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173 Pages


university, Karolinska Institute, INRA (France) and Virginia Polytechnic Institute .... Snaevar Sigurdsson, post doc (started in February) ..... Monika Johansson, postdoc ...... [10.1002/9780470015902.a0000875.pub2. ..... proteins (p17gag, p24gag, p6gag, p7gag, PR, RT, IN, gp41, gp120, vif, vpr, tat, rev, nef ...



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INTRODUCTIONThe past year has seen many positive developments at the Department of Medical Biochemistry and Microbiology (Institutionen för medicinsk biokemi och mikrobiologi, or IMBIM). Two research groups have joined the department, one led by Professor Birgitta Heyman and another by Associate Professor Anna-Karin Olsson. Professor Heyman’s group accounts for much of the research in experimental immunology at the Medical Faculty in Uppsala. The group is a valuable addition to IMBIM, engendering the second ‘I’ in the ‘IMBIM’ acronym with quality and content. The research focus of Associate Professor Olsson and co-workers lies where the fields of immunology, vascular and tumor biology intercept, consolidating a prominent area of research at the Department. Furthermore, as part of a University initiative entitled ‘Quality and Renewal 07’, the Department expects to increase its scientific personnel with new professors and assistant professors. Recruitments to these new positions have already commenced and are expected to be finalized by the end of 2008 and early in 2009.
A major relocation of research laboratories was completed during 2008. The total laboratory space at the Department decreased, several groups moved to new corridors and most groups have reduced their space. This relocation has meant that groups with similar research interests have come closer thereby increasing possibilities for creative interactions. In addition, and importantly, the relocations decreased IMBIM’s costs for rent; it can be hoped that a desire to decrease costs for rent will permeate all levels of the University.
During the year, Professor Emeritus Torvard C. Laurent received the prestigious large gold medal from the Royal Swedish Academy of Engineering Sciencesfor his seminal research on hyaluronan. IMBIM extends its sincere congratulations to Professor Laurent for this well-deserved mark of recognition.Research carried out at IMBIM during 2008 has been of the highest caliber, with the publication of more than 70 original scientific papers, many in high impact journals, around 20 reviews or commentaries and presentations at congresses and symposia. Five graduate students received their doctorates and many scientists at IMBIM successfully applied for external grants.
Details of the research activities at IMBIM are summarized in the following pages of this annual report. Here are just a few of the highlights:
The white horse, an icon for dignity, has had a huge impact on human culture across the world. Dr Gerli Rosengren-Pielberg and her colleagues identified the mutation causing this spectacular trait. They showed that white horses carry a 4.5 kb duplication in intron 6 of syntaxin17. The mutation is a cis-acting regulatory mutation that up-regulates the expression of both syntaxin17 and the neighboring gene, NR4A3. The finding is of considerable medical significance as the mutation in humans predisposes the carrier to melanoma development (Rosengren-Pielberget al.,Nature Genetics).
Many domestic chickens have yellow skin. This is due to a recessive allele that allows the deposition of colorful carotenoids in the skin. Jonas Eriksson and his colleagues 2
demonstrated that this is caused by a regulatory mutation that inhibits the expression of the gene encoding the enzyme,-carotene dioxygenase 2 (BCDO2), which cleaves colorful carotenoids into colorless apocarotenoids. This is the first identification of a gene controlling carotenoid-based pigmentation (Erikssonet al., PLoS Genetics).
Heparan sulfate proteoglycans influence embryonic development and adult physiology through interactions with protein ligands. The interactions depend on heparan sulfate structure. Recent results from Professor Lena Kjellén’s group support a model in which the enzymes of heparan sulfate biosynthesis form a complex, a “GAGosome”, where the relative levels of the enzymes determine the outcome of biosynthesis (Prestoet al., 2008 PNAS).
Associate Professor Per Jemth and co-workers conducted studies on fundamental aspects of protein chemistry, such as the landscape of the protein folding reaction and the role of intra-domain allostery in protein-ligand interactions. They discovered a specific polypeptide sequence exhibiting great entropic freedom at the early stages of the folding reaction but much more restricted by native topology later on in the reaction. The study reassessed the function of an evolutionarily conserved amino acid network in a protein domain, and found that it did not contribute to ligand binding, as previously thought (Chiet al., 2008, PNAS).
