Integrative Molecular Phenotyping

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Updated: 39 min 20 sec ago

Use of muscle relaxant during general anaesthesia increases risk of pulmonary complications

Tue, 18/09/2018 - 09:32
Muscle relaxants that are used during general anaesthesia increase the risk of pulmonary complications after surgery, according to the European multicentre study POPULAR, in which Karolinska Institutet researchers are involved. The study is published in the journal Lancet Respiratory Medicine. Increasing numbers of people around the world undergo anaesthesia and surgery, and in Sweden over 10 per cent of the population are exposed to anaesthesia every year. In the case of general anaesthesia, in order to reduce the dose of the anaesthetic and morphine-like drugs, so-called neuromuscular blockers are often also administered, thus mitigating the risk of complications. Even if this group of anaesthetic drugs has contributed to safer and more effective anaesthesia, several patient studies and smaller studies on healthy participants indicate that the addition of neuromuscular blockers to anaesthesia increase the risk of respiratory complications. In the current study, the researchers sought to ascertain if the use of these muscle relaxants in combination with anaesthesia and surgery increases the risk of developing post-surgical pulmonary complications, such as infections, respiratory insufficiency or lung collapse. Large European study Data from over 22,800 patients in 28 European countries who had received general anaesthetic, including some 1,200 patients from ten Swedish hospitals, were gathered from between July 2014 to April 2015. “The study shows that the use of neuromuscular blockers significantly increases the risk of pulmonary complications after anaesthesia and surgery,” says Malin Jonsson Fagerlund, consultant and docent at the Department of Physiology and Pharmacology, Karolinska Institutet. “More targeted studies need to be made to find out the underlying mechanisms behind this finding.” The study also shows that neither neuromuscular monitoring nor the use of drugs that reverse the neuromuscular blockade reduce the risk of post-surgical pulmonary complications. The study was financed by the European Society of Anaesthesiology. Publication “Post-anaesthesia Pulmonary Complications after Use of Muscle Relaxants: A Prospective Multicentre Observational Study (POPULAR)” Kirmeier E, Eriksson LI, Lewald H, Jonsson Fagerlund M, Hoeft A, Hollmann M, Meistelman C, Hunter JM, Ulm K, Blobner M and the POPULAR Contributors Lancet Respiratory Medicine, online 14 September 2018, doi: 10.1016/S2213-2600(18)30294-7

Structural map of bacterial toxins raises hopes for new anti-infectives

Mon, 17/09/2018 - 12:05
The bacteria Pseudomonas aeruginosa can cause serious and difficult to treat infections. The infection process involves the activation of toxic substances from the bacteria by a common protein in our cells. Researchers at Karolinska Institutet now show how this happens and that the activation can be stopped with drug-like molecules. The results are presented in Nature Communications. Pseudomonas aeruginosa infections are a common problem in hospitals. Antibiotic-resistant strains of the bacteria can cause life-threatening infections in patients with reduced immunity or large, open wounds. The bacteria also cause infection of the airways, which makes people with respiratory impairment, such as cystic fibrosis, particularly vulnerable. To find new means of treating these infections, researchers at Karolinska Institutet, Umeå University and Yale University have mapped the three-dimensional structure of two toxic proteins that the bacteria use to trigger the infection process. Protected by human protein The researchers have determined the structure of these toxins, called ExoS and ExoT, along with a human protein, called 14-3-3, which is known to be necessary for the toxins to become active. Previously, only little was known of the structure of one of the toxins (ExoS) and how it binds to the human protein. But it was unclear how this contact could give rise to the bacterium’s toxic effects. The team has now found a large, hydrophobic contact interface between the human protein and the bacterial toxins and shown that if this surface is not protected by the human protein, the toxins form inactive clusters in the cell’s water-soluble environment. In other words, the protein makes the bacterial toxins active by acting as a protective “chaperone”. A step towards new anti-infectives This newly identified contact interface presents a possible target for drug molecules. The study identified two small organic molecules that can prevent the infection between the bacterial toxins and the human protein. It also shows that the toxins lose their toxic activity when these molecules are introduced. The effect is weak, but according to the researchers, the results show that the principle works. The previously known contact between the bacterial toxins and the human protein takes place in an area where many other proteins in the cell bind. Affecting this region with drug molecules would probably therefore cause serious adverse effects. The newly discovered surface can prove a more specific target. “Our study shows that it’s possible to block toxin activity with drug-like molecules via an interface where no other proteins have yet been shown to interact,” says principal investigator Herwig Schüler, associate professor of structure biology at the Department of Biosciences and Nutrition, Karolinska Institutet. The study was financed by the Swedish Research Council, The Swedish Foundation for Strategic Research, the Wenner-Gren Foundation and the IngaBritt and Arne Lundberg Research Foundation. Publication “14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface” Tobias Karlberg, Peter Hornyak, Ana Filipa Pinto, Stefina Milanova, Mahsa Ebrahimi, Mikael Lindberg, Nikolai Püllen, Axel Nordström, Elinor Löverli, Rémi Caraballo, Emily V. Wong, Katja Näreoja, Ann-Gerd Thorsell, Mikael Elofsson, Enrique M. De La Cruz, Camilla Björkegren and Herwig Schüler Nature Communications, online 17 September 2018, doi: 10.1038/s41467-018-06194-1

Discovery of new neurons in the inner ear can lead to new therapies for hearing disorders

