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Ekeberg, Ö., Fransén, E., Hellgren Kotaleski, J., Herman, P., Kumar, A., Lansner, A. & Lindeberg, T. (2016). Computational Brain Science at CST, CSC, KTH. KTH Royal Institute of Technology
Open this publication in new window or tab >>Computational Brain Science at CST, CSC, KTH
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2016 (English)Other, Policy document (Other academic)
Abstract [en]

Mission and Vision - Computational Brain Science Lab at CST, CSC, KTH

The scientific mission of the Computational Brain Science Lab at CSC is to be at the forefront of mathematical modelling, quantitative analysis and mechanistic understanding of brain function. We perform research on (i) computational modelling of biological brain function and on (ii) developing theory, algorithms and software for building computer systems that can perform brain-like functions. Our research answers scientific questions and develops methods in these fields. We integrate results from our science-driven brain research into our work on brain-like algorithms and likewise use theoretical results about artificial brain-like functions as hypotheses for biological brain research.

Our research on biological brain function includes sensory perception (vision, hearing, olfaction, pain), cognition (action selection, memory, learning) and motor control at different levels of biological detail (molecular, cellular, network) and mathematical/functional description. Methods development for investigating biological brain function and its dynamics as well as dysfunction comprises biomechanical simulation engines for locomotion and voice, machine learning methods for analysing functional brain images, craniofacial morphology and neuronal multi-scale simulations. Projects are conducted in close collaborations with Karolinska Institutet and Karolinska Hospital in Sweden as well as other laboratories in Europe, U.S., Japan and India.

Our research on brain-like computing concerns methods development for perceptual systems that extract information from sensory signals (images, video and audio), analysis of functional brain images and EEG data, learning for autonomous agents as well as development of computational architectures (both software and hardware) for neural information processing. Our brain-inspired approach to computing also applies more generically to other computer science problems such as pattern recognition, data analysis and intelligent systems. Recent industrial collaborations include analysis of patient brain data with MentisCura and the startup company 13 Lab bought by Facebook.

Our long term vision is to contribute to (i) deeper understanding of the computational mechanisms underlying biological brain function and (ii) better theories, methods and algorithms for perceptual and intelligent systems that perform artificial brain-like functions by (iii) performing interdisciplinary and cross-fertilizing research on both biological and artificial brain-like functions. 

On one hand, biological brains provide existence proofs for guiding our research on artificial perceptual and intelligent systems. On the other hand, applying Richard Feynman’s famous statement ”What I cannot create I do not understand” to brain science implies that we can only claim to fully understand the computational mechanisms underlying biological brain function if we can build and implement corresponding computational mechanisms on a computerized system that performs similar brain-like functions.

Place, publisher, year, pages
KTH Royal Institute of Technology, 2016. p. 1
National Category
Computer and Information Sciences Neurosciences
Identifiers
urn:nbn:se:kth:diva-180669 (URN)
Note

QC 20160121

Available from: 2016-01-19 Created: 2016-01-19 Last updated: 2018-01-10Bibliographically approved
Tigerholm, J., Petersson, M. E., Obreja, O., Eberhardt, E., Namer, B., Weidner, C., . . . Fransén, E. (2015). C-Fiber Recovery Cycle Supernormality Depends on Ion Concentration and Ion Channel Permeability. Biophysical Journal, 108(5), 1057-1071
Open this publication in new window or tab >>C-Fiber Recovery Cycle Supernormality Depends on Ion Concentration and Ion Channel Permeability
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2015 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 5, p. 1057-1071Article in journal (Refereed) Published
Abstract [en]

