Neuromorphic responses of nanofluidic memristors in symmetric and asymmetric ionic solutions.

We show that ionic conduction properties of a multipore nanofluidic memristor can be controlled not only by the amplitude and frequency of an external driving signal but also by chemical gating based on the electrolyte concentration, presence of divalent and trivalent cations, and multi-ionic systems in single and mixed electrolytes. In addition, we describe the modulation of current rectification and hysteresis phenomena, together with neuromorphic conductance responses to voltage pulses, in symmetric and asymmetric external solutions. In our case, memristor conical pores act as nanofluidic diodes modulated by ionic solution characteristics due to the surface charge-regulated ionic transport. The above facts suggest potential sensing and actuating applications based on the conversion between ionic and electronic signals in bioelectrochemical hybrid circuits.

Electrical conductance of conical nanopores: Symmetric and asymmetric salts and their mixtures.

We have studied experimentally the electrical conductance-voltage curves of negatively and positively charged conical nanopores bathed in ionic solutions with monovalent, divalent, and trivalent cations at electrochemically and biologically relevant ionic concentrations. To better understand the interaction between the pore surface charge and the mobile ions, both single salts and salt mixtures have been considered. We have paid attention to the effects on the conductance of the cation valency, the pore charge asymmetry, and the pore charge inversion phenomena due to trivalent ions, both in single salts and salt mixtures. In addition, we have described how small concentrations of multivalent ions can tune the nanopore conductance due to monovalent majority ions, together with the effect of these charges on the additivity of ionic conductance and fluoride-induced negative differential conductance phenomena. This compilation and discussion of previously presented experimental data offers significant insights on the interaction between fixed and mobile charges confined in nanoscale volumes and should be useful in establishing and checking new models for describing ionic transport in the vicinity of charged surfaces.

Enhancement of heavy ion track-etching in polyimide membranes with organic solvents.

The effect of organic solvents on the ion track-etching of polyimide (PI) membranes is studied to enhance the nanopore fabrication process and the control over pore diameter growth. To this end, two approaches are employed to investigate the influence of organic solvents on the nanopore fabrication in PI membranes. In the first approach, the heavy ion irradiated PI samples are pretreated with organic solvents and then chemically etched with sodium hypochlorite (NaOCl) solution, resulting up to ∼4.4 times larger pore size compared to untreated ones. The second approach is based on a single-step track-etching process where the etchant (NaOCl) solution contains varying amounts of organic solvent (by vol%). The experimental data shows that a significant increase in both the bulk-etch and track-etch rates is observed by using the etchant mixture, which leads to ∼47% decrease in the nanopore fabrication time. This enhancement of nanopore fabrication process in PI membranes would open up new opportunities for their implementation in various potential applications.

Ionic circuitry with nanofluidic diodes.

Ionic circuits composed of nanopores functionalized with polyelectrolyte chains can operate in aqueous solutions, thus allowing the control of electrical signals and information processing in physiological environments. We demonstrate experimentally and theoretically that different orientations of single-pore membranes with the same and opposite surface charges can operate reliably in series, parallel, and mixed series-parallel arrangements of two, three, and four nanofluidic diodes using schemes similar to those of solid-state electronics. We consider also different experimental procedures to externally tune the fixed charges of the molecular chains functionalized on the pore surface, showing that single-pore membranes can be used efficiently in ionic circuitry with distinct ionic environments.

Lithium Ion Recognition with Nanofluidic Diodes through Host-Guest Complexation in Confined Geometries.

The lithium ion recognition is receiving significant attention because of its application in pharmaceuticals, lubricants and, especially, in energy technology. We present a nanofluidic device for specific lithium ion recognition via host-guest complexation in a confined environment. A lithium-selective receptor molecule, the aminoethyl-benzo-12-crown-4 (BC12C4-NH2), is designed and functionalized on single conical nanopores in polyethylene terephthalate (PET) membranes. The native carboxylic acid groups on the pore walls are covalently linked with the crown ether moieties and the process is monitored from the changes in the current-voltage ( I- V) curves. The B12-crown-4 moieties are known to specifically bind with lithium ions and when the modified pore is exposed to different alkali metal chloride solutions separately, significant changes in the ion current and rectification are only observed for lithium chloride. This fact suggests the generation of positively charged B12C4-Li+ complexes on the pore surface. Furthermore, the nanofluidic diode is able to recognize the lithium ion even in the presence of high concentrations of potassium ions in the external electrolyte solution. Thus, this nanodevice suggests a strategy to miniaturize nanofluidic porous systems for efficient recognition, extraction, and separation of lithium from raw materials.