Wed, 12/09/2018 - 11:03
Researchers at Karolinska Institutet have identified four types of neurons in the peripheral auditory system, three of which are new to science. The analysis of these cells can lead to new therapies for various kinds of hearing disorders, such as tinnitus and age-related hearing loss. The study is published in Nature Communications. When sound reaches the inner ear, it is converted into electrical signals that are relayed to the brain via the ear’s nerve cells in cochlea. Previously, most of these cells were considered to be of two types: type 1 and type 2 neurons, type 1 transmitting most of the auditory information. A new study by scientists at Karolinska Institutet shows that the type 1 cells actually comprise three very different cell types, which tallies with earlier research showing variations in the electrical properties and sonic response of type 1 cells. Three different routes “We now know that there are three different routes into the central auditory system, instead of just one,” says François Lallemend, research group leader at the Department of Neuroscience, Karolinska Institutet, who led the study. “This makes us better placed to understand the part played by the different neurons in hearing. We’ve also mapped out which genes are active in the individual cell types.” The team conducted their study on mice using the relatively new technique of single-cell RNA sequencing. The result is a catalogue of the genes expressed in the nerve cells, which can give scientists a solid foundation for better understanding the auditory system as well as for devising new therapies and drugs. “Our study can open the way for the development of genetic tools that can be used for new treatments for different kinds of hearing disorders, such as tinnitus,” says Dr Lallemend. “Our mapping can also give rise to different ways of influencing the function of individual nerve cells in the body.” Crucial function The study shows that these three neuron types probably play a part in the decoding of sonic intensity (i.e. volume), a function that is crucial during conversations in a loud environment, which rely on the ability to filter out the background noise. This property is also important in different forms of hearing disorders, such as tinnitus or hyperacusis (oversensitivity to sound). “Once we know which neurons cause hyperacusis we’ll be able to start investigating new therapies to protect or repair them,” explains Dr Lallemend. “The next step is to show what effect these individual nerve cells have on the auditory system, which can lead to the development of better auditory aids such as cochlear implants.” The researchers have also shown through comparative studies on adult mice that these different types of neurons are already present at birth. The study was financed by grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), the Swedish Brain Fund, Karolinska Institutet, the Ragnar Söderberg Foundation and the Silent School Foundation. Publication ”Neuronal heterogeneity and stereotyped connectivity in the auditory afferent system” Charles Petitpré, Haohao Wu, Anil Sharma, Anna Tokarska, Paula Fontanet, Yiqiao Wang, Françoise Helmbacher, Kevin Yackle, Gilad Silberberg, Saida Hadjab and François Lallemend Nature Communications, online 12 September 2018

New explanation for the cause of MS

Fri, 07/09/2018 - 09:49
In multiple sclerosis (MS), not only the T cells of the immune system, but also its B cells, play an important role. This is shown by researchers at Karolinska Institutet and the University of Zurich in a study published in the journal Cell. The findings explain how a new class of MS drugs works, and can open up for more precise ways of treating the disease. MS is a chronic disease where the body's immune cells attack and damage its own nerve tissue. The disease affects around 2.5 million people worldwide, with a higher risk among women. Now, a key aspect in the development of the disease has been found by researchers at Karolinska Institutet and the University of Zurich. The results are published in the journal Cell. Faiez Al Nimer, researcher at the Department of Clinical Neuroscience at KI, is co-first author of the study. Attack the nerve cells Until recently, MS research has mainly focused on a type of immune cells called T cells. They normally help protecting the body against intruders. In some people, however, they attack the protective layer surrounding the nerve cells – marking the onset of MS. The new study shows that not only T cells, but also B cells of the immune system, play a role in the development of the disease, by activating the T cells. By analysing blood samples, the researchers saw that blood from people with MS contained increased numbers and activation status of T cells known to be important for MS disease activity.  When the B cells were eliminated, the activation status of these disease-driving T cells returned to normal, suggesting that B cells play a crucial role in the activation of autoimmune T cells in MS. Migrate to the brain The team also discovered that these activated T cells detectable in the blood notably included those that also occur in the brain in MS patients during flare-ups of the disease. These T cells were shown to recognise the structures of a protein that is produced by the B cells as well as nerve cells in the brain. The researchers conclude that after being activated in the blood by B cells, the T-cells migrate to the brain, where they destroy the nerve tissue. The study explains the previously unclear mechanism of a new class of MS drugs (rituximab and ocrelizumab) and can, according to researchers, pave the way for more precise ways of treating MS in the future. The research is funded mainly by the European Research Council (ERC Advanced Grant). Further funds come from the University of Zurich, the Swiss Multiple Sclerosis Society, the Swiss National Science Foundation and a number of Swedish funding sources. This news article is based on a press release from the University of Zurich. Publication "Memory B Cells Activate Brain-Homing, Autoreactive CD4 + T Cells in Multiple Sclerosis" Ivan Jelcic, Faiez Al Nimer, Jian Wang, Verena Lentsch, Raquel Planas, Ilijas Jelcic, Aleksandar Madjovski, Sabrina Ruhrmann, Wolfgang Faigle, Katrin Frauenknecht Clemencia Pinilla, Radleigh Santos, Christian Hammer, Yaneth Ortiz, Lennart Opitz, Hans Grönlund, Gerhard Rogler, Onur Boyman, Richard Reynolds, Andreas Lutterotti, Mohsen Khademi, Tomas Olsson, Fredrik Piehl, Mireia Sospedra, and Roland Martin Cell, online 30 August 2018, doi: 10.1016 / j.cell.2018.08.011

President of Karolinska Institutet cleared of misconduct charges

Thu, 06/09/2018 - 18:09
France’s Institut Pasteur’s ethical committee has cleared Karolinska Institutet’s President Ole Petter Ottersen from all suspicions of scientific misconduct, committee chairperson François Rougeon has announced on the conclusion of the investigation. On 19 July this year Karolinska Institutet received a complaint of suspected scientific misconduct against its president, Ole Petter Ottersen. The complaint concerned a scientific paper published in the Journal of Neuroscience almost twenty years ago (1999), of which Professor Ottersen listed as co-author. The case aroused considerable attention in the Swedish and Norwegian media, which connected it with the misconduct verdict that the President announced on 25 June 2018 concerning the so-called Macchiarini affair. The research on which the Journal of Neuroscience article is based was not conducted at KI, which means that the matter cannot be investigated here. The complaint was therefore dismissed. KI contacted the research principal, the Institut Pasteur in Paris, to check if they had considered the article in question and found it to qualify as scientific misconduct. On 5 September 2018, François Rougeon, chairperson of the Institut Pasteur’s ethical committee announced that, following a review of the data published in the article, the investigators found no grounds to bring a verdict of scientific misconduct: ”In our opinion, the analyses of the data does not support the allegation of scientific misconduct”.

