Ionic conductance of nanopores in microscale analysis systems: where microfluidics meets nanofluidics

In this tutorial review we illustrate the origin and dependence on various system parameters of the ionic conductance that exists in discrete nanochannels as well as in nanoporous separation and preconcentration units contained as hybrid configurations, membranes, packed beds, or monoliths in microscale liquid phase analysis systems. A particular complexity arises as external electrical fields are superimposed on internal chemical and electrical potential gradients for tailoring molecular transport. It is demonstrated that the variety of geometries in which the microfluidic/nanofluidic interfaces are realized share common, fundamental features of coupled mass and charge transport, but that phenomena behind the key steps in a particular application can be significantly tuned, depending on the morphology of a material. Thus, the understanding of morphology-related transport in internal and external electrical potential gradients is critical to the performance of a device. This addresses a variety of geometries (slits, channels, filters, membranes, random or regular networks of pores, etc.) and applications, e. g., the gating, sensing, preconcentration, and separation in multifunctional miniaturized devices. Inherently coupled mass and charge transport through ion-permselective (charge-selective) microfluidic/nanofluidic interfaces is analyzed with a stepwise-added complexity and discussed with respect to the morphology of the charge-selective spatial domains. Within this scenario, the electrostatics and electrokinetics in microfluidic and nanofluidic channels, as well as the electrohydrodynamics evolving at microfluidic/nanofluidic interfaces, where microfluidics meets nanofluidics, define the platform of central phenomena.     

Ion channels of biological membranes: prediction of single channel conductance

The Poisson-Boltzmann equation was solved numerically for models of the pore regions of the Shaker K⁺ channel and of two glycoporins (LamB and ScrY) to yield electrostatic potential profiles along the pore axes. From these potential profiles, single-channel current-voltage (I–V) relations were calculated. The importance of a proper treatment of the ionisation state of two rings of aspartate sidechains at the mouth of the K⁺ channel pore emerged from such calculations. The calculated most likely state, in which only two of the eight aspartate sidechains were deprotonated, yielded better agreement with experimental conductance data. An approximate calculation of single-channel conductances based simply on pore geometry yielded very similar conductance values for the two glycoporins. This differed from an␣experimentally determined conductance ratio of ScrY:LamB=10:1. Preliminary electrostatics calculations appeared to reproduce the observed difference in conductance between the two glycoporins, confirming that single-channel conductance is determined by electrostatic as well as geometric considerations. Received: 25 May 1998 / Accepted: 4 August 1998 / Published online: 2 November 1998     

Structure-based prediction of the conductance properties of ion channels

The HOLE procedure allows the prediction of the absolute conductance of an ion channel model from its structure. The original prediction method uses an empirically corrected Ohmic method. It is most successful, with predictions being reliable to within a factor of two. A new modification of the procedure is presented in which the self-diffusion coefficients of water molecules from molecular dynamics simulation are used to replace the empirical correction factor. A "prediction" of the conductance for the porin OmpF by the new method is made and shown to be very close to the experimental value. HOLE also allows the prediction of the effect that the addition of non-electrolyte polymers will have on channel conductance. The method has great potential to yield structural information from data provided by single channel recordings but needs further validation by making measurements on channels of known structure. Preliminary results are given of single channel records establishing the effects of non-electrolytes on the conductance of gramicidin D channels. As an example of the potential uses of the procedure application is made to examine the oligomerization of alpha-toxin (alpha-hemolysin) channels. A model for the alpha-toxin hexamer, based on the crystal structure for the heptamer, is generated using molecular mechanics methods. The compatibility of the structures with single channel conductance data is assessed using HOLE.     

Aircrew exposure to cosmic radiation: New analysis,recommendations EURADOS

The ICRP report recommends to include aircrew members among occupationally exposed persons. Many theoretical and experimental studies have been realized since 1991, and several international bodies have taken part in discussion of the topic. Most of these results are based on studies and analysis realized in the laboratory of the authors.Work partially supported by EC Project FI3P-CT92-0026.     

Targeting DNA bulged microenvironments with synthetic agents: lessons from a natural product

Bulged regions of nucleic acids are important structural motifs whose function has been linked to a number of key nuclear processes. Additionally, bulged intermediates have been implicated in the etiology of several genetic diseases and as targets for viral regulation. Despite these obvious ramifications, few molecules are capable of selective binding to bulged sequences. Prompted by the remarkable affinity of a natural product metabolite, we have designed and prepared a series of readily accessible synthetic agents with selective bulge binding activity. Furthermore, by screening a library of bulge-containing oligodeoxynucelotides, correlations between structure and affinity of the agents can be drawn. In addition to potential applications in molecular biology, the availability of these spirocyclic agents now opens the door for rational drug design.     

Structure-activity relationships, kinetics, selectivity, and mechanistic studies of synthetic hydraphile channels in bacterial and mammalian cells

Hydraphile compounds are shown to be cytotoxic to Gram-negative and Gram-positive bacteria, yeast, and mammalian cells. Their cellular toxicity compares favorably with other synthetic ionophores and rivals that potency of natural antibiotics. The effects of structural variations on toxicity are described. The effects of these variations correlate well with previous studies of ion transport in liposomes. Whole cell patch clamping with mammalian cells confirms a channel mechanism in living cells suggesting that this family may comprise novel and flexible pharmacological agents.     

