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  • 51.
    Ekeberg, Örjan
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    A combined neuronal and mechanical model of fish swimming1993Inngår i: Biological Cybernetics, ISSN 0340-1200, E-ISSN 1432-0770, Vol. 69, nr 5-6, s. 363-374Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A simulated neural network has been connected to a simulated mechanical environment. The network is based on a model of the spinal central pattern generator producing rhythmic swimming movements in the lamprey and the model is similar to that used in earlier simulations of fictive swimming. Here, the network has been extended with a model of how motoneuron activity is transformed via the muscles to mechanical forces. Further, these forces are used in a two-dimensional mechanical model including interaction with the surrounding water, giving the movements of the different parts of the body. Finally, these movements are fed back through stretch receptors interacting with the central pattern generator. The combined model provides a platform for various simulation experiments relating the currently known neural properties and connectivity to the behavior of the animal in vivo. By varying a small set of parameters, corresponding to brainstem input to the spinal network, a variety of basic locomotor behaviors, like swimming at different speeds and turning can be produced. This paper describes the combined model and its basic properties.

  • 52.
    Ekeberg, Örjan
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Blümel, Marcus
    University of Köln.
    Büschges, Ansgar
    University of Köln.
    Dynamic simulation of insect walking2004Inngår i: Arthropod structure & development, ISSN 1467-8039, E-ISSN 1873-5495, Vol. 33, nr 3, s. 287-300Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insect walking relies on a complex interaction between the environment, body segments, muscles and the nervous system. For the stick insect in particular, previous investigations have highlighted the role of specific sensory signals in the timing of activity of central neural networks driving the individual leg joints. The objective of the current study was to relate specific sensory and neuronal mechanisms, known from experiments on reduced preparations, to the generation of the natural sequence of events forming the step cycle in a single leg. We have done this by simulating a dynamic 3D-biomechanical model of the stick insect coupled to a reduced model of the neural control system, incorporating only the mechanisms under study. The neural system sends muscle activation levels to the biomechanical system, which in turn provides correctly timed propriosensory signals back to the neural model. The first simulations were designed to test if the currently known mechanisms would be sufficient to explain the coordinated activation of the different leg muscles in the middle leg. Two experimental situations were mimicked: restricted stepping where only the coxatrochanteral joint and the femur-tibia joint were free to move, and the unrestricted single leg movements on a friction-free surface. The first of these experimental situations is in fact similar to the preparation used in gathering much of the detailed knowledge on sensory and neuronal mechanisms. The simulations show that the mechanisms included can indeed account for the entire step cycle in both situations. The second aim was to test to what extent the same sensory and neuronal mechanisms would be adequate also for controlling the front and hind legs, despite the large differences in both leg morphology and kinematic patterns. The simulations show that front leg stepping can be generated by basically the same mechanisms while the hind leg control requires some reorganization. The simulations suggest that the influence from the femoral chordotonal organs on the network controlling levation-depression may have a reversed effect in the hind legs as compared to the middle and front legs. This, and other predictions from the model will have to be confirmed by additional experiments.

  • 53.
    Ekeberg, Örjan
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Grillner, Sten
    Karolinska Institutet.
    Simulations of neuromuscular control in lamprey swimming1999Inngår i: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 354, nr 1385, s. 895-902Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The neuronal generation of vertebrate locomotion has been extensively studied in the lamprey. Models at different levels of abstraction are being used to describe this system, from abstract nonlinear oscillators to interconnected model neurons comprising multiple compartments and a Hodgkin-Huxley representation of the most relevant ion channels. To study the role of sensory feedback by simulation, it eventually also becomes necessary to incorporate the mechanical movements in the models. By using simplifying models of muscle activation, body mechanics, counteracting water forces, and sensory feedback through stretch receptors and vestibular organs, we have been able to close the feedback loop to enable studies of the interaction between the neuronal and the mechanical systems. The neuromechanical simulations reveal that the currently known network is sufficient for generating a whole repertoire of swimming patterns. Swimming at different speeds and with different wavelengths, together with the performance of lateral turns can all be achieved by simply varying the brainstem input. The neuronal mechanisms behind pitch and roll manoeuvres are less clear. We have put forward a 'crossed-oscillators' hypothesis where partly separate dorsal and ventral circuits are postulated. Neuromechanical simulations of this system show that it is also capable of generating realistic pitch turns and rolls, and that vestibular signals can stabilize the posture during swimming.

  • 54.
    Ekeberg, Örjan
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Grillner, Sten
    Karolinska Institutet.
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    The Neural Control of Fish Swimming studied through Numerical Simulations1995Inngår i: Adaptive Behavior, ISSN 1059-7123, E-ISSN 1741-2633, Vol. 3, nr 4, s. 363-384Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The neuronal generation of vertebrate locomotion has been extensively studied in the lamprey. Computer simulations of this system have been carried out with different aims and with different techniques. in this article, we review some of these simulations, particularly those leading toward models that describe She interaction that occurs between the neuronal system and its mechanical environment during swimming. Here we extend these models, enabling two new experiments to be conducted. The first one addresses the role of sensory feedback by exposing the neuromechanical system to unexpected perturbations. The second one tests the validity of an earlier proposed hypothesis for the neural generation of three-dimensional (3D) steering by coupling this central pattern generator to a mechanical 3D simulation.

  • 55.
    Ekeberg, Örjan
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Pearson, Keir
    Univ of Alberta.
    Computer simulation of stepping in the hind legs of the cat: An examination of mechanisms regulating the stance-to-swing transition2005Inngår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 94, nr 6, s. 4256-4268Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Physiological studies in walking cats have indicated that two sensory signals are involved in terminating stance in the hind legs: one related to unloading of the leg and the other to hip extension. To study the relative importance of these two signals, we developed a three- dimensional computer simulation of the cat hind legs in which the timing of the swing- to- stance transition was controlled by signals related to the force in ankle extensor muscles, the angle at the hip joint, or a combination of both. Even in the absence of direct coupling between the controllers for each leg, stable stepping was easily obtained using either a combination of ankle force and hip position signals or the ankle force signal alone. Stable walking did not occur when the hip position signal was used alone. Coupling the two controllers by mutual inhibition restored stability, but it did not restore the correct timing of stepping of the two hind legs. Small perturbations applied during the swing phase altered the movement of the contralateral leg in a manner that tended to maintain alternating stepping when the ankle force signal was included but tended to shift coordination away from alternating when the hip position signal was used alone. We conclude that coordination of stepping of the hind legs depends critically on load- sensitive signals from each leg and that mechanical linkages between the legs, mediated by these signals, play a significant role in establishing the alternating gait.

  • 56.
    Elofsson, Arne
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden..
    Hess, Berk
    KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Lindahl, Erik
    KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Onufriev, Alexey
    Virginia Tech, Dept Comp Sci, Ctr Soft Matter & Biol Phys, Blacksburg, VA USA.;Virginia Tech, Dept Phys, Ctr Soft Matter & Biol Phys, Blacksburg, VA USA..
    van der Spoel, David
    Uppsala Univ, Dept Cell & Mol Biol, Sci Life Lab, Uppsala Ctr Computat Chem, Uppsala, Sweden..
    Wallqvist, Anders
    US Army Med Res & Mat Command, Dept Def Biotechnol High Performance Comp Softwar, Telemed & Adv Technol Res Ctr, Ft Detrick, MD USA..
    Ten simple rules on how to create open access and reproducible molecular simulations of biological systems2019Inngår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 15, nr 1, artikkel-id e1006649Artikkel i tidsskrift (Annet vitenskapelig)
  • 57.
    Eriksson, David
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Fransén, Erik
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Zilberter, Y.
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Effects of short-term synaptic plasticity in a local microcircuit on cell firing2003Inngår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 52-54, s. 7-12Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Effects of short-term synaptic plasticity on cell firing properties in a microcircuit formed by a reciprocally connected pyramidal cell and FSN interneuron in layer 2/3 of neocortex were analyzed in a biophysical model. Induction of synaptic depression by backpropagating dendritic action potentials was replicated, as well as the resulting time dependent depression of IPSP amplitudes. Results indicate that the effect of the depression becomes significant above 30 Hz input frequency. The magnitude of the effect depends on the time constant of the dendritic calcium regulating the depression. The frequency range depends on the time constant of the IPSP.