Laura Fratiglioni, Håkan Eriksson and Bertil Fredholm awarded Karolinska Institutet’s Grand Silver Medal

Wed, 05/09/2018 - 15:54
Laura Fratiglioni, Håkan Eriksson and Bertil Fredholm are awarded Karolinska Institutet’s Grand Silver Medal 2018. They are given the medal for their great contributions to support KI’s activities. Since 2010, Karolinska Institutet awards medals to people who have made special contributions to support KI. Now this years recipients of the Grand Silver Medal are announced: Laura Fratiglioni, professor, Department of Neurobiology, Care Sciences and Society, KI Laura Fratiglioni is one of the leading international researchers in epidemiology of aging. She is awarded the medal for her outstanding contributions to Karolinska Institutet in science, doctoral education and leadership and innovation. With her strong clinical and scientific background, Laura Fratiglioni is often sought out as an expert in aging and she has strongly contributed to the international profile of KI in this field. Her work has contributed to the use of epidemiologic methods in agin research. Thereto, Laura Fratiglioni is devoted to communicating her research findings to the general public. Bertil Fredholm, professor emeritus, Department of Physiology and Pharmacology, KI Bertil Fredholm is awarded for his outstanding contributions to research and doctoral education in the area of pharmacology. Bertil Fredholm is one of KI’s most internationally acclaimed researchers. His discoveries are related to the molecule adenosine and its receptors, and he was among the first to describe ways in which caffein affects the body. Bertil Fredholm has been a member of the Nobel Committee for eighteen years, including two as its chairperson. He has also devoted a great deal of time to teaching, and was a highly regarded teacher at bot the undergraduate and doctoral levels. Håkan Eriksson, professor emeritus, Department of Women’s and Children’s Health, KI Håkan Eriksson is awarded the medal for his exceptional contributions to KI and to Swedish medical research. Håkan Eriksson is distinguished by a strong and innovative research career within reproduction biology, but also his extensive contributions to KI and to Swedish research policy. For fifteen years he was the Director of Studies at the Department of Medical Chemistry, and a driving force behind efforts to strengthen the clinical connection of the education. His work was of crucial importance, particular during the 1990s, when KI underwent a period of great change. The result of these changes included more efficient processes and higher quality research, education and collaboration throughout KI. The medals will be awarded in conjunction with the installation ceremony in Aula Medica in October.

New project to improve drugs safety in East Africa

Tue, 04/09/2018 - 09:27
In recent years access to drugs and vaccines has been increasing in many African countries, but the systems for monitoring treatment effects and reporting side-effects require further development. Karolinska Institutet will now lead an international collaboration project on pharmacovigilance – drugs safety – in four countries in East Africa. Those taking part in the project, known as PROFORMA, are researchers from Karolinska Institutet, researchers and experts from universities and regulatory authorities in Ethiopia, Kenya, Tanzania and Rwanda, and some regional and international stakeholders in the field of drugs safety. The total project funding is EUR 6 million, of which the major part is provided by the EU Framework Programme for Research and Innovation-Horizon2020, via the European and Developing Countries Clinical Trials Partnership (EDCTP). Among other significant funding bodies is the Swedish International Development Cooperation Agency (SIDA).  “The main aim of this project is to strengthen the national infrastructures for drugs safety monitoring in our partner countries in Africa. This involves developing regulatory capacity for routine surveillance and reporting, and training of staff working in healthcare and medical services and regulatory authorities,” says Dr Eleni Aklillu, senior researcher at the Department of Laboratory Medicine at Karolinska Institutet and scientific coordinator for the project. Right now, she is in Ethiopia attending the national kick-off meeting for PROFORMA. PROFORMA is estimated to last five years. The project also involve training at Master’s and postgraduate level and exchange of knowledge in general between researchers and experts. “The increasing number of clinical trials and different types of mass drug administration and vaccination programmes in African countries underlines the need to strengthen pharmacovigilance infrastructure. One important tool is to improve collaboration between the Medical Universities and regulatory authorities in the countries concerned, and we’ve already made good progress in this area during the few months we’ve been working on the project,” says Eleni Aklillu. Facts about PROFORMA Project title: Pharmacovigilance infrastructure and post-marketing surveillance system capacity building for regional medicine regulatory harmonization in East Africa (PROFORMA) Project funding: EUR 6 million, to be spread over five years, of which approx EUR 3 million will be funded by Horizon2020/EDCTP. Other funding bodies are SIDA, Karolinska Institutet, the Pharmacy and Poisons Board (Kenya), Muhimbili University of Health and Allied Sciences (Tanzania) and the Tanzania Food and Drugs Authority. Project period: 1 March 2018 – 28 February 2023 (60 months) Coordinator: Dr Eleni Aklillu, Associate Professor, Karolinska Institutet.  Website:

Similar changes in the brains of patients with ADHD and emotional instability

Fri, 31/08/2018 - 08:48
In both ADHD and emotional instability disorders (e.g. borderline and antisocial personality disorder as well as conduct disorder in children), the brain exhibits similar changes in overlapping areas, meaning that the two types of conditions should be seen as related and attention should be paid to both during diagnosis. This according to researchers at Karolinska Institutet behind a new study published in Molecular Psychiatry. The results can lead to a broader treatment for both conditions. Clinical attention has long been paid to the fact that individuals with ADHD also demonstrate emotional problems, such as chaotic emotional responses, anxiety and depression. Yet the relationship between ADHD and impaired emotional regulation has not been identified, even if theories have been proposed that both conditions are rooted in a dysfunction in how the brain controls its information processing. A new study by researchers at Karolinska Institutet in Sweden substantiated the hypothesis by showing how both ADHD and a form of emotional instability trait (conduct disorder trait in children) exhibit similar, overlapping changes in the brain. The study included more than 1 000 adolescents. Sibling conditions “We can call them sibling conditions, since they both involve partly overlapping underlying brain mechanisms, and therefore attention should be paid to both dimensions during diagnosis,” says Predrag Petrovic, associate professor at the Department of Clinical Neuroscience at Karolinska Institutet and consultant psychiatrist at North Stockholm Psychiatry. It was with the help of structural brain imagery (MR) that the team was able to show how both ADHD and conduct disorder traits in adolescents manifested themselves in the form of reduced brain volume and surface area in parts of the frontal lobe and nearby regions. The affected parts of the brain were generally overlapping, but the researchers also found changes that were specifically related to ADHD symptoms or symptoms seen in conduct disorder. The study also included behavioural experiments that demonstrated both conditions. “These results are important not least for the patients with emotional instability, since in many cases they are treated with scepticism and feel frustrated at not being taken seriously,” says Dr Petrovic. “We now show that this is related to changes in the brain that resemble those that have been observed in patients with ADHD, which can lead to a broader understanding and better diagnosis.” Broader treatment The study was part of the IMAGEN-project, an EU-funded collaboration amongst several European countries that aims towards a better understanding of how the brain and behaviour develop. The hope is that the study will not only lead to better diagnoses but also to better treatments, where people with an ADHD diagnosis can receive special therapy to help them better handle their emotions. “We also need to do more research to understand if central stimulant medication used for ADHD can also produce positive results for people with emotional instability disorders,” says Dr Petrovic. The study was financed with grants from several bodies, including the European Commission, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (Formas), the Swedish Research Council, the National Institute for Health Research (NIHR), the Bundesministerium für Bildung und Forschung, the Swedish Society for Medical Research (SSMF) and Karolinska Institutet. Publication “Distinct brain structure and behavior related to ADHD and conduct disorder traits” Frida Bayard, Charlotte Nymberg Thunell, Christoph Abé, Rita Almeida, Tobias Banaschewski, Gareth Barker, Arun L. W. Bokde, Uli Bromberg, Christian Büchel, Erin Burke Quinlan, Sylvane Desrivières, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Andreas Heinz, Bernd Ittermann, Jean-Luc Martinot, Marie-Laure Paillère Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Tomáš Paus, Luise Poustka, Patricia Conrod, Argyris Stringaris, Maren Struve, Jani Penttilä, Viola Kappel, Yvonne Grimmer, Tahmine Fadai, Betteke van Noort, Michael N. Smolka, Nora C. Vetter, Henrik Walter, Robert Whelan, Gunter Schumann and Predrag Petrovic. Molecular Psychiatry, online 14 August 2018, doi: 10.1038/s41380-018-0202-6