Effects of Stern layer conductance on electrokinetic energy conversion in nanofluidic channels

A thermo-electro-hydro-dynamic model is developed to analytically account for the effects of Stern layer conductance on electrokinetic energy conversion in nanofluidic channels. The optimum electrokinetic devices performance is dependent on a figure of merit, in which the Stern layer conductance appears as a nondimensional Dukhin number. Such surface conductance is found to significantly reduce the figure of merit and thus the efficiency and power output. This finding may explain why the recently measured electrokinetic devices performances are far below the theoretical predictions where the effects of Stern layer conductance have been ignored.     

Ionic N-B-N- and B-N-B-substituted benzene analogues: a theoretical analysis

Calculations are presented on six-π-electron N-B-N- and B-N-B-substituted benzene rings, [C(3)BN(2)H(6)](+) and [C(3)NB(2)H(6)](-), and their isomers. These compounds display a wide range of thermodynamic stability in those molecules, with N-B-N connectivity favored strongly in the cation, B-N-B in the anion. That stability order is easily understood using the charge distribution in a benzene polarized by heteroatom substitutions or the underlying allyl anion and cation. Deprotonation at N in [C(3)BN(2)H(6)](+) leads to a set of BN-substituted pyridines. The calculations predicted three B-N-substituted pyridines clearly more stable thermodynamically than those synthesized so far. The order of stability of the B-N-B-substituted benzenoid systems, which are as yet not well known experimentally, shows similar features. We investigated in a preliminary way the reactivity and potential stabilization by substitution of the energetically most stable structures and by examining possible escape routes by dimerization. Our study suggests new N-B-N and B-N-B molecules that could be made.     

Voltage-dependent formation of anion channels by synthetic rigid-rod push-pull beta-barrels

Ion channels formed by p-octiphenyls equipped with amphiphilic, cationic tripeptide strands and either with (5) or without (6) axial dipole moment are described (preliminary communication: N. Sakai, S. Matile, J. Am. Chem. Soc. 2002, 124, 1184-1185). Fluorescence kinetics with variably polarized neutral or anionic vesicles, together with planar bilayer conductance measurements, reveal voltage dependence with weakly lyotropic anion selectivity, and deactivation by competing surface potentials of the ion channels formed by asymmetric 5. In planar bilayers, 5 forms short-lived, poorly organized channels--similar to those produced by alpha-helical natural antibiotics--capable of transforming into stable, ohmic p-octiphenyl "beta-barrel" ion channels similar to those of the >99 % homologous but symmetric 6. Fluorescence depth quenching and circular dichroism studies confirm the effect of membrane potentials in promotion of the partitioning of 5 (but not 6) into the bilayers, identifying partitioning as the voltage-dependent step.     

基于离子液体和二芳基乙烯的离子凝胶的光致变色、导电、自修复及柔性传感性能

在丙烯酸聚合中原位引入4,4''-(全氟环戊烯-1,2-二基)双(5-甲基噻吩-2-甲醛)(DEA)和离子液体1-丁基-3-甲基咪唑四氟硼酸盐((BMIm)BF₄),制备了一种同时具有光致变色、导电、自黏附且具有宽温度工作区间等性能的新型离子自修复凝胶DPZI。由于(BMIm)BF₄的高热稳定性和低蒸气压,所获得的DPZI凝胶在-20~40℃较宽的温度下表现出高度稳定的机械和离子导电性能。DPZI系统中引入的Zn²⁺与—COO^-形成动态配位键,使得凝胶具有快速的自修复能力,0.06s即可超快恢复电阻响应;离子液体的引入同时赋予了凝胶优异的抗冻性。DPZI因光致变色单元DEA的异构化可在10s内快速发生黄-蓝颜色可逆转变,且光致变色单元的开环/闭环异构化能够实现对凝胶导电性的调节。此外,DPZI凝胶应变/压力式传感器可迅速、精准感知人体不同部位的运动并做出相应的响应;也可对呼吸、心率、声音做出精准识别,应变灵敏度为0.2%。     

基于离子液体和二芳基乙烯的离子凝胶的光致变色、导电、自修复及柔性传感性能

在丙烯酸聚合中原位引入4,4′-(全氟环戊烯-1,2-二基)双(5-甲基噻吩-2-甲醛)(DEA)和离子液体1-丁基-3-甲基咪唑四氟硼酸盐((BMIm)BF₄),制备了一种同时具有光致变色、导电、自黏附且具有宽温度工作区间等性能的新型离子自修复凝胶DPZI。由于(BMIm)BF₄的高热稳定性和低蒸气压,所获得的DPZI凝胶在-20～40℃较宽的温度下表现出高度稳定的机械和离子导电性能。DPZI系统中引入的Zn²⁺与—COO^- 形成动态配位键,使得凝胶具有快速的自修复能力,0.06 s即可超快恢复电阻响应;离子液体的引入同时赋予了凝胶优异的抗冻性。DPZI因光致变色单元DEA的异构化可在10 s内快速发生黄-蓝颜色可逆转变,且光致变色单元的开环/闭环异构化能够实现对凝胶导电性的调节。此外,DPZI凝胶应变/压力式传感器可迅速、精准感知人体不同部位的运动并做出相应的响应;也可对呼吸、心率、声音做出精准识别,应变灵敏度为0.2%。     

