Compound Heterozygous KCNQ1 Mutations Causing Recessive Romano–Ward Syndrome: Functional Characterization by Mutant Co-expression

Next Generation Sequencing has identified many KCNQ1 genetic variants associated with type 1 long QT or Romano-Ward syndrome, most frequently inherited in an autosomal dominant fashion, although recessive forms have been reported. Particularly in the case of missense variants, functional studies of mutants are of aid to establish variant pathogenicity and to understand the mechanistic basis of disease. Two compound heterozygous KCNQ1 mutations (p.A300T and p.P535T) were previously found in a child who suffered sudden death. To provide further insight into the clinical significance and basis for pathogenicity of these variants, different combinations of wildtype, A300T and P535T alleles were co-expressed with the accessory β-subunit minK in HEK293 cells, to analyze colocalization with the plasma membrane and some biophysical phenotypes of homo and heterotetrameric channels using the patch-clamp technique. A300T homotetrameric channels showed left-shifted activation V1/2 as previously observed in Xenopus oocytes, decreased maximum conductance density, slow rise-time300ms, and a characteristic use-dependent response. A300T slow rise-time300ms and use-dependent response behaved as dominant biophysical traits for all allele combinations. The P535T variant significantly decreased maximum conductance density and Kv7.1-minK-plasma membrane colocalization. P535T/A300T heterotetrameric channels showed decreased colocalization with plasma membrane, slow rise-time300ms and the A300T characteristic use-dependent response. While A300T left shifted activation voltage dependence behaved as a recessive trait when co-expressed with WT alleles, it was dominant when co-expressed with P535T alleles.Conclusions: The combination of P535T/A300T channel biophysical properties is compatible with recessive Romano Ward syndrome. Further analysis of other biophysical traits may identify other mechanisms involved in the pathophysiology of this disease.

Dust Pollution Reduced Stomatal Conductance and Photosynthetic Pigments of Selected Medicinal Plants Growing at Lokpa Ukwu Quarry Site in Abia State, Nigeria

Aims: We investigated the influence of dust pollution on stomatal conductance and photosynthetic pigments in some medicinal plants growing at Lokpa Ukwu quarry site, Abia State, Nigeria. Place and Duration of Study: Samples were collected from Lokpa Ukwu, Abia State while laboratory analyses were carried out in the Department of Pharmacognosy and Environmental Medicines, University of Nigeria, Nsukka between February and April, 2019. Methodology: A total of nine (9) plants were sampled for the study. Leaf epidermises were prepared by clearing method and stomata were observed and studied quantitatively. Stomatal conductance was estimated from the anatomical variables following standard procedures. Total chlorophyll and β-carotene contents were also analysed and compared with control groups. Results: We observed some physiological changes in the plants from dust-polluted site such as stretched epidermal cells, deformed stomata and plasmolysed guard cells. It reduced the potential conductance indices (PCI) of the plants by 87.4% in Aspilia africana and 67% in Chromolaena odorata. The least reduction in PCI was observed in Celosia trigyna (7.2%). Operating conductance (gop) and maximum conductance (gmax) were reduced by 69.2% and 72.3% in C. odorata and A. africana respectively. Celosia trigyna was least affected with percentage reductions of 18.3% and 1.4% for gop and gmax respectively. Reduction in PCI and gmax followed the order: C. trigyna ˂ C. papaya ˂ P. discoideus ˂ D. oliveri ˂ T. rhomboidea ˂ T. orientalis ˂ V. doniana ˂ C. odorata ˂ A. africana. Total chlorophyll and β-carotene contents were reduced the most in V. doniana (45.73%) and C. odorata (40.31%) respectively and least reduced in T. orientalis by 19.54% and 13.24% respectively. Conclusion: Our findings validate previous reports of negative effects of dust pollution from quarry industries on both humans and plants alike.

Modulation of the Neisseria gonorrhoeae drug efflux conduit MtrE

ABSTRACTWidespread antibiotic resistance, especially of Gram-negative bacteria, has become a severe concern for human health. Tripartite efflux pumps are one of the major contributors to resistance in Gram-negative pathogens, by efficiently expelling a broad spectrum of antibiotics from the organism. In Neisseria gonorrhoeae, one of the first bacteria for which pan-resistance has been reported, the most expressed efflux complex is MtrCDE. Here we present the electrophysiological characterisation of the outer membrane component MtrE and the membrane fusion protein MtrC, obtained by a combination of planar lipid bilayer recordings and in silico techniques. Our in vitro results show that MtrE can be regulated by periplasmic binding events and that the interaction between MtrE and MtrC is sufficient to stabilize this complex in an open state. In contrast to other efflux conduits, the open complex only displays a slight preference for cations. The maximum conductance we obtain in the in vitro recordings is comparable to that seen in our computational electrophysiology simulations conducted on the MtrE crystal structure, indicating that this state may reflect a physiologically relevant open conformation of MtrE. Our results suggest that the MtrC/E binding interface is an important modulator of MtrE function, which could potentially be targeted by new efflux inhibitors.