Lorelei Lingard is awarded the Karolinska Institutet Prize for Research in Medical Education

Tue, 28/08/2018 - 10:43
Professor Lorelei Lingard is awarded the 2018 Karolinska Institutet Prize for Research in Medical Education. Her research has contributed significantly to our understanding of how healthcare professionals interact and communicate with each other, which has led to new clinical practices and increased patient safety. Professor Lingard, Professor in the Department of Medicine at the Schulich School of Medicine & Dentistry and cross-appointed in the Faculty of Education at Western University in Canada, will receive the award and a prize amount of €50,000 at a ceremony in Stockholm, Sweden, on 11 October. This international prize is awarded for outstanding research in medical education. The purpose of the prize is to recognise and stimulate high-quality research in the field and to promote long-term improvements of educational practices in medical training. "Medical" includes all education and training for any health science profession. The prize is made possible through financial support from the Gunnar Höglund and Anna-Stina Malmborg Foundation. It is currently awarded every second year. Significant contributions “I’m happy to announce Professor Lingard as this year’s prize winner. She has contributed significantly to our understanding of how healthcare teams interact and communicate. Her research has been a major force in changing the way medical education views teamwork and has led to new clinical practices and increased patient safety,” says Professor Sari Ponzer, Chair of the Prize Committee. Since the late 1990s, Professor Lingard has been studying how healthcare teams function – both in providing patient care and during clinical training. She and her research team have studied expert and novice team members in settings as diverse as the operating room, the critical care unit, the heart function clinic, the organ transplantation team, the rehabilitation hospital, and the inpatient medicine ward. Communication is fundamental “My entry point into teamwork is always language. I’m interested in how teams communicate, because their communication is fundamental to how they collaborate and how they educate. My disciplinary training is in rhetoric – the study of how language works in social situations. Applying rhetoric to healthcare, I have worked to unravel what language does on teams. My research asks: what does language make possible in a team, and what does it constrain? As it turns out, language does many things that are critical for medical education and for care delivery. As a consequence of my research, we now pay systematic and critical attention to how clinical team members communicate with each other,” says Professor Lingard. My entry point into teamwork is always language. Her research has helped shape medical education policy in her native Canada as well as internationally. As a result, the role of language is today emphasised in clinical training, which was not previously the case. Her research has also inspired the recognition that teamwork is essential to how trainees learn. As clinical teams are the setting for most workplace-based learning in medicine, their structures and practices have a profound influence on that learning. Just a few decades ago, teamwork was not seen as important within medical education but today, thanks to Professor Lingard’s collaborative research programme, it’s recognised as a critically important aspect of what and how medical trainees learn. I’m very proud to be the first woman to win this prestigious prize Commenting on her Prize win, Professor Lingard says: “I’m deeply honoured to be recognised for this prize. Professionally, it’s a huge recognition of the work that I do together with my wonderful collaborative research teams, and the impact it has had. The field of team communication research didn’t exist 20 years ago and I’m enormously proud to have contributed to its development in our medical education community. From a more personal perspective, I’m very proud to be the first woman to win this prestigious prize.”    

Microvascular dysfunction: a common cause of heart failure with preserved pumping capacity

Mon, 27/08/2018 - 16:45
Microvascular dysfunction, or small vessel disease, can be an important cause of heart failure with preserved ejection fraction (preserved pumping capacity), an international team including researchers from Karolinska Institutet and AstraZeneca report in a study published in The European Heart Journal. The results can play a crucial part in identifying people in the risk zone for this type of heart failure and in the development of effective drugs. Heart failure is the most common reason for hospitalisation and causes much suffering. Heart failure with preserved ejection fraction, which is one of the two main types of heart failure, lacks scientifically proven treatments and more research is needed to understand how the disease develops and is to be treated. Scientists at Karolinska Institutet, along with colleagues from AstraZeneca and four other groups in Sweden, the USA, Finland and Singapore have now conducted a study of over 200 patients with this type of heart failure. An innovative coronary imaging protocol developed The study involved the use of an innovative coronary imaging protocol developed by Professor Li-Ming Gan’s research group in the IMED Biotech Unit in order to obtain a patient-friendly, cost-effective way to test coronary artery’s ability to increase its blood flow (Coronary Flow Reserve - CFR) in addition to the traditional imaging approach to generate overall picture of the heart’s structure and function. “Being able to identify patients with heart failure with preserved ejection fraction is not only key to improving patient outcomes through early diagnosis but also for us to understand the causal mechanisms underlying the disease so we can develop future targeted therapies”, says Professor Li-Ming Gan, Chief Scientist and Senior Medical Director, IMED Biotech Unit, AstraZeneca. Damage to the endothelium The results of the study, which is the first of its kind, show that 75 per cent of the patients had what is known as microvascular dysfunction. This is a disease in which the coronary artery shows no sign of narrowing or plaque in radiographs, but has damage to the endothelium that coats the inside of the blood vessels. The blood vessels do not work as they should, which can lead to adverse changes in the heart muscle. The researchers therefore draw the conclusion that microvascular dysfunction can be a critical underlying disease mechanism in patients with heart failure in which the ejection fraction is preserved. “The results will be useful in identifying patients at risk of developing the disease, but above all they’ll make an essential contribution to the development of drugs for patients with heart failure with preserved ejection fraction,” says Lars Lund, Senior Consultant and Professor at Karolinska Institutet’s Department of Medicine in Solna. The results will be presented at the European Society of Cardiology (ESC) congress in Munich and are published in The European Heart Journal. The project was financed by AstraZeneca and the researchers are in receipt of grants from the Swedish Research Council, the Swedish Heart and Lung Foundation, the U.S. National Institutes of Health, the American Heart Association, the National Medical Research Council of Singapore, and the Academy of Finland, Finnish Foundation for Cardiovascular Research. Publication “Prevalence Of Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction: PROMIS-HFpEF” Sanjiv J. Shah, Carolyn S. P. Lam, Sara Svedlund, Antti Saraste, Camilla Hage, Ru-San Tan, Lauren Beussink-Nelson, Maria Lagerström Fermer, Malin A. Broberg, Li-Ming Gan and Lars H. Lund. European Heart Journal, online 27 August 2018, doi: XX

