Our immune system is powerful in fighting infection, but can also specifically kill malignant body cells such as cancer cells. When we get vaccinated, the immune system gets trained and prepared for these fights. But it is believed that vaccines might also have the potential to educate our immune system to fight cancer cells.

A major challenge is that the most effective immune cells to kill cancer cells, so-called CD8+ cytotoxic T lymphocytes (CTLs), are difficult to activate with currently available vaccination strategies. This is thought to be a major reason why we do not have more effective vaccines against cancer. In a collaboration project between the Center for Molecular Inflammation Research (CEMIR) at NTNU, Oslo University Hospital and PCI Biotech AS, we have recently published that a novel and innovative vaccination technology holds great potential to realize therapeutic vaccination against cancer.

Most of today’s vaccines contain small particles with proteins from a virus or bacterium (antigens) which are recognized and taken up by immune cells (such as macrophages and dendritic cells). The vaccine particles are degraded within membrane-enclosed vesicles in the immune cells. Subsequently, small degradation fragments of the vaccine are presented on the cell surface and can be recognized by other cells of the immune system. This results for example in production of antibodies that target and inactivate bacterial or viral proteins, but does not efficiently activate CTL responses.

In our current study, we investigated the potential of a novel vaccination technology on twisting the outcome of vaccination towards increased activation of CTL responses as this is important for development of effective vaccines against cancer. “PCI vaccination” is a vaccination technology that is based on the principle of photochemical internalization (PCI), which uses a photoactive compound, a so-called photosensitizer, and light of a specific wavelength to delivers the vaccine.

In PCI vaccination, the photosensitizer compound is delivered to immune cells together with the vaccine antigen. After internalization, the photosensitizer incorporates into the membranes of the vesicles that contain the vaccine. If the immune cells are subsequently exposed to light of a specific wavelength, the photosensitizer is activated and generates a small and short-lived local damage in the membranes of the vesicles. The damage leads to rupture of the vesicles, the vaccine can escape and access the cytosolic space of the cell. This light-induced translocation of the vaccine from the vesicles to the cytosolic space of the immune cell is the key feature of PCI vaccination, since vaccines located in the cytosolic space of immune cells are very efficient in activating CTL responses.

We performed experiments with PCI vaccination technology both in a cell culture system as well as in a mouse model. We found that PCI-mediated vaccine delivery to immune cells made vaccines 30-100-fold more effective in activating CTL responses compared to vaccine-delivery without PCI technology. In addition, it was found that the PCI vaccination treatment in itself had an enhancing (“adjuvant”) effect by stimulating immune cells, probably due to the low-grade cell damage generated by the treatment. We could confirm these findings in mice by demonstrating that PCI vaccination was able to effectively induce specific CTL responses to two cancer antigens. We thus show new and compelling evidence that PCI technology may provide a feasible strategy to improve the outcome of vaccines that aim at inducing CTL responses that can fight cancer cells.

The vaccine compounds used in our study were small fragments of proteins (“peptide antigens”) derived from cancer cells, which usually are poorly immunogenic. Our findings may be of particular interest since these short peptides have attractive features for therapeutic cancer vaccination: They are generally non-toxic, cheap and easy to produce and can be tailored to the patient-specific cancer. We therefore believe that PCI-mediated vaccination may provide a promising novel approach to realize effective therapeutic vaccination against cancer by raising specific CTL responses against cancer cells found in patients. The PCI method is minimally invasive, well-tolerated and has been tested in clinical trials for other purposes. PCI Biotech currently conducts a clinical validation of the PCI vaccination technology (fimaVACC) in a Phase I (“Proof of Principle!) study in healthy volunteers.

The paper is published in the journal “Frontiers in Immunology”.

My personal experience from the Nepal Earthquake in 2015, and lessons learned from Dhulikhel Hospital (DH). 

It was a beautiful Saturday (25 April 2015) with the clear blue sky, the only day we get off from the work. I was in my room working on my laptop, and my husband sitting nearby me watching the television. Middle of the day at 11:56, I felt a shake, and then I immediately turned towards my husband. We were silent for a second; he told me that it is an earthquake.

He ran out and asked me to run with him. I was unable to move for a few seconds then I tried to hide under the bed instead of running out. I was seven months pregnant expecting our first baby in July.  My husband came back to take me out. I could hear people screaming and running to the safest place that they would think of. My family and I was safe and our house was still standing.

