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A new study from Karolinska Institutet shows that the same mechanisms behind the beneficial effects of exercise training on the brain also help to counteract fat and to strengthen the immune system. The results, which are published in the journal Cell Metabolism, can ultimately give rise to new obesity and diabetes drugs. In 2014, researchers at Karolinska Institutet reported that they had discovered a mechanism behind the beneficial effect of exercise training on the brain. A follow-up study now demonstrates that the same process also boosts fat metabolism and strengthens the anti-inflammatory properties of the immune system. “We’ve linked the two parts of the expression ‘sound mind, sound body’,” says Jorge Ruas, principal investigator at the Department of Physiology and Pharmacology, Karolinska Institutet. “Our research adds to the understanding of why exercise training benefits the body and in the long run can lead to the development of new treatments for obesity or diabetes.” In the earlier study, the researchers were able to show that trained muscles help to clean the blood in a way similar to the kidneys and liver. Through exercise training, the muscles can convert the stress marker kynurenine into kynurenic acid. High levels of kynurenine have been measured in people with depression and mental illness. Fed on a fat-rich diet For this present study, the researchers further examined the function of kynurenic acid. Using mice fed on a fat-rich diet that made them overweight and raised their blood sugar levels, they found that a daily dose of kynurenic acid stopped the mice putting on weight and gave them better glucose tolerance, despite no change in their food intake. The researchers posit the explanation that kynurenic acid activated the cell receptor GPR35, which is found in both fat cells and immune cells. This led in the former to a conversion of white fat into energy-burning brown fat, and in the latter to an enhancement of their anti-inflammatory properties. “We’ve shown that kynurenic acid prevents weight gain despite excessive energy intake,” says Dr Ruas. “Our next step is to identify the complex chain of interacting molecules that’s affected by diet and training.” The study was financed by the Berth von Kantzow Foundation, the Diabetes Research & Wellness Foundation, the European Research Council, the Erling-Persson Family Foundation, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Novo Nordisk Foundation, Skandia, the Stichting af Jochnick Foundation, the Swedish Diabetes Association, the Swedish Society for Medical Research and the Swedish Research Council. Publication Kynurenic acid and GPR35 regulate adipose tissue energy homeostasis and inflammation Leandro Z. Agudelo, Duarte M. S. Ferreira, Igor Cervenka, Galyna Bryzgalova, Shamim Dadvar, Paulo R. Jannig, Amanda T. Pettersson-Klein, Tadepally Lakshmikanth, Elahu G. Sustarsic, Margareta Porsmyr-Palmertz, Jorge C. Correia, Manizheh Izadi, Vicente Martínez-Redondo, Per M. Ueland, Øivind Midttun, Zachary Gerhart-Hines, Petter Brodin, Teresa Pereira, Per-Olof Berggren, and Jorge L. Ruas Cell Metabolism, online 6 February 2018, DOI: https://doi.org/10.1016/j.cmet.2018.01.004

Hello Maria Ankarcrona, Alzheimer's Researcher at the Division of Neurogeriatrics. Recently the reputable scientific journal Current Biology published one of your studies, what is it about? "A cell has several constituents, one of which is mitochondria. They produce energy in the cell and are also important for regulation of cell death, production of fatty acids and calcium levels. In this paper we show a new role of the mitochondrial protein TOM70 (translocase of the outer membrane 70). We report that TOM70 interacts with IP3R3 (inositol 1,4,5-triphosphate receptor 3) sustaining cell bioenergetics". Which are the most important results, and what new knowledge does the paper add?  "For the first time, we show that TOM70 acts as a modulator of calcium-transfer between endoplasmic reticulum (ER) and mitochondria at specific contact points between these two organelles, also known as mitochondria-associated membranes (MAM). We also show that TOM70 clusters at ER-mitochondria contact sites and interacts with IP3R3, a regulator of ER calcium release. Upon deletion of TOM70, IP3R3s translocate out from these subcellular hubs resulting in decreased calcium transfer from ER to mitochondria. Our data show that the decrease in calcium shuttling affects mitochondrial activity, cell proliferation and autophagy". How can this new knowledge contribute to improving human health? "The discovery that TOM70 depletion affects cell bioenergetics suggests that modulation of TOM70 expression or activity could be a promising pharmacological target.  It is known that the ER-mitochondria interplay is affected in multiple diseases. Here we show that depletion of TOM70 selectively affects the shuttling of calcium between ER and mitochondria, while the physical contacts between the two organelles are unchanged.  These findings open up a novel approach to pharmacologically modulate MAM-function and calcium transfer which would be potentially beneficial in the treatment of a wide-range of pathologies associated with alteration in mitochondria ER contact sites, such as Alzheimer’s disease". The publication TOM70 sustains cell bioenergetics by promoting IP3R3-mediated ER to mitochondria Ca2+ transfer Riccardo Filadi, Nuno Santos Leal, Bernadette Schreiner, Alice Rossi, Giacomo Dentoni, Catarina Moreira Pinho, Birgitta Wiehager, Domenico Cieri, Tito Calì, Paola Pizzo, Maria Ankarcrona Current Biology, 5 februari 2018

