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Mechanism identified behind enzyme involved in liver and other human cancers

Press Releases   •   Dec 07, 2017 17:00 GMT

To understand what has gone wrong when cancer occurs and to create new possibilities for treatment, it is important to understand the molecular mechanisms behind what is happening at the cellular level. New research, which is now published in the journal Molecular Cell, explains how the motor of an enzyme in DNA damage repair is switched on and off and how these processes might go awry in cancer.

Our genetic information is packaged into highly compact structures called chromatin. The way in which chromatin is packaged regulates many vital processes that require access to the cell’s genetic material. ATP-dependent chromatin remodelers are enzymes specialised in altering the structure and packaging of chromatin.

This study, which was carried out by principal investigators Sebastian Deindl (Uppsala University) and Simon Boulton (Francis Crick Institute) together with their research teams, sheds light on the molecular mechanisms that cause such an enzyme, Amplified in Liver Cancer 1 (ALC1), to “switch on and off”. This enzyme is connected to liver and several other human cancers.

The active portion of ALC1 is a “motor” that, just like in other chromatin remodeling enzymes, can use ATP as fuel to move the enzyme along the DNA molecule and change the packaging state of chromatin.

“What is special about this enzyme is that it also possesses a specific portion, a ‘macro domain’ that can recognise a type of polymer that accumulates at sites where DNA has been damaged. Thus it is involved in repairing damage to DNA,” says Laura Lehmann, one of the researchers in the group.

By applying biophysical techniques to elucidate the overall shape of ALC1, combined with cell-based and live-cell imaging approaches, the researchers could map the molecular mechanisms at play in controlling the remodeling activity of the enzyme by its ‘macro domain’. The researchers show that the ‘macro domain’ of the chromatin remodeler ALC1 physically interacts with its ATPase motor and that this effectively shuts off the motor’s activity when it is not needed.

“It can be described as a molecular brake that switches off the motor when there is no DNA damage. When damage occurs, the ‘macro domain’ binds to polymer chains at the damage site, which recruits the ALC1 enzyme to the site and simultaneously shifts its shape in such a way that the brake is released from the motor. Activated ALC1 could then make the damaged DNA accessible for repair processes,” explains Sebastian Deindl.

This discovery is a possible explanation for the fact that several mutations reported in human cancer may compromise the “off switch” for the enzyme ALC1. The researchers also show that when such cancer mutations are deliberately introduced in their experiments, a hyperactive, permanently “on” ATP motor is observed.

“Such uncontrolled activity of ALC1 in the absence of DNA damage is expected to have severe consequences for the cell. Ultimately, a better molecular-level understanding of the mechanisms that control ALC1 activity may in the long term open up new horizons for therapeutic intervention strategies,” says Sebastian Deindl.

The research has been funded by the Swedish Research Council, Knut and Alice Wallenberg Foundation, SciLifeLab, the European Research Council (ERC), the Wellcome Trust, the UK Medical Research Council, and Cancer Research UK.

Reference:

Mechanistic Insights into Autoinhibition of the Oncogenic Chromatin Remodeler ALC1
L. Lehmann, G. Hewitt, S. Aibara, A. Leitner, E. Marklund, S. Maslen, V. Maturi, Y. Chen, D. van der Spoel, M. Skehel, A. Moustakas, S. Boulton, and S. Deindl
Molecular Cell, Volume 68, Issue 5, December 7, 2017.

Watch a video about the reseach.

Visit laboratory website.

Science for Life Laboratory (SciLifeLab) is a national centre for molecular biosciences with a focus on health and environmental research. The centre combines technical expertise and advanced instruments with a broad knowledge of translational medicine and molecular biosciences.

For more information, please contact: Sebastian Deindl, phone: +46 (0)18 471 50 45, email: sebastian.deindl@icm.uu.se

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

To understand what has gone wrong when cancer occurs and to create new possibilities for treatment, it is important to understand the molecular mechanisms behind what is happening at the cellular level. New research, which is now published in the journal Molecular Cell, explains how the motor of an enzyme in DNA damage repair is switched on and off and how these processes might go awry in cancer.

