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Bistability and Hysteresis of Sodium Channels at Neuromuscular Junction
Get PDFAll voluntary movements in mammals are accomplished by muscles which are controlled by the brain through a specialized synapse called neuromuscular junction (NMJ). To have full control over the movement disorders caused due to dysfunctions of neuromuscular junction (e.g., Myasthenia Gravis, Lambert-Eaton Myasthenic Syndrome) and for the engineering of rehabilitation neuroprosthetic devices, a clear knowledge about the neuromuscular junction transmission mechanism during the communication between the neuron and the muscle is essential.
The NMJ is the place where the axon terminal of a motor neuron and the motor endplate of a muscle fiber meet creating a synapse. The pulse carried by the presynaptic neuron when reaches the synapse causes release of Acetylcholine (ACh) into the synaptic cleft which binds to the AChR at the motor end plate causing the sodium ions to flow in and potassium ions to flow out of the muscle's cytosol producing a local depolarization of the motor end plate called end-plate synaptic potential. The extracellular potential in the narrow extracellular space between nerve cell and muscle fiber (cleft) is affected by the current flow generated by the opening of sodium channels; consequently, voltage-dependent processes may be affected in the adjacent membranes. This phenomenon of current passing through weakly opened sodium channels and decreasing the potential of the extracellular space by boosting channels activation and by a positive feedback is termed “self-gating”. According to this hypothesis applied to NMJ, the extracellular voltage drop in the cleft may modify the voltages across the muscle fiber membrane, thus increasing the probability of opening the voltage-gated ion channels.
In the last few decades some mathematical models of NMJ have been derived considering different aspects. But in the existing models the effect of voltage in the cleft is left unnoticed. The proposed model incorporates the voltage of the synaptic cleft and self-gating effect of the sodium channel at the NMJ to study for the NMJ properties of rat and frog.
In modeling the NMJ a barrel shaped muscle is considered (50 μm diameter × 500 μm long). To form a synapse, an axon terminal is connected to the highly-excitable muscle fiber with a synaptic cleft (distance: 50 nm). The potential at the cleft (Vj) is calculated using the sodium conductance of the endplate motoneuron (global conductance) and the resistance of the cleft. The Acetylcholine Receptor current (AChR) together with the endplate sodium current (EPINa) act as stimulus current for the Hodgkin-Huxley based membrane potential (Vm) calculation at the muscle fiber.
The conductance associated to the voltage-gated sodium channels depends on the voltage drop between the potentials of the junction and the membrane. The junction potential calculated for different membrane potentials shows that the voltage-dependent sodium conductance at the NMJ demonstrates self-gating behavior. This is mainly due to the drop of junction potential in the synaptic cleft caused by depolarization of the muscle membrane.
We have studied the activation, inactivation, voltage and time dependency of recovery from inactivation of sodium channel and voltage and time dependent Hodgkin-Huxley model parameters under voltage clamp condition for both self-gating and non-self-gating states to check out the effect of junction potential drop in the muscle membrane. Some action potential generation based performance i.e., Overshoot, Maximum Rate of Rise have been evaluated. Implications for the firing frequency have been addressed. A Radius-Conductance factor has been proposed to get a clear idea about the relation among the size of the radius of the motorneuron, maximum sodium conductance and the AChR based stimulus current.
The proposed transmission model considering the contribution of sodium channels at the muscle membrane infolds and extracellular voltages in the cleft detect the ability of neuromuscular transmission to remain effective under various physiological conditions and stresses (safety-factor) of the NMJ around 15%.
During the self-gating condition a switching behavior was noticed in the sodium channels conductance: from low to high during depolarization and from high to low during repolarization of membrane potential. At this time bistability and hysteresis of sodium channels occurred which explains the transmission efficiency of the NMJ under self-gating condition.
The remedies of several NMJ diseases (i. e., Myasthenia Gravis, Lembert-Eaton Myasthenic Syndrome) are also hampered by limited understanding of the transmission process at the NMJ. The proposed model explores the transmission mechanism at the NMJ and may be used to plan therapy for such diseases. However, more experimental validations have to be performed before implementing it at clinical level. Also, the model may contribute to the engineering of bio-inspired neuroprosthetic devices for rehabilitation and therapy in patients with motor impairments.I movimenti volontari nel muscolo di mammifero sono controllati dal cervello tramite una sinapsi specializzata: la giunzione neuro-muscolare (NMJ). Al fine di comprendere nel dettaglio le origini fisiopatologiche di disfunzioni di questa giunzione (ad es. Miastenia Gravis, Sindrome miastenica di Lambert-Eaton) e per favorire l’ingegnerizzazione di raffinate neuroprotesi a scopo riabilititativo, è necessario approfondire le nostre conoscenze sull’esatto meccanismo di comunicazione tra neurone e muscolo a livello dell NMJ.
La NMJ è la sede in cui il terminale assonico di un motoneurone e la membrana post-sinaptica della fibra muscolare si giustappongono per creare una sinapsi. L’impulso inviato dal neurone pre-sinaptico causa un rilascio del neurotrasmettitore, l’acetilcolina, nella fessura sinaptica che, a sua volta, induce un potenziale intracellulare post-sinaptico nella fibra muscolare. Il potenziale extracellulare nello spazio sinaptico è influenzato dalla corrente ionica generata dall’apertura di canali del sodio voltaggio-dipendenti localizzati nelle pieghe post-giunzionali della NMJ (v. dopo). Di conseguenza, il gating voltaggio-dipendente degli stessi canali può essere influenzato dal voltaggio extracellulare. Questo fenomeno in cui correnti che passano attraverso canali del sodio diminuendo il potenziale extracellulare e attivando i canali con meccanismo a feed-back positivo, viene chaimato “self-gating”. Secondo questa ipotesi, applicata alla NMJ, la caduta del voltaggio extracellulare potrebbe modificare il potenziale transmemebrana a livello della fibra e aumentare la probabilità di apertura dei canali del sodio.
