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Here you can read about everything that's happening in the ISB Group.

Invited lecture (and possibly teaser-performance) in upcoming MBM workshop

Events, News Posted on Thu, September 10, 2020 00:57:45

There are quite a few public lectures planned for this autumn, and one of the ones I am looking forward to a little bit extra is the MBM workshop, in Gothenburg, on October 15-16, 2020. MBM stands for Modelling in Biology and Medicine, and this is the second edition of the workshop. The workshop started as an initiative by a couple of enthusiastic Ph.D. students at the Math Department at Chalmers/Gothenburg University. But since it turned out so successful, they easily got both the support by the more senior leadership at the department, and enough positive feedback to decide to do a second edition. I really liked attending it last year, both since it was a Swedish workshop on systems biology, which means that it helps foster and grow the Swedish systems biology community, and since they managed to create a nice and cosy athmosphere. Partially because of this, the post-conference informal conversations last year led to me mentioning some of the bigger plans I am working on, which are going to become more public this year.

My dual life: scientist by day, pianist by night. Now they are starting to come together at last!

Those plans involve me combining my science and create careers into one, by doing joint lecture-performances, mixing piano, dancing, and digital twin-based stories. The original plan for this year’s workshop was to do some version of such a lecture-performance at the physical workshop. But since the physical edition had to be cancelled – due to the pandemic – the lecture will be held online. Nevertheless, in the presentation text of me at the home page, my CV covers – for the first time in a scientific event! – both my science and creative careers are mentioned side by side, and as two parts of the same thing. Already this feels really cool! And during the lecture, I plan to say, and probably also show, something short about those new and border-crossing plans in action. The workshop is held completely online, so you will be able to see it, also if you are not living in Sweden. And, later in the autumn, a more proper trailer for the first such lecture-performance will be released. The first proper such lecture-performance is planned be held during the autumn of 2021.

An exciting autumn awaits! And, the workshop is still open for abstract submissions!

 



Upcoming lecture in new European webinar series on 3R, Sept 22-24

3R and animal experiments, Events, News Posted on Sun, September 06, 2020 22:56:51

A new international webinar series on 3R – replacement, reduction, and refinement of animal experiments – is about to start! And we are present with a lecture!

From our group, Gunnar Cedersund and Elin Nyman are members of the National Committee on 3Rs, which also serves as the steering committee for the Swedish 3R center (S3RC). Our S3RC has now joined forces with a few other corresponding national centres, and this has led to the launch of a new webinar series. The first edition of this will take place on Sept 22-24, lunch times i.e. 12.30-13.30 CET. Gunnar will present a lecture on digital twins on the last day, i.e. Sept 24.

This is a great initiative, and I hope it will be the start of more collaborations between the centres!

More info, and sign-up here.



Upcoming Ph.D. defense, Sebastian Sten, “Mathematical modelling of neurovascular coupling”

Events, News Posted on Sat, September 05, 2020 01:59:22

On Friday, this coming week, September 11, 2020, at 9AM CET, our Ph.D. student Sebastian Sten will defend his Ph.D. thesis, entitled “Mathematical modelling of neurovascular coupling”.

Sebastian has been co-supervised between Gunnar Cedersund (who leads this group), Fredrik Elinder (BKV and electrophysiological expert), and Maria Engström (who was the main supervisor, and who is an expert on fMRI). In the thesis, Sebastian presents four papers which incrementally unravels more and more mechanistic details of how the main signal in fMRI – the BOLD signal – is generated. In Paper 1, he demonstrates that the main part of the BOLD signal response can not be caused by a negative feedback, as was first believed, but by a combination of a fast positive and a slow negative feedforward arm. In Paper 2, the model from paper 1 is extended with GABA, which makes it able to describe the negative BOLD response. In Paper 3, he unravels more mechanistic details of the two arms, and finds out that there are in fact at least three arms: the fastest positive is the NO-arm from interneurons, the slightly slower positive arm is the PGE2 arm from pyramidal cells, and the slowest negative arm is caused by NPY interneurons. In the final paper 4 (still in ms), these mechanistic details for the signalling and the control of the arteriolar diameter is embedded in a larger model, which also contains the biomechanical flow to capillariies and venules, and the creation of the actual BOLD signal. The final model is – to the best of our knowledge – the most complete and comprehensive model for the BOLD signal, and it simultaneously describes data and extracts information from informative optogenetic stimulation experiments in mice, from unique BOLD and Local Field Potential (LFP) experiments in monkeys, and from advanced MRI measurements of BOLD, volumes and flows, in humans.