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The origin of a new species of Darwin’s finches

Press Releases   •   Nov 23, 2017 20:35 GMT

Darwin’s finches in the Galápagos archipelago provide an iconic model for the evolution of biodiversity on earth due to natural selection. A team of scientists from Princeton University and Uppsala University now reports that they have observed the origin of a new species. A new lineage was formed by the hybridization of two different species of Darwin’s finches. The study is published today in Science.

Direct observation of the origin of a new putative species occurred during field work carried out by Rosemary and Peter Grant, Princeton University, on the small island of Daphne Major for 40 consecutive years. In 1981 they observed an immigrant male that sang an unusual song and differed in size from all resident species on the island. The male bred with a resident medium ground finch female and thereby initiated a new lineage which they named the Big Bird lineage. They followed the new lineage for 6 generations over 30 years. DNA sequence data now reveal that the immigrant male was a large cactus finch. Remarkably, it must have flown to Daphne from Española Island, which is more than 100 km to the southeast.

‘A critical step in speciation is the establishment of reproductive isolation. It is usually assumed that this process takes a very long time but in the Big Bird lineage it happened in just two generations, say Rosemary and Peter Grant.’

‘One important reason for this is the unique song of the immigrant male, since sons learn the song of their father and females mate with males that sing like their fathers, continue Peter and Rosemary Grant. A second reason is the new lineage differed from the resident species in beak morphology, which is also a major cue for mate choice.’

All 18 species of Darwin’s finches have been derived from a single ancestral species that colonized the Galápagos 1-2 million years ago. They have diversified into different species, and changes in beak morphology in particular have allowed different species to utilize different food sources on the Galápagos. Thus, another critical requirement for speciation to occur through hybridization is the new lineage must be ecologically competitive, and this has been the case for the Big Bird lineage.

'It is very striking that when we compare the size and shape of the Big Bird beaks with the beak morphologies of the other three species inhabiting Daphne Major island the Big Birds occupy their own niche in the beak morphology space’, explains Sangeet Lamichhaney, currently post-doctoral fellow at Harvard University. ‘Thus, the combination of gene variants contributed from the two interbreeding species in combination with natural selection led to the evolution of a beak morphology that was competitive and unique.’

A classical definition is that good species respect species boundaries and cannot produce fully fertile progeny if hybridization happens, as is the case for the horse and the donkey for example. However, in recent years it has become clear that some closely related species, which normally avoid breeding with each other, exchange genes by hybridization surprisingly often. The authors of this study have previously reported that there has been a considerable amount of gene flow going on among species of Darwin’s finches for thousands of years.

‘The interesting aspect of this study is that a hybridization between two distinct species led to the development of a new lineage that after only two generations behaved as any other species of Darwin’s finches. If a naturalist had come to Daphne Major island without knowing that this lineage arose very recently it would have been recognized as one of the four species on the island. This clearly demonstrates the value of long-running field studies’, says Leif Andersson at Uppsala University, the Swedish University of Agricultural Sciences and Texas A&M University.

‘It is very likely that new lineages like the Big Birds have originated many times during the evolution of Darwin’s finches. The majority of these have gone extinct but some may have led to the evolution of contemporary species. We have no idea about the long-term survival of the Big Bird lineage but it has the potential to become a success, and it provides a beautiful example of one way in which speciation occurs. Charles Darwin would have been excited to read this paper’, ends Leif Andersson.


For more information please contact:

Professor Leif Andersson, Uppsala University, Swedish University of Agricultural Sciences & Texas A&M University, cellular phone +46 70 425 0233, e-mail: Leif.Andersson@imbim.uu.se

Professors Peter and Rosemary Grant, Princeton University, Princeton, N.J. 08544-1003, phone: +01-609 258 3845, e-mail:prgrant@princeton.edu

Dr. Sangeet Lamichhaney, Museum of Comparative Zoology, Harvard University, 02138, MA, Phone: +1 919 908 3095, email: slamichhaney@fas.harvard.edu


S. Lamichhaney; F. Han; M.T. Webster; L. Andersson, B.R. Grant; P.R. Grant (2017) Rapid hybrid speciation in Darwin's finches, Science, DOI: 10.1126/science.aao4593

Acknowledgements: The study was supported by the Galápagos National Parks Service, The Charles Darwin Foundation, the National Science Foundation, the Knut and Alice Wallenberg Foundation and The Swedish Research Council.