Karolinska Institutet returns remains to Australia

Mon, 27/08/2018 - 09:03
On 23 August, Karolinska Institutet handed the remains of seven indigenous Australians over to the Australian Government. The remains were part of Karolinska Institutet's anatomical collections from the mid- to late-1800s. They were transported to Sweden by a sea captain, a doctor and an exploratory zoologist, but have now been returned to Australia. The ceremony took place in Stockholm and was attended by representatives of Karolinska Institutet, the Australian Ambassador to Sweden, and Saami representatives. “It is very important for these communities that the remains of their ancestors will now rest in their homeland, in dignity and peace,” said Jonathan Kenna, Australia's Ambassador to Sweden, after the ceremony. The Australian Government's repatriation program supports the unconditional repatriation of the remains of indigenous peoples – Aboriginal and Torres Strait Islanders – from foreign collections and private owners, which contributes to reconciliation. “I would like to thank everyone from Karolinska Institutet and the Swedish State who worked long and hard so that this would come to pass,” said Jonathan Kenna. The President of Karolinska Institutet, Ole Petter Ottersen: “On behalf of KI, I am very pleased to be able to help restore the humanity and dignity of these seven individuals – it is our moral obligation to do so. There is nothing we can do to alter the mistakes of yesterday. What we can do is make sure that we get it right today,” he said. The President of the Sami Parliament Plenary Assembly, Paul Kuoljok, participated in the ceremony, in which a joik was sung directly to the seven individuals. The ceremony ended with a healing circle ritual, conducted by Johannes Vestly.

Oxygen therapy for patients suffering from a heart attack does not prevent heart failure

Sun, 26/08/2018 - 14:49
Oxygen therapy does not prevent the development of heart failure. Neither does it reduce the long-term risk of dying for patients with suspected heart attack. This has been proven for the first time by researchers at Karolinska Institutet as a result of a major Swedish study. The study is to be presented at the European Society of Cardiology’s (ESC) cardiology congress in Munich and published at the same time in the journal Circulation. The researchers expect their results to have a global impact on recommended healthcare for treating heart attacks. Oxygen has been used to treat patients suffering a heart attack for more than a century, despite the fact that such treatment has not had any scientifically proven effect on patients who have normal oxygen levels in their blood. Since the turn of the millennium, researchers worldwide have started to question whether oxygen therapy for heart attacks is ineffective – or may even be harmful. “Our new study has filled a central gap in knowledge regarding how to treat patients suffering a heart attack. One year ago, we were able to confirm that oxygen therapy does not appear to reduce the risk of dying up to one year after the heart attack. We can now substantiate these findings for a long-term perspective and show that oxygen therapy does not reduce the development of heart failure, the most worrying complication of heart attacks. On this basis, the routine use of oxygen can now be eliminated, and healthcare personnel can concentrate on more efficient measures and rapid transport to hospital,” confirms Robin Hofmann, senior consultant cardiologist and researcher at the Department of clinical science and education, Södersjukhuset, at Karolinska Institutet. The DETO2X-AMI study was conducted at 35 Swedish hospitals, involving random treatment with or without oxygen of 6,629 patients with suspected heart attack. The result shows that oxygen therapy in a moderate dose is not harmful but does not increase the survival rates or reduce complications, such as the development of heart failure or new heart attacks. The research project was financed by the Swedish Heart-Lung Foundation and the Swedish Research Council. Publication ”Long-term effects of oxygen therapy on death or hospitalization for heart failure in patients with suspected acute myocardial infarction” Tomas Jernberg, Robin Hofmann, et al for the DETO2X-SWEDEHEART investigators. Circulation, 26 August, 2018, doi: 10.1161/CIRCULATIONAHA.118.036220

