Daguesh Science #71 by L'ambassade de France en Israël

Juin 2010 ‫ יוני‬n°

YEARS OF THE FRENCH-ISRAELI HIGH COUNCIL FOR SCIENCE & TECHNOLOGY

Daguesh Science n°

Sommaire

‫הענינים‬-‫תוכן‬ L’édito

Trois regards sur le Haut Conseil pour la Science et la Technologie

4-9

Vingt projets sélectionnés par les experts pilotes du Haut Conseil Genetics

10-29

Sustainable Agronomy

13-15

Bioinformatics

16-18

Neuroscience and robotics

19-21

Medical and biological imaging

22-25

Mathematics

26-27

Astrophysic

28-29

• • •

• • • •

• •

‫דבר העורך‬ ‫שלוש נקודות מבט על הועדה העליונה‬ ‫למדע וטכנולוגיה‬ ‫עשרים הצעות נבחרו על ידי חברי וועדת‬ ‫הערכה של הוועדה העליונה‬

10-12

The Involvment of Nuclear Envelope Proteins and TBCE in HRD Syndrome and Autosomal Recessive Laminopathies Search for Altered Nuclear Genes in Patients with Impaired Synthesis of Mitochondrial DNA-Encoded Proteins Replication dynamic and chromosomal instability in the human genome

Novel Genes From Wild Emmer Wheat for Improving Yield and Sustainability Under Water-Limited Agriculture Effect of Wastewater Irrigation on Plant and Soil Microbiology and Interaction Efficient Allocation of Water Resources among Competing Users: Economic, Environmental and Organizational Considerations

Study of Two Important Pathogenic Genera: Legionella and Streptococcus Analysis and Representation of Cancer-Related Signalling Networks Phylogeny, Genomics, and Evolution of Tunicates

Transfer of Adaptation between Feedback and Feed-Forward Controllers Mathematical Modeling of 3D Human Arm Movements A Mechanistic Approach to Buridan’s Paradox

Imaging the Retina in Depth Following the Activity of Genes in Living Human Cells Geometric Reconstruction of Organs from Freehand Ultrasound Vessel Segmentation on Computed Tomography Angiography (CTA)

Time-Reversal Techniques for Detection and Imaging The Investigation of Convex Bodies: Probabilistic and Geometric Methods

Topics in Molecular Astrophysics: From the Milky Way to Starburst and Active Galaxies Studies of Transiting Extra-Solar Planets

Call For Proposal

30-31

Revue du Service de Coopération et d’Action Culturelle de l’Ambassade de France en Israël ISSN : numéro ISSN en cours Directeur de la publication Éric Seboun Rédacteur en chef David Steinboim La reprise des articles est libre de droits, sous mention © DAGUESH SCIENCE.

Traductions en hébreu Emmanuel Doubchak, Dafna Lebowitz. Relecture des pages en Anglais Esther Halac Impression GOLDPRINT

Abonnements & Informations Science & Technologie AMBASSADE DE FRANCE EN ISRAËL 7 boulevard Rothschild Tel Aviv 66881 - ISRAËL Tél. : +972 (0)3 796 80 41 Fax : +972 (0)3 796 80 45 daguesh@ambfr-il.org http://fitscience.wordpress.com

L’édito

Daguesh Science n°

‫צ‬

a France est le 3ème partenaire scientifique d’Israël, au coude à coude avec le Royaume-Uni et l’Italie, derrière les USA, en première position, et l’Allemagne en seconde position. Israël peut être un acteur important dans l’Union pour la Méditerranée (UPM), notamment dans les domaines de l’agronomie et de l’agriculture en zones arides, de l’eau, des énergies renouvelables ou de la recherche biomédicale.

,‫רפת הינה שותפתה השלישית של ישראל בתחום המדע‬ ‫ ומאחורי‬,‫וזאת כמעט בשווה עם בריטניה ואיטליה‬ ‫ המככבת במקום הראשון וגרמניה‬,‫ארצות הברית‬ ‫ ישראל תוכל להוות גורם חשוב במסגרת איחוד‬.‫במקום השני‬ ‫ בייחוד בתחומי האגרונומיה והחקלאות‬,‫מדינות הים התיכון‬ ‫ האנרגיות המתחדשות או‬,‫ בתחומי המים‬,‫באזורים צחיחים‬ .‫המחקר הביורפואי‬

Ce numéro de Daguesh-Science consacré aux 5 ans du Haut Conseil Franco-Israélien pour la Science et la Technologie (HCST) dresse le bilan de la coopération scientifique entre la France et Israël depuis la création du HCST en 2004. Plus de 120 projets de recherche en réseau (P2R) ont été financés entre 2004 et 2009 dans le cadre de 7 programmes : agronomie, astrophysique, bioinformatique, génétique humaine, imagerie biologique et biomédicale, mathématiques et neurosciences et robotique. Vingt projets, les plus emblématiques de ces programmes, sont présentés dans les pages qui suivent. Ils confirment la qualité de ces collaborations.

‫ שהוא מוקדש לחמש שנות קיומה של‬,‫סיינס‬-‫גיליון זה של דגש‬ ‫ מציג‬,‫המועצה העליונה הצרפתית ישראלית למדע ולטכנולוגיה‬ ‫את הסיכום של שיתוף הפעולה המדעי בין צרפת לישראל מימי‬ ‫ פרויקטים‬120-‫ יותר מ‬.2004 ‫הקמת המועצה העליונה בשנת‬ :‫ במסגרת שבע תוכניות‬2009-‫ ו‬2004 ‫) מומנו בין‬P2R( ‫ברשת‬ ‫ דימות‬,‫ גנטיקה אנושית‬,‫מחשוב‬-‫ ביו‬,‫ אסטרופיסיקה‬,‫חקלאות‬ ‫ בדפים‬.‫ מתמטיקה ומדעי המוח ורובוטיקה‬,‫ביולוגי וביורפואי‬ ‫ שהם המיזמים‬,‫הבאים יוצגו לפניכם עשרים פרויקטים‬ ‫ ומעידים על איכות שיתופי‬,‫הייצוגיים ביותר לתוכניות אלו‬ .‫הפעולה האמורים‬

L’excellence scientifique de la France et d’Israël est internationalement reconnue. La France, comme état membre de l’Union Européenne (UE), et Israël, comme état associé, participent aux programmes cadres de l’UE. Leurs taux de réussite les placent dans le peloton de tête des pays de l’UE. Le renforcement de la coopération scientifique bilatérale, initié par le HCST, pourrait se poursuivre avec la création d’une fondation binationale pour la science. Dotée d’un comité scientifique et de moyens financiers renforcés, sa vocation serait de soutenir des projets de recherche binationaux ambitieux qui trouveraient, ensuite, leur épanouissement dans le cadre de l’UE ou de l’UPM.

‫רמתן המדעית המצויינת של צרפת ושל ישראל מוכרות בכל‬ ,‫ בתור מדינה החברה באיחוד האירופי וישראל‬,‫ צרפת‬.‫העולם‬ ‫ משתתפות בתוכניות המסגרת של האיחוד‬,‫בתור מדינה שותפה‬ ‫ אחוזי ההלצחה מציבים אותן בקבוצה המובילה בין‬.‫האירופי‬ -‫ חיזוק שיתוף הפעולה המדעי הדו‬.‫מדינות האיחוד האירופי‬ ‫ בו החלה המועצה העליונה עשוי להוביל להקמתה של‬,‫צדדי‬ ‫ בזכות מועצה מדעית ואמצעים פיננסים‬.‫לאומית למדע‬-‫קרן דו‬ ‫לאומיים‬-‫ יעלה בידה לתמוך במיזמי מחקר דו‬,‫מוגברים‬ ‫שאפתניים העשויים בהמשך לבוא לידי בטוי במסגרת האיחוד‬ .‫האירופי או איחוד מדינות הים התיכון‬

Professeur Eric Seboun Attaché pour la Science et la Technologie

‫פרופסור אריק ֽסּבּון‬ ‫הנספח למדע וטכנולוגיה‬

4 « Le rôle du conseil est d’identifier les sujets pertinents pour la coopération entre les deux pays et de lancer de larges programmes de recherche en conséquence. »

Rabbin Pr. Daniel Hershkowitz, ministre israélien de la Science et de la Technologie

Daguesh Science n°

es relations scientifiques entre Israël et la France au niveau gouvernemental existent depuis 1958, lorsque fut signé l’accord culturel et scientifique entre les deux pays. Depuis 1985 les relations scientifiques ont connu un essor grâce à la création de l’AFIRST, qui a promu la réalisation de recherches communes entre scientifiques des deux pays. À l’initiative des chefs de gouvernement de l’époque – Jacques Chirac et Ariel Sharon – il fut décidé en 2004 d’établir le Haut Conseil Israël-France pour la Science et la Technologie. Le rôle du conseil est d’identifier les sujets pertinents pour la coopération entre les deux pays et de lancer de larges programmes de recherche en conséquence. Depuis le début de son activité et jusqu’à aujourd’hui, des programmes communs ont été réalisés dans les domaines suivants : la génétique humaine, l’imagerie médicale et biologique, l’agriculture durable, les mathématiques, la bio-informatique, l’astrophysique, les neurosciences et la neuro-robotique, la biophysique, la biologie structurale, les systèmes multi-informatiques, l’écologie, les énergies renouvelables, la gestion des ressources d’eau et la biologie complexe. Les deux pays allouent une somme d’un million de dollars par an aux programmes de recherche communs, programmes auxquels participentles scientifiques des deux pays les plus avancés dans leur domaine. Les Recherches communes ont engendré un grand nombre de publications scientifiques communes de premier ordre dans le monde. Le succès du travail bilatéral est un tremplin pour soumettre des propositions de projets communs pour le Programme Cadre de Recherche de l’Union européenne. Le Haut Conseil encourage également la tenue de conférences binationales dans des domaines de recherche choisis. Ces conférences donnent l’occasion aux scientifiques d’une meilleure connaissance mutuelle et de lancer des recherches communes, en mettant l’accent sur l’excellence scientifique et sur l’augmentation de la participation de jeunes chercheurs et de scientifiques femmes des deux pays. Nous considérons qu’il est important de cultiver la jeune génération de chercheurs talentueux dans les deux pays, et nous travaillons également pour le resserrement des liens à ce niveau. En mars de cette année, nous avons

organisé à Jérusalem une conférence pour les jeunes chercheurs de France et d’Israël boursiers du prestigieux Conseil Européen de la Recherche. Je suis convaincu que cette conférence a contribué à créer de nouvelles rencontres et à l’approfondissement des relations déjà établies, ainsi qu’à un élargissement significatif de la base sur laquelle repose la coopération scientifique entre la France et Israël. Les relations scientifiques entre Israël et la France se sont développées au fil des années et sont aujourd’hui parmi les plus avancées et les plus stables parmi les programmes de coopération internationale que mène le Ministère de la Science et de la Technologie. Je suis convaincu qu’elles contribueront également à approfondir la coopération régionale dans l’espace Méditerranéen, une coopération à la promotion de laquelle la France participe. Je tiens à féliciter l’heureuse initiative à l’origine de la publication de la présente brochure, qui résume les activités des cinq premières années d’activité du Haut Conseil pour la Science et la Technologie IsraëlFrance. Ces années reflètent l’amitié entre les deux pays tant au niveau des États qu’au niveau personnel – entre les scientifiques. Elles reflètent également l’excellente coopération avec les organismes de recherche nationaux français et l’Ambassade de France en Israël, qui œuvrent inlassablement afin de promouvoir les relations scientifiques bilatérales conjointement avec le Ministère de la Science et de la Technologie, et avec le Ministère israélien des Affaires Etrangères. Je souhaite voir se poursuivre cette fructueuse coopération entre les scientifiques de France et d’Israël pour l’intérêt mutuel des deux pays.

‫‪5‬‬

‫‪71‬‬

‫‪Daguesh Science‬‬ ‫‪n°‬‬

‫ק‬

‫שרי המדע בין ישראל לבין צרפת‬ ‫ברמה הממשלתית קיימים מאז שנת‬ ‫‪ ,1958‬כאשר נחתם הסכם התרבות‬ ‫והמדע בין שתי המדינות‪ .‬החל משנת ‪1985‬‬ ‫קיבלו קשרי המדע דחיפה כתוצאה מהקמת‬ ‫‪ ,AFIRST‬שקידמה ביצוע מחקרים משותפים‬ ‫בין המדענים משתי המדינות‪.‬‬

‫“ תפקידה של הוועדה העליונה הוא‬ ‫לזהות נושאים הרלבנטיים לשיתוף‬ ‫פעולה בין שתי המדינות וליזום‬ ‫תכניות מחקר גדולות בהתאם‪” .‬‬

‫הרב פרופ’ דניאל הרשקוביץ‪,‬‬ ‫שר המדע והטכנולוגיה‬

‫ביוזמת ראשי הממשלות דאז – ז'אק שיראק‬ ‫ואריאל שרון – הוחלט בשנת ‪ 2004‬על הקמת‬ ‫הוועדה העליונה הישראלית‪-‬צרפתית למחקר‬ ‫מדעי וטכנולוגי‪ .‬תפקידה של הוועדה העליונה‬ ‫הוא לזהות נושאים הרלבנטיים לשיתוף‬ ‫פעולה בין שתי המדינות וליזום תכניות מחקר‬ ‫גדולות בהתאם‪ .‬מתחילת פעולתה ועד היום‬ ‫בוצעו תכניות משותפות בתחומים‪ :‬גנטיקה‬ ‫אנושית‪ ,‬הדמיה רפואית וביולוגית‪ ,‬חקלאות‬ ‫בת‪-‬קיימא‪ ,‬מתמטיקה‪ ,‬ביו‪-‬אינפורמטיקה‪,‬‬ ‫אסטרופיזיקה‪ ,‬מדעי העצב ונוירו‪-‬רובוטיקה‪,‬‬ ‫ביופיזיקה‪ ,‬ביולוגיה מבנית‪ ,‬מערכות רב‪-‬‬ ‫חישוביות‪ ,‬איכות סביבה‪ ,‬אנרגיה חליפית‪,‬‬ ‫ניהול משאבי מים וביולוגיה מורכבת‪ .‬שתי‬ ‫המדינות מקצות סכום של מיליון דולר לשנה‬ ‫לתכניות המחקר המשותפות‪ ,‬בהן לוקחים‬ ‫חלק המדענים המובילים בתחומיהם בשתי‬ ‫המדינות‪ .‬המחקרים המשותפים הניבו מספר‬ ‫גדול של פרסומים משותפים בכתבי עת מדעיים‬ ‫מהשורה הראשונה בעולם‪ .‬הצלחת העבודה‬ ‫המשותפת ברמה הבילטראלית מהווה קרש‬ ‫קפיצה להגשת הצעות משותפות לתכניות‬ ‫המסגרת במו"פ של האיחוד האירופי‪.‬‬ ‫הוועדה העליונה מעודדת גם עריכתם של‬ ‫כנסים דו‪-‬לאומיים בתחומי מחקר נבחרים‪.‬‬ ‫כנסים אלה מעניקים הזדמנות להיכרות טובה‬ ‫יותר בין מדענים וליצירת בסיס למחקרים‬ ‫משותפים‪ ,‬כשהדגש הוא על מצוינות מדעית ועל‬ ‫הגדלת השתתפותם של חוקרים צעירים ונשים‬ ‫מדעניות משתי המדינות‪.‬‬ ‫חשוב לנו לטפח את הדור הצעיר של המדענים‬ ‫המוכשרים בשתי המדינות‪ ,‬ואנו פועלים‬ ‫להידוק הקשרים גם ברמה הזו‪ .‬במרץ השנה‬ ‫קיימנו בירושלים כנס למדענים הצעירים‬ ‫מצרפת ומישראל שזכו במלגות היוקרתיות‬ ‫של ה‪ .European Research Council -‬אני‬ ‫סמוך ובטוח שהכנס תרם ליצירת היכרויות‬ ‫חדשות‪ ,‬להעמקת היכרויות קיימות ולהרחבה‬ ‫משמעותית של הבסיס שעליו עומד שיתוף‬ ‫הפעולה המדעי בין צרפת לבין ישראל‪.‬‬ ‫קשרי המדע בין ישראל לבין צרפת הלכו והתרחבו‬ ‫במשך השנים‪ ,‬וכיום הם מהמתקדמים והיציבים‬ ‫ביותר בין תכניות שיתוף הפעולה הבינלאומיות‬ ‫שמוביל משרד המדע והטכנולוגיה‪.‬‬ ‫אני משוכנע שהם יתרמו גם להעמקת שיתוף‬ ‫הפעולה האזורי במרחב הים התיכון‪ ,‬שצרפת‬ ‫שותפה לקידומו‪.‬‬

