Cation Transport Research Articles

Landscape of Cyclic Vomiting Syndrome: From Bedside to Bench, Past to Present.

Investigations into mechanisms of cyclic(al) vomiting syndrome (CVS) began at the bedside more than a century ago. The modern era started with the formation of the Cyclic Vomiting Syndrome Association in 1993 that helped initiate robust efforts in education, advocacy, family physician conferences, scientific symposia, dedicated clinical programs, therapeutic guidelines, and research. Even today, bedside clues continue to emerge with the recent description of cannabinoid hyperemesis syndrome (CHS) and subsequent evidence of a perturbed endocannabinoid system. The clinical picture of CVS has evolved from that of a straightforward emetic disorder related to migraine requiring short-term antiemetics or prophylactic anti-migraine therapy, to a complicated, heterogenous one with multiple comorbid associations (anxiety, dysautonomia) and endophenotypes (migraine, Sato, CHS). This expanded view has important therapeutic implications which necessitate managing the comorbidities which can in turn impact the disease itself and proffered promising evidence that behavioral management (meditation) and vagal neuromodulation appear efficacious with few untoward effects, perhaps by reestablishing autonomic (parasympathetic) balance. The pathophysiologic picture now appears to be inscribed on an autonomic polyvagal design but multiple additional pathways interact, some confirmed (NK1, CB1, HPA axis, PPM1D gene, biological calendar, estrogen), and others, possible (TRPV-1, CGRP, GDF-15, mitochondrial dysfunction, impaired cation transport). CVS and its cousin CHS continue to challenge clinicians and perplex investigators and in the current era require not only a critical mass of specific pathway expertise but also syncretic biopsychosocial thinking to integrate these disparate threads. We may have reached such a tipping point at this Symposium.

Ultra-robust Single-Ion Conducting Composite Electrolytes for Stable Li-Metal Batteries.

With significantly high lithium-ion (Li+) transport efficiency, single-ion conducting polymer electrolytes (SIPEs) often suffer from low ionic conductivity due to the covalently bonded anions to the polymer backbone. Adding plasticizers to SIPEs to improve ionic conductivity usually reduces the polymer matrix's mechanical robustness, negatively affecting overall performance as solid electrolytes. Herein, to surpass such a trade-off relationship, we successfully designed a single-ion conducting composite membrane (c-SIPM60) with cross-linked linear SIPEs and incorporated glass-mesh substrate, which shows a cation transport number close to 1, ultrahigh tensile strength of 22 MPa (modulus of 547.3 MPa), and high ionic conductivity of 1.2 × 10-4 S/cm at 25 °C. The resultant Li/c-SIPM60/Li symmetric cell showed stable cycling performance up to 1200 h, and the LiFePO4/c-SIPM60/Li cell presented good reversibility at C/10. Meanwhile, with additional lithium salts, a high cationic-transport composite membrane (c-HTPM60) was designed to increase the ionic conductivity with retained high Li+ transport efficiency. The LiFePO4/c-HTPM60/Li cell exhibited a stable cycling performance with a capacity retention of >75.6% after 700 cycles at 25 °C. This work provides new insights into designing solid electrolytes with simultaneously high tLi+, ionic conductivity, and mechanical robustness, affording effective Li+ transport for energy storage systems.

Silicon reduces lead accumulation in Moso bamboo via immobilization and suppression of metal cation transporter genes in roots.

Lead (Pb) is a hazardous element that affects the growth and development of plants, while silicon (Si) is a beneficial element for alleviating the stress caused by heavy metals, including Pb. However, the mechanisms of Si reduce Pb accumulation in Moso bamboo remain unclear. In this study, physiological assessments and transcriptome analyses were conducted to investigate the interaction between Si and Pb. Our findings showed that Si application has no significant effect on alleviating Pb-induced inhibition of root elongation and dry weight in short-term and long-term experiments, respectively. However, it did rescue leaf yellowing, reduce Pb accumulation, particularly in the shoot. Pre-treatment with Si led to a reduction in Pb uptake, translocation, and accumulation, coupled with an increase in Pb fixation within the hemicellulose of the root cell wall, resulting in a lower Pb concentration in the cell sap. At the cellular level, Pb was found to be distributed in all cells of roots, and Si pre-treatment did not alter Pb distribution. Additionally, Si application down-regulated the expression of genes related to ABC and metal cation transporters. These findings indicate that Si reduces Pb accumulation in Moso bamboo by immobilizing Pb in the hemicellulose of root cell walls and down-regulating the expression of transporter genes involved in Pb uptake and transport.