Following each action potential, C-fiber nociceptors undergo cyclical changes in excitability, including a period of superexcitability, before recovering their basal excitability state. The increase in superexcitability during this recovery cycle depends upon their immediate firing history of the axon, but also determines the instantaneous firing frequency that encodes pain intensity. To explore the mechanistic underpinnings of the recovery cycle phenomenon a biophysical model of a C-fiber has been developed. The model represents the spatial extent of the axon including its passive properties as well as ion channels and the Na/K-ATPase ion pump. Ionic concentrations were represented inside and outside the membrane. The model was able to replicate the typical transitions in excitability from subnormal to supernormal observed empirically following a conducted action potential. In the model, supernormality depended on the degree of conduction slowing which in turn depends upon the frequency of stimulation, in accordance with experimental findings. In particular, we show that activity-dependent conduction slowing is produced by the accumulation of intraaxonal sodium. We further show that the supernormal phase results from a reduced potassium current K-dr as a result of accumulation of periaxonal potassium in concert with a reduced influx of sodium through Na(v)1.7 relative to Na(v)1.8 current. This theoretical prediction was supported by data from an in vitro preparation of small rat dorsal root ganglion somata showing a reduction in the magnitude of tetrodotoxin-sensitive relative to tetrodotoxin - resistant whole cell current. Furthermore, our studies provide support for the role of depolarization in supernormality, as previously suggested, but we suggest that the basic mechanism depends on changes in ionic concentrations inside and outside the axon. The understanding of the mechanisms underlying repetitive discharges in recovery cycles may provide insight into mechanisms of spontaneous activity, which recently has been shown to correlate to a perceived level of pain.

Keyword
Innervating Human Skin, Repetitive Stimulation, Electrical-Stimulation, Diabetic-Neuropathy, Nerve Excitability, Spontaneous Pain, Sensory Neurons, Nociceptors, Conduction, Inactivation
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-165975 (URN)10.1016/j.bpj.2014.12.034 (DOI)000350969000008 ()25762318 (PubMedID)2-s2.0-84924787587 (Scopus ID)
Funder
Swedish Research Council, VR 621-2007-4223
Note

QC 20150504

Available from: 2015-04-30 Created: 2015-04-30 Last updated: 2018-01-11Bibliographically approved
Petersson, M. E., Obreja, O., Lampert, A., Carr, R. W., Schmelz, M. & Fransén, E. (2014). Differential Axonal Conduction Patterns of Mechano-Sensitive and Mechano-Insensitive Nociceptors - A Combined Experimental and Modelling Study. PLoS ONE, 9(8), e103556
Open this publication in new window or tab >>Differential Axonal Conduction Patterns of Mechano-Sensitive and Mechano-Insensitive Nociceptors - A Combined Experimental and Modelling Study
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e103556-Article in journal (Refereed) Published
Abstract [en]

Cutaneous pain sensations are mediated largely by C-nociceptors consisting of both mechano-sensitive (CM) and mechano-insensitive (CMi) fibres that can be distinguished from one another according to their characteristic axonal properties. In healthy skin and relative to CMi fibres, CM fibres show a higher initial conduction velocity, less activity-dependent conduction velocity slowing, and less prominent post-spike supernormality. However, after sensitization with nerve growth factor, the electrical signature of CMi fibres changes towards a profile similar to that of CM fibres. Here we take a combined experimental and modelling approach to examine the molecular basis of such alterations to the excitation thresholds. Changes in electrical activation thresholds and activity-dependent slowing were examined in vivo using single-fibre recordings of CM and CMi fibres in domestic pigs following NGF application. Using computational modelling, we investigated which axonal mechanisms contribute most to the electrophysiological differences between the fibre classes. Simulations of axonal conduction suggest that the differences between CMi and CM fibres are strongly influenced by the densities of the delayed rectifier potassium channel (Kdr), the voltage-gated sodium channels Na(V)1.7 and Na(V)1.8, and the Na+/K+-ATPase. Specifically, the CM fibre profile required less K-dr and Na(V)1.8 in combination with more Na(V)1.7 and Na+/ K(+)AT-Pase. The difference between CM and CMi fibres is thus likely to reflect a relative rather than an absolute difference in protein expression. In support of this, it was possible to replicate the experimental reduction of the ADS pattern of CMi nociceptors towards a CM-like pattern following intradermal injection of nerve growth factor by decreasing the contribution of Kdr (by 50%), increasing the Na+/K+-ATPase (by 10%), and reducing the branch length from 2 cm to 1 cm. The findings highlight key molecules that potentially contribute to the NGF-induced switch in nociceptors phenotype, in particular NaV1.7 which has already been identified clinically as a principal contributor to chronic pain states such as inherited erythromelalgia.

