Happy 20 th Anniversary

Transcription

1 Happy 20 th Anniversary Cell Signalling to Systems Biology Research TURKU CENTRE FOR BIOTECHNOLOGY REPORT 2009

2 Annual Report 2009 Turku Centre for Biotechnology Published by: Turku Centre for Biotechnology P.O. Box 123, FI Turku, Finland Tel. int , fax int Editorial Board Riitta Lahesmaa (Chair) Tero Aittokallio Eleanor Coffey Garry Corthals Michael Courtney Konstantin Denessiouk Attila Gyenesei John Eriksson Jyrki Heino Johanna Ivaska Panu Jaakkola Marko Kallio Olli Kallioniemi Päivi Koskinen Linnéa Linko Tassos Papageorgiou Lea Sistonen Jukka Westermarck Photographs: Roni Lehti, Photograph archives of the Centre for Biotechnology. Front cover image: Patrik Jones, back cover images: (2nd from top) Tassos Papageorgiou, (bottom) Marko Kallio, Photograph archives of the Centre for Biotechnology. Graphic Design: Anne Asplund, Finepress Oy Printed by: Finepress Oy, Turku ISSN

3 CONTENTS Board of Trustees... 2 Chairman s Foreword... 3 From the Director... 4 Year 2009 in a Nutshell... 6 PhD and MSc Theses... 9 Funding Personnel The Finnish DNA Microarray Centre The Proteomics Facility Cell Imaging Core (CIC) Virus Vector Facility Protein Crystallography Core Facility Data Mining and Modeling Group Protein Kinase Regulation of Brain Development and Disease Organisation of Neuronal Signaling Pathways Cytoskeletal and Survival Signaling Cell Adhesion and Cancer Hypoxia in Cell Survival Bioenergy Group Kinetochore and Cancer Research Group Canceromics Research Programme Signaling Pathways regulated by Oncogenic Pim Kinases Molecular and Systems Immunology and Stem Cell Biology Protein Crystallography Bioinformatics Unit Cell Fate Targeting Strategies for Gene Therapy Transcriptional Regulation of Heat Shock Gene Expression Cancer Cell Signaling Publications Life outside the Lab

4 ORGANIZATION Board of Trustees 2009 Chairman HEINO Jyrki, Professor, University of Turku, Department of Biochemistry and Food Chemistry, Scientific Director, BioCity Turku Vice-chairman ERIKSSON John, Professor, Åbo Akademi University, Department of Biology Secretary LAHESMAA Riitta, Professor, Director, Turku Centre for Biotechnology Assistant Secretary JAAKKOLA Minttu, Coordinator, Turku Centre for Biotechnology and BioCity Turku Members ARO Eva-Mari, Academy Professor, the Academy of Finland, University of Turku, Department of Biology JALKANEN Sirpa, Professor, University of Turku, MediCity Research Laboratory JOHNSON Mark, Professor, Åbo Akademi University, Department of Biochemistry and Pharmacy KOUVONEN Ilkka, CEO, Turku Science Park Ltd LAHTI Reijo, Professor, University of Turku, Department of Biochemistry and Food Chemistry LASSILA Olli, Professor, University of Turku, Department of Medical Microbiology PYRHÖNEN Seppo, Professor, University of Turku, Department of Oncology SAXÉN Henrik, Vice Rector, Research Professor, Åbo Akademi University, Heat Engineering Laboratory TÖRNQUIST Kid, Professor, Åbo Akademi University, Department of Biology Vice-members ARO Hannu, Professor, University of Turku, Department of Surgery HINKKANEN Ari, Professor of Cell and Molecular Biology, Åbo Akademi University, Department of Biochemistry HUPA Leena, Lecturer, Åbo Akademi University, Åbo Akademi Process Chemistry PIISPANEN Tero, Project Manager, Turku Science Park Ltd SALAKOSKI Tapio, Professor, University of Turku, Department of Information Technology SISTONEN Lea, Academy Professor, the Academy of Finland SOUKKA Tero, Academy Research Fellow, Academy of Finland, University of Turku, Department of Biotechnology TOPPARI Jorma, Professor, University of Turku, Department of Physiology CHAIRMAN S FOREWORD During the past years the expenses of the top-of-line instruments and the new research technologies have increased much faster than the budgets of the Universities. It is a well-known fact that the financing of the research infrastructure has become a major problem, not least in Finland. The six Finnish biocenters established in August 2006 a common organization, named as Biocenter Finland, to coordinate the development of national infrastructure and core facilities in life science area. Recently, the Finnish government decided to finance Biocenter Finland activities during the period by 45 M. The board of Biocenter Finland has already allocated most of its budget for different biocenters, including BioCity Turku. This funding allows Turku Centre for Biotechnology to renew its instrumentation in genomics, proteomics and bioimaging. Some funding has also been granted to bioinformatics, structural biology and virus vectors. Biocenter Finland financing will also be used to support core facilities in the Turku Center for Disease Modeling and the Turku PET centre. It is fair to say that without the support from Biocenter Finland it would have not anymore been possible to provide modern equipment and technologies for Finnish life scientists. Despite this positive development, the future of the research infrastructure remains to be a major concern in all Finnish biocenters, since the present support ends after year We should all work actively to secure the continuation of national infrastructure funding also after that. Turku Centre for Biotechnology has a long tradition in the building of high quality core facilities that have had numerous users also outside Turku. During the progression of the Biocenter Finland process the Turku core facilities will get even more important national role. It has been satisfying to realize that the organization and the administration of the core facilities are more advanced in Turku than anywhere else in Finland and that the working methods developed in Turku are often announced as ideal models for other biocenters. The beginning of the year 2010 brought remarkable changes in the Finnish university administration and implementation of new full-cost model in the research grants. For many scientists this has meant a huge increase in the number of hours used in the administration of the departments and the research projects. Similarly, the workload of the persons, who are directly involved in the maintenance of the departments has also dramatically increased. The complexity of the financial systems and the lack of proper computer programs have caused a lot of extra work and uncertainty. We can only hope that during the years to come the scientists will again be allowed to concentrate on research instead of administrative problems. Jyrki Heino, M.D., Ph.D., Professor of Biochemistry, Scientific Director of the BioCity Turku and Chairman of the Board of the Turku Centre for Biotechnology 2 3

5 FROM THE DIRECTOR Turku Centre of Biotechnology (CBT) was established in 1989 as a joint independent department of University of Turku and Åbo Akademi University. Today, it has evolved into a multidisciplinary research and service unit successfully crossing the boundaries of departments, faculties and even two universities! During the past 20 years Turku University and Åbo Akademi University have been centralizing demanding and expensive core facilities and research services to CBT to enable the most cost efficient use of the facilities for the local research community. CBT has developed into an internationally recognized research environment and today provides state-of the-art core facilities for altogether 80 BioCity Turku research groups and six research programs featuring altogether seven Academy of Finland Centers of Excellence. In June 2009 CBT celebrated its 20th anniversary with a symposium From Cell Signaling to Medical Systems Biology with participation of world class scientists many of whom are closely linked to CBT. The symposium dinner in Turku Castle was the highlight of the festivities. CBT has three key focus areas: 1) research, 2) education and training, and 3) providing core facilities and state-of the-art technologies and research services in selected areas. The central areas of research are cell signaling, regulation of gene and protein expression and their interactions and systems biology. In 2009 we published 54 papers and 7 Ph.D.s were completed. Our group leaders were very active in organizing seminars, courses and symposia. Two new international group leaders were recruited. The Centre s core facilities developed technology platforms and services in a close interaction with researchers. A significant investment has been made in developing the state-of-the-art platforms in genomics and functional genomics, proteomics, cell imaging and bioinformatics supporting the omics technologies. The animal core facility takes up a sizeable portion of basic resources in serving researchers and Turku Centre for disease modelling. A joint organization of the Finnish biocenters, Biocenter Finland, was established in 2006 to facilitate national collaboration and to coordinate development of research infrastructures in Finland. In 2009, several of CBT group leaders worked intensively in various Biocenter Finland infrastructure networks and prepared for applications to develop infrastructures with funds Ministry of Education allocated to Biocenter Finland for this purpose. An international evaluation process resulted in substantial support to develop infrastructures, many of them at CBT. Hence, in addition to serving local needs, CBT now further develops and provides national services in several areas within the Biocenter Finland infrastructure network. Bioimaging and systems biology are the central infrastructures in the research strategy of Biocity Turku, and in the research strategy of both our universities. Vigorous development of technology platforms, research core facilities, and research infrastructures will continue, and support for both instrumentation and personnel will be provided. This extended collaborative network and available funding should provide us with new efficient ways to further develop the research infrastructure in Finland. The universities prepared for going through a major change in the beginning of This included definition of new strategies for universities and Biocity Turku. Both the University of Turku and Åbo Akademi University chose to profile themselves as a research university, which is an excellent environment for CBT to build and develop on its strengths in research and research infrastructure. Moreover, molecular biosciences, CBT s core competence is one of the central strategic strong areas of research. An important strategic goal of our universities is internationalization and international competitiveness. The universities strive towards strategic recruitment practice, to attract researchers with international merit. This has always been a practice at CBT. In fact, Finnish group leaders are a minority at our Centre. Our host universities commitment in internationalization will hopefully improve also availability of important administrative documents and meetings in English so that our foreign researchers and personnel can fully contribute to the development of our organizations. The past year was very successful. Active participation to Biocenter Finland infrastructure networks and numerous administrative challenges and changes increased the workload of our researchers as well as technical and administrative personnel. In spite of that, scientific achievements include several special awards and grants as well as papers published in top ranked journals by our scientists. It is my great pleasure to congratulate our scientists for their excellent achievements and thank everyone involved - including the CBT technical and administrative staff for their outstanding contributions. My special thanks to Dr. Eleanor Coffey, our current Vice Director, for taking the responsibility of directing and taking care of several duties of our Centre in 2009 and enabling me to carry out a sabbatical at Harvard Medical School. She took an extraordinary and outstanding care of the Centre. Thank you! Riitta Riitta Lahesmaa, M.D., Ph.D., Professor Director Turku Centre for Biotechnology University of Turku and Åbo Akademi University 4 5

