Channel Dynamics Research Articles

Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels.

Brain enriched voltage-gated sodium channel (VGSC) Nav1.2 and Nav1.6 are critical for electrical signaling in the CNS. Previous studies have extensively characterized cell-type-specific expression and electrophysiological properties of these two VGSCs and how their differences contribute to fine-tuning of neuronal excitability. However, because of a lack of reliable labeling and imaging methods, the subcellular localization and dynamics of these homologous Nav1.2 and Nav1.6 channels remain understudied. To overcome this challenge, we combined genome editing, super-resolution, and live-cell single-molecule imaging to probe subcellular composition, relative abundances, and trafficking dynamics of Nav1.2 and Nav1.6 in cultured mouse and rat neurons and in male and female mouse brain. We discovered a previously uncharacterized trafficking pathway that targets Nav1.2 to the distal axon of unmyelinated neurons. This pathway uses distinct signals residing in the intracellular loop 1 between transmembrane domain I and II to suppress the retention of Nav1.2 in the axon initial segment and facilitate its membrane loading at the distal axon. As mouse pyramidal neurons undergo myelination, Nav1.2 is gradually excluded from the distal axon as Nav1.6 becomes the dominant VGSC in the axon initial segment and nodes of Ranvier. In addition, we revealed exquisite developmental regulation of Nav1.2 and Nav1.6 localizations in the axon initial segment and dendrites, clarifying the molecular identity of sodium channels in these subcellular compartments. Together, these results unveiled compartment-specific localizations and trafficking mechanisms for VGSCs, which could be regulated separately to modulate membrane excitability in the brain.SIGNIFICANCE STATEMENT Direct observation of endogenous voltage-gated sodium channels reveals a previously uncharacterized distal axon targeting mechanism and the molecular identity of sodium channels in distinct subcellular compartments.

Premixed hydrogen-air flame front dynamics in channels with central and peripheral ignition

Experimental and analytical study of burning hydrogen-air mixtures with 12, 13, and 15 vol% hydrogen concentrations in channels with central and peripheral ignition was performed. Flame propagation speeds were determined by shadow and infrared high-speed imaging in the transverse and longitudinal directions, respectively. It was found that the increase in the flame front speed during the peripheral ignition reaches up to 1.7 times compared to the central ignition depending on mixture content. The pressure growth rate was examined in a closed channel. It was estimated that the time to reach a maximum pressure is 1.1 times less in the case or peripheral ignition than the central one. An analytical model was formed to describe the dynamics of the flame front in both cases. The model of a “reversed finger-flame” generated by a peripheral ignition was presented. The obtained results could be used in designing hydrogen-fueled combustible engines with the reduced knock-effect.

Microscopic Tridomain Model of Electrical Activity in the Heart with Dynamical Gap Junctions. Part 1 – Modeling and Well-Posedness

We present a novel microscopic tridomain model describing the electrical activity in cardiac tissue with dynamical gap junctions. The microscopic tridomain system consists of three PDEs modeling the tissue electrical conduction in the intra-and extra-cellular domains, supplemented by a nonlinear ODE system for the dynamics of the ion channels and the gap junctions. We establish the global existence and uniqueness of the weak solutions to our microscopic tridomain model. The global existence of solution, which constitutes the main result of this paper, is proved by means of an approximate non-degenerate system, the Faedo-Galerkin method, and an appropriate compactness argument.

Investigation and Quantification of Erosions in the Margins of Water Bodies: A Systematic Review

Erosive processes along the margins of water bodies are driven by various phenomena. Understanding and quantifying these processes require multidisciplinary approaches spanning across geology, ecology, and engineering. Accordingly, a variety of quantification approaches and techniques have been previously applied. To this end, the objective of the present research was to conduct a systematic review of the subject literature, with an aim to identify the techniques adopted in the quantification of erosion in the margins of water bodies. This study used a systematic review strategy based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses—PRISMA. The results showed that the primary focuses of the investigations were channel dynamics and the use and coverage of riparian soils. Two of the identified research focuses remain scarcely discussed due to the logistical difficulties surrounding continuous monitoring: (1) the direct impacts of rain on the removal of soil from the margin, and (2) the influence of water content on soil surfaces. Seven field techniques for measuring erosion in the margin were identified and summarily compared in this review. There is a consensus in the literature that the application of each technique is dependent on the characteristics of the study site, as well as the available resources for analysis; however, to overcome certain limitations, different techniques have been used simultaneously for a combination of data. The use of models has stood out in relation to the use of field techniques.