Figure legends:
Figure 1. Schematic illustration of the evolution of the Big Bird lineage on the Daphne Major island in the Galápagos archipelago. Initially an immigrant large cactus finch male (Geospiza conirostris) bred with a medium ground finch female (Geospiza fortis). Their offspring bred with each other and established the Big Bird lineage. Photos © K. Thalia Grant for G. conirostris and Peter R. Grant for the remainder. Reproduced with permission from K. Thalia Grant, and Princeton University Press, which first published the remaining images in 40 Years of Evolution (P. R. Grant & B. R. Grant, 2014).

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

Darwin’s finches in the Galápagos archipelago provide an iconic model for the evolution of biodiversity on earth due to natural selection. A team of scientists from Princeton University and Uppsala University now reports that they have observed the origin of a new species. A new lineage was formed by the hybridization of two different species of Darwin’s finches.

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Genome sequencing reveals extensive inbreeding in Scandinavian wolves

Press Releases   •   Nov 20, 2017 16:00 GMT

Researchers from Uppsala University and others have for the first time determined the full genetic consequences of intense inbreeding in a threatened species. The large-scale genomic study of the Scandinavian wolf population is reported in Nature Ecology & Evolution.

The Scandinavian wolf population was founded in the 1980s by only two individuals. This has subsequently led to intense inbreeding, which is considered a long-term threat to the population. To reveal the genetic consequences of inbreeding, the whole genome of some 100 Scandinavian wolves has now been analysed.

‘Inbreeding has been so extensive that some individuals have entire chromosomes that completely lack genetic variation’, says Hans Ellegren, Professor at the Evolutionary Biology Centre, Uppsala University and leader of the study. ‘In such cases identical chromosome copies have been inherited from both parents.’

A surprising discovery was that also some immigrant wolves were partly inbred, and related. This was the case, for example, for two wolves that 2013 were translocated by management authorities from northernmost Sweden, due to conflict with reindeer husbandry, to southern Sweden. This is counter to the often-made assumption of unrelated and non-inbred founders when inbreeding is estimated from pedigrees.

‘The degree of inbreeding determined at high precision with genome analysis agreed rather well with inbreeding estimated from established pedigrees’, says Hans Ellegren. ‘However, for stochastic reasons, some wolves were found to be a bit more, and others a bit less, inbred than estimated from pedigrees.’

Moreover, wolves were generally more inbred than expected from recent mating between relatives in the contemporary population. This is because the two copies of a chromosome in an individual can originate from one and the same ancestor further back in time.

The study is a collaboration between Uppsala University, Swedish University of Agricultural Sciences, Inland Norway University, and Norwegian Institute for Nature Research.


Source: Kardos, Åkesson, Fountain, Flagstad, Liberg, Olason, Sand, Wabakken, Wikenros & Ellegren (2017) Genomic consequences of intensive inbreeding in an isolated wolf population. Nature Ecology & Evolution doi: 10.1038/s41559-017-0375-4

For more information please contact Hans Ellegren: hans.ellegren@ebc.uu.se

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

Researchers from Uppsala University and others have for the first time determined the full genetic consequences of intense inbreeding in a threatened species. The large-scale genomic study of the Scandinavian wolf population is reported in Nature Ecology & Evolution.

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Dog ownership linked to lower mortality

Press Releases   •   Nov 17, 2017 10:00 GMT

A team of Swedish scientists have used national registries of more than 3.4 million Swedes aged 40 to 80 to study the association between dog ownership and cardiovascular health. Their study shows that dog owners had a lower risk of death due to cardiovascular disease or to other causes during the 12-year follow-up.

A total of more than 3.4 million individuals without any prior cardiovascular disease in 2001 were included in the researchers’ study linking together seven different national data sources, including two dog ownership registers. The results are being published for the first time in Scientific Reports. The goal was to determine whether dog owners had a different risk of cardiovascular disease and death than non-dog owners.