Front page of the thesis, illustration done by our other group member Christian Simonsson, who wanted to capture not only the brain, but that experiments, analysis, and mathematical modelling has come together.

Overview of the main processes studied in the thesis.

After the defense, Sebastian will work for two more weeks, wrapping up the final paper. Thereafter, other people in the group will continue to work on these models, e.g. by connecting them to more detailed models for metabolism, electrophysiology, and – eventually – to clinical practice, e.g. by allowing for more measurements to come together into a more comprehensive and complete analysis of fMRI data. However, Sebastian himself will thereafter start a position at AstraZeneca, in the group we have the most contact with there: their metabolic and cardiovascular preclinical modelling group.

A link to the Ph.D. thesis is found here, and a link to the youtube event where the defense is broadcasted is found here.

Sebastian about to do the final formal step before the actual defense: nailing his thesis to the “thesis tree” of the medical faculty.



Presentations at the VPH Virtual Physiological Human conference

3R and animal experiments, Events, News Posted on Sun, August 30, 2020 01:43:23

As usual, we have attended the Virtual Physiological Human conference, which this year was given as an eConference. This year, our group was represented with two oral presentations, and three poster presentations. The first oral presentation was held by Gunnar Cedersund, with the title: “Multi-organ and multi-level digital twin models enters the clinic”, and it was similar to the presentation already held at numerous earlier occasions, e.g. at Almedalen, in the Swedish Parliament, at NIH, etc.

Screen short from Peter Gennemark’s presentation at the VPH conference

The second presentation was of a new project: Belén Casas’ postdoc project on modelling of microphysiological systems. This project is financed by AstraZeneca, who are the ones who do the experiments, in collaboration with the company TissUse. This modelling has allowed us to both understand the available system better, and to create a first translation up to humans. This brings us one step closer to finding a workable replacement for animal experiments regarding research on type 2 diabetes and Nonalcoholic SteatoHepatitis (NASH) in the liver. The postdoc project has been supervised by Gunnar Cedersund and Peter Gennemark (AstraZeneca, but also adjoint associate professor in our group). Since Belen is now away on parental leave, Peter gave the presentation. The three final poster presentations were on digital twins and multi-level modelling (Tilda Herrgårdh), on modelling of fatty acid fluxes in the fat tissue (Kajsa Tunedal), and on a new model for exercise (Antonia Klingsäter). Apart from our own presentations, it was interesting to see that the new ASME V&V40 guidelines from FDA, on usage of modelling in certification, are getting more and more traction. Another interesting presentation was the keynote held by Tarique Hussain, who talked about how he has been using advanced modelling of the heart, to help guide treatment planning of complicated cases in child cardiology.

Screen short from the presentation by Tarique Hussain


Ph.D. defense of Markus Karlsson: MRI-based modelling of liver function

Events Posted on Thu, January 30, 2020 11:26:55
Markus preparing for his Ph.D. defense.

Today there is a new Ph.D. defense in ISB group: that of Markus Karlsson. Markus has been working with usage of magnetic resonance imaging techniques to characterize the liver, and the formal title of the Ph.D. thesis is: “Non-Invasive Characterization of Liver Disease – by multimodal quantitative magnetic resonance”. Various techniques have been tested, MRS-PDFF (to measure liver fat), T1 relaxation (to estimate fibrosis), R2* (to estimate iron in the liver), etc. In three of the papers (Paper 1,2 and 4), normal MRI analysis has been done in different patient cohorts, and in two of the papers (Paper 3 and 5), mathematical modelling has been done in collaboration with ISB group. More specifically:

Paper 1 established a relationship between R2* and MRS-PDFF, and saw that liver fat distorts the R2* signal with about one R2* unit per MRS-PDFF unit. This could be used to device a simpe correction method when using R2* to estimate liver iron levels.

Paper 2 looked at the relationship between T1 and liver fibrosis in a cohort of approximately 100 patients with various degrees of diffuse liver disease, ranging from no fibrosis to cirrhosis. In the literature, different degrees of connection between T1 and liver fibrosis have been reported, and this paper unfortunately supports the conclusion that there is low correlation.