6 YEAR 2009 IN A NUTSHELL RESEARCH AND EDUCATION scientific papers were published Seven new Ph.D. s graduated CBT was awarded substantial funding (approximately 4 million ) from the Biocenter Finland infrastructure networks Two new international group leaders were recruited For undergraduate training, CBT again organized lecture courses and practical demonstrations including a laboratory course on Functional Genomics for Health Bioscience and Biology students (4 study points) and on Medical Biotechnology for Medical students (5 study points) The 20th anniversary was celebrated with a symposium From Cell Signaling to Medical Systems Biology 8 M.Sc. theses were completed DEVELOPMENT OF INFRASTRUCTURE, RESEARCH SERVICES AND CORE FACILITIES 2009 Finnish DNA Microarray Centre 2009 The next-generation sequencing instrument: ABI SOLiD 3 was acquired and almost immediately upgraded to version 3Plus FDMC s website was renovated to improve the visibility of the centre s services Several events were organized in collaboration with various instrument manufacturers throughout the year to spread information on available and emerging technologies related to our services FDMC personnel gave talks in many scientific events and organized training courses to educate researchers on various topics Major efforts were carried out to further develop our project consultation services to help customers design their experiments. Also the centre s bioinformatics team continued developing bioinformatics data analysis services Proteomics and Mass spectrometry Laboratory 2009 We became national coordinator of the new Proteomics and Metabolomics network of Biocentre Finland and secured BCF funding for personnel and instrumentation We coordinated three Nordic Networks on proteomics and mass spectrometry Several courses were organised nationally and internationally in collaboration with Nordforsk networks, FinnProt and the local universities QStar Elite: A second-hand Elite mass spectrometer was purchased and configured to run in-line with Dionex 3000 LC system Converted HCT Esquire (Ion trap, Bruker) for nanospray LC-MS/MS Cell Imaging Core 2009 CIC was awarded substantial funding for in vivo and high resolution imaging from the Biocenter Finland Biological Imaging network CIC coordinated the Nordic Network on Imaging in Biology and Medicine with participation from Finland, Sweden, Norway, Russia, Denmark and Ireland. Network symposia and training events were held in Finland, Sweden, Ireland and Norway The Leica TCS-SP5 Stimulated Emission Depletion (STED) microscope for high resolution imaging were installed Daniel Abankwa was recruited from the Institute for Molecular Bioscience in Brisbane. He joined CBT as group leader and head of CIC CIC coordinated a plan to provide centralized, large scale data storage to the imaging community in Turku. This will be realized during 2010 in cooperation with Prof. Mark Johnson at Åbo Akademi Viral vector facility 2009 Lenti vector production was added to its service repertoire Funding was secured from the Biocenter Finland Viral Gene Transfer infrastructure network to provide gene transfer tools to researchers Ketlin Adel was recruited as a new lab technician dedicated to service provision The Bio-safety level 2 lab was furnished with an inverted fluorescence microscope Jari Heikkilä, consultant on Lenti virus production, produced an exciting study on the use of oncolytic alphavirus for glioma treatment. This work was published in PLoS One in January 2010 Bioinformatics Unit 2009 The High-throughput bioinformatics group organized a two-day Chipster microarray data analysis course in collaboration with CSC High-throughput screening of natural molecules was established in conjunction with Prof. Pia Vuorela at Åbo Akademi University Increased collaboration between our unit and CSC in high power computing and cloud computing Participated in projects involving analysis of protein-protein and protein-ligand interactions, computer-aided prediction and intelligent molecular modeling and design; computerbased ligand docking and analysis; effects of molecular recognition and mutations on protein function Training of Ph.D. students in Bioinformatics and Computational Biology within the National Graduate School of Informational and Structural Biology. Contribution to courses organized by CBT and Åbo Akademi University Plans made to increase high-capacity storage infrastructure for archiving services to support Structural Bioinformatics, Structural Biology, Translational Area, Drug Discovery, Chemical Informatics and Bioimaging 6 7

7 Protein crystallography facility 2009 Continued participation in several courses (Medical Biochemistry, TERBIO) and initiation of new ones (Protein Crystallography and Structural Genomics, How to solve a protein structure) with lectures and demonstrations in the X-ray facility Organised workshop How to get the most from the protein structures New collaborative projects initiated with other groups in Finland and abroad All major crystallographic programs were kept upgraded to latest versions Funding received from Biocenter Finland towards a new X-ray generator Quality Assurance Unit 2009 Organized courses for the university on (1) quality assurance and metrology and (2) how to assure the reliability of your laboratory test results Individual training for graduate and post-graduate students Carried out GLP inspections for the Central Animal Laboratory PhD and MSc Theses 2009 PhD Theses Name Supervisor Site besides CBT Anckar, Julius Sistonen, Lea, ÅA/ Dept. of Biology Kaunisto, Aura Eriksson, John UTU/ Dept. of Biology Kochin, Vitaly Eriksson, John ÅA/ Dept. of Biology Mattila, Elina Ivaska, Johanna VTT/ UTU/Department of Medical Biochemistry and Genetics Mialon, Antoine Westermarck, Jukka UTU/Department of Medical Biochemistry and Genetics Pellinen, Teijo Ivaska, Johanna VTT/ UTU/Department of Medical Biochemistry and Genetics Åkerfelt, Malin Sistonen, Lea ÅA/ Dept. of Biology MSc Theses Name Supervisor Site besides CBT Männistö, Katja Koskinen, Päivi UTU/Dept. of Biology Lindquist, Julia Eriksson, John UTU/Dept. of Biology Rautoma, Karoliina Sistonen, Lea ÅA/ Dept. of Biology Rosenberg, Susanna Eriksson, John UTU/Dept. of Biology Sachin, Wakadkar Papageorgiou, Tassos University of Skövde, Sweden Stykki, Heidi Eriksson, John UTU/ Dept. of Biology Sun, Lihua Coffey, Eleanor Tampere University of Technology CBT staff from left to right, front row: Virpi Korpiranta, Sarita Heinonen, Taina Kalevo-Mattila, Hannele Vuori, second row: Marjo Hakkarainen, Riitta Lahesmaa, Riina Plosila, Aila Jasmavaara, Susanna Pyökäri, Eva Hirvensalo, Sirkku Grönroos, back row: Juha Strandén, Jouko Sandholm, Markku Saari, Pasi Viljakainen, Mikael Wasberg, Satu Alanko, Perttu Terho, Petri Vahakoski, Mårten Hedman, Petri Kouvonen, Arttu Heinonen. 8 9

8 FUNDING PERSONNEL 2009 Sources of funding received by Centre for Biotechnology in 2009 (9.4 Million ) Services 20% Academy of Finland 15% Tekes 3% Universities 37% Others 12% EU 13% Administration LAHESMAA Riitta, Director, Professor, Group Leader GRÖNROOS Sirkku, Senior Administrative Assistant HEINO Ilona, Student HIRVENSALO Eva, Clerical Official JAAKKOLA Minttu, Coordinator JASMAVAARA Aila, Clerical Official PLOSILA Riina, Coordinator BioCity Turku HEINO Jyrki, Biocity Turku Scientific Director, Professor JAAKKOLA Minttu, Coordinator Technical Staff ANDERSEN Raija, Laboratory Technician HEDMAN Mårten, Systems Manager KORPIRANTA Virpi, Instrument Maintenance SARA Rolf, WASBERG Mikael, Laboratory Manager SOITAMO Ann-Christine, Student STRANDÉN Juha, Laboratory Engineer VAHAKOSKI Petri, Systems Manager VILJAKAINEN Pasi, Senior Technician VUORI Hannele, Instrument Maintenance Data Mining and Modeling AITTOKALLIO Tero, Group Leader, Adjunct Professor ELO Laura, Postdoctoral Fellow GAO Bin, Undergraduate Student HIISSA Jukka, Graduate Student JÄRVINEN Aki, Undergraduate Student KOSKINEN Ville, Undergraduate Student LAAJALA Essi, Undergraduate Student LAAJALA Teemu Daniel, Undergraduate Student LINDEN Rolf, Graduate Student NATRI Lari, Undergraduate Student OKSER Sebastian, Graduate Student PIIPPO Mirva, Undergraduate Student SALMELA Pekka, Undergraduate Student SALMI Jussi, Postdoctoral Fellow TUIKKALA Johannes, Graduate Student VÄHÄMAA Heidi, Graduate Student Protein Kinase Function in Brain Development and Disease COFFEY, Eleanor, Group Leader, Academy of Finland Research Fellow BIALEK Agnieska, Undergraduate Student DESHPANDE Prasannakumar, Graduate Student HEALY Mary-Ann, Undergraduate HEIKILÄ. Hanna, Undergraduate Student KOMULAINEN, Emilia, Graduate Student MOHAMMAD Hasan, Graduate Student MYSORE, Raghavendra, Graduate Student PADZIK, Artur, Graduate Student Pyökäri Susanna, Laboratory Technician SUN Lihua, Graduate Student TUITTILA Minna, Postdoctoral Researcher WANG Yubao, Graduate student ZDROJEWSKA, Justyna, Graduate student Proteomics and Mass Spectrometry CORTHALS Garry, Group Leader, Head of Proteomics ANDERSÉN Raija, Laboratory Technician CARREIRA DOS SANTOS Hugo Miguel Baptista, Visiting Graduate Student HEINONEN Arttu, Project Engineer KANNASTE Olli, Undergraduate Student KAUNISMAA Katri, Undergraduate Student KOUVONEN Petri, Researcher RALPH Eliza, Systems Administrator ROKKA Anne, Postdoctoral Fellow SUNI Veronika, Graduate Student VEHMAS Anni, Undergraduate Student NEES Susanne, Coordinator SAEDI Firouz, Undergraduate student Organisation of Neuronal Signaling Pathways COURTNEY Michael, Professor, Group Leader HO, Franz, Postdoctoral Researcher LI, Lili, Graduate Student LIU, Xiaonan, Graduate Student LOPEZ RODRIGUES, Maykel, Graduate Student MARTINSSON, Peter, Postdoctoral Researcher PEVGONEN, Veera, Technicain TUITTILA Minna, Postdoctoral Researcher VERGUN, Olga, Postdoctroal Researcher WANG, Xijun, Graduate Student YADAV, Leena, Graduate Student Protein Phosphorylation Group ERIKSSON John, Group Leader, Professor ASAOKA Tomoko, Graduate Student FERRARIS Saima, Graduate Student HYDER Claire, Graduate Student IMANISHI Susumu, Postdoctoral Fellow KASTU Juha, Project Engineer KAUNISTO Aura, Post-doctoral Fellow KOCHIN Vitaly, Graduate Student LAZARO, Glorianne, Exchange Student LINDQVIST Julia, Graduate Student ISONIEMI Kimmo, Graduate Student PALLARI Hanna-Mari, Graduate Student PEUHU Emilia, Graduate Student REMES Mika, Graduate Student SAARENTO Helena, Research Associate SÖDERSTRÖM Thomas, Post-doctoral fellow TORVALDSON Elin, Graduate student Cell Imaging Core COFFEY Eleanor, Academy of Finland Research Fellow, Coordinator of the Cell Imaging Unit ERIKSSON John, Group Leader, Professor 10 11