“A very interesting finding in our study was that dog ownership was especially prominent as a protective factor in persons living alone, which is a group reported previously to be at higher risk of cardiovascular disease and death than those living in a multi-person household. Perhaps a dog may stand in as an important family member in the single households. The results showed that single dog owners had a 33% reduction in risk of death and 11% reduction in risk of myocardial infarction during follow-up compared to single non-owners. Another interesting finding was that owners to dogs from breed groups originally bred for hunting were most protected,” says Mwenya Mubanga, lead junior author of the study and PhD student at the Department of Medical Sciences and the Science for Life Laboratory, Uppsala University.

In Sweden, every person carries a unique personal identity number. Every visit to a hospital is recorded in national databases, accessible to researchers after de-identification of data. Even dog ownership registration has been mandatory in Sweden since 2001. These scientists studied whether being registered as a dog-owner was associated with later diagnosis of cardiovascular disease or death from any cause.

“These kind of epidemiological studies look for associations in large populations but do not provide answers on whether and how dogs could protect from cardiovascular disease. We know that dog owners in general have a higher level of physical activity, which could be one explanation to the observed results. Other explanations include an increased well-being and social contacts or effects of the dog on the bacterial microbiome in the owner,” says Tove Fall, senior author of the study and Associate Professor in Epidemiology at the Department of Medical Sciences and the Science for Life Laboratory, Uppsala University.

“There might also be differences between owners and non-owners already before buying a dog, which could have influenced our results, such as those people choosing to get a dog tending to be more active and of better health. Thanks to the population-based design, our results are generalisable to the Swedish population, and probably also to other European populations with similar culture regarding dog ownership,” says Tove Fall.

The study was conducted by researchers at Uppsala University, Karolinska Institutet, Stanford University and the Swedish University of Agricultural Sciences.

For further information, please contact:

Tove Fall, Associate professor in Epidemiology, Department of Medical Sciences, Molecular Epidemiology, and the Science for Life Laboratory, Uppsala University, Mobile: +46 (0)70-221 58 59, E-mail: tove.fall@medsci.uu.se

Publication: Mwenya Mubanga, Liisa Byberg, Christoph Nowak, Agneta Egenvall, Patrik K Magnusson, Erik Ingelsson, Tove Fall (2017) Dog ownership and the risk of cardiovascular disease and death – a nationwide cohort study, Scientific Reports. In press. DOI: 10.1038/s41598-017-16118-6

Financial support was provided by the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS), grant number 2013-1673, Agria and SKK Research Foundation and the Göran Gustafsson Foundation.

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

Science for Life Laboratory (SciLifeLab) is a Swedish national centre for molecular biosciences with focus on health and environmental research. The centre combines advanced technical know-how and state-of-the-art equipment with a broad knowledge of translational medicine and molecular bioscience.

A team of Swedish scientists have used national registries of more than 3.4 million Swedes aged 40 to 80 to study the association between dog ownership and cardiovascular health. Their study shows that dog owners had a lower risk of death due to cardiovascular disease or to other causes during the 12-year follow-up.

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Breastfeeding does not protect children against asthma and allergies

Press Releases   •   Nov 13, 2017 09:48 GMT

The effect of breastfeeding on the risk of developing asthma and allergy has been debated for a long time. In a recent study, Uppsala University researchers show that breastfeeding might in fact increase the risk of developing hay fever and eczema, while not having any clear effect on the risk of asthma. The results have been published in the Journal of Allergy and Clinical Immunology.

Your risk of developing asthma and allergies depends on your genes, environment and lifestyle factors. Several lifestyle risk factors have already been well established in the scientific community, such as smoking. However, studies on breastfeeding have shown inconsistent results. Many studies have found breastfeeding to have a protective effect against asthma and allergy, while other studies have reported increased risk.

The current study looks at the effect of breastfeeding on asthma, hay fever and eczema. It includes self-reported data from more than 330,000 middle-aged individuals in the UK, making it the largest study of its kind to date.