Multiphysics Simulation of an Electrorefiner with Continuous Circulation of Molten Salt for Separation of Uranium and Neptunium

A 3-D continuous electrorefiner is designed and investigated using multiphysics simulation for the separation of uranium and neptunium from spent nuclear fuel in molten salt. The concentration distribution field, the electric field, the ionic flux density field, and the flow field are evaluated under galvanostatic and pulse electrorefining by numerical integration of the governing equations using finite element method. During the electrorefining without molten salt recirculation, the transport of the electroactive cations is controlled by diffusion and electromigration and high concentration gradient is built near electrodes. In a galvanostatic electrorefining with a current density of 50 A·m–2, the concentration of U3+ decreases to 26.7 mol·m–3 near cathode and increases to 62.5 mol·m–3 near anode within 40 s, and no co-deposition of uranium and neptunium occurs. In a galvanostatic electrorefining with a current density of 200 A·m–2, the concentration of U3+ decreases to 1.3 mol·m–3 near cathode and increases to 62.6 mol·m–3 near anode within 6.7 s, and the co-deposition of uranium and neptunium occurs after 0.28 mg of pure uranium is collected. With moderate molten salt recirculation, the transport of the electroactive cations is controlled by convection. The local concentrations of uranium ions approach steady near the electrodes within 32 s in a galvanostatic electrorefining of 50 A·m–2, and no co-deposition of uranium and neptunium occurs. Though the concentration of U3+ decreases to 21.1 mol·m–3 near cathode and increases to 62.6 mol·m–3 near anode within 6.7 s with a current density of 200 A·m–2, there is no co-deposition of uranium and neptunium occurred. In addition, it is proved that the pulse electrorefining does not improve the recovery of uranium compared with galvanostatic electrorefining with a corresponding average current.

A diode-like integrated hydrogel for piezoionic generators and sensors

Wearable sensing electronic devices based on hydrogel are gradually developing towards multifunction and portability, however, efficiently harvesting energy from the surrounding environment to power traditional hydrogel-based wearable electronic devices is a major challenge. The assembly of multilayer heterogeneous hydrogels is a potential strategy to address this challenge. Herein, inspired by the structure of diodes, a diode-like integrated hydrogel composed of a three-tier structure of anionic polyelectrolyte hydrogel, polyacrylamide hydrogel and cationic polyelectrolyte hydrogel is developed. By the connection of polyacrylamide hydrogel, the composite hydrogel exhibits excellent structural stability and mechanical properties. Notably, due to the introduction of MXene ion-conducting microchannels, the directional transport of free cations and anions ionized by anionic and cationic polyelectrolytes is achieved, thereby improving the conductivity (74.58 mS/cm), sensing (gauge factor = 7.47) and piezoionic output performance of the composite hydrogel. The composite hydrogel-based sensor can sense tiny facial movements and recognize the direction of human movement, and the composite hydrogel-based piezoionic generator exhibit more efficient mechanical-electric conversion performance, which can output the maximum voltage of 1410mV, current of 28 μA, and power density of 2.9mW/m2 for a composite hydrogel of 5×5 cm2. The integration of multilayer heterogeneous hydrogels proposes a versatile strategy for the development of high-performance hydrogel-based self-powered sensing electronic devices, expanding the application of hydrogels in artificial intelligence and human-computer interaction.

Effects of Magnesium Forms on the Magnesium Balance and Jejunal Transporters in Healthy Rats.

Magnesium (Mg) is a mineral necessary for many biological activities in mammals. Here, we compared the effect of two Mg compounds [Mg picolinate (MgPic) to Mg oxide (MgO)] on Mg bioavailability and intestinal Mg and calcium transporter protein levels. Three groups of 21 male Wistar-Albino rats were randomly allocated and fed a standard diet (control) or a 500 mg/kg Mg-supplemented (MgPic or MgO) diet for 8 weeks. The serum and liver Mg levels, Mg absorptivity, and retentivity were augmented in the MgPic group compared with the MgO group (P<0.05). Only MgPic supplementation elevated the expression of the genes encoding CLDN2, CLDN15, CNNM4, NCX1, PMCA1b, NCX2, and Calbindin-D9k in the jejunum by 1.59, 1.58, 1.70, 1.82, 2.02, 2.03, and 2.31 fold, respectively (P<0.05). Compared to the MgO-fed rats, MgPic rats had higher expression of the genes encoding NCX1, NCX2, PMCA1b, and Calbindin-D9k in the jejunum by 1.43, 1.72, 1.54, and 1.69 fold, respectively (P<0.01). These results suggest that MgPic increases Mg absorptivity and retentivity more than Mg bioavailability. In addition, MgPic can improve the paracellular and transcellular cationic mineral transport process. Thus, Mg deficiency disorders might be alleviated by MgPic more effectively than MgO.