Symmetry, delocalization, and molecular conductance

Molecules bonded between two metal contacts form the simplest possible molecular devices. Coupled by the molecule, the left and right contact-based states form symmetric and antisymmetric pairs near the Fermi level. We relate the size of the resulting energy splitting DeltaE to the symmetry and degree of delocalization of the coupling molecular orbital. Qualitative trends in molecular conductances are then estimated from the variations in DeltaE. We examine benzenedithiol and other molecules of interest in transport.     

Electrophysiological response of cultured trabecular meshwork cells to synthetic ion channels

The response of living cells of the trabecular meshwork to synthetic ion channels is described. The THF-gramicidin hybrids THF-gram and THF-gram-TBDPS as well as a linked gA-TBDPS and gramicidin A were applied to cultured ocular trabecular meshwork cells. THF-gram application (minimal concentration, 10(-8) M; saturation, 10(-7) M) led to an additional conductance which displayed characteristics of weak Eisenman-I-selective cation channels, no cell destruction, an asymmetric change of the inward/outward currents, and higher current densities using Cs(+) as charge carrier compared to Na(+) and K(+). Linked-gA-TBDPS showed at 10(-12) M increases of the membrane conductance comparable to gA at 10(-7) M and a much faster response of the cells. Thus, THF-gramicidin hybrids form a basis for the use of synthetic ion channels in biological systems, which eventually may lead to new therapeutic approaches.     

New synthetic quinaldine conjugates: Assessment of their anti-cholinesterase,anti-tyrosinase and cytotoxic activities,and molecular docking analysis

Despite all the progress made to enrich the existing bank of drugs used to treat and cure Alzheimer and cancer patients, there is still a need to research and develop new bioactive candidates with superior efficacy but minimal side effects. In this context, a new series of anti-butyrylcholinesterase (anti-BChE), anti-tyrosinase and cytotoxic succinimide linked quinaldine conjugates 3a-i was designed and synthesized starting from 8-hydroxyquinaldine. The condensation of quinoleine-hydrazide 2 with electrophilic species such as aromatic and nonaromatic anhydrides provided the new compounds 3a-i. These synthesized heterocycles were characterized by spectroscopic means (¹H NMR, ¹³C NMR and ESI-HRMS). Their anti-butyrylcholinesterase, anti-tyrosinase and cytotoxic (cervical cancer cell (HeLa) and lung cancer cell (A549)) activities have been evaluated in vitro. Compounds 3e and 3 g were found to be more anti-BChE than Galanthamine. Compounds 3d, 3e and 3 g exerted better anti-tyrosinase activity than kojic acid. Also, 3a, 3f and 3 g showed interesting cytotoxic potential towards HeLa cell lines. These results were supported by the molecular docking analysis (structure–activity relationship (SAR)) to estimate and discuss possible interactions between these derivatives and active sites of proteins butyrylcholinesterase (PDB: 4B0P), tyrosinase (PDB: 2Y9X) and cytotoxic (topoisomerase IIα enzyme (PDB: 5GWK)).     

Cyanohydridoborate Anions: Synthesis,Salts, and Low-Viscosity Ionic Liquids

High-yield syntheses up to molar scales for salts of [BH(CN)₃]⁻ ( 2 ) and [BH₂(CN)₂]⁻ ( 3 ) starting from commercially available Na[BH₄] (Na 5 ), Na[BH₃(CN)] (Na 4 ), BCl₃, (CH₃)₃SiCN, and KCN were developed. Direct conversion of Na 5 into K 2 was accomplished with (CH₃)₃SiCN and (CH₃)₃SiCl as a catalyst in an autoclave. Alternatively, Na 5 is converted into Na[BH{OC(O)R}₃] (R=alkyl) that is more reactive towards (CH₃)₃SiCN and thus provides an easy access to salts of 2 . Some reaction intermediates were identified, for example, Na[BH(CN){OC(O)Et}₂] (Na 7 b ) and Na[BH(CN)₂{OC(O)Et}] (Na 8 b ). A third entry to 2 and 3 uses ether adducts of BHCl₂ or BH₂Cl such as the commercial 1,4-dioxane adducts that react with KCN and (CH₃)₃SiCN. Alkali metal salts of 2 and 3 are convenient starting materials for organic salts, especially for low viscosity ionic liquids (ILs). [EMIm] 3 has the lowest viscosity and highest conductivity with 10.2 mPa s and 32.6 mS cm⁻¹ at 20 °C known for non-protic ILs. The ILs are thermally, chemically, and electrochemically robust. These properties are crucial for applications in electrochemical devices, for example, dye-sensitized solar cells (Grätzel cells).