“Our study shows that individuals that were breastfed as babies have an increased risk of developing hay fever and eczema, while breastfeeding doesn’t seem to have an effect on asthma,” says Weronica Ek, researcher at Uppsala University’s Department of Immunology, Genetics and Pathology, who led the study.

The data also show that increased socioeconomic status lowers the risk of asthma while it increases the risk of developing hay fever. These results are in line with the ‘hygiene hypothesis’, which states that growing up in a cleaner environment increases the risk of being diagnosed with allergies due to a lack of early childhood exposure to microorganisms, among other things. This study also shows that a high BMI increases the risk for asthma, hay fever and eczema, while the risk decreases in individuals with higher birth weight.

It is important to remember that this study is an observational study, which does not allow for clinical recommendations to be made. In such studies there may always be underlying factors that the researchers do not have information about, which are the true causes of the observed effects. For instance, mothers who have the studied diseases themselves may have been recommended to breastfeed or not to breastfeed, which may affect the findings of the study.

It is well established that breastfeeding has a positive effect on the health of the baby. Even though we do not see a protective effect of breastfeeding on the risk of developing asthma or allergies, these results should not be used to recommend or discourage breastfeeding since the present study only investigates the effect of breastfeeding on allergies and asthma.

“However, we hope that our study can give a more correct picture of the health benefits of breastfeeding,” says Weronica Ek.

For more information, please contact:
Weronica Ek, tel: + 46 18-471 4806, email: weronica.ek@igp.uu.se


Ek. Weronica E, Karlsson Torgny, Azuaje Hernandez Carlos, Rask-Andersen Mathias, Johansson Åsa, (2017) Breastfeeding and risk of asthma, hay fever and eczema, Journal of Allergy and Clinical Immunology
DOI: http://dx.doi.org/10.1016/j.jaci.2017.10.022

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

The effect of breastfeeding on the risk of developing asthma and allergy has been debated for a long time. In a recent study, Uppsala University researchers show that breastfeeding might in fact increase the risk of developing hay fever and eczema, while not having any clear effect on the risk of asthma. The results have been published in the Journal of Allergy and Clinical Immunology.

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Novel open source software for drug combination analysis reveals complex effects of combining clinically used drugs

Press Releases   •   Nov 06, 2017 06:59 GMT

The effect of combining clinically used drugs for the treatment of colon cancer can vary widely depending on concentrations, ranging from cases where the drugs counteract each other to cases where they reinforce each other. This is the main conclusion from a cell culture analysis in which collected data were analysed using novel open source software developed by Uppsala researchers.

The study, published in the prestigious scientific journal Oncotarget, reveals complex concentration-dependent synergistic and antagonistic interactions between clinically used drugs for colon cancer when the cancer cells are cultured in test tubes.

More and more individuals are treated with multiple drugs that will hopefully be more powerful in combination than alone. However, basic research has been hindered by the lack of readily available methods for identifying promising combinations. In a recent article in Oncotarget, Dr Muhammad Kashif and colleagues report a novel open source software package for drug combination analysis called COMBIA. The software is based on robust statistics for drug synergy analysis developed in a team at the Department of Medical Sciences led by Professor Mats Gustafsson.

In the article, the software is used to reveal complex patterns of synergy/antagonism in colon cancer cells exposed to different combinations of clinically used drugs. An interesting finding was the presence of both synergistic and antagonistic effects of the same clinical drug combinations, but at different concentration ranges. This suggests that more effective treatment can be achieved by taking greater care in the selection of anti-cancer drug combinations and doses.

Complex patterns of synergy and antagonism are discernible in COMBIA analyses due to its in-built robustness originating from the use of non-parametric statistical analysis. The analysis takes into account the fact that the experimental errors are dependent on the magnitudes of the collected data (heteroscedasticity) and also performs controlled resampling and global (omnibus) testing. This means that COMBIA provides multiple improvements compared with established academic and commercial software available for drug combination synergy analysis.

