Rdc) 09h45 -10h00 Réunion à huis-clos / Comité de visite + Délégué Scientifique de l-clos / Comité de visite

 Supervising bodies' general comments

1 ,  Mr.

4  Team by team analysis


 Introduction History and geographical location of the unit

The research unit was created in 1991 in the context of the collaboration between the "Ecole Nationale Vétérinaire d'Alfort" (ENVA) and of the Institut National de la Recherche Agronomique (INRA) and was then entitled "Biomécanique du Cheval".

Since 1999, the unit is organized in two teams which have two locations. One team « Biomécanique articulaire et tendineuse » (BAT), directed by Pr Nathalie CREVIER-DENOIX, is at ENVA, in Maison-Alfort. The other team, directed by Pr Jean-Marie DENOIX and named « Imagerie et pathologie osteoarticulaires »(IPOA), is located at Goustranville (Calvados). In the recent past, since 2009, the unit has the status of an own unit, « unité propre » attached to DGER (Direction Générale en Enseignement et Recherche), but the BAT team is also attached to INRA as an under contract unit (USC 957).

The IPOA team was set up when in 1999 the « Centre d'Imagerie et de Recherche sur les Affections Locomotrices Equines » (CIRALE), located in Calvados and founded with the support of the "Basse-Normandie" Region, started its work. Horse breeding is very important In this area and has major impact on the economy as well as on the social and cultural life. Research about all factors inducing pathologies of the locomotor system in the equine species and especially research in preventing such pathologies is of a very high value for all people whose income is based on breeding or the use of horses because these pathologies are the most important causes of premature ending of the sportive career of horses.

Management team

Pr Nathalie CREVIER-DENOIX is director of the unit and Pr Jean-Marie DENOIX is co-director. 2  Assessment of the unit

AERES nomenclature

The unit "Equine Biomechanics and Locomotor Pathology" ("Biomécanique et Pathologie Locomotrice du cheval" or "BPLC") has two main objectives: a) To find and document the site of different lesions in the locomotor system, and to use this as a base for treating and preventing those pathologies; b) To acquire knowledge in the biomechanical factors which induce the pathologies related to the sportive use of the horses.

With their small teams, the unit was able to establish diagnostic methods and a precise documentation of results, especially concerning the juvenile joint lesions and tendon lesions of horses. The knowledge of the forces and the kinematics of the horses limbs provides a solid basis for research on the prevention of the numerous orthopaedic pathologies which frequently induce lameness.

Strengths and opportunities related to the context

The unit is very innovative and established excellent new methods and concepts in diagnostic, prophylaxis and treatment of the equine locomotor apparatus and its pathologies. The high standard of the technical equipment and the very creative approach in diagnostic and in kinematic of horses is a special and outstanding strength of the unit.

In growing up, training and working on different tracks, the unit succeeded to transform the new results for the benefit of the horses and their users. The numerous papers and presentations of the members are responsible that the scientific results are world-wide recognized. Therefore the unit has an outstanding national and international reputation and its experts are highly estimated world-wide.

The perspectives for continuing the development of the research carried out in excellent conditions in Calvados are favorable because the extension of the CIRALE in Goustranville (as stage III of the expansion of the center) is ensured by the region Basse-Normandie.

During the visit, the Director of the ENVA states that he knows and appraises the outstanding quality of the research in the unit and that he will give all his support for a successful future of this unit.

Weaknesses and threats related to the context

The small number of long-time employees (only 3 per team) is a big disadvantage. In all the investigations of the unit, an intense and long-lasting collaboration between veterinarians and engineers is absolutely necessary; however, the positions of the engineers are in the rule only limited contracts of two years.

The long distance between the two sites (Maisons Alfort and the CIRALE) renders that the exchange between both groups is more difficult. Teaching or assisting in the daily work between one team and the other can not be realized spontaneously and has to be scheduled long-time ahead.

Recommendations

With the superb methods it developed, the unit is able to do long-time follow-ups of the locomotor apparatus of many horses, which have been trained or treated under defined conditions. The research unit has the unique possibility to draw conclusions regarding how the pathologies develop or how they can be treated or even better can be avoided. Therefore it is very important, that the unit can continue with the long time research program, because it uses many years until you get reliable results in horses. As mentioned above, the prophylaxis of pathologies, based on very numerous measurements and documentations of the clinical state, are of an enormous value for all users of the horses.

In order to contribute to the long-term existence and the further success of the research unit, which already has done a highly estimated work for the health and the well being of horses and their users, the committee considers that the renovation and enlargement of rooms and laboratories in Maison-Alfort appear as an absolute necessity.

The committee also considers that the unit is still highly fragile and suggests that a very strong attention should be paid in recruting collaborators on more long-time positions in order to maintain and to ensure its productivity and its attractiveness for young researchers.

 Detailed assessments

Assessment of scientific quality and outputs

The small unit had a big number of publications in peer-reviewed journals of a high standard. The total number of 73 papers in 5 years means an average of 15 papers per year. Besides many articles in the veterinary sciences journals, the fact that the unit published some of their main results in more general journals has to be pointed out. More than 70 communications at national or international congresses have also been given. Team members wrote also several books or chapters in books.

Assessment of the unit's academic reputation and appeal

The unit is the only one in France dealing with the physiology and pathology of the locomotion apparatus in horses. Besides the national reputation the work of this unit is well known and estimated over the whole world, not only by veterinary and equine specialists, but also by non-veterinary researchers in the disciplines of comparative medicine and biomechanics. Many collaborations already exist between the unit and research groups of biomechanics in Paris, Uppsala (Sweden) and Davies (California, USA).

