• MeSH
• Eye Movements MeSH
• Psychomotor Disorders MeSH
• Saccades MeSH

• Conspectus
• Psychologie
• NML Fields
• oftalmologie
• psychologie, klinická psychologie
• NML Publication type
• kolektivní monografie

The mechanisms underlying the emergence of seizures are one of the most important unresolved issues in epilepsy research. In this paper, we study how perturbations, exogenous or endogenous, may promote or delay seizure emergence. To this aim, due to the increasingly adopted view of epileptic dynamics in terms of slow-fast systems, we perform a theoretical analysis of the phase response of a generic relaxation oscillator. As relaxation oscillators are effectively bistable systems at the fast time scale, it is intuitive that perturbations of the non-seizing state with a suitable direction and amplitude may cause an immediate transition to seizure. By contrast, and perhaps less intuitively, smaller amplitude perturbations have been found to delay the spontaneous seizure initiation. By studying the isochrons of relaxation oscillators, we show that this is a generic phenomenon, with the size of such delay depending on the slow flow component. Therefore, depending on perturbation amplitudes, frequency and timing, a train of perturbations causes an occurrence increase, decrease or complete suppression of seizures. This dependence lends itself to analysis and mechanistic understanding through methods outlined in this paper. We illustrate this methodology by computing the isochrons, phase response curves and the response to perturbations in several epileptic models possessing different slow vector fields. While our theoretical results are applicable to any planar relaxation oscillator, in the motivating context of epilepsy they elucidate mechanisms of triggering and abating seizures, thus suggesting stimulation strategies with effects ranging from mere delaying to full suppression of seizures.

• MeSH
• Models, Biological MeSH
• Electroencephalography methods   MeSH
• Humans MeSH
• Seizures physiopathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The Sec translocon is a highly conserved membrane assembly for polypeptide transport across, or into, lipid bilayers. In bacteria, secretion through the core channel complex-SecYEG in the inner membrane-is powered by the cytosolic ATPase SecA. Here, we use single-molecule fluorescence to interrogate the conformational state of SecYEG throughout the ATP hydrolysis cycle of SecA. We show that the SecYEG channel fluctuations between open and closed states are much faster (~20-fold during translocation) than ATP turnover, and that the nucleotide status of SecA modulates the rates of opening and closure. The SecY variant PrlA4, which exhibits faster transport but unaffected ATPase rates, increases the dwell time in the open state, facilitating pre-protein diffusion through the pore and thereby enhancing translocation efficiency. Thus, rapid SecYEG channel dynamics are allosterically coupled to SecA via modulation of the energy landscape, and play an integral part in protein transport. Loose coupling of ATP-turnover by SecA to the dynamic properties of SecYEG is compatible with a Brownian-rachet mechanism of translocation, rather than strict nucleotide-dependent interconversion between different static states of a power stroke.

• MeSH
• Adenosine Triphosphate metabolism   MeSH
• Adenosine Triphosphatases genetics   metabolism   MeSH
• Bacterial Proteins * metabolism   MeSH
• Nucleotides metabolism   MeSH
• SecA Proteins metabolism   MeSH
• Escherichia coli Proteins * metabolism   MeSH
• SEC Translocation Channels chemistry   MeSH
• Protein Transport MeSH
• Publication type
• Journal Article MeSH

Molecular motions of free and pheromone-bound mouse major urinary protein I, previously investigated by NMR relaxation, were simulated in 30 ns molecular dynamics (MD) runs. The backbone flexibility was described in terms of order parameters and correlation times, commonly used in the NMR relaxation analysis. Special attention was paid to the effect of conformational changes on the nanosecond time scale. Time-dependent order parameters were determined in order to separate motions occurring on different time scales. As an alternative approach, slow conformational changes were identified from the backbone torsion angle variances, and "conformationally filtered" order parameters were calculated for well-defined conformation states. A comparison of the data obtained for the free and pheromone-bound protein showed that some residues are more rigid in the bound form, but a larger portion of the protein becomes more flexible upon the pheromone binding. This finding is in general agreement with the NMR results. The higher flexibility observed on the fast (fs-ps) time scale was typically observed for the residues exhibiting higher conformational freedom on the ns time scale. An inspection of the hydrogen bond network provided a structural explanation for the flexibility differences between the free and pheromone-bound proteins in the simulations.