COMBIA is available at the comprehensive R archive network (http://cran.r-project. org/). The software produces analysed data and graphs ready for use in scientific publications. It does not require manual data entry; data can be directly input from different plate readers, which makes it compatible with automated high-throughput and robotic drug discovery platforms.

Full reference: Muhammad Kashif, Claes Andersson, Sharmineh Mansoori, Rolf Larsson, Peter Nygren and Mats G. Gustafsson. Bliss and Loewe interaction analyses of clinically relevant drug combinations in human colon cancer cell lines reveal complex patterns of synergy and antagonism. Oncotarget https://doi.org/10.18632/oncotarget.21895

For more information, contact:
Mats Gustafsson, mats.gustafsson@medsci.uu.se, +46-18-611 42 41
Muhammad Kashif, kashifbioinfo@gmail.com, +46-76-313 8440

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

​The effect of combining clinically used drugs for the treatment of colon cancer can vary widely depending on concentrations, ranging from cases where the drugs counteract each other to cases where they reinforce each other. This is the main conclusion from a cell culture analysis in which collected data were analysed using novel open source software developed by Uppsala researchers.

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Threats from infectious diseases on Uppsala Health Summit agenda

Press Releases   •   Oct 06, 2017 08:05 BST

At the Uppsala Health Summit Tackling Infectious Disease Threats, due to start next week, experts and decision makers from ministries, academia, companies and voluntary organisations are meeting to discuss how jointly to reduce the risk of severe outbreaks.

The theme for the 2017 Summit on 10–11 October is threats from new and recurrent infectious diseases. Of all new communicable diseases, 75 per cent are zoonotic: humans and animals infect each other. Intensive animal production, climate change, population growth and our global travels are boosting the risk of infections breaking out. Growing antibiotic resistance is exacerbating the risk. The complexity of these diseases means that veterinarians, public-health experts, doctors, biologists, ecologists and social scientists must work together to prevent, detect and control their spread. How this can be achieved will be discussed in lectures and workshops on the following themes:

- Zoonotic Diseases in Livestock – Mitigating Risk Behaviour
- Empowered and Resilient Communities – A Need for New Perspectives
- A Roadmap for Effective Diagnostics to Combat Global Infectious Disease
- New Vaccines and Medicines: Monitor Safety in Emergency Situations
- Innovation and Big Data in Health Surveillance
- Whose Priorities Count? Empowering Scientific Capacities for Locally-Relevant and Sustainable Solutions
- Drivers and Constraints in Modern Typing Tools for Detection of Foodborne Disease

The lecturers will include Dr Pierre Formenty, head of the Viral and Haemorrhagic Fever team (VHF) in WHO; Dr Paul Richards, anthropologist and author of the book Ebola: How a People’s Science Helped End an Epidemic; Dr Beth-Ann Griswold of the American pharmaceutical company Merck, in charge of further development and production of vaccine against Ebola; and Dr Peter Dazsak, President of EcoHealth Alliance, who is working to enhance our understanding of how the health of ecosystems affects human beings and what can be done to reverse current trends.

More information about Uppsala Health Summit, the programme and the speakers.

Read the report issued ahead of the Summit.

Uppsala Health Summit is held by Uppsala University; the Swedish University of Agricultural Sciences (SLU); the Swedish Medical Products Agency; the Swedish National Food Agency; the Swedish National Veterinary Institute (SVA); Region Uppsala; the Uppsala Monitoring Centre; the Swedish Research Council for Health, Working Life and Welfare (Forte), the Municipality of Uppsala; and the World Class Uppsala network.

To sign up or for more information, contact Senior Press Officer Anneli Waara, phone +46-(0)70-425 0718, anneli.waara@uadm.uu.se

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

At the Uppsala Health Summit Tackling Infectious Disease Threats, due to start next week, experts and decision makers from ministries, academia, companies and voluntary organisations are meeting to discuss how jointly to reduce the risk of severe outbreaks.

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Patients’ expectations influence the effectiveness of SSRI antidepressants

Press Releases   •   Oct 03, 2017 08:00 BST

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety but their superiority over placebo has been questioned, generating considerable debate among researchers and clinicians. In a new study, Uppsala University researchers show that the way in which the treatment is described to the patient can be as important as the treatment itself.