‫אני מברך על היוזמה הברוכה להוצאת חוברת‬ ‫זו‪ ,‬המסכמת את חמש השנים הראשונות‬ ‫לפעילותה של הוועדה העליונה לקשרי מדע‬ ‫ישראל‪-‬צרפת‪ .‬שנים אלה משקפות את הידידות‬ ‫בין שתי המדינות הן ברמה הממלכתית והן‬ ‫ברמה האישית – בין המדענים‪ .‬הן משקפות‬ ‫גם את שיתוף הפעולה המעולה עם משרדי‬ ‫המחקר והחוץ הצרפתיים ועם שגרירות צרפת‬ ‫בישראל‪ ,‬הפועלים ללא הרף לקידום קשרי‬ ‫המדע הבילטראליים יחד עם משרד המדע‬ ‫והטכנולוגיה ומשרד החוץ בישראל‪ .‬אני מאחל‬ ‫המשך שיתוף פעולה פורה בין קהילות המדענים‬ ‫בצרפת ובישראל לתועלתן ההדדית של שתי‬ ‫המדינות‪.‬‬

Daguesh Science n°

« Le dernier médaillé Fields en 2006 figurait parmi les bénéficiaires de notre programme. »

Pr. Laurence Paye Jeanneney, co-présidente française du Haut Conseil pour la Science et la Technologie

a France est l’un des premiers partenaires scientifiques d’Israël, pays dont le nombre de chercheurs par habitant est l’un des plus élevé au monde. Notre coopération est très ancienne et s’est développée selon plusieurs volets : depuis 1984 et pendant 20 ans dans le cadre de l’Association Franco-Israélienne pour la Recherche Scientifique et Technologique (AFIRST) de nombreuses recherches ont été menées en commun entre des scientifiques des deux pays ; Parallèlement, divers programmes cofinancés comme le programme Arc-en-Ciel et les bourses Chateaubriand, ainsi que la présence dans des universités israéliennes de jeunes chercheurs français en tant que volontaires internationaux ont facilité la mobilité et les échanges de jeunes chercheurs ou de boursiers en formation. Enfin des projets de valorisation technologique et industrielle en partenariat avec le secteur privé ont été soutenus par l’association ARIEL. Sans aucun doute ces diverses actions ont permis la conduite d’excellentes recherches menées ensemble et souvent bien valorisées. Néanmoins cette coopération, quoique dense, souffrait de dispersion, manquait de visibilité et d’impulsion politique : c’est pourquoi en 2003 les deux gouvernements ont décidé d’un commun accord de créer le Haut Conseil pour la Recherche et la Coopération Scientifique et Technologique. Cette structure de pilotage conjoint a pour vocation de conduire notre coopération scientifique, sous la forme de programmes de recherche en réseau financés conjointement par les ministères des Affaires étrangères et de l’Enseignement supérieur et de la recherche. Le Haut conseil, avec un budget de 4 M € financés à parité par les 2 pays sur six ans (2004-2009), a mis en place, depuis sa création, 10 programmes, principalement dans les domaines de l’imagerie médicale et biologique, de la génétique médicale, des mathématiques, de l’agronomie et développement durable, de la bioinformatique, de l’astrophysique, des neurosciences et de la robotique, de la biophysique, de l’informatique,

de l’énergie et l’environnement, en biologie structurale et en biophysique. La qualité scientifique des équipes et des travaux ainsi conduits dans ces différents domaines est incontestable. Le dernier médaillé Fields en 2006 figurait parmi les bénéficiaires de notre programme. Les projets retenus ont impliqué pour chacun d’eux près d’une centaine de chercheurs. Certains ont permis l’élaboration de plusieurs logiciels informatiques et ont bénéficié d’un accès facilité au synchrotron « Soleil ». Ils devaient faciliter une transversalité et être aux frontières de la science et de la technologie. Depuis sa dernière réunion à Paris, le 29 juin 2009, deux nouveaux programmes ont été lancés pour 2010 et dédiés, l’un aux sciences de l’eau et au management des ressources aquatiques et l’autre à la complexité en biologie appliquée en particulier aux maladies infectieuses. Par ailleurs, conformément à la mission du Haut Conseil, des recherches liées à des développements industriels dans le domaine des énergies renouvelables pourraient également être financées et favoriser ainsi le volet technologique des recherches conduites en partenariat. Mais ceci implique, compte tenu des financements actuels, qu’une contribution complémentaire des ministères de l’industrie des deux pays soit accordée au Haut Conseil. Le soutien de ces 14 programmes de recherche ne constitue toutefois qu’une partie de la coopération initiée. Chaque année, plusieurs colloques scientifiques en Israël ou en France ont permis, soit de renforcer certaines coopérations, soit de permettre à de nouvelles équipes de se rencontrer ou de partager les résultats. Ainsi, à l’initiative du Haut Conseil, le premier symposium interdisciplinaire qui a réuni 28 lauréats du Conseil Européen de la Recherche s’est tenu, début mars 2010, à Jérusalem. Ainsi, sept ans après sa création, grâce notamment à l’impulsion du Pr. Hubert Curien et de Pr. Yuval Neeman, puis de Gilles Kahn, premier président français du Haut Conseil, malheureusement trop vite disparu, et du Pr.

Hillel Bercovier qui a été six ans le président israélien avant de passer cette année le flambeau au Pr. Henri Atlan, force est de constater que le Haut Conseil, constitue aujourd’hui une instance utile et permanente de dialogue et d’échanges. Elle a engendré et structuré des collaborations fortes, qui constituent des étapes importantes de la circulation des connaissances entre les deux communautés et permettent un travail en commun dans des domaines nouveaux. Le développement de la capacité de valorisation de la recherche, mise en œuvre par le partenaire israélien, souvent plus réactif que la partie française, demeure l’un des objectifs pour l’avenir.

‫‪7‬‬

‫‪71‬‬

‫‪Daguesh Science‬‬ ‫‪n°‬‬

‫“ חתן מדליית פילדס לשנת ‪ 2006‬האחרון היה בין מי שנהנו מתוכניתנו זו‪” .‬‬

‫פרופ’ לורנס פיי‪-‬ז’אננה‪ ,‬נשיאת הועדה העליונה מהצד הצרפתי‬

‫צ‬

‫רפת הינה אחד מן השותפים המדעיים‬ ‫הבכירים של ישראל‪ ,‬מדינה שבה‬ ‫מספר החוקרים לנפש הוא מן הגבוהים‬

‫בעולם‪.‬‬

‫שיתוף הפעולה בינינו קיים מזה שנים רבות‬ ‫והתפתח בכיוונים מספר‪ :‬מאז ‪ 1984‬ובמשך‬ ‫‪ 20‬שנה במסגרת האגודה הצרפתית ישראלית‬ ‫למחקר מדעי וטכנולוגי (פירסט)‪ ,‬נערכו‬ ‫מחקרים משותפים רבים בין מדעני שתי‬ ‫המדינות‪ .‬במקביל‪ ,‬מספר תוכניות במימון‬ ‫משותף כגון תוכנית “הקשת בענן” ומלגות‬ ‫שאטובריאן‪ ,‬וכן נוכחותם באוניברסיטאות‬ ‫ישראליות של חוקרים צרפתים צעירים בתור‬ ‫מתנדבים בינלאומיים עודדו את ניידותם ואת‬ ‫חילופי החוקרים הצעירים או בעלי המלגות‬ ‫בתקופת הכשרה‪ .‬לבסוף‪ ,‬זכו לתמיכתה של‬ ‫עמותת אריאל פרויקטים למסחור טכנולוגי‬ ‫ותעשייתי שנעשו בשיתוף עם המגזר הפרטי‪.‬‬ ‫אין כל ספק כי פעולות שונות אלה אפשרו את‬ ‫עריכתם של מחקרים מצויינים המנוהלים ביחד‬ ‫ולעיתים קרובות ממוסחרים כראוי‪.‬‬

‫לעודד טרנסוורסאליות ולנשוק לגבול בין מדע‬ ‫לבין טכנולוגיה‪.‬‬ ‫מאז כינוסה האחרון בפריס ב‪ 29-‬ביוני ‪,2009‬‬ ‫הושקו שתי תוכניות חדשות לשנת ‪ 2010‬והן‬ ‫מוקדשות‪ ,‬האחת‪ ,‬למדעי המיים וניהול משאבי‬ ‫המים‪ ,‬והשניה למורכבות בביולוגיה המיושמת‬ ‫בפרט על מחלות זיהומיות‪ .‬חוץ מזה‪ ,‬בהתאם‬ ‫ליעודה של המועצה העליונה‪ ,‬ייתכן כי בקרוב‬ ‫ימומנו גם מחקרים הקשורים לפיתוחים‬ ‫תעשייתיים בתחום האנרגיות המתחדשות‬ ‫ויש בהם כדי לעודד את הפן הטכנולוגי של‬ ‫המחקרים המתנהלים בשותפות‪ .‬עם זאת‪,‬‬ ‫הדבר מחייב‪ ,‬בהתחשב במימונים הקיימים‪ ,‬כי‬ ‫תוענק למועצה בידי משרדי התעשיה של שתי‬ ‫המדינות תרומה נוספת‪.‬‬ ‫התמיכה ב‪ 10-‬תוכניות מחקר אלו מהווה‬ ‫עם זאת רק חלק משיתוף הפעולה בו הוחל‬ ‫אז‪ .‬מספר רבי שיח מדעיים בישראל ובצרפת‬ ‫המתקיימים מדי שנה‪ ,‬אפשרו את חיזוקם‬

‫יחד עם זאת‪ ,‬שיתוף הפעולה‪ ,‬על אף היותו‬ ‫הדוק‪ ,‬סבל מפיזור‪ ,‬היה חסר ניראות ונעדר‬ ‫ממנו כוח פוליטי שידחוף אותו‪ :‬זאת הסיבה‬ ‫שבגללה בשנת ‪ 2003‬שתי הממשלות החליטו‬ ‫בעצה אחת להקים את המועצה העליונה למחקר‬ ‫ולשיתוף פעולה מדעי וטכנולוגי‪ .‬יעודו של גוף‬ ‫מנחה משותף זה הוא לנהל את שיתוף הפעולה‬ ‫המדעי בינינו‪ ,‬בצורה של תוכניות מחקר ברשת‬ ‫הממומנות במשותף ע”י משרד החוץ והמשרד‬ ‫להשכלה הגבוהה ולמחקר‪.‬‬ ‫המועצה העליונה‪ ,‬שברשותה תקציב של ‪4‬‬ ‫מיליון אירו‪ ,‬המתחלקים בשווה בין שתי‬ ‫המדינות לאורך תקופה של שש שנים (‪2004-‬‬ ‫‪ )2009‬הקימה מאז הקמתה ‪ 10‬תוכניות‪ ,‬בעיקר‬ ‫בתחומי הדימות הרפואי והביולוגי‪ ,‬בגנטיקה‬ ‫רפואית‪ ,‬במתמטיקה‪ ,‬בחקלאות ובפיתוח בר‬ ‫קיימא‪ ,‬בביו‪-‬מחשוב‪ ,‬באסטרופיסיקה‪ ,‬במדעי‬ ‫מערכת העצבים והרובוטיקה‪ ,‬בביופיסיקה‪,‬‬ ‫במחשבים‪ ,‬באנרגיה ובסביבה‪ ,‬בביולוגייה‬ ‫מבנית ובביופיסיקה‪ .‬איכותם המדעית של‬ ‫הצוותים ושל המחקרים שנערכו בתחומים‬ ‫השונים מדברת בעד עצמה‪ .‬חתן מדליית פילדס‬ ‫לשנת ‪ 2006‬האחרון היה בין מי שנהנו מתוכניתנו‬ ‫זו‪ .‬בכל אחד מן המיזמים שנבחרו היו מעורבים‬ ‫כמאה חוקרים‪ .‬חלקם איפשרו את פיתוחן של‬ ‫מספר תוכנות מחשב וזכו להקלה בגישה למאיץ‬ ‫החקלקים סינכרוטרון “השמש”‪ .‬היה בהם כדי‬

‫של כמה שיתופי פעולה‪ ,‬או שאפשרו לצוותים‬ ‫נוספים להיפגש ולהתחלק בתוצאות מחקריהן‪.‬‬ ‫כך‪ ,‬ביוזמתה של המועצה העליונה‪ ,‬התקיים‬ ‫בירושלים בתחילת מרס ‪ 2010‬הסימפוזיון‬ ‫הבין תחומי הראשון שכינס יחדיו ‪ 28‬חתני פרס‬ ‫המועצה האירופית למדע‪.‬‬ ‫אם כן‪ ,‬שבע שנים אחרי הקמתה‪ ,‬ותודות לדחיפה‬ ‫שנתנו לה פרופ’ הובר קוריין ופרופ’ יובל נאמן‪,‬‬

‫ואחריהם ז’יל קאן ז”ל‪ ,‬שהיה נשיאה הראשון‬ ‫של המועצה העליונה‪ ,‬ונלקח מאיתנו בטרם‬ ‫עת‪ ,‬ופרופ’ הלל ברקוביה‪ ,‬שהיה במשך שש‬ ‫שנים נשיאה הישראלי לפני שהעביר השנה את‬ ‫השבריט לפרופ’ אנרי אטלן‪ ,‬עלינו רק להווכח‬ ‫בכך שהמועצה העליונה מהווה היום מוסד יעיל‬ ‫וקבוע לדו‪-‬שיח ולחילופי רעיונות‪ .‬היא הולידה‬ ‫ועיצבה שיתופי פעולה איתנים‪ ,‬המהווים שלבים‬ ‫חשובים לתזרים המידע בין שתי הקהיליות‬ ‫ומאפשרים שיתופי פעולה בתחומים חדשים‪.‬‬ ‫פיתוח יכולת מסחור המחקר‪ ,‬שאותה הדגים‬ ‫השותף הישראלי‪ ,‬שהוא לעיתים קרובות זריז‬ ‫יותר בתגובתו מן הצד הצרפתי‪ ,‬נותר אחת מן‬ ‫המטרות לעתיד‪.‬‬

Daguesh Science n°

a coopération scientifique France-Israël remonte à l’origine de la création de l’état d’Israël. En effet dès sa création, une grande sympathie fut établie entre la France et Israël se traduisant par de larges échanges dans tous les domaines. Qu’en estil aujourd’hui ? La coopération France-Israël peut être quantifiée par une recherche rapide sur Google. En effet si l’on tape ces mots clés on trouve 800,000 entrées pour la coopération USA-Israël, 347,000 pour Allemagne-Israël et 230,000 pour France-Israël loin devant tous les autres pays européens (UK-Israël 230,000, Italie-Israël 180,000).