Within an hour after this first quake, the ambulances, motorbikes, trucks, cars or any kind of transport system that were available started rushing towards the hospital. Some of the victims were even carried by their family members & neighbors with some heavy bleeding. I was living in a few minutes distance from the Dhulikhel Hospital (DH). DH is one of the tertiary level hospital for the Kavrepalanchok district and for few other neighboring districts.

Most of the regular health facilities were closed because of the weekend. My husband decided to go to the hospital the first day. After a while, I received a phone call and it was my supervisor, Professor Erik Solligård, who was asking if we were safe. I was very happy to hear him.

We were outside the whole day. I was very scared to go back to the house and the same feeling was with my family members and my neighbors. We bought some dry foods from the local shops and spend that night in a public bus that was parked in the bus station. We spend our nights outside under the tents and sometimes inside the bus for almost a month after the first earthquake.

I started to go to the hospital from the second day to help in the areas that I could. Personally, I also felt more safe being in the hospital and making myself busy. I usually started my work from 8:00 in the morning until 20:00

Second day of the earthquake in front of the main hospital building. Photo credit: Dhulikhel Hospital

Triage zone established at the main entrance of the hospital

DH located in one of the most earthquake-affected districts of Nepal started providing 24 hours health services from day one to the earthquake victims. The hospital set up immediate medical direction, 24-hour surgical services, infection control teams, and logistical management teams, who had a vital role in managing unexpected workloads and providing efficient and quality health care.

One of the major task force was the establishment of triage zone at the main entrance of the hospital consisting of medical team and volunteers. We started a systematic screening of patients arriving at the hospital using a simplified triage system, and prioritized patients for effective surgical services. We used color ribbons (red, orange, yellow and green) to distinguish the patient according to the severity and were treated in respective treatment zones. This was evaluated as a useful tool by the staffs at the hospital. I believe this is a great example of teamwork in a local hospital with dedicated staffs working 24 hours prioritizing their profession and humanity rather than their family. On the other hand, collaborations between the two institutions could deliver the quality of health service to the people on right time.

At the same time, I was collecting the patient information from the triage zone and the treatment area. I thought this would be useful to report for the future preparedness in similar disasters. I find very challenging to have patient’s information during this emergency phase because the situation was very emotional, hospital had large number of caseloads, and in the first few days the hospital was not able to establish the systematic patient registry system. My two dedicated and hardworking research nurses helped me to accomplish this tremendous work.I still remember, the second day after the earthquake when I was in the hospital, the number of earthquake injuries escalated in the hospital, all the beds and almost all the space in the courtyard was occupied. The working conditions were continuously demanding. No one was prepared to deal with such a large number of injured patients.

This was Nepal’s first experience in responding to a major disaster almost after eight decades and DH had never been the first-line health care provider after an earthquake. However, the hospital was in the process of improving emergency health care through the “Dhulikhel Hospital Patient Care (DHPCARE)” project, a collaborative project initiated in 2013 between DH, the Norwegian University of Science and Technology (NTNU) and St. Olav’s Hospital, University Hospital Trondheim, Norway [1].

The main interventions in this project were the introduction of a systematic emergency registry, a systematic triage system, and simulator training among health personnel in the emergency department (ED). As part of the project, the ED was reorganized to separate patients into three treatment zones (red, orange/yellow, and green) according to four triage categories (red, orange, yellow and green), with separate staff attending each zone since Feb 2015. I was the coordinator from the DH in implementing the project.

The scariest moment I ever experienced in my life

On 12^th of May where things were more stable, I was at the hospital gate collecting the patient’s information. At 12:50 during the middle of the day, we experienced the second biggest shake. That day, my husband with the team was travelling to one of the outreach center of the hospital to investigate the earthquake damage and to identify the possibilities to start the health services. Afterwards I heard in the news that the place he went was the epicenter of that hit. I started to call him in his mobile, the phone was not reachable. Then I started to seek help of police if they can reach someone from that place, they tried to help me but the phone to the local police was also not reachable.

Afterwards the news were creepier, I heard people talking with worry that there are many casualties who were trapped by the landslides on that road where my husband was supposed to be traveling at that time. In few minutes, the number of patients arriving to the hospital increased. I was completely paralyzed. Few hours had passed but I have no updates, I was losing my hope but I have no other option than just to wait and try to reach him in his mobile. At around 16:30 I had a call in my mobile from a new mobile number. I was very scared to receive that call but I picked that phone call. I heard “Hello Samita”, it was my husband. I was speechless; I said “how are you and where are you?”. He told me that he is fine and he is in safe place. I just wanted to see him as soon as possible. He was later rescued by the army helicopter.