9 KORHONEN Jari, Project Engineer SANDHOLM Jouko, Research Engineer TERHO Perttu, Project Engineer Cell Adhesion and Cancer IVASKA Johanna, Group Leader, Professor ARJONEN Antti, Undergraduate Student HÖGNÄS Gunilla, Undergraduate Student MARTTILA Heidi, Laboratory Technician MAI Anja, Graduate student MATTILA Elina, Graduate student NEVO Jonna, Graduate Student PELLINEN Teijo, Graduate student SIIVONEN Jenni, Laboratory Technician TUOMI Saara, Graduate Student VELTEL Stefan, Postdoctoral Fellow VUORILUOTO Karoliina, Graduate Student Hypoxia Group JAAKKOLA Panu, Group Leader, Adjunct Professor, Academy Research Fellow, the Academy of Finland HEIKKINEN Pekka, Graduate Student HIMANEN Virpi, Undergraduate Student HÖGEL Heidi, Graduate Student JOKILEHTO Terhi, Graduate Student KALEVO-MATTILA Taina, Laboratory Technician KULJU Tuomas, Undergraduate Student NUMMELA Marika, Graduate Student PURSIHEIMO Juha-Pekka, Postdoctoral Fellow RANTANEN Krista, Graduate Student RÄMÖ Olli, Undergraduate Student VUORINEN Raisa, Laboratory Technician Kinetochore and Cancer Research Group KALLIO Marko, Group Leader, Senior Research Scientist, Adjunct Professor AHONEN Leena, Postdoctoral Fellow HALONEN Tuuli, Undergraduate Student JAAKKOLA Kimmo, Postdoctoral Fellow KUKKONEN-MACCHI Anu, Graduate Student MÄKI-JOUPPILA Jenni, Graduate Student NARVI Elli, Postdoctoral Fellow OETKEN-LINDHOLM Christina, Postdoctoral Fellow SALMELA Anna-Leena, Graduate Student TOIVONEN Pauliina, Laboratory Technician WINSEL Sebastian, Postdoctoral Fellow VUORILUOTO Mariaana, Graduate Student Canceromics Reasearch Programme KALLIONIEMI Olli, Group Leader, Director PLOSILA Riina, Coordinator AAKULA Anna, Graduate Student BUCHER Elmar, Graduate Student BJÖRKMAN Mari Graduate Student GUPTA Santosh, Graduate Student KETOLA Kirsi, Graduate Student KOHONEN Pekka, Graduate Student POLLARI Sirkku, Graduate Student VAINIO Paula, Graduate Student Signaling Pathways Regulated by Oncogenic Pim Kinases KOSKINEN Päivi, Group Leader, Adjunct Professor EEROLA Sini, Undergraduate Student LAITERÄ Tiina, Undergraduate Student MÄNNISTÖ Katja, Undergraduate Student RAINIO Eeva-Marja, Postdoctoral Fellow SANDHOLM Jouko, Graduate Student SANTIO Niina, Undergraduate Student VAHAKOSKI Riitta, Graduate Student VIRTANEN Juho, Undergraduate Student Molecular Immunology Group LAHESMAA Riitta, Director, Professor, Group Leader AHLFORS Helena, Graduate Student FILEN Sanna, Graduate Student GUPTA Bhawna, Postdoctoral Fellow HAKKARAINEN Marjo, Laboratory Technician HEINONEN Mirkka, Graduate Student HEINONEN Sarita, Laboratory Technician JÄRVENPÄÄ Henna, Graduate Student KORHONEN Juha, Graduate Student KUMAR Sunil, Postdoctoral Fellow KYLÄNIEMI Minna, Graduate Student LAHTI Essi, Undergraduate Student LUND Riikka, Postdoctoral Fellow LÖNNBERG Tapio, Graduate Student MOULDER Robert, Senior Scientist NYSTRÖM Joel, Undergraduate Student NÄRVÄ, Elisa, Undergraduate Student RAHKONEN Nelly, Undergraduate Student RASOOL Omid, Adjunct Professor, Senior Scientist SALONEN Verna, Graduate Student TAHVANAINEN Johanna, Graduate Student TRIPATHI Subhash, Graduate Student TUOMELA Soile, Graduate Student Quality Assurance Unit LINKO Linnéa, Group Leader, Adjunct Professor Computational Systems Biology ORESIC Matej, Group Leader, Adjunct Professor, Chief Research Scientist KATAJAMAA Mikko, Graduate Student LÖNNBERG Tapio, Graduate Student Protein Crystallography PAPAGEORGIOU Tassos, Group Leader, Adjunct Professor AGIUS Jeremie, Exchange Student ANDERSSON Charlotta, Graduate Student CHOUHAN Bhanupratap Singh, Undergraduate student DHAVALA Prathusha, Undergraduate Student DUBREUIL Christine, Student HAIKARAINEN Teemu, Graduate Student HAVUKAINEN Heli, Graduate Student KAUKO Anni, Postdoctoral Fellow ROUE Carole, Undergraduate Student SAARINEN Susanna, Graduate Student WECKSTRÖM Kristian, Senior Scientist Bioinformatics Unit DENESSIOUK Konstantin, Group Leader (Structural Bioinformatics) GYENESEI Attila, Group Leader (High-throughput Bioinformatics) CHOUHAN Bhanupratap Singh, Graduate Student JUNTTILA Sini, Graduate Student LAIHO Asta, Project Engineer KYTÖMÄKI Leena, Undergraduate Student TAMMINEN Seppo, Undergraduate Student Cell fate SAHLGREN Cecilia, Group Leader, Academy of Finland Research Fellow MAMAEVA Veronika, Postdoctoral Fellow HIETAMÄKI Marika, Graduate Student LANDOR Sebastian, Graduate Student BATE-EYA Laurel Tabe, Graduate Student ANTFOLK Daniel, Undergraduate Student ANTILA Christian, Undergraduate Student GRANQVIST Cecilia, Undergraduate Student NIEMI Rasmus, Undergraduate Student SAARENTO, Helena, Laboratory Technician Targeting Strategies for Gene Therapy SAVONTAUS Mikko, Group Leader, Adjunct Professor EEROLA Kim, Graduate Student MATTILA Minttu, Undergraduate Student TOIVONEN Raine, Graduate Student Transcriptional Regulation of Heat Shock SISTONEN Lea, Group Leader, Professor, Academy Professor until July 2009 AALTO Anna, Undergraduate Student AHLSKOG Johanna, Graduate Student ANCKAR Julius, Postdoctoral Fellow BERGMAN Heidi, Undergraduate Student BJÖRK Johanna, Graduate Student BLOM Malin, Undergraduate Student BLOMSTER Henri, Graduate Student BUDZYNSKI Marek, Graduate Student CHITIKOVA Zhanna, Graduate Student ELSING Alexandra, Graduate Student HENRIKSSON Eva, Postdoctoral Fellow KARLBERG Henrica, Undergraduate Student RAUTOMA Karoliina, Undergraduate Student SAARENTO Helena, Research Associate SANDQVIST Anton, Graduate Student SIIMES Jenny, Undergraduate Student VARTIAINEN Aki, Undergraduate Student VIHERVAARA Anniina, Graduate Student ÅKERFELT Malin, Postdoctoral Fellow Finnish DNA Microarray Centre GYENESEI Attila, Group Leader SARA Rolf, Technical Team Leader, Laboratory Manager Juha-Pekka Pursiheimo, Senior Scientist HEINONEN Tiia, Laboratory Technician JUNNI Päivi, Laboratory Technician NURMI Miina, Laboratory Technician RISSANEN Oso, Laboratory Technician SIPILÄ Anna, Undergraduate Student VENHO Reija, Laboratory Technician VIRTANEN Eveliina, Project Engineer KYTÖMÄKI Leena, Biotechnology Engineer LAIHO Asta, Project Engineer TAMMINEN Seppo, Undergraduate Student JUNTTILA Sini, Project Engineer Cancer Cell Signaling WESTERMARCK Jukka, Group Leader, Professor, CÕME Christophe, Postdoctoral Fellow HALONEN Tuuli, Graduate Student KALEVO-MATTILA Taina, Laboratory Technician KAUR Amanpreeet, Graduate student LAINE Anni, Graduate Student MANNERMAA Leni, Scientist MIALON Antoine, Graduate Student NIEMELÄ Minna, Graduate Student OKKERI Juha, Postdoctoral fellow POKHAREL Yuba, Postdoctoral fellow VENTELÄ Sami, Postdoctoral Fellow Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) VUORIO Eero, BBMRI Executive Manager, Chancellor SALMINEN-MANKONEN Heli, Adjunct professor, Project manager GRÖNROOS Sirkku, Project assistant 12 13