Aortic aneurysm – the dilation of the aorta – is a serious condition that lacks effective drug treatment. Researchers at Karolinska Institutet report in the journal PNAS, however, that a common asthma drug can retard the development of aortic aneurysm in mice. ­“Our results are exciting and open the way for a medical treatment of this serious vascular disease,” says Professor Jesper Z. Haeggström at Karolinska Institutet’s Department of Medical Biochemistry and Biophysics. An aortic aneurysm occurs when the wall of the body’s largest artery, the aorta, weakens and swells. The disease progresses slowly and affects some 5 per cent of men and 1 per cent of women over the age of 60. The condition is largely symptom-free and is normally therefore not discovered until late in its development when it threatens to rupture and cause life-threatening haemorrhaging. There are currently no drugs for preventing and treating aortic aneurysm. In earlier studies, the research group found high levels of particular inflammatory signal substances called leukotrienes in the vascular walls of patients operated on for aortic aneurysm. Leukotrienes drive inflammation and are known for their potential to cause asthma. Since the asthma drug montelukast blocks leukotrienes, the team decided to examine whether it could also have an effect on aortic aneurysm. Very few side-effects Their studies on mice revealed that the treatment did indeed reduce the swelling of the aorta and reduced levels of an enzyme that can break down the vascular wall and a protein involved in inflammatory processes. “This study is particularly interesting from a therapeutic perspective since montelukast is a safe drug with very few side-effects, which means it can be taken over a long period of time,” explains Professor Haeggström. “In the study we used drug doses equivalent to those used in the treatment of asthma patients.” The researchers hope to be able to start a controlled clinical trial to test the drug’s efficacy on patients with aortic aneurysm. The study was conducted with researchers at Linköping University and the Technical University of Munich, Germany and financed by the Swedish Research Council, Stockholm County Council, the Novo Nordisk Foundation, the Heart and Lung Foundation, the Ragnar Söderberg Foundation, Karolinska Institutet and the European Research Council (ERC). Publication Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm Antonio Di Gennaro, Ana Araujo, Albert Busch, Hong Jin, Dick Wågsäter, Emina Vorkapic, Kenneth Caidahl, Per Eriksson, Bengt Samuelsson, Lars Maegdefessel, Jesper Z. Haeggström PNAS, online the week of 5-9 February 2018.

During their visit to Sweden and Stockholm in the company of Crown Princess Victoria and Prince Daniel, Prince William and Kate Middleton specifically requested to learn more about the Youth Aware of Mental Health (YAM) Programme and the work being carried out at the National Centre for Suicide Research and Prevention of Mental Ill-Health at Karolinska Institutet. The royal couple were also keen to learn more about research being carried out at Karolinska Institutet into physical activity and its prophylactic effects. The Duke and Duchess have a history of involvement in issues related to mental illness among children and young people in general, and suicide prevention in particular. During their visit to Karolinska Institutet Prince William and Kate Middleton met Danuta Wasserman, professor of psychiatry and suicidology and Carl Johan Sundberg, professor of molecular and applied exercise physiology, as well as vice-chancellor Ole Petter Ottersen. The couple were informed about the YAM model and listened to a presentation by KI researchers about the effects of physical activity on young people’s mental health and cognitive functions. Another issue discussed was the connection between the ever-increasing use of smartphones and increased levels of mental illness in children and young people. After visiting Karolinska Institutet, the Duke and Duchess continued on to Matteusskolan, a school in Stockholm, to meet pupils and teachers who have participated in the YAM Programme. Together with the Swedish royal couple and Swedish Minister for Education Gustav Fridolin, they participated in role-play exercises that form part of the YAM programme. “The royal couple expressed a desire to participate personally to see how it feels,” says Danuta Wasserman. “They were quite clear in their wish to contribute to young people being able to discuss mental health. As a medic, it is pleasing to me that young people today are interested in all aspects affecting mental health, including the biological, and how lifestyles affect the brain’s functions.” Prince William and Kate Middleton have previously spoken about their own experiences of suicide, depression and mental illness. In his previous role as an ambulance pilot, the Prince came into contact with many young people with suicidal thoughts. The YAM Programme was created within the EU project SEYLE, and combines role play with discussions on mental health based on young people sharing their own experiences under the guidance of two experienced instructors who always remain in the classroom. The programme is designed to teach young people about what they can do to affect their own psychological wellbeing, including how this is affected by eating habits, physical activity and sleep. Using a randomised controlled study of 11,000 teenagers from 168 schools in 10 European countries, published in The Lancet, researchers were able to show that the risk of suicide among young people who were involved in the YAM Programme was half that of a control group. The project has also produced a comprehensive database of facts relating to mental health among young people, for example it revealed that 29% of those involved in the study had minor symptoms of depression. Even if suicide continues to be the single greatest cause of death among the 16-29 age group in Sweden, there are signs of a long-term decline in the number of suicides over several decades. Behind this decline lies not only improved diagnosis and treatment of depression, but also a general increase in awareness regarding the problem. “If one begins to discuss a problem, it is almost always a step towards alleviating it,” says Danuta Wasserman. “The greatest contribution of the YAM Programme is preventative but, as we distribute questionnaires to all pupils, we are also able to catch those who are already in a situation where they need help.”

On Tuesday, Karolinska Institutet’s vice-chancellor Ole Petter Ottersen reached the decision to find Paolo Macchiarini, Philipp Jungebluth, Bernhard Holzgraefe and Håkan Kalzén guilty of scientific misconduct. The case relates to the article “Autologous peripheral blood mononuclear cells as treatment in refractory acute respiratory distress syndrome”, published in 2015 in Respiration. The article is a case study of a patient suffering from acute lung damage who, in 2011, received ECMO treatment at Karolinska University Hospital and thereafter experimental treatment. On 22 April 2016, then acting vice-chancellor Karin Dahlman-Wright decided to initiate an inquiry into suspected scientific misconduct due to concerns expressed to KI regarding the article. According to the Swedish Higher Education Ordinance, universities are required to investigate suspected scientific misconduct and, during such an inquiry, may obtain an opinion from the Expert Group for Misconduct in Research at the Central Ethical Review Board, something that was done in the case in question. According to the Vice-Chancellor’s decision, Respiration should be notified with a request that the article be immediately withdrawn. None of the researchers who have been found guilty of scientific misconduct are employed by Karolinska Institutet and therefore they will not be subject to any disciplinary measures under employment legislation. A decision is expected from the Vice-Chancellor in the spring regarding scientific misconduct relating to six articles of which Paolo Macchiarini was the main author. These include an article published in The Lancet describing the transplantation of a synthetic prosthesis into human trachea.