What we know and what can we learn from a local hospital?

We know that the earthquakes have a devastating impact on people lives, economy and the medical infrastructure. However, the impact of earthquakes has been reported to be highest in low-resource settings where health facilities are often damaged and the emergency response capacity is reduced [2, 3]. Disaster preparedness is a key element to resilient health systems [4, 5]. Although, considerable effort has been devoted to better disaster planning [6], there is still little evidence to support disaster planning and disaster risk reduction activities in low and middle-income countries [5, 7]. A national strategy for disaster risk management in Nepal does not include a separate plan for each type of disasters. Reports have stated that the national health information system of Nepal lack injury details from the earthquakes [8, 9]. The national disaster policy was often limited to the paper and was independent to the evidence [8, 9]. This can result in inadequate management of the patients.

DH provided emergency health services to more than 2,000 patients. The caseload was unexpected and was almost five times higher during the first five days than the pre-incident daily average. The majority of injuries were lower limb fractures and over 100 severely injured patients were treated. The proportion of severely injured and in-hospital deaths were relatively low indicating that the most severely injured did not reach the hospital. Most earthquake-affected regions in Nepal were rural and mountainous and there was continuous landslides, which affect transportation and prevent timely access to health facilities. The burden of emergency cases was high before the international field hospitals could be established. The international medical teams need some days after a disaster to initiate their services in the disaster affected areas. Until they arrive, patients are often treated by the poorly developed local health system, and many severely injured likely die prior to receiving medical treatment. Our study result and the local hospital experience underline the importance of developing own consistent and robust local health services capable of managing natural disasters such as an earthquake.

I am a PhD student at the Medical Faculty at NTNU under the supervision of Erik Solligård and Kari Risnes who are the project leaders in the DHECARE project. We present the experiences from DH including follow-up of earthquake victims in the article “Impact of 2015 Earthquakes on a local hospital in Nepal: A Prospective Hospital-based Study” in PLOS ONE, February 2 2018.

References

1. Maria Dønnem KE. Introduction of systematic triage in the emergency room at Dhulikhel Hospital, Nepal: Evaluation of a quality improvement project [dissertation]. Trondheim: NTNU; 2016.
2. Doocy S, Daniels A, Packer C, Dick A, Kirsch TD. The human impact of earthquakes: a historical review of events 1980-2009 and systematic literature review. PLoS currents. 2013;5.
3. MacKenzie JS, Banskota B, Sirisreetreerux N, Shafiq B, Hasenboehler EA. A review of the epidemiology and treatment of orthopedic injuries after earthquakes in developing countries World J Emerg Surg. 2017;12:9.
4. Dai ZY, Li Y, Lu MP, Chen L, Jiang DM. Clinical profile of musculoskeletal injuries associated with the 2008 Wenchuan earthquake in China. Ulus Travma Acil Cerrahi Derg. 2010;16(6):503-7.
5. Cartwright C, Hall M, Lee ACK. The changing health priorities of earthquake response and implications for preparedness: a scoping review. Public Health. 2017;150:60-70.
6. Lee AC, Phillips W, Challen K, Goodacre S. Emergency management in health: key issues and challenges in the UK. BMC public health. 2012;12:884.
7. Lee AC, Booth A, Challen K, Gardois P, Goodacre S. Disaster management in low- and middle-income countries: scoping review of the evidence base. Emergency medicine journal : EMJ. 2014;31(e1):e78-83.
8. Landry MD, Sheppard PS, Leung K, Retis C, Salvador EC, Raman SR. The 2015 Nepal Earthquake(s): Lessons Learned From the Disability and Rehabilitation Sector’s Preparation for, and Response to, Natural Disasters. Phys Ther. 2016;96(11):1714-23.
9. Hall ML, Lee AC, Cartwright C, Marahatta S, Karki J, Simkhada P. The 2015 Nepal earthquake disaster: lessons learned one year on. Public Health. 2017;145:39-44.

At the Center for Molecular Inflammation Research (CEMIR) we have discovered a new mechanism for how our immune cells recognize streptococcal bacteria that can cause serious infections in both newborns and adults.

Complicated infections such as blood poisoning are still among the most common causes of people dying in hospitals, despite the fact that we have had access to antibiotics for over 70 years. It is important with increased knowledge about our immune system to develop better treatment and thus survival among those with serious infections.

