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  • 1. Brodin, L
    et al.
    Shupliakov, O
    Pieribone, V
    Hellgren Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Hill, R.H.
    The reticulospinal glutamate synapse in lamprey: plasticity and presynaptic variability1994In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 72, p. 592-604Article in journal (Refereed)
    Abstract [en]

    1. The glutamatergic synapses formed between the unbranched giant reticulospinal axons onto spinal neurons in lamprey offer a central vertebrate synapse in which the presynaptic element can be impaled with one or several microelectrodes, which may be used for recording as well as microinjection of different substances. To provide a basis for the use of this synapse in studies of release mechanisms, we have examined the use-dependent modulation of the synaptic response under conditions of conventional cell body stimulation, and during direct stimulation of the presynaptic axon. 2. To examine the stability of the mixed electrotonic and chemical reticulospinal excitatory postsynaptic potential (EPSP) over time, action potentials were evoked at a rate of 1 Hz for 800-1000 trials. In three out of seven synapses the chemical component remained at a similar amplitude, while in four cases a progressive decrease (up to 35%) occurred. The electrotonic component remained at a similar amplitude in all cases. 3. During paired pulse stimulation of the reticulospinal cell body (pulse interval 65 ms) the chemical EPSP component showed a net facilitation in all cases tested [from 0.64 +/- 0.35 to 0.89 +/- 0.48 (SD) mV, n = 13], while the peak amplitude of the electrotonic component was unchanged (1.37 +/- 0.68 and 1.36 +/- 0.66 mV, respectively). Recording of the axonal action potential during paired pulse stimulation showed that the width of the first and second action potential did not differ [1/2 width (2.48 +/- 0.39 ms and 2.48 +/- 0.42 ms, respectively; n = 8)]. 4. The degree of facilitation varied markedly between different synapses, ranging from an increase of a few percent to a two-fold increase (24 +/- 16% mean change of total EPSP amplitude, corresponding to 44 +/- 26% mean change of chemical EPSP amplitude). This type of variability was also observed in synapses made from the same unbranched reticulospinal axon onto different postsynaptic cells. 5. When paired pulse stimulation was applied to the reticulospinal axon in the very vicinity of the synaptic area (0.1-1 mm) a net depression of the chemical component occurred in 11 out of 19 cases, and in the remaining cases the level of net facilitation was lower as compared with cell body stimulation (range between +17 and -23% change of total EPSP amplitude; mean -5%; n = 19). 6. To test if the change of the EPSP plasticity during local stimulation correlated with an increased transmitter release, two microelectrodes were placed in the same reticulospinal axon at different distances from the synaptic area.(ABSTRACT TRUNCATED AT 400 WORDS)

  • 2. Dickson, C. T.
    et al.
    Magistretti, J.
    Shalinsky, M. H.
    Fransén, Erik
    KTH, Superseded Departments, Numerical Analysis and Computer Science, NADA.
    Hasselmo, M. E.
    Alonso, A.
    Properties and role of I-h in the pacing of subthreshold oscillations in entorhinal cortex layer II neurons2000In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 83, no 5, p. 2562-2579Article, review/survey (Refereed)
    Abstract [en]

    Various subsets of brain neurons express a hyperpolarization-activated inward current (I-h) that has been shown to be instrumental in pacing oscillatory activity at both a single-cell and a network level. A characteristic feature of the stellate cells (SCs) of entorhinal cortex (EC) layer II, those neurons giving rise to the main component of the perforant path input to the hippocampal formation, is their ability to generate persistent, Na+-dependent rhythmic subthreshold membrane potential oscillations, which are thought to be instrumental in implementing theta rhythmicity in the entorhinal-hippocampal network. The SCs also display a robust time-dependent inward rectification in the hyperpolarizing direction that may contribute to the generation of these oscillations. We performed whole cell recordings of SCs in in vitro slices to investigate the specific biophysical and pharmacological properties of the current underlying this inward rectification and to clarify its potential role in the genesis of the subthreshold oscillations. In voltage-clamp conditions, hyperpolarizing voltage steps evoked a slow, noninactivating inward current, which also deactivated slowly on depolarization. This current was identified as I-h because it was resistant to extracellular Ba2+, sensitive to Cs+, completely and selectively abolished by ZD7288, and carried by both Na+ and K+ ions. I-h in the SCs had an activation threshold and reversal potential at approximately -45 and -20 mV, respectively. Its half-activation voltage was -77 mV. Importantly, bath perfusion with ZD7288, but not Ba2+ gradually and completely abolished the subthreshold oscillations, thus directly implicating I-h in their generation. Using experimentally derived biophysical parameters for I-h and the low-threshold persistent Na+ current (I-NaP) present in the SCs, a simplified model of these neurons was constructed and their subthreshold electroresponsiveness simulated. This indicated that the interplay between I-NaP and I-h can sustain persistent subthreshold oscillations in SCs. I-NaP and I-h operate in a push-pull fashion where the delay in the activation/deactivation of I-h gives rise to the oscillatory process.