10 The Finnish DNA Microarray Centre Head: Attila Gyenesei, Ph.D., Senior Scientist, Group leader Contact information: Turku Centre for Biotechnology, BioCity, Tykistökatu 6A, P.O. Box 123, FIN-2050 Turku, Finland. Tel Fax Personnel: Tiia Heinonen, Päivi Junni, Leena Kytömäki, Asta Laiho, Miina Nurmi, Oso Rissanen, Rolf Sara, Reija Venho, Eveliina Virtanen, Juha- Pekka Pursiheimo, Riikka Lund, Sini Junttila, Seppo Tamminen, Sarita Heinonen, Ritva Ala-Kulju, Anna Sipilä General description: The Finnish DNA Microarray Centre (FDMC) is an internationally recognised Functional Genomics Core Facility that is part of the Turku Centre for Biotechnology. As a national core facility, we provide state-of-the-art research technologies and services in the areas of genomics, epigenomics, transcriptomics and bioinformatics for the Finnish as well as the international scientific community. Our services include next-generation sequencing, microarray based services (gene expression analysis, exon-specific expression analysis, mirna analysis, ChIP-on-chip analysis, acgh and SNP genotyping), Real-Time PCR and traditional DNA sequencing. Our service covers all steps from experimental planning and design to sample processing and bioinformatics data analysis. The centre also regularly organizes courses, symposia and training for its users. FDMC hosts commercial microarray platforms for genome-wide RNA expression profiling, SNP genotyping and comparative genomic hybridization needs. These platforms include Affymetrix GeneChip, Illumina Sentrix Bead Array and Agilent DNA technology services for all of which we have been granted the Certified Service Provider status. All platforms have dedicated scanners and software for array data analysis. Diverse aspects of the microarray techniques are continuously developed and tested. During 2009 the Centre acquired a high-throughput nextgeneration sequencing (NGS) instrument SOLiD TM 3Plus from Applied Biosystems. The system supports a wide range of genetics applications covering genomics, transcriptomics and epigenomics and it is distinguished by its unmatched accuracy and capability of generating more than 60 gigabases of map-able sequence data per run. The combination of increased throughput, shorter run times, and improved data analysis make the SOLiD technology an ideal choice for research applications in any genetics project. The system enables for example distinguishing strand specific expression patterns, discovery of novel transcripts and splice variations without the bias of microarrays, detecting SNPs at low coverage with a low false positive rate, global assessment of DNA-protein binding interactions and characterization of structural rearrangements including balanced translocations. The Microarray Centre offers a number of other genomic analysis technologies for gene expression, SNP and genotyping studies including a sequencing facility and real-time PCR service. Services include BioRad Experion runs for verifying the RNA quality. Bioinformatics data analysis and data mining are included in the data analysis service that is provided for microarray and nextgeneration sequencing customers. The data handling is done by our bioinformaticians, using both commercial and R/Bioconductor software tools. Seminars and practical courses on microarrays and related bioinformatics are held frequently to facilitate knowledge transfer within the field, often this is done in collaboration with graduate schools. Funding: Ministry of Education and the Centre of Expertise of Southwest Finland Users: Finnish DNA Microarray Centre has customers from Finnish universities, biocenters and research institutes in the field of biosciences as well as local companies and foreign companies and universities - altogether from more than 200 research groups. Illumina Sentrix Bead Array service was started with whole human and mouse genome transcriptomic profiling and from the beginning of 2007 rat arrays have also been offered for gene expression studies. Illumina s GoldenGate Assay protocol provides high-quality and high-multiplex genotyping. Affymetrix GeneChip service has provided whole transcript expression arrays for human, mouse and rat, and expression arrays for a wide selection of organisms. Platform also provides many arrays for SNP detection and copy number variation. Agilent DNA technology service has provided whole genome expression arrays, which are designed and validated for onecolor and two-color processing. From 2007 these have been also available as multi-packs. Beside catalog arrays also custom arrays have been processed. Also micro RNA arrays are available. From left to right: Leena Kytömäki, Sini Junttila, Päivi Junni, Leni Mannermaa, Sanna Vuorikoski, Attila Gyenesei, Riikka Lund, Juha-Pekka Pursiheimo, Eveliina Virtanen, Reija Venho, Sarita Heinonen

11 THE PROTEOMICS FACILITY Head: Garry Corthals, Ph.D. (2005). Address: Turku Centre for Biotechnology, BioCity, Tykistökatu 6, P.O. Box 123, FI Turku, Finland. Tel , Fax Personnel: Senior scientists: Dr. Anne Rokka, Ph.D.; Associate scientist: Petri Kouvonen, M.Sc. (Ph.D. student); Laboratory Engineer: Arttu Heinonen; Technician: Raija Andersen; Bioinformatician: Eliza Ralph Steering Committee: Prof. Eva-Mari Aro (University of Turku), Dr. Eleanor Coffey (Åbo Akademi University), Prof. John Eriksson (Åbo Akademi University), Prof. Jyrki Heino (University of Turku), Prof. Riitta Lahesmaa (CBT), Prof. Matti Poutanen, Prof. Craig Primmer (University of Turku), Prof. Jukka Westermarck (CBT) and Prof. Johanna Ivaska (VTT & CBT) General description: The facility aims to support life science research in need of proteomics and MS services. Key questions revealed by proteomics technologies are differences in protein abundance, measurement of post translational modifications, defining protein complexes that carry out specific functions and localisation of proteins in tissues. To address these questions, the facility develops and innovates, in collaboration with national research groups, new methodologies in proteomics. Most services provided by the facility focus on mass spectrometric strategies integrated with protein and peptide enrichment workflows for large-scale quantitative analysis of proteomes or detailed characterisation of single proteins, such as their state of phosphorylation. In recent years the facility has developed a wide basis of operation and expertise, which are: Quantitative proteomics several groups are independently using labelling itraq and more recently SILAC based quantitation. In addition, several projects are providing a framework for development of label-free quantitative analysis, especially useful for clinical samples. Post-translational modifications several groups have now published new tools in analysis of protein phosphorylation and sumoylation. Mass spectrometry imaging MS imaging continues to develop locally, with expansion of the activities taken up in the new Master s Degree Programme in Biomedical Imaging. Biological mass spectrometry numerous groups use the Facility for additional analytical services that are not directly related to proteomics, such as protein, peptide and small molecule structure determination, mass determination and peptide and protein purity analysis. Protein separation by liquid chromatography and a variety of gel based methods such as 1-DE, 2-DE, peptide-ipg and blue native gel electrophoresis. Bioinformatics identification, quantitation and validation studies, reporting and software development. From left to right: Anne Rokka, Arttu Heinonen, Petri Kouvonen, Eliza Ralph