In the debate among clinics and researchers on SSRIs, it has been argued that SSRIs may lack specific therapeutic properties and that their beneficial effects observed in clinical trials, could be explained by different expectancies in the drug and placebo groups. In a double-blind study, the participant may come to realise that he or she has been given the drug instead of placebo because of the experienced side effects, and this may in turn result in increased expectations of improvement and a better effect is reported. However, as of yet, it has not been tested experimentally to what extent the clinical effect of SSRIs can be influenced by the patient’s expectancies induced by the information patients are given at prescription.

In a study published in EBioMedicine, a group of researchers at Uppsala University’s Department of Psychology, Sweden, now demonstrate considerably better effects of the SSRI escitalopram when given with correct as compared to incorrect verbal information.

In the randomised study, all patients with social anxiety disorder were treated with the same dosage of escitalopram for nine weeks, but only one group was correctly informed about the drug and its effectiveness. By use of a cover story the other group was led to believe they were treated with a so called ‘active placebo’, yielding similar side effects as the SSRI but out of which no clinical improvement could be expected.

“Our results show that the number of responders was three times higher when correct information was given than when patients thought they were treated with an ineffective active placebo, even though the pharmacological treatment was identical,” says author Vanda Faria.

Moreover, assessments with MR neuroimaging showed that the SSRI had different effects on brain activity when associated with expectations of improvement or not. There were differences between the two groups in activations of the posterior cingulate cortex and the coupling between this region and the amygdala which is central to fear and anxiety.

“This may reflect an interaction between cognition and emotion as the brain changes differently with medication pending on the patient’s expectancies,” says co-author Malin Gingnell.

The results imply a marked placebo component, related to expectancies, in SSRI treatment, underscoring the importance of the communication between prescriber and patient.

“We don’t think SSRIs are ineffective or lack therapeutic properties for anxiety but our results suggest that the presentation of the treatment may be as important as the treatment itself,” says Professor Tomas Furmark, who led the study.

Contact information:
Vanda Faria, PhD, vanda.faria@psyk.uu.se, phone +49 152 23048254
Malin Gingnell, Ph.D., M.D., malin.gingnell@psyk.uu.se, phone +46 070 7544148
Tomas Furmark, professor, tomas.furmark@psyk.uu.se, phone +46 18 4712153

Faria, V., Gingnell, M., Motilla Hoppe, J., Hjorth, O., Alaie, I., Frick, A., Hultberg, S., Wahlstedt, K., Engman, J., Månsson, K.N.T., Carlbring, P., Andersson, G., Reis, M., Larsson, E.-M., Fredrikson, M., & Furmark, T. (2017) Do you believe it? Verbal suggestions influence the clinical and neural effects of escitalopram in social anxiety disorder: a randomized trial. EBioMedicine, doi: 10.1016/j.ebiom.2017.09.031

Uppsala University -- quality, knowledge, and creativity since 1477
World-class research and outstanding education of global benefit to society, business, and culture.
Uppsala University is one of northern Europe's highest ranked academic institutions. www.uu.se

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety but their superiority over placebo has been questioned, generating considerable debate among researchers and clinicians. In a new study, Uppsala University researchers show that the way in which the treatment is described to the patient can be as important as the treatment itself.

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Exhibition: Viking Age patterns may be Kufic script

Press Releases   •   Oct 02, 2017 16:36 BST

What was previously thought to be typical Viking Age, silver patterns on woven silk bands, could in fact be geometric Kufic characters. As part of an exhibition at the Enköping Museum, ongoing research is presented where a textile archaeological analysis suggests that both Allah and Ali are invoked in the pattern of the bands.

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Modern humans emerged more than 300,000 years ago new study suggests

Press Releases   •   Sep 28, 2017 19:01 BST

​A genomic analysis of ancient human remains from KwaZulu-Natal revealed that southern Africa has an important role to play in writing the history of humankind. A research team from Uppsala University, Sweden, the Universities of Johannesburg and the Witwatersrand, South Africa, presents their results in the September 28th early online issue of Science.

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