PI(4,5)P2 Clustering and Its Impact on Biological Functions.

Located at the inner leaflet of the plasma membrane (PM), phosphatidyl-inositol 4,5-bisphosphate [PI(4,5)P2] composes only 1-2 mol% of total PM lipids. With its synthesis and turnover both spatially and temporally regulated, PI(4,5)P2 recruits and interacts with hundreds of cellular proteins to support a broad spectrum of cellular functions. Several factors contribute to the versatile and dynamic distribution of PI(4,5)P2 in membranes. Physiological multivalent cations such as Ca2+ and Mg2+ can bridge between PI(4,5)P2 headgroups, forming nanoscopic PI(4,5)P2-cation clusters. The distinct lipid environment surrounding PI(4,5)P2 affects the degree of PI(4,5)P2 clustering. In addition, diverse cellular proteins interacting with PI(4,5)P2 can further regulate PI(4,5)P2 lateral distribution and accessibility. This review summarizes the current understanding of PI(4,5)P2 behavior in both cells and model membranes, with emphasis on both multivalent cation- and protein-induced PI(4,5)P2 clustering. Understanding the nature of spatially separated pools of PI(4,5)P2 is fundamental to cell biology.

Croscarmellose Sodium as Pelletization Aid in Extrusion-Spheronization.

Only few excipients are known to be suitable as pelletization aids. In this study, the potential use of croscarmellose sodium (CCS) as pelletization aid was investigated. Furthermore, the impact of cations on extrusion-spheronization (ES) of CCS was studied and different grades of CCS were tested. The influence of different cations on the swelling of CCS was investigated by laser diffraction. Mixtures of CCS with lactose monohydrate as filler with or without the inclusion of different cations were produced. The mixtures were investigated by mixer torque rheometry and consequently extruded and spheronized. Resulting pellets were analyzed by dynamic image analysis. In addition, mixtures of different CCS grades with dibasic calcium phosphate anhydrous (DP) and a mixture with praziquantel (PZQ) as filler were investigated. Calcium and magnesium cations caused a decrease of the swelling of CCS and influenced the use of CCS as pelletization aid since they needed to be included for successful ES. Aluminum, however, led to an aggregation of the CCS particles and to failure of extrusion. The inclusion of cations decreased the uptake of water by the mixtures which also reduced the liquid-to-solid-ratio (L/S) for successful ES. This was shown to be dependent on the amount of divalent cations in the mixture. With DP or PZQ as filler, no addition of cations was necessary for a successful production of pellets, however the optimal L/S for ES was dependent on the CCS grade used. In conclusion, CCS can be used as a pelletization aid.

Mechanical Properties of Alginate Hydrogels Cross-Linked with Multivalent Cations.

Ionically, cross-linked alginate gels have a potential to be used in a wide range of biomedical, environmental and catalytic applications. The study deals with preparation of alginate hydrogels cross-linked with various cations and the analysis of their equilibrium swelling and mechanical properties. It is shown that the type of cations used in the cross-linking process affects the elastic moduli and the equilibrium degree of swelling of the gels. The experimental data in small-amplitude oscillatory tests are fitted with a model that involves two material parameters: the elastic modulus of a polymer network and a measure of its inhomogeneity. The influence of cations on these quantities is studied numerically. It is revealed that the dependence of the elastic modulus of ionically cross-linked alginate gels on their equilibrium degree of swelling differs from that predicted by the conventional theory for covalently cross-linked gels.

Aggregation and construction mechanisms of microbial extracellular polymeric substances with the presence of different multivalent cations: Molecular dynamic simulation and experimental verification.

Interactions between cations and extracellular polymeric substances (EPS) play an important role in the formation of microbial aggregates and have key effects on the physical properties of activated sludge across wastewater and sludge treatment process. Here, a molecular model of EPS cluster in activated sludge was constructed and simulated by molecular dynamics (MD) to probe the structural properties of EPS and the interaction between EPS and prevalent multivalent cations (Ca2+, Mg2+, Al3+). Then the predicted changes in physical properties were validated against the dynamic light scattering, XAD resin fractionation and rheology test. The binding dynamics and interactions mechanisms between multivalent cations and EPS functional groups were further investigated using MD in combination with spectroscopic analysis. Results suggest that biopolymers are originally aggregated by electrostatic and intermolecular interactions forming dynamic clusters with negatively charged surface functional groups, which induced electrostatic repulsion preventing further agglomeration of biopolymer clusters. In the presence of multivalent cations, surface polar functional groups in biopolymers are connected, causing the rearrangement of EPS molecular conformation that forms larger and denser agglomerates. Reduced solvent accessible surface area, enhanced hydrophobicity, and increased binding free energy lead to a strong gel-like network of EPS. Ca2+ and Al3+ predominantly interact with functional groups in polysaccharides, promoting agglomeration of macromolecules. In contrast, Mg2+ and Al3+ disrupted the secondary structure of proteins, exposing hydrophobic interaction sites. Al3+ can better agglomerate biopolymers with its higher positive charge and shorter coordination distance as compared to Ca2+ and Mg2+, but compromised by the effect of hydration. This work offers a novel approach to explore the construction and molecular aggregation of EPS, enriching the theoretical basis for optimization of wastewater and sludge treatment.