  • 58. Eriksson, Johan
    et al.
    Vogel, Edward K.
    Lansner, Anders B.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Department of Numerical Analysis and Computer Science, Stockholm University, Sweden.
    Bergstrom, Fredrik
    Nyberg, Lars
    Neurocognitive Architecture of Working Memory2015Inngår i: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 88, nr 1, s. 33-46Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    A crucial role for working memory in temporary information processing and guidance of complex behavior has been recognized for many decades. There is emerging consensus that working-memory maintenance results from the interactions among long-term memory representations and basic processes, including attention, that are instantiated as reentrant loops between frontal and posterior cortical areas, as well as sub-cortical structures. The nature of such interactions can account for capacity limitations, lifespan changes, and restricted transfer after working-memory training. Recent data and models indicate that working memory may also be based on synaptic plasticity and that working memory can operate on non-consciously perceived information.

  • 59.
    Eriksson, Olivia
    et al.
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Jauhiainen, Alexandra
    AstraZeneca, IMED Biotech Unit, Early Clin Dev, Biometr, Gothenburg, Sweden..
    Sasane, Sara Maad
    Lund Univ, Ctr Math Sci, Lund, Sweden..
    Kramer, Andrei
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Nair, Anu G.
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Sartorius, Carolina
    Lund Univ, Ctr Math Sci, Lund, Sweden..
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Uncertainty quantification, propagation and characterization by Bayesian analysis combined with global sensitivity analysis applied to dynamical intracellular pathway models2019Inngår i: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, nr 2, s. 284-292Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Motivation: Dynamical models describing intracellular phenomena are increasing in size and complexity as more information is obtained from experiments. These models are often over-parameterized with respect to the quantitative data used for parameter estimation, resulting in uncertainty in the individual parameter estimates as well as in the predictions made from the model. Here we combine Bayesian analysis with global sensitivity analysis (GSA) in order to give better informed predictions; to point out weaker parts of the model that are important targets for further experiments, as well as to give guidance on parameters that are essential in distinguishing different qualitative output behaviours. Results: We used approximate Bayesian computation (ABC) to estimate the model parameters from experimental data, as well as to quantify the uncertainty in this estimation (inverse uncertainty quantification), resulting in a posterior distribution for the parameters. This parameter uncertainty was next propagated to a corresponding uncertainty in the predictions (forward uncertainty propagation), and a GSA was performed on the predictions using the posterior distribution as the possible values for the parameters. This methodology was applied on a relatively large model relevant for synaptic plasticity, using experimental data from several sources. We could hereby point out those parameters that by themselves have the largest contribution to the uncertainty of the prediction as well as identify parameters important to separate between qualitatively different predictions. This approach is useful both for experimental design as well as model building.

  • 60.
    Fagergren, Anders
    et al.
    Karolinska Institutet.
    Ekeberg, Örjan
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Forssberg, Hans
    Karolinska Institutet.
    Control strategies correcting inaccurately programmed fingertip forces: Model predictions derived from human behavior2003Inngår i: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 89, nr 6, s. 2904-2916Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    When picking up a familiar object between the index finger and the thumb, the motor commands are predetermined by the CNS to correspond to the frictional demand of the finger-object contact area. If the friction is less than expected, the object will start to slip out of the hand, giving rise to unexpected sensory information. Here we study the correction strategies of the motor system in response to an unexpected frictional demand. The motor commands to the mononeuron pool are estimated by a novel technique combining behavioral recordings and neuromuscular modelling. We first propose a mathematical model incorporating muscles, hand mechanics, and the action of lifting an object. A simple control system sends motor commands to and receives sensory signals from the model. We identify three factors influencing the efficiency of the correction: the time development of the motor command, the delay between the onset of the grip and load forces (GF-LF-delay), and how fast the lift is performed. A sensitivity analysis describes how these factors affect the ability to prevent or stop slipping and suggests an efficient control strategy that prepares and corrects for an altered frictional condition. We then analyzed fingertip grip and load forces (GF and LF) and position data from 200 lifts made by five healthy subjects. The friction was occasionally reduced, forcing an increase of the GF to prevent the object being dropped. The data were then analyzed by feeding it through the inverted model. This provided an estimate of the motor commands to the motoneuron pool. As suggested by the sensitivity analysis the GF-LF-delay was indeed used by the subjects to prevent slip. In agreement with recordings from neurons in the primary motor cortex of the monkey, a sharp burst in the estimated GF motor command (NGF) efficiently arrested any slip. The estimated motor commands indicate a control system that uses a small set of corrective commands, which together with the GF-LF-delay form efficient correction strategies. The selection of a strategy depends on the amount of tactile information reporting unexpected friction and how long it takes to arrive. We believe that this technique of estimating the motor commands behind the fingertip forces during a precision grip lift can provide a powerful tool for the investigation of the central control of the motor system.

  • 61.
    Fagergren, Anders
    et al.
    Karolinska Institutet.
    Ekeberg, Örjan
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Forssberg, Hans
    Karolinska Institutet.
    Precision grip force dynamics: A system identification approach2000Inngår i: IEEE Transactions on Biomedical Engineering, ISSN 0018-9294, E-ISSN 1558-2531, Vol. 47, nr 10, s. 1366-1375Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A linear model of the dynamics of the human precision grip is presented. The transfer function is identified as representing the peripheral motor subsystem, from the motoneuron pool to the final production of a grip force between the tip of the index finger and the thumb. The transfer function captures the limiting isometric muscle dynamics that, e.g., cortical motor areas have to act through. When identifying the transfer function we introduce a novel technique, common subsystem identification. This characterizes a specific subsystem in a complex biomechanical system. This technique requires data from two functionally different experiments that both involve the subsystem of interest. Two transfer functions, one for each experiment, are then estimated using a linear black box technique. The common mathematical factors, represented by poles and zeros, are used to form a new transfer function. It is concluded that this transfer function represents the common biological subsystem involved in both experiments. Here, we use one active and one reactive isometric grip force experiment to capture the subsystem of interest, i.e., the motoneuron pool, motor units, muscles, tendons and fingertip tissue. The characteristics of the dynamics are in agreement with previously published experiments on human neuro-muscular systems. The model, H(s) = 280/(s(2) + 22s + 280), is well suited for the representation of a force producing end-effector in simulations including a control system with sensory feedback.

  • 62.
    Fernández-Pozo, Noé
    et al.
    University of Malaga.
    Canales, Javier
    University of Malaga.
    Guerrero-Fernández, Darío
    University of Malaga.
    Villalobos, David P
    University of Malaga.
    Díaz-Moreno, Sara M
    University of Malaga.
    Bautista, Rocío
    University of Malaga.
    Flores-Monterroso, Arantxa
    University of Malaga.
    Guevara, M Ángeles
    CIFOR-UNIA.
    Perdiguero, Pedro
    Universidad Politecnica de Madrid.
    Collada, Carmen
    Universidad Politecnica de Madrid.
    Cervera, M Teresa
    Universidad Politecnica de Madrid.
    Soto, Alvaro
    Universidad Politecnica de Madrid.
    Ordás, Ricardo
    University of Oviedo.
    Cantón, Francisco R
    University of Malaga.
    Avila, Concepción
    University of Malaga.
    Cánovas, Francisco M
    University of Malaga.
    Claros, M Gonzalo
    University of Malaga.
    EuroPineDB: a high-coverage web database for maritime pine transcriptome2011Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 12, s. 366-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Pinus pinaster is an economically and ecologically important species that is becoming a woody gymnosperm model. Its enormous genome size makes whole-genome sequencing approaches are hard to apply. Therefore, the expressed portion of the genome has to be characterised and the results and annotations have to be stored in dedicated databases.