The immune system’s main task is to protect us against infections. The first step is to recognize and see the difference between what is foreign (the enemy) and what is the body’s own structures. From earlier we know that there are receptors both on the surface and inside the cells that are called Toll-like receptors (TLRs). These constitute the first line of defense in the body.

TLR is one of the most important parts of the immune system that reacts quickly upon encountering parts of bacteria and viruses. When these receptors are activated by foreign organisms, a cascade of warning signals starts activating other parts of the immune system to fight the invader. Earlier it was thought that it is primarily TLRs on the surface of the white blood cells that detect bacteria, while TLRs inside the cell is specialized in detecting viruses.

In our project, we have examined how the immune system reacts to group B streptococci (usually abbreviated GBS). We have investigated what happens when the white blood cells called monocytes come into contact with the GBS.

Monocytes are very important in the immune system and both direct other parts of the defense and digest bacteria that enter the body. We have found that TLR number 8 (TLR8) located within the monocytes is important for detecting GBS. TLR8 recognizes and is activated by fragments DNA-copies from the bacteria that is called RNA.

When RNA from GBS comes into contact with TLR8, the receptor is activated and sends signals that activate the monocyte and other parts of the immune system to fight the streptococcus. TLR8 seems to be particularly important for the detection of streptococci like GBS, but also golden staphylococci. E. coli-bacteria, on the other hand, were not recognized by TLR8.

These findings have recently been published in the Journal of Frontiers of Immunology and are a piece of the puzzle in making a clearer picture of how the body detects invading bacteria.

Reference: Birgitta Ehrnström, Kai Sandvold Beckwith, Mariia Yurchenko, Siv Helen Moen, June Frengen Kojen, Germana Lentini, Giuseppe Teti, Jan Kristian Damås, Terje Espevik, Jørgen Stenvik. Toll-Like Receptor 8 Is a Major Sensor of Group B Streptococcus But Not Escherichia coli in Human Primary Monocytes and Macrophages . Front Immunol. 2017; 8: 1243. Published online 2017 Oct 3.

Using a new ultrasound technique, we have been able to visualize and measure how efficiently blood flows through the heart chambers in young children with congenital heart disease. We studied 37 children aged two weeks to 10 years, and among the 26 children, which had congenital heart disease, we found less efficient hearts, meaning they use more energy than a normal heart. The technology, known as blood speckle tracking, has been developed by our colleagues at CIUS.

Tetralogy of Fallot is one of the most common types of congenital heart disease, accounting for 10% of all congenital heart disease. It consists mainly of a large hole between the pumping chambers and narrowing below the lung artery valve. The surgical repair is usually undertaken within the first 6 months of life but comes at the cost of causing a severe leak of the lung artery valve. Although well tolerated in young age, this can cause the right ventricle, the ventricle pumping through the lung artery valve, to become progressively bigger and increasingly dysfunctional with an increasing risk of life-threatening events. It is thought that replacing the lung artery valve can interrupt the progression and prevent these adverse events from occurring.

Predicting these events and intervening preventatively has been the focus of much work but remains challenging, with cutoffs of ventricular volumes measured by cardiac MRI constantly being changed. Lung artery replacement has been shown to procure some symptomatic relief, however, no survival benefit has been demonstrated. Given this realization, we can wonder whether ventricular volumes are really the best guide to optimally time surgery for these patients or is there a better avenue?

It has been suggested, from foetal life and beyond, that the shape and size of cardiac structures change in response to changes in blood flow patterns. These flow patterns are now within the reach of a new echocardiographic imaging technique combining high-frame-rate imaging of clusters of red blood cells. The resulting images open a window into the disturbed flow patterns of these patients. Abnormalities in flow result in ventricular inefficiencies and energy-losses which can now be quantified and localized using custom software, PyUSview. This analysis tool is the result of a tight collaboration between the clinicians and engineers in our group lead by Lasse Løvstakken at CIUS.

High frame rate blood flow speckle tracking echocardiography: Blood flow patterns and energy loss maps. using in-house developed software, 2D blood velocity fields were processed without in-plane flow assumptions. Energy losses were calculated within a region encompassing the RV, using a spline-based segmentation and reconstruction approach.

Using PyUSview, we studied a group of patients with repaired tetralogy of Fallot with severe lung artery leak (15 patients). We compared them to a group with another type of congenital heart disease, atrial septal defect (ASD) (communication between the upper chambers of the heart; 11 patients) and 11 healthy controls. We calculated energy-loss in the right ventricle during contraction (systole) and relaxation (diastole) and found that energy-loss in diastole was similar for both groups with congenital heart lesions, but significantly higher than controls.