« La France est le 3ème partenaire d’Israël en matière de coopération scientifique après les Etats-Unis et l’Allemagne. »

Pr. Hillel Bercovier, coprésident du Haut Conseil pour la Science et la Technologie (2003-2009)

En termes de co-publications, Israël est le 14ème partenaire de la France dans l’Espace Européen de la Recherche (EER). Environ 51% des Co-publications franco-israéliennes sont produites par des unités de recherche affiliées au CNRS, principalement en physique (17%), biologie fondamentale (11%), chimie (7%) et mathématiques (7%). La France est le 3ème partenaire d’Israël en matière de coopération scientifique après les Etats-Unis et l’Allemagne. Cette coopération réelle reflète aussi une réalité économique. Selon les chiffres du Service israélien des Douanes, la France en 2009 était le 7ème client d’Israël (2,3% de ses exportations) derrière les Etats-Unis, la Hollande, l’Allemagne, l’Angleterre, l’Inde et la Turquie. En sens inverse, la France était le 9ème fournisseur de marchandises d’Israël avec une part de marché de 3%, derrière les Etats-Unis, la Chine, l’Allemagne, la Suisse, l’Italie, la Hollande, le Japon et l’Angleterre. Et pour être sur d’être objectif dans notre évaluation, il suffit de regarder les sites internet des groupes les plus critiques envers Israël ou nous pouvons lire, je cite, “ Bien que certaines des positions prises par l’Etat français au cours des cinquante dernières années puissent lui donner l’image pro-palestinienne et pro-arabe en général, la France a toujours représenté un soutien de poids pour l’Etat d’Israël ” et de conclure : “ Le couple franco-israélien est solide et les partenariats étroits et fructueux.” (http://www.enfantsdepalestine.org/ar,570). Depuis 2004, le haut conseil pour la coopération scientifique a développé une politique de coopération fondée sur l’excellence. Les sujets des appels d’offres de recherche ont toujours été choisis en fonction d’un seul critère :

l’excellence dans les domaines spécifiques choisis des deux pays. Les moyens financiers de cette coopération étant limités, pour ne pas dire très limités, il a fallu favoriser les domaines de pointe uniquement. Le succès de cette initiative, en dehors des sujets choisis, revient aux comites scientifiques “ ad hoc ” de haute qualité qui ont été responsables du choix final des projets soumis. La coopération scientifique France-Israël n’est pas limitée à l’activité du Haut conseil. En effet les programmes comme le Centre de Recherche Français de Jérusalem (Le CRFJ est le plus ancien établissement du CNRS à l’étranger en 1963), unité de service et de recherche du CNRS en partenariat avec le ministère des Affaires étrangères et européennes, l’accord Pasteur Weizmann, les Laboratoires Européens associés au CNRS (Laboratoire Franco-Israélien en Neurosciences – (FILN) à l’Université Hébraïque de Jérusalem, Nano-Bio Science – (NaBi) avec l’Institut Weizmann) montrent un environnement riche de coopération scientifique. Toutefois, ces initiatives un peu trop saupoudrées, mériteraient d’être cristallisées dans une fondation richement dotée (à l’exemple de l’Allemagne et des USA) qui pourrait favoriser la coopération scientifique dans tous les domaines scientifiques y compris les sciences humaines et sociales et ce indépendamment des situations économiques ou politiques.

‫‪9‬‬ ‫“ צרפת היא שותפתה השלישית‬ ‫של ישראל בתחום שיתוף הפעולה‬ ‫המדעי אחרי ארצות הברית‬ ‫וגרמניה‪” .‬‬

‫פרופ’ הלל ברקוביה‪ -‬נשיא‬ ‫הועדה העליונה למדע‬ ‫וטכנולוגיה מהצד הישראלי‬ ‫(‪)2003- 2009‬‬

‫‪71‬‬

‫‪Daguesh Science‬‬ ‫‪n°‬‬

‫ש‬

‫יתוף הפעולה המדעי בין צרפת‬ ‫לישראל החל כבר בעת הקמתה‬ ‫של מדינת ישראל‪ .‬הרי שכבר בעת‬ ‫הקמתה‪ ,‬נוצרה סימפתיה גדולה בין צרפת לבין‬ ‫ישראל‪ ,‬דבר שהתבטא ביחסי גומלין נרחבים‬ ‫בכל התחומים‪ .‬מהו המצב כיום?‬

‫מוגבלים ביותר‪ ,‬מכאן שנהיה צורך להעדיף‬ ‫את התחומים המובילים בלבד‪ .‬את ההצלחה‬ ‫שזכתה בה יוזמה זו‪ ,‬בנוסף לנושאים שנבחרו‪,‬‬ ‫ניתן לזקוף לזכותן של הוועדות המדעיות “אד‬ ‫הוק” ברמה גבוהה שהיו אמונות על הבחירה‬ ‫הסופית של הנושאים שהוגשו‪.‬‬

‫את שיתוף הפעולה בין צרפת לישראל ניתן‬ ‫לכמת בעזרת חיפוש מהיר בגוגל‪ .‬למעשה‪ ,‬אם‬ ‫תקלידו את מילות המפתח האלה‪ ,‬יימצאו‬ ‫‪ 800,000‬תוצאות עבור שיתוף הפעולה בין‬ ‫ארצות הברית לישראל‪ 347,000 ,‬לגבי שיתוף‬ ‫הפעולה בין גרמניה לישראל ו‪ 230,000 -‬עבור‬ ‫שיתוף הפעולה בין צרפת לישראל‪ ,‬הרבה לפני‬ ‫שאר כל מדינות אירופה (בין בריטניה לישראל‬ ‫‪ - 230,000‬בין איטליה לישראל ‪.)180,000‬‬

‫שיתוף הפעולה בין צרפת לישראל אינו מוגבל‬ ‫אך ורק לפעילותה של המועצה העליונה‪ .‬על‬ ‫כך מעידות למשל תוכניות כגון אלו של המרכז‬ ‫הצרפתי למחקר שבירושלים (הוא המוסד‬ ‫הוותיק ביותר של המכון הלאומי למחקר‬ ‫מדעי של צרפת מחוץ לארץ זו משנת ‪,)1963‬‬ ‫שהיא יחידת השירות והמחקר של המכון‬ ‫הלאומי למחקר מדעי בשיתוף עם המשרד‬ ‫לענייני חוץ ולעינייני אירופה‪ ,‬וההסכם בין‬ ‫המכונים פאסטור וויצמן‪ ,‬המעבדות האירופיות‬ ‫השותפות למכון הלאומי למחקר מדעי (המעבדה‬ ‫הצרפתית ישראלית במדעי מערכת העצבים‬ ‫(‪ )FILN‬שבאוניברסיטה העברית בירושלים‪,‬‬ ‫ותוכנית (‪ ) NaBI‬נָאבי הוא ננו ביו מדע עם‬ ‫מכון וויצמן) החושפות סביבה עשירה בשיתופי‬ ‫פעולה מדעים‪.‬‬

‫במונחים של פרסומים משותפים‪ ,‬ישראל‬ ‫היא במקום הארבע עשר בשיתופים עם צרפת‬ ‫במסגרת המרחב האירופי למחקר‪ .‬כ‪51%-‬‬ ‫מן הפרסומים המשותפים בין צרפת לישראל‬ ‫מופקים בידי יחידות מחקר המסונפות למכון‬ ‫הלאומי למחקר מדעי של צרפת בעיקר בתחומי‬ ‫הפיסיקה (‪ ,)17%‬הביולוגיה העיונית (‪,)11%‬‬ ‫הכימיה (‪ )7%‬והמתמטיקה (‪ .)7%‬צרפת היא‬ ‫שותפתה השלישית של ישראל בתחום שיתוף‬ ‫הפעולה המדעי אחרי ארצות הברית וגרמניה‪.‬‬ ‫שיתוף פעולה ממשי זה משקף גם מציאות‬ ‫כלכלית‪ .‬על סמך מספרים מטעם רשות המכס‬ ‫הישראלית‪ ,‬בשנת ‪ ,2009‬צרפת הייתה במקום‬ ‫ה‪ 7-‬בין לקוחותיה של ישראל (‪ 2,3%‬מן הייצוא)‬ ‫אחרי ארצות הברית‪ ,‬הולנד‪ ,‬גרמניה‪ ,‬אנגליה‪,‬‬ ‫הודו וטורקיה‪ .‬בכיוון ההפוך‪ ,‬צרפת הייתה‬ ‫הספקית התשיעית של סחורות לישראל עם‬ ‫פלח של ‪ 3%‬מן השוק‪ ,‬מאחורי ארצות הברית‪,‬‬ ‫סין‪ ,‬גרמניה‪ ,‬שוויץ‪ ,‬הולנד‪ ,‬יפן ואנגליה‪.‬‬ ‫על מנת שנהיה בטוחים באובייקטיביות של‬ ‫הערכתנו‪ ,‬די בכך שנצפה באתרי האינטרנט של‬ ‫הקבוצות הביקורתיות ביותר ביחס לישראל‪,‬‬ ‫שם נוכל לקרוא‪ ,‬בין השאר כי ‪“ :‬למרות‬ ‫העובדה שחלק מן העמדות שבהן נקטה צרפת‬ ‫כמדינה במהלך חמישים השנים שחלפו‪ ,‬יש בהן‬ ‫כדי ליצור רושם שהיא פרו‪-‬פלסטינאית ופרו‪-‬‬ ‫ערבית בכלל; למעשה‪ ,‬צרפת תמיד הדגימה‬ ‫תמיכה נכבדת במדינת ישראל והאתר מסכם‬ ‫כך‪ “ :‬הזוג הצרפתי‪-‬ישראלי הינו זוג איתן‬ ‫ושיתופי הפעולה הדוקים ופורים” ‪http://‬‬ ‫‪www.enfantsdepalestine.org/ar,570‬‬ ‫מאז שנת ‪ ,2004‬המועצה העליונה לשיתוף‬ ‫הפעולה פיתחה מדיניות של שיתוף פעולה‬ ‫המבוססת על מצויינות‪ .‬נושאי המכרזים‬ ‫בתחום המחקר תמיד נבחרו בכפוף לקריטריון‬ ‫אחד בלבד‪ :‬המצוינות המדעית בתחומים‬ ‫הספציפיים שנבחרו בידי שתי המדינות‪.‬‬ ‫האמצעים הכספיים המועמדים לרשות שיתוף‬ ‫הפעולה האמור מוגבלים‪ ,‬ואף ניתן לאמר‬

‫יחד עם זאת‪ ,‬ראוי שיוזמות אלו הסובלות‬ ‫מפיזור יתר‪ ,‬תגובשנה במסגרתה של קרן אשר‬ ‫תזכה לנדוניה נדיבה (לדוגמת גרמניה וארצות‪-‬‬ ‫הברית) שיש בה כדי לעודד שיתוף פעולה מדעי‬ ‫בכל תחומי המחקר‪ ,‬כולל מדעי הרוח והחברה‪,‬‬ ‫וזאת ללא קשר עם הנסיבות הכלכליות או‬ ‫המדיניות‪.‬‬

Human Genetics (2005-2007)

Daguesh Science n°

The Involvment of Nuclear Envelope Proteins and TBCE in HRD Syndrome and Autosomal Recessive Laminopathies Prof. Ruti Parvari - PI (Ben-Gurion University), Israel Prof. Nicolas Levy - PI (INSERM UMR 910), France

he research had a large scope: elucidating the effect of mutations identified by the groups on cellular function, collecting families affected by severe genetic diseases and identifying the causing mutations. The following are the goals put forward in this project and their results: 1. Span the bridge between basic research and clinical research, integrating a detailed analysis of patient material and clinical phenotype with the analysis of lamin and microtubular cytoskeleton in cell culture. Mutations in genes that encode essential proteins for the nuclear and cytoplasm skeletons assemblies leading to devastating diseases (Figure) were identified by the French and Israeli groups, respectively. We wanted to explore the effect of each of the mutations on the structure of the cellular components. Fibroblasts from a French patient with muscle diseases and a defined mutation, were shared with the Israeli group. The research contributed to the elucidation of microtubular cytoskeleton defects and a paper was published (Delague et al., 2007). Fibroblasts of patients with mutations causing laminopathies were tested for tubulin distribution by immunohistochemistry. Specifically two types of fibroblasts: LMNA (two mutations: one in LMNA the R289C and one in EMD the DelK37) and FACE1 (a Thymin insertion in exon 9 leading to a loss of expression of the Zmptse24 enzyme that processes the conversion of prelamin A precursor into lamin A). No considerable differences were found in tubulin structure or in its amounts and distribution in the cells comparatively to control fibroblasts. Fibroblasts of patients with Hypoparathiroid-Retardation and Dismorphism (HRD) with mutations in the tubulin cofactor (TBCE) showed no disturbance of the nuclear lamina by immunohistochemistry. Thus, a major defect in one cellular compartment

does not seem to specifically affect the other compartment. 2. Screen for genes involved in the structure of the nuclear envelope and lamina, the nuclear matrix and the processing of type-A and B Lamins. We have identified nuclear localization of TBCE by immunohistochemistry using a purified antibody. This finding was supported by subcellular fractionation and Western blot analysis. Moreover, immunoprecipitation and pull down assays indicate direct interactions between TBCE and lamin A. Several nuclear proteins were suggested by yeast two hybrid experiments to interact with TBCE, additional protein-protein interactions with nuclear proteins are highly suggestive by bioinformatics studies. These studies are ongoing. 3. Collect, essentially from endogamic populations in Israel, and to study patients issued from consanguineous unions, who are potentially affected with autosomal recessive (AR) laminopathies. Three families of Bedouins of the Negev, one with merosine positive muscular dystrophy, the second with limb girdle muscular dystrophy LGMD) and the third with CMT and Neurofibromatosis, were collected and DNAs of affected shared with the French group to identify the mutated gene. In two of the families, the LGMD family and the family with CMT and Neurofibromatosis the mutations were identified and proven not to be novel. The merosine positive muscular dystrophy was further tested for the most common genes encoding extra-cellular matrix proteins which were excluded as carrying disease causing mutations. This family, as well as additional identified families in the Israeli and French groups are now further evaluated at the genomic level. Such explorations take

Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H. Delague V, Jacquier A, Hamadouche T, Poitelon Y, Baudot C, Boccaccio I, Chouery E, Chaouch M,

advantage of the high throughput technologies that are now available in the French group (gene specific CGH and sequence capture Chips followed by massive sequencing) through a specific European project dedicated to the exhaustive identification of genes and mutations in Neuromuscular disorders (FP7NMDChip). The collaboration between the 2 groups led to major exchanges. Several meetings have been organised in Israel and France towards advancing on the collaboration between these groups and further maintaining the partnership in the future. In a united effort, this fruitful collaboration that was established between our groups will undoubtedly lead to : 1- the publication of the cellular findings related to nuclear functions of TBCE (coordinated by R. Parvari); 2The identification of genetics causes and mechanisms involved in autosomal recessive (neuromuscular) diseases (coordinated by R. Parvari and N. Lévy). NB : In addition to the fruitful and continuing partnership between the Israeli and French groups, other collaborations and exchanges have emerged between partners involved in different funded projects the Franco-Israeli program and further led to initially unplanned projects. In particular, a collaboration between Aaron Bensimon and Nicolas Lévy (who first met during the 1st meeting in PetachTiqvah) led to the development of a novel and patented exploration tool for patients affected with Facio-scapulo-humeral dystrophy, and based on Molecular Combing of single DNA molecules. This approach intends to become the gold standard for molecular explorations in FSHD worldwide.