12 The core operations of the facility are in services and training in proteomics to the local and national biosciences community. In doing so the facility aims to cover diverse fields requiring the analysis of proteins in cells, tissues, organisms and body fluids. To achieve this, the facility is active in the following three activities: Analytical services The aim is to offer the best possible analytical proteomics services to bioscience researchers in academia and industry, both locally and nationally through Biocentre Finland coordinated activities. Locally, a broad range of MS analyses are performed, whilst at the national level the facility spearheads developments in two of its services; MS-based quantitative proteomics and phosphorylation determination. Training Our aim is to organise and coordinate of training events and symposia focusing on Proteomics, mass spectrometry and computational tools and procedures for the analysis of MS data. Innovation The facility develops tools and procedures in collaboration with facility users and groups. Through activities linked to Biocenter Finland services, two focus areas of development for the facility are in quantitation and phosphorylation analysis. The facility has excellent instrumentation for a wide range of MS analyses, including four different mass spectrometers: an Ultraflex II (MALDI-TOF/TOF), a QStar Pulsar and Elite (ESI-QqTOF) and a Esquire HTC (ESI-ion trap MS). The ESI instruments are all in-line coupled to nanohplc systems, and can also be used for direct nanospray ESI. Additional nanohplc systems robotic microfraction collectors enable real-time collection of peptide fractions, direct on MALDI targets. A LIMS system and computational analysis pipeline. The facility also hosts hotel services where visiting scientists can use shared facility space for sample preparation and analysis. In addition to analytical services, the facility organises and participates in national collaborative programs and research efforts with others throughout the Nordic region and worldwide. The facility also participates actively in national and international educational programs in Europe and abroad, such as Nordforsk, EuPA and HUPO. Funding: Biocenter Finland, The Academy of Finland, TEKES, City of Turku, Ministry of Education/Proteomics and the Centre of Expertise of Southwest Finland, Turku University and Åbo Akademi University, Bruker Daltonics, the Systems Biology Research Program. Users: Biocentre Finland universities, The University of Turku, Åbo Akademi University, Turku Polytechnic. CoE s in: Translational Genome-Scale Biology; Evolutionary Genetics and Physiology; Integrative Photosynthesis and Bioactive Compound Research at Systems Biology Level; and Åbo Akademi CoE in Cell Stress. The Systems Biology Research Program, national research groups, Turku Hospitals, the Finnish Red Cross and the National Animal Research Centre. CELL IMAGING CORE (CIC) Coordinator and group leader: Eleanor Coffey, Ph.D., Adjunct Professor in Cellular and Molecular Biology, Turku Centre for Biotechnology, BioCity, 5 th floor, Tykistökatu 6, FI-20521, Finland. Tel , Fax eleanor.coffey@btk.fi Technical Team: Jouko Sandholm, M.Sc., Senior Researcher Microscopy, jouko.sandholm@btk.fi, Perttu Terho, B.Sc., Technical Engineer Flow Cytometry, perttu.terho@btk.fi Imaging Consultants: Prof. Michael Courtney, Ph.D., Research Director, A.I.Virtanen Institute, University of Kuopio, Finland. mjczmjc@gmail.com Kaisa Heiskanen, Ph.D., Orion Pharma. kaisa.heiskanen@ orionpharma.com Steering Committee: Prof. Olli Carpén, M.D., Ph.D., Prof. John Eriksson (chairman), Ph.D., Prof. Jyrki Heino, M.D., Ph.D., Prof. Pekka Hänninen, Ph.D., Prof. Sirpa Jalkanen, M.D., Ph.D., Prof. Riitta Lahesmaa, M.D., Ph.D., Prof. Olli Lassila, M.D., Ph.D., Prof. Matti Poutanen, Ph.D., Prof. Lea Sistonen, Ph.D., Kid Törnquist, Ph.D. The Cell Imaging Core (CIC) is a centralised facility that coordinates biological imaging activities between the University of Turku, Åbo Akademi University, VTT Technical Research Centre, Turku Functional Genomics Centre, the National Centre for Disease Models and the biophysics community, while providing services at the national level. The mission of CIC is to provide state-of-theart cell imaging and cell sorting technologies and to make them available to academic and industrial researchers. The primary goal of CIC is to enhance the research and teaching environment of BioCity Turku. To help meet these goals, the core unit provides technical training to local and visiting researchers and to industries offers consultation on experimental design and image analysis evaluates new methods and fluorescence tools and communicates acquired knowledge to users implements advances in hardware and software relevant for biomedical sciences provides ongoing education in theory and practice by organising training courses and international workshops As a result, CIC has grown in significance, the services provided being instrumental to the publication of over 200 international scientific articles in recent years, many of which are in the most prestigious journals. Our staff include a coordinator and experienced applications specialists who maintain the instruments, learn new technologies and most importantly, provide personal training to users. Our areas of technical expertise are confocal microscopy 18 19

13 University Medical School, Chicago), Irina Majoul (Royal Holloway, London), Scott Brady (University of Illinois at Chicago), Gyorgy Hajnoczky (Thomas Jefferson University, Philadelphia), Michael Courtney (University of Kuopio), Teng Leong-Chew (Northwestern University Medical School, Chicago), Stephen Ogg (Institute of Medical Biology, Singapore), Kota Miura (EMBL, Heidelberg), Martin Leahy (University of Limerick), Gregory McNerny (Univeristy of California Davis). The CIC-initiated Nordic Network on Imaging in Medicine and Biology adds to this list a range of additional participants, principally from the Nordic area. Ongoing intimate collaboration between these experts and the Cell Imaging Core ensures continued transfer of advanced imaging skills from these leading labs. To strengthen bioscience imaging in the Turku region, CIC has expanded its web pages to include imaging technologies and contacts across the campus. CIC maintains close contact with imaging specialists locally and is a major player in the Turku Bioimaging initiative, an active discussion forum established in 2007 to promote imaging in the Turku region. From left to right: Jouko Sandholm, Eleanor Coffey, Perttu Terho, Markku Saari. (including timelapse and spectral detection), widefield fast CCD imaging, laser microdissection, high throughput cell sorting and advanced flow cytometry software development. To maintain the advanced, national level service provided so far, we organise training programmes, service existing equipment, sustain research on new imaging techniques, and implement the latest technological advances demanded by the Finnish research community. CIC has succeeded both as a service provider and as a point of integration of emerging imaging technologies. Added value is achieved by the present local expertise in the Turku area in the fields of fluorescence-activated cell sorting, confocal microscopy, fluorescence-based screening and robotic instrumentation, imaging-based high-content screening, in vivo animal imaging, and viral gene transfer, and by the presence of the National Centre for Disease Models and the transgenic animal core facility. CIC coordinates the Nordic Network on Imaging in Medicine and Biology. This network gathers the leading units on cellular and medical imaging in the Nordic region and was funded initially by the Joint Committee of the Nordic Research Councils and currently by Nordforsk, the funding agency of the Nordic Council of Ministers. The network assembles 38 prominent research groups and aims to improve interdisciplinary training and cooperation between diverse imaging fields. The following international leaders in the field have contributed to advanced imaging education in Turku providing during their visits practical as well as theoretical training: Jennifer Lippincott- Schwartz (NIH, USA), Stefan Hell (Max Planck Institute for Biophysical Chemistry, Gottingen University, Germany), Rainer Duden (Royal Holloway, London), Robert Goldman (Northwestern 20 21

14 VIRUS VECTOR FACILITY Coordinator: Eleanor Coffey, Ph.D., Adjunct Professor in Cellular and Molecular Biology, Turku Centre for Biotechnology, BioCity, 5 th floor, Tykistokatu 6, FI-20521, Finland. Tel , Fax ecoffey@btk.fi To build on local expertise in gene transfer technologies, the Virus Vector Facility networks with experts in viral vector design. Thus a number of local experts on retroviruses and alpha-viruses are available for consultation on vector design, production and concentration. Research, Development and Training: Anna Cvrljevic, postdoctoral researcher (Westermarck lab), Turku Centre for Biotechnology, BioCity 5th floor, Tykistökatu 6, FI-20521, Finland. anna.curljev@btk.fi Technical Team: Marjo Hakkarainen, Laboratory Technician, marjo.hakkarainen@btk.fi Susanna Pyökäri, Laboratory Technician, susanna.pyökäri@btk.fi Ketlin Adel, Laboratory Technician, kadel@btk.fi The Virus Vector Facility produces viral vectors for local and national research groups. During 2009, the Virus Vector Facility joined the national infrastructure network on Viral Gene Transfer, funded by Biocenter Finland. Our primary function is to facilitate the use of viral vectors by national researchers. To meet these goals the virus vector facility Produces on demand adenoviruses and lentiviruses expressing genes of interest, as a research service provides a fully equipped bio-safety level-2 lab for researchers wishing to produce their own vectors (replication deficient viruses only) supplies working protocols for production of adeno and lenti vectors and trains researchers in the safe preparation and handling of viral vectors organises seminars and courses emphasizing practical issues related to gene transfer technology coordinates a network of local experts from whom consultation on design of viral vectors can be sought The virus vector facility has a national user base with regular customers from the universities of Turku, Oulu and Helsinki as well as customers from biotech companies. In addition to customer service, our infrastructure is used by 16 local research groups producing adenoviruses, adeno-associated virus, retro- and lentivirus for their own research purposes. These viruses are typically used to obtain high efficiency gene transfer in difficult to transfect cells such as primary cultures of T lymphocytes and neurons and for in vivo cancer studies. Another typical application is the use of viral vectors for delivery of shrna. Protocol optimization has been completed for high efficiency gene silencing in primary cultured neurons and T lymphocytes and more recently investigators are using virally delivered mirnas for gene knockdown studies. From left to right: Susanna Pyökäri, Anna Cvrljevic, Jukka Westermarck, Marjo Hakkarainen, Eleanor Coffey