• MeSH
• Pheromones chemistry   MeSH
• Financing, Organized MeSH
• Protein Conformation MeSH
• Models, Molecular MeSH
• Computer Simulation MeSH
• Motion MeSH
• Proteins chemistry   MeSH
• Thiazoles chemistry   MeSH

We have used a previously published computer model of the rat cardiac ventricular myocyte to investigate the effect of changing the distribution of Ca(2+) efflux pathways (SERCA, Na(+)/Ca(2+) exchange, and sarcolemmal Ca(2+) ATPase) between the dyad and bulk cytoplasm and the effect of adding exogenous Ca(2+) buffers (BAPTA or EGTA), which are used experimentally to differentially buffer Ca(2+) in the dyad and bulk cytoplasm, on cellular Ca(2+) cycling. Increasing the dyadic fraction of a particular Ca(2+) efflux pathway increases the amount of Ca(2+) removed by that pathway, with corresponding changes in Ca(2+) efflux from the bulk cytoplasm. The magnitude of these effects varies with the proportion of the total Ca(2+) removed from the cytoplasm by that pathway. Differences in the response to EGTA and BAPTA, including changes in Ca(2+)-dependent inactivation of the L-type Ca(2+) current, resulted from the buffers acting as slow and fast "shuttles," respectively, removing Ca(2+) from the dyadic space. The data suggest that complex changes in dyadic Ca(2+) and cellular Ca(2+) cycling occur as a result of changes in the location of Ca(2+) removal pathways or the presence of exogenous Ca(2+) buffers, although changing the distribution of Ca(2+) efflux pathways has relatively small effects on the systolic Ca(2+) transient.

• MeSH
• Models, Biological MeSH
• Time Factors MeSH
• Egtazic Acid analogs & derivatives   pharmacology   MeSH
• Ion Channel Gating drug effects   MeSH
• Intracellular Space drug effects   metabolism   MeSH
• Myocytes, Cardiac drug effects   metabolism   MeSH
• Cell Compartmentation MeSH
• Rats MeSH
• Computer Simulation MeSH
• Buffers MeSH
• Sodium-Calcium Exchanger metabolism   MeSH
• Sarcolemma drug effects   metabolism   MeSH
• Heart Ventricles cytology   MeSH
• Calcium metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Fast field cycling (FFC) NMR relaxometry has been used to study the conformational properties of aqueous solutions of hyaluronan (HYA) at three concentrations in the range 10 to 25 mg mL(-1). Results revealed that, irrespective of the solution concentration, three different hydration layers surround hyaluronan. The inner layer consists of water molecules strongly retained in the proximity of the HYA surface. Because of their strong interactions with HYA, water molecules in this inner hydration layer are subject to very slow dynamics and have the largest correlation times. The other two hydration layers are made of water molecules which are located progressively further from the HYA surface. As a result, decreasing correlation times caused by faster molecular motion were measured. The NMRD profiles obtained by FFC-NMR relaxometry also showed peaks attributable to (1)H-(14)N quadrupole interactions. Changes in intensity and position of the quadrupolar peaks in the NMRD profiles suggested that with increasing concentration the amido group is progressively involved in the formation of weak and transient intramolecular water bridging adjacent hyaluronan chains. In this work, FFC-NMR was used for the first time to obtain deeper insight into HYA-water interactions and proved itself a powerful and promising tool in hyaluronan chemistry.

• MeSH
• Carbohydrate Conformation MeSH
• Hyaluronic Acid chemistry   MeSH
• Magnetic Resonance Spectroscopy methods   MeSH
• Water chemistry   MeSH
• Publication type
• Journal Article MeSH
• Evaluation Study MeSH
• Research Support, Non-U.S. Gov't MeSH

AMPA glutamate receptors (AMPARs) are ion channel tetramers that mediate the majority of fast excitatory synaptic transmission. They are composed of four subunits (GluA1-GluA4); the GluA2 subunit dominates AMPAR function throughout the forebrain. Its extracellular N-terminal domain (NTD) determines receptor localization at the synapse, ensuring reliable synaptic transmission and plasticity. This synaptic anchoring function requires a compact NTD tier, stabilized by a GluA2-specific NTD interface. Here we show that low pH conditions, which accompany synaptic activity, rupture this interface. All-atom molecular dynamics simulations reveal that protonation of an interfacial histidine residue (H208) centrally contributes to NTD rearrangement. Moreover, in stark contrast to their canonical compact arrangement at neutral pH, GluA2 cryo-electron microscopy structures exhibit a wide spectrum of NTD conformations under acidic conditions. We show that the consequences of this pH-dependent conformational control are twofold: rupture of the NTD tier slows recovery from desensitized states and increases receptor mobility at mouse hippocampal synapses. Therefore, a proton-triggered NTD switch will shape both AMPAR location and kinetics, thereby impacting synaptic signal transmission.