Pt@WS2 Mott-Schottky Heterojunction Boosts Light-Driven Active Ion Transport for Enhanced Ionic Power Harvesting.

Bioinspired light-driven ion transport in two-dimensional (2D) nanofluidics offers exciting prospects for solar energy harvesting. Current single-component nanofluidic membranes often suffer from low light-induced driving forces due to the easy recombination of photogenerated electron-hole pairs. Herein, we present a Pt@WS2 Mott-Schottky heterojunction-based 2D nanofluidic membrane for boosting light-driven active ion transport and solar enhanced ionic power harvesting. The photovoltaic effect in the Mott-Schottky heterojunctions and photoconductance effect in WS2 multilayers account for more efficient charge separation across the nanofluidic membrane. In an equilibrium electrolyte solution, we observe directional cationic transport from the WS2 to the Pt region under visible-light illumination. In 10-3 M KCl electrolyte, the photocurrent and photovoltage reach 11.84 μA cm-2 and 30.67 mV, respectively. Moreover, the output power can reach up to 5.02 W m-2 under light illumination, compared to a value of 2.56 W m-2 without irradiation. This work not only introduces a driving mechanism for boosting ion transport but also offers a pathway for integrating multiple energy sources.

Phase Evolution of Li-Rich Layered Li-Mn-Ni-(Al)-O Cathode Materials upon Heat Treatments in Air

The phase evolution of Li-rich Li-Mn-Ni-(Al)-O cathode materials upon heat treatments in the air at 900 °C was studied by X-ray and neutron powder diffraction. In addition, the structures of Li1.26Mn0.61−xAlx Ni0.15O2, x = 0.0, 0.05, and 0.10, were refined from neutron powder diffraction data. For two-phase mixtures containing a monoclinic Li2MnO3 type phase M and a rhombohedral LiMn0.5Ni0.5O2 type phase R, the structures, compositions, and phase fractions change with heat treatment time. This is realized by the substitution mechanism 3Ni2+ ↔ 2Li+ + 1Mn4+, which enables cation transport between the phases. A whole-powder pattern fitting analysis of size and strain broadening shows that strain broadening dominates. The X-ray domain size increases with heat treatment time and is larger than the sizes of the domains of M and R observed by electron microscopy. For heat-treated samples, the domain size is smaller for R than for M and decreases with increasing Al doping.

Testing the Antigenic Potential of Transmembrane Proteins To Develop a Thermostable Tuberculosis MOF-Liposomal Vaccine.

Tuberculosis is one of the deadliest infectious diseases and continues to be a major health risk in many parts of the world. Even today, the century-old Bacillus Calmette-Guerin (BCG) vaccine is the only formulation on the market and is ineffective for several sections of the global population responsible for transmission. In the search for antigens that can mount a robust immune response, we have reported the recombinant expression and purification of two novel membrane proteins, the Cation transporter protein V (CtpV) and the Mycobacterial copper transporter B (MctB) present on the membrane surface of Mycobacterium tuberculosis. CtpV was tested as an antigen against the plasma of tuberculosis patients and was found to have a unique immune response profile compared with more commonly studied tuberculosis (TB) antigens. CtpV and MctB were reconstituted into proteoliposomes─individually and in combination─to stabilize them in a lipid bilayer and create a nanoparticle vaccine platform. In vivo experiments demonstrated that when delivered with an adjuvant, these antigens generated a robust Th1-biased T-cell response in mice, with the combination of both antigens performing the best and generating a response comparable to BCG. Since tuberculosis vaccines often need to be shipped to areas with fluctuating power supply, we encapsulated the proteoliposomes and the adjuvant in ZIF-8 to create a shelf-stable formulation. Complementary in vivo studies were carried out to confirm that the ZIF-8 coating did not interfere with or compromise the immunogenicity of the antigens.