    DESCRIPTION: EuroPineDB is the largest sequence collection available for a single pine species, Pinus pinaster (maritime pine), since it comprises 951 641 raw sequence reads obtained from non-normalised cDNA libraries and high-throughput sequencing from adult (xylem, phloem, roots, stem, needles, cones, strobili) and embryonic (germinated embryos, buds, callus) maritime pine tissues. Using open-source tools, sequences were optimally pre-processed, assembled, and extensively annotated (GO, EC and KEGG terms, descriptions, SNPs, SSRs, ORFs and InterPro codes). As a result, a 10.5× P. pinaster genome was covered and assembled in 55 322 UniGenes. A total of 32 919 (59.5%) of P. pinaster UniGenes were annotated with at least one description, revealing at least 18 466 different genes. The complete database, which is designed to be scalable, maintainable, and expandable, is freely available at: http://www.scbi.uma.es/pindb/. It can be retrieved by gene libraries, pine species, annotations, UniGenes and microarrays (i.e., the sequences are distributed in two-colour microarrays; this is the only conifer database that provides this information) and will be periodically updated. Small assemblies can be viewed using a dedicated visualisation tool that connects them with SNPs. Any sequence or annotation set shown on-screen can be downloaded. Retrieval mechanisms for sequences and gene annotations are provided.

    CONCLUSIONS: The EuroPineDB with its integrated information can be used to reveal new knowledge, offers an easy-to-use collection of information to directly support experimental work (including microarray hybridisation), and provides deeper knowledge on the maritime pine transcriptome.

  • 63.
    Ferreira, Tiago
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB. Aalto, School of Science.
    Catch the dream Wave: Propagation of Cortical Slow Oscillation to the Striatum in anaesthetised mice2014Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Under anaesthesia or in deep sleep, different parts of the brain have a distinctive slow oscillatory activity, characterised by states of high membrane potential and intensive spiking activity, the Up-states; followed by hyperpolarisation and quiescence, the Down-states. This activity has been previously described in vitro and in vivo in the cortex and the striatum, across several species. Here, we look into it, during anaesthesia, in the mouse brain. Using whole-cell patch-clamp recordings of cortical cells, it was possible to compare different signal processing methods used to extract the Up-and- Down states in extracellular recordings of the cortex. Our results show that the method based on the Multi-Unit Activity (> 200Hz) have better ac- curacy than High-Gamma Range (20 100Hz) or wavelet decomposition (< 2Hz band).

    After establishing the most robust method, this was used to compare the intracellular recordings of striatal cells to different parts of the cortex. The results obtained here support a functional connection between the dorsolateral striatal neurons and the ipsilateral barrel field. They also support a functional connection between dorsomedial striatal cells and the primary visual cortex.

    The analysis of delay between recordings allowed to establish temporal relationships between the contralateral barrel field, the ipsilateral barrel field, and the dorsolateral striatum; and between the ipsilateral barrel field, the ipsilateral primary visual field and the dorsomedial striatum. 

  • 64.
    Fiebig, Florian
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST).
    Active Memory Processing on Multiple Time-scales in Simulated Cortical Networks with Hebbian Plasticity2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis examines declarative memory function, and its underlying neural activity and mechanisms in simulated cortical networks. The included simulation models utilize and synthesize proposed universal computational principles of the brain, such as the modularity of cortical circuit organization, attractor network theory, and Hebbian synaptic plasticity, along with selected biophysical detail from the involved brain areas to implement functional models of known cortical memory systems. The models hypothesize relations between neural activity, brain area interactions, and cognitive memory functions such as sleep-dependent memory consolidation, or specific working memory tasks. In particular, this work addresses the acutely relevant research question if recently described fast forms of Hebbian synaptic plasticity are a possible mechanism behind working memory. The proposed models specifically challenge the “persistent activity hypothesis of working memory”, an established but increasingly questioned paradigm in working memory theory. The proposed alternative is a novel synaptic working memory model that is arguably more defensible than the existing paradigm as it can better explain memory function and important aspects of working memory-linked activity (such as the role of long-term memory in working memory tasks), while simultaneously matching experimental data from behavioral memory testing and important evidence from electrode recordings.

  • 65.
    Fiebig, Florian
    et al.
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST).
    Herman, Pawel
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST).
    Lansner, Anders
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST). Department of Mathematics, Stockholm University, 10691 Stockholm, Swed.
    An Indexing Theory for Working Memory based on Fast Hebbian PlasticityManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Working memory (WM) is a key component of human memory and cognitive function. Computational models have been used to uncover the underlying neural mechanisms. However, these studies have mostly focused on the short-term memory aspects of WM and neglected the equally important role of interactions between short- and long-term memory (STM, LTM). Here, we concentrate on these interactions within the framework of our new computational model of WM, which accounts for three cortical patches in macaque brain, corresponding to networks in prefrontal cortex (PFC) together with parieto-temporal cortical areas. In particular, we propose a cortical indexing theory that explains how PFC could associate, maintain and update multi-modal LTM representations. Our simulation results demonstrate how simultaneous, brief multi-modal memory cues could build a temporary joint memory representation linked via an "index" in the prefrontal cortex by means of fast Hebbian synaptic plasticity. The latter can then activate spontaneously and thereby reactivate the associated long-term representations. Cueing one long-term memory item rapidly pattern-completes the associated un-cued item via prefrontal cortex. The STM network updates flexibly as new stimuli arrive thereby gradually over-writing older representations. In a wider context, this WM model suggests a novel explanation for "variable binding", a long-standing and fundamental phenomenon in cognitive neuroscience, which is still poorly understood in terms of detailed neural mechanisms.

  • 66.
    Fiebig, Florian
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Lansner, Anders
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Memory consolidation from seconds to weeks: a three-stage neural network model with autonomous reinstatement dynamics2014Inngår i: Frontiers in Computational Neuroscience, ISSN 1662-5188, E-ISSN 1662-5188, Vol. 8, s. 64-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Declarative long-term memories are not created in an instant. Gradual stabilization and temporally shifting dependence of acquired declarative memories in different brain regions called systems consolidation- can be tracked in time by lesion experiments. The observation of temporally graded retrograde amnesia(RA) following hippocampal lesions points to a gradual transfer of memory from hippocampus to neocortical long-term memory. Spontaneous reactivations of hippocampal memories, asobserved in place cell reactivations during slow wave- sleep, are supposed to driven eocortical reinstatements and facilitate this process. We proposea functional neural network implementation of these ideas and further more suggest anextended three-state framework that includes the prefrontal cortex( PFC). It bridges the temporal chasm between working memory percepts on the scale of seconds and consolidated long-term memory on the scale of weeks or months. Wes how that our three-stage model can autonomously produce the necessary stochastic reactivation dynamics for successful episodic memory consolidation. There sulting learning system is shown to exhibit classical memory effects seen in experimental studies, such as retrograde and anterograde amnesia(AA) after simulated hippocampal lesioning; further more the model reproduces peculiar biological findings on memory modulation, such as retrograde facilitation of memory after suppressed acquisition of new longterm memories- similar to the effects of benzodiazepines on memory.