Late Holocene mangrove dynamics of the Doce River delta, southeastern Brazil: Implications for the understanding of mangrove resilience to sea-level changes and channel dynamics

This work aims to understand mangrove resilience to changes in a wave-influenced delta in southeastern Brazil during the late Holocene using an integrated analysis of palynology, sedimentology, and geochemistry (δ13C, δ15N, C:N and C:S ratio), and radiocarbon dating on two sediment cores. The data indicated three mangrove succession phases: 1) an estuarine point bar/tidal flat occupied by a mixture of mangrove species (~2660 - ~ 2050 cal yr BP); 2) a tidal flat dominated by Laguncularia mangroves (~2050 - ~ 900 cal yr BP); and 3) tidal flats with Laguncularia mangroves upstream and establishment of Rhizophora/Avicennia mangrove at the river mouth (~900 cal yr BP until present). The geochemical results suggest a dominance of C3 terrestrial plants with a mixture of C4 plants and organic matter of marine/estuarine origin throughout the late Holocene. Laguncularia and Rhizophora trees were established since ~ 2660 cal yr BP as pioneers, followed thereafter by Avicennia. Currently, tidal flats upstream are occupied by mangroves mainly represented by Laguncularia. Rhizophora/Avicennia mangroves occur at the mouth of the river. The relative sea-level fall during the late Holocene, as well as the channel dynamics, caused the development of tidal flats and mangrove succession inland. The succession of Rhizophora, Laguncularia, and Avicennia, followed by the permanence of only Laguncularia, is likely related to the resilience of each mangrove genus to habitat disturbance (e.g., salinity and sediment grain size fractions) caused by sea-level changes and channel dynamics. Our results show that mangroves may be resilient to the effects of Atlantic sea-level fluctuations, but the floristic structure in the past is different from that of today.

Epithelial Sodium Channel Inhibition by Amiloride Addressed with THz Spectroscopy and Molecular Modeling.

THz spectroscopy is important for the study of ion channels because it directly addresses the low frequency collective motions relevant for their function. Here we used THz spectroscopy to investigate the inhibition of the epithelial sodium channel (ENaC) by its specific blocker, amiloride. Experiments were performed on A6 cells’ suspensions, which are cells overexpressing ENaC derived from Xenopus laevis kidney. THz spectra were investigated with or without amiloride. When ENaC was inhibited by amiloride, a substantial increase in THz absorption was noticed. Molecular modeling methods were used to explain the observed spectroscopic differences. THz spectra were simulated using the structural models of ENaC and ENaC—amiloride complexes built here. The agreement between the experiment and the simulations allowed us to validate the structural models and to describe the amiloride dynamics inside the channel pore. The amiloride binding site validated using THz spectroscopy agrees with previous mutagenesis studies. Altogether, our results show that THz spectroscopy can be successfully used to discriminate between native and inhibited ENaC channels and to characterize the dynamics of channels in the presence of their specific antagonist.

Changes in meander geometry over the last 250 years along the lower Guadalquivir River (southern Spain) in response to hydrological and human factors

Meandering rivers and their morphological changes have been extensively investigated in fluvial geomorphology, but little knowledge is available on the meander geometry response in rivers heavily impacted by dams and their relative importance compared to natural hydrological and climatic variability. Understanding the causes of planimetric changes has several implications for assessing channel dynamics hazards and alterations of physical habitats and ecosystems. A multi-temporal analysis of meandering changes along the lower Guadalquivir River over the last 250 years was conducted with the aim of investigating possible climatic and human factors. Changes in controlling factors were investigated by hydrological analysis. A sequence of historical maps and aerial photos, and data analysis by GIS were used to analyse changes in meander geometry at the bend scale and planform parameters at the segment scale. The results showed two periods of changes in meander geometry influenced by different factors: (i) a historical period (1750–1915) of dynamic oscillations during a period of high concentration of floods; (ii) the period 1915–2010, with a drastic reduction in meandering size and sinuosity and a fragmentation of the active band, representing a rapid response to the extensive construction of dams in the catchment and the associated flow regime and sediment transfer alterations.