Dynamic compensation mechanism gives rise to period and duty-cycle level sets in oscillatory neuronal models

Rhythmic oscillation in neurons can be characterized by various attributes, such as the oscillation period and duty cycle. The values of these features depend on the amplitudes of the participating ionic currents, which can be characterized by their maximum conductance values. Recent experimental and theoretical work has shown that the values of these attributes can be maintained constant for different combinations of two or more ionic currents of varying conductances, defining what is known as level sets in conductance space. In two-dimensional conductance spaces, a level set is a curve, often a line, along which a particular oscillation attribute value is conserved. In this work, we use modeling, dynamical systems tools (phase-space analysis), and numerical simulations to investigate the possible dynamic mechanisms responsible for the generation of period and duty-cycle levels sets in simplified (linearized and FitzHugh-Nagumo) and conductance-based (Morris-Lecar) models of neuronal oscillations. A simplistic hypothesis would be that the tonic balance between ionic currents with the same or opposite effective signs is sufficient to create level sets. According to this hypothesis, the dynamics of each ionic current during a given cycle are well captured by some constant quantity (e.g., maximal conductances), and the phase-plane diagrams are identical or are almost identical (e.g., cubic-like nullclines with the same maxima and minima) for different combinations of these maximal conductances. In contrast, we show that these mechanisms are dynamic and involve the complex interaction between the nonlinear voltage dependencies and the effective time scales at which the ionic current's dynamical variables operate.

Proliferating conduction by isomerism

The electrical conduction of isomers of anthracene molecule attached between two semi-infinite gold electrodes was simulated using extended Huckel theory (EHT)-based on semi-empirical model in this research work. The electron transport parameters were examined in two epochs by buffering anthracene and its isomer phenanthrene alternatively between gold electrodes using sulphur as an alligator clip, under variegated bias voltages. Differential NDR effect was observed in both the cases but phenanthrene exhibited more linear I–V curve than its counterpart, anthracene. The simulated results discovered phenanthrene as a better candidate than anthracene towards contributing to electrical conduction in molecular junctions. Phenanthrene reported maximum conductance of 0.74G0 whereas anthracene exhibited 0.03[Formula: see text]G0 at 0.8[Formula: see text]V.

Augmenting Molecular Junctions with Different Transition Metal Contacts

In this research paper, the effect of the material of electrodes at the nanometer scale was elucidated towards measuring the electron transport properties of a single molecular junction comprising of anthracenedithiol molecule (ADT) stringed to two semi-infinite metallic electrodes using Extended Huckle Theory (EHT)-based semi-empirical modelling approach. The electron transport parameters i.e., I–V curves, Conductance-Voltage curves and transmission spectrum were investigated through ADT molecule by buffering it between different electrodes composed of rhodium, palladium, nickel and copper, all from transition metals series, under finite bias voltages within Keldysh's non equilibrium green function formulism (NEGF). The simulated results revealed that the copper electrodes showed maximum conduction whereas palladium showed least. The maximum conductance of 0.82 G0 and 43 μA current was exhibited by copper and thus affirmed to be the most effective electrode at nanometre scale when compared with other electrodes viz. nickel, rhodium and palladium.

AROMATIC MOLECULAR JUNCTIONS WITH INERT GASES AS ALLIGATOR CLIPS

In this research paper, we examined the effect of placing the elements of Group 0 as alligator clips with Anthracene molecule binding gold electrodes on the nanometer scale using Extended Huckle Theory (EHT) based semi-empirical model. The electron transport parameters i.e., I-V curves, Conductance-Voltage curves and transmission spectrum were investigated through Anthracene molecule by buffering it between two semi-infinite gold electrodes but via different alligator clips-Helium, Neon, Argon, Krypton, Xenon and Radon, all from Noble gas group or group-0 under finite bias voltages within Keldysh's nonequilibrium green function formalism (NEGF). The simulated results revealed that the Xenon and Radon showed maximum conduction whereas Krypton, Neon, Helium and Argon showed least. The maximum conductance of 0.62G0 and 70.4 μA current was exhibited by Xenon and thus affirmed to be the most optimal alligator clip amongst noble gases at nanometre scale.

Study on Dynamic Characteristics of the Hippocampal Neuron under Current Conductance's Changing

The hippocampal CA1 pyramid neuron has plenty of discharge actions. In the thesis, the dynamic characteristics of the hippocampal neuron model are analyzed and discussed by the neurodynamic theory and methods. Under a certain amplitude currents stimulation, the change of (the maximum conductance of the transient sodium channel) and (the maximum conductance of the delay rectification potassium channel) can cause different dynamic characteristics of the neuron model. The transient Na+current () caused by is indispensable in the discharges formation process of the model. The model can generate the discharge process only when reaches a certain threshold. In the discharge process of the neuron model,s changing affects little and the ISIs approximate to a straight line. The delay rectification K+current () caused by isnt indispensable in the discharges formation process of the model. Buts changing affects much in the discharge process of the neuron model. Withs changing, the neuron model undergoes different dynamic bifurcation process, and has plenty of discharge patterns such as the chaos, period, and so on. This investigation is helpful to know and investigate deeply the dynamic characteristics and the bifurcation mechanism of the hippocampal neuron; and it provides a certain theory assist to investigate the neural diseases such as the Alzheimer disease by neurodynamics.

MAXIMUM ELECTRICAL CONDUCTANCE OF A METALLIC PARABOLIC QUANTUM DOT VERSUS DOT-LEAD COUPLING

Starting from assuming that the electrical zero-bias conductance in a metallic quantum dot may be represented well by the Breit–Wigner model (which, on the other hand, is certainly appropriate for one-atom metallic wires), the strength of the coupling between a metallic parabolic quantum dot and the involved leads is determined for maximum conductance through the dot. In fact, this maximal conductance is calculated and issues related to off-resonant conduction states are discussed.