A digital simulation study of two-dimensional convection diffusion for channel electrode

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Padé approximation of ECE and DISP processes at channel electrodes

A two-point Padé approximation is derived for ECE and DISP1 reactions occurring at channel electrodes for all rate constants. These are shown to be in excellent agreement with previous studies.     

Near threshold Cl(-)·CH3I photodetachment: apparent 2P1/2 channel suppression and enhanced 2P3/2 channel vibrational excitation

Cl(-)·CH(3)I cluster anion photoelectron images are recorded over a range of detachment wavelengths in the immediate post threshold region. The photoelectron spectral features fall into two categories. A number of weak, photon energy dependent transitions are observed and attributed to atomic anion fragmentation products. Several more intense, higher electron binding energy transitions result from single photon cluster anion detachment. Comparison with I(-)·CH(3)I suggests that the detachment process is more complicated for Cl(-)·CH(3)I. The single photon transition spacing is consistent with CH(3)I ν(3) mode excitation, but the two distinct vibronic bands of I(-)·CH(3)I detachment are not easily distinguished in the Cl(-)·CH(3)I spectra. Similarly, while the spectral intensities for both cluster anions show non-Franck Condon behavior, the level of vibrational excitation appears greater for Cl(-)·CH(3)I detachment. These observations are discussed in terms of low lying electronic states of CH(3)I along the C-I coordinate, and the influence of the CH(3)I moiety on the neutral halogen atom states.     

Motion of a lithium ion over a graphene–silicene channel: A computer model

The motion of a lithium ion over a channel formed by sheets of perfect and defect (with monovacancies) silicene with a graphene support at different values of the channel gap is studied by means of molecular dynamics. It is established that the lithium ion enters the channel and passes through it at gap widths of 0.75 and 0.8 nm; at the same time, the monovacancies in the silicene sheets have a decelerating effect on the lithium transport over the channel. The ion passes through the channel in 12.6 and 8.6 ps for ideal silicene and 27.7 and 31.8 ps for defect silicene, respectively. It is shown that graphene sheets have a stabilizing effect that prevents the gap value from changing appreciably.

     

How do aminoadamantanes block the influenza M2 channel, and how does resistance develop?

The interactions between channels and their cognate blockers are at the heart of numerous biomedical phenomena. Herein, we unravel one particularly important example bearing direct pharmaceutical relevance: the blockage mechanism of the influenza M2 channel by the anti-flu amino-adamantyls (amantadine and rimantadine) and how the channel and, consequently, the virus develop resistance against them. Using both computational analyses and experimental verification, we find that amino-adamantyls inhibit M2's H(+) channel activity by electrostatic hindrance due to their positively charged amino group. In contrast, the hydrophobic adamantyl moiety on its own does not impact conductivity. Additionally, we were able to uncover how mutations in M2 are capable of retaining drug binding on the one hand yet rendering the protein and the mutated virus resistant to amino-adamantyls on the other hand. We show that the mutated, drug-resistant protein has a larger binding pocket for the drug. Hence, despite binding the channel, the drug remains sufficiently mobile so as not to exert a H(+)-blocking positive electrostatic hindrance. Such insight into the blocking mechanism of amino-adamantyls, and resistance thereof, may aid in the design of next-generation anti-flu agents.     

Rac-mediated actin remodeling and myosin II are involved in KATP channel trafficking in pancreatic β-cells

AMP-activated protein kinase (AMPK) is a metabolic sensor activated during metabolic stress and it regulates various enzymes and cellular processes to maintain metabolic homeostasis. We previously reported that activation of AMPK by glucose deprivation (GD) and leptin increases K_ATP currents by increasing the surface levels of K_ATP channel proteins in pancreatic β-cells. Here, we show that the signaling mechanisms that mediate actin cytoskeleton remodeling are closely associated with AMPK-induced K_ATP channel trafficking. Using F-actin staining with Alexa 633-conjugated phalloidin, we observed that dense cortical actin filaments present in INS-1 cells cultured in 11 mM glucose were disrupted by GD or leptin treatment. These changes were blocked by inhibiting AMPK using compound C or siAMPK and mimicked by activating AMPK using AICAR, indicating that cytoskeletal remodeling induced by GD or leptin was mediated by AMPK signaling. AMPK activation led to the activation of Rac GTPase and the phosphorylation of myosin regulatory light chain (MRLC). AMPK-dependent actin remodeling induced by GD or leptin was abolished by the inhibition of Rac with a Rac inhibitor (NSC23766), siRac1 or siRac2, and by inhibition of myosin II with a myosin ATPase inhibitor (blebbistatin). Immunocytochemistry, surface biotinylation and electrophysiological analyses of K_ATP channel activity and membrane potentials revealed that AMPK-dependent K_ATP channel trafficking to the plasma membrane was also inhibited by NSC23766 or blebbistatin. Taken together, these results indicate that AMPK/Rac-dependent cytoskeletal remodeling associated with myosin II motor function promotes the translocation of K_ATP channels to the plasma membrane in pancreatic β-cells.     