  • 3.
    Ekeberg, Örjan
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, 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 transition2005In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 94, no 6, p. 4256-4268Article in journal (Refereed)
    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.

  • 4.
    Fagergren, Anders
    et al.
    Karolinska Institutet.
    Ekeberg, Örjan
    KTH, Superseded Departments (pre-2005), Numerical Analysis and Computer Science, NADA.
    Forssberg, Hans
    Karolinska Institutet.
    Control strategies correcting inaccurately programmed fingertip forces: Model predictions derived from human behavior2003In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 89, no 6, p. 2904-2916Article in journal (Refereed)
    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.

  • 5.
    Filipovic, Marko
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). Univ Freiburg, Bernstein Ctr Freiburg, Freiburg, Germany;Univ Freiburg, Fac Biol, Freiburg, Germany.
    Ketzef, Maya
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Reig, Ramon
    CSIC, Inst Neurociencias, Alacant, Spain.;Univ Miguel Hernandez, Alacant, Spain..
    Aertsen, Ad
    Univ Freiburg, Bernstein Ctr Freiburg, Freiburg, Germany.;Univ Freiburg, Fac Biol, Freiburg, Germany..
    Silberberg, Gilad
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Kumar, Arvind
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Direct pathway neurons in mouse dorsolateral striatum in vivo receive stronger synaptic input than indirect pathway neurons2019In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 122, no 6, p. 2294-2303Article in journal (Refereed)
    Abstract [en]

    Striatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1- or D2-type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modeling of the suiatal network has predicted that under healthy conditions dMSNs should receive more total input than iMSNs. To test this prediction, we analyzed in vivo whole cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (60HDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials. we found that dMSNs depolarized toward the spike threshold significantly faster than iMSNs did. Together, these findings (in particular the STA analysis) corroborate the theoretical prediction that direct-pathway MSNs receive stronger total input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question of how the lack of dopamine may lead to behavioral deficits associated with Parkinson's disease. NEW & NOTEWORTHY The direct and indirect pathways of the basal ganglia originate from the D1- and D2-type dopamine receptor expressing medium spiny neurons (dMSNs and iMSNs). Theoretical results have predicted that dMSNs should receive stronger synaptic input than iMSNs. Using in vivo intracellular membrane potential data, we provide evidence that dMSNs indeed receive stronger input than iMSNs, as has been predicted by the computational model.

  • 6.
    Hellgren Kotaleski, Jeanette
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Plenz, D.
    Blackwell, K. T.
    Using potassium currents to solve signal-to-noise problems in inhibitory feedforward networks of the striatum2006In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 95, no 1, p. 331-341Article in journal (Refereed)
    Abstract [en]

    Using potassium currents to solve signal-to-noise problems in inhibitory feedforward networks of the striatum. J Neurophysiol 95: 331 - 341, 2006. First published September 28, 2005; doi: 10.1152/jn. 00063.2005. Fast-spiking (FS) interneurons provide the main route of feedforward inhibition from cortex to spiny projection neurons in the striatum. A steep current-firing frequency curve and a dense local axonal arbor suggest that even small excitatory inputs could translate into powerful feedforward inhibition, although such an arrangement is also sensitive to amplification of spurious synaptic inputs. We show that a transient potassium (KA) current allows the FS interneuron to strike a balance between sensitivity to correlated input and robustness to noise, thereby increasing its signal-to-noise ratio (SNR). First, a compartmental FS neuron model was created to match experimental data from striatal FS interneurons in cortex - striatum - substantia nigra organotypic cultures. Densities of sodium, delayed rectifier, and KA channels were optimized to replicate responses to somatic current injection. Spontaneous alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and gamma-aminobutyric acid ( GABA) synaptic currents were adjusted to the experimentally measured amplitude, rise time, and interevent interval histograms. Second, two additional adjustments were required to emulate the remaining experimental observations. GABA channels were localized closer to the soma than AMPA channels to match the synaptic population reversal potential. Correlation among inputs was required to produce the observed firing rate during up-states. In this final model, KA channels were essential for suppressing down-state spikes while allowing reliable spike generation during up-states. This mechanism was particularly important under conditions of high dopamine. Our results suggest that KA channels allow FS interneurons to operate without a decrease in SNR during conditions of increased dopamine, as occurs in response to reward or anticipated reward.