Allosteric coupling between transmembrane segment 4 and the selectivity filter of TALK1 potassium channels regulates their gating by extracellular pH

Opening of two-pore domain K+ channels (K2Ps) is regulated by various external cues, such as pH, membrane tension, or temperature, which allosterically modulate the selectivity filter (SF) gate. However, how these cues cause conformational changes in the SF of some K2P channels remains unclear. Herein, we investigate the mechanisms by which extracellular pH affects gating in an alkaline-activated K2P channel, TALK1, using electrophysiology and molecular dynamics (MD) simulations. We show that R233, located at the N-terminal end of transmembrane segment 4, is the primary pHo sensor. This residue distally regulates the orientation of the carbonyl group at the S1 potassium-binding site through an interacting network composed of residues on transmembrane segment 4, the pore helix domain 1, and the SF. Moreover, in the presence of divalent cations, we found the acidic pH-activated R233E mutant recapitulates the network interactions of protonated R233. Intriguingly, our data further suggested stochastic coupling between R233 and the SF gate, which can be described by an allosteric gating model. We propose that this allosteric model could predict the hybrid pH sensitivity in heterodimeric channels with alkaline-activated and acidic-activated K2P subunits.

Estuarine morphodynamics and development modified by floodplain formation

Abstract. Rivers and estuaries are flanked by floodplains built by mud and vegetation. Floodplains affect channel dynamics and the overall system's pattern through apparent cohesion in the channel banks and through filling of accommodation space and hydraulic resistance. For rivers, effects of mud, vegetation and the combination are thought to stabilise the banks and narrow the channel. However, the thinness of estuarine floodplain, comprised of salt marsh and mudflats, compared to channel depth raises questions about the possible effects of floodplain as constraints on estuary dimensions. To test these effects, we created three estuaries in a tidal flume: one with recruitment events of two live vegetation species, one with mud and a control with neither. Both vegetation and mud reduced channel migration and bank erosion and stabilised channels and bars. Effects of vegetation include local flow velocity reduction and concentration of flow into the channels, while flow velocities remained higher over mudflats. On the other hand, the lower reach of the muddy estuary showed more reduced channel migration than the vegetated estuary. The main system-wide effect of mudflats and salt marsh is to reduce the tidal prism over time from upstream to downstream. The landward reach of the estuary narrows and fills progressively, particularly for the muddy estuary, which effectively shortens the tidally influenced reach and also reduces the tidal energy in the seaward reach and mouth area. As such, estuaries with sufficient sediment supply are limited in size by tidal prism reduction through floodplain formation.

Arrhythmogenic influence of mutations in a myocyte-based computational model of the pulmonary vein sleeve

In the heart, electrophysiological dysregulation arises from defects at many biological levels (from point mutations in ion channel proteins to gross structural abnormalities). These defects disrupt the normal pattern of electrical activation, producing ectopic activity and reentrant arrhythmia. To interrogate mechanisms that link these primary biological defects to macroscopic electrophysiologic dysregulation most prior computational studies have utilized either (i) detailed models of myocyte ion channel dynamics at limited spatial scales, or (ii) homogenized models of action potential conduction that reproduce arrhythmic activity at tissue and organ levels. Here we apply our recent model (EMI), which integrates electrical activation and propagation across these scales, to study human atrial arrhythmias originating in the pulmonary vein (PV) sleeves. These small structures initiate most supraventricular arrhythmias and include pronounced myocyte-to-myocyte heterogeneities in ion channel expression and intercellular coupling. To test EMI’s cell-based architecture in this physiological context we asked whether ion channel mutations known to underlie atrial fibrillation are capable of initiating arrhythmogenic behavior via increased excitability or reentry in a schematic PV sleeve geometry. Our results illustrate that EMI’s improved spatial resolution can directly interrogate how electrophysiological changes at the individual myocyte level manifest in tissue and as arrhythmia in the PV sleeve.