Keyword
Nerve Growth-Factor, Innervating Human Skin, C-Nociceptors, Sodium-Channels, Fibers, Pain, Neurons, Identification, Excitability, Currents
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-151338 (URN)10.1371/journal.pone.0103556 (DOI)000340742100010 ()
Funder
Swedish Research Council, VR 621-2007-4223
Note

QC 20140918

Available from: 2014-09-18 Created: 2014-09-18 Last updated: 2018-01-11Bibliographically approved
Fransén, E. (2014). Ionic Mechanisms in Peripheral Pain. In: Blackwell, K.T. (Ed.), Computational Neuroscience: (pp. 23-51). Elsevier
Open this publication in new window or tab >>Ionic Mechanisms in Peripheral Pain
2014 (English)In: Computational Neuroscience / [ed] Blackwell, K.T., Elsevier, 2014, p. 23-51Chapter in book (Refereed)
Abstract [en]

Chronic pain constitutes an important and growing problem in society with large unmet needs with respect to treatment and clear implications for quality of life. Computational modeling is used to complement experimental studies to elucidate mechanisms involved in pain states. Models representing the peripheral nerve ending often address questions related to sensitization or reduction in pain detection threshold. In models of the axon or the cell body of the unmyelinated C-fiber, a large body of work concerns the role of particular sodium channels and mutations of these. Furthermore, in central structures: spinal cord or higher structures, sensitization often refers not only to enhanced synaptic efficacy but also to elevated intrinsic neuronal excitability. One of the recent developments in computational neuroscience is the emergence of computational neuropharmacology. In this area, computational modeling is used to study mechanisms of pathology with the objective of finding the means of restoring healthy function. This research has received increased attention from the pharmaceutical industry as ion channels have gained increased interest as drug targets. Computational modeling has several advantages, notably the ability to provide mechanistic links between molecular and cellular levels on the one hand and functions at the systems level on the other hand. These characteristics make computational modeling an additional tool to be used in the process of selecting pharmaceutical targets. Furthermore, large-scale simulations can provide a framework to systematically study the effects of several interacting disease parameters or effects from combinations of drugs.

Place, publisher, year, edition, pages
Elsevier, 2014
Series
Progress in Molecular Biology and Translational Science, ISSN 1877-1173 ; 123
Keyword
Biophysical model, C-fiber, Chronic pain, Compartment model, Computational neuropharmacology, Computational neuroscience, Hodgkin-Huxley model, Intrinsic excitability, Mechano-insensitive fiber, Nav1.7, Nav1.8, Nav1.9, Neuropathic pain, Nociception, Nociceptive axon, Peripheral nerve, Peripheral pain, Sensory nerve
National Category
Bioinformatics (Computational Biology) Biochemistry and Molecular Biology Neurology
Identifiers
urn:nbn:se:kth:diva-145616 (URN)10.1016/B978-0-12-397897-4.00010-3 (DOI)000333380100002 ()2-s2.0-84926091475 (Scopus ID)978-0-12-397897-4 (ISBN)
Note

QC 20140523

Available from: 2014-05-23 Created: 2014-05-23 Last updated: 2018-01-11Bibliographically approved
Fransén, E. & Ahlström, P. (2014). Ionic mechanisms of post spike excitability changes during high-frequency firing rates. Scandinavian Journal of Pain, 5(3), 208
Open this publication in new window or tab >>Ionic mechanisms of post spike excitability changes during high-frequency firing rates
2014 (English)In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 5, no 3, p. 208-Article in journal (Refereed) Published
National Category
Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-165973 (URN)10.1016/j.sjpain.2014.05.013 (DOI)
Note