Fabrication of Porous MXene/Cellulose Nanofibers Composite Membrane for Maximum Osmotic Energy Harvesting.

Two-dimensional (2D) nanofluidic channels are emerging as potential candidates for harnessing osmotic energy from salinity gradients. However, conventional 2D nanofluidic membranes suffer from high transport resistance and low ion selectivity, leading to inefficient transport dynamics and limiting energy conversion performance. In this study, we present a novel composite membrane consisting of porous MXene (PMXene) nanosheets featuring etched nanopores, in conjunction with cellulose nanofibers (CNF), yielding enhancement in ion flux and ion selectivity. A mild H2O2 oxidant is employed to etch and perforate the MXene sheets to create a robust network of cation transportation nanochannels that effectively reduces the energy barrier for cation transport. Additionally, CNF with a unique nanosize and high charge density further enhances the charge density and mechanical stability of the nanofluidic system. Under neutral pH and room temperature, the PMXene/CNF membrane demonstrates a maximum output power density of 0.95 W·m-2 at a 50-fold KCl gradient. Notably, this represents a 43% improvement over the performance of the pristine MXene/CNF membrane. Moreover, 36 nanofluidic devices connected in series are demonstrated to achieve a stable voltage output of 5.27 V and power a calculator successfully. This work holds great promise for achieving sustainable energy harvesting with efficient osmotic energy conversion utilization.

OCTN1 (SLC22A4) as a Target of Heavy Metals: Its Possible Role in Microplastic Threats.

Microplastics represent a threat due to their ability to enter the food chain, with harmful consequences for living organisms. The riskiness of these particles is also linked to the release of other contaminants, such as heavy metals. Solute Carriers (SLCs) represent eminent examples of first-level targets of heavy metals due to their localization on the cell surface. Putative targets of heavy metals are the organic cation transporters that form a sub-clade of the SLC22 family. Besides the physiological role in the absorption/release of endogenous organic cations, these transporters are crucial in drug disposition and their interaction with xenobiotics. In this work, the human SLC22A4, commonly known as OCTN1, was used as a benchmark to test interactions with heavy metals released by microplastics, exploiting the proteoliposome tool. The potency of metals to interfere with the OCTN1 function has been evaluated by measuring IC50 values calculated in the micromolar range. The molecular mechanism of interaction has been defined using site-directed mutagenesis and computational analyses. Finally, some chemical and physiological thiol-reacting compounds show the capacity to rescue the metal-inhibited OCTN1 function. The conclusions drawn on OCTN1 can be extended to other members of the SLC22 family and orthologous transporters in fish.

Prognostic significance of CNNM4 in ovarian cancer: a comprehensive bioinformatics analysis.

Ovarian cancer (OV) is a common malignancy in the female reproductive system, characterized by poor prognosis and high recurrence rates. The discovery of dependable molecular markers is crucial for improving the timeliness of detection, diagnosis, and treatment, ultimately aiming to lower fatality rates. CNNM4 (cyclin and CBS domain divalent metal cation transport mediator 4), a member of the CNNM (Cyclin M) family, binds to PRL (prolactin) to regulate magnesium homeostasis and influence tumor cell proliferation. Although CNNM4 is implicated in various cancers, its role in OV remains unclear. In vitro experiments assessed CNNM4 expression and its impact on the proliferation and migration of OV cells. Comparisons of TCGA and GTEx data were used to identify correlations between clinical features and outcomes. The role of CNNM4 in OV was further explored through comprehensive bioinformatics analyses. Elevated levels of CNNM4 expression were observed in OV cells and tissues, and were linked to a poor prognosis. CNNM4 could modulate the proliferation and migration of various OV cell lines, including IOSE-80, SKOV-3, and A2780. Through involvement in multiple signaling pathways, evidenced by GSVA and GSEA, CNNM4 was implicated in OV progression. CNNM4 positively regulated the infiltration level of Macrophages M2, T cells CD4 memory resting and NK cells resting, and had a negative regulation effect on NK cells activated and T cells gamma delta. Moreover, CNNM4 is related to drug sensitivity of OV. A prediction model based on CNNM4 expression and clinical symptoms was constructed to predict OV prognosis. CNNM4 may affect the progression of OV and is associated with a poor prognosis. It has potential as a biomarker for predicting survival and as a target for therapeutic interventions in OV patients.