Backbone NMR assignments of the extensive human and chicken TRPV4 N-terminal intrinsically disordered regions as important players in ion channel regulation

Transient receptor potential (TRP) channels are important pharmacological targets due to their ability to act as sensory transducers on the organismic and cellular level, as polymodal signal integrators and because of their role in numerous diseases. However, a detailed molecular understanding of the structural dynamics of TRP channels and their integration into larger cellular signalling networks remains challenging, in part due to the systematic absence of highly dynamic regions pivotal for channel regulation from available structures. In human TRP vanilloid 4 (TRPV4), a ubiquitously expressed homotetrameric cation channel involved in temperature, osmo- and mechano-sensation and in a multitude of (patho)physiological processes, the intrinsically disordered N-terminus encompasses 150 amino acids and thus represents > 17% of the entire channel sequence. Its deletion renders the channel significantly less excitable to agonists supporting a crucial role in TRPV4 activation and regulation. For a structural understanding and a comparison of its properties across species, we determined the NMR backbone assignments of the human and chicken TRPV4 N-terminal IDRs.

Structure deformation and curvature sensing of PIEZO1 in lipid membranes.

PIEZO channels respond to piconewton-scale forces to mediate critical physiological and pathophysiological processes1-5. Detergent-solubilized PIEZO channels form bowl-shaped trimers comprising a central ion-conducting pore with an extracellular cap and three curved and non-planar blades with intracellular beams6-10, which may undergo force-induced deformation within lipid membranes11. However, the structures and mechanisms underlying the gating dynamics of PIEZO channels in lipid membranes remain unresolved. Here we determine the curved and flattened structures of PIEZO1 reconstituted in liposome vesicles, directly visualizing the substantial deformability of the PIEZO1-lipid bilayer system and an in-plane areal expansion of approximately 300 nm2 in the flattened structure. The curved structure of PIEZO1 resembles the structure determined from detergent micelles, but has numerous bound phospholipids. By contrast, the flattened structure exhibits membrane tension-induced flattening of the blade, bending of the beam and detaching and rotating of the cap, which could collectively lead to gating of the ion-conducting pathway. On the basis of the measured in-plane membrane area expansion and stiffness constant of PIEZO1(ref. 11), we calculate a half maximal activation tension of about 1.9 pN nm-1, matching experimentally measured values. Thus, our studies provide a fundamental understanding of how the notable deformability and structural rearrangement of PIEZO1 achieve exquisite mechanosensitivity and unique curvature-based gating in lipid membranes.

Resonance behavior of a compliant piezo-driven inkjet channel with an entrained microbubble.

Microbubbles entrained in a piezo-driven drop-on-demand printhead disturb the acoustics of the microfluidic ink channel and, thereby, the jetting behavior. Here, the resonance behavior of an ink channel as a function of the microbubble size and number of bubbles is studied through theoretical modeling and experiments. The system is modeled as a set of two coupled harmonic oscillators: one corresponds to the compliant ink channel and the other corresponds to the microbubble. The predicted and measured eigenfrequencies are in excellent agreement. It was found that the resonance frequency is independent of the bubble size as long as the compliance of the bubble dominates over that of the piezo actuator. An accurate description of the eigenfrequency of the coupled system requires the inclusion of the increased inertance of the entrained microbubble due to confinement. It is shown that the inertance of a confined bubble can be accurately obtained by using a simple potential flow approach. The model is further validated by the excellent agreement between the modeled and measured microbubble resonance curves. The present work, therefore, provides physical insight into the coupled dynamics of a compliant ink channel with an entrained microbubble.