Negli ultimi decenni sono stati proposti alcuni modelli matematici della NMJ, ma nessuno ha considerato il potenziale ruolo del potenziale extracellulare nello spazio sinaptico della giunzione. Il modello proposato in questa tesi prende in considerazione questo effetto, simulando il comportamento della NMJ nel caso del ratto e della rana.
Nel simulare la NMJ, si è presa in considerazione una fibra di forma tubulare (diametro 50 μm e longhezza 500 μm). La sinapsi è costituita da un terminale assonico che si affaccia sulla membrana della fibra muscolare con una distanza di 50 nm. Il potenziale della giunzione (Vj) è calcolato usando la conduttanza del sodio della membrana post-sinaptica (conduttanza globale) e la resitenza della fessura sinaptica. La corrente del sodio nella membrana post-sinaptica (EPINa) è calcolata usando il ptenziale della giunzione e la conduttanza globale. Il recettore per l’acetilcolina (AChR) assieme con la EPINa agisce come corrente di stimolo per la fibra che viene simulata, da un punto di vista elettrico, mediante un modello di tipo Hodgkin-Huxley. La conduttanza associata ai canali voltaggio dipendenti dipende dalla caduta di potenziale tra l’esterno e l’interno della membrana post-sinaptica. Il potenziale nello spazio sinaptico della NMJ calcolato per diversi potenziali di membrana dimostra che la conduttanza dei canali voltaggio dipendenti del sodio ha un comportamento compatibile con un effetto di self-gating.
Abbiamo studiato l’attivazione, l’inattivazione e il recupero dall’inattivazione (e dei parametri Hodgkin-Huxley ad essi legati) in condizioni normali (di self-gating) e assumendo uno spazio sinaptico con distanza infinita (condizioni di non self-gating). In tal modo, abbiamo verificato l’effetto del potenziale extracellulare sul gating dei canali e sulla trasmissione sinaptica focalizzandoci su parametri del potenziale d’azione generato nella fibra muscolare quali l’overshoot, la massima velocità di salita e la frequenza di firing. E’ stato anche introdotto un fattore Raggio-Conduttanza per rendere più chiara e immediata la relazione tra la dimensione del raggio del terminale assonico del motoneurone, la conduttanza massima del sodio e la corrente di stimolo dovuta agli AChR. La dipendenza dal raggio della bistabilità dei canali è stata simulata. Il modello di trasmissione proposto, considerando il contributo dei canali del sodio nelle pieghe post-giunzionali e il potenziale extracellulare nella fessura sinaptica, dimostra la capacità della trasmissione neuromuscolare di rimanere efficace in varie condizioni fisiologiche e di stress, con un fattore di sicurezza (safety-factor) del 15%.
In condizioni di self-gating si può notare un comportamento di switching della conduttanza del sodio: da bassa a alta, durante la depolarizzazione e da alta a bassa durante la ripolarizzazione della fibra. Durante questo processo, si evidenziano bistabilità ed isteresi dei canali del sodio.
Le terapie per diverse patologie della NMJ (ad es. Miastenia Gravis, sindorme miastenica di Lambert-Eaton) sono limitate da incompleta caratterizzazione dei meccanismi che governano la trasmissione tra motoneurone e muscolo. Il modello qui proposto esplora il meccanismo di trasmissione nella NMJ e potrebbe essere usato in futuro per migliorare le terapie di queste patologie. Tuttavia, ulteriori validazioni sperimentali dovranno essere condotte. Inoltre, il modello potrebbe ispirare nuove e più efficienti neuroprotesi per pazienti con disabilità motorie
Thermophysical properties of methanol based nanofluids / Mohd. Mostafizur Rahman
Get PDFNanofluids are defined as colloidal suspension of solid particles with the size smaller than 100 nanometer. In this study, Al2O3, SiO2 and TiO2 nanoparticles were suspended into methanol without any surfactant to investigate their characteristics, stability and thermophysical properties. Nanoparticles size, shape, elemental proportion and suspension uniformity were characterized. The stability of methanol based nanofluids was analyzed using Uv-Vis spectrometer and zeta potential. Thermophysical properties of nanofluids, namely thermal conductivity, viscosity and density of nanofluids were measured by KD2 pro analyzer, LVDV III ultra–programmable rheometer and KEM-DA 130N density meter, respectively. All experiments were conducted at five different volume concentrations (0.005, 0.01, 0.05, 0.10 and 0.15 vol%) and five different temperatures (1, 5, 10, 15 and 20 ºC). In this study, Al2O3-methanol nanofluid appeared to be more stable compared to SiO2-methanol and TiO2-methanol nanofluids. It was found that thermal conductivity increased with the increase of volume concentration of nanoparticles for all types of nanoparticles. Thermal conductivity enhancements is shown between 1–8% for every 0.05 vol% increase with Al2O3 having the highest enhancement increase in nanoparticle volume concentration. Thermal conductivity also increased between 0.5–3.9% for every 5 °C increment in temperature with SiO2 showing the least change. The shear stress and viscosity increased with volume concentration but decreased with increase in temperature and shear rate. The results showed that the fluids appeared as a non-Newtonian fluid with a shear thickening or dilatant behavior. The increment was higher in TiO2–methanol nanofluids compared to the other two with the highest increment of 17.8%. Besides, density of the methanol based nanofluids increased with volume concentrations. However, density decreased accordingly with increased temperature. This study demonstrates that thermal conductivity, viscosity and density of methanol based nanofluids depend on the volume concentration and temperature
Bistability of Sodium channels increases the safety-factor at the Neuromuscular Junction
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Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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