A most interesting finding came from inspecting the location of maximal energy-loss, with marked differences between the groups (Figure 1). In the ASD group, the pattern of energy-loss was similar to that of normal controls. In the repaired tetralogy of Fallot group however, there was an additional area of increased energy loss at the right ventricular apex, corresponding to the collision of blood leaking back from the lung artery and the blood coming in normally to the ventricle during filling.

This is the first study of ventricular energetics in a paediatric population with dilated right ventricles. The methodology behind the imaging, its planned integration into the newest release of the GE Vivid E95 scanner as well as our results were presented by our group at the 2017 American Society of Echocardiography meeting (Pic 1-4).  Although the clinical significance of these findings is not yet clear, ventricular energetics, as assessed by echocardiography, may become a valuable tool in developing an approach based on blood flow patterns and energy-loss calculations to select a more optimal time for intervention.

Wadi Mawad was awarded a top 25 investigator prize for his presentation at the ASE-meeting 2017.

 Blogger: Ekaterina Zotcheva, PhD Candidate, Department of Public Health and Nursing

Ekaterina Zotcheva, Stpendiat, CERG employee

In 2015, approximately 47 million people worldwide were living with dementia. As populations across the globe age, this number is predicted to almost triple by 2050 [1]. Dementia is one of the most burdensome conditions among older people worldwide, and has a large impact both on the societal and individual level. The World Alzheimer Report on the global impact of dementia states that the total estimated global cost of dementia in 2015 was an astonishing US$818 billion, where almost 85% of the costs were related to family and social care [1]. Thus, new knowledge about prevention and treatment of dementia is of great value.

In July, the Lancet Commission on Dementia Prevention and Care published an article presenting an extensive review of risk and protective factors for dementia. Theoretically, approximately one third of dementia cases can be avoided by eliminating a number of risk factors, according to the authors. Based on the literature review, a striking 9.1% of dementia cases are attributable to hearing loss in midlife, whereas 7.5% can be attributed to low education. Other important risk factors are smoking, depression, physical inactivity, social isolation, hypertension, diabetes, and obesity [2].

Prevention is better than cure

So, I can just start exercising, stop smoking, and live a healthier life, right? The authors recommend that efforts must be made on both the individual and the societal level to reduce the prevalence of these risk factors. “Prevention is better than cure”, and while reducing or even eliminating the mentioned risk factors may not get rid of a whole third of dementia cases, it may delay the onset of many cases by several years [2]. Researchers have estimated that the prevalence of dementia could be halved if we could delay its onset by 5 years [3]!

The road ahead

Hearing loss, smoking, depression, social isolation and obisity are some of the risk factors for dementia [2]

The Health Study in Nord-Trøndelag (HUNT), one of the world’s largest and most successful population studies, started collecting data from the population in Nord-Trøndelag County in Norway in 1984. HUNT provides unique data on health and lifestyle factors, as well as on the prevalence of mental and somatic diseases. The fourth wave of the study (HUNT4) starts this fall. In the sub-study HUNT4 70+, researchers will gather valuable information on cognitive function, dementia, physical activity and function, nutrition, and oral health, in addition to the standard surveys included in HUNT4, from inhabitants aged 70 and up. Of approximately 20 000 inhabitants in this age group, 18 700 have previously participated in at least one of the three earlier waves of HUNT. Geir Selbæk, one of the authors of the aforementioned Lancet Commission article and research director at the Norwegian National Advisory Unit on Ageing and Health, is responsible for the part of HUNT4 70+ regarding cognitive function and dementia. The results from the HUNT and HUNT4 70+ studies will provide a substantial database for studying risk factors for dementia, hopefully helping us further disentangle and understand the complex relationship between lifestyle, cognitive function, and dementia.

Sources

1. Prince M, Wimo A, Guerchet M, Ali G-C, Wu Y-T, Prina M. World Alzheimer Report 2015. The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends. Alzheimer’s Disease International, 2015.
2. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. The Lancet. 2017. doi: 10.1016/S0140-6736(17)31363-6.
3. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand. 1987;76(5):465-79.
4. Cherbuin N, Kim S, Anstey KJ. Dementia risk estimates associated with measures of depression: a systematic review and meta-analysis. BMJ open. 2015;5(12):e008853. doi: 10.1136/bmjopen-2015-008853.
5. Snowden MB, Atkins DC, Steinman LE, Bell JF, Bryant LL, Copeland C, et al. Longitudinal Association of Dementia and Depression. Am J Geriatr Psychiatry. 2015;23(9):897-905. doi: 10.1016/j.jagp.2014.09.002.