On the primary devolatilization of hemicellulose

This paper presents validation cases on a reaction mechanism for the primary devolatilization of hemicellulose called “hemi-FC.” The analysis incorporates depolymerization via random scission; charring via monomer decomposition, semichar decomposition, and thermal annealing; fragmentation statistics; and the flash distillation analogy. It predicts the yields and elemental compositions of bio-oil and char, oil molecular weight distributions, and the yields of CO, CO2, H2O, H2, and light oxygenates. A single set of model parameters accurately interprets the partitioning of hemicellulose with cation levels from 5000 to 30,000 ppmw into oil, noncondensables, and solid residue for temperatures to 900 °C, heating rates from 10 °C/min to 6000 °C/s, contact times after heatup to 1800 s, and pressures of vacuum and 0.1 MPa. The model results are generally within useful quantitative tolerances of the measured values across the domain of test conditions. Nonetheless, the commercial xylans that have been tested devolatilize at much cooler temperatures than cellulose and produce more gas and char and less bio-oil primarily because their decomposition is strongly catalyzed by excessive residual amounts of Na and Ca from the hemicellulose extraction process. These cation loadings are definitely heavy enough to grossly distort the dynamics of the spontaneous reaction channels and ultimate devolatilization behavior. Consequently, the spontaneous, uncatalyzed reaction channels for hemicellulose devolatilization remain uncharacterized even while they are bound to be prominent in the devolatilization of many natural hemicellulose forms.

Rotational Dynamics of The Transmembrane Domains Play an Important Role in Peptide Dynamics of Viral Fusion and Ion Channel Forming Proteins-A Molecular Dynamics Simulation Study.

Focusing on the transmembrane domains (TMDs) of viral fusion and channel-forming proteins (VCPs), experimentally available and newly generated peptides in an ideal conformation of the S and E proteins of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and SARS-CoV, gp41 and Vpu, both of human immunodeficiency virus type 1 (HIV-1), haemagglutinin and M2 of influenza A, as well as gB of herpes simplex virus (HSV), are embedded in a fully hydrated lipid bilayer and used in multi-nanosecond molecular dynamics simulations. It is aimed to identify differences in the dynamics of the individual TMDs of the two types of viral membrane proteins. The assumption is made that the dynamics of the individual TMDs are decoupled from their extra-membrane domains, and that the mechanics of the TMDs are distinct from each other due to the different mechanism of function of the two types of proteins. The diffusivity coefficient (DC) of the translational and rotational diffusion is decreased in the oligomeric state of the TMDs compared to those values when calculated from simulations in their monomeric state. When comparing the calculations for two different lengths of the TMD, a longer full peptide and a shorter purely TMD stretch, (i) the difference of the calculated DCs begins to level out when the difference exceeds approximately 15 amino acids per peptide chain, and (ii) the channel protein rotational DC is the most affected diffusion parameter. The rotational dynamics of the individual amino acids within the middle section of the TMDs of the fusion peptides remain high upon oligomerization, but decrease for the channel peptides, with an increasing number of monomers forming the oligomeric state, suggesting an entropic penalty on oligomerization for the latter.

Flow in Pillow-Plate Channels for High-Speed Turbomachinery Heat Exchangers

In numerous turbomachinery applications, e.g., in aero-engines with regenerators for improving specific fuel consumption (SFC), heat exchangers with low-pressure loss are required. Pil low-plate heat exchangers (PPHE) are a novel exchanger type and promising candidates for high-speed flow applications due to their smooth profiles avoiding blunt obstacles in the flow path. This work deals with the overall system behavior and gas dynamics of pillow-plate channels. A pillow-plate channel was placed in the test section of a blow-down wind tunnel working with dry air, and compressible flow phenomena were investigated utilizing conventional and focusing schlieren optics; furthermore, static and total pressure measurements were performed. The experiments supported the assumption that the system behavior can be described through a Fanno–Rayleigh flow model. Since only wavy walls with smooth profiles were involved, linearized gas dynamics was able to cover important flow features within the channel. The effects of the wavy wall structures on pressure drop and Mach number distribution within the flow path were investigated, and a good qualitative agreement with theoretical and numerical predictions was found. The present analysis demonstrates that pressure losses in pillow-plate heat exchangers are rather low, although their strong turbulent mixing enables high convective heat transfer coefficients.