  • 67.
    Fransén, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    A synapse which can switch from inhibitory to excitatory and back2005Inngår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 65, s. 39-45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Co-release of transmitters has recently been observed at synapse terminals and can even be a combination such as glutamate and GABA. A second recent experimental finding is a short-term synaptic plasticity, which depends on postsynaptic depolarization releasing a dendritic transmitter, which affects presynaptic release probability. In this work we are investigating the functional consequences for a synapse if it had both co-release and conditioning depression. If initially the GABA component is larger than the glutamate component, the synapse has an inhibitory net effect. However, if the postsynaptic cell is conditioned, the GABA component will be suppressed yielding an excitatory synapse.

  • 68.
    Fransén, Erik
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Coexistence of synchronized oscillatory and desynchronized rate activity in cortical networks2003Inngår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. apr-52, s. 763-769Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The basis of MRI and PET experiments is the finding that neuronal cell firing levels are modulated in a task dependent manner. Results from EEG and MEG experiments on the other hand point to the importance of synchrony, e.g. the peak frequency may depend on the difficulty of the task. In most models only one of these activity modes of firing is desirable or possible to produce. In this work we show how a cortical microcircuit can produce either synchronized or desynchronized firing, and how this solves problems of present day rate and synchronization models.

  • 69.
    Fransén, Erik
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Functional role of Entorhinal cortex in working memory and information processing of the medial temporal lobe2004Inngår i: 2004 IEEE INTERNATIONAL JOINT CONFERENCE ON NEURAL NETWORKS, VOLS 1-4, PROCEEDINGS, 2004, s. 621-624Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Our learning and memory system has the challenge to work in a world where items to learn are dispersed in space and time. From the information extracted by the perceptual systems, the learning system must select and combine information. Both these operations may require a temporary storage where significance and correlations may be assessed. This work builds on the common hypothesis that hippocampus and subicular, entorhinal and parahippocampal/postrhinal areas are essential for these functions. We bring up two examples of models, one modeling in vivo and in vitro data from entorhinal cortex layer II of delay match-to-sample working memory experiments, and one modeling slice data from layer V showing cellular "integrator-like" intrinsically generated stable graded levels of spiking activity. In both cases we discuss how cationic currents might be involved and relate their kinetics and pharmacology to behavioral and cellular experimental results.

  • 70.
    Fransén, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Numerisk Analys och Datalogi, NADA.
    Functional role of entorhinal cortex in working memory processing2005Inngår i: Neural Networks, ISSN 0893-6080, E-ISSN 1879-2782, Vol. 18, nr 9, s. 1141-1149Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Our learning and memory system has the challenge to work in a world where items to learn are dispersed in space and time. From the information extracted by the perceptual systems, the learning system must select and combine information. Both these operations may require a temporary storage where significance and correlations could be assessed. This work builds on the common hypothesis that hippocampus and subicular, entorhinal and parahippocampal/postrhinal areas are essential for the above-mentioned functions. We bring up two examples of models: the first one is modeling of in vivo and in vitro data from entorhinal cortex layer 11 of delayed match-to-sample working memory experiments, the second one studying mechanisms in theta rhythmicity in EC. In both cases, we discuss how cationic currents might be involved and relate their kinetics and pharmacology to behavioral and cellular experimental results.

  • 71.
    Fransén, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ionic Mechanisms in Peripheral Pain2014Inngår i: Computational Neuroscience / [ed] Blackwell, K.T., Elsevier, 2014, s. 23-51Kapittel i bok, del av antologi (Fagfellevurdert)
    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.

  • 72.
    Fransén, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Neural response profile design: Reducing epileptogenic activity by modifying neuron responses to synchronized input using novel potassium channels obtained by parameter search optimization2007Inngår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 70, nr 10-12, s. 1630-1634Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neurons obtain their dynamical electrical characteristics by a set of ion channels. These properties may not only affect the function of the neuron and the local network it forms part of, but it may also eventually affect behavior. We were interested to study whether epileptogenic activity could be reduced by adding an ion channel. In this work, we used computational search techniques to optimize ion channel properties for the goal of modifying neural response characteristics. Our results show that this type of parameter search is possible and reasonably efficient. Successful searches were generated using the direct method PRAXIS, and by systematic searches in low-dimensional sub-spaces. We also report on unsuccessful searches using a simplex-type method, a gradient-based method, and attempts to reduce goal function evaluation time. Importantly, using this search strategy, our study has shown that it is possible to change a neuron's characteristics selectively with regard to response to degree of synchronicity in synaptic input.

  • 73.
    Fransén, Erik A.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Mechanisms of Graded Persistent Activity: Implications for Epilepsy2008Inngår i: Computational Neuroscience in Epilepsy, Elsevier, 2008, s. 215-231Kapittel i bok, del av antologi (Annet vitenskapelig)
    Abstract [en]

    One major topic in epilepsy is factors contributing to neuronal excitability. This chapter considers depolarizing sources from cationic currents. These ion channels of the TRP-type are permeable to Na, K and sometimes Ca, and show a slow time dynamics. They can therefore provide the dendrites with integrative properties over seconds and perhaps even minutes. This makes them powerful as integrators of synaptic input. Further, their activation depends to a large degree on intracellular calcium. They may therefore during seizures become strongly activated and thereby further contribute to epileptogenic activity directly by depolarization and indirectly by their calcium permeability. Cationic currents are widely distributed throughout the nervous system, including cortical, cerebellar and subcortical neurons. This chapter describes the work in entorhinal cortex and, specifically, the plateau firing characteristics found in pyramidal cells of layer V. These cells show persistent action potential firing at plateaus, which may last over ten minutes. Intriguingly, these plateaus are graded in that input, synaptic or by current injection, can shift them up and down in frequency. After the original finding, graded plateaus have been found also in perirhinal cortex and amygdala. Functionally, cationic neuronal integrator capacity has been shown to be involved in sensory-motor integration. Finally, anticonvulsants like lamotrigine and phenytoin have been found to reduce depolarizations involving cationic currents. Cation currents may therefore be targets in treatments of epilepsy.

  • 74.
    Fransén, Erik
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ahlström, Peter
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Ionic mechanisms of post spike excitability changes during high-frequency firing rates2014Inngår i: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 5, nr 3, s. 208-Artikkel i tidsskrift (Fagfellevurdert)
  • 75.
    Fransén, Erik
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Alonso, A. A.
    Dickson, C. T.
    Magistretti, J.
    Hasselmo, M. E.
    Ionic mechanisms in the generation of subthreshold oscillations and action potential clustering in entorhinal layer II stellate neurons2004Inngår i: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 14, nr 3, s. 368-384Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A multi compartmental biophysical model of entorhinal cortex layer II stellate cells was developed to analyze the ionic basis of physiological properties, such as subthreshold membrane potential oscillations, action potential clustering, and the medium afterhyperpolarization. In particular, the simulation illustrates the interaction of the persistent sodium current (I-NaP) and the hyperpolarization activated inward current (I-h) in the generation of subthreshold membrane potential oscillations. The potential role of I-h in contributing to the medium hyperpolarization (mAHP) and rebound spiking was studied. The role of I-h and the slow calcium-activated potassium current I-K(AHP) in action potential clustering was also studied. Representations of I-h and I-NaP were developed with parameters based on voltage-clamp data from whole-cell patch and single channel recordings of stellate cells (Dickson et A, J Neurophysiol 83:2562-2579, 2000; Magistretti and Alonso, J Gen Physiol 114:491-509, 1999; Magistretti et al., J Physiol 521:629-636, 1999a; J Neurosci 19:7334-7341, 1999b). These currents interacted to generate robust subthreshold membrane potentials with amplitude and frequency corresponding to data observed in the whole cell patch recordings. The model was also able to account for effects of pharmacological manipulations, including blockade of I-h with ZD7288, partial blockade with cesium, and the influence of barium on oscillations. In a model with a wider range of currents, the transition from oscillations to single spiking, to spike clustering, and finally tonic firing could be replicated. In agreement with experiment, blockade of calcium channels in the model strongly reduced clustering. In the voltage interval during which no data are available, the model predicts that the slow component of I-h does not follow the fast component down to very short time constants. The model also predicts that the fast component of I-h is responsible for the involvement in the generation of subthreshold oscillations, and the slow component dominates in the generation of spike clusters.