Kassouri N, Jabbour R, Grid D, Mégarbané A, Haase G, Lévy N. Am J Hum Genet. 2007 Jul;81(1):1-16. Epub 2007 May 15.

Daguesh Science n°

Search for Altered Nuclear Genes in Patients with Impaired Synthesis of Mitochondrial DNA-Encoded Proteins Dr. Anne Lombès - PI, Dr. Manuel Rojo (INSERM UMR 582), Dr. Robert Martin & Dr. Yvan Tarassov (CNRS UMR 2375), France Dr. Orly Elpeleg - PI, Dr. Ann Saada, Dr. Avraham Shaag (Hadassah, The Hebrew University of Jerusalem), Israel by the previous molecular analyses and, when possible, by linkage analysis. Over the two years of the study, we shared techniques, molecular tools and samples, and identified several genetic alterations responsible for defects of mitochondrial protein synthesis. In two cases, the involved gene had not been previously reported as a disease-causing gene.

hirteen of the mitochondrial respiratory chain (MRC) proteins are encoded in mitochondrial DNA (mtDNA). Most of the factors that are required for their synthesis, including those involved in the replication, transcription and translation of mtDNA, are encoded in the nuclear DNA. Defects in these factors resulting in impaired synthesis of mitochondrial-encoded proteins were the subject of this study. The objective was to identify the genes involved in disorders of mtDNA replication and protein synthesis. To this end, patients with combined MRC defects were screened for putative replication, transcription or translation defects with complementary analyses, which included: 1. Determination of the amount of mtDNA. 2. Analysis of the sequence of mtDNA genes relevant to its replication, transcription and translation. 3. Evaluation of mtDNA transcription and translation products. 4. Study of mitochondrial nucleoids. 5. In proven defects of mtDNA translation and in the absence of a causal mtDNA alteration, study of the mitochondrial tRNAs aminoacylation; and 6. Analysis of nuclear genes designated

J Med Genet. 2007 Dec; 44(12):784-6. Epub 2007 Sep 14. Antenatal mitochon¬drial disease caused by mitochondrial ribosomal protein (MRPS22) mutation. Saada A, Shaag A, Arnon S, Dolfin T, Miller C, Fuchs-Telem D, Lombes A, Elpeleg O. Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Edvardson S, Shaag A,

The binational nature of the project allowed intensive exchange of knowledge and methods. There is no doubt that without the setting up of the real-time PCR method for the analysis of transcriptional steady-state in cultured fibroblasts we would never have identified the disease-causing gene in family AK. The disease was linked to a 50 Mb region in this family, which is far too large for prenatal diagnosis. The finding will not only help the family, but has also unraveled a novel protein essential for the stability of the small ribosomal subunit. There remains much to be done. The finding of a specific pattern of alteration in transcripts levels, translation profile, histochemical and nucleoid appearance will help to group patients and improve efficiency of linkage analysis. Several mutations in mtDNA have been found, the deleterious potential of which remains dubious despite intensive investigation. Mutations in tRNA genes in particular will be assessed in depth with the methods newly set up in the Strasburg laboratory.

Kolesnikova O, Gomori JM, Tarassov I, Einbinder T, Saada A, Elpeleg O. Am J Hum Genet. 2007 Oct;81(4):857-62. Acute infantile liver failure due to mutations in the TRMU gene. Zeharia A, 3. Shaag A, Pappo O, Mager-Heckel AM, Saada A, Beinat M, Karicheva O, Man¬del H, Ofek N, Segel R, Marom D, Rötig A, Tarassov I, Elpeleg O. Am J Hum Genet. 2009 Sep;85(3):401-7.

Human Genetics (2005-2007)

Brain MRI of a patient with pontocerebellar hypoplasia, in whom a deleterious mutation in the mitochondrial arginyl–transfer RNA synthetase gene was found.

The objective of this project was the identification of the genes involved in disorders of mtDNA replication and protein synthesis. This was accomplished with the identification of six nuclear genes with the additional input of molecular investigation and linkage analysis.

Human Genetics (2005-2007)

Daguesh Science n°

Replication dynamic and chromosomal instability in the human genome Prof. Batsheva Kerem - PI (The Hebrew University of Jerusalem), Israel Dr. Aaron Bensimon - PI (Institut Pasteur), France

he aims of this project was to investigate the possibility that under conditions that perturbed DNA replication, specific chromosomal regions in the human genome, defined as fragile sites, fail to accomplish replication, and thus are preferentially prone to chromosomal instability. In this study we used a high-resolution DNA combing technique, developed at the Pasteur Institute. This method combines major technical developments of molecular combing generating evenly stretched DNA molecules, with fluorescent hybridization, and enables for the first time, cytogenetic analysis of single DNA molecules, in the resolution of few kb. The analysis along 2 fragile regions included: 1. mapping of origins and terminations of replication 2. visualization of fork progression and 3. mapping of sequences that perturb the replication elongation. 1. Enrichment of replication fibers. One limiting factor of the single molecule replication analysis at specific locus is the number of fibers showing both the replication labeling and the “Genomic Morse Code” FISH signals. To overcome this difficulty, we developed a protocol to enrich the samples with such molecules by sorting of cells in S-phase following replication labeling. In this procedure, asynchronous cells were labeled by IdU (detected by green fluorescence) and CldU (detected by red fluorescence) as in the original protocol. Following this step, the cells were fixed and sorted by FACS. S-phase cells were collected and further used for DNA preparation. As shown in Fig. 2, the density of fibers is simmilar between DNA preparations before and following the sorting as evident by the YOYO stain. However, the number of replication signals that can be detected following sorting is much higher (compare right upper and lower pannels). This step significantly improved our ability to scan and collect single molecules of interest.

2. The effect of aphidicolin on replication progression. As a first step to investigate the effect of aphidicolin (0.4μM for 24h) on the global genome replication, cells were grown and labeled with IdU and CldU, in the absence or presence of aphidicolin. Following 20 minutes with each nucleotide after replication stress, the replication signals were very short in comparission to signals under normal growth conditions, representing the effect of aphidicolin on the global replication progression (Fig. 3). Since these signals were too short to be measured, we had to extend the pulses of replication labeling to 90min with each nucleotide. We found that the replication rate under normal growth conditions is 1.9 ± 0.08Kb/min and in the presence of 0.4μM aphidicolin is only 0.26±0.01Kb/min. Hence, under replication stress, which induces fragile site expression, Replication forks are around 7 times slower.

Prof. Batsheva Kerem

3. Replication pattern at FRA16C under normal conditions. Currently, we have preliminary results for the replication pattern at FRA16C from cells grown under normal growth conditions. The replication pattern (origin and termination positions) was analyzed only when the

replication signals denoting initiation or termination co-localized with a decodable set of probes. Figure 5 presents the analysis of 21 molecules: a. Origins of replication: : 21 origins of replication, scattered along the region (long white arrows on the upper part of Fig. 5), were found. We found six regions in which origin firing clustered in a region of up to 10Kb (white boxes in Fig. 5). Some of these regions may indicate replication zones. As reported recently by the laboratory of Bensimon [Lebofsky et al., (2006) 17; 5337-5345], replication zones are defined for clusters of three or more initiation events. Under this restriction, the zones vary in size (2.6 -21.6kb) and inter-zone distances (14.3Kb-93.1Kb). At this early stage of our data collection at FRA16C, from the six potential zones indicated in Fig. 5, only one is composed of more than two initiation sites. Hence, we must collect more data in order to determine if the firing pattern in fragile sites is different from that in non fragile regions. In 4/21 analyzed molecules, we detected more than one origin that fired on the same molecule (see molecules 68, 3, 95 and 126, Fig. 6 and Fig. 5). The appearance of multiple initiations on the same fiber allows the analysis of inter - origin distances . The distance between two functional origins varied between 65Kb and 420Kb (Fig. 6A). The inter-origin distance reported recently for chromosome 14q11.2, revealed between 31.4Kb and 390Kb. In addition, in FRA16C, we found some long fibers which showed only one active origin in a ~600Kb (see molecules 110 and 333, Fig. 6B) were found. This phenomenon was not reported for the 1.5Mb region analyzed at chromosome 14. Although the results are very preliminary, they might suggest that that fragile sites are enriched in long distances between active origins. In the proposed research, we will further investigate the pattern of adjacent active origins, and the potential of this pattern to contribute to the specific sensitivity of fragile sites to replication perturbation.

Kassouri N, Jabbour R, Grid D, Mégarbané A, Haase G, Lévy N. Am J Hum Genet. 2007 Jul;81(1):1-16. Epub 2007 May 15.

Daguesh Science n°

Novel Genes From Wild Emmer Wheat for Improving Yield and Sustainability Under Water-Limited Agriculture Prof. Tamar Krugman - PI, Prof. Tzion Fahima, Prof. Abraham B. Korol (University of Haifa), Dr. Yehoshua Saranga, Dr. Zvi Peleg (The Hebrew University of Jerusalem), Israel Prof. Véronique Chagué - PI, Prof. Boulos Chalhoub (INRA - DR2), France

Wild emmer wheat (Triticum dicoccoides), the ancestor of domesticated wheat, has been found to harbour wide genetic diversity for various agronomic traits, including drought tolerance (Nevo et al. 2002; Peleg et al. 2005, 2007). The main objective of our collaborative project was to explore the potential of wild emmer wheat as a source of novel genes for improving drought resistance in domesticated wheat. The approach applied in this study relies primarily on the hypothesis that genes that are differentially regulated in response to drought in a drought-resistant genotype as compared to a sensitive genotype are likely to be associated with drought resistance. These genes are therefore regarded as candidate genes for improving drought resistance in wheat. A whole genome comparative expression approach was used to provide insight into the molecular networks that are involved in adaptation to drought, and to identify drought-resistance candidate genes for crop improvement.

•

Remarkable differences were identified in gene expression between the drought-resistant (R) and drought-susceptible (S) genotypes that were characterized by a burst of gene activity, mainly in the R genotype, in leaves (Krugman et al. 2010a) and roots (Krugman et al. 2010b) of these plants. Towards candidate gene discovery we identified a set of 200 genes in leaves and 120 genes

Wild emmer wheat (Triticum dicoccoides) – a promising source for improving yield and sustainability of wheat under waterlimited agriculture

in roots that were uniquely expressed in the drought resistant genotype in response to drought. Interestingly, 26% of these leaf genes and 43 % of the root genes were involved in multilevel regulation and endogenous signalling. Additional genes were indicated as involved in cell wall adjustment, cuticular wax deposition, lignification, sugar metabolism, osmoregulation, cell homeostasis, and dehydration protection. These mechanisms are known to enable plants to withstand unpredictable environmental fluctuations. The results of our study are expected to facilitate

Krugman T, Chagué V, Peleg Z, Just J, Korol AB, Nevo E, Saranga Y, Chal¬houb B, and Fahima T (2010) Multilevel Regulation and Signalling Processes Associated with Adaptation to Terminal Drought in Wild Emmer Wheat. Func¬tional and Integrative Genomics DOI: 10.1007/s10142-010-0166-3. Krugman T, Peleg Z, Chagué V, Just J, Korol AB, Nevo E, Saranga Y, Chal¬houb B, and Fahima T (2010) Phytohotmones Signalling and Multilevel

•

the breeding of novel drought-resistant wheat cultivars as well as other crops and enhance their yield and sustainability under drought conditions, with a particular relevance to Mediterranean-like environments. These future cultivars are expected to reduce the year-to-year yield fluctuations typical to drought-prone regions, and by that contribute to the economical stability and food security as well as to the sustainability of agricultural production and rural communities in these regions. The current cooperative research was carried out by three research groups, two from Israel and one from France. The expertise of the various groups in plant physiology, structural and functional genomics and bioinformatics was synergistically integrated. The close collaboration between the Israeli and the French groups is demonstrated by numerous scientific visits, meetings and training. The project results were presented in several international conferences and published in scientific journals (Krugman et al. 2010a; Krugman et al. 2010b). The main investigators of the current project participate in a European BIOEXPLOIT consortium funded by the sixth framework program (FP6) aiming at exploiting natural plant biodiversity for the pesticidefree production of food. Additionally, the PIs are members of the European network for the Triticeae genomics for the advancement of essential European crops (COST Action FA0604 Tritigen).

Re¬gulation as Major Components of Roots Drought Adaptation in Wild Emmer Wheat (in preparation). Nevo E, Korol AB, Beiles A, Fahima T (2002) Evolution of Wild Emmer and Wheat Improvement: Population Genetics, Genetic Resources and Genome Organization of Wheat’s Progenitor, Triticum dicoccoides. Springer Heidel¬berg.

Sustainable Agronomy (2005-2007)

ow water availability is the major environmental factor limiting crop productivity and agricultural sustainability. This problem is expected to grow with the projected global climatic change and the rise in food demand for the world’s increasing population. Developing genetically droughtresistant crop plants is a major strategy for alleviating future threats to food security. This solution, however, requires a comprehensive exploration of potential genetic resources and an in-depth understanding of their adaptive mechanisms and response to water stress. Drought resistance is a complex trait as it encompasses a wide range of characteristics involving multiple genetic, physiological, cellular and biochemical strategies in the plant.

Sustainable Agronomy (2005-2007)

7071

Daguesh Daguesh Science Science n°

Effect of Wastewater Irrigation on Plant and Soil Microbiology and Interaction Dr. Uri Yermiyahu, Dr. Dror Minz, Dr. Gozal Ben-Hayyim (Agricultural Research Organization), Prof. Yona Chen (The Hebrew University of Jerusalem), Israel Dr. Laurent Grasset, Prof. André Amblès (CNRS), Dr. Wolfram Kloppmann, Dr. Catherine Guerrot (Bureau de Recherches Géologiques et Minières - BRGM), France

rrigation with reclaimed wastewater is a major option for coping with droughts induced by global or regional climate changes in arid regions. However, treated wastewater from both urban and rural sources usually contains high levels of soluble organic molecules (SOM), boron (B), and salts. In soil, interactions between wastewater compounds, soil microorganisms and plants are complex. To investigate boron uptake by plants, growth experiments were conducted under various B and pH conditions. Boron isotope fractionation between water, roots and leaves was investigated. The complex interactions between wastewater compounds (soluble organic molecules, salinity and boron) and the different compartments of the system soilmicrobiota-plant required an interdisciplinary approach involving plant physiologists and microbiologists (ARO, Hebrew University), specialists in organic matter characterisation (CNRS) and geochemists (BRGM). Common experiments were conducted involving scientists from both countries: • Plant growth experiments at varied concentrations of B, pH, salinity using wild type (WT) tomatoes and transgenic (TR) tomato combined with B isotope tracing of B uptake by tomatoes for varying B concentrations, pH, d11B of feed solutions. Plant growth experiments were conducted by ARO and part of the samples were prepared according to a common protocol (BRGM-ARO) and subsequently analysed in the BRGM isotope laboratories. • Characterisation of soil organic matter (SOM): ARO provided Israeli soil samples from five-years cultivated plots and plots under bare fallow both amended with either fresh water or waste water. These were characterised for their SOM compounds in the CNRS UMR 6514 labs with a special focus on: •

→→

Signatures of various classes of soil OM compounds (humic acids, lipids and sugars). →→ Origins of the organic matter (from microbial or from higher plants sources) depending on land use. →→ Impact of waste water irrigation on microbial community deduced from the composition of the soil organic matter. These common experiments were completed by an ARO-specific research program on retroactions between B content and soil microbial activity: bacterial strains were isolated from wastewater and wastewaterirrigated soils and grown in rich media with different concentrations of B. Boron isotope fractionation between water, roots and leaves was investigated. Two series of experiments were conducted: tomato plants were grown at five different pHs (5-9 for the first series, 5 to 10 for the second series) in 5 L flask (three replicates). The initial B was 0.2 ppm (d11B around -10 ‰ vs. NBS951) for the first and 2 ppm (d11B+31.3 to +35.5 ‰) for the second series. Blanks contained B at low ppb level. At low pH (undissociated boric acid dominating), tomato leaves from the first experiment showed a slight constant isotopic fractionation between growth water and leaves. At high pH, this fractionation grows to up to 10 ‰. In the second experiment, at low pH, the fractionation between the growth solution and the leaves is negligible. From pH 8 to 10 the leaves are enriched in 11B compared to the solution by 1.3 to 9 ‰. At high pH, the borate ion is largely predominant in the solution but the observed d11B values in the leaves at pH 10 correspond to the isotopic composition of undissociated boric acid, which is the minor species at this pH (figure 1). It can be concluded that the tomato plants assimilated mainly undissociated boric acid in the high

Kloppmann W., Guerrot, C., Yermiyahu, U., Minz, D. (2009) Effect of Wastewater Irrigation on Plants: Boron Uptake Investigated through Boron Isotopes. Geochim. Cosmochim. Acta, 73, 13, Supplement 1 (June 2009), A669. Goldschmidt Conference 2009, Davos, Switzerland, June 21-26, 2009.