• MeSH
• Receptors, AMPA * metabolism   chemistry   MeSH
• Cryoelectron Microscopy * MeSH
• Hippocampus metabolism   MeSH
• Kinetics MeSH
• Hydrogen-Ion Concentration MeSH
• Protein Conformation MeSH
• Humans MeSH
• Mice MeSH
• Synaptic Transmission MeSH
• Protein Domains MeSH
• Protons * MeSH
• Molecular Dynamics Simulation * MeSH
• Synapses * metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: The patients with the long QT syndrome type-1 (LQT-1) have an impaired adaptation of the QT interval to heart rate changes. Yet, the description of the dynamic QT-RR coupling in genotyped LQT-1 has never been thoroughly investigated. METHOD: We propose a method to model the dynamic QT-RR coupling by defining a transfer function characterizing the relationship between a QT interval and its previous RR intervals measured from ambulatory Holter recordings. Three parameters are used to characterize the QT-RR coupling: a fast gain (Gain(F) ), a slow gain (Gain(L) ), and a time constant (τ). We investigated the values of these parameters across genders, and in genotyped LQT-1 patients with normal QTc interval duration (QTc < 470 ms). RESULTS: The QT-RR dynamic profiles are significantly different between LQT-1 patients (97) and controls (154): LQT-1 have longer QTc interval (453 ± 35 vs. 384 ± 26 ms, P < 0.0001), and an increased dependency of the QT interval to previous RR changes revealed by a larger Gain(L) (0.22 ± 0.06 vs. 0.18 ± 0.07, P < 0.0001) and Gain(F) (0.05 ± 0.02 vs. 0.03 ± 0.01, P < 0.0001). Importantly, LQT-1 patients have a faster QT dynamic response to previous RR changes described by τ: 122 ± 44 vs. 172 ± 92 beats (P < 0.0001). This faster QT dynamic response of the QT-RR dynamic coupling remained in LQT-1 patients with QTc in a normal range (<430 ms). CONCLUSIONS: The measurement of QT-RR dynamic coupling could be used in patients suspected to carry a concealed form of the LQT-1 syndrome, or to provide insights into the types of arrhythmogenic triggers a patient may be prone to.

• MeSH
• Circadian Rhythm MeSH
• Adult MeSH
• Electrocardiography, Ambulatory methods   statistics & numerical data   MeSH
• Adaptation, Physiological MeSH
• Cohort Studies MeSH
• Humans MeSH
• Young Adult MeSH
• Reference Values MeSH
• Heart Rate MeSH
• Long QT Syndrome diagnosis   physiopathology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Although animals often learn and monitor the spatial properties of relevant moving objects such as conspecifics and predators to properly organize their own spatial behavior, the underlying brain substrate has received little attention and hence remains elusive. Because the anterior cingulate cortex (ACC) participates in conflict monitoring and effort-based decision making, and ACC neurons respond to objects in the environment, it may also play a role in the monitoring of moving cues and exerting the appropriate spatial response. We used a robot avoidance task in which a rat had to maintain at least a 25cm distance from a small programmable robot to avoid a foot shock. In successive sessions, we trained ten Long Evans male rats to avoid a fast-moving robot (4cm/s), a stationary robot, and a slow-moving robot (1cm/s). In each condition, the ACC was transiently inactivated by bilateral injections of muscimol in the penultimate session and a control saline injection was given in the last session. Compared to the corresponding saline session, ACC-inactivated rats received more shocks when tested in the fast-moving condition, but not in the stationary or slow robot conditions. Furthermore, ACC-inactivated rats less frequently responded to an approaching robot with appropriate escape responses although their response to shock stimuli remained preserved. Since we observed no effect on slow or stationary robot avoidance, we conclude that the ACC may exert cognitive efforts for monitoring dynamic updating of the position of an object, a role complementary to the dorsal hippocampus.

• MeSH
• GABA-A Receptor Agonists pharmacology   MeSH
• Gyrus Cinguli drug effects   physiology   MeSH
• Rats MeSH
• Muscimol pharmacology   MeSH
• Neurons drug effects   physiology   MeSH
• Cues MeSH
• Rats, Long-Evans MeSH
• Attention drug effects   physiology   MeSH
• Spatial Behavior drug effects   physiology   MeSH
• Reaction Time physiology   MeSH
• Avoidance Learning drug effects   physiology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

A novel model for the coupling between ventricular repolarisation and heart rate (QT/RR) is presented. It is based upon a transfer function (TRF) formalism that describes the static and dynamic properties of this coupling, i.e., the behaviour after a sudden change in heart rate. Different TRF models were analysed by comparing their capability to describe experimental data collected from 19 healthy volunteers using several RR stimulation protocols: (i) rest with deep breathing at 0.1 Hz; (ii) tilt with controlled breathing at 0.1 and 0.33 Hz; and (iii) cycling. A search for the best TRF led to unambiguous identification of a three-parameter model as the most suitable descriptor of QT/RR coupling. Compared with established static models (linear or power-law), our model predictions are substantially closer to the experimental results, with errors approximately 50% smaller. The shape of the frequency and step responses of the TRF presented is essentially the same for all subjects and protocols. Moreover, each TRF may be uniquely identified by three parameters obtained from the step response, which are believed to be of physiological relevance: (i) gain for slow RR variability; (ii) gain for fast RR variability; and (iii) time during which QT attains 90% of its steady-state value. The TRF successfully describes the behaviour of the RR control following an abrupt change in RR interval, and its parameters may offer a tool for detecting pharmacologically induced changes, particularly those leading to increased arrhythmogenic risk.

• MeSH
• Financing, Organized MeSH
• Ventricular Function, Left physiology   MeSH
• Humans MeSH
• Models, Cardiovascular MeSH
• Computer Simulation MeSH
• Heart Conduction System physiology   MeSH
• Ventricular Function physiology   MeSH
• Heart Rate physiology   MeSH
• Check Tag
• Humans MeSH