Blogger: Richard Kumaran Kandasamy Associate Professor and Onsager Fellow at Centre of Molecular Inflammation Research (SFF-CEMIR)

Our innate immune system is the first and most important barrier of microbial threats such as viruses and bacteria.  It will sense, and in most cases, clear out these pathogens – but not always. A new approach to studying macrophage response to viral threats have resulted in a vastly expanded knowledgebase of the dynamics of the host response to viral infection, and in turn how antiviral innate immunity works. The data is freely available at www.infectome-map.org.

Richard Kumaran Kandasamy.
Photo: Thor Nielsen.

Digging deeper with big data
Our immune system is comprised of different types of cells such as macrophages that carry out these specialized tasks of handling the intruder. Although antiviral innate immune response has been widely studied over the past decades and used for development of therapeutics, most of these are based on candidate approach due to the lack of sensitive high-throughput technologies. With the emergence of systems biology and developments in the OMICS technologies (transcriptomics, proteomics and phosphoproteomics etc), the classical view of one-gene-does-everything-in-a-cell is challenged and it is becoming evident that cellular systems are more like a highly connected network that work in a coherent fashion. There are several studies in the recent past that have highlighted that cells indeed have multiple regulatory options (chromatin remodeling, transcription, translation, post-translational modifications (PTMs), folding, cellular localization, etc.) in how it achieves homeostasis under various perturbation scenarios such as viral or bacterial infection (Figure 1).

Figure 1: Multiple regulatory options of a cell during perturbations such as infection

Using state-of-the-art orthogonal OMICS approaches, we envisioned to understand the dynamics of the host response to viral infection by which we could assess the extent and the molecular logic of the host cellular response. This has the potential to provide unique and complementary information that can allow us to precisely map the systems-level perturbation caused by the viral infection and the viral circumvention of the host response, which will further add to the growing knowledgebase of antiviral innate immunity.

Answers hiding in the shadows of existing research
During our study we learned that post-translational modifications such as phosphorylation are crucial for innate immune response, but also highly understudied.
We performed a temporal genome-wide transcriptomics, proteomics and phosphoproteomics analysis of the cellular response of mouse macrophages to Vesicular Stomatitis Virus (VSV) infection. This was followed by integrative bioinformatics analyses to get a global overview of the cellular response (Figure 2).

Figure 2: Temporal OMICS integration of RIG-I signaling pathway during VSV infection

In practice we sampled the macrophage response at times 20 minutes, 3 hours and 6 hours after infection.

Figure 3. Overview of the experimental outline

We discovered that immune cells have multiple regulatory options during antiviral response. A novel phosphorylation site as well as four other genes were functionally validated for their role in type-I interferon activation, NFkB activation and VSV life cycle.

The vast and complex molecular changes measured could be decomposed in a limited number of clusters within each category (transcripts, proteins, protein phosphorylation), each with its own kinetic parameters and characteristic pathways and processes, suggesting multiple regulatory options and a specific process logic within the overall sensing and homeostatic program.

Phosphorylation is crucial for tailor-made defence
Overall, the data highlighted a predominant executive function to phosphorylation, likely evolved due to the requirement of a fast response to pathogens. Functional validation of a novel phosphorylation site S328-S330 on the innate immunity adaptor MAVS, identified its essential role in activation of type-I interferon and NFkB response. Further, we evaluated the kinase-substrate relationships (Figure 4) and identified RAF1, and to a smaller degree, ARAF to be suppressing VSV replication and needed for NFκB activation, and AKT2 to be favouring VSV replication. Integrative analysis of the omics data showed coregulation of membrane transporters including SLC7A11 which we validated as a host factor in the VSV life cycle.

Figure 4: Evaluation of the kinase-substrate relationships.

Open access to the data
The results of the study are published in  ” A time-resolved molecular map of the macrophage response to VSV infection in Nature – Systems Biology and Applications .  The dataset is presented, and freely available, on the website www.infectome-map.org and represents a large and unique starting platform for further systems-level as well as targeted mechanistic investigations on the functional organization of the response of macrophages to viral infection.

Anne Lise Ryel, Secretary-General in the Society, highlighted the research on big patient groups like gastrointestinal cancers. – This can really make a difference, colorectal cancer are among the cancer types that affects the most people. The chosen projects is top class, also in international standards, and they will contribute to prevention and treatment.  As a result even more people can live longer and better with cancer.