Effect of SLC22A1 polymorphism on the pharmacokinetics of proguanil in Korean: A semi-physiologic population pharmacokinetic approach.

Proguanil, an antimalarial drug, undergoes hepatic uptake by the polymorphic organic cation transporter 1 (OCT1) and is subsequently metabolized by the cytochrome P-450 2C19 (CYP2C19) enzyme into its active metabolite, cycloguanil. This study aims to evaluate and mechanistically characterize the effect of genetic polymorphism of SLC22A1, which encodes OCT1, on the pharmacokinetics (PKs) of proguanil and cycloguanil in Korean. This study was based on a post hoc analysis of the PK results of a CYP2C19 mediated drug-drug interaction study (NCT04568772). Among the 16 CYP2C19 normal metabolizers enrolled in the previous study, 13 were prospectively genotyped for six SLC22A1 single nucleotide polymorphisms (SNPs) associated with a decreased function of OCT1. Among these, only the SNP SLC22A1 1022C>T (rs2282143) was observed, with four subjects being heterozygous (CT) and nine subjects homozygous for the wild-type allele (CC). The CT genotype showed a 1.2-fold higher systemic exposure of proguanil and a 0.6-fold lower exposure of cycloguanil compared to those in subjects with the CC genotype, resulting in a 0.5 to 0.6-fold lower metabolic ratio. Based on the PK and genotype data, a parent-metabolite joint population PK model including a well-stirred liver compartment was developed using a nonlinear mixed-effect modeling approach. The OCT1 activity of the CT genotype was estimated to be 0.42-fold lower compared to the CC genotype. In conclusion, the genetic polymorphism of SLC22A1 1022C>T increased the systemic exposure of proguanil, while decreasing the systemic exposure of cycloguanil by reducing the hepatic uptake of proguanil, as mechanistically described by a population PK approach.

Effects of genetic variants of organic cation transporters on metformin response in newly diagnosed patients with type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is a chronic disease that affects millions of people worldwide. Metformin is the optimal initial therapy for patients with T2DM. Genetic factors play a vital role in metformin response, including variations in drug efficacy and potential side effects. To determine the effects of genetic variants of multidrug and toxin extrusion protein 2 (MATE2), ataxia telangiectasia mutated (ATM), and serine/threonine kinase 11 (STK11) genes on metformin response in a cohort of Saudi patients. This prospective observational study included 76 T2DM newly diagnosed Saudi patients treated with metformin monotherapy and 80 control individuals. Demographic data, lipid profiles, creatinine levels, and hemoglobin A1c (HbA1c) levels were collected before and after treatment. All participants were genotyped for 5 single-nucleotide polymorphisms (SNPs), including rs4621031, rs34399035, rs2301759, rs1800058, and rs11212617, using TaqMan R genotyping assays. This study included 156 subjects. The subjects' mean ± SD age was 50.4 ± 10.14 years. The difference in HbA1c levels in T2DM after treatment ranged from -1.20% to 8.8%, with a mean value of 0.927 ± 1.73%. In general, 73.7% of the patients with T2DM showed an adequate response to metformin (HbA1c < 7%). STK11 (rs2301759) significantly affects the response to metformin in T2DM patients. In the rs2301759 single-nucleotide polymorphisms, the prevalence of an adequate response to metformin was significantly higher among patients with C/C and T/C genotypes than among non-responders (P = .021). However, no statistically significant associations were observed for the other tested SNPs. Our study provides evidence of an association between STK11 (rs2301759) and response to metformin in Saudi patients with T2DM. The need for targeted studies on specific gene-drug associations is emphasized, and further studies with a larger population should be conducted.

Genome-Wide Identification of the CAT Genes and Molecular Characterization of Their Transcriptional Responses to Various Nutrient Stresses in Allotetraploid Rapeseed.