  • 76.
    Fransén, Erik
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Alonso, A. A.
    Hasselmo, M. E.
    Entorhinal neuronal activity during delayed matching tasks may depend upon muscarinic-induced non-specific cation current I(CANM)2001Inngår i: Neurocomputing, ISSN 0925-2312, E-ISSN 1872-8286, Vol. 38, s. 601-606Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Biophysical compartmental models of stellate, pyramidal-like and interneurons in layer II of the rat entorhinal cortex were used to explore cellular and synaptic components involved in neuronal responses to stimuli in a delayed match to sample (DMS) task. Simulations demonstrate that the muscarinic receptor-induced non-specific cation current, I(CANM), could contribute to these phenomena. Facilitation of I(CANM) by calcium influx during spikes induced by the sample stimulus can cause enhanced responses for matches as well as delay activity. In a network, lateral inhibition can produce match suppression, and in conjunction with stimulus selective/non-selective cells produce non-match enhancement and suppression.

  • 77.
    Fransén, Erik
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Alonso, A. A.
    Hasselmo, M. E.
    Simulations of the role of the muscarinic-activated calcium-sensitive nonspecific cation current I-NCM in entorhinal neuronal activity during delayed matching tasks2002Inngår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 22, nr 3, s. 1081-1097Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Entorhinal lesions impair performance in delayed matching tasks, and blockade of muscarinic cholinergic receptors also impairs performance in these tasks. Physiological data demonstrate that muscarinic cholinergic receptor stimulation activates intrinsic cellular currents in entorhinal neurons that could underlie the role of entorhinal cortex in performance of these tasks. Here we use a network biophysical simulation of the entorhinal cortex to demonstrate the potential role of this cellular mechanism in the behavioral tasks. Simulations demonstrate how the muscarinic-activated calcium-sensitive nonspecific cation current I-NCM could provide a cellular mechanism for features of the neuronal activity observed during performance of delayed matching tasks. In particular, I-NCM could underlie (1) the maintenance of sustained spiking activity during the delay period, (2) the enhancement of spiking activity during the matching period relative to the sample period, and (3) the resistance of sustained activity to distractors. Simulation of a larger entorhinal network with connectivity chosen randomly within constraints on number, distribution, and weight demonstrates appearance of other phenomena observed in unit recordings from awake animals, including match suppression, non-match enhancement, and non-match suppression.

  • 78.
    Fransén, Erik
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Lansner, Anders
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    A model of cortical associative memory based on a horizontal network of connected columns1998Inngår i: Network, ISSN 0954-898X, E-ISSN 1361-6536, Vol. 9, nr 2, s. 235-264Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An attractor network model of cortical associative memory functions has been constructed and simulated. By replacing the single cell as the functional unit by multiple cells in cortical columns connected by long-range fibers, the model is improved in terms of correspondence with cortical connectivity. The connectivity is improved, since the original dense and symmetric connectivity of a standard recurrent network becomes sparse and asymmetric at the cell-to-cell level. Our simulations show that this kind of network, with model neurons of the Hodgkin-Huxley type arranged in columns, can operate as an associative memory in much the same way as previous models having simpler connectivity. The network shows attractor-like behaviour and performs the standard assembly operations despite differences in the dynamics introduced by the more detailed cell model and network structure. Furthermore, the model has become sufficiently detailed to allow evaluation against electrophysiological and anatomical observations. For instance, cell activities comply with experimental findings and reaction times are within biological and psychological ranges. By introducing a scaling model we demonstrate that a network approaching experimentally reported neuron numbers and synaptic distributions also could work like the model studied here.

  • 79.
    Fransén, Erik
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Tahvildari, B.
    Egorov, A. V.
    Hasselmo, M. E.
    Alonso, A. A.
    Mechanism of graded persistent cellular activity of entorhinal cortex layer V neurons2006Inngår i: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 49, nr 5, s. 735-746Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Working memory is an emergent property of neuronal networks, but its cellular basis remains elusive. Recent data show that principal neurons of the entorhinal cortex display persistent firing at graded firing rates that can be shifted up or down in response to brief excitatory or inhibitory stimuli. Here, we present a model of a potential mechanism for graded firing. Our multicompartmental model provides stable plateau firing generated by a nonspecific calcium-sensitive cationic (CAN) current. Sustained firing is insensitive to small variations in Ca2+ concentration in a neutral zone. However, both high and low Ca2+ levels alter firing rates. Specifically, increases in persistent firing rate are triggered only during high levels of calcium, while decreases in rate occur in the presence of low levels of calcium. The model is consistent with detailed experimental observations and provides a mechanism for maintenance of memory-related activity in individual neurons.

  • 80.
    Fransén, Erik
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Tigerholm, Jenny
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Role of A-type potassium currents in excitability, network synchronicity, and epilepsy2010Inngår i: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 20, nr 7, s. 877-887Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A-type potassium current (K-A). Epileptogenic activity comprises a rich repertoire of characteristics, one of which is synchronized activity of principal cells as revealed by occurrences of for instance fast ripples. Synchronized activity of this kind is particularly efficient in driving target cells into spiking. In the recipient cell, this synchronized input generates large brief compound excitatory postsynaptic potentials (EPSPs). The fast activation and inactivation of K-A lead us to hypothesize a potential role in suppression of such EPSPs. In this work, using computational modeling, we have studied the activation of K-A by synaptic inputs of different levels of synchronicity. We find that K-A participates particularly in suppressing inputs of high synchronicity. We also show that the selective suppression stems from the current's ability to become activated by potentials with high slopes. We further show that K-A suppresses input mimicking the activity of a fast ripple. Finally, we show that the degree of selectivity of K-A can be modified by changes to its kinetic parameters, changes of the type that are produced by the modulatory action of KChIPs and DPPs. We suggest that the wealth of modulators affecting K-A might be explained by a need to control cellular excitability in general and suppression of responses to synchronicity in particular. We also suggest that compounds changing K-A-kinetics may be used to pharmacologically improve epileptic status.

  • 81.
    Frintrop, Simone
    KTH, Skolan för datavetenskap och kommunikation (CSC), Datorseende och robotik, CVAP.
    VOCUS: A visual attention system for object detection and goal-directed search2006Inngår i: Lecture Notes in Computer Science, ISSN 0302-9743, E-ISSN 1611-3349, s. 1-228Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Visual attention is a mechanism in human perception which selects relevant regions from a scene and provides these regions for higher-level processing as object recognition. This enables humans to act effectively in their environment despite the complexity of perceivable sensor data. Computational vision systems face the same problem as humans: there is a large amount of information to be processed and to achieve this efficiently, maybe even in real-time for robotic applications, the order in which a scene is investigated must be determined in an intelligent way. A promising approach is to use computational attention systems that simulate human visual attention. This monograph introduces the biologically motivated computational attention system VOCUS (Visual Object detection with a Computational attention System) that detects regions of interest in images. It operates in two modes, in an exploration mode in which no task is provided, and in a search mode with a specified target. In exploration mode, regions of interest are defined by strong contrasts (e.g., color or intensity contrasts) and by the uniqueness of a feature. For example, a black sheep is salient in a flock of white sheep. In search mode, the system uses previously learned information about a target object to bias the saliency computations with respect to the target. In various experiments, it is shown that the target is on average found with less than three fixations, that usually less than five training images suffice to learn the target information, and that the system is mostly robust with regard to viewpoint changes and illumination variances. Furthermore, we demonstrate how VOCUS profits from additional sensor data: we apply the system to depth and reflectance data from a 3D laser scanner and show the advantages that the laser modes provide. By fusing the data of both modes, we demonstrate how the system is able to consider distinct object properties and how the flexibility of the system increases by considering different data. Finally, the regions of interest provided by VOCUS serve as input to a classifier that recognizes the object in the detected region. We show how and in which cases the classification is sped up and how the detection quality is improved by the attentional front-end. This approach is especially useful if many object classes have to be considered, a frequently occurring situation in robotics. VOCUS provides a powerful approach to improve existing vision systems by concentrating computational resources to regions that are more likely to contain relevant information. The more the complexity and power of vision systems increase in the future, the more they will profit from an attentional front-end like VOCUS.