The female sex hormone oestrogen can perform an important role in neuroblastoma, a form of cancer mainly affecting young children. In laboratory experiments, researchers at Karolinska Institutet demonstrate that oestrogen treatment and overexpression of the oestrogen receptor cause malignant neuroblastoma cells to mature into neuron-like cells. The study, which is published in PNAS, gives hope of new treatment possibilities. Neuroblastoma forms in the peripheral nervous system and is one of the most common forms of solid cancer in young children. The disease mainly affects babies and young children, and while in some cases the tumours can disappear of their own accord, the majority are aggressive, metastasising cancer tumours that are resistant to modern combinations of surgery, radiotherapy and intensive chemotherapy. The most aggressive forms of neuroblastoma are often associated with a more active MYCN gene, which drives tumour cell growth and spread and inhibits the maturation of the cells. A possible target for new drugs “Our research focuses particularly on the activity of this gene and how it relates to neuroblastoma,” says Professor Marie Arsenian-Henriksson at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet. “MYCN is often seen only as a marker for a poor prognosis, but it’s critical to the disease and is a possible target for new drugs.” In a previous study, her group discovered that activation of MYCN results in the formation of specific microRNAs, which are relatively small RNA molecules that regulate proteins. Some of these microRNAs disable the oestrogen receptor ERalpha. The present study shows that the inhibition of these microRNA molecules or oestrogen therapy in combination with an overexpression of the oestrogen receptor can cause aggressive neuroblastoma cells with MYCN activation to mature into neuron-like cells which behave more like normal cells. Studied human and mouse tissue The researchers studied tumour tissue from patients, cultivated human tumour cells and tumours in mouse models for neuroblastoma. In the mice, the neuron-like cells did not grow as quickly as the original cancer cells, and analyses of the tumour tissue from patients show that those with a high level of the oestrogen receptor have a better survival rate that those with a low. “Our data suggests that oestrogen could be a therapeutic method for patients who express high levels of the oestrogen receptor,” continues Professor Arsenian-Henriksson. “Another possible therapy could involve deregulating MYCN or upregulating the oestrogen receptor and then treating with oestrogen. We have previously shown that the deregulation of MYCN leads to a high expression of the oestrogen receptor.” The study was financed by the Lars Hierta Memorial Foundation, the Mary Béve Foundation for Childhood Cancer Research, the Anna-Brita and Bo Castegren Memorial Foundation, the Swedish Cancer Society, the Swedish Research Council, the Swedish Childhood Cancer Foundation, the King  Gustaf V’s Jubilee Fund and Karolinska Institutet. Publication “MYCN-amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling” Johanna Dzieran, Aida Rodriguez Garcia, Ulrica Kristina Westermark, Aine Brigette Henley, Elena Eyre Sánchez, Catarina Träger, Henrik Johan Johansson, Janne Lehtiö, Marie Arsenian-Henriksson Proceedings of the National Academy of Sciences, online 26 January 2018

A master’s student from China who has paid tuition fees for her education at Karolinska Institutet has been denied a renewed residence permit for her fourth and final term. The Swedish Migration Agency considers that the student cannot prove that she can support herself and therefore has to leave the country within four weeks. “The situation for third-country guest students has changed dramatically since tuition fees were introduced. The rules for residence permits now need to be adapted so that paying students with approved academic results can be granted a residence permit for the whole of the study period,” says Per Bengtsson, University Director at KI. Since the autumn of 2017 around ten master's students at Karolinska Institutet (KI) from non-EU countries have received deportation notices. Most have appealed to the Migration Court of Appeal but some are still waiting for a decision. The student who is now being deported has had her request to have her case reviewed by the Migration Court of Appeal refused. The question now is how the student will be able to complete her studies that she has already paid for. “The situation has huge consequences, first and foremost for the affected students but also for KI’s and other educational institutions’ ability to attract international students and contribute to Sweden’s reputation as a leading knowledge nation,” Per Bengtsson continues. In order to be granted a residence permit in Sweden the students, according to the Swedish Migration Agency's rules, need to be able to demonstrate that they have their own personal funds or, for example, through scholarships, to cover their living costs of SEK 8,064 a month for ten months. The Migration Agency’s reason for its refusal is that the students have not been able to prove that they have their own means of support to the required extent. So despite the students’ bank statements where money was available for their support, the Migration Agency considered that it is not credible that the funds are for them, but only temporarily deposited in the accounts. “These students are usually supported by their parents or other relatives, which is natural because it is unusual for young people to have personal assets equivalent to between 500,000 and 600,000 kronor, which is the total cost for a student from a non-EU country to study a master’s programme at KI,” says Per Bengtsson. KI has written to the Migration Agency and the Ministry of Education and Research about the matter and is working with other universities and the Swedish Institute to achieve a solution to the question of residence permits for studies. FACTS about tuition fees The Ordinance (2010:543) on application fees and tuition fees at higher education institutions for students from outside the EU/EEA came into effect on 1 July 2010. The ordinance was applied for the first time on 1 August 2011. The term fee to study on one of the university's 9 global master’s programmes is about 90,000 kronor.