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pH range and borate only to a lesser degree. These first results on environmental B isotope signatures in plant tissues (not isotopically spiked B) are promising as indicators of the plant’s assimilation mode of the principal B species in irrigation water. Retroactions between B content and soil microbial activity: Bacterial strains were isolated from wastewater and wastewater irrigated soils and grown in rich media with different concentrations of B. Above 70 ppm, B acts as an inhibitor of bacterial growth, this effect depending on the bacterial strain. At lower concentrations (<20 ppm), no effect on growth was observed. Solution-grown bacteria are capable of removing boron from the solution, up to 7% of the initial B by RA strain, and 1 to 3% by E. coli a Pimetobacter strain. Characterisation of SOM: organic matter from Israeli soil samples from five-years cultivated plots and plots under bare fallow both amended with either fresh water or wastewater were analysed. Signatures of various classes of soil OM compounds (humic acids, lipids and sugars) were compared. Results indicate that the origins of the organic matter (from microbial or from higher plants sources) strongly differ depending of land use. It appears that wastewater irrigation would significantly modify microbial community and, as a result, the nature and composition of the soil’s organic matter. The main conclusion of this part of the study is that distributions of lipids (such as fatty acids) and the drastic changes of the carbohydrates quantity and distributions show that wastewater irrigation will strongly modify the microbial biomass and its activity over the period of the experiments. These results are confirmed by the D/L ratio of the isolated amino acids.

Grasset, L. and A,b;es, A. (2007) Effect of Wastewater Irrigation, a Comparative Study of the Chemical Composition of Organic Matter from Israeli Sandy Loam Agricultural Soils. International Symposium on Organic Matter Dynamics in Agro-Ecosystems, July 16-19, 2007, Poitiers, France.

Daguesh Science n°

Efficient Allocation of Water Resources among Competing Users: Economic, Environmental and Organizational Considerations Prof. Jean-Philippe Terreaux - PI (CEMAGREF*), Dr. Mabel Tidball (INRA*), Dr. Jean-Marc Berland, Dr. Jean-Antoine Faby (Office International de l’Eau - OIEau), France - * CEMAGREF and INRA are members of ALLENVI Dr. Gilad Axelrad - PI (D.G.A. Projects Ltd.), Prof. Eli Feinerman (The Hebrew University of Jerusalem), Israel

Our principal objective was for both countries to evaluate the consequences of new alternatives for the allocation of this scarce resource, in order to guarantee economically efficient water sharing subject to several environmental constraints. Through this cooperation, we shared both theoretical tools (mathematical programming, mechanism design, game theory) and knowledge of the practical difficulties in water sharing in tense conditions. Of course we based our work on the relevant state of the art literature, especially the literature that deals with water pricing practices under uncertain conditions and asymmetric information. We developed and implemented agro-economics models which describe the economic, environmental and organizational aspects involved in sharing different types of water (i.e., fresh, recycled, etc.) by the agricultural sector (with different types of irrigated cultures and crop mixes), the environmental sector, and the urban and industrial sectors, at the regional or waterbasin levels. The models evaluate and compare several schemes of cost and profit allocations among the economic entities

involved: (i) direct negotiation by utilizing a mechanism design model; (ii) allocation via an agreed upon objective/neutral middleman who uses different approaches from game theory, and (iii) allocation via an adequate pricing system. In addition to our cooperation on the definition of problems and model formulation, we had to adapt our models to the local conditions. For the Israeli part, we determined the optimal crop mix and the optimal allocation of the limited (fresh and recycled) water and land resources among all potential water users. The selected area (the Sharon region in central Israel) includes four economic entities: a city (the wastewater producer), two groups of farmers and a river authority. The model suggests that all economic entities will gain from cooperation in the water arena: the farmers will increase their irrigated areas and benefits, and the river authority will increase its stream flow and environmental benefits. Since wastewater is “bad” for the city and “good” for its consumers, the city’s utility will increase from a paid transfer of recycled water to the latter. In France, we studied an original pricing scheme aiming at the improvement of the ecological state in the river, by guaranteeing a minimum water flow and an increase in farmer’s profit so that they would accept to adopt such a pricing system, while a constraint was the budget equilibrium of the water user association. Our results are very encouraging, since we see that locally there is real demand for such theoretical and analytical results in order to accompany the ad hoc tentative essays of one water user association. Practically too, we show that the economic efficiency of the agricultural water may be considerably enhanced, while the environmental conditions may be improved, with a pricing system that field studies showed acceptable.

We discussed the difficulties involved in implementing our models in our respective countries while taking into consideration the current experiences and possible solutions currently applied in both. This cooperation allowed a participation in other research projects (we thank French Agence Nationale de la Recherche ‘Agriculture and Sustainable Development’ Appeau project, and the European Union Noviwam project). In addition, the research has yielded two papers published in peer-reviewed journals. Moreover, discussions on the use of wastewater in Israel showed there is some interesting work to do on sludge management and disposal in both countries. Future collaboration would be very promising and would give us an opportunity to investigate in depth the links between the ‘pricing’ and the ‘planning’ approaches, and to develop a pricing mechanism for wastewater in Israel, working on the implementation in the European Union Water Framework Directive in France.

Sustainable Agronomy (2005-2007)

t is now well recognized that an efficient management of scarce water resources is crucial for guaranteeing the sustainability of agriculture in Israel and often in France. As competition with other sectors (urban, industrial and environmental) increases, Israeli farmers find themselves relying more and more on the utilisation of recycled and saline water. In France, an increase of irrigated areas in the last two decades has led in case of drought to severe degradation of the environment and to inefficient administrative banning on water uses. Thus new policies and approaches need to be designed to improve water management strategies.

Bioinformatics (2006-2008)

Daguesh Science n°

Study of Two Important Pathogenic Genera: Legionella and Streptococcus Dr. Uri Gophna - PI (Tel Aviv University), Israel Prof. Carmen Buchrieser - PI, Prof. Philippe Glaser (Institut Pasteur), France

ithin the program in bioinformatics of the High Council for Science and Technology Research and the Israeli Ministry of Science and Technology, we performed an evolutionary study of two important pathogenic genera –Legionella and Streptococcus – focusing on lateral gene transfer, an evolutionary phenomenon in which bacteria can obtain genes horizontally rather than exclusively from their ancestors. Legionella pneumophila is a Gram-negative bacterial intracellular pathogen causing the respiratory infections known as Legionnaires’ disease and Pontiac fever. Although Legionella infections are relatively rare, causing a little more than 1200 recognized cases per year in France, about 8000-18000 cases per year in the US, and a significant number of travel-associated legionnaires’ disease in Europe, the relatively high mortality rate (10-20% and up to 50% in nosocomial outbreaks) makes Legionella a serious health concern. Streptococcus agalactiae that often asymptomatically colonize the human gut is a leading cause of septicemia, meningitis and pneumonia in neonates with an incidence of 0.5 infections per 1000 births. Furthermore, it is also a serious cause of mortality and morbidity in non-pregnant adults, particularly in elderly persons and those with underlying diseases. Legionella pneumophila is known to be an intracellular pathogen of multiple species of protozoa (unicellular eukaryotes), and has coevolved with these organisms for many millions of years. Genome sequencing of Legionella pneumophila strains has revealed an abundance of eukaryotic-like proteins (ELPs), some of which were shown to have a role in virulence. We screened the gene content of 217 L. pneumophila strains and 32 other Legionella (non-pneumophila) strains that were isolated from humans and the environment, and like some core genes, many eukaryotic-like genes were highly conserved •

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across strains indicating strong selection pressures for their preservation. This work was published in the journal Genome Research. We then studied the evolution of ELPs in order to investigate their origin. Phylogenetic analyses demonstrated that both lateral gene transfer from eukaryotic hosts and bacterial genes that became eukaryotic-like by gradual adaptation to the intracellular milieu or gene fragment acquisition contributed to the existing repertoire of ELPs. One ELP is common to several strains of Legionella, but outside this genus has homologs only in Acanthamoeba polyphaga mimivirus, indicating that gene exchange involving eukaryotic viruses and intracellular bacterial pathogens may also contribute to the evolution of virulence in either or both of these groups of organisms. Information on selection patterns and eukaryotic-like status was combined as a novel approach to predict type IV secretion system effectors of Legionella, which represent promising targets for future study. This work is soon to be published in the International Journal of Medical Microbiology.

ancestors, suggesting that large exchanges have contributed to the genome dynamics in the natural population. The analysis of resulting genetic flux allowed us to propose a new model for the evolutionary history of this species, in which clonal complexes of strains of clinical importance derived from a single clone that evolved by exchanging large chromosomal regions with more distantly related strains. The emergence of this clone could be linked to selective sweeps associated with the reduction of genetic diversity in three regions within a large panel of human isolates. Since sex in bacteria was assumed to mainly involve small regions, this work brings out S. agalactiae as a new paradigm in the study of bacterial evolution. This work was published in the journal Proceedings of the National Academy of Sciences of the USA (PNAS).

Streptococci have coevolved with mammalian hosts for millions of years and live in bacteriarich environments like the gut and the skin. Thus, differences in selective pressures and partners for gene exchange are expected to be reflected in the evolutionary histories of their genes and genomes. We analyzed genome sequences for eight isolates of S. agalactiae strains in order to trace the evolutionary events leading to genetic changes and thereby infer the history of this species. Combining experimental and in-silico approaches, we demonstrated that large DNA segments of up to 334 Kb of the chromosome of S. agalactiae can be transferred through conjugation from multiple initiation sites. Consistently, a genome-wide map analysis of nucleotide polymorphisms among eight human isolates demonstrated that each chromosome is in fact a mosaic of large chromosomal fragments from different S. agalactiae

Brochet M, Rusniok C, Couvé E, Dramsi S, Poyart C, Trieu-Cuot P, Kunst F, Glaser P. Shaping a Bacterial Genome by Large Chromosomal Replacements, the Evolutionary History of Streptococcus Agalactiae. Proc Natl Acad Sci U S A. 2008 Oct 14; 105(41):15961-15966. Cazalet C, Jarraud S, Ghavi-Helm Y, Kunst F, Glaser P, Etienne J, Buchrieser C. Multigenome Analysis Identifies a Worldwide Distributed Epidemic

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Le¬gionella Pneumophila Clone that Emerged within a Highly Diverse Species. Genome Res. 2008 Mar;18(3):431-441. Lurie-Weinberger, M. Gomez-Valero, V. Merault, M., Glöckner, G., Buchrie¬ser, C., Gophna, U., The Origins of eukaryotic-Like Proteins in Legionella Pneu¬mophila. IJMM (in final revision).

Daguesh Science n°

Analysis and Representation of Cancer-Related Signalling Networks Prof. Ron Shamir - PI (Tel Aviv University), Israel Dr. Emmanuel Barillot - PI (Institut Curie), France

Development and analysis of a cancer pathway model The Curie team collected and organized the existing knowledge about a cancer-related pathway in a model represented in the form of a map of molecular interactions employing upto-date systems biology standards. Building on a former project by Barillot and Radvanyi at Curie, a map of the Rb/E2F pathway was extended based on literature analysis (1). This pathway was chosen as it was shown to be involved in most human cancers. The map was created using the Systems Biology Graphical Notation language with the help of CellDesigner software. The constructed map recapitulates biological facts from about 350 publications, and preliminary results in bladder tumour analysis have shown that it can lead to new insights in the understanding of tumour progression. Bridging between the modelling approaches of the two teams The Tel Aviv University (TAU) team is developing SPIKE, a tool for recording, modelling and visualizing signalling pathways. The Curie team has been using CellDesigner. The two tools represent biological knowledge at different levels of detail and are based on different formalizations. To facilitate exchange of information and cross talk, the two teams created a software “bridge” that allows transformation of the map from one tool to the other. By adapting the BiNOM tool developed by the Curie team (2) and the SPIKE tool developed by the TAU team (3), hundreds of regulations were exchanged between the teams. A comparison of modelling methodologies was published as part of the joint project (3).

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Analysis of biological networks The two groups are developing methods for the analysis of biological networks. The goal within this project was to extend the development of the tools, and allow researchers at Curie to utilize tools developed in TAU. The BiNoM tool from Curie (2) was extended to include functionalities for decomposing pathways. This tool was applied to the Rb/E2F pathway and identified 16 network modules. TAU, as part of an EU project, has developed a computational

enriched in genes affected following oncogene induction, in order to identify the transcription regulatory network found “downstream” of the EWS-FLI1 fusion gene, In order to disseminate the TAU tools in Curie, a workshop was conducted at Curie in April 2008. It included a detailed presentation of the EXPANDER, SPIKE, MATISSE and AMADEUS tools developed at TAU, followed by a hands-on session where participants used EXPANDER, SPIKE and MATISSE to

Logical models for biological networks. Left: Boolean network. Right: Petri net. From a review by Karlebach and Shamir

framework for detection of pathways with a significantly dysregulated gene expression in diseased individuals. TAU used this tool to dissect the Rb pathway of Curie in the context of a larger protein interaction network represented in the SPIKE database, and patient data from Ewing Sarcoma provided by Curie (Olivier Delattre, INSERM/Institut Curie). This analysis revealed a key network up-regulated in poor prognosis tumours, significantly enriched with both known poorprognosis signature genes (e.g., cell cyclerelated) and mRNA modification genes. Other advanced tools for analysis of high-throughput data developed by TAU, EXPANDER and AMADEUS (see acgt.cs.tau.il), were used to analyze the high-throughput private data of Olivier Delattre for an Ewing tumour model. In particular, the AMADEUS tool was used to detect transcription factor binding sites

Calzone L, Gelay A, Zinovyev A, Radvanyi F, Barillot E. A Comprehensive Modular Map of Molecular Interactions in RB/E2F Pathway. Mol Syst Biol. 4:173 (2008). Zinovyev A, Viara E, Calzone L, Barillot E. BiNoM: A Cytoscape Plugin for

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analyze gene expression and network data. Several groups at Curie have started to use the TAU tools as a result of this workshop. In addition, several visits between the two teams during the two years of the project allowed exchange of information and software, further strengthening the collaboration. Continuation of the collaboration In addition to the specific results described above, the collaboration forged a link between the two teams, and they continue to work together on research topics of common interest. Both teams are now participating in the European project APO-SYS – Apoptosis Systems Biology Applied to Cancer and AIDS, in which they continue to develop and share some of the methodologies and tools initiated in this project.