  • 82.
    Frånberg, Mattias
    et al.
    KTH, Skolan för elektroteknik och datavetenskap (EECS). KTH, Centra, Science for Life Laboratory, SciLifeLab. Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden ; Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden.
    Lagergren, Jens
    KTH, Skolan för elektroteknik och datavetenskap (EECS), Beräkningsvetenskap och beräkningsteknik (CST). KTH, Centra, SeRC - Swedish e-Science Research Centre.
    Sennblad, Bengt
    Cardiovascular Medicine Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden ; Dept of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    BESIQ: A tool for discovering gene-gene and gene-environment interactions in genome-wide association studiesManuskript (preprint) (Annet vitenskapelig)
  • 83.
    Frånberg, Mattias
    et al.
    KTH, Skolan för elektroteknik och datavetenskap (EECS). KTH, Centra, Science for Life Laboratory, SciLifeLab. Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; Department of Numerical Analysis and Computer Science, Stockholm University, Stockholm, Sweden ; .
    Sabater-Lleal, Maria
    Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; Unit of Genomics of Complex Diseases, Institut d’Investigació Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain.
    Hamsten, Anders
    Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lagergren, Jens
    KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Centra, SeRC - Swedish e-Science Research Centre. KTH, Skolan för elektroteknik och datavetenskap (EECS).
    Sennblad, Bengt
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden ; .
    Discovering gene-environment interactions with LassoManuskript (preprint) (Annet vitenskapelig)
  • 84.
    George, Koshy
    et al.
    PES Univ, Dept Elect & Commun Engn, Bengaluru 560085, India.;PES Univ, PES Ctr Intelligent Syst, Bengaluru 560085, India..
    Mutalik, Prabhanjan
    KTH, Skolan för elektroteknik och datavetenskap (EECS).
    A Multiple Model Approach to Time-Series Prediction Using an Online Sequential Learning Algorithm2019Inngår i: IEEE Transactions on Systems, Man & Cybernetics. Systems, ISSN 2168-2216, E-ISSN 1349-2543, Vol. 49, nr 5, s. 976-990Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Time-series prediction is important in diverse fields. Traditionally, methods for time-series prediction were based on fixed linear models because of mathematical tractability. Researchers turned their attention to artificial neural networks due to their better approximation capability. In this paper, we use feedforward neural networks with a single hidden layer, and present a rather simple online sequential learning algorithm (OSLA) together with its proof. The convergence properties of this algorithm are those of the well-known recursive least squares algorithm. We demonstrate that the prediction performance is better than other OSLAs, and show that it is statistically different from them. In addition, we also present the multiple models, switching, and tuning methodology that enhances the prediction performance of the learning algorithm.

  • 85. Giocomo, Lisa M.
    et al.
    Zilli, Eric A.
    Fransén, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Hasselmo, Michael E.
    Temporal frequency of subthreshold oscillations scales with entorhinal grid cell field spacing2007Inngår i: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 315, nr 5819, s. 1719-1722Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Grid cells in layer II of rat entorhinal cortex fire to spatial locations in a repeating hexagonal grid, with smaller spacing between grid fields for neurons in more dorsal anatomical locations. Data from in vitro whole-cell patch recordings showed differences in frequency of subthreshold membrane potential oscillations in entorhinal neurons that correspond to different positions along the dorsal-to-ventral axis, supporting a model of physiological mechanisms for grid cell responses.

  • 86. Giordano, Bruno
    et al.
    Bresin, Roberto
    KTH, Skolan för datavetenskap och kommunikation (CSC), Tal, musik och hörsel, TMH, Musikakustik.
    Walking and playing: What's the origin of emotional expressiveness in music?2006Inngår i: Proceedings of the 9th International Conference on Music Perception & Cognition (ICMPC9), Bologna/Italy, August 22-26 2006 / [ed] Baroni, M.; Addessi, A. R.; Caterina, R.; Costa, M., Bologna: Bononia University Press, 2006, s. 436-Konferansepaper (Fagfellevurdert)
  • 87.
    Golumbeanu, Monica
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Applying Hidden Markov Models to RNA-seq data2013Rapport (Annet vitenskapelig)
    Abstract [en]

    Enterococcus faecalis is one of the most controversial commensal bacteria of the human intestinal flora that is also responsible for lethal nosocomial infections. Determining the factors that influence its pathogenicity is at present a great challenge. Cutting-edge approaches analyze the E. faecalis bacterium trough the next generation RNA-sequencing technology. Since next generation sequencing is recent and yields a large amount of data, there is a continuous need for appropriate statistical methods to interpret its output. We propose an approach based on hidden Markov models to explore RNA-seq data and show an example of how we can apply this statistical tool to detect transcription start sites. We compare this application with a previously developed method based on signal processing.

  • 88.
    Golumbeanu, Monica
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Statistical Analysis of PAR-CLIP data2013Independent thesis Advanced level (degree of Master (Two Years)), 60 poäng / 90 hpOppgave
    Abstract [en]

    From creation to its degradation, the RNA molecule is the action field of many binding proteins with different roles in regulation and RNA metabolism. Since these proteins are involved in a large number of processes, a variety of diseases are related to abnormalities occurring within the binding mechanisms. One of the experimental methods for detecting the binding sites of these proteins is PAR-CLIP built on the next generation sequencing technology. Due to its size and intrinsic noise, PAR-CLIP data analysis requires appropriate pre-processing and thorough statistical analysis.

    The present work has two main goals. First, to develop a modular pipeline for preprocessing PAR-CLIP data and extracting necessary signals for further analysis. Second, to devise a novel statistical model in order to carry out inference about presence of protein binding sites based on the signals extracted in the pre-processing step.

  • 89. Granholm, Viktor
    et al.
    Käll, Lukas
    Quality assessments of peptide-spectrum matches in shotgun proteomics2011Inngår i: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 11, nr 6, s. 1086-1093Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The peptide identification process in shotgun proteomics is most frequently solved with search engines. Such search engines assign scores that reflect similarity between the measured fragmentation spectrum and the theoretical spectra of the peptides of a given database. However, the scores from most search engines do not have a direct statistical interpretation. To understand and make use of the significance of peptide identifications, one must thus be familiar with some statistical concepts. Here, we discuss different statistical scores used to show the confidence of an identification and a set of methods to estimate these scores. We also describe the variance of statistical scores and imperfections of scoring functions of peptide-spectrum matches.