A study by researchers at Karolinska Institutet, the University of Manchester and Chalmers University of Technology published in CHEM shows that our immune system handles graphene oxide (GO) in a manner similar to pathogens, paving the way for safer biomedical applications of this two-dimensional material. Graphene is the thinnest material known to man, a million times thinner than a human hair. Graphene oxide (GO), in turn, is an atomically thin material consisting only of carbon and oxygen atoms. GO is currently being considered for numerous uses including drug delivery and other medical applications. However, it is of critical importance to understand how these materials interact with the body. In a new study led by Professor Bengt Fadeel at the Institute of Environmental Medicine, Karolinska Institutet, it is shown that neutrophils, the most common type of white blood cell that is specialised in combating infections, release so-called neutrophil extracellular traps (NETs) when encountering GO. NETs are made up of a “spider-web” of DNA decorated with proteins that help neutrophils to destroy microorganisms such as bacteria and fungi. The researchers found that GO causes specific changes in the lipid composition of the cell membrane of neutrophils leading to the release of NETs. They could also show that antioxidant treatment reversed this process. In a companion study published in Nanoscale, it was shown that GO is degraded in NETs, much like bacteria and other pathogens. Part of the Graphene Flagship Project “Taken together, these studies show that GO can be trapped and degraded in NETs just like pathogens. Understanding how the immune system senses and handles GO paves the way for safer biomedical applications of GO and other graphene-based materials, for instance in the context of drug delivery”, says Professor Bengt Fadeel. The current study, performed at Karolinska Institutet in collaboration with Professor Kostas Kostarelos at the National Graphene Institute, University of Manchester, and the National Center of Imaging Mass Spectrometry at Chalmers University of Technology, is part of the EU's largest research initiative, the Graphene Flagship Project which has over 150 academic and industrial partners and a total budget of €1 billion. The research was funded by the European Commission through the Graphene Flagship Project, and the Swedish Research Council. Publication “Graphene Oxide Elicits Membrane Lipid Changes and Neutrophil Extracellular Trap Formation” Mukherjee SP, Lazzaretto B, Hultenby K, Newman L, Rodrigues AF, Lozano N, Kostarelos K, Malmberg P, Fadeel B Chem-Cell Press, online January 25, 2018, doi: 10.1016/j.chempr.2017.12.017, February 8, issue 4, pp 1-25

The benefits of low-intensity physical activity, such as standing, walking or doing household chores, can be more health beneficial than once thought. According to a study from Karolinska Institutet published in the journal Clinical Epidemiology, replacing half an hour’s sedentariness a day with everyday activity reduces the risk of fatal cardiovascular disease by 24 per cent. Cardiovascular diseases are the primary cause of death in Sweden, and while it is known that moderate to intense physical activity reduces the risk of cardiovascular disease, the benefits of low-intensity activity have yet to be agreed upon. For the present study, the researchers analysed how different levels of physical activity in 1,200 people across Sweden affected the mortality rate due to cardiovascular disease (amongst other causes) 15 years later. Data were gathered from the ABC (Attitude, Behaviour and Change) study, in which the activity level of the participants is measured using motion trackers, and compared them with data on deaths and causes of death from Swedish registries. Objective measures of physical activity “This is a unique study, since we’ve been able to analyse a large number of people with objective measures of physical activity for up to 15 years,” says study leader Maria Hagströmer, senior lecturer at Karolinska Institutet’s Department of Neurobiology, Care Sciences and Society. “Previous studies asked participants about levels of physical activity, but this can lead to reporting error since it’s hard to remember exactly for how long one has been sitting and moving around.” The study shows that there are considerable health benefits to be gained not only from moderate or intense physical activity but also from low-intensity (everyday) activity. Replacing half an hour’s sedentariness a day with such low-level activity can reduce the risk of dying from cardiovascular disease by an estimated 24 per cent. The more the better Replacing sedentariness with physical activity of at least moderate level equivalent to a brisk walk, or higher intensity training, had, as expected, an even greater effect on cardiovascular-related mortality. Ten minutes of moderate to intense activity a day reduced the risk of death due to cardiovascular disease by 38 per cent, 30 minutes a day by a full 77 per cent, according to their calculations. The study adjusted for other potential confounding factors, such as age, sex, smoking habits, educational level and previous morbidity. “In an earlier study, we also showed that people who sit still for more than 10 hours a day have a 2.5 times higher risk of early death than people who sit for less than 6.5 hours a day,” says first author Ing-Mari Dohrn, postdoc at Karolinska Institutet’s Department of Neurobiology, Care Sciences and Society. External funding for the study was obtained from insurance company Folksam. The ABC study was financed by Stockholm County Council, the Swedish Research Council for Sport Science and the EU-financed ALPHA (Assessing Levels of PHysical Activity) project. Publication “Replacing sedentary time with physical activity – a 15 year follow-up of mortality in a national cohort” Ing-Mari Dohrn, Lydia Kwak, Pekka Oja, Michael Sjöström, Maria Hagströmer Clinical Epidemiology, online 25 January 2018