Optimizing Energy Transduction of Fluctuating Signals with Nanofluidic Diodes and Load Capacitors.

The design and experimental implementation of hybrid circuits is considered allowing charge transfer and energy conversion between nanofluidic diodes in aqueous ionic solutions and conventional electronic elements such as capacitors. The fundamental concepts involved are reviewed for the case of fluctuating zero-average external potentials acting on single pore and multipore membranes. This problem is relevant to electrochemical energy conversion and storage, the stimulus-response characteristics of nanosensors and actuators, and the estimation of the accumulative effects caused by external signals on biological ion channels. Half-wave and full-wave voltage doublers and quadruplers can scale up the transduction between ionic and electronic signals. The network designs discussed here should be useful to convert the weak signals characteristic of the micro and nanoscale into robust electronic responses by interconnecting iontronics and electronic elements.

Cesium-Induced Ionic Conduction through a Single Nanofluidic Pore Modified with Calixcrown Moieties.

We demonstrate experimentally and theoretically a nanofluidic device for the selective recognition of the cesium ion by exploiting host-guest interactions inside confined geometry. For this purpose, a host molecule, i.e., the amine-terminated p-tert-butylcalix[4]arene-crown (t-BuC[4]C-NH2), is successfully synthesized and functionalized on the surface of a single conical nanopore fabricated in a poly(ethylene terephthalate) (PET) membrane through carbodiimide coupling chemistry. On exposure to the cesium cation, the t-BuC[4]C-Cs+ complex is formed through host-guest interaction, leading to the generation of positive fixed charges on the pore surface. The asymmetrical distribution of these groups along the conical nanopore leads to the electrical rectification observed in the current-voltage (I-V) curve. On the contrary, other alkali cations are not able to induce any significant change in the rectification characteristics of the nanopore. The success of the chemical modification is monitored from the changes in the electrical readout of the nanopore. Theoretical results based on the Nernst-Planck and Poisson equations further demonstrate the validity of the experimental approach to the cesium-induced ionic conduction of the nanopore.

Label-Free Pyrophosphate Recognition with Functionalized Asymmetric Nanopores.

The label-free detection of pyrophosphate (PPi) anions with a nanofluidic sensing device based on asymmetric nanopores is demonstrated. The pore surface is functionalized with zinc complexes based on two di(2-picolyl)amine [bis(DPA)] moieties using carbodiimide coupling chemistry. The complexation of zinc (Zn(2+) ) ion is achieved by exposing the modified pore to a solution of zinc chloride to form bis(Zn(2+) -DPA) complexes. The chemical functionalization is demonstrated by recording the changes in the observed current-voltage (I-V) curves before and after pore modification. The bis(Zn(2+) -DPA) complexes on the pore walls serve as recognition sites for pyrophosphate anion. The experimental results show that the proposed nanofluidic sensor has the ability to sense picomolar concentrations of PPi anion in the surrounding environment. On the contrary, it does not respond to other phosphate anions, including monohydrogen phosphate, dihydrogen phosphate, adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate. The experimental results are described theoretically by using a model based on the Poisson-Nernst-Planck equations.

Transport properties of track-etched membranes having variable effective pore-lengths.

The transport rate of molecules through polymeric membranes is normally limited because of their micrometer-scale thickness which restricts their suitability for more practical application. To study the effect of effective pore length on the transport behavior, polymer membranes containing cylindrical and asymmetric-shaped nanopores were prepared through a two-step ion track-etching technique. Permeation experiments were performed separately to investigate the transport properties (molecular flux and selectivity) of these track-etched membranes. The permeation data shows that the molecular flux across membranes containing asymmetric nanopores is higher compared to those having cylindrical pores. On the other hand, the cylindrical pore membranes exhibit higher selectivity than asymmetric pores for the permeation of charged molecules across the membrane. Current-voltage (I-V) measurements of single-pore membranes further verify that asymmetric pores exhibit lower resistance for the flow of ions and therefore show higher currents than cylindrical pores. Moreover, unmodified and polyethyleneimine (PEI) modified asymmetric-shaped pore membranes were successfully used for the separation of cationic and anionic analyte molecules from their mixture, respectively. In this study, two distinct effects (pore geometry and pore density, i.e. number of pores cm(-2)), which mainly influence membrane selectivity and molecular transport rates, were thoroughly investigated in order to optimize the membrane performance. In this context, we believe that membranes with high molecular transport rates could readily find their application in molecular separation and controlled drug delivery processes.