  • 90. Granholm, Viktor
    et al.
    Noble, William Stafford
    Käll, Lukas
    On using samples of known protein content to assess the statistical calibration of scores assigned to peptide-spectrum matches in shotgun proteomics2011Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 10, nr 5, s. 2671-2678Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In shotgun proteomics, the quality of a hypothesized match between an observed spectrum and a peptide sequence is quantified by a score function. Because the score function lies at the heart of any peptide identification pipeline, this function greatly affects the final results of a proteomics assay. Consequently, valid statistical methods for assessing the quality of a given score function are extremely important. Previously, several research groups have used samples of known protein composition to assess the quality of a given score function. We demonstrate that this approach is problematic, because the outcome can depend on factors other than the score function itself. We then propose an alternative use of the same type of data to validate a score function. The central idea of our approach is that database matches that are not explained by any protein in the purified sample comprise a robust representation of incorrect matches. We apply our alternative assessment scheme to several commonly used score functions, and we show that our approach generates a reproducible measure of the calibration of a given peptide identification method. Furthermore, we show how our quality test can be useful in the development of novel score functions.

  • 91.
    Gutierrez-Arenas, Omar
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Handling and Analyzing Meshed Rendering of Segmented Structures From 3D Image Stacks in Blender2015Inngår i: Neuroinformatics, ISSN 1539-2791, E-ISSN 1559-0089, Vol. 13, nr 2, s. 151-152Artikkel i tidsskrift (Annet vitenskapelig)
  • 92.
    Gutierrez-Arenas, Omar
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Eriksson, O.
    Hellgren Kotaleski, Jeanette
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Segregation and Crosstalk of D1 Receptor-Mediated Activation of ERK in Striatal Medium Spiny Neurons upon Acute Administration of Psychostimulants2014Inngår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 10, nr 1, s. e1003445-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The convergence of corticostriatal glutamate and dopamine from the midbrain in the striatal medium spiny neurons (MSN) triggers synaptic plasticity that underlies reinforcement learning and pathological conditions such as psychostimulant addiction. The increase in striatal dopamine produced by the acute administration of psychostimulants has been found to activate not only effectors of the AC5/cAMP/PKA signaling cascade such as GluR1, but also effectors of the NMDAR/Ca2+/RAS cascade such as ERK. The dopamine-triggered effects on both these cascades are mediated by D1R coupled to Golf but while the phosphorylation of GluR1 is affected by reductions in the available amount of Golf but not of D1R, the activation of ERK follows the opposite pattern. This segregation is puzzling considering that D1R-induced Golf activation monotonically increases with DA and that there is crosstalk from the AC5/cAMP/PKA cascade to the NMDAR/Ca2+/RAS cascade via a STEP (a tyrosine phosphatase). In this work, we developed a signaling model which accounts for this segregation based on the assumption that a common pool of D1R and Golf is distributed in two D1R/Golf signaling compartments. This model integrates a relatively large amount of experimental data for neurons in vivo and in vitro. We used it to explore the crosstalk topologies under which the sensitivities of the AC5/cAMP/PKA signaling cascade to reductions in D1R or Golf are transferred or not to the activation of ERK. We found that the sequestration of STEP by its substrate ERK together with the insensitivity of STEP activity on targets upstream of ERK (i.e. Fyn and NR2B) to PKA phosphorylation are able to explain the experimentally observed segregation. This model provides a quantitative framework for simulation based experiments to study signaling required for long term potentiation in MSNs.

  • 93.
    Hagrot, Erika
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Industriell bioteknologi. AdBIOPRO, VINNOVA Competence Centre for Advanced Bioproduction by Continuous Processing, Sweden.
    Oddsdóttir, Hildur Æsa
    KTH, Skolan för teknikvetenskap (SCI), Matematik (Inst.), Optimeringslära och systemteori.
    Mäkinen, Meeri
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Industriell bioteknologi. AdBIOPRO, VINNOVA Competence Centre for Advanced Bioproduction by Continuous Processing, Sweden.
    Forsgren, Anders
    KTH, Skolan för teknikvetenskap (SCI), Matematik (Inst.), Optimeringslära och systemteori.
    Chotteau, Véronique
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Industriell bioteknologi. AdBIOPRO, VINNOVA Competence Centre for Advanced Bioproduction by Continuous Processing, Sweden; WCPR, Wallenberg Centre for Protein Research, Sweden.
    Novel column generation-based optimization approach for poly-pathway kinetic model applied to CHO cell culture2019Inngår i: Metabolic Engineering Communications, ISSN 2214-0301, Vol. 8, artikkel-id e00083Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mathematical modelling can provide precious tools for bioprocess simulation, prediction, control and optimization of mammalian cell-based cultures. In this paper we present a novel method to generate kinetic models of such cultures, rendering complex metabolic networks in a poly-pathway kinetic model. The model is based on subsets of elementary flux modes (EFMs) to generate macro-reactions. Thanks to our column generation-based optimization algorithm, the experimental data are used to identify the EFMs, which are relevant to the data. Here the systematic enumeration of all the EFMs is eliminated and a network including a large number of reactions can be considered. In particular, the poly-pathway model can simulate multiple metabolic behaviors in response to changes in the culture conditions. We apply the method to a network of 126 metabolic reactions describing cultures of antibody-producing Chinese hamster ovary cells, and generate a poly-pathway model that simulates multiple experimental conditions obtained in response to variations in amino acid availability. A good fit between simulated and experimental data is obtained, rendering the variations in the growth, product, and metabolite uptake/secretion rates. The intracellular reaction fluxes simulated by the model are explored, linking variations in metabolic behavior to adaptations of the intracellular metabolism.

  • 94. Hahn, Gerald
    et al.
    Bujan, Alejandro F
    Frégnac, Yves
    Aertsen, Ad
    Kumar, Arvind
    Univ Freiburg, Germany.
    Communication through resonance in spiking neuronal networks2014Inngår i: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 10, nr 8, artikkel-id e1003811Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The cortex processes stimuli through a distributed network of specialized brain areas. This processing requires mechanisms that can route neuronal activity across weakly connected cortical regions. Routing models proposed thus far are either limited to propagation of spiking activity across strongly connected networks or require distinct mechanisms that create local oscillations and establish their coherence between distant cortical areas. Here, we propose a novel mechanism which explains how synchronous spiking activity propagates across weakly connected brain areas supported by oscillations. In our model, oscillatory activity unleashes network resonance that amplifies feeble synchronous signals and promotes their propagation along weak connections ("communication through resonance''). The emergence of coherent oscillations is a natural consequence of synchronous activity propagation and therefore the assumption of different mechanisms that create oscillations and provide coherence is not necessary. Moreover, the phase-locking of oscillations is a side effect of communication rather than its requirement. Finally, we show how the state of ongoing activity could affect the communication through resonance and propose that modulations of the ongoing activity state could influence information processing in distributed cortical networks.

  • 95.
    Halloran, John T.
    et al.
    Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA..
    Zhang, Hantian
    Swiss Fed Inst Technol, Dept Comp Sci, CH-8092 Zurich, Switzerland..
    Kara, Kaan
    Swiss Fed Inst Technol, Dept Comp Sci, CH-8092 Zurich, Switzerland..
    Renggli, Cedric
    Swiss Fed Inst Technol, Dept Comp Sci, CH-8092 Zurich, Switzerland..
    The, Matthew
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Zhang, Ce
    Swiss Fed Inst Technol, Dept Comp Sci, CH-8092 Zurich, Switzerland..
    Rocke, David M.
    Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA..
    Käll, Lukas
    KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Noble, William Stafford
    Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA.;Univ Washington, Paul Allen Sch Comp Sci & Engn, Seattle, WA 98195 USA..
    Speeding Up Percolator2019Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 18, nr 9, s. 3353-3359Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The processing of peptide tandem mass spectrometry data involves matching observed spectra against a sequence database. The ranking and calibration of these peptide-spectrum matches can be improved substantially using a machine learning postprocessor. Here, we describe our efforts to speed up one widely used postprocessor, Percolator. The improved software is dramatically faster than the previous version of Percolator, even when using relatively few processors. We tested the new version of Percolator on a data set containing over 215 million spectra and recorded an overall reduction to 23% of the running time as compared to the unoptimized code. We also show that the memory footprint required by these speedups is modest relative to that of the original version of Percolator.