The activities of the unit members as experts for equine sportive events or for problems related to equine locomotion show how the knowledge and the expertise of the unit is demanded and estimated in the national environment and world-wide. The numerous invitations of the teams leaders at conferences in Europe and other continents are indicators of their outstanding reputation in the scientific world. In the 5-year period, 111 conferences were given as invited speakers (77 by the IOAP and 34 by the BAT-team respectively).

Apart from this the unit received 4 research prizes for its work and organized 2 international congresses: the international congress on locomotion and the 23 rd Congress of the European Association of Veterinary-Anatomists in 2010.

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

The unit succeeded to bring their results of basic sciences to a wide public, who can apply the results for the benefit of the horses and their users. In this sense the unit created an optimal transfer from basic research to applied sciences. The research of both teamss is complementary and clearly defined. The unit achieved a patent in France for measuring the tension in tendons and another in USA for producing a model of fibrous structure of fibrous tissue.

The contracts with companies and public institutions for research projects provided with more than 2.2 Million € during the five years period and it is a strong proof of the good examplary interactions with the environment and a sign of a very high confidence of all partners in the research unit.

Assessment of the unit's organisation and life

Based on the documents and the interviews with unit members, the committee had the impression of a very good and harmonic team life within and between both teams of the unit. The meetings and scientific exchanges occur on a very regular base in the CIRALE and daily in Maisons-Alfort (because the members of that team live closer together). The two teams have an excellent complementarity and synergy. The long distance between the two locations is a disadvantage, which is however overruled by the great advantage to have a field-station at the best conditions and an environment where horses are bred and trained.

Assessment of the unit's involvement in training through research

The unit is intensely involved in training through research and their members have many responsibilities in teaching and in daily clinical diagnostic work and care for equine patients. The success of both groups is only due to an enormous engagement and idealism of all members, whose leaders are well estimated over the whole world. During the period, there were 110 people welcomed for practice in the CIRALE, from whose 18 were residents or veterinarians of foreign countries; in addition, 2 seminaries with 40 participants in diagnostic were performed as well as trainings for farriers.

In the unit, 3 theses were finished and 5 theses are in progress; 11 Master diplomas were finished. Sixteen theses de Doctorat vétérinaire were completed and 4 diplomas within the DESV (Diplôme d'études spécialisées Vétérinaires) were obtained.

During the thesis the doctoral students have a great opportunity to realize experiments with methods of engineering or natural sciences to answer questions of biomechanics or veterinary medicine in equine locomotion. In this way it was possible to get results concerning tension of the superficial flexor tendon of the horse in motion or detecting biomarkers for tendon lesions in horses. Such theses are of very good reputations for the further career of the candidates.

During the visit, the committee members had a short exchange with the Directors of the Doctoral Schools 435 and 497 (telephone call) to which the teams are respectively attached. Both of them confirmed that the theses submitted by the unit are regularly of a high standard and they hope that the good collaboration will continue. However, the foreign members of the committee were astonished to hear that French Veterinarians are only admitted for a doctoral thesis after supplemental master degrees in other sciences like engineers or natural sciences as pharmacist, chemist etc.. The veterinarians of the committee think that young veterinarians would be more encouraged for scientific work if they could participate in research for a doctoral thesis after their veterinarian diploma without preliminary studies of other disciplines and they altogether consider that a Diploma in Veterinary Medicine of France is accepted in Europe as a very good qualification.

Assessment of the strategy and the five-year plan

The strategy and the five year plan for the next period was presented in a clear manner and includes both continuation of the former projects and the start of new projects.

These projects are all very ambitious, but realistic, and can be well performed with the existing equipment and in collaboration with other units.

The expected results will give very important impacts for therapy and prevention of pathologies in equine locomotion and are therefore of a high economic value. The projects will be mentioned in the chapter for each team. For the realisation of research of such a high quality in future, the conditions should give a certain relief of the daily duties for the team leaders. A wider distribution of the work to long-time experienced collaborators should be attempted. Moreover the environment and the laboratories could be improved in Maisons-Alfort. The IPOA team is working in the context of CIRALE which is financing itself since 1999 and is able to pay the expenses of a large part of the crew and the maintenance costs of the centre and its machines by the income of the diagnostic work. The personal consists of 14 veterinarians and 7 non veterinarians; 4 persons are employed by the ENVA, the rest of salaries are self-financed for an amount of 450.000 € per year.

The documentation and follow-up of a wide range of locomotory pathologies allows IPOA to draw conclusions on the development and the causes of the lesions. The study of 392 foals of the breeds Trotters, Thoroughbreds and Selle Français showed that the hind fetlock joint was in 28.3 % of the foals the most common location for osteochondrosis, and that this condition was most frequently seen in Selle Français horses. An evolution of radiological findings between 6 and 18 month was also possible. The follow-up study in 328 yearlings was of special interest and showed that horses with few or mild radiological findings as yearlings were later better positioned in races than those with higher grades of radiological changes. The cited examples indicate how important the IPOA/CIRALE-research is in favour of improvement of the health condition of horses and the income in the horse industry. No other research unit in the world has such facilities and would be able to do such a widely disposed research with horses as it has been performed in the CIRALE.

IPOA published 50 articles in peer-reviewed journals of a high standard (impact factors of more than 2, a high standing in veterinary medicine), which during the period corresponds to an average of 3.3 papers per year per scientist. The team gave 34 communications at national or international congresses. The highlight of the team publication was the special issue in "The Veterinary Journal" (Nr. 197, 1, 2013) to the difficult and very important subject on juvenile osteochondral conditions in horses, which comprised the follow-up of 392 foals in the breeds Selle Francais, French trotters and Thoroughbreds.