Paper 3 was the main paper deviced by us:

Model-inferred mechanisms of liver function from magnetic resonance imaging data: Validation and variation across a clinically relevant cohort. Forsgren MF, Karlsson M, Dahlqvist Leinhard O, Dahlström N, Norén B, Romu T, Ignatova S, Ekstedt M, Kechagias S, Lundberg P, Cedersund G. PLoS Comput Biol. 2019 Jun 25;15(6):e1007157.

In this paper, the data consists of DCI-MRI data, i.e. dynamic MRI images which have been enhanced by the contrast agent gadoxetate, which has been injected into the arm at the beginning of the time-series. By combining this data with a previously developed compartment transport model, we could estimate reliable uptake rates into the liver for all patient groups. Furthermore, in this paper we also showed that these estimated uptake rates, only accesible using the model, serve as new useful biomarkers for estimating liver function and fibrosis. In this paper, we also demonstrated how nonlinear mixed-effects modelling could be used to simplify the currently used protocol, to save money and time in the clinic.

Paper 4 looked at the relationship between magnetic resonance cholangiopancreatography (MRCP) and liver function estimated using DCI-MRI.

Paper 5 again looks at modelling of DCI-MRI data, to characterize the transport rates in and out of hepatocytes. In this paper, we compare uptake rates in humans and rats, and in rats with different exposures to a drug which impacts liver function. This allows us to establish a translational framework, that can predict the likely effect of a drug in humans, based on these available data and new data for the effect of the drug in rats. This is useful for drug development, when one wants to estimate the likely effect of a drug in humans based on available pre-clinical and clinical evidence.

Opponent for the defense is Steven Sourbron, who has worked with similar uptake and perfusion modelling in many of the central organs for many years, and who is one of the leading authorities in the field. In the examination committee sits Sven Månsson (Malmö), Lennart Blomqvist (Stockholm) and Zoltan Szabo (Linköping), who have complementary radiological and clinical competence.



Seminar day on non-animal perspectives in biomedicine and drug development with 3R

3R and animal experiments, Events, Systems biology and science Posted on Tue, January 14, 2020 19:28:05

Today, parts of the group participated at a seminar day with the Swedish 3R center in stockholm, both with posters, presentations and in discussions.

The day consisted of presentations from people doing research that can/could lead to replacement of animal testing – specifically on organs on a chip and mathematical modelling – and a panel discussions. In the panel discussions, among other things, the capabilities of the presented research to replace animal testing was discussed, what they can replace, and what the hurdels of making that happen are. All in all, the day gave a clearer vision on where we are, where we couldget, and how to do it.

From the panel discussion. From left to right, Per Artursson, Uppsala University, Karin Stenkula, Lund University, Lotte Martoft, AstraZeneca, Peter Gennemark, AstraZeneca, and Gunnar Cedersund chairing the discussions.



Precise4Q meeting in Linköping

Events, News Posted on Tue, November 12, 2019 16:02:17

During 7th and 8th of the November, we have had meeting with our partners in the PRECISE4Q project here in Linköping. In PRECISE4Q, we are working wit developing hybrid models for a decision support for Stroke treatment together with scientists within health informatics, computer science, machine learning, medicine, etc.

During the meetings, we discussed our upcoming EU review (we are financed by EUs Horizon 2020 project), how we should move forward in general, and met with local scientists here in Linköping that are working with similar things.



Ellen’s master thesis defence

Events Posted on Wed, January 23, 2019 14:53:04

Today, Ellen
Lesshammar defended her master thesis project: ‘Mathematical modelling of TLR4-activated
macrophages in inflammation’. The project aimed to use a model-based approach to
investigate the synthesis and release of
cytokines from macrophages during inflammation and also when inflammatory
response is suppressed by anti-inflammatory drugs. The models Ellen constructed
have the potential of being further refined and extended to include other
aspects of inflammation and might thus hold the possibility to contribute to
the further understanding of inflammation and how it can be the root cause to
several common diseases.

The work was done here in the ISB-group but also at the
Linköping based company Wolfram MathCore. We would like to congratulate Ellen on a
job well done, and we wish her luck with all future endeavours!



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