15 PROTEIN CRYSTALLOGRAPHY CORE FACILITY Head: Anastassios C. Papageorgiou, Ph.D., Adjunct Professor in Biochemistry and Structural Biology Turku Centre for Biotechnology, BioCity, Tykistökatu 6A, FI Turku, Finland. Tel , Fax Technical Team: Technical support: Juha Strandén, Pasi Viljakainen Computational support: Petri Vahakoski, Mårten Hedman Steering committee: Jyrki Heino, Professor, Department of Biochemistry and Food Chemistry, University of Turku Reijo Lahti, Professor, Department of Biochemistry and Food Chemistry, University of Turku Tiina Salminen, Senior lecturer, Department of Biochemistry, Åbo Akademi Description of the Facility X-ray crystallography is a proven technique for detailed structurefunction studies of biological macromolecules. The Protein Crystallography Core Facility at CBT uses state-of-the-art equipment to determine the crystal structures of various proteins and their complexes. The Facility consists of an X-ray generator, Mar345 imaging plate detector, Osmic confocal mirrors, a Cryostream Cooler (Oxford Cryosystems) and several computers running under Unix or Linux operating systems for heavy duty calculations. The Unit has several workstations to run variety of graphic software (O, XtalView, Grasp, COOT, CCP4mg, PyMol), modeling and docking programs (MODELLER, Hex, Discovery Studio), and various crystallographic packages (HKL, CNS, CCP4, SHELX, SOLVE, SHARP, PHENIX) for data processing, analysis, phasing and refinement. The Facility has long expertise in all steps of a crystal structure determination: protein purification, crystallization, data collection (both in-house and in synchrotron radiation sources), data processing, phase determination, refinement and detailed analysis of the final structure. Incubators at different temperatures (4 C, 16 C and 23 C) for crystallization set-ups and a number of commercial screens for establishing initial crystallization conditions are available. In addition, we can provide homology modeling services and design of mutants for functional studies as well as ab initio predictions of protein structures. Since protein crystallography requires highly pure protein prepapations, we can offer full support and consultation on protein purification strategies apart from the services in structure determination and modeling. The Unit is able to undertake research projects for academic groups and companies, either in the form of collaborative efforts or as services. Protein Crystallography requires a multi-disciplinary approach and we are especially interested in bringing together expertise from various groups in order to better understand the structure-function relationship of biological macromolecules in key biological processes. Funding: Systems Biology research program, Biocenter Finland DATA MINING AND MODELING GROUP Principal investigators: Tero Aittokallio, Ph.D., Docent in Biomathematics, Department of Mathematics, University of Turku, FI Turku, Finland. Tel , Fax tero.aittokallio@utu.fi Olli Nevalainen, Ph.D., Professor of Computer Science, Turku Centre for Computer Science, Joukahaisenkatu 3-5 B, FI Turku, Finland. Tel ; olli.nevalainen@utu.fi Biographies: Tero Aittokallio received his Ph.D. in Applied Mathematics from the University of Turku in In , he was a postdoctoral research fellow in the Systems Biology Group at Institut Pasteur, Paris. Currently he is an Academy Research Fellow in the Biomathematics Research Group. Olli S. Nevalainen received his Ph.D. degree in From 1972 to 1976, he was a lecturer with the Department of Computer Science, University of Turku. From 1976 to 1999, he was an Associate Professor, and since 1999 a Professor in the same department. Personnel: Post-doctoral researchers: Laura Elo, Ph.D., Jussi Salmi, Ph.D., Graduate students: Bin Gao, M.Sc., Jukka Hiissa, M.Sc., Ville Koskinen, M.Sc., Rolf Linden, M.Sc., Sebastian Okser, M.Sc., Johannes Tuikkala, M.Sc., Heidi Vähämaa, M.Sc., Undergraduate students: Aki Järvinen, Essi Laajala, Teemu Daniel Laajala, Lari Natri, Mirva Piippo. Description of the project: The research group develops mathematical modeling methods and implements computational analysis tools for mining data generated by modern high-throughput biotechnologies. The large number of components probed together with high technical and biological variability can make it difficult to extract pertinent biological information from the background noise. This has increased the need for computational models and tools that can efficiently integrate, visualize and analyze the experimental data so that the most important questions can be addressed and the meaningful interpretations can be made. The eventual aim is to model and explain the observations as a dynamic interaction of key molecular components and mechanisms controlling the underlying system. Data mining protocols developed so far cover a wide range of highthroughput biotechnologies, such as gene and exon arrays (cdna, Affymetrix and Illumina platforms) for global gene expression profiling, together with RNA interference (RNAi) and chromatin immunoprecipitation (ChIP) studies (ChIP-chip and ChIP-seq) for monitoring transcriptional regulation on a global scale, as well as mass-spectrometry (MS)-based assays for large-scale proteomic studies and comparative genomic hybridizations (CGH) for detecting gene amplification or deletion events. One of the most important computational challenges is to take full advantage of all the accumulated data, both from own laboratory and from public 24 25

16 repositories, to obtain a more comprehensive view of the system under study. We are developing a data integration approach, which can effectively correct for the technical variation characteristic to various experimental platforms, and hence improve the comparability of different experiments, identification of differentially expressed genes and proteins, and inference of their interaction partners in global cellular networks. Such integrative network-based modeling approach can provide robust and unbiased means to reveal the key molecular mechanisms behind the systems behavior and to predict its response to various perturbations. In clinically-oriented research, the modeling approach has the potential to improve our understanding of the disease pathogenesis and help us to identify novel molecular markers for pharmaceutical or diagnostics applications. Funding: The Academy of Finland, Systems Biology research programme, and the Graduate School in Computational Biology, Bioinformatics, and Biometry (ComBi). Collaborators: Riitta Lahesmaa (Turku Centre for Biotechnology), Tuula Nyman (University of Helsinki), Matej Orešic (VTT Biotechnology), Benno Schwikowski (Pasteur Institute, Paris), Mats Gyllenberg (University of Helsinki), Esa Uusipaikka (University of Turku), Samuel Kaski (Helsinki University of Technology), Timo Koski (Royal Institute of Technology, Stockholm), Eija Korpelainen (CSC IT Center for Science), Jan Westerholm (Åbo Akademi University), Esa Tyystjärvi (University of Turku), and Mauno Vihinen (University of Tampere). Selected Publications: Okser, S., Lehtimäki, T., Elo, L.L., Mononen, N., Peltonen, N., Kähönen, M., Juonala, M., Fan, Y.M., Hernesniemi, J.A., Laitinen, T., Lyytikäinen, L.P., Rontu, R., Eklund, C., Hutri-Kähönen, N., Taittonen, L., Hurme, M., Viikari, J.S.A., Raitakari, O.T., and Aittokallio, T. (2010).Genetic variants and their interactions in the prediction of increased pre-clinical carotid atherosclerosis -- The Cardiovascular Risk in Young Finns Study, PLoS Genetics (in press). Eronen, V.P., Lindén, R.O., Lindroos, A., Kanerva, M., and Aittokallio T. (2010) Genome-wide scoring of positive and negative epistasis through decomposition of quantitative genetic interaction fitness matrices, PLoS ONE (in press). Moulder, R., Lönnberg, T., Elo, L.L., Filén, J.J., Rainio, E., Corthals, G., Orešic, M., Nyman, T.A., Aittokallio, T., and Lahesmaa, R. (2010) Quantitative proteomics analysis of the nuclear fraction of human CD4+ cells in the early phases of IL-4 induced Th2 differentiation, Molecular & Cellular Proteomics (in press). Lahti, L., Elo, L.L., Aittokallio, T., and Kaski, S. (2010) Probabilistic analysis of probe reliability in differential gene expression studies with short oligonucleotide arrays, IEEE Transactions on Computational Biology and Bioinformatics (in press). Codrea, M.C., Hakala-Yatkin, M., Kårlund-Marttila, M., Nedbal, L., Aittokallio, T., Nevalainen, O.S., and Tyystjärvi, E. (2010) Mahalanobis distance screening of Arabidopsis mutants with chlorophyll fluorescence, Photosynthesis Research (in press). Elo, L.L., Järvenpää, H., Tuomela, S., Raghav, S., Ahlfors, H., Laurila, K., Gupta, B., Lund, R.J., Tahvanainen, J., Hawkins, R.D., Orešic, M., Lähdesmäki, H., Rasool, O., Rao, K.V.S., Aittokallio, T., and Lahesmaa, R. (2010) Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming, Immunity 32: Elo, L.L., Mykkänen, J., Järvenpää, H., Nikula, T., Simell, S., Aittokallio, T., Hyöty, H., Ilonen, J., Veijola, J., Simell, T., Knip, M., Simell, O., and Lahesmaa, R. (2010) Early suppression of immune response pathways characterizes children with pre-diabetes in genome-wide gene expression profiling, Journal of Autoimmunity 35: Aittokallio, T. (2010) Dealing with missing values in large-scale studies - microarray data imputation and beyond, Invited Review, Briefings in Bioinformatics 11: Korolainen, M.A., Nyman, T.A., Aittokallio, T., and Pirttilä, T. (2010) An update on clinical proteomics in Alzheimer s research, Journal of Neurochemistry 112: Laajala, E., Aittokallio T., Lahesmaa, R. and Elo, L.L. (2009) Probelevel estimation improves the detection of differential splicing in Affymetrix exon array studies. Genome Biology 10: R77. Laajala, T.D., Raghav, S., Tuomela, S., Lahesmaa, R., Aittokallio, T. and Elo, L.L. (2009) A practical comparison of methods for detecting transcription factor binding sites in ChIP-seq experiments. BMC Genomics 10:618. Salmi, J., Nyman, T.A., Nevalainen, O.S. and Aittokallio, T. (2009) Filtering strategies for improving protein identification in highthroughput MS/MS studies. Proteomics 9:

17 Elo, L.L., Hiissa, J., Tuimala, J., Kallio, A., Korpelainen, E. and Aittokallio, T. (2009) Optimized detection of differential expression in global profiling experiments: case studies in clinical transcriptomic and quantitative proteomic datasets. Briefings in Bioinformatics 10: Hiissa, J., Elo, L.L., Huhtinen, K., Perheentupa, A., Poutanen, M. and Aittokallio, T. (2009) Resampling reveals sample-level differential expression in clinical genome-wide studies. OMICS Journal of Integrative Biology 13: Huhtinen, K., Suvitie, P., Hiissa, J., Junnila, J., Huvila, J., Kujari, H., Setälä, M., Härkki, P., Jalkanen, J., Fraser, J., Mäkinen, J., Auranen, A., Poutanen, M. and Perheentupa, A. (2009) Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts. Br J Cancer 100: Clément-Ziza, M., Malabat, C., Weber, C., Moszer, I., Aittokallio, T., Letondal, C. and Rousseau, S. (2009) Genoscape: a Cytoscape plug-in to automate the retrieval and integration of gene expression data and molecular networks. Bioinformatics 25: Aittokallio, T. (2009) Module finding approaches for protein interaction networks. In: Li, X.-L. and Ng, S.-K. (eds.) Biological Data Mining in Protein Interaction Networks, Medical Information Science Series, Chapter 18, pp IGI Global, Hershey, Pennsylvania, U.S.A. Merisaari, H., Parkkola, R., Alhoniemi, E., Teräs, M., Lehtonen, L., Haataja, L., Lapinleimu, H., Nevalainen, O.S. (2009) Gaussian mixture model-based segmentation of MR images taken from premature infant brains. J Neurosci Methods 182: PROTEIN KINASE REGULATION OF BRAIN DEVELOPMENT AND DISEASE Principal investigator: Eleanor Coffey, Ph.D., Academy of Finland Research Fellow, Turku Centre for Biotechnology, Åbo Akademi and Turku University, BioCity, Tykistokatu 6B, FI Turku, Finland. Tel , Fax ecoffey@btk.fi Biography: Eleanor Coffey (b. 1967) graduated from Trinity College Dublin in 1990 and received her Ph.D. from the University of Dundee in She was awarded a Wellcome Trust fellowship to carry out postdoctoral research in Prof. Karl Åkerman s laboratory from In 1997 she founded the Neuronal Signaling group at Åbo Akademi and in 2000 joined Turku Centre for Biotechnology as a group leader in molecular and cellular biology. In addition to running a research group, she directs the Cell Imaging Core at Turku Centre for Biotechnology and coordinates the Nordic Network on Imaging in Biology and Medicine. She currently holds an Academy of Finland Research Fellow position. Personnel: Postdoctoral researcher: Minna Tuittila, Ph.D., Graduate students: Artur Padzik, M.Sc., Justyna Zdrojewska, M.Sc., Emilia Komulainen, M.Sc., Raghavendra Mysore, M.Sc., Yubao Wang, M.Sc., Undergraduate and exchange students: Hanna Heikelä, Lihua Sun, Agnieszka Bialek, Prasannakumar Deshpande. Description of the project: Neurodegenerative disorders such as Alzheimer s and Parkinson s disease as well as stroke are characterised by the irreversible loss of nerve cell function. These diseases for which no cure is known are among the most costly to society. The protein kinase JNK is recognised as a critical player in stroke and neurodegeneration. However exactly how this family of kinases mediates cell death in the brain remains largely unknown. Although targeting of JNK for drug-based therapy is already underway, our understanding of the physiological function of JNK in the brain is in its infancy. From left to right: Johannes Tuikkala, Heidi Vähämaa, Laura Elo, Rolf Linden, Jussi Salmi, Olli Nevalainen, Ville Koskinen, and Tero Aittokallio. A major challenge for signal transduction therapy is to selectively target the pathological function of signaling molecules without interfering with important physiological roles. To achieve this, our lab established a proteomics-based screen to identify protein kinase substrates and thereby broaden our understanding of kinase function. While we have used this methodology to successfully identify both novel and known substrates for JNK, p38 and PIM kinases (collaboration with Päivi Koskinen), among others (collaboration Erwin Wagner), the main focus of our research is to elucidate the molecular mechanism of JNK and JNK targets in the brain. Identification of novel JNK targets such as SCG10 and MAP2, as well as other targets under study, has highlighted a critical role for JNK in maintaining microtubule homeostasis and subsequently regulating axodendritic architecture. Identification of the JNK phosphorylation site on kinesin-1 helped characterize a role for JNK in regulation of fast axonal transport in neurons. We combine biochemical, proteomic, cell biology and imaging methods 28 29

18 with neuronal and organotypic cultures as well as transgenic mice to validate kinase targets and elucidate their function. In collaboration with Laurent Nyguen, we have established methods to track radial migration of neurons in the developing telencephalon using 4D imaging. In addition, we are examining dendrite and spine morphology in JNK1-/- brains using lucifer yellow iontophoretic loading followed by quantitative 3D image analysis. An important finding that we stumbled upon regarding JNK function in the nervous system, was the compartmental segregation of physiological verses pathological JNK function to the cytoplasm and nucleus respectively. By using compartment-targeted peptide inhibitors of JNK, we have shown that nuclear JNK activity is critical for neuronal death in response to trophic deprivation (the type of neuronal death that occurs during brain development) and in response to excitotoxic stimuli (the type of neuronal death that occurs in epilepsy, stroke and contributes to neurodegenerative disorders). Interestingly, although JNK is highly localised to the cytoplasm in neurons, we have shown that cytosolic JNK does not to contribute to these modes of neuronal death. Instead, we find that cytosolic JNK regulates physiological processes that maintain neuritic architecture and regulate migration. These functions of JNK are in turn mediated via cytosol-localised targets, independent of JNK-dependent transcriptional regulation. To realise the therapeutic potential of compartmental targeted JNK inhibitors, we are collaborating with Peter Clarke (University of Lausanne). This study investigates the value of nuclear-targeted peptide inhibitors of JNK as protectants from brain damage that occurs following stroke. By gaining information on how apoptotic and physiological functions of signaling molecules are partitioned within the cell allows selective targeting of inhibitors towards loci where pro-apoptotic events take place. This work provides proof of principal that subcellular targeting of inhibitor molecules provides increased specificity with reduced physiological disturbance. Funding: EU 6 th framework STREP STRESSPROTECT, EU 6 th framework ToK grant, GAMIDI, the Academy of Finland, Åbo Akademi University, Turku University Biomedical Sciences Graduate School, Finnish Graduate School in Neurosciences, Drug Discovery Graduate School, Magnus Ehrnrooth s Stiftelse, CIMO, Sitra and the Torr Joe och Pentti Borgs Foundation. Collaborators: Michael Courtney (University of Kuopio), Tuula Kallunki (Danish Cancer Society), Thomas Herdegen (University of Kiel), Peter Clarke (University of Lausanne), Erwin Wagner (Research Institute of Molecular Pathology), Scott Brady (Univeristy of Illinois at Chicago), Laurent Nguyen (University of Liege), Päivi Koskinen (University of Turku), Aideen Long (Trinity College, Dublin). Selected Publications: J Immunol. Neurochem Int. Nat Neurosci. Signalling, Mol Cell Biol. Cell Adhesion and Migration, Journal of Biological Chemistry, Cellular Molecular and Cellular Biology, Dan Johansen, L., Naumanen, T., Knudsen, A., Westerlund, N., Gromova, I., Junttila, M., Nielsen, C., Bottzauw, T., Tolkovsky, A., Westermarck, J., Coffey, E.T., Jäättelä, M., Kallunki, T. (2008) IKAP localizes to membrane ruffles with filamin A and regulates actin cytoskeleton organization and cell migration. Journal of Cell Science, 121: Westerlund, N., Zdrojewska, J., Courtney, M., Coffey, E. (2008) SCG10 as a molecular effector of JNK1: Implications for the therapeutic targeting of JNK in nerve regeneration. Expert Opinion on Therapeutic Targets. 12: Review. Semanova, M.M., Mäki-Hokkanen, A.M.J., Cao, C., Komarovski, V., Forsberg, K.M., Koistinaho, M., Coffey, E.T., Courtney, M.J. (2007) Rho mediates calcium-dependent activation of p38a and subsequent excitotoxic cell death. Nature Neuroscience, 10(4): Tararuk, R., Östman, N., Li, W., Björkblom, B., Padzik, A., Zdrojewska, J., Hongisto, V., Herdegen, T., Konopka, W., Courtney, M.J., Coffey, E.T. (2006) JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length. Journal of Cell Biology. 173: Björkblom, B., Östman, N., Hongisto, V., Komarovski, V., Filen, J., Nyman, T., Kallunki, T., Courtney, M., Coffey, E. (2005) Constitutively active cytoplasmic JNK1 is a dominant regulator of dendritic architecture; role of MAP2 as an effector. Journal of Neuroscience. 25: Yang, J., Lindahl, M., Lindholm, P., Virtanen, H., Coffey, E., Runeberg-Roos, P., Saarma, M. (2004) PSPN/GFRalpha4 has a significantly weaker capacity than GDNF/GFRalpha1 to recruit RET to rafts, but promotes neuronal survival and neurite outgrowth. FEBS Letters.569:

19 Cao, J., Semenova, M.M., Solovyan, V.T., Han, J., Coffey, E.T., Courtney, M.J. (2004) Distinct requirements for p38alpha and c-jun N-terminal kinase stress-activated protein kinase s in different forms of apoptotic neuronal death. Journal of Biological Chemistry. 279: Hongisto, V., Smeds, N., Brecht, S., Herdegen, T., Courtney, M.J., Coffey, E.T. (2003) Lithium blocks the c-jun stress response and protects neurons via its action on glycogen synthase kinase 3. Molecular and Cellular Biology. 23: Coffey, E.T., Smiciene, G., Hongisto, V., Cao, J., Brecht, S., Herdegen, T., Courtney, M.J. (2002) c-jun N-terminal protein kinase (JNK) 2/3 is specifically activated by stress, mediating c-jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons. Journal of Neuroscience. 22: Hietakangas, V., Elo, I., Rosenstrom, H., Coffey, E.T., Kyriakis, J.M., Eriksson, J.E., Sistonen, L. (2001) Activation of the MKK4-JNK pathway during erythroid differentiation of K562 cells is inhibited by the heat shock factor 2-beta isoform. FEBS Letters. 505: Coffey, E.T., Hongisto, V., Dickens, M., Davis, R.J. and Courtney, M.J. (2000) Dual roles for c-jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons. Journal of Neuroscience. 20: Courtney, M.J. and Coffey, E.T. (1999) The mechanisms of ARA-C induced apoptosis of differentiating cerebellar granule neurons. European Journal of Neuroscience. 11: Biochem. Soc. Trans. Courtney, M.J., Åkerman, K.E.O. and Coffey, E.T. (1997) Neurotrophins protect cultured cerebellar granule cells against the early phase of cell death by a two-component mechanism. Journal of Neuroscience. 17: From left to right, front row: Hasan Mohammad, Emilia Komulainen, Justyna Zdrojewska, Eleanor Coffey, back row: Raghavendra Mysore, Lihua Sun, Prasannakumar Deshpande. Missing from the photo: Artur Padzik, Hanna Heikelä. Organisation of Neuronal Signaling Pathways Principal investigator: Michael Courtney, Ph.D., Research manager, Professor of Cell Signaling. Contact information: Molecular Signaling Laboratory, Department of Neurobiology, A.I. Virtanen Institute, University of Kuopio, P.O. Box 1627, Neulaniementie 2, FIN Kuopio, Finland. mcourtne@btk.fi Biography: Michael Courtney (b. 1967) graduated from University of Cambridge in 1988 (B.A.), and the University of Dundee in 1991(Ph.D). Postdoctoral fellowships from the Royal Society, Wellcome Trust, Academy of Finland and Sigrid Jusélius Foundation supported his quantitative imaging development and application activities from 1992 in Prof. Karl Åkerman s laboratory in Åbo Akademi, Turku. After group leader positions at BTK from 1998, he was appointed from 2000 to a position at the A.I. Virtanen Institute, Kuopio and from 2006 to BTK. He has been affiliated with the Cell Imaging Core since its inception, and established and is running the Multimodal Imaging Unit at Kuopio University. He was appointed to an Academy of Finland Researcher post from , and Professor of Cell Signaling at the University of Kuopio from Personnel: Post-doctoral researchers: Franz Ho Ph.D.Ph.D., Peter Martinsson Ph.D., Minna Tuittila Ph.D., Olga Vergun Ph.D. Graduate students: Dorota Kaminska M.Sc., Kaisa Kosonen B.Sc., Lili Li, B.Sc., Xiaonan Liu, M.Sc., Maykel Lopez-Rodriguez M.Sc., Leena Yadav M.Sc. Undergraduate students: Tim Church, Soila Tossavainen Description of the project: Neuronal cells possess a complex architecture consisting of multiple subcellular compartments. Disease states place cells under stressful conditions. The p38 and JNK stress-activated protein kinase pathways are widely accepted to play a significant role in cell death in and outside the nervous system, and drugs directly targeting stress activated protein kinases have been under development for many years. However, these pathways also contribute to development, differentiation, and even survival and proliferation. This suggests that direct stress-activated protein kinase inhibitors may be of only limited use. In order to exploit the pathways for the development of novel neuroprotective drugs, it will be necessary to elucidate the mechanisms that organise these pathways into pools with neurodegenerative or physiological functions within the complex structure of neuronal cells. Only then can the neurodegenerative activities of the pathways be selectively eliminated. It has been suggested that this may help reduce the neuronal death that contributes to neurodegenerative conditions such as Alzheimer s and Parkinson s diseases, increasingly major causes of death, disability and socioeconomic impact in society Previous studies of mammalian stress-activated MAPK pathway have revealed the existence of a plethora of upstream regulators competent to recruit this pathway. In particular, proteins with putative scaffolding actions have been found. Such components could in principle have a number of effects on the associated upstream regulator, including (i) to potentiate their ability to activate 32 33

20 the pathway, (ii) to restrict accessibility to activators, (iii) to channel the downstream consequence to select targets and (iv) to localise these properties to specific compartments within a cell. Our lab s aim is to elucidate how neuronal cells compartmentalise the endogenous components of the stress-activated protein kinase pathway and how specific stresses recruit only select components of these pathways. To achieve this, we currently focus on 3 areas: i) The impact of post-synaptic density proteins on neuronal stressactivated protein kinase signaling pathways; ii) Small G-protein signaling pathways regulating stress-activated protein kinases in neurons; iii) Development and implementation of approaches to imaging of intracellular signaling pathways. Recent publications revealed protein complexes of the postsynaptic compartment as upstream regulators of p38mapk in neuronal stress responses (Cao et al., 2005; Semenova et al., 2007). The mechanisms which maintain selective responsiveness to upstream stimuli and restricted downstream consequences are anticipated to be a fruitful source of potential targets for future neuroprotective strategies. Thus we also utilise the information gleaned from studies of neuronal signaling mechanisms to develop and evaluate novel neuroprotective molecules in cooperation with collaborating partners from both the pharmaceutical industry and from academia. While pursuing these scientific goals, we also implement imaging methodologies. We adapt and establish the use of a wide range of FRET-based probes of cell signaling and on multiparameter imaging that allows spatiotemporal measurement of several pathways simultaneously in the same cells. We established facilities (physically located within Biocentre Kuopio, to make available to all researchers live cell high High-Content Analysis (HCA)), as well as TIR-FRET and TIR-FRAP techniques. Total Internal Reflection methods exploit the spatially restricted evanescent wave formed at the interface between media of different refractive indices, thereby surpassing the classical diffraction limits. These methods are ideally suited to measure signaling events and protein turnover at protein complexes in the plasma-membrane proximal zones of living cells. The live-cell HCA unit is nationally unique and is now supported as a platform by two Biocenter Finland networks as part of the national Biocenter infrastructure. Funding: The Academy of Finland, The EU 6 th framework STREP STRESSPROTECT, the EU 7 th framework project MEMOLOAD, The Sigrid Juselius Foundation, The University of Kuopio, The Drug Discovery Graduate School, The Molecular Medicine Graduate School. Collaborators: Eleanor Coffey and Tassos Papageorgiou (BTK, Åbo Akademi and University of Turku), Christophe Bonny (University of Lausanne and Xigen Pharma AG), Denise Manahan-Vaughan (University of Bochum), Mark Spaller (Brown University, Providence, RI), Olli Pentikäinen (University of Jyväskylä), Antti Poso (University of Eastern Finland), Markus Rehm (Royal College Of Surgeons of Ireland), Anita Truttman (CHUV, Lausanne University Hospital), Mingjie Zhang (Hong Kong Institute of Science and Technology). Selected Publications: Waetzig, V., Wacker, U., Haeusgen, W., Björkblom, B., Courtney, M.J., Coffey, E.T. and Herdegen, T. (2009) Concurrent protective and destructive signaling of JNK2 in neuroblastoma cells. Cell Signal. 21, Hellwig, C.T., Kohler, B.F., Lehtivarjo A.-K., Dussmann, H., Courtney, M.J., Prehn, J.H. and Rehm, M. (2008) Real-time analysis of TRAIL/ CHX-induced caspase activities during apoptosis initiation. J. Biol. Chem. 283, Björkblom, B., Vainio, J.C., Hongisto, V., Herdegen, T., Courtney, M.J. and Coffey, E.T. (2008) All JNKs can kill but nuclear localization is critical for neuronal death. J. Biol. Chem. 283, Hongisto, V., Vainio, J.C., Thompson, R., Courtney, M.J. and Coffey, E.T. (2008) The Wnt pool of GSK-3β is critical for trophic deprivation induced neuronal death. Mol. Cell. Biol. 28, Westerlund, N., Zdrojewska, J., Courtney, M.J. and Coffey, E.T. (2008) SCG10 as a molecular effector of JNK1: Implications for the therapeutic targeting of JNK in nerve regeneration. Expert Opin. Ther. Targets, 12, Semenova, M.M., Mäki-Hokkonen, A.M.J., Cao, J., Komarovski, V., Forsberg, K.M., Koistinaho, M. Coffey E.T. and Courtney, M.J. (2007) Rho mediates calcium-dependent activation of p38α and subsequent excitotoxic cell death. Nat. Neurosci. 10, Tararuk, T., Östman N., Li, W., Björkblom, B., Padzik, A., Zdrojewska, J., Hongisto, V., Herdegen, T., Konopka, W., Courtney M.J. and Coffey, E.T. (2006) JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length. J. Cell Biol. 173, Björkblom, B., Östman, N., Hongisto, V., Komarovski, V., Filén, J., Nyman, T.A., Kallunki, T., Courtney, M.J. and Coffey, E.T. (2005) Constitutively active cytoplasmic JNK1 is a dominant regulator of dendritic architecture; role of MAP2 as an effector. J. Neurosci. 25, Cao, J., Viholainen, J.I., Dart, C., Warwick, H.K., Leyland, M.L. and Courtney, M.J. (2005) The nnos-psd95 interface - a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death. J. Cell Biol. 168, Cao, J., Semenova, M.M., Solovyan, V.T., Han, J., Coffey, E.T and Courtney, M.J. (2004) Distinct requirements for p38α and JNK stress-activated protein kinases in different forms of apoptotic neuronal death. J. Biol. Chem. 279, Solovyan, V.T., Bezvenyuk, Z., Salminen, A., Austin, C.A. and Courtney M.J. (2002) The role of topoisomerase II beta in the excision of DNA loop domains during apoptosis. J. Biol. Chem. 277, Coffey, E.T., Smiciene, G., Hongisto, V., Cao, J., Brecht, S., Herdegen, T. and Courtney, M.J. 2002) JNK2/3 is specifically activated by stress, mediating c-jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons. J. Neurosci. 22,