Karolinska Institutet is now starting organised international alumni networks for its overseas students. At its launch, the first of these, KI Alumni China, already has 50 members. “As alumni, we can provide a reliable platform for KI in the Chinese healthcare sector,” says Claire Ye, newly appointed alumni ambassador to China. Until now, Karolinska Institutet’s (KI) various departments have each dealt with their own overseas alumni in a variety of ways, but now KI is investing in an overall strategy for maintaining relationships with former students from around the world. On 22 January, a launch event was organized at Solna campus with approximately 80 participants. “Alumni are truly our most important tool for building collaboration and recruiting international students. We now have a structure in place for these contacts,” says Maria Masucci, deputy vice-chancellor for international affairs at Karolinska Institutet. She is also delighted to be able to offer students a basic professional network after graduation. Megan Osler, alumni coordinator at KI, is responsible for the practical administration of the project. She hopes that KI Alumni China will provide a working model for alumni networks in other countries. This year will see the launch of an alumni network in Vietnam, while Megan also sees a solid basis for future networks in Uganda, Columbia and Brazil. “The key is to have an ambassador in place, something we have in Vietnam,” she explains, and underlines that this is a voluntary position, even if KI can meet the costs of the organisation. It is no coincidence that China was first. Claire Ye from Shanghai completed her master’s in bioentrepreneurship at Karolinska Institutet between 2008-2010. Today, she works as senior manager of marketing, products and services at a newly opened private hospital that has gone from 20 to 500 employees in only two years. In 2012, Claire began to get in touch with KI alumni to create a network. There are currently around 50 members in various sectors of Chinese academia and business, all educated at KI. “When I returned home, I wanted to maintain contact with KI and wished that there was a network,” she says. Claire Ye sees several purposes behind KI Alumni China: For alumni, it is valuable to maintain contact with others who share the experience of studying at Karolinska Institutet in Sweden: “The experience we few share is unique once we have returned home.” It may prove even more important for current and future Chinese KI students: “They will be able to get advice from us about how they can get the most out of their time at KI, and how they should go about choosing a career once they return home,” says Claire Ye. For KI, this will be an important platform for student recruitment and collaboration with Chinese universities, hospitals and, eventually, businesses. “We want to build bridges for KI between Sweden and China, including commercial ties. This requires a little more effort but in the long-term will prove really valuable to Sweden and KI,” says Claire Ye. She believes that KI alumni can provide reliable contacts for Swedish businesses that wish to enter the Chinese life science and biotech markets. Ole Petter Ottersen, KI’s vice-chancellor and a guest at the dinner, concurs with Claire Ye’s assessment: “Karolinska Institutet has a clear ambition to maintain contacts with our Chinese students and alumni,” he says. For examples of Chinese alumni’s desire to maintain contact with KI after graduation, one need look no further than many video greetings from members of KI Alumni China played at the launch in Aula Medica. One of these was from 76-year-old Xu Qunyuan, previously a researcher and head of neuroscience at Capital Medical University and Chinese Minister of Health. Between 1981 and 1988, he was one of the first Chinese doctoral students at KI. Together with Megan Osler at KI, Claire Ye and three other KI alumni in Shanghai, Beijing and Shenzhen will now prepare an biotech markets. Ole Petter Ottersen, KI’s vice-chancellor and a guest at the dinner, concurs with Claire Ye’s assessment: “Karolinska Institutet has a clear ambition to maintain contacts with our Chinese students and alumni,” he says. For examples of Chinese alumni’s desire to maintain contact with KI after graduation, one need look no further than many video greetings from members of KI Alumni China played at the launch in Aula Medica. One of these was from 76-year-old Xu Qunyuan, previously a researcher and head of neuroscience at Capital Medical University and Chinese Minister of Health. Between 1981 and 1988, he was one of the first Chinese doctoral students at KI. Together with Megan Osler at KI, Claire Ye and three other KI alumni in Shanghai, Beijing and Shenzhen will now prepare an annual activity plan for the alumni network in China. Daily contact will mostly take place on social media, primarily on WeChat. “As a rule, we are people with fully-booked calendars, so it is a challenge to arrange meetings that sufficient numbers can attend,” says Claire Ye.  Megan Osler is delighted to see that organised collaboration is now underway: “Karolinska Institutet is a small university in a small, isolated country in a global backwater. However, because such a large proportion of our study courses are in English, we are a good choice for overseas students. And our alumni are an important channel for reaching them.” Text: Ulrika Fjällborg

The 2018 Louis-Jeantet Prize for Medicine is awarded to Christer Betsholtz, Director of the Integrated Cardio Metabolic Centre at Karolinska Institutet, and Professor at Uppsala University. Christer Betsholtz is awarded the prize of SEK 5.8 million for his seminal discoveries in vascular biology, in particular the characterisation of specialised cells – pericytes – and their role in vascular development and permeability. The 2018 Louis-Jeantet Foundation grants the sum of CHF 700,000 for each of the two prizes, of which CHF 625,000 is for the continuation of the prize-winner's research and CHF 75,000 for their personal use.    

Karolinska Institutet’s Silver Medal for 2017 is awarded to Lars-Olof Wahlund and Eva Mattsson. The medals are awarded to those who have made a special contribution to supporting KI’s activities. The vice-chancellor, in consultation with the pro-vice-chancellor, university director and the deans of research, doctoral education and higher education, awards Karolinska Institutet’s various medals based on recommendations from the Medals Committee. Extracts from the Committee’s reasons for awarding the silver medals: Lars-Olof Wahlund, senior professor in geriatrics, receives the medal for the major impact his work as a teacher, clinician and researcher has had on KI’s leading position in the field of dementia research. His scientific productivity is high, with in the region of 450 publications, and he is a leader within KI in the field of magnetic resonance-based research into dementia disorders.   Eva Mattsson, professor emerita in physiotherapy, receives the medal for her distinguished contribution to doctoral and higher education and research at Karolinska Institutet. Throughout the course of her professional life, she has been an eminent researcher who has influenced clinical praxis, as well as a forceful proponent of quality in first cycle, second cycle and doctoral education, not only in KI’s physiotherapy programme, but also within KI as a whole. The medals are being presented in conjunction with the “För nit och redlighet i rikets tjänst”, NOR, awarding ceremony, on 15 February.