The authorship of chapters in books (radiology of the tarsus and stifle joint) by a team member and of the book entitled "Biomechanics and physical training of the horse" by the team leader give also a clear view of the deep knowledge and experience of the IPOA team.

As a whole, the scientific production of IPOA is more than excellent and of the highest interest in term of quality and innovation, especially because it is based on the use of the more moderm imaging methodologies and the collection of many observations on a large population of horses which have beenvestigated together with information on their environmental conditions.

Assessment of the unit's academic reputation and appeal

The team-leader and his crew are worldwide estimated as experts in all disciplines of equine locomotion. In the academic world their experience and their didactic skills are well known, which is reflected by the very high number of invitations to national and international congresses and conferences as invited speakers.

In addition, the team leader has become Diplomate of the American College of Veterinary Sport Medicine and Rehabilitation (2013) and a team member is Vice-president of the European Large Animal Diagnostic Imaging Society (2011).

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

The interaction with the environment is extremely intense in this team. As particular examples, it can be mentioned that the team leader was expert of the FEI (Fédération Equestre Internationale) in the Equine World Championship in Lexington (Kentucky, USA) and that the CIRALE will assure the veterinarian activities concerning imaging and diagnosis of sport injuries in the World Equestrian Championship in 2014.

The numerous contracts for collaboration and financial contracts prove the high confidence of many public institutions and companies in the work of the team. There was an amount near 800.000 € assured for this 5-year period (Projects: Hippocart, Tendimage and Equitend). A great success for the team is that a further stage (stage III) of the extension of the CIRALE, which includes the installation of a new and very powerful MRI for a total of about 4 millions €, is assured.

The results concerning osteochondrosis and other locomotor pathologies mean that this knowledge should be considered by the professionals and change some strategies. This should occur in the selection of sound animals for breeding and in avoiding too intense nutrition and the very ambitious and strong training programs of the young horses.

Assessment of the unit's organisation and life

In order to complete what has already been mentioned with regard to the whole unit, the team appeared very well organised. Meetings for all duties with the patients, journal-clubs, discussions of research projects and the state of affairs are held on a regular basis with the members of the staff.

Assessment of the unit's involvement in training through research

The CIRALE is accredited for the education of European residents since 2010.

Many veterinarians are trained in equine practice and research. A great number of pre-and postgraduate students were accepted and trained (masters, engineers and veterinarians), with very good success.

In the context of the doctoral school, the CIRALE acquired an excellent reputation.

Assessment of the strategy and the five-year plan

In the strategy and the 5-year plan IPOA has presented, the following projects were discussed, which for some of them are partially already started:

1. The project "Tendimage" identified markers, which are sensitive and specific for tendinopathies. The new project "Equitend" will evaluate the compatibility and therapeutic effect of the application of the biopolymer RGTA in tendon lesions; 2. The project "Tendolyse" tries to induce the fibrinolysis of the intratendinous clot at early stage of lesions, so that the regeneration can be studied afterwards by imaging methods and histology; 3. The project "Trotter races without shoes" -a project with high relevance for animal welfare, aims to assess the lesions that occur when horses race without shoes, and to give recommendations on what is tolerable for the horse's feet; 4. "Radiculopathies cervicales" is a project on the diagnosis and management of compressive cervical neuropathies in the horse. Identification of clinical cases with irritations of the spinal cord and its nerves increased during the last years together with the pathologies of the cervical articulations, which are near to the spinal nerves. The project aims to developp the present knowledge on the inflammations and compressions of the nerves and the spinal cord which may induce pain and ataxies; 5. The project "Hippocart" shall develop new diagnostic approaches and stem cell therapies for arthropathies in the horse. A model of fetlock osteoarthritis has been developed and by means of cell engineering it shall be tried to obtain cartilage matrix regeneration; 6. A project "Physiotherapy" wants to evaluate the effects of physiotherapy and training in the swimming pool and the functional effect and therapeutic indications of electro-stimulation in the horse.

The mentioned projects have partially connections among them. They all consider the urgent questions of equine practice. Despite it will represent a very high effort for a small team to conduce the projects, the committee note that it has already been the case with outstanding results in the last decades. All the projects are ambitious, contain creative orginality, and they have a high relevance for the welfare of horses and for the equine practitioners. The material equipment and the location of the CIRALE are optimal conditions for the realization of the projects.

Conclusion  Strengths and opportunities:

The IPOA team has well known experts in the field of equine locomotion and there is a very good synergy between veterinary clinicians and engineer or practioners.

The CIRALE centre which has a wide recruitment of horses for clinical diagnosis of locomotor disorders, is the optimal environment for equine diagnostic research.

The stage III of the expansion of the CIRALE has been decided and is ensured by the region Basse-Normandie and this opens very positive perspectives for continuing the development of the research carried out.

 Weaknesses and threats:

The personal, who is only connected to contracts is a problem for the continuity of the research.

The daily duties to run a large equine diagnostic centre with a great part of teaching diminish, for this relatively small team, the time available for research.

 Recommendations:

The IPOA-team should have more experienced leaders, dealing with the daily diagnostic work and attending the research projects.

The committee considers that in the future, the immense work in publishing and in education with conferences, workshops etc. should rely on several team members instead of mainly one today.