QC 20150504

Available from: 2015-04-30 Created: 2015-04-30 Last updated: 2018-01-11Bibliographically approved
Tigerholm, J., Petersson, M., Obreja, O., Lampert, A., Carr, R., Schmelz, M. & Fransén, E. (2014). Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors. Journal of Neurophysiology, 111(9), 1721-1735
Open this publication in new window or tab >>Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors
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2014 (English)In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 111, no 9, p. 1721-1735Article in journal (Refereed) Published
Abstract [en]

Action potential initiation and conduction along peripheral axons is a dynamic process that displays pronounced activity dependence. In patients with neuropathic pain, differences in the modulation of axonal conduction velocity by activity suggest that this property may provide insight into some of the pathomechanisms. To date, direct recordings of axonal membrane potential have been hampered by the small diameter of the fibers. We have therefore adopted an alternative approach to examine the basis of activity-dependent changes in axonal conduction by constructing a comprehensive mathematical model of human cutaneous C-fibers. Our model reproduced axonal spike propagation at a velocity of 0.69 m/s commensurate with recordings from human C-nociceptors. Activity-dependent slowing (ADS) of axonal propagation velocity was adequately simulated by the model. Interestingly, the property most readily associated with ADS was an increase in the concentration of intra-axonal sodium. This affected the driving potential of sodium currents, thereby producing latency changes comparable to those observed for experimental ADS. The model also adequately reproduced post-action potential excitability changes (i.e., recovery cycles) observed in vivo. We performed a series of control experiments replicating blockade of particular ion channels as well as changing temperature and extracellular ion concentrations. In the absence of direct experimental approaches, the model allows specific hypotheses to be formulated regarding the mechanisms underlying activity-dependent changes in C-fiber conduction. Because ADS might functionally act as a negative feedback to limit trains of nociceptor activity, we envisage that identifying its mechanisms may also direct efforts aimed at alleviating neuronal hyperexcitability in pain patients.

Keyword
activity-dependent slowing, recovery cycles, mechano-insensitive nociceptor, computer modeling
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-93681 (URN)10.1152/jn.00777.2012 (DOI)000335779300002 ()2-s2.0-84900796575 (Scopus ID)
Funder
Swedish Research Council, 621-2007-4223
Note

QC 20140602. Updated from manuscript to article in journal.

Available from: 2012-04-23 Created: 2012-04-23 Last updated: 2018-01-12Bibliographically approved
Tigerholm, J., Migliore, M. & Fransén, E. (2013). Integration of synchronous synaptic input in CA1 pyramidal neuron depends on spatial and temporal distributions of the input. Hippocampus, 23(1), 87-99
Open this publication in new window or tab >>Integration of synchronous synaptic input in CA1 pyramidal neuron depends on spatial and temporal distributions of the input
2013 (English)In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 23, no 1, p. 87-99Article in journal (Refereed) Published
Abstract [en]

Highly synchronized neural firing has been discussed in relation to learning and memory, for instance sharp-wave activity in hippocampus. We were interested to study how a postsynaptic CA1 pyramidal neuron would integrate input of different levels of synchronicity. In previous work using computational modeling we studied how the integration depends on dendritic conductances. We found that the transient A-type potassium channel KA was able to selectively suppress input of high synchronicity. In recent years, compartmentalization of dendritic integration has been shown. We were therefore interested to study the influence of localization and pattern of synaptic input over the dendritic tree of the CA1 pyramidal neuron. We find that the selective suppression increases when synaptic inputs are placed on oblique dendrites further out from the soma. The suppression also increases along the radial axis from the apical trunk out to the end of oblique dendrites. We also find that the KA channel suppresses the occurrence of dendritic spikes. Moreover, recent studies have shown interaction between synaptic inputs. We therefore studied the influence of apical tuft input on the integration studied above. We find that excitatory input provides a modulatory influence reducing the capacity of KA to suppress synchronized activity, thus facilitating the excitatory drive of oblique dendritic input. Conversely, inhibitory tuft input increases the suppression by KA providing a larger control of oblique depolarizing factors on the CA1 pyramidal neuron in terms of what constitutes the most effective level of synchronicity. Furthermore, we show that the selective suppression studied above depends on the conductance of the KA channel. KA, as several other potassium channels, is modulated by several neuromodulators, for instance acetylcholine and dopamine, both of which have been discussed in relation to learning and memory. We suggest that dendritic conductances and their modulatory systems may be part of the regulation of processing of information, in particular for how network synchronicity affects learning and memory.