DNA repair systems involved in repairing common spontaneous mutations caused by oxidized and deaminated bases strongly influence the GC content of bacterial genomes. Peter Lind and Professor Dan Andersson showed that mutations caused by the oxidized base, 8-oxo-G, are very common and if not repaired by the repair system (MutYM) these specific mutations result in rapid reduction in GC content. Intracellular parasitic and endosymbiotic bacteria typically have low GC content and also lack the MutYM repair system. This study suggests that it is likely that in such bacteria, unrepaired 8-oxo-G mutations generate a mutational bias towards reduced GC content (Lind and Andersson, 2008, PNAS).
IMBIM has invested significantly in undergraduate teaching and contributes to five of the study programs given by the Science Area of Medicine and Pharmacy at Uppsala University. Starting in 2006, the MD program is now being radically changed so that each course is centered on a specific medical topic. To stimulate student interest, medical cases are discussed in small groups of about eight students. The department, therefore, no longer offers coherent courses in the core subjects of IMBIM. Rather, our teachers are active over several semesters and strive to ensure that the core curriculum of the various subjects is filled when the diversified courses are integrated. The major part of the teaching carried out by IMBIM staff takes place during the first three semesters of the academic year. Therefore most of the time-consuming planning in conjunction with the change of the study program has now been accomplished.
The Bologna process is a strategy aimed at harmonizing study programs throughout Europe. This reform has meant that many four-year university programs in Sweden (magister)have  3
been or are being converted into programs consisting of bachelor and master components requiring three and two years of studies, respectively. This change has had a major effect on only one of the programs in which teachers from IMBIM are involved, that of Biomedicine. The modifications are now gradually being implemented. In addition to teaching during the bachelor component of this program, IMBIM is also responsible for a master program in Infection Biology, which is presently in the planning stage.
About one third of the faculty funding to IMBIM income is derived from undergraduate teaching. Funding is based on the number of students who have passed the exams. This year, fewer students than planned passed their first year exams in the Biomedicine and the Dispensing Pharmacy programs, partly due to fewer enrolled students but also due to a higher failure rate. The reasons for this are complex and several. One possibility is that the high school students attracted to these programs are less well prepared for university studies. Another possibility is that the courses have failed to maintain the motivation of the students. In an effort to improve motivation, the syllabus of the course in Molecular Biology and Gene Technology in the Dispensing Pharmacy program has now been revised to better reflect future professional needs.
Several researchers from IMBIM have ongoing collaborations with industry, including local enterprises. Dr. Cecilia Annerén, a senior scientist at GE Healthcare in Uppsala, has placed her academic research, funded by the Swedish Science Council and the Juvenile Diabetes Foundation (USA), at IMBIM. We welcome the possibilities for collaboration with GE Healthcare that may arise from this initiative. In addition, several other research groups at IMBIM maintain established collaborations with industrial partners. The Department also participates in various programs with visiting high school students. Researchers at IMBIM have also contributed several papers in popular science journals during 2008.
Semi-autonomous groups directed by principal investigators carry out research at the Department, many of which have been successful in their quest for external grants during 2008. Research and graduate (research) education are largely funded by external grants. The Department is completely dependent on the success of our scientists in their search for external grants to maintain a sizeable and internationally recognized body of research graduate education. Furthermore, the distribution of competitive government funds to the universities will become increasingly dependent on external grants and citations of published work. It is therefore of central importance for IMBIM to provide the conditions and an environment that is conducive to the work carried out by the research groups in order to maintain their motivation.
The situation for the small to medium sized groups requires particular scrutiny. These groups form the core of any research department and, thanks to their number, they are responsible for most of the publications that generate citations and attract grants. However, an increasing number of initiatives, legislation and rulings from central agencies at the university and governmental bodies impose a threat to the possibility for individual scientists to carry out quality research at a reasonable cost of effort. This is also a potential problem for teaching in undergraduate courses. To maintain the academic tradition of teachers as active researchers and  4
thereby contribute to the content of courses with the most up to date information, we need to find ways to guarantee that small and medium sized groups continue to produce internationally competitive research. It remains a major task for IMBIM to increase its competitiveness by allowing the system of competitive grants to work as effectively as possible. To achieve this, IMBIM must keep overheads down and reduce unnecessary administrative burdens. Furthermore, it is important to generate structures where several small to medium-sized groups co-operate.