Among the various actions expected to support this successful research team, a specific attention should be given to recruit more long-time positions in order to maintain its very attractive position and its reputation in the whole world. The BAT team in Maisons-Alfort consists of 7-8 members and only 4 of them are permanent teachers and researchers. At first, the team members have a great deal of work in teaching Anatomy to the students of the École Nationale Vétérinaire de Maisons-Alfort. It is admirable that this team could achieve so successful results in their biomechanical research in the horse, a species with a complex dynamic locomotor system, which brings many difficulties in the measurement of forces.

BAT succeeded in establishing non-invasive methods for measuring the forces working on the different components of the equine distal limb in horses moving in their natural environment. The methods were first tested under laboratory conditions in an intense collaboration between veterinarians and engineers.

The forces of the superficial flexor tendon were measured at first in tension tests with tendons of slaughtered horses and a sonographic sensor, and it could be demonstrated that with increasing tension the speed of ultrasounds linearly increased. Next, the team also succeeded to measure the tendon tension in the superficial digital flexor tendon at the level of the Metacarpus and Metatarsus in the life horse in movement.

For measurement of the forces and the accelerations in the hooves, BAT developed a new dynamometric horseshoe with pressure receptors at the level of the sole and a receptor for accelerations at the dorsal hoof wall. The dynamic horseshoe allows to measure the forces and movements in different circumstances of work (e.g. on different race tracks). This is a field where up to now only rough assessments could be made. The project "Sequisol" was performed with trotters, which run with a sulky. Large differences in forces acting on the distal limb between hard sandtracks and tracks containing waxed fibres were seen; the track with waxed fibres resulted in much lower vertical forces to the hooves. In the subsequent project "Safetrack" the dynamic horseshoe and the sonographic measurements of tendon tension are combined and adapted for the ridden horse.

The developped experimental methods of the BAT-team are up to now unique in the world. It is a great success of the team that they could adapt the results of laboratory studies to field conditions, where measurements of the life animal in motion are possible. The development of these methods was a very time consuming process, but now it enables to get correct informations about the forces induced on the limbs and the influence of the tracks. The excellent kinematic methods allow to study in the slow motion modus, how the mouvements proceed in the different positions. This gives realistic informations for all people who want to learn more about equine locomotion.

BAT published 23 articles in peer-reviewed journals of a high standard, which correponds to an average of 1.2 papers per year per scientist during the five years period. Besides the articles in the Equine Veterinary Journal, the team could publish their results on tendon loads and the force measurements in hooves and limb kinematics of horses in the Journal of Biomechanics. This is a fact, which must be pointed out as a sign of an intense and very effective collaboration of veterinarians and engineers.

The team gave 40 communications at national or international congresses. The publication of scientific and technical reports, as the "rapport technique sur le project Sequisol" also attests of the skills and experience of the BAT-team.

The intense collaboration between veterinarians and engineers created outstanding methods to realize measurements in equine locomotion, which seemed to be impossible for years. The knowledge of the immense forces, and the big influence of the different race tracks, which can now be measured as well in the ridden horse, gives exact informations about the various impacts on the locomotor apparatus in motion. This is only due to the outstanding and unique productive work of the BAT-team.

Assessment of the unit's academic reputation and appeal

The excellent reputation of the research of the BAT team resulted in an increasing number of invitations as speakers in national and international conferences world wide and in requests for collaborations. In this respect, a collaboration with a research group in Davies (California, USA), whose work is complementary to the BAT-activities, is on the way.

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

The increased knowledge on equine locomotion which is obtained by the results of the BAT team constitutes a sound scientific base in the development of strategies to prevent musculoskeletal injuries in the horse. This is very important in a field where many "facts" were up to now speculative. A first practical application would be a good scientific advice for the choice of race-tracks based on the results of the studies performed.

The measuring devices developed are very well adapted for practical use, as they allow to obtain objective data on the stress and strain to the equine locomotor system in different circumstances "on the field". Therefore different equestrian organizations are enthusiastic for a good collaboration with the team, because they realize that studies on the measurement of load to the limbs and the influence of the different soils serve for the health and the well being of the horses and for their own benefit.

The BTA team had contracts of more than 1 400 000 € (Projects: Sequisol, SIM, Safe Track and one thesis) over the last five years, and that situation can be seen as a sign of high confidence and estimation to the outstanding work of the group.

The applied biomechanics of equine locomotion is a new field, which gives realistic informations about the forces and the influences of different tracks to the horses in motion. This is a very good chance for the industry and the users of the horses to improve the conditions and to do profitable investments for the welfare of the horses and their users.

Assessment of the unit's organisation and life

The organisation and life of the team seemed to be very well and harmonic. In Maisons-Alfort, the research team has good facilities for in vitro-tests and dissections and all the research work is done next to a wide duty in teaching anatomy to Veterinary Medicine students. The committee also noted that the research work in the field has a very distinct long-term plan.

Assessment of the unit's involvement in training through research

BAT participates in continuous training through research. One thesis is accepted, one is ongoing, and, during the period, 3 persons reached a Masters degree and in addition 8 reports of engineers were accepted thanks to their practice in the research team. Furthermore, one colleague received the diploma HDR.

Assessment of the strategy and the five-year plan

The research program shall continue with intense field studies planned in the context of the project Safe-track will be very important, because it is essential for equine sports to get more data on the wide field of influences of the different tracks and work of the horses (different disciplines) on their locomotor system. In this context the team wants to get information about the pathologies induced to the musculoskeletal system by tracks of inferior quality or by certain trainings -this in collaboration with the IPOA-group.