Nernst-Planck model of photo-triggered, pH-tunable ionic transport through nanopores functionalized with "caged" lysine chains.

We describe the fabrication of asymmetric nanopores sensitive to ultraviolet (UV) light, and give a detailed account of the divalent ionic transport through these pores using a theoretical model based on the Nernst-Planck equations. The pore surface is decorated with lysine chains having pH-sensitive (amine and carboxylic acid) moieties that are caged with photo-labile 4,5-dimethoxy-2-nitrobenzyl (NVOC) groups. The uncharged hydrophobic NVOC groups are removed using UV irradiation, leading to the generation of hydrophilic "uncaged" amphoteric groups on the pore surface. We demonstrate experimentally that polymer membranes containing single pore and arrays of asymmetric nanopores can be employed for the pH-controlled transport of ionic and molecular analytes. Comparison between theory and experiment allows for understanding the individual properties of the phototriggered nanopores, and provides also useful clues for the design and fabrication of multipore membranes to be used in practical applications.

Cation pumping against a concentration gradient in conical nanopores characterized by load capacitors.

We study the cation transport against an external concentration gradient (cation pumping) that occurs in conical nanopores when zero-average oscillatory and white noise potentials are externally applied. This pumping, based on the electrically asymmetric nanostructure, is characterized here by a load capacitor arrangement. In the case of white noise signals, the conical nanopore acts as an electrical valve that allows extraction of order from chaos. No molecular carriers, specific ion pumps, and competitive ion-binding phenomena are required. The nanopore conductance on/off states mimic those of the voltage-gated ion channels in the cell membrane. These channels allow modulating membrane potentials and ionic concentration gradients along oscillatory pulses in circadian rhythms and the cell cycle. We show that the combination of asymmetric nanostructures with load capacitors can be useful for the understanding of nanofluidic processes based on bioelectrochemical gradients.

Thermally controlled permeation of ionic molecules through synthetic nanopores functionalized with amine-terminated polymer brushes.

We present temperature-dependent ionic transport through an array of nanopores (cylindrical and conical) and a single conical nanopore functionalized with amine-terminated poly(N-isopropylacrylamide) [PNIPAAM-NH2] brushes. For this purpose, nanopores are fabricated in heavy ion irradiated polyethylene terephthlate (PET) membranes by a controlled chemical track-etching technique, which leads to the generation of carboxyl (COOH) groups on the pore surface. End-functionalized polymer chains are immobilized onto the inner pore walls via a 'grafting-to' approach through the covalent linkage of surface COOH moieties with the terminal amine groups of the PNIPAAM molecules by using carbodiimide coupling chemistry. The success of the chemical modification reaction is corroborated by measuring the permeation flux of charged analytes across the multipore membranes in an aqueous solution, and for the case of single conical pore by measuring the current-voltage (I-V) characteristics, which are dictated by the electrostatic interaction of the charged pore surface with the mobile ions in an electrolyte solution. The effective nanopore diameter is tuned by manipulating the environmental temperature due to the swelling/shrinking behaviour of polymer brushes attached to the inner nanopore walls, leading to a decrease/increase in the ionic transport across the membrane. This process should permit the thermal gating and controlled release of ionic drug molecules through the nanopores modified with thermoresponsive polymer chains across the membrane.

Metal ion affinity-based biomolecular recognition and conjugation inside synthetic polymer nanopores modified with iron-terpyridine complexes.

Here we demonstrate a novel biosensing platform for the detection of lactoferrin (LFN) via metal-organic frameworks, in which the metal ions have accessible free coordination sites for binding, inside the single conical nanopores fabricated in polymeric membrane. First, monolayer of amine-terminated terpyridine (metal-chelating ligand) is covalently immobilized on the inner walls of the nanopore via carbodiimide coupling chemistry. Second, iron-terpyridine (iron-terPy) complexes are obtained by treating the terpyridine modified-nanopores with ferrous sulfate solution. The immobilized iron-terPy complexes can be used as recognition elements to fabricate biosensing nanodevice. The working principle of the proposed biosensor is based on specific noncovalent interactions between LFN and chelated metal ions in the immobilized terpyridine monolayer, leading to the selective detection of analyte protein. In addition, control experiments proved that the designed biosensor exhibits excellent biospecificity and nonfouling properties. Furthermore, complementary experiments are conducted with multipore membranes containing an array of cylindrical nanopores. We demonstrate that in the presence of LFN in the feed solution, permeation of methyl viologen (MV(2+)) and 1,5-naphthalenedisulphate (NDS(2-)) is drastically suppressed across the iron-terPy modified membranes. On the basis of these findings, we envision that apart from conventional ligand-receptor interactions, the designing and immobilization of alternative functional ligands inside the synthetic nanopores would extend this method for the construction of new metal ion affinity-based biomimetic systems for the specific binding and recognition of other biomolecules.