  • 96.
    Hammarlund, Per
    et al.
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Ekeberg, Örjan
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Large neural network simulations on multiple hardware platforms1998Inngår i: Journal of Computational Neuroscience, ISSN 0929-5313, E-ISSN 1573-6873, Vol. 5, nr 4, s. 443-459Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To efficiently simulate very large networks of interconnected neurons, particular consideration has to be given to the computer architecture being used. This article presents techniques for implementing simulators for large neural networks on a number of different computer architectures. The neuronal simulation task and the computer architectures of interest are first characterized, and the potential bottlenecks are highlighted. Then we describe the experience gained from adapting an existing simulator, sWIM, to two very different architectures-vector computers and multiprocessor workstations. This work lead to the implementation of a new simulation library, SPLIT, designed to allow efficient simulation of large networks on several architectures. Different computer architectures put different demands on the organization of both data structures and computations. Strict separation of such architecture considerations from the neuronal models and other simulation aspects makes it possible to construct both portable and extendible code.

  • 97.
    Harischandra, Nalin
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Computer Simulation of the Neural Control of Locomotion in the Cat and the Salamander2011Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Locomotion is an integral part of a whole range of animal behaviours. The basic rhythm for locomotion in vertebrates has been shown to arise from local networks residing in the spinal cord and these networks are known as central pattern generators (CPG). However, during the locomotion, these centres are constantly interacting with the sensory feedback signals coming from muscles, joints and peripheral skin receptors in order to adapt the stepping or swimming to varying environmental conditions. Conceptual models of vertebrate locomotion have been constructed using mathematical models of locomotor subsystems based on the neurophysiological evidence obtained primarily in the cat and the salamander, an amphibian with a sprawling posture. Such models provide opportunity for studying the key elements in the transition from aquatic to terrestrial locomotion. Several aspects of locomotor control using the cat or the salamander as an animal model have been investigated employing computer simulations and here we use the same approach to address a number of questions or/and hypotheses related to rhythmic locomotion in quadrupeds. Some of the involved questions are, the role of mechanical linkage during deafferented walking, finding inherent stabilities/instabilities of muscle-joint interactions during normal walking and estimating phase dependent controlability of muscle action over joints. Also we investigate limb and body coordination for different gaits, use of side-stepping in front limbs for turning and the role of sensory feedback in gait generation and transitions in salamanders.

         This thesis presents the basics of the biologically realistic models of cat and salamander locomotion and summarizes computational methods in modeling quadruped locomotor subsystems such as CPG, limb muscles and sensory pathways. In the case of cat hind limb, we conclude that the mechanical linkages between the legs play a major role in producing the alternating gait. In another experiment we use the model to identify open-loop linear transfer functions between muscle activations and joint angles while ongoing locomotion. We hypothesize that the musculo-skeletal system for locomotion in animals, at least in cats, operates under critically damped condition.

         The 3D model of the salamander is successfully used to mimic locomotion on level ground and in water. We compare the walking gait with the trotting gait in simulations. We also found that for turning, the use of side-stepping alone or in combination with trunk bending is more effective than the use of trunk bending alone. The same model together with a more realistic CPG composed of spiking neurons was used to investigate the role of sensory feedback in gait generation and transition. We found that the proprioceptive sensory inputs are essential in obtaining the walking gait, whereas the trotting gait is more under central (CPG) influence compared to that of the peripheral or sensory feedback.

         This thesis work sheds light on understanding the neural control mechanisms behind vertebrate locomotion. Additionally, both neuro-mechanical models can be used for further investigations in finding new control algorithms which give robust, adaptive, efficient and realistic stepping in each leg, which would be advantageous since it can be implemented on a controller of a quadruped-robotic device.

  • 98.
    Harischandra, Nalin
    et al.
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Cabelguen, Jean-Marie
    Neurocentre Magendie, Bordeaux University, Bordeaux Cedex, France.
    Ekeberg, Örjan
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    A 3D musculo-mechanical model of the salamander for the study of different gaits and modes of locomotion2010Inngår i: Frontiers in neurorobotics, ISSN 1662-5218, Vol. 4, s. 112-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Computer simulation has been used to investigate several aspects of locomotion in salamanders. Here we introduce a three-dimensional forward dynamics mechanical model of a salamander, with physically realistic weight and size parameters. Movements of the four limbs and of the trunk and tail are generated by sets of linearly modeled skeletal muscles. In this study, activation of these muscles were driven by prescribed neural output patterns. The model was successfully used to mimic locomotion on level ground and in water. We compare the walking gait where a wave of activity in the axial muscles travels between the girdles, with the trotting gait in simulations using the musculo-mechanical model. In a separate experiment, the model is used to compare different strategies for turning while stepping; either by bending the trunk or by using side-stepping in the front legs. We found that for turning, the use of side-stepping alone or in combination with trunk bending, was more effective than the use of trunk bending alone. We conclude that the musculo-mechanical model described here together with a proper neural controller is useful for neuro-physiological experiments in silico.

  • 99. Hasselmo, M. E.
    et al.
    Fransén, Erik
    KTH, Tidigare Institutioner, Numerisk analys och datalogi, NADA.
    Dickson, C.
    Alonso, A. A.
    Computational modeling of entorhinal cortex2000Inngår i: PARAHIPPOCAMPAL REGION: IMPLICATIONS FOR NEUROLOGICAL AND PSYCHIATRIC DISEASES / [ed] Scharfman, HE; Witter, MP; Schwarcz, R, NEW YORK: New York Academy of Sciences, 2000, Vol. 911, s. 418-446Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Computational modeling provides a means for linking the physiological and anatomical characteristics of entorhinal cortex at a cellular level to the functional role of this region in behavior. We have developed detailed simulations of entorhinal cortical neurons and networks, with an emphasis on the role of acetylcholine in entorhinal cortical function. Computational modeling suggests that when acetylcholine levels are high, this sets appropriate dynamics for the storage of stimuli during performance of delayed matching tasks. In particular, acetylcholine activates a calcium-sensitive nonspecific cation current which provides an intrinsic cellular mechanism which could maintain neuronal activity across a delay period. Simulations demonstrate how this phenomena could underlie entorhinal cortex delay activity as described in previous unit recordings. Acetylcholine also induces theta rhythm oscillations which may be appropriate for timing of afferent input to be encoded in hippocampus and for extraction of individual stored sequences from multiple stored sequences. Lower levels of acetylcholine may allow sharp wave dynamics which can reactivate associations encoded in hippocampus and drive the formation of additional traces in hippocampus and entorhinal cortex during consolidation.

  • 100. Hasselmo, Michael E.
    et al.
    Brandon, Mark P.
    Yoshida, Motoharu
    Giocomo, Lisa M.
    Heys, James G.
    Fransén, Erik
    KTH, Skolan för datavetenskap och kommunikation (CSC), Beräkningsbiologi, CB.
    Newman, Ehren L.
    Zilli, Eric A.
    A phase code for memory could arise from circuit mechanisms in entorhinal cortex2009Inngår i: Neural Networks, ISSN 0893-6080, E-ISSN 1879-2782, Vol. 22, nr 8, s. 1129-1138Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Neurophysiological data reveals intrinsic cellular properties that suggest how entorhinal cortical neurons could code memory by the phase of their firing. Potential cellular mechanisms for this phase coding in models of entorhinal function are reviewed. This mechanism for phase coding provides a substrate for modeling the responses of entorhinal grid cells, as well as the replay of neural spiking activity during waking and sleep. Efforts to implement these abstract models in more detailed biophysical compartmental simulations raise specific issues that could be addressed in larger scale population models incorporating mechanisms of inhibition.

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