Another great and ambitious perspective is the project "Biomechanics of the back and the interactions with the saddle". In this project pressure-measurements of different saddles shall be performed combined with kinematic studies of the motion in the region of the spinal column. The painful pathologies in the back as well as in the cervical region indeed became serious hot item in the last decades.

The projects for the five-year period depend to the needs of the equine practice. They are ambitious, based on excellent self-developped methods and let expect, like in the last period, results of a high relevance for the benefit of the horses. It is of special interest to get further informations about the severe mechanical influences on the locomotor apparatus in motion. The need of the projects is evident, and the high motivation and the wide knowledge of the team should bring again new and outstanding results. These results about equine locomotion under field conditions will be the base for many improvements in equine health and will have as well a benefit for the equine users.

Conclusion  Strengths and opportunities:

This team has developed very sophisticated methods for measuring forces and motions to the hooves and tendons of the distal limbs. These newly developed experimental methods are world-wide unique and give the opportunity to measure the various influences of tracks and working conditions of horses under field circumstances. The results have high relevance to the practice of veterinarians, horsemen and for the well-being of sport horses.

 Weaknesses and threats:

In Maisons-Alfort, the buildings and rooms are suboptimal, although the deficiency in rooms induces a good interactions within the members of the team.

All experiments and measurements with life horses occur outside Maisons-Alfort at different locations under defined conditions. They need to be planned a long time before they can be realized and these experiments also require the participation of the entire team. The high costs for maintaining the technical instruments is a further difficulty.

A weak point in this team is the small size and the always existing problem of a loss of qualified personal. A great part of the personal is employed with contracts only for a certain time and the presence of a colleague in charge of the administrative work should not be prolonged in the plan of 2015. This is a continuous menace to the group.

 Recommendations:

The BAT-team should have in future a constant supply for creating the technical equipment and its modifications, which are continuously needed in the difficult field of measurements in equine locomotion under field conditions.

Similar to the IPOA-team the staff should have in future more long-time experienced specialists, for fulfilling the large duties in research and in the wide field of publishing and teaching for the different users of its experimental work.

The narrowness in old rooms instead of new laboratories and offices could constitute a real disadvantage for the development of the team in the future. The absence of reinforcement in permanent positions for continuous research could also constitute another limiting element.

The team should be encouraged to continue with its excellent work in future and with the same enthusiasm and success as up to now.

N4:

  Other permanent staff (without research duties) 1 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* Number of Research Supervisor Qualifications (HDR) taken 1 Qualified research supervisors (with an HDR) or similar positions 4 5

4

   Team-by-team analysis Team 1 : Osteoarticular Imaging and Pathology « Imagerie et pathologie osteoarticulaires » (IPOA) Name of team leader: Mr Jean-Marie DENOIX Workforce Permanent professors and similar positions 3 3 N2: Permanent EPST or EPIC researchers and similar positions N3: Other permanent staff (without research duties) N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.) 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 2  Detailed assessments Assessment of scientific quality and outputsIn Goustranville (Calvados) an excellent possibility exists for investigations in horses of three disciplines (Warmbloods,Trotters and Thoroughbreds) and the team has very strong connections to the horse breeders of the environment. Together with new buildings and a very modern equipment in Radiology, Ultrasonography, Scintigraphy and Magnetic Resonance Imaging (MRI), optimal conditions exist for clinically based research. The diagnostic work on 1'000-1'200 horses per year, suffering from lameness or other locomotor disorders, is a big effort for the relatively small research team, but forms a solid base for clinical research.

N3:N4:

  Permanent EPST or EPIC researchers and similar positions 1 1 Other permanent staff (without research duties) 1 Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers(DREM, Postdoctoral students, visitors, etc.)

  Général de gaulle, 94704 Maisons-Alfort Conduct or programme of visit: 8:00 am Welcome & Closed-door Meeting of Visiting Committee with AERES Scientific Advisor 8:45 am Introduction of Plenary Session: AERES Role & Procedures: AERES Scientific Advisor 9:00 General Presentation of the Unit & Discussion; Ms Nathalie CREVIER-DENOIX and Mr Jean-Marie DENOIX (presentation of CIRALE) 10:15 am Presentations of Research Teams & Discussion: Team 1: Osteoarticular Imaging and Pathology; Mr Jean-Marie DENOIX and Mr Fabrice AUDIGIÉ Team 2: Articular and Tendon Biomechanics); Ms Nathalie CREVIER-DENOIX and Mr Henry CHATEAU 12:15 am Discussion of the Strategies and Perspectives of the Unit 12:30 am Closed-door Discussion with the Director(s) of the Doctoral School(s


Qiuping A Wang

Probability distribution and entropy as a measure of uncertainty

Keywords: numbers : 05.20.-y, 02.50.-r, 02.50.Tt

The relationship between three probability distributions and their maximizable entropy forms is discussed without postulating entropy property. For this purpose, the entropy I is defined as a measure of uncertainty of the probability distribution of a random variable x by a variational relationship

, a definition underlying the maximization of entropy for corresponding distribution.

1) Introduction

It is well known that entropy and information can be considered as measures of uncertainty of probability distribution. However, the functional relationship between entropy and the associated probability distribution has since long been a question in statistical and informational science. There are many relationships established on the basis of the properties of entropy. In the conventional information theory and some of its extensions, these properties are postulated, such as the additivity and the extensivity in the Shannon information theory.