Brassica napus is an important oil crop in China and has a great demand for nitrogen nutrients. Cationic amino acid transporters (CAT) play a key role in amino acid absorption and transport in plants. However, the CATs family has not been reported in B. napus so far. In this study, genome-wide analysis identified 22 CAT members in the B. napus genome. Based on phylogenetic and synteny analysis, BnaCATs were classified into four groups (Group I-Group IV). The members in the same subgroups showed similar physiochemical characteristics and intron/exon and motif patterns. By evaluating cis-elements in the promoter regions, we identified some cis-elements related to hormones, stress and plant development. Darwin's evolutionary analysis indicated that BnaCATs might have experienced strong purifying selection pressure. The BnaCAT family may have undergone gene expansion; the chromosomal location of BnaCATs indicated that whole-genome replication or segmental replication may play a major driving role. Differential expression patterns of BnaCATs under nitrate limitation, phosphate shortage, potassium shortage, cadmium toxicity, ammonium excess and salt stress conditions indicated that they were responsive to different nutrient stresses. In summary, these findings provide a comprehensive survey of the BnaCAT family and lay a foundation for the further functional analysis of family members.

Development of Fluoride-Ion Primary Batteries

The primary lithium-carbon monofluoride (Li-CFx) cell offers the highest specific energy of any commercial lithium metal battery chemistry known. However, the practical discharge voltage even at low current densities (ca. 2.5-2.7 V) is significantly lower relative to the theoretical value (4.57 V), causing a significant penalty in specific energy. To reduce the overpotential at the CFx electrode, we altered the electrochemical reaction mechanism to defluorinating the CFx electrode upon discharge, without concomitant lithiation. Here, using a room temperature fluoride-ion (F-ion) conducting electrolyte, we demonstrate the electrochemical defluorination of CFx cathodes paired with either lead (Pb) or tin (Sn) metal anodes for the first time.The primary F-ion Pb-CFx and Sn-CFx cells yielded capacities of 700 mAh g-1 and 400 mAh g-1, without optimization. Importantly, the discharge voltage of the Pb-CFx cell suggested that polarization loss of the cell was reduced by 1 V compared to a Li-CFx cell, indicating that a much higher operating voltage could be achieved with this design. XRD measurements show that the metal fluorides PbF2 or SnF2 form on the Pb or Sn anodes, respectively. Solid-state 19F and 119Sn{19F} NMR measurements of a F-ion Sn-CFx discharged Sn electrode and electrode components revealed the presence of both SnF2 and SnF4, where the latter is the main discharge product. Solid-state 2D 19F{19F} dipolar-correlation NMR experiments of the discharged Sn electrode revealed the amorphous nature of the electrochemically formed SnF4, confirming the reason it was not observed by XRD. The presence of nano-ordered regions with some amorphous in nature is also validated by Raman scattering and surface morphology changes of the electrodes upon discharge. Metal fluorides were discovered on the discharged CFx cathode of both the F-ion Pb-CFx and Sn-CFx cells, as evidenced by XRD, XRF, and solid-state NMR. ICP and XRF, quantified at ca. 5.4%, and ca. 3% contribution to the discharge capacity due to Pband Sn cation transport and reaction. Thus, a two-fold reduction in metal fluoride dissolution, transport, and reaction at the CFx electrode was achieved when using Sn, compared to the Pb.Solid-state 19F NMR measurements of a pristine and discharged CFx electrode from a Sn-CFx cell establish unambiguously that C-F bonds are broken upon discharge. The 19F molar percentage of CF bonds consumed (39%) was compared to the cell capacity extracted related to the theoretic capacity of CFx (36.4%), confirming the electrochemical defluorination of CFx as well as a minor contribution due to Sn2+ cation transport. Overall, we have demonstrated a new electrochemical discharge mechanism relative to conventional Li–CFx cells, which reduces polarization loss and raises the possibility of improvement to a higher practical discharge voltage by using alternative metal anodes. Future work will address the lithium metal counter electrode reactivity to enable a F-ion based Li-CFx cell.

(Invited) Change of Paradigms in Solid State Electrochemistry: Double-Cait Experiments with Two Clouds of Charge Carriers Representing Ideal Reversible Electrodes