Investigation of calcium antagonist–L-type calcium channel interactions by a vascular smooth muscle cell membrane chromatography method

The dissociation equilibrium constant (K _D) is an important affinity parameter for studying drug–receptor interactions. A vascular smooth muscle (VSM) cell membrane chromatography (CMC) method was developed for determination of the K _D values for calcium antagonist–L-type calcium channel (L-CC) interactions. VSM cells, by means of primary culture with rat thoracic aortas, were used for preparation of the cell membrane stationary phase in the VSM/CMC model. All measurements were performed with spectrophotometric detection (237 nm) at 37 °C. The K _D values obtained using frontal analysis were 3.36 × 10⁻⁶ M for nifedipine, 1.34 × 10⁻⁶ M for nimodipine, 6.83 × 10⁻⁷ M for nitrendipine, 1.23 × 10⁻⁷ M for nicardipine, 1.09 × 10⁻⁷ M for amlodipine, and 8.51 × 10⁻⁸ M for verapamil. This affinity rank order obtained from the VSM/CMC method had a strong positive correlation with that obtained from radioligand binding assay. The location of the binding region was examined by displacement experiments using nitrendipine as a mobile-phase additive. It was found that verapamil occupied a class of binding sites on L-CCs different from those occupied by nitrendipine. In addition, nicardipine, amlodipine, and nitrendipine had direct competition at a single common binding site. The studies showed that CMC can be applied to the investigation of drug–receptor interactions.     

Catching S2− and Cu2+ by a highly sensitive and efficient salamo-like fluorescence-ultraviolet dual channel chemosensor

Abstract

A highly sensitive and efficient fluorescence-ultraviolet dual channel chemical sensor H₂L based on the salamo-like bisoxime (6,6′-dimethoxy-2, 2′-[ethylenediyldioxybis(nitrilomethylidyne)]diphenol) was synthesized, Cu²⁺ and S^2? ions can be detected respectively. For the identification of metal cations, the Cu²⁺ can quench the fluorescence intensity of probe H₂L at the excitation wavelength of 311?nm, and when the same equivalent of EDTA was added, the fluorescence intensity of L-Cu complex returned to its original intensity practically, completing the fluorescence “OFF-ON-OFF” cycle after adding the same amount of Cu²⁺ again. The mechanism was confirmed by high resolution mass spectrometry, and it was concluded that the probe H₂L and Cu²⁺ formed a complex. For the identification of anions, UV–Vis spectral identification and naked-eye recognition for S^2? were performed. The binding mode of the probe to the sulfur anion and the recognition mechanism were confirmed by ¹H NMR titration. In addition, the probe H₂L showed high selectivity and sensitivity to Cu²⁺ and S^2?, the detection limits of L-Cu and L-S systems toward Cu²⁺ and S^2? are 46 and 25?nM respectively. In terms of application, the content of Cu²⁺and S^2? in different water samples (distilled water, Yellow River water and tap water) with probe H₂L was successfully tested. These results indicated that the probe H₂L can be used as a highly selective and sensitive dual channel sensor to detect both Cu²⁺ and S^2? ions in the environment and biological systems.     