Manipulating and Analyzing biological Networks. Bioinformatics. 24(6):876-7 (2008). G. Karlebach, R. Shamir. Modelling and Analysis of Regulatory Networks. Nature Reviews Molecular Cell Biology, Vol. 9 771-780 (2008).

Bioinformatics (2006-2008)

he objective of the collaboration was to develop a systems biology approach to the analysis and representation of cancer-related signalling networks. Here is a brief summary of the main tasks.

Bioinformatics (2006-2008)

Daguesh Science n°

Phylogeny, Genomics, and Evolution of Tunicates Dr. Dorothée Huchon - PI, Dr. Yossi Loya, Dr. Tal Pupko (Tel Aviv University), Israel Frédéric Delsuc, Dr. Nicolas Galtier (ISEM / CNRS UMR 5554), Prof. Vincent Berry, Prof. Emmanuel J. P. Douzery - PI ( LIRMM / CNRS UMR 5554), France

t has recently been suggested by others and our group that urochordates (sea squirts) and not cephalochordates (lancelets) are the closest relatives of vertebrates. These animals are thus a key taxon for studying vertebrate origin and evolution. Our project had three main objectives: 1. To improve our knowledge of chordate evolutionary relationships using molecular markers. 2. To compare the vertebrate and tunicate evolution of protein genes. 3. To develop better bioinformatics algorithms for evolutionary rate analyses in DNA and protein sequences. Results Chordate evolutionary relationships To improve our knowledge of urochordate relationships, thirty new 18S rRNA sequences were acquired with a focus on previously poorly sampled urochordate groups. An updated phylogenetic framework for tunicates was obtained using the most advanced evolutionary models currently available for

ribosomal molecules. Overall, this analysis enabled us to clearly define the major tunicate lineages (Tsagkogeorga et al. 2009). In addition to the 18S rRNA sequence analysis, we studied the evolution of urochordate mitochondria. While the mitochondrial gene order is almost invariant in vertebrates and lancelets, sea squirts have been characterized by frequent and extensive gene rearrangements. We sequenced the complete genome of Herdmania Momus, an invasive species in the Mediterranean Sea. Annotation of the genome confirmed that the mitochondrial genome is a valuable phylogenetic marker to investigate molecular biodiversity and speciation events in urochordates. It also confirmed the close relatedness between tunicates and vertebrates (Singh et al. 2009). Finally, we conducted the pyrosequencing of cDNA banks from the species Microcosmus squamiger, another invasive species in the Mediterranean Sea. The random sequencing of thousands of ESTs from this cDNA library provides a first glimpse into the diversity of the genes expressed in this species. The data obtained are currently used to conduct an analysis of evolutionary rate shifts.

Herdmania momus. This solitary ascidian (Tunicata: Ascidiacea: Stolidobranchia: Pyuridae) is an Indo-Pacific species that was introduced into the Mediterranean Sea via the Suez Canal (photo Noa Shenkar).

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Developing better algorithms for sequence analysis One of the main challenges of sequence analysis is the development of adequate algorithms that accurately model the evolutionary processes. The neutral theory of evolution suggests that most genetic differences marginally affect the function of the encoded proteins (hence neutral) and thus

Tsagkogeorga G., Turon X., Hopcroft R. R., Tilak M.-K., Feldstein T., Shenkar N., Loya Y., Huchon D., Douzery E. J. P. & Delsuc F., 2009. An Updated 18S rRNA Phylogeny of Tunicates Based on Mixture and Secondary Structure Models. BMC Evolutionary Biology 9:187. [Open access, freely available at http://www.biomedcentral.com/1471-2148/9/187 ]. Singh T. R., Tsagkogeorga G., Delsuc F., Blanquart S., Shenkar N., Loya Y., Douzery E. J. P. & Huchon D., 2009. Tunicate Mitogenomics and Phylogenet¬ics: Peculiarities of the Herdmania Momus Mitochondrial Genome and Sup¬port

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occur randomly. Alternatively, changes in protein function are reflected by a pattern of nonrandom genetic differences. A novel computational algorithm was developed to detect deviations from neutrality. These deviations represent functional shifts in the evolution of the proteins analyzed. HIV1 sequences were used to validate our method. Using a large sample of available HIV-1 protein sequences, we discovered that part of the variability among the HIV subtypes is not random and possibly reflects different functional constraints imposed on the subtypes during the course of their evolution. An in-depth inspection of these nonrandom changes revealed a correlation with biological traits such as drug resistance and mechanisms facilitating viral entry into the host cell (Penn et al. 2008). Cooperation Our network was composed of marine zoologists (one Israeli team), experimental molecular biologists (one Israeli team and one French team) and bioinformaticians (one Israeli team and two French teams). Throughout the project, the French and Israeli teams fully shared their sequencing effort and data. Similarly, computational algorithms and source codes were compared, discussed, and new algorithms were codeveloped. An Israeli student (Adi Stern) and a French student (Julien Duthiel) also visited the partner labs for a month during the project. A true dialogue between the French and Israelis was thus established during the collaborative work. The joint effort initiated thanks to this research network program will surely continue.

for the New Chordate Phylogeny. BMC Genomics 10:534 [Open access, freely available at http://www.biomedcentral.com/1471-2164/10/534]. Penn O., Stern A., Rubinstein N.D., Dutheil J., Bacharach E., Galtier N., Pupko T. 2008. Evolutionary Modelling of Rate Shifts Reveals Specificity Determinants in HIV-1 Subtypes. PLoS Comput Biol. 4 (11). [Open access, freely avail¬able at http://www.ploscompbiol.org/article/info:doi%2F10.1371%2Fjournal. pcbi.1000214].

Daguesh Science n°

Transfer of Adaptation between Feedback and Feed-Forward Controllers Prof. Pierre Baraduc - PI (CNRS UMR 5229), France Prof. Amir Karniel - PI (Ben Gurion University), Israel in Seville, Spain, and are pleased to present some of the results of this collaboration at the 20th Meeting in Naples, Florida. During this project, Amir Karniel visited Lyon and Paris, and Pierre Baraduc visited Jerusalem and Beer-Sheva for work meetings, talks, brainstorming, lab meeting sessions and status seminars.

Illustration of a subject probing a virtual object. We found that perceived properties of the object vary with the probing joint. These results should appear in one of the next issues of the Journal of Neurophysiology, Nisky et al. (in press). The illustration was prepared by Raz Lieb using Poser ®.

t is believed that the control of movement is generated by feedback as well as feed-forward control mechanisms which gradually obtain information about the arm and the controlled environment. It has also been observed that the feedback operates at various time scales involving several neural pathways. In this study, we ask whether these multiple control mechanisms adapt separately or share the same information about the arm and the environment. We have conceived these ideas during a casual meeting at the 17th Annual Meeting of the Society for Neural Control of Movements,

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Nisky I, Baraduc P, and Amir Karniel (in press) Proximodistal Gradient in the Perception of Delayed Stiffness. Journal of Neurophysiology. Peled A, Baraduc P, and Karniel Amir (2010) Adaptation and Lack of

We developed a target jump paradigm to address the main question of transfer between feedback and feed-forward controllers and found that both adapt together in the tested conditions. These results were recently presented at the annual meeting of the Society of Neural Control of Movement (April 2010). The motor system clearly involves a fused multiple-loops hierarchical structure. In this project, we have just started to unravel some of the features of this complex system. We built an experimental setup, developed several new experimental methodologies, and found some interesting results about the proximodistal gradient and about feedback and feed-forward adaptation. Further studies are required to understand the complex multiple feedback and feed-forward controlled motor system which is responsible for our magnificent dexterous behaviour.

Adap¬tation to Rotated Visual Feedback During Reaching Movement and Target Jump, the 20th Annual Meeting of the Society for Neural Control of Move¬ment, Naples, Florida, April 20-25, 2010.

Neuroscience and Robotics (2007-2009)

Using a recently developed paradigm of probing virtual objects, we demonstrate a proximodistal gradient in perception of stiffness, indicating that the multiple feedback loops might involve proximal and distal joints separately. Our finding, which will appear in the Journal of Neurophysiology, suggest that when we probe objects with our shoulder we use more force control, and when we probe objects with our wrist we employ more position control.

Neuroscience and Robotics (2007-2009)

Daguesh Science n°

Mathematical Modeling of 3D Human Arm Movements Dr. Sigal Berman - PI (Ben Gurion University), Dr. Dario G. Liebermann (Tel Aviv University), Israel Joe McIntyre - PI (CNRS UMR 7060), France

Constrained motion on a virtual hemisphere

ccumulating evidence supports the notion that human motion is comprised of discrete stereotyped fragments termed submovements. It is thought that the brain constructs more intricate movements from these fundamental building blocks as a means of dealing with the multiple, redundant degrees of freedom that make up the human motor system. Results show that reaching and pointing movements may be segmented into single-axis submovements based on the spatial velocity of the arm. We therefore set out to examine submovements for different classes of hand movements towards visual targets. Specifically, we looked at reaching movements, reach-to-grasp movements, and surface-constrained movements. We also examined possible practical applications of submovement-based measures both for objective diagnosis in clinical conditions (i.e., stroke patients) and for the synthesis of robotic motions. The collaboration between the groups let to exchange of ideas, research tools, and to four experiments conducted in Tel Aviv, Paris, and Beer Sheva. The experiments led to new unexpected findings mainly in constrained motion control and for objective diagnosis in stroke patients.

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Humans perform many actions in which the movements of the hand are physically constrained by features of the environment. For example, when polishing an object, the surface of the object constrains the hand to move along only two out of the three possible spatial dimensions at any one point. On the other hand, the hand is free to exert forces of varying amplitudes in the direction perpendicular to the surface. This class of constrained motions has yet to be studied in terms of submovements. Performing constrained motions on a curved surface poses an interesting control problem, as the direction of force application perpendicular to the surface is not orthogonal to the directions of motion along the surface, as is the case in planar surfaces. We looked at such constrained motion along the surface of a virtual hemispheric surface with subjects receiving both visual and tactile feedback of their actions (Fig. 1). The subjects were asked to make rapid movements between targets by sliding along the inner surface of the hemisphere. One of the interesting findings that emerged was that between oblique points, subjects typically moved either along straight line paths in the frontal plane projected on the spherical surface, along geodesics (i.e., along great-circle routes representing the shortest path between two points on a sphere), or along parallels (i.e., motion with a constant distance from the hemispheres’ rim). Both parallel and straight-line projections are related to perceptual affordances of the environment. The parallel is located at a constant distance from the rim of the hemisphere, which is a clearly visible cue. A straight line in the frontal plane may facilitate simplification of

D.G. Liebermann, S. Berman, M.F. Levin, H.P. Weingarden, P.L. Weiss 2009. 1. “Kinematic Features of Arm and Trunk Movements in Stroke Patients

visual motion tracking by ignoring the depth dimension. These results contribute to the understanding of path planning and seem to support theories relating to action and perception rather than biomechanical-based path planning. Additionally, they seem to point at separate rather than unified path and speed planning. The need for objective indices of changes in motor performance during and after physiotherapy treatment is constantly growing. New robot-based motor rehabilitation technologies have been rapidly evolving in the last few years, and yet, the issue of assessment of motor training using such machines is not resolved. Previous study in planar movements indicated submovement may be utilized for this purpose. A large proportion of daily movements are not planar, thus we examined reaching movements in space comparing motion of stroke survivors with that of aged match controls (Fig. 2). We looked at two different basic submovement speed profiles, Minimum jerk (MJ) speed profile, and the support-bounded lognormal (LGNB) speed profile. The LGNB profile has more tunable parameters, allowing a closer fit to the data, but the MJ profile is theoretically grounded. We additionally looked at two different decomposition termination criteria: a fixed a-priori set error value, as was applied in previous research, and theoretically groundedmodel fitting criteria (AIC criterion). Although the number of extracted submovements significantly differed between the controls and the stroke survivors, it had a lower discrimination power compared with other parameters. Thus, we found that simpler to derive parameters, such as hand time to peak speed, peak speed, and path length, may be better performance descriptors.

and Age-Matched Healthy Controls during Reaching in Virtual and Physical Environ¬ments”, Int. Conf. Virtual Rehabilitation, Haifa, Israel.

Daguesh Science n°

A Mechanistic Approach to Buridan’s Paradox Dr. Yonatan Loewenstein - PI (The Hebrew University of Jerusalem), Israel Dr. David Hansel - PI, Dr. Gianluigi Mongillo, Dr. Thomas Boraud (CNRS UMR 8119), France

alternatives. If the symmetry is broken by the internal “noise”, the subject would make his decision as if by the tossing of an unbiased coin. This is because choice is determined by the internal noise at the time of the decision, which varies from trial to trial. By contrast, if the symmetry is broken as a result of local fluctuations in network circuitry, subjects should always choose the same alternative because the asymmetry in the network architecture does not change from trial to trial.

We considered a standard network model for decision making in which the two alternatives are represented by two large populations of spiking neurons whose architecture is drawn from the same distribution. Decision emerges from the competition between these populations, mediated by lateral inhibition. We showed that the contributions of the internal noise and the local heterogeneities are comparable, independently of the size of the network. As a result, the distribution of choice preference when considering decision making in a large number of symmetrical settings is expected to be wide. Moreover, we showed that the shape of this distribution depends on To disentangle these two possible mechanisms, the rapidity of the decision: the width of the we consider a repeated choice experiment in distribution of preferences decreases with which a subject is repeatedly asked to choose decision time. We tested our theory through between the same two equally appealing a series of monkey and human psychophysics experiments in which subjects repeatedly chose between two symmetrical alternatives. Choice preference was quantified by measuring the fraction of trials in which a subject chose one of the alternatives. Interestingly, for both monkeys and humans, the distribution of preferences was wide, From left to right : Yonatan Loewenstein, David Hansel and Gianluigi Mongillo as predicted by our

theory. We reported these results in abstract form at the Society for Neuroscience (USA) and Société des Neurosciences (France) meetings, as well as at the Third France-Israel Binational Conference in Neuroscience (Haifa, 2010). Two students, one in Bordeaux, Steeve Laquitaine, and one in Jerusalem, Yoni Yalovitsky, were involved in this joint project conducted in the framework of the FranceIsrael Laboratory of Neuroscience (FILNe). FILNe is an extra-muros laboratory (“laboratoire européen associé”, LEA) that groups French and Israeli researchers, experimentalists and theoreticians working in the field of computational neuroscience, sensorimotor neurophysiology, and learning and memory. The French FILNe members belong to the CNRS (Paris-Descartes University and Victor Segalen University (Bordeaux)). The Israeli researchers are affiliated to the Hebrew University of Jerusalem. Our collaboration also triggered the organization of two workshops in partnership with LEA-FILNe. One, organized in Jerusalem in 2008 by D. Hansel, and Y. Loewenstein, was entitled “Basal Ganglia, Decision Making and Working Memory”. The second workshop, which dealt with the Biology of Decision Making (Bordeaux, 2009, organized by S. Ahmed, T. Boraud and D. Hansel) was also included in the prospective meetings series of the Agence Nationale de la Recherche (ANR). Last but not least, the collaboration has led to new joint projects forming the basis for future grant proposals to the ANR.

“…the men who, though exceedingly hungry and thirsty, and both equally, yet being equidistant from food and drink, is therefore bound to stay where he is…” Aristotle (384 BC – 322 BC), On The Heavens, Book II.

Neuroscience and Robotics (2007-2009)

he question of choice between equally appealing alternatives has been debated for over two millennia. In its more modern formulation, known as Buridan’s paradox, a donkey is placed equidistant from two stacks of hay. Unable to decide which stack to choose, it starves to death. In real life, human and animal subjects choose one of the alternatives when confronted with similar dilemmas. In this project, we investigated how such choice preference emerges from the collective neural dynamics of the brain. Two sources of asymmetry in the brain can lead to a choice preference even in a symmetrical setting: 1. There is ample evidence that the activity of cortical neurons is highly irregular and is well described by a Poisson process. Such stochasticity could tip the balance between the two symmetrical alternatives and lead to the choosing of one alternative. 2. Local heterogeneities in the cortical architecture are another source of asymmetry that can break the symmetry between the two alternatives, leading to the choosing of one of them.