From the Norwegian Cancer Society, Deputy Secretary General Ole Alexander Opdalshei and Menno Oudhoff
(Photo: Linda Skjærvik)

Gastrointestinal cancers

– Colorectal cancer is the third most common cancer diagnosed, and 1 in 22 people will get it at some point in their lives, says Oudhoff. – It currently accounts for approximately 8% of all cancer-related deaths worldwide. Fortunately, the mortality rate for these type of cancers has been dropping for several decades. However, this is primarily attributed to better and more frequent screening rather than new therapeutics.

– The project awarded will study intestinal tumor initiation and development. Specifically, we will study the interplay between two major regulators of intestinal cancers called the Hippo and the Wnt pathways. Previous work has identified a new regulatory mechanism of these two pathways, and this proposal is aimed to strengthen the basic knowledge about this regulatory mechanism. Furthermore, we will attempt to target this mechanism to test if it has potential for drug development.

Among these we find our very own group leader and Professor of  Computational Neuroscience  Yasser Roudi.

Both “Meet 10 scientists who are making their mark” in Science News, and the story on Yasser Roudis research “Yasser Roudi: Creating maps in the brain“, are well worth reading.

Over the last couple of years Edvard Moser and scientists of the MPI of Neurobiology are closely collaborating. As part of this scientific exchange, Edvard Moser has spent many days and weeks at the Institute in Martinsried. Currently, he and Tobias Bonhoeffer, director at the MPI of Neurobiology, work on imaging the activity of grid cells with the help of 2-Photon-Microscopy. Based on the existing intense collaboration the directors of the Institute proposed to appoint Edvard Moser as External Scientific Member of the MPI of Neurobiology. Edvard Moser has accepted this offer and has thereby also become a Scientific Member of the Max Planck Society. The MPI of Neurobiology has now three External Scientific Members:

• Prof. Dr. Yves-Alain Barde, Cardiff School of Biosciences (UK)
• Prof. Dr. Reinhard Hohlfeld, Institute for Clinical Neuroimmunology of the Ludwig-Maximilians-University of Munich
• Prof. Dr. Edvard Moser, Kavli Institute for Systems Neuroscience and Centre for Neural Computation (Trondheim/Norway)

“Through this donation I want to recognize and encourage the world-leading neuroscience research in Trondheim, which is led by the remarkable Nobel Prize winners May-Britt and Edvard Moser,” says Pauline Braathen. Photo: Private

Pauline Braathen was married to Egil Braathens for 46 years. He died in 2009 after a prolonged period of advanced Alzheimer’s disease.

Braathen announced today that she would donate US $5 million to establish The Egil and Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits at the Kavli Institute for Systems Neuroscience at the Norwegian University of Science and Technology. The Centre will be established in cooperation with The Kavli Foundation in the USA.

Responded to Norwegian Prime Minister’s challenge

“Through this donation, I want to recognize and encourage the world-leading neuroscience research in Trondheim, which is led by the remarkable Nobel Prize winners May-Britt and Edvard Moser,” says Mrs. Braathen. “At the same time I wish to honour my deceased husband, Egil Braathen, who had a lot to be grateful to St. Olavs Hospital for. The research led by May-Britt and Edvard Moser has great importance for a world in need of increased knowledge about how the brain works, in order to prevent and cure brain-related diseases and illnesses. I believe that this unique combination of research and clinical excellence has the qualities we need to find the answers to the Alzheimer’s mystery. It is therefore with a great joy that I and some of Egil’s heirs in Norway take action in accordance with Prime Minister Erna Solberg’s call to give money to this purpose.”

“The unknown billionaire”

Egil Braathen was an extremely successful property developer who became one of Norway’s richest men, and has been referred to as “the unknown billionaire”. He created a large property development business in Oslo before he left Norway with his British wife in the mid-1980s.

He continued his investments abroad and left behind a substantial fortune, a small part of which went to his wife Pauline, who has previously given substantial grants to medical purposes. Braathen is donating the remaining amount of her inheritance to the Trondheim research centre. “I would truly have wished it to be a much larger contribution, matching that in the United States,” Mrs. Braathen says, “but my inheritance was limited to a small percentage of the considerable amount of wealth that my husband created during our years in Norway and the United States.”