In common with most other preclinical departments in Sweden, graduate education at IMBIM is largely funded by external grants. Together with increasing salary costs, this is likely to result in a reduction of graduate students. Due to the recent growth of IMBIM, the relative number of graduate students has indeed decreased over the last ten years. The number of graduate students from non-EU states that have financial support from their country of origin has, however, increased in recent years. Currently around 15% of the graduate students belong to this latter category. This development is welcomed and enriches IMBIM in many ways.
It is a pleasure to report many positive developments at IMBIM in 2008. There is, however, a need for caution and a readiness to meet potential future problems, including financial problems. An important task in the immediate future is to recapture some of the atmosphere and interactions of a coherent scientific department that were lost during the re-organization of the faculty during the 1990s. This could possibly be achieved by creating scientific areas with a higher degree of autonomy.
Kristofer Rubin, chairman
Uppsala, January, 2009
LIST OF CONTENTS ADDRESS LISTORGANIZATIONSCIENTIFIC REPORTS OF RESEARCH GROUPSFunctional Genomics Andersson, Leif:Functional genomics in domestic animals Bjerling, Pernilla:Studies of epigentics using fission yeast as a  model system Lindblad-Toh, Kerstin: Canine disease gene mapping and  functional genomics Ronne, Hans:Functional genomics in model organisms Glycobiology  Heparan sulfate - Structure, biosynthesis and biological functions  Kjellén, Lena:Functional studies of heparan sulfate and its biosynthesis Li, Jin-ping:Heparan sulfate: Implications to animal development and  pathophysiological processes  Spillmann, Dorothe– Sticky tentacles or: Glycosaminoglycans  well designed functional modulators?Immunology Immune regulationHeyman, Birgitta:Antibody feedback regulation + + Grönvik, Kjell-Olov:Cytokine profiles of isolated CD4and CD8 mouseT-cells are modulated by their differentiation and by antigen  presenting cells Hallgren Martinsson, Jenny: The role of mast cells and IgE in allergic airway inflammation (asthma) Molecular and Cell Biology  Annerén, Cecilia:Molecular mechanisms regulating pluripotency and  self-renewal of embryonic stem cells Fries, Erik:Intracellular processing of secretory proteins Forsberg Nilsson, Karin:Neural stem cell biologyMolecular Bacteriology Andersson, Dan:Variability and stability of bacterial genomes Aro, Helena:The interplay between pathogenic bacteria and  epithelial cells Jonsson, Ann-Beth:Bacterial pathogenesis and cell signalling  Sundström, Lars:Recombinational spread of antibiotic resistance Swedberg, Göte:Mutations and genetic transfer contribute to evolution  and stable persistence of drug resistant microorganisms 6
6264 66
81 85 91
Molecular Virology/Viral Model Systems  Akusjärvi, Göran:Adenovirus in basic and medical research Magnusson, Göran:Replication and genetic stability of polyomavirusSchwartz, Stefan:Viral gene regulationSvensson, Catharina:Adenovirus induced reprogramming of  host cell activitiesProteins - Structure/Function  Ek, Pia:Regulation by phosphorylation  Engström, Åke:Expression proteomics Jemth, Per:Structure-function relationships of proteins Schedin Weiss, Sophia:Molecular mechanisms behind the activities  of multifunctional serine proteases and their inhibitors in blood Tomkinson, Birgitta:Structure, function and physiological role of  tripeptidyl-peptidase II Tumor Biology and Inflammation Gerwins, Pär:Mechanisms of tissue vascularization Johansson, Staffan:Adhesion-dependent