Study of the interaction of unaggregated and aggregated amyloid β protein (10-21) with outward potassium channel

Metal ion-induced aggregation of Aβ into insoluble plaques is a central factor in Alzheimer’s disease. Zn2 is the only physiologically available transition metal ion responsible for aggregating Aβ at pH 7.4. To make it clear that the neurotoxicity of Zn2 -induced aggregation of Aβ on neurons is the key to un- derstand Aβ mechanism of action further. In this paper, we choose Aβ (10-21) as the model fragment to research hippocampal CA1 pyramidal neurons. For the first time, we adopt the combination of spectral analysis with patch-clamp technique for the preliminary study of the mutual relations of Zn2 , Aβ and ion channel from the cell level. The following expounds upon the effects and mode of action of two forms (unaggregated and aggregated) of Aβ (10-21) on hippocampus outward potassium channel three processes (activation, inactivation and reactivation). It also shows the molecular mechanics of AD from the channel level. These results are significant for the further study of Aβ nosogenesis and the devel- opment of new types of target drugs for the treatment of AD.     

Variable chemical species and thermo-diffusion Darcy–Forchheimer squeezed flow of Jeffrey nanofluid in horizontal channel with viscous dissipation effects

This research communicates the applications of thermos-diffusion effect associated to the squeezing flow of Jeffrey nanofluid due to horizontal channel. The problem presents the applications of inertial effects by following the Darcy–Forchheimer flow. Moreover, the effects of viscous dissipation and activation energy phenomenon has been discussed. The dimensionless attention of problem is retained. The shooting technique is implemented to present the numerical computations. The numerical validation of results is reported. The essential assessment of physical flow parameters is studied. The numerical outcomes are presented for heat and mass transfer phenomenon. It is observed that presence of inertial forces control to velocity flow in the regime. The enhancing contribution of thermal and concentration rate is noted for inertial constant.     

Dendroaspis natriuretic peptide regulates the cardiac L-type Ca2+ channel activity by the phosphorylation of α1c proteins

Dendroaspis natriuretic peptide (DNP), a new member of the natriuretic peptide family, is structurally similar to atrial, brain, and C-type natriuretic peptides. However, the effects of DNP on the cardiac function are poorly defined. In the present study, we examined the effect of DNP on the cardiac L-type Ca(2+) channels in rabbit ventricular myocytes. DNP inhibited the L-type Ca(2+) current (I(Ca,L)) in a concentration dependent manner with a IC(50) of 25.5 nM, which was blocked by an inhibitor of protein kinase G (PKG), KT5823 (1 μM). DNP did not affect the voltage dependence of activation and inactivation of I(Ca,L). The α(1c) subunit of cardiac L-type Ca(2+) channel proteins was phosphorylated by the treatment of DNP (1 μM), which was completely blocked by KT5823 (1 μM). Finally, DNP also caused the shortening of action potential duration in rabbit ventricular tissue by 22.3 ± 4.2% of the control (n = 6), which was completely blocked by KT5823 (1 μM). These results clearly indicate that DNP inhibits the L-type Ca(2+) channel activity by phosphorylating the Ca(2+) channel protein via PKG activation.     

Is the mobility of the pore walls and water molecules in the selectivity filter of KcsA channel functionally important?

We performed in-depth analysis of the forces which act on the K(+) ions in the selectivity filter of the KcsA channel in order to estimate the relative importance of static and dynamic influence of the filter wall and water molecules on ion permeation and selectivity. The forces were computed using the trajectories of all-atom molecular dynamics simulations. It is shown that the dynamics of the selectivity filter contributes about 3% to the net force acting on the ions and can be neglected in the studies focused on the macroscopic properties of the channel, such as the current. Among the filter atoms, only the pore-forming carbonyl groups can be considered as dynamic in the studies of microscopic events of conduction, while the dynamic effects from all other atoms are negligible. We also show that the dynamics of the water molecules in the filter can not be neglected. The fluctuating forces from the water molecules can be as strong as net forces from the pore walls and can effectively drive the ions through the local energy barriers in the filter.     

Fragmentation of size-selected Xe clusters: Why does the monomer ion channel dominate the Xen and ionization?