Keyword
A-type potassium channel, Kv 4.2, sharp waves, dendritic spikes
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-93679 (URN)10.1002/hipo.22061 (DOI)000312537800010 ()2-s2.0-84870954627 (Scopus ID)
Funder
Swedish Research Council, 621-2007-4223 13043
Note

QC 20130121

Available from: 2012-04-23 Created: 2012-04-23 Last updated: 2018-01-12Bibliographically approved
Smolinski, T., Patel, P., Fransén, E., Hasselmo, M. & Schultheiss, N. (2012). A computational intelligence approach to evaluation of membrane conductance interactions underlying persistent spiking, the f-I curve, and adaptive properties of medial entorhinal cortex neurons. In: : . Paper presented at 2012 Neuroscience Meeting Planner. New Orleans, LA: Society for Neuroscience, October 12/17 2012 (pp. 648.04).
Open this publication in new window or tab >>A computational intelligence approach to evaluation of membrane conductance interactions underlying persistent spiking, the f-I curve, and adaptive properties of medial entorhinal cortex neurons
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2012 (English)Conference paper, Poster (with or without abstract) (Refereed)
National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-138871 (URN)
Conference
2012 Neuroscience Meeting Planner. New Orleans, LA: Society for Neuroscience, October 12/17 2012
Note

QC 20150217

Available from: 2013-12-20 Created: 2013-12-20 Last updated: 2018-01-11Bibliographically approved
Tigerholm, J., Börjesson, S., Lundberg, L., Elinder, F. & Fransén, E. (2012). Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels. PLoS ONE, 7(9), e44388
Open this publication in new window or tab >>Dampening of Hyperexcitability in CA1 Pyramidal Neurons by Polyunsaturated Fatty Acids Acting on Voltage-Gated Ion Channels
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e44388-Article in journal (Refereed) Published
Abstract [en]

A ketogenic diet is an alternative treatment of epilepsy in infants. The diet, rich in fat and low in carbohydrates, elevates the level of polyunsaturated fatty acids (PUFAs) in plasma. These substances have therefore been suggested to contribute to the anticonvulsive effect of the diet. PUFAs modulate the properties of a range of ion channels, including K and Na channels, and it has been hypothesized that these changes may be part of a mechanistic explanation of the ketogenic diet. Using computational modelling, we here study how experimentally observed PUFA-induced changes of ion channel activity affect neuronal excitability in CA1, in particular responses to synaptic input of high synchronicity. The PUFA effects were studied in two pathological models of cellular hyperexcitability associated with epileptogenesis. We found that experimentally derived PUFA modulation of the A-type K (K-A) channel, but not the delayed-rectifier K channel, restored healthy excitability by selectively reducing the response to inputs of high synchronicity. We also found that PUFA modulation of the transient Na channel was effective in this respect if the channel's steady-state inactivation was selectively affected. Furthermore, PUFA-induced hyperpolarization of the resting membrane potential was an effective approach to prevent hyperexcitability. When the combined effect of PUFA on the K-A channel, the Na channel, and the resting membrane potential, was simulated, a lower concentration of PUFA was needed to restore healthy excitability. We therefore propose that one explanation of the beneficial effect of PUFAs lies in its simultaneous action on a range of ion-channel targets. Furthermore, this work suggests that a pharmacological cocktail acting on the voltage dependence of the Na-channel inactivation, the voltage dependences of K-A channels, and the resting potential can be an effective treatment of epilepsy.