Research and development in the field of solid state electrochemistry (SSE) is currently shaped by technical applications in particular regarding energy conversion and storage. There, the general goal is to safely transport as much charge as possible per unit time. For this purpose, the electrical circuit has to be closed. The classical circuit consist of a central sample (in general solid or liquid) connected to two electrodes (or series of electrodes) and an outer circuit in which the work is done. This implies the fact that there are at least two different interfaces between the sample and the electrodes. These are difficult to address selectively in classical approaches. The classical approach in solid state electrochemistry is built on a number of paradigms, which blur the view on and the access to new improved understanding and knowledge-based advance 1. Among these are:Paradigm #1: Electrochemical experiments require two or more massive (solid or liquid) electrodes in contact with the sample.Paradigm #2 Blocking of charge carrier transport is an unavoidable ingredient of SSE research.The goal of this project is to bring about a change of paradigms in solid state electrochemistry. The pivotal concept is to replace the two classical massive electrodes by two charge carrier clouds, which represent ideal reversible electrodes. The charge carriers can e.g. be alkali ions, protons, electrons or oxygen anions. In one prototypical implementation, a beam of positive charge carriers, e.g. Li+ ions, is aimed at one side of a mixed ionic electronic conductor (MIEC) and an electron beam is aimed at the other side. The Li+ and electrons charge up the two sides positively and negatively respectively. This leads to well defined electrochemical surface potentials, + surf and surf. Their corresponding gradients induce transport of cations and electrons inside the sample. This constitutes a double charge attachment induced transport experiment, Double-CAIT. The result of such macroscopic transport is quantified by means of secondary ion mass spectrometry (SIMS) and analyzed by means of the time dependent Nernst-Planck-Poisson (NPP) theory and time dependent Onsager theory. One pivotal characteristic is that any blocking of charge carrier transport can be completely avoided.The experiment proposed here is the logical advancement of 10 years of CAIT experiments in the authors group, where so far still one side of the sample was connected to a metal electrode 2,3,4,5,6,7,8,9. In the future Double-CAIT experiment, there will be no metal electrode in contact with the sample.As a result of these studies we expect to arrive at a new view on SSE free from the interference with any solid (or liquid) electrode. This includes equilibrium properties as well as transport properties but also their mutual relation. As an example of equilibrium properties we mention the advancement of a redox potential scale referenced to the vacuum state (sometimes not very clearly called “absolute redox scale”). The determination of transport coefficients will involve a truly time dependent approach.1 K.-M. Weitzel, Charge attachment--induced transport -- Toward new paradigms in solid state electrochemistry, Curr. Opin. Electrochem., 2021, 26, 100672, DOI:10.1016/j.coelec.2020.100672.2 M. Schäfer and K.-M. Weitzel, Bombardment induced ion transport. Part I, Physical Chemistry Chemical Physics : PCCP, 2011, 13, 20112–20122, DOI:10.1039/c1cp21215j.3 P. V. Menezes, J. Martin, M. Schäfer, H. Staesche, B. Roling and K.-M. Weitzel, Bombardment induced ion transport--part II. Experimental potassium ion conductivities in borosilicate glass, Physical Chemistry Chemical Physics : PCCP, 2011, 13, 20123–20128, DOI:10.1039/c1cp21216h.4 L. Rossrucker, P. V. Menezes, J. Zakel, M. Schäfer, B. Roling and K.-M. Weitzel, Bombardment Induced Potassium Ion Transport Through a Sodium Ion Conductor: Conductivities and Diffusion Profiles, Z. Phys. Chem., 2012, 226, 11083, DOI:10.1524/zpch.2012.0215.5 K. M. Weitzel, Bombardment Induced Ion Transport through Ion Conducting Glasses, DF, 2016, 6, 107–143, DOI:10.4028/www.scientific.net/DF.6.107.6 J. Martin, M. Gräf, T. Kramer, C. Jooss, M.-J. Choe, K. Thornton and K.-M. Weitzel, Charge attachment induced transport -- bulk and grain boundary diffusion of potassium in PrMnO$_3$, Phys. Chem. Chem. Phys., 2017, 19, 9762–9769, DOI:10.1039/C7CP00198C.7 M. Schäfer and K.-M. Weitzel, Site energy distribution of ions in the potential energy landscape of amorphous solids, Materials Today Physics, 2018, 5, 12–19, DOI:10.1016/j.mtphys.2018.05.002.8 M. Schäfer, D. Budina and K.-M. Weitzel, Site energy distribution of sodium ions in a sodium rubidium borate glass, Physical Chemistry Chemical Physics : PCCP, 2019, 21, 26251–26261, DOI:10.1039/c9cp05194e.9 J. L. Wiemer, M. Schaefer and K.-M. Weitzel, Li+ Ion Site Energy Distribution in Lithium Aluminum Germanium Phosphate, J. Phys. Chem. C, 2021, 125, 4977–4985, DOI:10.1021/acs.jpcc.0c11164.