  • 7.
    Huss, Mikael
    et al.
    KTH, School of Computer Science and Communication (CSC), Numerical Analysis and Computer Science, NADA. KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Lansner, Anders
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Wallén, Peter
    Department of Neuroscience, Nobel Institute for Neurophysiology, Karolinska Institutet.
    El Manira, Abdeljabbar
    Department of Neuroscience, Nobel Institute for Neurophysiology, Karolinska Institutet.
    Grillner, Sten
    Department of Neuroscience, Nobel Institute for Neurophysiology, Karolinska Institutet.
    Hellgren Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Roles of ionic currents in lamprey CPG neurons: a modeling study2007In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 97, no 4, p. 2696-2711Article in journal (Refereed)
    Abstract [en]

    The spinal network underlying locomotion in the lamprey consists of a core network of glutamatergic and glycinergic interneurons, previously studied experimentally and through mathematical modeling. We present a new and more detailed computational model of lamprey locomotor network neurons, based primarily on detailed electrophysiological measurements and incorporating new experimental findings. The model uses a Hodgkin Huxley-like formalism and consists of 86 membrane compartments containing 12 types of ion currents. One of the goals was to introduce a fast, transient potassium current (K-t) and two sodium-dependent potassium currents, one faster (K-NaF) and one slower (K-NaS), in the model. Not only has the model lent support to the interpretation of experimental results but it has also provided predictions for further experimental analysis of single-network neurons. For example, K-t was shown to be one critical factor for controlling action potential duration. In addition, the model has proved helpful in investigating the possible influence of the slow afterhyperpolarization on repetitive firing during ongoing activation. In particular, the balance between the simulated slow sodium-dependent and calcium-dependent potassium currents has been explored, as well as the possible involvement of dendritic conductances.

  • 8. Tegner, J
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Lansner, A
    Grillner, S
    Low voltage activated calcium channels in the lamprey locomotor network - simulation and experiment1997In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 77, p. 1795-1812Article in journal (Refereed)
    Abstract [en]

    To evaluate the role of low-voltage-activated (LVA) calcium channels in the lamprey spinal locomotor network, a previous computer simulation model has been extended to include LVA calcium channels. It is also of interest to explore the consequences of a LVA conductance for the electrical behavior of the single neuron. The LVA calcium channel was modeled with voltage-dependent activation and inactivation using the m3h form, following a Hodgkin-Huxley paradigm. Experimental data from lamprey neurons was used to provide parameter values of the single cell model. The presence of a LVA calcium conductance in the model could account for the occurrence of a rebound depolarization in the simulation model. The influence of holding potential on the occurrence of a rebound as well the latency at which it is elicited was investigated and compared with previous experiments. The probability of a rebound increased at a more depolarized holding potential and the latency was also reduced under these conditions. Furthermore, the effect of changing the holding potential and the reversal potential of the calcium dependent potassium conductance were tested to determine under which conditions several rebound spikes could be elicited after a single inhibitory pulse in the simulation model. A reduction of the slow afterhyperpolarization (sAHP) after the action potential reduced the tendency for a train of rebound spikes. The experimental effects of gamma-aminobutyric acid-B (GABA(B)) receptor activation were simulated by reducing the maximal LVA calcium conductance. A reduced tendency for rebound firing and a slower rising phase with sinusoidal current stimulation was observed, in accordance with earlier experiments. The effect of reducing the slow afterhyperpolarization and reducing the LVA calcium current was tested experimentally in the lamprey spinal cord, during N-methyl-D-aspartate (NMDA)-induced fictive locomotion. The reduction of burst frequency was more pronounced with GABA(B) agonists than with apamin (inhibitor of K(Ca) current) when using high NMDA concentration (high burst frequency). The burst frequency increased after the addition of a LVA calcium current to the simulated segmental network, due to a faster recovery during the inhibitory phase as the activity switches between the sides. This result is consistent with earlier experimental findings because GABA(B) receptor agonists reduce the locomotor frequency. These results taken together suggest that the LVA calcium channels contribute to a larger degree with respect to the burst frequency regulation than the sAHP mechanism at higher burst frequencies. The range in which a regular burst pattern can be simulated is extended in the lower range by the addition of LVA calcium channels, which leads to more stable activity at low locomotor frequencies. We conclude that the present model can account for rebound firing and trains of rebound spikes in lamprey neurons. The effects of GABA(B) receptor activation on the network level is consistent with a reduction of the calcium current through LVA calcium channels even though GABA(B) receptor activation will affect the sAHP indirectly and also presynaptic inhibition.