Trends in hepatitis A research indexed in the Web of Science: a bibliometric analysis over the period from 1985 to 2019.

OBJECTIVE: A bibliometric analysis was conducted to build an all-inclusive view of the status of research on hepatitis A virus (HAV) for facilitating researchers, health professionals, and policymakers to understand the characteristics of research output in this particular domain. METHODS: A comprehensive search was conducted in the Web of Science database. The obtained data were exported into Microsoft Excel 2019, OriginPro 2018 and VOSviewer software for windows. RESULTS: From 1985 to 2019, a total of 5,950 studies on HAV were published, with an overall h-index of 105, and 90,350 total citations. The most cited article on HAV was "Classification of chronic viral hepatitis: a need for reassessment" authored by Scheuer in the Journal of Hepatology with a total of 1,121 citations. The most cited article on HAV vaccine was "A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children" by Werzberger et al. in the New England Journal of Medicine with 401 citations. The most frequent year of publication was 2019 (n = 250). The largest number of studies were funded by the United States Department of Health Human Services (n = 199). The organization with the highest number of publications was the United States Centers for Disease Control and Prevention (n = 228). The United State of America (n = 1,500) was the country with the most publications. 'Vaccine' was the leading journal with 299 publications. CONCLUSIONS: The highest numbers of studies were published in developed countries. There is a clear need for interdisciplinary research approaches to evaluate and intervene in HAV endemic areas.

Epidemiology, diagnosis, vaccines, and bibliometric analysis of the 100 top-cited studies on Hepatitis E virus.

INTRODUCTION: In low-income countries, Hepatitis E infection is a common cause of acute hepatitis. So far, only two recombinant vaccines (rHEV and HEV 239) have been developed against Hepatitis E virus (HEV). Of which HEV 239 is licensed in China, but is not yet available in any other country. OBJECTIVE: This study aims to discuss epidemiology, diagnosis, available vaccines for HEV, and provides an overview of 100 top-cited studies on HEV. METHODS: A bibliometric analysis was conducted on the topic "HEV" through a systematic search of the Web of Science. The keywords used were "Hepatitis E" and retrieved articles were assessed for number of attributes. RESULTS: The search returned a total of 3,235 publications, cited 95,858 times with h-index 129. The main finding for the 100 top-cited articles on HEV showed: number of authors ranging from 1 to 23, cited references range from 4 to 304, global citations score per year range from 6.61 to 175, and global citations score range from 148 to 791. Of the 100 top-cited studies, the authors who published most articles are Purcell (n = 18), Meng (n = 17), and Emerson (n = 15). Most The largest share of articles on HEV was contributed by United States of America (n = 49) with 12,795 citations. The National Institute of Allergy andInfectious Diseases was leading institute with greatest number of publications (n = 16), cited 3,950 times. CONCLUSIONS: The studies conducted on HEV have increased over time. The information presented would be very useful in decision making for policy makers providing health care, and for academicians in providing a reference point for future research.

Fluoride-Induced Negative Differential Resistance in Nanopores: Experimental and Theoretical Characterization.

We describe experimentally and theoretically the fluoride-induced negative differential resistance (NDR) phenomena observed in conical nanopores operating in aqueous electrolyte solutions. The threshold voltage switching occurs around 1 V and leads to sharp current drops in the nA range with a peak-to-valley ratio close to 10. The experimental characterization of the NDR effect with single pore and multipore samples concern different pore radii, charge concentrations, scan rates, salt concentrations, solvents, and cations. The experimental fact that the effective radius of the pore tip zone is of the same order of magnitude as the Debye length for the low salt concentrations used here is suggestive of a mixed pore surface and bulk conduction regime. Thus, we propose a two-region conductance model where the mobile cations in the vicinity of the negative pore charges are responsible for the surface conductance, while the bulk solution conductance is assumed for the pore center region.

Phosphoprotein Detection with a Single Nanofluidic Diode Decorated with Zinc Chelates.