Treatment for severe heartburn prevents cancer

Thu, 23/08/2018 - 17:00
Medical or surgical treatment of severe heartburn prevents cancer of the oesophagus, a study from Karolinska Institutet with almost one million Nordic patients reveals. The results will be published in the scientific journal JAMA Oncology. Pathological heartburn and acid reflux affects 10-20 per cent of the adult population. Long and severe reflux is the strongest risk factor for cancer of the oesophagus (type adenocarcinoma), an aggressive cancer that is difficult to treat. Reflux is usually treated with medicine to make the stomach contents less acidic, which usually eliminates or reduces symptoms. One alternative is to have an operation (anti-reflux surgery) which prevents the stomach contents from coming up into the oesophagus. Previous studies have not conclusively demonstrated that these treatments prevent oesophageal cancer, but the studies have not been sufficiently large or had enough follow-up time to ensure that conclusions can be drawn on any long-term cancer-preventive effects. 940,000 patients with reflux included in the study In the present study, researchers used health data records from 1964 to 2014 from the five Nordic countries. Of the more than 940,000 patients with reflux in the study, about 895,000 received medical treatment and of those nearly 2,370 patients (0.3 per cent) developed cancer of the oesophagus during the follow-up period. The risk of cancer of the oesophagus decreased over time following treatment and was similar to that of the corresponding population after 15 years or more in those who received medication. Of the more than 48,400 patients who had anti-reflux surgery, 177 (0.4 per cent) developed cancer of the oesophagus during the follow-up period. The risk of oesophageal cancer clearly fell also in this group and was at the same level as in the corresponding population 15 years or more after the operation. When the patients with reflux who had an operation were compared with those with reflux who received medication, the patients who had been operated on had a slightly higher risk of oesophageal cancer during the entire follow-up period, but the risk did not increase over time. This is probably caused by the fact that the operated patients had more serious reflux from the beginning. “The results show that effective medical or surgical treatment of reflux prevents cancer of the oesophagus. But because the individual’s risk of developing oesophageal cancer is low, even in those with reflux disease, the results do not justify treating reflux solely as a cancer-preventive measure. The symptoms and complications of reflux disease should continue to govern treatment,” says John Maret-Ouda, physician and scientist at the Department of Molecular Medicine and Surgery at Karolinska Institutet and the first author of the study. However, he points out that for the small percentage of people with severe reflux in combination with other risk factors for oesophageal cancer, such as obesity, male gender and mature age, effective and continuous medical treatment or an operation to treat reflux is recommended. Statistically significant results “Previous research results have shown poor cancer-preventive effects from anti-reflux surgery. The difference now is that for the first time we can show statistically significant results because we have a sufficiently large study with a long follow-up period of over 15 years following the operation,” says Jesper Lagergren, consultant surgeon and professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet, who led the study. The research is funded by the Nordic Cancer Union, the Swedish Research Council and the Swedish Cancer Society. Publication ”The risk of esophageal adenocarcinoma following antireflux surgery in the five Nordic countries” John Maret-Ouda, Karl Wahlin, Miia Artama, Nele Brusselaers, Martti Färkkilä, Elsebeth Lynge, Fredrik Mattsson, Eero Pukkala, Pål Romundstad, Laufey Tryggvadóttir, My von Euler-Chelpin and Jesper Lagergren. JAMA Oncology, online 23 August, 2018, doi:

Dramatic development of immune system after birth

Thu, 23/08/2018 - 17:00
As soon as a baby is born, its immune system starts to change dramatically in response to the bacteria, viruses and so forth in its new environment, a phenomenon that is common to all babies, researchers from Karolinska Institutet in Sweden write in a paper published in Cell. The study was made possible using new techniques of immune cell analysis. Examining how the neonatal immune system changes has been difficult since the analyses are made from samples taken from the umbilical cord directly after delivery. Researchers have now exploited a new technique of immune cell analysis to monitor how babies develop for the first few weeks of life outside the womb. “This is the first time we’ve pinned down how the human immune system adapts itself to birth and the new environment,” says Petter Brodin, doctor and researcher at the Science for Life Laboratory (SciLifeLab) and the Department of Women’s and Children’s Health, Karolinska Institutet. “We saw drastic changes in the babies’ immune system between each sampling, which shows that it is highly dynamic early in life.” The study compared blood samples from 100 babies, both premature and full-term, taken during the first, fourth and twelfth week. The comparison was achieved using an advanced technique of immune cell analysis: mass cytometry in combination with extensive plasma protein analyses. Only small amounts of blood, just a few drops from each baby, are needed to analyse all the white blood cells and hundreds of proteins circulating in the blood. The researchers were also able to show that the babies who had abnormal development of the gut flora during the first weeks also demonstrated a disorder of the immune system. “Our results are important for better understanding the infection-sensitivity of newborn babies and the risks of premature birth,” says Dr Brodin. “If we can monitor the development of the immune system and steer it in different directions, we make it possible to prevent autoimmune diseases and allergies, which are partly related to the development of the immune system, and to even develop better vaccines, tailored to the neonatal immune system.” The adaptation of the immune system is thought to be triggered by the microbes, bacteria, fungi and so forth that the baby encounters outside the womb. The process begins primarily in the lungs, gut, skin and mucosa, which is to say the body’s points of contact with the outside world. “What surprised us was how similar the changes were amongst babies,” says Dr Brodin. “It seems as if all babies follow one and the same pattern, with their immune systems responding with exactly the same sequence of dramatic changes. It’s almost like a well-choreographed dance, a practised routine.” The researchers will now be broadening out the study to encompass more babies, all of whom will be monitored into childhood. This will enable the team to see which of them develop diabetes, allergies, asthma and inflammatory bowel disease. “Many of these diseases can definitely be traced back to how a baby is born and how its immune system adapts to the external environment,” explains Dr Brodin. “What we’re bringing to the table is the specific changes in the immune system that underlie this. It’s a piece of the puzzle that was formerly missing.” The study was made possible through the close collaboration of Karolinska University Hospital. “For ethical, practical and logical reasons it’s difficult to put together a study like this,” says Dr Brodin. “The key to our success is that those of us leading the study also work as doctors and when we manage to combine patient-end work with the most advanced techniques, we make wonderful discoveries.” The researchers who conducted the study are active at the Science for Life Laboratory, Karolinska Institutet, and Karolinska University Hospital. The study was financed with grants from the European Research Council (ERC), the Swedish Research Council, Karolinska Institutet and the Swedish Society for Medical Research (SSMF). Publication:  “Stereotypic immune system development in newborn children”, Axel Olin, Ewa Henckel, Yang Chen, Tadepally Lakshmikanth, Christian Pou, Jaromir Mikes, Anna Gustafsson, Anna Karin Bernhardsson, Cheng Zhang, Kajsa Bohlin, Petter Brodin. Cell, online 23 August 2018, doi: 10.1016/j.cell.2018.06.045.    