cell signaling  Kreuger, Johan:The role of proteoglycans in angiogenesis Olsson, Anna-Karin:Tumor vascular biology  Rubin, Kristofer:Tumor stroma as a target for novel cancer therapy  Rydén, Cecilia:Connective tissue infectionsSundberg, Christian:Mechanisms of optimal tissue regeneration  versus fibrosis and the role of the microvasculature Åbrink, Magnus:The biological role of mast cells during inflammation  and pathogenic disorders SCIENTIFIC PAPERS PUBLISHED 2008DISSERTATIONS 2008ECONOMY 2008Undergraduate teaching at IMBIM MEDIGLY - Swedish network in medical glycobiology Uppsala Graduate School in Biomedical Research – UGSBR Proteomics Resource Center Uppsala University Transgenic Facility (UUTF)Facility for Recombinant Adenovirus Construction LIST OF AUTHORS
98 104 106
113 116 118
128 131 133 137 140 141
ADDRESS LIST Department of Medical Biochemistry and Microbiology, IMBIM Address: Uppsala University, Biomedical Center, Box 582, 751 23 Uppsala, Sweden Office: Fax +46 18 471 4673, Phone +46 18 471 4444, +46 18 471 4561 Abduraham Samir Akusjärvi Göran Alkemar Gunanr Ancsin John Andersson Dan Andersson Eva Andersson Leif Annerén Cecilia Aro Helena Backström Ellenor Bajak Edyta Barkefors Irmeli Bittkowski Cristina Bjerling Pernilla Boström Ewa Carlsson Anette Carlsson Mattias Carlsson Pernilla Ngang Chi Celestine Chumnarnsilpa Sakesit Dagälv Anders Edqvist Per-Henrik Ek Pia Eklund Anders Elfström Lisa Engström Åke Enström Erika Eriksson Anna Eriksson Inger Eriksson Jens Eriksson Jonas Eriksson Sandra Forsberg Maud Friman Tomas Fries Erik Fredlund Fuchs Peder Gerwins Pär Golovko Anna Gottfridsson Eva Grönvik Kjell-Olov Gunnarsson Ulrika Ulrika.Gunnarsson@im
Gustavsson Marie Haglund Åsa Hallgren Martinsson Jenny Hammargren Jenni Haq Syed Raza Hejll Eduar Hellström Anders Henningson Johnson Frida Hermansson Annika Heyman Birgitta Hjertson Eva Hjälm Göran Holmborn Garpenstrand Katarina Hu Guo-Zhen Huijbers Else Imsland Freyja Jansson Ylva Jemth Per Jia Juan Johansson Monika Johansson Staffan Jonsson Ann-Beth Kalamajski Sebastian Karched Maribasappa Karén Jakob Kerje Susanne Kheir Amany Kjellén Lena Koskiniemi Sanna Kreuger Johan Kristell Carolina Kuwae Asaomi Larsson Jimmy Laurent Torvard Le Jan Sébastien Li Jin-ping Lidholt Kerstin Lind Peter Lindahl Ulf Lindberg Catharina Lindblad-Toh Kerstin Linder Claës Lindroth Anders Lindström Sofia Lowisin Barbro Lundberg Kristina Lundin Lars Löfmark Sonja Magnusson Göran Anders.Hellströ Jakob.Karé Lars
Markljung Ellen Meaddows Jennifer Murén Eva Möller Lena Nilsson Anders Forsberg Nilsson Karin Nordberg Niklas Nordli Olav Näsvall Joakim Olofsson Anne-Mari Olsson Anna-Karin Olsson Maria Persson Lena Persson Ted Petersson Ludvig Pielberg Gerli Pränting Maria Ramachandra Rashmi Rask Lars Ratnakumar Abhirami Rinvall Maria Rodriguez Alejandro Ronne Hans Roy Ananya Rubin Kristofer Rutemark Christian Rydén Cecilia Sandegren Linus Sandwall Elina Schwartz Stefan Sigurdsson Snaevar Sjölinder Hong Sköld Ola Somberg Monika Spillmann Dorothe Stefansson Anne Strömbom Malin Sun Song Sun Wei Beckman Sundh Ulla Sundberg Christian Sundström Lars Swedberg Göte Svensson Catharina Svensson Mervi Söderhäll Carin Tamm Christoffer Tengvall Katarina Alfredsson Timmins Jenny
Tingsbord Susanne Tobin Christina Tomkinson Birgitta Tranell Anna Thulin Åsa Törmänen Heidi Ulfstedt Mikael Wahlberg Per Wallenquist Ulrika Webster Matthew Van Wieringen Tijs Wehelie Rahma Schedin Weiss Sophia Wernersson Jonny Wigenius Marianne Vielfort Katarina Wärmegård Birgitta Xu Ning Zeller Kathrin Zetterqvist Örjan Zhang Xiao-Qun Zody Michael Zorzet Anna Åbrink Magnus Åkerblom Rehné Östberg Sara