The reader can refer to the references [1] to [8] to see several examples of entropies proposed on the basis of postulated entropy properties. Among all these entropies, the most famous one is the Shannon informational entropy ( p p S i i i ln ∑ -=

) [2] which was almost the only one widely used in equilibrium thermodynamics (Boltzmann-Gibbs entropy) and in nonequilibrium dynamics (Kolmogorov-Sinai entropy for example). But the question remains open in the scientific community about whether or not Shannon entropy is the unique useful measure of statistical uncertainty or information [START_REF] Uffink | Can the maximum entropy principle be explained as a consistency requirement[END_REF].

The origin of this question can be traced back to the principle of maximum entropy (maxent) by Jaynes [START_REF] Jaynes | The evolution of Carnot's principle, The opening talk at the EMBO Workshop on Maximum Entropy Methods in x-ray crystallographic and biological macromolecule structure determination[END_REF] who claimed the Shannon entropy was singled out to be the only consistent measure of uncertainty to be maximized in maxent. In view of the fact that this uniqueness was argued from the Shannon postulates of information property [2], one naturally asks what happens if some of these properties are changed. Some of the entropies in the list of [1] are found by mathematical considerations which change the logic of Shannon. Recently, a nonextensive statistics [6][7] [8] (NES) proposed to use some entropies for thermodynamics and stochastic dynamics of certain nonextensive systems. NES has given rise to a large number of papers with very different viewpoints dealing with equilibrium and nonequilibrium systems and incited considerable debate [11][12][13] within the statistical physics community.

Some key questions in the debate are: whether or not it is necessary to replace Boltzmann-Gibbs-Shannon entropy with other ones in different physical situation? what are the possible entropy forms which can be maximized in order to derive probability distribution according to maxent?

One remembers that in the actual applications of maxent the used entropy forms are either directly postulated or derived from postulated properties of entropy [1][2][START_REF] Rényi | Calcul de probabilit´e[END_REF][4][5][6][7][8]. The correctness of these entropies is then verified through the validity of derived probability distributions. In the present work, we will invert this reasoning in order to find maximizable entropy form directly from known probability distributions without postulating the properties of entropy. For this purpose, we need a generic entropy definition underlying in addition variational approach or maxent. Inspired by the first and second laws of thermodynamics for reversible process, we introduce a variational definition of entropy I such as

dx x d dI - =
for the measure of probabilistic uncertainty of the simple situation with only one random variable x. We stress that the main objective of this work is to show the non-uniqueness of Shannon entropy as maximizable uncertainty measure. Other entropy forms must be introduced for different probability distributions. We would like to stress also that this is a conceptual work tackling the mathematical form of entropy without considering the detailed physics behind the distribution laws used in the calculations. In what follows, we first talk about three probability distributions and their invariant properties. The maximizable entropy form for each of them is then derived thanks to the definition dx x d dI -= .

2) Three probability laws and their invariance

In this section, by some trivial calculations one can find in textbooks, we want to underline the fact that a probability distribution may be derived uniquely from its invariance.

By invariance of a function f(x), we means that the dependence on x is invariant at transformation of x into x', i.e., f(x')∝ f(x). We consider three invariances corresponding to exponential, power law and q-exponential distributions, respectively.

a) Translation invariance and exponential law

Suppose

that ) (x f is invariant by a translation of b x x + → , i.e. ) ( ) ( ) ( x f b g b x f = + (1)
where ) (b g depends on the form of f(x). We have

) ( ) ( ' ) ( ) ( ) ( x f b g b x d b x df db b x df = + + = + and ) ( ) 0 ( ) ( ' x f g dx x df = or dx g f x df ) 0 ( ) ( ' = (b=0)
. This means

c x g x f + = ) 0 ( ' ) ( ln or ce x f x g ) 0 ( ' ) ( = . ( 2
)
where c is some constant. If f(x) gives a probability such as

) ( 1 ) ( x f Z x p = where ∑ = x x f Z ) ( , the normalization condition 1 ) ( = ∑ x x p
will make p(x) strictly invariant versus the transformation

b x x x + = → ' , i.e., ) ( ) ( 1 ) ' ( ' 1 ) ' ( x p x f Z x f Z x p = = = since ) ( ) ( ) ( ) ( ) ' ( ' ' b Zg x f b g b x f x f Z x x x = ∑ = ∑ + = ∑ = .
b) Scale invariance and power law

Now suppose that ) (x f is scale invariant, we should have ) ( ) ( ) ( x f b g bx f = (3)
where b is the scale factor of the transformation. We make following calculation

) ( ) ( ) ( ) ( ) ( ' x f b g x bx d bx df db bx df = = to get ) ( ) 1 ( ) ( ' x f g x dx x df = , which means x c x f g ) 1 ( ' ) ( = . ( 4
)
This kind of laws is widely observed in nature for different dynamical systems such as language systems [START_REF] Li | Random texts exhibit Zipf's-law-like word frequency distribution[END_REF] and scale free networks [START_REF] Newman | The structure and function of complex networks[END_REF] among many others [START_REF] Newman | Power laws, Pareto distributions and Zipf's law[END_REF]. The well known Levy flight for large x is a good example of power law with α

- - = 1 ) 1 ( ' g where 2 0 < <α .
c) The q-exponential and its invariance properties

Here we would like to mention a probability which has attracted a lot of attention in the last years:

[ ]a x a c x f 1 1 ) ( β + = . ( 5
)
where a and β are some constants. The Zipf-Mandelbrot law

[ ] α - + = x 1 c ) x ( f observed in
textual systems and other evolutionary systems [START_REF] Silagadze | Citations and the Zipf-Mandelbrot's law[END_REF] can be considered as a kind of qexponential law. Another example of this law is the equilibrium thermodynamic distribution for finite systems in equilibrium with a finite heat bath, where a can be related to the number of elements N of the heat bath and tends to zero if N is very large [START_REF] Terletskii | Statistical physics[END_REF], which implies