Medical and Biological Imaging (2006-2008)

Daguesh Science n°

Imaging the Retina in Depth Dr. Erez Ribak - PI (Technion), Israel Prof.Claude Boccara - PI (ESPCI Paris Tech), France

he project consisted of efforts by both groups to see fine details inside the retina. Because of aberrations in the eye, resolution on the retina is smeared significantly, from several micrometers to tens of micrometers. This is usually not noticed by the subject, the ophthalmologist has difficulties discerning fine details, and early detection of retinal diseases is nearly impossible.

aberrations are not noticeable.

In addition, the retina reflects very little light, and even that light is scattered to create speckles when laser light is shone on it. In the first experiment, we developed an acoustic modulation of the laser light to randomize the speckle pattern reflected from the eye. This reduced the amount of noise and allowed us to see finer details.

Another approach using speckle dynamics enabled to follow up blood flow in the retina. We have obtained a number of experimental data on rat eyes and are modelling them in the framework of Diffuse Wave Spectroscopy.

Today, the effect of ocular blurring is reduced with adaptive optics. This is a method to correct continuously the aberrations of the eye, and at the same time take a sharper image of the retina. To simplify the process and avoid the cumbersome optics and electronics, we tried to use nulling optics, namely to smooth out the aberrations by immersing the eye in artificial tear fluid. This fluid has the same refractive index as the cornea, and thus the corneal

100 to 200 Hz

5000 to 10000 Hz

1000 to 2000 Hz

To complement the retinal images we obtained, we also performed calculations of light propagation through the retina. It turns out that the light is guided directly into the photoreceptors at the bottom of the retina, and we were able to show that, as a result, vision acuity was improved.

The project resulted in a number of publications (two more are pending) and further EU collaborative work in Galway funded by Science Foundation Ireland.

10000 to 20000 Hz

Spectral image of the rat eye fundus for four frequency bands. Optical power is displayed in logarithmic scale (white is for high signal).

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V Albanis, E N Ribak, and Y Carmon: Reduction of Speckles in Retinal Reflection, Applied Physics Letters 91, 054104 (2007). V Albanis, E N Ribak and Y. Carmon: “Speckle Reduction in Wave-Front Sensing”. Adaptive Optics: Analysis and Methods, Optical Society of America. Ed. B Ellerbroek, Vancouver, Canada (2007). A Stup, E M Cimet, E N Ribak and V Albanis: Acousto-Optic Wave-Front Sensing and Reconstruction, Applied Optics 48, A1-A4 (2008).

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M Labin and E N Ribak: “Vision Effects Caused by Glial Cells in the Retina”. Bulletin of the Israel Physical Society 54 B3.6 (2008). Y Carmon and E N Ribak: Centroid Distortion of a Wave-Front with Varying Amplitude Due to Asymmetry in Lens Diffraction, Journal of the Optical Society of America A 26, 85-90 (2009). S. Labiau, G. David, S. Gigan, A.C. Boccara. Opt. Lett., 34, 1576-1578 (2009).

Daguesh Science n°

Following the Activity of Genes in Living Human Cells Dr. Xavier Darzacq - PI, Sebastien Z Causse (CNRS), France Dr. Yaron Shav-Tal - PI, Dr. Yehuda Brody (Bar Ilan University), Israel

he cell nucleus contains the genetic information required for the development and growth of an organism. Molecules that form long polymers called DNA, first coined “chromosomes” in 1888 by the German anatomist Heinrich von Waldeyer-Hartz, contain the genetic information. DNA molecules contained in chromosomes store the genetic information in a discontinuous manner and the functional information-containing unit is called a gene. Genes contain the code (plan) sufficient to assemble the functional effectors responsible for cellular function. Genes are the library of all cell properties although a cell will use only a subset of them in order to define proteins bearing cellular function. DNA can be seen as a huge storing unit for genes as it never leaves the cell nucleus. Whereas DNA is present in the cell nucleus, proteins are synthesized in the cytoplasm, and therefore information must move in between both compartments. Indeed, the genetic information is not interpreted directly from DNA, but rather is first copied into a socalled messenger molecule (messenger RNA, mRNA) that is used to drive protein synthesis in the cell cytoplasm (if the gene is a plan, then the mRNA is its blueprint). The mRNA is degraded after use. Two molecular machines

are controlling the potentiation of inert genes into effector proteins: the RNA polymerase (Chemistry Nobel Prize 2006) copies DNA/ genes into mRNAs, while the second one is called the ribosome (Chemistry Nobel Prize 2009) and generates the proteins. This process of DNA making RNA making protein is termed ‘Gene Expression’. The nuclear process of generating mRNAs from the genes in the DNA is called ‘transcription’. Both of our laboratories are interested in the transcriptional process occurring in the DNA, in the nucleus. The process of transcription has been studied for decades but mostly by biochemical approaches. This means that the contents of large populations of cells must be extracted in order to study the molecules involved in transcription. This is performed in test tubes or in vitro. Our groups chose a different approach for studying gene expression. We try to imitate the physiological state of a cell and therefore perform experiments on living cells. Since in such a manner we cannot isolate molecules from within the cells, instead we label the molecules we are interested in with a fluorescent label and follow them using stateof-the-art fluorescence microscopy. This is called live-cell microscopy, in which time-lapse

In order to follow transcription in a live-cell setup we label the gene we are interested in examining with a red fluorescent label. This is then seen as one red dot in the cell nucleus (see figure). The mRNA molecules transcribed from this gene are labelled with a green fluorescent label (GFP, Chemistry Nobel Prize 2008). The figure shows many green dots throughout the cell – these are the many mRNA molecules made by the gene. A strong green dot is also observed, correlating to the red DNA dot in the nucleus. These are in fact the mRNAs that are being generated upon the gene itself. Once we can detect these mRNAs at the site of transcription in a living cell, we can examine the kinetics of the process and whether different molecules can perturb the transcriptional process. Using this system, we have managed to demonstrate that the rates of transcription actually taking place in a cell are three times faster than what has been measured in biochemical experiments. This means that the molecular machinery that transcribes DNA into mRNA is much more efficient than what we had ever imagined. The use of such unique techniques for monitoring biological processes in living cells will have a major impact on the way we observe the life of a cell.

Medical and Biological Imaging (2006-2008)

movies of living cells are acquired and provide information about the kinetics of biological processes taking place right under our eyes.

A living human cell where a nuclear DNA locus is labelled with a red fluorescent protein (the red cannot be clearly seen since is superimposes with the green signal forming a yellow dot in the nucleus). The mRNA produced from the red-labelled gene is in turn visualized in green, and individual molecules are visible throughout the cell (green dots). The protein made from these mRNA templates is cyan and visible as blue dots in the cell cyto¬plasm. In this cell, the whole “gene expression pathway” is simultaneously visualized and can be quantified.

Medical and Biological Imaging (2006-2008)

Daguesh Science n°

Geometric Reconstruction of Organs from Freehand Ultrasound Prof. Gill Barequet - PI, Dr. Amir Vaxman (Technion), Israel Prof. Jean-Daniel Boissonnat - PI, Dr. Pooran Memari (INRIA Sophia-Antipolis), France

3D sections from a liver (magenta) and a kidney (green)

he problem is to reconstruct a shape from unorganized cross-sections. The main motivation comes from medical imaging applications where cross-sections of human organs are obtained by means of a freehand ultrasound apparatus. The position and orientation of the slices may be freely chosen, which makes the problem substantially more difficult than in the case of parallel cross-sections, for which rich literature exists. These slices may be collected and used to reconstruct a full 3D model of the anatomy. The input data consist of (the parameters of) the cutting planes and (an approximation of) their intersection with the object, specified as contours within these planes. Two main approaches have been proposed. The first is an interpolation method. First, we defined a 3D scalar “characteristic” function that has the value 1 inside the contours and 0 outside. Then, we use an implicit surface mesher to produce the resulting mesh. The main idea is to approximate the 3D indicator function as a linear combination of basis functions. The reconstructed boundary of the •

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object is the level set of the value 0.5 of the computed function. The method can handle the case of multi-labelled sets, which is useful when dealing with segmented images and also for sections that are only partially known, which is of interest when dealing with noisy data. The second, a more geometric approach, consists of two main steps. First, the arrangement of the cutting planes is computed. Then, in each cell of the arrangement, an approximation of the object is reconstructed from its intersection with the boundary of the cell. Lastly, the various pieces are glued together. The two teams suggest different implementations of the second step. While the French team makes use of the Delaunay triangulation, generalizing the reconstruction method of Boissonnat and Geiger for the case of parallel planes, the Israeli team uses the straight skeleton of each cell of the arrangement of planes to guide the reconstruction within each cell. This approach can reconstruct thin structures like arteries networks.

G. Barequet, D. Eppstein, M.T. Goodrich, and A. Vaxman, Straight Skele¬tons of Three-Dimensional Polyhedra, Proc. 16th Ann. European Symp. on Algorithms, Karlsruhe, Germany, Lecture Notes in Computer Science, 5193, Springer-Verlag, 148—160, 2008. G. Barequet and A. Vaxman, Reconstruction of Multi-Label Domains from Partial Planar Cross-Sections, Computer Graphics Forum (CGF), vol. 28 (5), 1327-1337, 2009. J.-D. Boissonnat and P. Memari, Shape Reconstruction from Unorganized Cross-Sections, Proc. 5th Eurographics Symp. on Geometry Processing,

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Both methods have been implemented and first experiments have been conducted. As interesting byproducts of our methods, we developed new data structures that are of independent interest, like straight skeletons of polyhedra in three dimensions, Moebius diagrams (a special type of Voronoi diagram), and a geometric dual of the Voronoi diagram of polygonal regions in 3-space. Prior to this project, no theoretical analysis was available for this problem, even in the simpler case of parallel sections. We provided the first theoretical results for the general problem of arbitrarily oriented sections. Most notably, one of the partners (INRIA) succeeded in proving that (a restricted variant of) the algorithm developed by the other partner (Technion) provides a topologically correct solution under some reasonable sampling conditions.

Barcelona, 89—98, 2007. P. Memari and J.-D. Boissonnat, Provably Good 2D Shape Reconstruction from Unorganized Cross-Sections, Computer Graphics Forum, 27 (2008), 1403—1410. O. Amini, J-D. Boissonnat and P. Memari, Geometric Tomography with Topological Guarantees, ACM Symp. on Comp. Geometry, 2010. Sidlesky, G. Barequet, and C. Gotsman, Polygon Reconstruction from Line Cross-Sections, Proc. 18th Canadian Conf. on Computational Geometry, Kingston, Ontario, Canada, 81—84, August 2006.

Daguesh Science n°

Vessel Segmentation on Computed Tomography Angiography (CTA) Prof. Laurent D. Cohen - PI, Dr. Fethallah Benmansour (CEREMADE), Prof. Philippe Douek, Prof. Maciej Orkisz, Dr. Maria Alejandra Zuluaga, Dr. Eduardo Davila (Creatis Lyon), France Prof. Ron Kimmel - PI, Dr. Alexander Brook (Technion), Prof. Nir Sochen (Tel Aviv University), Israel

The French Hospital Partner in Lyon provided a large set of CTA studies, including sets with two studies performed on each patient and about 20 studies suitable for work on other aspects of cardiac vessel segmentation. The partner in Paris has years of experience in vessel segmentation and improved, in the framework of this project, an approach based on minimal paths and front propagation for 3D vascular tree segmentation and on tubular anisotropy. The key is to represent the trajectory of the vessel not as a 3D curve but to go up a dimension and represent the entire vessel as a 4D curve, where each point represents a 3D sphere (three coordinates for the centre point and one for the radius). The 3D vessel structure is then obtained as the envelope of the family of spheres traversed along this 4D curve. Since this 3D surface is defined simply from a 4D curve, we can fully exploit

minimal path techniques to obtain globally minimizing trajectories between two or more user supplied points in order to reconstruct vessels from noisy or low contrasted 3D data. This approach has the advantage of not being sensitive to local minima inherent in most active surface techniques. This 4D curve yields a natural notion of a vessel’s centreline and its envelope, which corresponds to the boundary of the vessel. An important aspect of our approach consists in building a multiresolution metric that guides the propagation in this 4D space. This means we extract the local geometry (orientation and scale) of the image using the so-called optimally oriented flux. With the partners in Lyon (CREATIS team), we developed an interactive tool for minimal interaction vessel segmentation based on their black box toolkit (BBTK). This tool is useful for the physician to obtain a segmentation of a vascular tree and centreline paths that enable to make efficient visualization and allows the clinician to perform a quantitative assessment of the vessel morphology.

invariant under non-rigid transformations. With cardiac CTA usage on the rise, there appeared a growing population of patients who underwent more than one CTA study. Our initial proposal was to use the segmentation from the first study to automate the segmentation of subsequent studies. We adopted a representation similar to that described above for minimal paths, where a vessel is described by the centreline and the radius at each point. We developed an algorithm which, given an existing segmentation, registers it with another study, thus providing an automatic segmentation. The algorithm progresses from the proximal end of the vessel distally, predicting the next point based on the existing segmentation and then correcting it based on the image data. In conclusion, we have proposed minimally interactive methods for vessels and vascular tree segmentation (tubular branching structures), where the user provides only one initial point. These are used for shape prior to segmentation, allowing non-rigid deformation of the surface.

The Israeli partners focused on the creation of a rough shape prior model for segmentation

Right coronary arteries seg¬mentation using the tubular anisotropy approach shown on a selected subvolume of the 3D image. Only several points are required (the extremities of the red paths). The tubular anisotropy method provides the centrelines as well as vessels boundaries.

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New Interactive Methods for Tubular Structure Segmentation of Medical Images, Fethallah Benmansour, Laurent Cohen, E. Davilla, P.C. Douek, M. Orkisz and M.A. Zuluaga. In Proc. 12th Israeli Symposium on Computer-Aided Sur¬gery, Medical Robotics, and Medical Imaging (ISRACAS ’09), Tel Aviv, Israel, May 7th, 2009.

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Tubular Structure Segmentation Based on Minimal Path Method and Aniso¬ tropic Enhancement, Fethallah Benmansour and Laurent D. Cohen, in Inter¬national Journal of Computer Vision, 2010.

Medical and Biological Imaging (2006-2008)

his short paper describes our contribution in the research aimed at model-based vessel segmentation on CTA. Although each partner was involved in a main subject among what follows, the contribution is a joint effort of all the partners as a result of regular visits in France and Israel, as well as between partners in each country.

Daguesh Science nÂ°

Time-Reversal Techniques for Detection and Imaging Prof. Franck Assous - PI (Bar Ilan University), Prof. Elie Turkel (Tel Aviv University), Israel Dr. Frederic Nataf - PI, Dr. Marie Kray (UniversitĂŠ Pierre et Marie Curie), France

ime reversal is a subject of very active research, and in which France has a special place. The field was established by M. Fink in 1992 (LOA, ESPCI, Paris). Many French and foreign teams are working on this topic in its physical, numerical and theoretical aspects. The basic principle is that the equations of acoustic and electromagnetic waves are reversible in time. This feature makes it possible to propose innovative methods. There are many applications of the time-reversal method, including medical imaging and therapy (e.g., detecting a cancerous tumour or treating kidney stones), marine acoustic (detection of frogmen and underwater acoustics), waves in complex medium to study earthquakes, etc.