Quantitative contributions of hepatic and renal organic cation transporters to the clinical pharmacokinetic cimetidine-metformin interaction.

The widely prescribed oral anti-diabetic drug metformin is eliminated unchanged in the urine primarily through active tubular secretion. This process is mediated by organic cation transporter 2 (OCT2), an uptake transporter expressed on the basolateral membrane of renal proximal tubule cells. Metformin uptake into the liver, the site of action, is mediated by OCT1, which is expressed on the sinusoidal membrane of hepatocytes. Sixteen healthy adults participated in a clinical pharmacokinetic drug-drug interaction study in which they were orally administered metformin (50 mg) as a dual OCT1/2 substrate alone (baseline) and with cimetidine (400 mg) as an OCT inhibitor. Relative to baseline, metformin systemic plasma exposure increased by 24% ( p <0.05) in the presence of cimetidine, which was accompanied by a disproportional decrease (8%) in metformin renal clearance ( p =0.005). Genetic variants of OCT1 and OCT2 moderately impacted the significance and magnitude of the interaction. Collectively, we hypothesized that the cimetidine-metformin interaction involves inhibition of hepatic OCT1 as well as renal OCT2. We tested this hypothesis by developing a physiologically based pharmacokinetic (PBPK) model and assessing potential OCT biomarkers in plasma and urine to gain mechanistic insight into the transporters involved in this interaction. The PBPK model predicted that cimetidine primarily inhibits hepatic OCT1 and, to a lesser extent, renal OCT2. The unchanged renal clearance of potential OCT2 biomarkers following cimetidine exposure supports a minimal role for renal OCT2 in this interaction.

Exploring Ion Transmission Mechanisms in Clay-Based 2D Nanofluidics for Osmotic Energy Conversion.

Clay-based 2D nanofluidics present a promising avenue for osmotic energy harvesting due to their low cost and straightforward large-scale preparation. However, a comprehensive understanding of ion transport mechanisms, and horizontal and vertical transmission, remains incomplete. By employing a multiscale approach in combination of first-principles calculations and molecular dynamics simulations, the issue of how transmission directions impact on the clay-based 2D nanofluidics on osmotic energy conversion is addressed. It is indicated that the selective and rapid hopping transport of cations in clay-based 2D nanofluidics is facilitated by the electrostatic field within charged nanochannels. Furthermore, horizontally transported nanofluidics exhibited stronger ion fluxes, higher ion transport efficiencies, and lower transmembrane energy barriers compared to vertically transported ones. Therefore, adjusting the ion transport pathways between artificial seawater and river water resulted in an increase in osmotic power output from 2.8 to 5.3Wm-2, surpassing the commercial benchmark (5Wm-2). This work enhanced the understanding of ion transport pathways in clay-based 2D nanofluidics, advancing the practical applications of osmotic energy harvesting.

Comparative genomics reveals putative copper tolerance genes in a Fusarium oxysporum strain.

Copper has been widely used as a main component in fungicides due to its versatility and effectivity. However, copper contamination from the environment creates selective pressure for the emergence of copper-tolerant pathogenic fungal strains that may proliferate and further cause damage to important agricultural crops. Although some studies focused on specific cellular mechanisms of copper tolerance, comprehensive genomic data is lacking. Here, we examined the genes potentially involved in copper tolerance by conducting a comparative analysis of newly sequenced genomes of two Fusarium oxysporum strains, IB-SN1W (copper-tolerant) and Foc-3429 (copper-sensitive), with other Fusarium species. Whole genome assembly and annotation identified ten core chromosomes shared between the two strains. Protein prediction revealed 16,894 and 15,420 protein coding genes for IB-SN1W and Foc-3429, respectively. There are 388 unique genes in IB-SN1W not found in Foc-3429, potentially contributing to copper tolerance. Furthermore, the identification of synteny between the two strains, including the analysis of orthologous genes within the Fusarium genus, confirmed the presence of accessory chromosomes that are specific to IB-SN1W, accounting for 13% of the genome. These accessory chromosomes consist of genes associated with cation transporter activity, vacuole, copper oxidases, and copper transporters which shed light on the potential mechanism of copper tolerance in this strain. Additionally, a region within an accessory chromosome contains a high density of copper-related genes, raising the possibility that horizontal transfer of these chromosomes may contribute to copper tolerance.