[ ] → e c x a c x f x a a β β 0 1 1 ) ( → + = .
This distribution is not a power law in the sense of Eq.( 4). It has neither the scale invariance nor the translation invariance mentioned above. The operator on x that keeps f(x)

invariant is a generalized addition xb a b x b x a β + + = + [19], i.e. [ ] a a xb a b x a c b x f 1 ) ( 1 ) ( β β + + + = + = [ ] [ ] ) ( ) ( ) 1 ) 1 1 1 x f b g x a c b a a a = + + β β where [ ]a b a b g 1 ) 1 ) ( β + = .
The derivation of Eq.( 5) from

) ( ) ( ) ( x f b g b x f a = +
is given as follows. First we make a derivative such as

) ( ) ( ' ) 1 ( ) ( ) ( ) ( ) ( ) ( ) ( x f b g x a b x d b x df db b x d b x d b x df db b x df a a a a a a = + + + = + + + = + β . Then let b=0, we get ) ( ) 0 ( ' ) 1 ( ) ( x f g x a dx x df = + β which means ) 1 ( ) 0 ( ' ) ( ) ( x a dx g x f x df β + = or c x a f a + + = / 1 ) 1 ln( ln β or Eq.(5) with ) 0 ( ' g = β .
3) A definition of entropy as a measure of dynamical uncertainty Suppose we have a random (discrete) variable x i with a probability distribution

) ( 1 x f Z p i i =
where i is the state index. The average of x i is given by p

x x i i i ∑ =
and the normalization is

1 = ∑ i i p .
The uncertainty in a probability distribution of x can be measured by many quantities.

The standard deviation σ or the variance 2 2 2

x x -= σ , for example, can surely be used if they exist. Shannon entropy, as some of other known entropy forms, can also be used as a measure of uncertainty of any p i . But certainly any given entropy form, including Shannon one, cannot be maximized for any distribution p i according to maxent rules, which can be seen below. The main task of this work, let us recall it, is to search for a general definition of uncertainty measure underlying maxent, in such a way that each derived entropy can be maximized to give the corresponding distribution. Here we propose a quite general measure I by a variational definition as follows

p d x dx x d dI i i i ∑ = - = . ( 6
)
where dx p dx

i i i ∑ =
. This definition has been in a way inspired by the first and second laws of thermodynamics in equilibrium thermodynamics. Considering the definition of internal

energy E p E i i i ∑ =
where E i is the energy of the microstate i with probability p i , we can write

E E p E p E p E i i i i i i i i i i δ δ δ δ δ + ∑ = ∑ + ∑ = in which ∑ ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ ∂ ∂ ∑ ∑ = = j j j i i i i i i i q q E p E p E δ δ δ
is the work done to the system by external forces

j i i i j q E p F ∂ ∂ ∑ =
where q j is the extensive variables such as volume, distance or electrical polarization. According to the first law of thermodynamics, the quantity

E E E p i i i i δ δ δ - = ∑
is the heat change in the system, that is,

S T Q E p i i i δ δ δ = = ∑
for a reversible process, where S is the thermodynamic entropy and T the absolute temperature. S has the following variational relation ( )

E E T S δ δ δ - = 1 . (7)
As is well known, S measures the dynamical disorder of the system or the uncertainty of the probability distribution of energy in the dynamics. In contrast with another measure 2 2 2 E E -= σ , S can be maximized in maxent for equilibrium system to derive probability distribution. At this point, we must mention a work by A. Plastino and EFM Curado [20] on the equivalence between the particular thermodynamic relation E S βδ δ = and maxent for probability assignment. In order to obtain this heat-energy relationship from the first and second laws of thermodynamics, they considered the particular reversible process affecting only the microstate population, i.e., the distribution p i has a variation δp i due to a heat transfer δQ=TδS. Although their variational approach from a particular process still needs further justification, their conclusion is important and consequential. Not only have they shown the equivalence between E S βδ δ = and maxent, they also reached a quite generic variational principle by virtue of the fundamental laws of thermodynamics. To our opinion, as a variational method, E S βδ δ = is much more general and powerful than maxent with originally a unique maximizable measure, since it enables one to maximize other form of entropy if any for equilibrium system, which opens the door for other development of statistical mechanics on the basis of maxent for equilibrium system.

Coming back to Eq.( 6) which is just an extension of Eq.( 7) to arbitrary random variables x and to arbitrary system (even out of equilibrium) and a generic definition of maximizable uncertainty measure for any random variable. The maximizability of this measure consists to put 0 = dx as discussed below.

The geometrical aspect of the uncertainty measure defined by Eq.( 6) can be illustrated in the examples of Figure 1 which shows that dI and I are related to the width of the distributions on the one hand, and to the form of the distribution on the other. dI is not an increasing function of the distribution width. For example, dI=0 for uniform distribution whatever the width of p(x)=constant. This means that I is a constant.