Mathematics (2007-2009)

The aim of our study was to test a procedure for finding the location of an object using the time-reversal method. The object can be either impenetrable or the waves can enter the body. We sketch here the principle. A source illuminates the target, which is surrounded by receivers. The target may be cancerous cells or buried mines. The goal is to find the location and shape of the target from the recorded data. Our method enables us to answer

the following question: Is the target inside a trial domain or not? For this, we perform a numerical simulation using time reversal. At the end of the computer experiment, if the signal is not zero, it means that our assumption was incorrect. If our assumption was correct, the signal is zero. In Fig. 1 we see that if the trial domain is smaller than the object, the signal is not zero at the end of the time-reversal simulation while it is zero if the trial domain is larger than the object. By trial and error, it is possible to approximate the shape of the object from both inside and outside. Compared to existing methods, we do not need to know anything about the properties of the target. All numerical results were very satisfactory. We can detect objects whose size is only 10% of the wavelength. The method proved to be very robust with respect to noise in the data. The grant enabled us to make the first implementations and tests of the method on simple problems. The investigation is continuing through the Ph.D. work of M. Kray under Franco-Israeli supervision. The goal is to be able to treat real-life applications.

Iso Value -0.01 -0.008 -0.006 -0.004 -0.002 -0.001 -0.0008 -0.0006 -0.0004 -0.0002 -0.0001 0.0001 0.0002 0.0004 0.0006 0.0008 0.001 0.002 0.004 0.006 0.008 0.01

Trial domain smaller (left) or larger (right) than the object

Daguesh Science n°

The Investigation of Convex Bodies: Probabilistic and Geometric Methods Prof. Olivier Guédon - PI (Université Pierre et Marie Curie), Prof. Matthieu Fradelizi, Prof. Mathieu Meyer (co-PI) (Université Marne-la-Vallée), France Prof. Shlomo Reisner - PI (University of Haifa), Prof. Yehoram Gordon (co-PI) (Technion), Israel

In addition to these activities, all the members of the team worked independently and in cooperation with other scientists, mainly on topics closely related to the topics of the project. Worth mentioning are the following major events in which members of our team were involved: The 4th Annual Meeting of the EU Research Program on “Phenomena in High Dimensions” that took place in Seville, Spain, June 23-27, 2008. Three members of the team (Fradelizi, Gordon and Guédon ) were invited to talk about their results. A significant part of their presentations was dedicated to results obtained in the framework of the project. On December 8, 2008, the Status Seminar • • • • • • • • •

of the program took place in Jerusalem. Prof. Gordon and Prof. Reisner represented there the progress of our team in the first year of the program. On February 17-20, 2009, a conference on “Probability and Geometry of Convex Sets” in honour of Y. Gordon took place at the Technion; it was organized by Y. Benyamini, S. Mendelson and S. Reisner (the Israeli PI of the project). Prof. Guédon and Prof. Meyer represented the French part of our team in this conference and presented subjects that are included in the project. On June 24-30, a conference on “The State of Geometry and Functional Analysis” in honor of V. Milman took place at Tel-Aviv University and a Dead Sea resort. Our project was represented there by Y. Gordon and S. Reisner on the Israeli side and by M. Fradelizi on the French side, who also presented a talk dealing with topics connected to our project. During the reported period, the team members published and submitted for publication a total of 23 papers. Many of these publications are authored jointly by several members of the team. This concludes the fourth year of our close and fruitful cooperation in the two successive French-Israeli mathematical projects, the first of which began in 2005.

Ministry of Foreign Affairs for establishing and promoting the important France-Israel cooperative mathematical project. We sincerely hope that the two countries will continue to support in the future mathematical projects between French and Israeli mathematicians in which we hope to be involved. The members of the team, in various subsets working on different aspects, worked on a wide spectrum of problems as can be seen from the list of publications that follows. Among these projects, one may find: • Problems on volume inequalities concerning convex bodies as well as integral inequalities concerning logconcave functions, for example, problems connected to Mahler‘s conjecture. • Geometric probabilistic problems and geometric statistical problems. Problems of harmonic analysis connected to geometric functional analysis. • Problems in the local theory of Banach spaces.

The authors wish to thank the support of the Israel Ministry of Science and the French

R. Adamczak, O. Guédon , A. Litvak, A. Pajor, N. Tomczak-Jaegermann: Smal¬lest Singular Value of Random Matrices with Independent Columns, C. R. Math. Acad. Sci. Paris 346 (2008), No. 15-16, 853-856. N. Dafnis, A. Giannopoulos, O. Guedon. On the Isotropic Constant of Random Polytopes, to appear in Advances in Geometry. Dimitriyuk, Y. Gordon: Generalizing the Johnson-Lindenstrauss Lemma to K- Dimensional Affine Subspaces, Studia Math. 195 (2009), 227-241. Fleury, O. Guédon , G. Paouris: A Stability Result for Mean width of Centroid Bodies, Advances in Mathematics, 214 (2007), no 2, 865--877. M. Fradelizi: Concentration Inequalities for S-Concave Measures of Dilations of Borel Sets and Applications. Electron. J. Probab. 14 (2009), no. 71, 20682090. M. Fradelizi, Y. Gordon, M. Meyer, S. Reisner: The Case of Equality for an Inverse Santaló Functional Inequality, Advances in Geometry, to appear. M. Fradelizi, M. Meyer: Functional Inequalities Related to Mahler’s Conjecture. Monatsh. Math. 159, No. 1-2 (2010), 13-25. M. Fradelizi, M. Meyer. Some Functional Forms of Blaschke-Santaló Inequality. Math. Z., 256, (2007), 379--395. M. Fradelizi, M. Meyer. Some Functional Inverse Santaló Inequalities. Adv.

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Math., 218 (2008), 1430--1452. M. Fradelizi, M. Meyer. Increasing Functions and Inverse Santaló Inequality for Unconditional Functions. Positivity 12 (2008), no. 3, 407-420. Y. Gordon, A. Litvak, A. Pajor, N. Tomczak-Jaegermann, Random ε Nets and Embeddings in Studia Math. 178 (2007), 91-98. Y. Gordon, A. Litvak, S. Mendelson, A. Pajor, Gaussian Averages of Interpolated Bodies and Applications to Approximate Reconstruction, J. Approx. Theory, 149 (2007), 59-73. Y. Gordon, M. Meyer: Geometric and Probabilistic Analysis of Convex Bodies with Unconditional Structures, and Associated Spaces of Operators, Positi¬vity, to appear. O. Guedon, A. Litvak: On the Symmetric Average of a Body, Advances in Geo¬metry, to appear. O. Guedon, S. Mendelson, A. Pajor, N. Tomczak-Jaegermann, Majorizing Measures and Proportional Subsets of Bounded Orthonormal Systems, Rev. Mat. Iberoam. 24 (2008), no. 3, 1075-1095. A. Lopez, S. Reisner, Hausdorff Approximation of 3D convex Polytopes, Information Processing Letters 107 (2008), 76-82.

Mathematics (2007-2009)

he joint research of the team over the period from September 2007 to December 2009 consisted of two types of activities: 1. There were a number of mutual visits of members of the team at the institutes of the members from the other country. One of these visits was an extended stay (over two months) of Y. Gordon in Paris (U. MLV and Paris VI) for joint work on the project. 2. During the periods between these visits, members worked on the ideas initiated during the visits and expanded them, maintaining contact by email.

Astrophysics (2007-2009)

Daguesh Science n°

Topics in Molecular Astrophysics: From the Milky Way to Starburst and Active Galaxies Ofer Biham - PI (The Hebrew University of Jerusalem), Amiel Sternberg (Tel Aviv University), Israel Evelyne Roueff - PI, Jacques Le Bourlot, Franck Le Petit (Laboratoire de l’Univers et de ses Theories, Observatoire de Paris-Meudon, et Université Paris Diderot), Francois Boulanger, Emmanuel Dartois (Institut d’Astronomie Spatiale, Université Paris-Sud), France

hile the night sky observed from earth by the naked eye is dominated by stars, the Milky Way and other galaxies also include cold regions called interstellar clouds. These are huge clouds of gas and dust, which exhibit a great variety of physical and chemical processes. To date, more than 150 different molecular species, from simple diatomics to complex hydrocarbons, have been detected in such clouds. Stars are born in molecular clouds when the clouds collapse due to their own weight. During the billions of years of stellar evolution, stars eject energy as well as heavy elements into the surrounding medium via winds, jets, outflows, and shock waves. Molecules play a major role in these processes. Molecular astrophysics is the quantitative study of molecules in space. Of particular importance is the interplay between stars, protostellar systems and other objects such as black holes with the surrounding dusty interstellar media in which these objects exist and evolve. Recent advances in this field have been driven by the development of sensitive ground-based submillimetre and millimetre telescopes and high-resolution mm-wave interferometers. Major roles have also been played by space-based missions that enable to study infrared radiation, which is blocked by earth’s atmosphere. Molecular astrophysics has matured to the point where specific molecular cloud properties such as chemical composition, density, temperature, and dynamical state are now thought to be associated with distinct evolutionary phases in the galactic stellar lifecycle. Molecular gas in starburst and active galactic nuclei is not as well understood, but progress is being driven by a wealth of new observational data. This project, supported by the High Council for Scientific and Technological Cooperation between France and Israel brought together

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a team of French and Israeli scientists with overlapping interests and complementary expertise in the field of molecular astrophysics. The focus of this joint effort has been the formation of interstellar molecules via gasgrain interactions and their effect on the state and dynamics of interstellar clouds in various astrophysical environments. It has been known for long now that hydrogen molecules cannot form in the gas phase. It was concluded that they must form on the surfaces of interstellar dust particles, and the resulting molecule are then released to the gas. However, this scenario tells nothing about the details of the processes that must take place on the grain surface. This is where the expertise developed in Israel and in France meets.

formaldehyde and methanol, which are of great importance in interstellar chemistry. The tools that were developed during this collaboration will help solve the numerous issues raised by the observations. The resulting outcome is a validation of our understanding of the chemical and physical processes at work, not only within our galaxy but also in more perplexing environments like starburst and active galaxies.

The Jerusalem group made a detailed analysis of experimental formation of HD on cold surfaces. They could deduce quantitative values of the various binding energies and surface characteristics needed to modelise adsorption of an H atom on a surface, its migration from site to site by thermal and/or quantum hoping, and its eventual evaporation from the surface if no collision partner is found. They could also find a very clever development of the statistical description of this random process by a master equation formalism in the form of moment equations [1]. These moment equations allowed us to compute the effective rate of molecular hydrogen formation on microscopic grains. The equations were successfully incorporated into the Meudon PDR code [2], leading to a joint paper [3] that describes in detail the methodology and the results for the formation rates of hydrogen molecules as well as HD molecules. Interaction of atoms or molecules on grain surface has also been extended to heavier species, and we are currently testing the formation routes to molecules such as

B. Barzel and O. Biham, J. Chem. Phys. 127, 4703 (2007) M. Gonzalez Garcia, J. Le Bourlot, F. Le Petit, and E. Roueff, Astron. Astrophys. 485, 127 (2008)

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© HST images - NASA/ESA Molecular pillar in M16. The molecular cloud is embedded in a strong UV radiation field produced by young nearby stars. These photons shape the cloud by a photo-evaporation mechanism. Inside the cloud, the gas goes from an atomic phase to a molecular phase. One of the main important chemical mechanisms controlling this transition is the H2 formation on dust grains we study in this article.

F. Le Petit, B. Barzel, O. Biham, E. Roueff and J. Le Bourlot, Astron. Astrophys. 505, 1153 (2009)

Daguesh Science n°

Studies of Transiting Extra-Solar Planets Francois Bouchy - PI (Institut d’Astrophysique de Paris - CNRS UMR 7095), France Tsevi Mazeh - PI (Tel Aviv University), Israel

The Florence and George Wise observatory with its domes of the 1-meter and the 18-inch telescopes.

ne of the most fascinating fields in astronomy is the study of extra-solar planets – planets orbiting other stars. Discovered only in the last 15 years, these objects have shown characteristics that are very different from what we see in the solar system. Transiting exoplanets, whose orbits pass in front of their parent stars, allow astronomers to measure their exact radius, mass, and density. The French-Israeli collaboration, led by Francois Bouchy from Haute-Provence-Observatoire and Tsevi

Haute Provence Observatory

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Mazeh from Tel Aviv University, is studying transiting extra-solar planets. One of their projects led to the discovery of two new planets – HAT-P5 and HAT-P9. The discovery was made in two stages. In the first stage, the intensity of thousands of stars was monitored with a set of small telescopes located in Israel, Arizona and Hawaii. The data indicated that several stars show periodic drop of their intensity, suggesting a planet that goes periodically in front of its parent star and blocks some the stellar light. In the second stage, the candidates were observed with the high-precision SOPHIE spectrograph at the French telescope at Haute-Provence Observatoire and stellar velocity was monitored. The astronomers noticed that two stars show stellar velocity modulation with the same periodicity as the previously observed brightness modulation. The combination of

Publications linked to the collaboration. T. Mazeh and F. Bouchy- HAT-P-5b: A Jupiter-Like Hot Jupiter Transiting a Bright Star. Bakos, G. Á.; Shporer, A.; Pál, A.; Torres, G.; Bouchy, F.; Mazeh,T., et al., 2007, ApJ, 671, 173. Refined Parameters and Spectroscopic Transit of the Super-Massive planet HD 147506b. Loeillet, B.; Shporer, A.; Bouchy, F, T. Mazeh et al., 2008, A&A, 481, 529.

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In the context of the French-Israeli collaboration, Tsevi Mazeh and Francois Bouchy joined their efforts for the groundbased follow-up of the space mission CoRoT devoted to the detection of transiting planets. Using the 1-m and the Centurion 18-inch telescopes at Wise Observatory, and the SOPHIE spectrograph at Haute Provence Observatory, they actively participated in the confirmation and characterization of the first seven CoRoT exoplanets, including the first transiting super-earth CoRoT-7b with a radius of 1.6 earth-radii and a mass of 5 earthmasses. This planet is the first known rocky planet outside the solar system. The notion that there are many hidden planets in the universe we did not know about until now is exciting. Like Columbus and Magellan in the 15 and 16 centuries, astronomers are now involved in the fantastic adventure of discovering new worlds, some of which are very different from what we have known for centuries in our neighbourhood.

HAT-P-9b: A Low Density Planet Transiting a Moderately Faint F star. Shporer, A., Bakos, G., Bouchy, F., Mazeh, T. et al., 2008, ApJ, 690, 1393. The Spin-Orbit Angle of the Transiting Hot Jupiter CoRoT-1b. Pont, F, Endl, M., Bouchy, F., Mazeh, T., Shporer, A., 2009, MNRAS, 402, L1. The CoRoT-7 Planetary System: Two Orbiting Super-Earths. Queloz, D., Bouchy, F., Mazeh, T., et al., 2009, A&A, 506, 303.

Astrophysics (2007 - 2009)

the two types of observations confirmed the existence of planets around these stars and enabled the study of their physical characteristics. Both planets have masses and radii similar to Jupiter, the largest planet in our solar system. However, as opposed to our Jupiter, both new planets orbit their parent stars in very close orbits, HAT-P5 in a period of about three days, and HAT-P9 in a period of four days. Both systems are quite distant: HAT-P5 is at a distance of 1000 light years, and HAT-P9 at 1500 light years from us.

Ministry of National Infrastructures State of Israel

Ministry of Science and Technology State of Israel

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‫כנס יש‬ ‫צרפתי‬-‫אנרראלי‬ ‫בנושא גיות מתחדשות‬

Energies Renouvelables Colloque franco-israélien