Joint Grant

Mrs. Braathen is joined in making this gift by three of her late husband’s nephew and nieces, who were also named in his will. They are making their own contribution of US $1 million in lasting memory of their uncle. The total donation of US $6 million (approximately NOK 50 million ) is being made to the Trondheim Foundation for Scientific Research, which manages the funds and contributes annual funding to the Kavli Institute for Systems Neuroscience at NTNU.

Will triple Foundation capital fund

The new Egil & Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits will be a central part of the Kavli Institute for Systems Neuroscience, directed by May-Britt and Edvard Moser.  The grant donation of US $6 million will be matched with a corresponding grant of US $6 million from the Kavli Foundation in the USA, so that the total grant to the Foundation in Trondheim is approximately NOK 100 million. This will triple the Foundation’s existing capital fund.

By building up the Foundation’s capital in Trondheim, these gifts will produce a yearly return that will give lasting contributions to brain research.  The payout by the Foundation from the NOK 100 million gift will result in a yearly research grant of NOK 5 million to the new Centre and to the Kavli Institute.  The money will also be matched with a grant of 25 per cent through a government fund called the “gaveforsterkningsordningen” (“gift enhancement arrangement”).

“My husband was so clever and never stopped working, so it was important for me to make a gift in a way that he would have approved,” Mrs. Braathen said. “Our donation means more funds are dedicated to this fantastic cause, and that the research can continue into the future. We will beat these debilitating diseases together by supporting Norway’s best researchers.”

A gift to her husband’s home country

“I have a great love for Norway and I am very pleased at last to be able to contribute directly to the creative genius of its medical researchers and its outstanding research potential,” says Pauline Braathen, shown here with her late husband, Egil Braathen. Photo: Private

Mrs. Braathen recently dedicated the Egil and Pauline Braathen Centre at the Cleveland Clinic in Florida, where she and Egil had a home, and to which she gave more than US $30 million. She said that she felt it was also very important and appropriate to celebrate her late husband’s success in his home country.

“I have a personal and special respect and affection for the University Hospital in Trondheim, because I know that Egil owes the continuance of his life to a team of doctors who, at my request, came from Trondheim to Oslo in 1995 to perform a new surgical procedure when all others could not,” Mrs. Braathen said. The new centre will operate within the framework of the integrated university hospital, and will carry out brain research and cooperate with St. Olavs Hospital.

“I have a great love for Norway and I am very pleased at last to be able to contribute directly to the creative genius of its medical researchers and its outstanding research potential. It is hard to imagine a better purpose than to strengthen an international leading research environment like the Moser’s institute, which has shown such promising results in its research on the mysteries of the brain, manifested by the awarding of the Nobel Prize to May-Britt and Edvard Moser,” Mrs. Braathen said.

One of the largest philanthropic grants in Trøndelag

Robert W. Conn, President and CEO of The Kavli Foundation, said “We want to thank Mrs. Braathen and Egil Braathen’s nephew and nieces for their very generous gifts. Having the new centre named for her, her late husband Egil Braathen and Fred Kavli honours Mrs. Braathen and joins the memory of two remarkable men from Norway. The Kavli Foundation’s new gift adds to its original gift of $7.5 million, given in 2007 to establish the Kavli Institute for Systems Neuroscience. Now, these additional new gifts will further strengthen the scientific efforts to understand the human brain and develop treatments and cures for the major diseases that affect the mind.”

The Centre’s objectives

The Centre will operate within the framework of the integrated university hospital, and will carry out brain research and cooperate with St. Olavs Hospital. One of several projects aims to study cellular and neural-network changes in early stage Alzheimer’s disease. This project will be conducted alongside a substantial body of basic research which draws on the strengths of the researchers at the Centre, and which is necessary for understanding the mechanisms and consequences of early-stage Alzheimer-related changes in the brain.

Scientists call the co-operation between nerve cells in the cerebral cortex cortical microcircuits. These microcircuits are the basis for all cognitive functions. The greatest advances in neuroscience are now being made in this area, and this is also where May-Britt and Edvard Moser and their research colleagues have made great contributions.

By conducting research on cortical microcircuits, the Centre must necessarily take a long-term perspective on its work. The cross-disciplinary nature of research on cortical microcircuits also means different research groups at the Centre will be involved in the effort, which also offers an opportunity for the Centre to grow and expand.

A basic understanding of how the brain works is needed to develop diagnostics and treatments for Alzheimer’s disease. But alone, it is not enough, which is why the establishment of the Egil & Pauline Braathen and Fred Kavli Centre for Cortical Microcircuits will speed up research in the direction of diagnostics and treatment of Alzheimer’s disease.