Pulsed high-current discharge in water: adiabatic model of expanding plasma channel and acoustic wave

This paper presents the results of a theoretical and experimental study of the use of a pulsed discharge in water to obtain a strong acoustic wave in a liquid medium. A discharge with a current amplitude of 10 kA, a duration of 400 ns, and an amplitude pulsed power of 280 MW in water at atmospheric pressure created an expanding acoustic wave with an amplitude of more than 100 MPa. To describe the formation of the discharge channel, an isothermal plasma model has been developed, which made it possible to calculate both the expansion dynamics of a high-current channel and the strong acoustic wave generated by it. Our calculations show that the number density of plasma in the channel reaches 1020 cm–3, while the degree of water vapor ionization is about 10%, and the channel wall extends with a velocity of 500 m s−1. The calculations for the acoustic wave are in good agreement with measurements.

Characterization of plasma in RF jet interacting with water: Thomson scattering versus spectral line broadening

In this work we carry out a detailed characterization of an Ar radiofrequency plasma jet interacting with liquid. The focus of the paper is measurement of the electron density by examining the Stark broadening of hydrogen Balmer α line and Thomson scattering (TS). Supporting diagnostics are done to investigate the channel evolution and movement, and gas temperature. The comparison of the two approaches shows the caveats and the advantages that should gain attention in future applications. In particular, the plasma channel dynamics have a significant impact on the TS signal and may result in physical phenomena being missed due to channel dislocations. The conclusions of the work elucidate the pitfalls for interpreting the results of TS when the discharge is a dynamic filamentary plasma. This work establishes the temporal evolution of the plasma and the gas parameters in a plasma–liquid system employed for investigation of plasma-induced electrodeless electrochemistry.

Numerical Simulations of Confined Braided River Morphodynamics: Display of Deterministic Chaos and Characterization Through Turbulence Theory

AbstractIn this paper, we utilize a numerical morphological simulation approach to study braiding channel dynamics under steady flow. We conduct 11 different runs in a laboratory configuration, with each initial condition featuring a unique small‐amplitude perturbation pattern of the bed topography. From these infinitesimal initial differences, braided channels evolve into patterns that are macroscopically different and unique to each run, thus showing sensitive dependence on the initial condition and hence a chaotic behavior. Leveraging the analogy of braiding and fluid turbulence put forward by Paola (1996), by introducing a Reynolds‐type decomposition of bed elevations into a reference and a fluctuating component we characterize braided channel dynamics through statistics of bed fluctuations. We observe that, over the simulation time frame, braiding is not statistically homogeneous, but is stationary in a spatially averaged sense. We prove that braiding is anisotropic and extract two distinct length scales associated with the correlations of bed fluctuations in the streamwise and cross‐channel direction. We observe that, under the time averaging window that yields stationary braiding, braiding shows hints of ergodic behavior, as the time statistics of one run converge to the ensemble statistics computed across all the other runs.

Kinetic and thermodynamic modeling of a voltage-gated sodium channel.

Like all biological and chemical reactions, ion channel kinetics are highly sensitive to changes in temperature. Therefore, it is prudent to investigate channel dynamics at physiological temperatures. However, most ion channel investigations are performed at room temperature due to practical considerations, such as recording stability and technical limitations. This problem is especially severe for the fast voltage-gated sodium channel, whose activation kinetics are faster than the time constant of the standard patch-clamp amplifier at physiological temperatures. Thus, biologically detailed simulations of the action potential generation evenly scale the kinetic models of voltage-gated channels acquired at room temperature. To quantitatively study voltage-gated sodium channels' temperature sensitivity, we recorded sodium currents from nucleated patches extracted from the rat's layer five neocortical pyramidal neurons at several temperatures from 13.5 to 30°C. We use these recordings to model the kinetics of the voltage-gated sodium channel as a function of temperature. We show that the temperature dependence of activation differs from that of inactivation. Furthermore, the data indicate that the sustained current has a different temperature dependence than the fast current. Our kinetic and thermodynamic analysis of the current provided a numerical model spanning the entire temperature range. This model reproduced vital features of channel activation and inactivation. Furthermore, the model also reproduced action potential dependence on temperature. Thus, we provide an essential building block for the generation of biologically detailed models of cortical neurons.