Researchers at Karolinska Institutet have developed an accessible therapy for children and adolescents suffering from dental phobia. The study, published in the Journal of Medical Internet Research, shows that guided internet-based CBT is highly effective in reducing anxiety and increasing the ability to deal with dental treatment. One year later, half of the children were completely free of their phobia. Dental anxiety often begins in childhood or adolescence, and can develop into a phobia with avoidance, strong negative feelings and thoughts aimed at dental care. Avoidance of dental care often leads to poor oral health, untreated caries or other dental problems. Cognitive behavioural therapy (CBT) is an effective treatment for most forms of specific phobia. However, with regard to children and adolescents with dental phobia, there are organisational, financial and geographic obstacles to providing such therapy. Researchers in this study have therefore developed an internet-based CBT treatment that they have tested in an open, uncontrolled study of 18 patients between the ages of 8 and 15. Treatment continued for 12 weeks During the study, participants used an internet platform to obtain weekly online guidance from a psychologist via a chat system. Treatment continued for 12 weeks and included texts, animations and dental-related video clips. The treatment also included an exercise package with a dental mirror, probe, local anaesthetic and cannula delivered to the home of the child/parent(s) with detailed instructions for the exercises. Through therapy and guidance from the psychologist, the home-based exercises were linked to real exposure and training visits to dental clinics around Sweden. The results show a statistically and clinically-significant increase in the children’s ability to manage dental treatment. The internet-based CBT also increased children’s and parents’ self-efficacy, led to fewer negative thoughts and reduced anxiety aimed at dental treatment. At a one-year follow up, 53 per cent of the children were completely free of their dental phobia. Surprisingly strong effects “Even though we expected positive effects from the therapy, it was still surprising to see the scope of improvement and the strong effects of the therapy among the patients, given that they did not have a single physical meeting with the psychologist,” explains Shervin Shahnavaz at Karolinska Institutet’s Department of Dental Medicine who is the researcher behind the development of the therapy. The researchers now hope to be able to repeat the results in an ongoing randomised controlled trial. “Internet-based CBT for dental phobia in children and adolescents may be an efficient form of therapy with the potential to increase access to effective treatment,” says Dr Shahnavaz. The study is the result of a collaboration with Stockholm County Council’s unit for internet psychiatry. The research project was supported with grants from SOF; board of dental research at Karolinska Institutet and Stockholm County Council and the Mayflower Charity Foundation for children. Publication Shahnavaz S, Hedman-Lagerlöf E, Hasselblad T, Reuterskiöld L, Kaldo V, Dahllöf G ”Internet-Based Cognitive Behavioral Therapy for Children and Adolescents With Dental Anxiety: Open Trial” J Med Internet Res 2018;20(1):e12, online 22 January 2018, doi:10.2196/jmir.7803

Researchers Petter Brodin and Carl Sellgren Majkowitz at Karolinska Institutet have been accepted into the Wallenberg Clinical Fellows research programme, meaning a three-year appropriation financed by the Marianne and Marcus Wallenberg Foundation. Petter Brodin is an assistant professor at Karolinska Institutet’s Department of Medicine, Solna and Science for Life Laboratory, as well as a resident in paediatrics at the Karolinska University Hospital. His research deals with how the immune systems of infants are formed by environmental factors such as bacteria, viruses and nutritional components. Together with his research group, he has developed a completely unique experimental method based on a new sampling method. Carl Sellgren Majkowitz is a senior researcher at KI’s Department of Physiology and Pharmacology, as well as an attending physician at Karolinska University Hospital. Carl Sellgren Majkowitz and his research group are attempting to develop a new treatment for those suffering from schizophrenia and bipolar disorder that will cause fewer side effects than existing treatments. The purpose of the Wallenberg Clinical Fellows research programme is to stimulate clinical research among Swedish physicians and to identify the leading researchers of tomorrow in a clinical environment. The programme is primarily aimed at younger doctors. The initiative is the work of the Marianne and Marcus Wallenberg Foundation with scientific support from the Royal Swedish Academy of Sciences.

On Thursday, Amnesty International’s Swedish section and Karolinska Institutet held a joint demonstration in support of the physician and researcher Ahmadreza Djalali, currently facing a death sentence in Iran. The demonstration in support of Ahmadreza Djalali, who has been imprisoned in Iran since April 2016, was held at Campus Solna. Ahmadreza Djalali’s wife, Vida Mehrannia, also attended the demonstration. Ahmadreza Djalali was sentenced to death in October 2017 for alleged espionage on behalf of the Israeli government. Although Djalali is an Iranian citizen, he has a permanent residence permit in Sweden and was previously a researcher in disaster medicine at Karolinska Institutet, where he also defended his thesis in 2012. Amnesty International considers Ahmadreza Djalali to be a prisoner of conscience who has been arbitrarily imprisoned and is demanding that the Iranian authorities quash the sentence and release him. Ole Petter Ottersen, Vice-Chancellor of Karolinska Institutet, participated in the demonstration. Among other things, he spoke of the human right to a free and just trial, the fact that the death penalty conflicts with human dignity, human rights and international standards, as well as every value for which Karolinska Institutet stands. “As academics, we have a great responsibility towards the fight to abolish the death penalty and to maintain academic freedom, so let us make ourselves heard,” declared Ole Petter Ottersen. In 2014, during his time as vice-chancellor of the University of Oslo, Ole Petter Ottersen was instrumental in starting the Universities Against the Death Penalty network. During the demonstration, Anna Lindenfors, Director at Amnesty International Sweden, explained that, as the Supreme Court of Iran confirmed the death penalty in December, the only remaining possibility is a judicial review of the entire case that may change the verdict. “This is a very serious situation. Ahmadreza Djalali must be immediately and unconditionally released so that he can be reunited with his wife and children in Sweden and continue his research,” said Anna Lindenfors. Lisa Kurland, previously Djalali’s supervisor and professor in emergency care at Örebro University, contributed a more personal picture of her friend and colleague. “Ahmadreza Djalali travelled to Iran, the land of his birth and a country he loved, in order to pass on his knowledge. It pains me that he is imprisoned, and it is beyond comprehension that he is sentenced to death,” she said.   Text: Helena Mayer