Cleverly located surface proteins make some pneumococcal strains especially dangerous

Thu, 23/08/2018 - 11:12
Successful pathogenic strains of pneumococci have two proteins that, owing to their location on the surface of the bacteria, enhance their survival and ability to cause disease, a study from Karolinska Institutet in Sweden published in Nature Communications, reports. Pneumococcal infections are one of the most common causes of disease and death in the world. One reason for the pathogenic potential of these bacteria is that they produce a sugar casing. This capsule prevents the important immune component C3b from attaching to and attacking the bacteria. Researchers at Karolinska Institutet and the Royal Institute of Technology in Sweden have now studied in detail how pneumococci interact with the part of the immune system called the “complement system”, which includes C3b. The complement system often works as the first line of defence against foreign substances and cells, triggering a number of immune reactions in the body. The researchers show that the capsule is weak at the bacteria’s point of division, which therefore presents an opening for C3b. By using super-resolution microscopy (STED) they found that C3b accumulates under the capsule primarily at the division sites. This accumulation can continue and cover the entire bacteria unless the pneumococcus can find a strategy to prevent it happening. The study also shows that a common surface protein on pneumococci called PspC1 is located right at the division site, where it recruits another protein called Factor H, which negatively regulates the complement system by, amongst other mechanisms, inactivating C3b. Some especially successful and pathogenic pneumococcal strains also express a closely related protein, PspC2, which is mainly localised at the bacterial poles. This separate location on the surface of the bacteria affects the two surface proteins’ functions. Unlike PspC1, which binds Factor H, PspC2 affects the bacteria’s ability to adhere to epithelial cells, which can be found in the respiratory tract, in mucus membranes and elsewhere. “Our study shows that the precise localisation of bacterial surface proteins in relation to the capsule layer affects the role they will have in the disease development,” says Birgitta Henriques-Normark, professor at the Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet. “This is an important piece of the puzzle to understand how pneumococci avoid the immune system and cause everything from otitis and sinusitis to severe pneumonia and septicaemia.” The study was financed by the Swedish Research Council, Stockholm County Council (ALF funding), the Swedish Foundation for Strategic Research and the Knut and Alice Wallenberg Foundation. Publication “Factor H binding proteins protect division septa on encapsulated Streptococcus pneumoniae against complement C3b deposition and amplification”. Anuj Pathak, Jan Bergstrand, Vicky Sender, Laura Spelmink, Marie-Stephanie Aschtgen, Sandra Muschiol, Jerker Widengren & Birgitta Henriques-Normark. Nature Communications, online 23 August 2018, doi: 10.1038/s41467-018-05494-w.

New scientific model reveals interaction between blood vessels and neurons in the brain

Mon, 20/08/2018 - 17:01
Micro-flow models of the blood-brain barrier and the brain reveal for the first time complex metabolic interactions between the brain’s blood vessels and nerve cells. The findings are published by an international team of researchers, including from Karolinska Institutet and the Royal Institute of Technology, in the journal Nature Biotechnology. Interaction and regulation between blood vessels and nerve cells in the brain are essential to its function, but how this interaction takes place has been difficult to pin down. Classic cell-culture models of nerve cells and blood vessel cells are too simplified to show interactions, and studies on brain tissue and animals are too complicated.   In order to understand how blood vessels and surrounding brain tissue interact, the team built up a so-called “organ-on-chip”-model, which is a micro-flow model with living cells. Using the model, the researchers were able to analyse all the smaller molecules issued by the cells and identify a previously undescribed link for how blood vessel cells metabolise glucose and how these metabolites influence the production of neurotransmitters by the neurons. The team is now working on using these systems to obtain new insights on the brain and to build models of brain diseases. The study was financed by the Wyss Institute for Biologically Inspired Engineering at Harvard University, Defense Advanced Research Projects Agency (DARPA), the Sweden-America Foundation, the Carl Trygger Foundation and the Erik and Edith Fernström Foundation. Publication “A linked organ-on-chip model of the human neurovascular unit reveals the metabolic coupling of endothelial and neuronal cells” Ben M Maoz, Anna Herland, Edward A FitzGerald, Thomas Grevesse, Charles Vidoudez, Alan R Pacheco, Sean P Sheehy, Tae-Eun Park, Stephanie Dauth, Robert Mannix, Nikita Budnik, Kevin Shores, Alexander Cho, Janna C Nawroth, Daniel Segrè, Bogdan Budnik, Donald E Ingber and Kevin Kit Parker Nature Biotechnology, online 20 August 2018, doi: 10.1038/nbt.4226

Karolinska Institutet keeps a leading position

Thu, 16/08/2018 - 11:14
The recently published Shanghai ranking (ARWU – Academic Ranking of World Universities) shows that Karolinska Institutet keeps a leading position as one of the world's strongest universities and the highest-ranked university in Sweden. KI has place 44 in the global list, which includes ”all fields and subjects”, which is the same as 2017 and 2016. In addition, more specific areas such as ”Pharmacy & pharmaceutical sciences”, ”Public health” and ”Nursing” is KI among the world's top five universities. The two USA universities Harvard and Stanford are in the top of the list. British University of Cambridge is number three in the ranking. Two further Swedish universities are featured at the top 100: Uppsala University (place 63) and Stockholm University (77).

Prestigious grant for research on ALS

Wed, 15/08/2018 - 15:07
KI researcher Fang Fang has been awarded the prestigious ERC Starting Grant for her research about the human gut microbiome and the development of the neurodegenerative disease ALS. In all, the European Research Council this year invests EUR 603 million in 403 talanted early career researchers. The purpose of the ERC Starting Grants is to support talented early-career scientist, who have already produced excellent supervised work, into becoming independent researchers and the research leaders of tomorrow. Dr Fang Fang, Principal Investigator at Karolinska Institutet’s Department of Medical Epidemiology and Biostatistics, receives EUR 1.5 million, distributed over five years for her project MegaALS. ”I think the grant provides a unique opportunity to do something different, in terms of how others have done previously in the specific research area and how myself has done as a researcher in the past”, comments Fang Fang. “It is certainly challenging, but mostly exciting and fun.” Full project title: Unravelling the Interplay between Metabolism, Gut Microbiome and Adaptive Immunity in Amyotrophic Lateral Sclerosis (MegaALS) Short description: Amyotrophic lateral sclerosis (ALS) is a rare but devastating neurodegenerative disorder that in lack of effective treatment leads to death within a few years of diagnosis. ALS is increasingly being recognized as a systemic disease affecting not only the central nervous system but also other physiological aspects. In the project now funded by the ERC, Fang Fang and her team intend to investigate the disease-specific interplay between metabolism, gut microbiome and adaptive immunity, which may substantially contribute to the development of ALS. The project also includes the assessment of a treatment that targets this interplay, conducted in mice. The researchers will use both epidemiological and experimental methods in their work.