We report a nanofluidic device for the label-free detection of phosphoprotein (PPn) analytes. To achieve this goal, a metal ion chelator, namely 4-[bis(2-pyridylmethyl)aminomethyl]aniline (DPA-NH2 ) compound was synthesized. Single asymmetric nanofluidic channels were fabricated in polyethylene terephthalate (PET) membranes. The chelator (DPA-NH2 ) molecules are subsequently immobilized on the nanochannel surface, followed by the zinc ion complexation to afford DPA-Zn2+ chelates, which act as ligand moieties for the specific binding of phosphoproteins. The success of the chemical reaction and biomolecular recognition process that occur in a confined geometry can be monitored from the changes in electrical readout of the nanochannel. The nanofluidic sensor has the ability to sensitively and specifically detect lower concentrations (≥1 nM) of phosphoprotein (albumin and α-casein) in the surrounding environment as evidenced from the significant decrease in ion current flowing through the nanochannels. However, dephosphoproteins such as lysozyme and dephospho-α-casein even at higher concentration (>1 µM) could not induce any significant change in the transmembrane ion flux. This observation indicated the sensitivity and specificity of the proposed nanofluidic sensor towards PPn proteins, and has potential for use in differentiating between phosphoproteins and dephosphoproteins.

Impact of Surface Charge Directionality on Membrane Potential in Multi-ionic Systems.

The membrane potential (Vmem), defined as the electric potential difference across a membrane flanked by two different salt solutions, is central to electrochemical energy harvesting and conversion. Also, Vmem and the ionic concentrations that establish it are important to biophysical chemistry because they regulate crucial cell processes. We study experimentally and theoretically the salt dependence of Vmem in single conical nanopores for the case of multi-ionic systems of different ionic charge numbers. The major advances of this work are (i) to measure Vmem using a series of ions (Na+, K+, Ca2+, Cl-, and SO42-) that are of interest to both energy conversion and cell biochemistry, (ii) to describe the physicochemical effects resulting from the nanostructure asymmetry, (iii) to develop a theoretical model for multi-ionic systems, and (iv) to quantify the contributions of the liquid junction potentials established in the salt bridges to the total cell membrane potential.

Ionic transport characteristics of negatively and positively charged conical nanopores in 1:1, 2:1, 3:1, 2:2, 1:2, and 1:3 electrolytes.

We study experimentally the current (I)-voltage (V) curves of 1:1, 2:1, 3:1, 2:2, 1:2, and 1:3 electrolytes in positively and negatively charged conically-shaped pores of nanoscale dimensions. The positive charges are poly(allylamine hydrochloride) chains functionalized on the pore surface by electrostatic interactions while the negative charges are carboxylic acid groups. Under physiological conditions, these fixed-charge groups are ionized and strongly interact with the different monovalent, divalent, and trivalent ions in the pore solution. The current rectification of the I-V curves and the membrane potentials provide fundamental information on the interaction of the pore charge groups with the mobile ions present at electrochemically and biologically relevant concentrations. The different pores and electrolytes studied, together with the abundant experimental data provided, can be useful to develop new theoretical simulations of transport phenomena in nanoscale solutions that are confined within charged surfaces.

Potassium-induced ionic conduction through a single nanofluidic pore modified with acyclic polyether derivative.

Solid-state nanofluidic pores have been attracting considerable attention of scientific community because of their structural and chemical resemblance with biological ion channels for mimicking biological processes in living systems. Compared to ion channels, synthetic nanopores exhibit high stability, control over pore dimensions (size and geometry) and their surface chemical properties can be tuned on demand. Therefore, they are considered perfect candidates to design and develop nanofluidic sensory devices by introducing a variety of functional moieties on the inner pore surface. Here, we present a nanofluidic pore for the recognition of potassium cations using acyclic polyether derivative in confined environment. To this end, amine terminated acyclic polyether derivative (bis-podand-NH2) is synthesized and covalently coupled with the carboxylic acid groups on the single conical nanopore walls prepared in polymer membrane. The bis-podand moieties fixed on the pore walls in the presence of potassium cation yield recognition domain for the specific binding of K+ cation. Therefore, the changes in rectified ion flux are only noticed on exposure to potassium chloride solution due to formation of positively charged bis-podand-K+ complexes on the pore surface. In contrast, for the case of other alkali metal chloride solutions, only slight changes in the ion current rectification are noticed. We believe that the proposed device provides a strategy to develop and miniaturize different nanofluidic pore based sensors for the efficient detection of other cations/anions by simply changing the length of polyethylene glycol units.