4) Three probability distribution laws and their entropy

In this section, on the basis of the uncertainty measure defined in Eq.( 6), we derive the entropy functionals for the three probability laws discussed in section 2.

a) Translation invariant probability and Shannon entropy

The following calculation is trivial. From Eq.( 6), for exponential distribution e Z p

x i i - = 1 ,
we have Figure 1, Three geometrical representations of the variation dI defined in Eq.( 6)

for some distributions. The hatched areas represent the value of the entropy

variation p d x dx x d dI i i i ∑ = - =
for each case. In general, dI for any increasing or decreasing part of a distribution curve is the area between the p(x)-axis and the considered part. So in this figure, dI for any part of the distribution curve is the area from p(x)-axis to the left of the part. The sign of dI depends on the way it is calculated. If it is calculated with increasing x, dI is positive for the increasing part of p(x) since dp i >0 (main parts of left panel) and negative for the decreasing part of p(x) since dp i <0 (right panel). In the middle panel, the hatched area is the difference of dI inc >0 for the increasing part and the dI dec <0 for the decreasing part.

Since the region of dI inc is smaller than that of dI dec , the difference is negative. It is easily seen that dI=0 if the width (uncertainty) of the distribution is zero or if the distribution is uniform. This is Shannon information if the constant c is neglected. Within the conventional statistical mechanics, this is the Gibbs formula for Clausius entropy. Remember that the maximization of this entropy using Lagrange multiplier associated with expectation of x yields exponential distribution law.

x p(x) p(x) x p(x) x ∑ - = ∑ - = ∑ - ∑ - = ∑ - = i i i i i i i i i i i i i i p p

b) Scale invariant probability and entropy functional

We have in this case power law probability distribution p i :

x Z p i a i - = 1 . ( 8
)
where

∑ = - i a i x Z
. Put it into Eq.( 6) to get

] ) 1 1 /( [ 1 1 1 ) ( 1 1 1 1 1 1 1 c a p d Z p d a Z p d Z p dI i i a a i i a a i i i a + ∑ - - = ∑ - = ∑ = - - - - - (9)
where c is an arbitrary constant. Since we are addressing a given system to find its entropy form, Z can be considered as a constant for the variation in x (the reader will find below that this constant can be given by the Lagrange multiplier in the maximum entropy formalism).

Hence we can write

c a p I i i a + ∑ - ∝ - ) 1 1 /( 1 1 . ( 10
)
In order to determine c, we imagine a system with two states i=1 and 2 with 0 1 = p and 1 2 = p . In this case, I=0 so that 0 1 1 (11) i.e.,

1 0 = + ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ - + c a
a c 1 1 1 - - = (12)
We finally get [START_REF] Li | Random texts exhibit Zipf's-law-like word frequency distribution[END_REF] Notice that this functional does not yield Shannon entropy for 1 → q . As a matter of fact, q must be positive and smaller than unity. I is negative if q is greater than unity or smaller than zero, which does not make sense. For large x Lévy flight for example, 3 1 < <a , so 1 3 1 < <q .

a p I i a i 1 1 1 1 1 - - ∑ = - (13) Let a q 1 = , we can write ∑ - - - = - ∑ - - = - - i q i i i q i q p p q p I 1 1 1 1 1
It can be calculated that

0 ln 1 → ∑ - - = p p q q S
, and If q→1,

∞ → ∑ + - ∑ - = p q S ln 1 1 1 . q x Z q x Z p q p p q p p I q i q i i q i i i q i i - - - ∑ = - - - = ∑ - - - = ∑ - - - = - - - 1 1 1 1 1 1 1 1 1 (15)
Its behavior with probability is shown in Figure 2 c) The entropy for q-exponential probability

+ ∑ + - = ∑ - = ∑ - = + β β β (16)
By the same tricks for determining c in the above section, we get c=-1. So we can write

∑ - - - = - ∑ - = + i q i i i a i q p p a p I 1 1 1 (17)
Where q=1+a and we have used the normalization 1 = ∑ i i p . This is the Tsallis entropy which tends to the Shannon entropy for 1

→ q or 0 → a . In this case [ ]a i i x a c p 1 1 β - =
tends to an exponential distribution.

5) Concluding remarks

We have derived the entropy functionals for three probability distributions. This was done on the basis of a variational definition of uncertainty measure, or entropy without postulating entropy property (such as additivity) as in the usual information theory. The variational

definition dx x d dI - =
is valid for any probability distributions of x as long as it has finite expectation value. According to the results, the exponential probability has the Shannon entropy, the power law distribution has an entropy q p I i q i -∑ --= -1 1 1 where 0<q<1, and the qexponential distribution has Tsallis entropy ∑ ---= i q i i q p p I 1 where q is positive.

It is worth mentioning again that the present definition of entropy as a measure of uncertainty offers the possibility of introducing the maximum entropy principle in a natural way with Lagrange multipliers associated with expectation of the random variables. It is easy to verify, with the above three entropies, that the maximum entropy calculus yields the original probability distributions. This is not an ordinary and fortuitous mutual invertibility, since the probability and the entropy are not reciprocal functions and the maximum entropy calculus is not a usual mathematical operation. As a matter of fact, this invertibility between entropy and probability resides in the variational definition dx x d dI -=

. As discussed in the section 3, dx can be considered as an extended work whatever the nature of x. So to get the "equilibrium state" or stable probability distribution, we can put 0 = dx just as in the mechanical equilibrium condition where the vector sum of all forces acting on an object should be 0, an underlying idea of the principle of virtual work in mechanics. We Curado [20] for thermodynamic equilibrium.

Figure 2 ,

 2 Figure 2, The variation of the scale invariant entropy ∑ ---= = -2 1

  . The maximization of I conditioned with a Lagrange multiplier β such as 0

  if we add the normalization condition. This reasoning leads in a more natural way to the maxent idea 0

Acknowledgements

We thank Professor F. Tsobnang and Professor S. Abe for useful discussion and comments.

We would like to express here our thanks to the referees for their pertinent criticism and very useful comments and suggestions.