Researchers at Karolinska Institutet have discovered that the risk of death from breast cancer is twice as high for patients with high heterogeneity of the oestrogen receptor within the same tumour as compared to patients with low heterogeneity. The study, which is published in The Journal of the National Cancer Institute, also shows that the higher risk of death over a span of 25 years is independent of other known tumour markers and also holds true for Luminal A breast cancer, a subtype with a generally good prognosis. The most common form of breast cancer is oestrogen-receptor-positive, so called hormone-sensitive breast cancer. This means that the tumour needs the female hormone oestrogen to grow. Women who develop this kind of breast cancer have a remaining long-term risk of dying of the disease. It is also known that the oestrogen receptor can change when a breast cancer tumour spreads, which affects survival. Why this is the case, however, is not known, but a possible explanation is that there are tumour cells in one and the same tumour with varying degrees of expression of the oestrogen receptor. This is known as intra-tumour heterogeneity. In the present study, Swedish and American researchers sought to discover if breast cancer patients with high heterogeneity of the oestrogen receptor in their breast cancer tumour have a higher long-term risk of dying. To this end, they studied the fates of 593 patients in a clinical study, who had been either treated with tamoxifen or not treated with systemic therapy after surgery. All women had been diagnosed with post-menopausal oestrogen-receptor-positive breast cancer between 1976 and 1990. Independent of other known tumour markers “Our study shows that patients with high intra-tumour heterogeneity of the oestrogen receptor were twice as likely to die up to 25-years after their diagnoses as compared to patients with low heterogeneity,” says Linda Lindström, researcher at the Department of Biosciences and Nutrition, Karolinska Institutet. “And this was independent of whether or not they’d received tamoxifen and of other known tumour markers.” The researchers also discovered that the greater risk of death for patients with high intra-tumour heterogeneity also applied to patients with Luminal A breast cancer, a subtype of oestrogen-receptor-positive breast cancer that is considered to have a good prognosis. “Patients with Luminal A breast cancer and high intra-tumour heterogeneity of the oestrogen receptor were also twice as likely to die from the disease,” continues Dr Lindström. “This is interesting given that patients with Luminal A breast cancer subtype are generally thought to have a good prognosis. We believe that if validated, these new findings should be useable within the near future.” The study was financed by the Swedish Research Council, the Cancer Society in Stockholm, the Gösta Milton Donation Fund and the California Breast Cancer Research Program BCRP award. Co-author Laura J. van’t Veer, is a founder, shareholder and part-time employee of Agendia. Publication ”Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer” Linda S. Lindström, Christina Yau, Kamila Czene, Carlie K. Thompson, Katherine A. Hoadley, Laura J. van’t Veer, Ron Balassanian, John W. Bishop, Philip M. Carpenter, Yunn-Yi Chen, Brian Datnow, Farnaz Hasteh, Gregor Krings, Fritz Lin, Yanhong Zhang, Bo Nordenskjöld, Olle Stål, Christopher C. Benz, Tommy Fornander, Alexander D. Borowsky, Laura J. Esserman Journal of The National Cancer Institute, online 19 January 2018, doi: 10.1093/jnci/djx270

Researchers at Karolinska Institutet, Uppsala University and the University of Oxford, have used a new strategy to understand how specific enzymes can be shut down to stop cells from dividing. The method, published in Cell Chemical Biology, allows scientists to better target an enzyme to fight cancer. Turning off enzymes that are important for the survival of growing cells is a promising strategy to fight cancer. But to be able to shut down only one specific enzyme out of thousands in the body, drugs have to be tailored to exactly fit their target. This is particularly difficult for membrane proteins, since they only function when incorporated into the cell lipid envelope, and often cannot be studied in isolation. In a study published in Cell Chemical Biology this week, researchers from Karolinska Institutet, KTH, Uppsala University, and the University of Oxford, used a new strategy to find out how anticancer drugs bind to the membrane protein dehydroorotate dehydrogenase (DHODH), a new cancer target. The groups of Sir David Lane and Sonia Lain at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet used native mass spectometry, a technique where a protein is gently removed from its normal environment and accelerated into a vacuum chamber. By measuring the time it takes for the protein to fly through the chamber, it is possible to determine its exact weight, which can, in turn, indicate whether the protein has bonded to another molecule and if so, what kind. The researchers used this highly accurate ”molecule scale” to see how drugs and lipids, the building blocks of the cell membrane, bind to DHODH. "We saw that one of the drugs seemed to bind better to the enzyme when lipid-like molecules were present", says assistant professor Michael Landreh. The team also found that DHODH binds a particular kind of lipid present in the cell’s power plant, the mitochondrial respiratory chain complex. "This means the enzyme might use special lipids to find its correct place on the membrane", Michael Landreh explains. To understand how lipids can help a drug recognize its target, the researchers worked with Dr Erik Marklund, group leader at the Department of Chemistry, Uppsala University, to build and compare computational models of free as well as membrane-bound DHODH. "The study helps to explain why some drugs bind differently to isolated proteins and proteins that are inside cells. By studying the native structures and mechanisms for cancer targets, it may become possible to exploit their most distinct features to design new, more selective therapeutics", says Sir David Lane, professor at the Department of Microbiology, Tumor and Cell Biology. The research was financed by: The Swedish Research Council, The Foundation for Strategic Research, the European Research Council, and Karolinska Institutet. Publication "Lipids shape the electron acceptor-binding site of the peripheral membrane protein dihydroorotate dehydrogenase," Costeira-Paulo J, Gault J, Popova G, Ladds M.J.G.W., van Leeuwen IMM, Sarr M, Olsson A, Lane DP, Laín S, Marklund EG, and Landreh M Cell Chemical Biology, online 18 January 2018 doi: 10.1016/j.chembiol.2017.12.012