The fragmentation of the small Xe_n n=2−5 clusters following 70 eV electron impact ionization has been investigated in a size selective experiment and simulated using non-adiabatic dynamics. The experimental results show that the clusters strongly fragment to yield monomer Xe⁺ (more than 90%) and dimer Xe₂⁺ fragments (the remaining few percent). Trimer Xe₃⁺ fragments first occur from the neutral pentamers Xe₅ in a very low yield of approximately 0.3%. The present results are compared with the previous ones for Kr and Ar clusters. It is shown that the Xe and Kr clusters exhibit a qualitatively similar behavior with a strong propensity for monomer fragments, while in the Ar case dimers prevail. The theoretical calculations also reveal a strong fragmentation to the dimer and monomer fragments. However, the dimer Rg₂⁺ is predicted to be the major product for all rare gases (Rg ≡ Ar, Kr, Xe). Possible reasons for the discrepancy between theory and experiment are discussed.     

Hydrothermal synthesis,structure and properties of a novel Zn(II) dicarboxylate containing nanometer channel by significant hydrogen bonds and π–π interactions

A two-dimensional supramolecular complex, [Zn(HA)₂(hmta)] · 2H₂O (1) (H₂A: 9-ethylcarbazole-3,6-dicarboxylic acid, hmta: 5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane), has been prepared by hydrothermal synthesis and characterized by IR spectra, elemental analysis, TG analysis. The result of single crystal X-ray analysis revealed that the 2D supramolecular open framework contains 9.932 × 12.059 Å channels formed by significant hydrogen bonds and π–π interactions. Furthermore, the solid state fluorescent determinations show that the complex exhibits a strong emission band at 432 nm.     

Design and synthesis of skeletal analogues of gambierol: attenuation of amyloid-β and tau pathology with voltage-gated potassium channel and N-methyl-D-aspartate receptor implications

Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K(v) channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage-gated potassium channels (K(v)) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (Aβ) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K(+) currents, a reduction in the extra- and intracellular levels of Aβ, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K(v) channels as well as the molecular mechanism of Aβ metabolism modulated by NMDA receptors.     

On the optimization of a vertical twisted tape arrangement in a channel subjected to MWCNT–water nanofluid by coupling numerical simulation and genetic algorithm

Journal of Thermal Analysis and Calorimetry - Heat transfer and fluid flow are optimized in a three-dimensional channel under the constant heat flux boundary condition employing a genetic algorithm...     

The separation of the enantiomers of some potassium channel activators on α1-acid glycoprotein: the effect of solute conformationglycoprotein: the effect of solute conformation

Summary The amide conformers of two compounds and their enantiomers have been separated by liquid chromatography on an ₁-acid glycoprotein column. The effects of organic modifier and pH on the separations obtained were investigated. The conformers of one of the compounds were separated micro-preparatively at low temperature on the same column using a D₂O-based eluent; D₂O had no deleterious effects on the chromatography obtained. Some preliminary competition experiments on one of the amides and a close analogue are presented.     

Correction to: On the optimization of a vertical twisted tape arrangement in a channel subjected to MWCNT–water nanofluid by coupling numerical simulation and genetic algorithm

Journal of Thermal Analysis and Calorimetry - Lignin-based polycaprolactone (PCL) graft copolymers with various graft ratios were prepared by ring-opening reaction in order to design new lignin...     

The open-close mechanism of M2 channel protein in influenza A virus:A computational study on the hydrogen bonds and cation-π interactions among His37 and Trp41

The M2 protein from influenza A virus is a tetrameric ion channel. It was reported that the permeation of the ion channel is correlated with the hydrogen bond network among His37 residues and the cation-π interactions between His37 and Trp41. In the present study,the hydrogen bonding network of 4-methyl-imidazoles was built to mimic the hydrogen bonds between His37 residues,and the cation-π interactions between 4-methyl-imidazolium and indole systems were selected to represent the interac-tions between His37 and Trp41. Then,quantum chemistry calculations at the MP2/6-311G level were carried out to explore the properties of the hydrogen bonds and the cation-π interactions. The calcula-tion results indicate that the binding strength of the N-H···N hydrogen bond between imidazole rings is up to -6.22 kcal·mol-1,and the binding strength of the strongest cation-π interaction is up to -18.8 kcal·mol-1(T-shaped interaction) or -12.3 kcal·mol-1(parallel stacking interaction). Thus,the calcu-lated binding energies indicate that it is possible to control the permeation of the M2 ion channel through the hydrogen bond network and the cation-π interactions by altering the pH values.