  • 9. Tegner, Jesper
    et al.
    Hellgren Kotaleski, Jeanette
    KTH, Superseded Departments, Numerical Analysis and Computer Science, NADA.
    Lansner, Anders
    KTH, Superseded Departments, Numerical Analysis and Computer Science, NADA.
    Grillner, Sten
    Low-voltage-activated calcium channels in the lamprey locomotor network: Simulation and experiment1997In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 77, no 4, p. 1795-1812Article in journal (Refereed)
    Abstract [en]

    To evaluate the role of low-voltage-activated (LVA) calcium channels in the lamprey spinal locomotor network, a previous computer simulation model has been extended to include LVA calcium channels. It is also of interest to explore the consequences of a LVA conductance for the electrical behavior of the single neuron. The LVA calcium channel was modeled with voltage-dependent activation and inactivation using the m(3)h form, following a Hodgkin-Huxley paradigm. Experimental data from lamprey neurons was used to provide parameter values of the single cell model. The presence of a LVA calcium conductance in the model could account for the occurrence of a rebound depolarization in the simulation model. The influence of holding potential on the occurrence of a rebound as well the latency at which it is elicited was investigated and compared with previous experiments. The probability of a rebound increased at a more depolarized holding potential and the latency was also reduced under these conditions. Furthermore, the effect of changing the holding potential and the reversal potential of the calcium dependent potassium conductance were tested to determine under which conditions several rebound spikes could be elicited after a single inhibitory pulse in the simulation model. A reduction of the slow afterhyperpolarization (sAHP) after the action potential reduced the tendency for a train of rebound spikes. The experimental effects of gamma-aminobutyric acid-B (GABA(B)) receptor activation were simulated by reducing the maximal LVA calcium conductance. A reduced tendency for rebound firing and a slower rising phase with sinusoidal current stimulation was observed, in accordance with earlier experiments. The effect of reducing the slow afterhyperpolarization and reducing the LVA calcium current was tested experimentally in the lamprey spinal cord, during N-methyl-D-aspartate (NMDA)-induced fictive locomotion. The reduction of burst frequency was more pronounced with GABA(B) agonists than with apamin (inhibitor of K-(Ca) current) when using high NMDA concentration (high burst frequency). The burst frequency increased after the addition of a LVA calcium current to the simulated segmental network, due to a faster recovery during the inhibitory phase as the activity switches between the sides. This result is consistent with earlier experimental findings because GABA(B) receptor agonists reduce the locomotor frequency. These results taken together suggest that the LVA calcium chancels contribute to a larger degree with respect to the burst frequency regulation than the sAHP mechanism at higher burst frequencies. The range in which a regular burst pattern can be simulated is extended in the lower range by the addition of LVA calcium channels, which leads to more stable activity at low locomotor frequencies. We conclude that the present model can account for rebound firing and trains of rebound spikes in lamprey neurons. The effects of GABA(B) receptor activation on the network level is consistent with a reduction of the calcium current through LVA calcium channels even though GABA(B) receptor activation will affect the sAHP indirectly and also presynaptic inhibition.

  • 10.
    Tigerholm, Jenny
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm Brain Institute, Stockholm, Sweden.
    Petersson, Marcus
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm Brain Institute, Stockholm, Sweden.
    Obreja, Otilia
    Anaesthesiology, Universitaetsmedizin Mannheim, Univ. of Heidelberg.
    Lampert, Angelika
    Inst. of Physiol. and Pathophysiology, Friedrich-Alexander-Uni versität Erlangen-Nürnberg.
    Carr, Richard
    Anaesthesiology, Universitaetsmedizin Mannheim, Univ. of Heidelberg.
    Schmelz, Martin
    Anaesthesiology, Universitaetsmedizin Mannheim, Univ. of Heidelberg,.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB. Stockholm Brain Institute, Stockholm, Sweden.
    Modeling activity-dependent changes of axonal spike conduction in primary afferent C-nociceptors2014In: Journal of Neurophysiology, ISSN 0022-3077, E-ISSN 1522-1598, Vol. 111, no 9, p. 1721-1735Article in journal (Refereed)
    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.

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