Icelandic President Guðni Thorlacius Jóhannesson and his wife Eliza Reid visited Karolinska Institutet on 18 January together with the Swedish King and Queen. KI and Iceland have enjoyed many years of collaboration, both in research and student exchanges. The visit to Karolinska Institutet (KI) took place as part of a three-day state visit to Sweden and, in addition to the royal couple, the President and First Lady were also accompanied by Karin Röding, State Secretary to the Minister for Higher Education and Research and former university director of KI. During a seminar at Nobel Forum, KI’s vice-chancellor Ole Petter Ottersen began by presenting KI and the university’s cooperation with Iceland. Around two percent of KI’s publications are the result of collaboration with researchers at Icelandic institutions, a notably high figure in relation to Iceland’s population. KI also has a number of student-exchange agreements with the University of Iceland. After a speech by Professor Anna Wedell, Chair of the Nobel Committee for Physiology or Medicine, presentations were made of research collaborations. Among the speakers was Unnur Valdimarsdottir, visiting professor at KI’s Department of Medical Epidemiology and Biostatistics, who presented her StressGene research programme, dealing with understanding the role played by genetic factors in the risk of serious illness and death resulting from psychological stress and difficult life events. Inga Dóra Sigfúsdóttir, visiting professor at the Department of Public Health Sciences, presented her research on risk and protective factors for health among young people, and also spoke about Iceland’s successful efforts to reduce smoking, drinking and drug use among young people. Frieder Braunschweig, associate professor in cardiology at the Department of Medicine, Solna, explained that many Icelandic physicians complete their doctoral education at Karolinska University Hospital and that, together with Karolinska University Hospital, KI researchers also collaborate closely in the field of cardiology with Landspitali - The National University Hospital of Iceland, both with regard to research, education and clinical care. Text: Helena Mayer

A study by researchers at Karolinska Institutet and the University of Copenhagen published in Nature provides new and important knowledge about how the brain controls locomotion. In research on mice, scientists have discovered that specific start cells in various locations in the brainstem control whether the mouse walks or runs. This research may lead to new treatments for diseases and injuries that adversely affect locomotion. Locomotion, or the ability to move from one place to another is a fundamental and necessary function for the survival of both people and animals. Locomotor behaviour is episodic in character, meaning that we move as and when we want or need to, and that we are able to easily interrupt ongoing movements. At the same time, locomotion is executed at different speeds to regulate how fast we travel from one place to another depending on the context or purpose that drives us e.g. slowly exploring the neighborhood in a new city or fast escaping an oncoming threat.  The precise coordination of locomotion is controlled by neural circuits in the spinal cord, but it is the brainstem that sends signals to the spinal cord to initiate, stop and modulate these movements. Still, how is the start and speed control executed? By which command pathways? And can these command pathways be recruited to support different types of locomotion dependent on the behavioural context? Part of a larger neural network In the present study, the researchers Vittorio Caggiano, Roberto Leiras, Haizea Goñi-Erro, Debora Masini, and colleagues together with Professor Ole Kiehn who led the study, address these questions. They have identified specific “start cells” that are important for initiation, speed and context dependent selection of locomotion in mice. These ‘start cells’ are part of a larger neural network located in two different areas of the midbrain, the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF).  “By identifying the midbrain ‘start neurons’ we complement a previous study in which we discovered specific ‘stop cells’ in the brainstem that perform the opposite task of making the mouse stop. Together, these cell types appear to be crucial to the episodic control of locomotive behaviour,” explains Professor Ole Kiehn, who works both at Karolinska Institutet’s Department of Neuroscience and at the Department of Neuroscience at the University of Copenhagen. Used light and designer drugs The researchers have utilised a number of advanced techniques, including optogenetics, to study which types of neurons are involved and the location of the neural networks. By using light and designer drugs, they have been able to activate or inactivate selected groups of nerve cells and then study how this affects the locomotor output in mice. They found that, in contrast to what has previously been thought, excitatory projection neurons in both PPN and CnF can start locomotion and contribute to the maintenance and speed regulation of slower locomotion. However, only CnF is able to elicit high-speed escape locomotor activity. In contrast, activity in PPN neurons favours explorative locomotion. “We have demonstrated that both brain regions collaborate and work independently of one another to select the gait and speed of locomotion,” says Ole Kiehn. Could be similar mechanisms in humans The researchers believe that similar mechanisms are at work in the selection of locomotion and speed in humans. The results of the study can therefore be important in developing treatments for spinal cord injuries and certain diseases that adversely affect locomotion. Parkinson’s Disease, where gait disturbances and freezing of gait are very pronounced, affects an area of the brain that sends signals to the PPN. By implanting fine electrodes in the brain – a technique called deep brain stimulation which is already used to treat some symptoms in Parkinson’s disease – circuits in either CnF or PPN might now be targeted with new precision and used to increase the locomotor capabilities. Similar approaches may also be used after damage to the spinal cord, where initiation of locomotion is strongly affected. The research was funded by the European Research Council (LocomotorIntegration), the US National Institute of Neurological Disorders and Stroke, The Swedish Research Council, StratNeuro and the Novo Nordisk Foundation- Laureate Award. Publication “Midbrain circuits that set locomotor speed and gait selection” Caggiano V, Leiras R, Goñi-Erro H, Masini D, Bellardita C, Bouvier J, Caldeira V, Fisone G & Kiehn O Nature, online 17 January 2018, doi: 10.1038/nature25448

Elisabeth Björk Brämberg, Assistant Professor at Karolinska Institutet’s Institute of Environmental Medicine, has been awarded a grant of approximately SEK 1.75 million for work environment and health-related research. Elisabeth Björk Brämberg’s research project: Enabling and constraining factors and ethical aspects related to cooperation aimed at increased return-to-work among people suffering from mental disorders. In this project, Elisabeth Björk Brämberg will, through interviews with employees, employers and representatives of healthcare centres, OHS providers and the Swedish Social Insurance Agency, collect and analyse experiences gained in collaborations connected with mental illness. The project includes the analyses of ethical issues linked to areas such as the health, personal rights and freedoms of those on extended sick leave and their ability to influence activities. One goal is the development of strategies to promote cooperation as a rehabilitation method. In the current round of grants, AFA Insurance has committed almost SEK 22 million to 10 new research projects in Sweden, aimed at contributing to a reduction in work-related injuries and long-term sick leave.