Keyword
epilepsy, synchronicity, hyperexcitability, ion channel modulation, PUFA
National Category
Neurosciences Bioinformatics (Computational Biology)
Identifiers
urn:nbn:se:kth:diva-93676 (URN)10.1371/journal.pone.0044388 (DOI)000309556100013 ()2-s2.0-84866695930 (Scopus ID)
Funder
Swedish Research Council, 621-2007-4223 13043
Note

QC 20121120. Updated from manuscript to article in journal.

Available from: 2012-04-23 Created: 2012-04-23 Last updated: 2018-01-12Bibliographically approved
Fransén, E., Petersson, M. E., Tigerholm, J., Andersson, S., Obreja, O., Lampert, A., . . . Schmelz, M. (2012). Differences in action potential propagation in mechanosensitive and insensitive C-nociceptors - a modeling approach. In: : . Paper presented at Neuroscience 2012, Annual Meeting of the Society for Neuroscience, Oct. 13 -17 2012, New Orleans (pp. 67.13).
Open this publication in new window or tab >>Differences in action potential propagation in mechanosensitive and insensitive C-nociceptors - a modeling approach
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2012 (English)Conference paper, Poster (with or without abstract) (Refereed)
Abstract [en]

C-fibers, unmyelinated afferent axons, convey information from the periphery of the nervous system to the spinal cord. They transmit signals originating from noxious stimulation evoking the sensations of itch and pain in the central nervous system. Different classes of C-fibers are characterized by functional, morphological and biochemical characteristics. In pain studies, a classification into mechano-insensitive (CMi) and mechano responsive fibers (CM) has proven useful as changes in proportions and response characteristics of these fibers have been observed in neuropathy patients (Weidner et al. 1999, 2000; Orstavik 2003, 2010). In this study, using computational modeling of a C-fiber, we have studied the possible contribution of different ion channel subtypes (Na-TTXs, Nav1.8, Nav1.9, Kdr, KA, KM, K(Na), h) as well as the Na/K-ATPase pump to conductive properties of C-fibers. In particular we investigated mechanisms that could generate the fiber-specific differences between CM and CMi fibers with regard to activity dependent slowing (ADS) and recovery cycles (RC). In our study we represent the axon by three cylindrical sections, one representing the peripheral thin end (branch, 2.5 cm), one the central part (parent, 10 cm) and a conical section between these (0.5 cm). In total 730 compartments are used. Temperature is set to 32 degrees C in branch and 37 degrees in parent sections. We represent variable ion concentrations of Na and K intra axonally, periaxonally and extracellularly, from which reversal potentials are calculated. We use ion channel models based on Hodgkin Huxley formalism. An ion pump (Na/K-ATPase) is included. We find that TTX-sensitive Na and Nav1.8 have the strongest influence on action potential conduction velocity as is expected since these are the major components of the rising phase of the action potential. Preliminary observations indicate that a small subset of Na and K currents play a key role in determining differences in activity dependent velocity changes (ADS) in the two fiber classes. We plan to also study contributions from morphological characteristics (superficial branch lengths) to activity dependent differences between the fiber classes (Schmidt et al. 2002). We further intend to investigate candidate ion channels which could play a role in changing the functional characteristics of a CMi fiber to that of a CM fiber. Our studies may provide insights into ionic changes underlying changes in the excitability of C-fibers associated with pain.

National Category
Neurosciences
Identifiers
urn:nbn:se:kth:diva-138890 (URN)
Conference
Neuroscience 2012, Annual Meeting of the Society for Neuroscience, Oct. 13 -17 2012, New Orleans
Note

QC 20150330

Available from: 2013-12-20 Created: 2013-12-20 Last updated: 2018-01-11Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0281-9450

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