Detailed atlas of the nervous system

Thu, 09/08/2018 - 11:30
Researchers at Karolinska Institutet have created a systematic and detailed map of the cell types of the mouse nervous system. The map, which can provide new clues about the origin of neurological diseases, is presented in the journal Cell. The researchers will now use the same methods to map out the human brain on a detailed level. The nervous system consists of hundreds, perhaps thousands, of different neurons, but also immune cells, supporting glia cells and cells that constitute vessels and membranes. Our knowledge of these cell types mainly stems from microscopy, which provides information about the shape of cells and can detect certain proteins, and from electrophysiology, where cells are distinguished based on their electrical properties. However, these methods are limited, and there is currently no systematic atlas of the various cell types that make up the mammalian nervous system. In recent years, Sten Linnarson’s research group, and others, have developed methods to map cell types of the brain more systematically in much greater detail than ever before, by measuring gene activity in individual cells. “You can compare it to the difference between a medieval map and a satellite image: thousands of details that were previously invisible become visible with the use of these new techniques, and the entire map becomes more reliable, explains Sten Linnarson, professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institute. Largest study of the architecture of the mammalian nervous system to date His research group now publishes the largest study of the architecture and composition of the mammalian nervous system to date, using the mouse as a model system. The researchers identified 265 different types of cells, and found that neurons had the greatest diversity with over 200 different types.  "What surprised us most was that we discovered several different types of astrocytes that were specialised in different parts of the brain. This suggests that astrocytes have specific functions in different parts of the brain, and that they play more of a key role in the functions of the brain than previously understood", says Sten Linnarson. The knowledge of the cell types of the brain can be used to understand the origin of different diseases. Roughly one third of all neurological diseases arise during embryonic development. In the past fifteen years a large number of genetic studies have identified the genes that contribute to diseases such as schizophrenia, multiple sclerosis, autism, Alzheimer’s and Parkinson’s disease. However, diseases originate from a specific type of cells, in a specific location and at a specific time depending on where and when the relevant genes are active. Atlas of the nervous system gives clues as to how the disease occurs —With the help of our new atlas of the nervous system, researchers are now able to place disease-causing genes in specific cell types, which provides us with clues as to how the disease occurs. In the long run this might contribute to the development of new drugs or other therapies, says Sten Linnarson. The mapping of the mouse nervous system is an important first step in a larger project where researchers are now mapping the human brain by using the same methods. The current study was funded by the Knut and Alice Wallenberg Foundation, the Swedish Foundation for Strategic Research and the Wellcome Trust. Publication ”Molecular Architecture of the Mouse Nervous System”. Amit Zeisel, Hannah Hochgerner, Peter Lönnerberg, Anna Johnsson, Fatima Memic, Job van der Zwan, Martin Häring, Emelie Braun, Lars Borm, Gioele La Manno, Simone Codeluppi, Alessandro Furlan, Kawai Lee, Nathan Skene, Kenneth D. Harris, Jens Hjerling Leffler, Ernest Arenas, Patrik Ernfors, Ulrika Marklund, Sten Linnarsson. Cell, online Aug 9, 2018, doi: xxx.

New method reveals cell development

Wed, 08/08/2018 - 19:05
Researchers at Karolinska Institutet and Harvard Medical School report in the journal Nature that they have developed a technique for capturing dynamic processes in individual cells. Apart from studying disease processes, the method can be used to observe in detail how specialised cells are formed during embryonic development. The body is composed of specialised cells that give each organ its unique function. The brain, for instance, is made up of hundreds of different kinds of neurons, while the kidneys have specialised cells for filtering blood and the heart muscle cells have a built-in pacemaker function. Organs are formed as the embryo develops through a process of gradual specialisation. The fertilised egg divides and as more cells are formed they start to take on more specific functions. Similar processes are also found in tumours, which gradually develop into a kind of organ with blood vessels and supporting cells that help the tumour grow. Difficult to study dynamic processes What determines the unique function of each cell is the specific genes that are active within it. In neurons, for example, genes are activated that control electrical signals, while muscle cells use genes for motor proteins. In recent years, Swedish and international researchers have developed methods for mapping the cellular composition of complex tissues by studying the gene activity of individual cells. The downside of these methods is that they are destructive. Measuring gene activity of individual cells involves destroying the cells so that their content can be analysed, which makes it difficult to study dynamic processes. “It’s like a photograph in which all movement is frozen in time,” explains Professor Sten Linnarsson at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, and one of the researchers who led the study. “We’ve now developed a new method that measures not only genetic activity but also changes in this activity in individual cells. You can compare this to a photo captured with a long exposure, which results in motion blur: stationary objects are sharp while objects in motion are blurred. Objects moving quickly are blurrier, and the direction of movement is revealed by the direction of blur.” Method to be used to study tumour formation, wound healing and the immune system The new method exploits the fact that when genes are activated, a series of RNA molecules are formed in a certain order. By separating out these molecules, the researchers can work out if a gene has just been activated or if, for example, it is about to be switched off. “This new method allows us to observe in detail how specialised cell types are formed in the embryo, including the human embryo,” says Professor Linnarsson. “It can also be used to study dynamic disease processes, such as tumour formation, wound healing and the immune system.” The study was conducted in close collaboration with Peter Kharchenko from Harvard Medical School in the USA, and with contributions from several other groups. It was financed with grants from the Swedish Foundation for Strategic Research (SSF), the Knut and Alice Wallenberg Foundation, the Erling-Persson Family Foundation, the Wellcome Trust, the Centre for Innovative Medicine (CIMED), the Swedish Research Council, the European Research Council, the Swedish Brain Fund, the Ming Wai Lau Centre for Reparative Medicine, the Swedish Cancer Society, Karolinska Institutet and the USA’s National Institutes of Health (NIH) and National Science Foundation (NSF). Publication “RNA velocity of single cells”, Gioele La Manno, Ruslan Soldatov, Amit Zeisel, Emelie Braun, Hannah Hochgerner, Viktor Petukhov, Katja Lidschreiber, Maria E. Kastriti, Peter Lönnerberg, Alessandro Furlan, Jean Fan, Lars E. Borm, Zehua Liu, David van Bruggen, Jimin Guo, Erik Sundström, Gonçalo Castelo-Branco, Patrick Cramer, Igor Adameyko, Sten Linnarsson, Peter V. Kharchenko. Nature, online Aug 8 2018, doi: xxx


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