Implication of cation-bridging interaction contribution to sorption of perfluoroalkyl carboxylic acids by soils.

Sorption of four perfluoroalkyl carboxylic acids (PFCAs) including perfluoropentanoic acid, perfluoroheptanoic acid, perfluorodecanoic acid, and perfluorododecanoic acid by three soils with cation exchange sites occupied by K+, Ca2+, or Fe3+ was measured using the batch equilibration method. We hypothesize that partitioning in soil organic matters (SOM) is the primarily operative mechanism for PFCA sorption by K+-soils, and sorption by Ca2+- or Fe3+-soils could be enhanced via cation-bridging interaction. The measured sorption isotherms for all four PFCAs by soils were linear within the aqueous concentration between 0 and 60 µg/L, and the distribution coefficients ranged between 14.8 and 173 L/kg. Long-chain PFCAs manifested greater sorption by the soils with higher SOM content. Compared to sorption by K+-soils, sorption of PFCAs by Ca2+- and Fe3+-soils increased by 19.9-90.2% and 38.5-219%, respectively. The relative contributions of cation-bridging interaction to the overall PFCA sorption were estimated to be 16.6-48.7% for Ca2+-soils and 27.8-67.7% for Fe3+-soils. These results demonstrate that multivalent exchangeable cations could play an important role, yet previously ignored, in controlling sorption and transport of PFCAs in soils.

An Amorphous Anode for Proton Battery.

Developing advanced electrode materials is crucial for improving the electrochemical performances of proton batteries. Currently, the anodes are primarily crystalline materials which suffer from inferior cyclic stability and high electrode potential. Herein, we propose amorphous electrode materials for proton batteries by using a general ion-exchange protocol to introduce multivalent metal cations for activating the host material. Taking Al3+ as an example, theoretical and experimental analysis demonstrates electrostatic interaction between metal cations and lattice oxygen, which is the primary barrier for direct introduction of the multivalent cations, is effectively weakened through ion exchange between Al3+ and pre-intercalated K+. The as-prepared Al-MoOx anode therefore delivered a remarkable capacity and outstanding cycling stability that outperforms most of the state-of-the-art counterparts. The assembled full cell also achieved a high voltage of 1.37 V. This work opens up new opportunities for developing high-performance electrodes of proton batteries by introducing amorphous materials.

Decreasing the Ion Diffusion Pathways for the Intercalation of Multivalent Cations into One-Dimensional TiS2 Nanobelt Arrays.

The sparse selection of available cathode materials that allow for reversible intercalation (deintercalation) of Al3+ species represents a major hurdle in the development of efficient Al-ion batteries. Herein, we developed cathodes based on TiS2 nanobelts that are capable of withstanding the high charge density of Al-ion species with minimal host lattice/ion interactions. The fabricated TiS2 nanobelts are highly anisotropic and are directly grown on a carbon current collector yielding a spatially controlled array. The sum of evidence presented in this work indicates that one-dimensional TiS2 nanobelt arrays can reversibly accommodate an unprecedented amount of Al ion species within their layered structure with no significant volume expansion as well as full retention of the nanobelt morphology. Thus, the one-dimensional morphology, nanoscale dimensions, short ion diffusion paths, high electrical conductivity, and absence of additives that hinder ion migration lead to Al-based TiS2 electrochemical devices exhibiting high specific capacity, less capacity fade, and resilience under higher cycling rates at both room temperature and elevated temperatures when compared to TiS2 platelets. We also present the effects of sulfur vacancies on the electrochemical performance of Al-based TiS2-x nanobelt array batteries. Although Al-ion batteries are still in their infancy, we believe our TiS2 nanobelt array cathode insertion hosts may play an important role in addressing the poor kinetics of solid-state Al-ion diffusion to enable efficient alternatives beyond lithium energy storage devices.

Effect of Multivalent Cations on Intermolecular Association of Isotactic and Atactic Poly(Methacrylic Acid) Chains in Aqueous Solutions.

The formation of nanoparticles of two poly(methacrylic acid) (PMA) isomers, atactic (aPMA) and isotactic (iPMA), was investigated in aqueous solutions in the presence of mono- (Na⁺) and multivalent cations (Mg2+ and La3+). Using dynamic (DLS) and static light scattering (SLS), we show that PMA nanoparticles have characteristics of microgel-like particles with a denser core and a swollen corona. iPMA aggregates are stable at a much higher degree of neutralization (αN) than the aPMA ones, indicating a much stronger association between iPMA chains. This is explained by proposing segregation of ionized and unionized carboxyl groups within the iPMA aggregates and subsequent cooperative hydrogen-bonding between COOH groups. The calculated shape parameter (ρ) suggests different behavior of both isomers in the presence of Mg2+ ions on one hand and Na⁺ and La3+ on the other. The microgel-like particles formed in the presence of Mg2+ ions have a more even mass distribution (possibly a no core-shell structure) in comparison with those in the presence of Na⁺ and La3+ ions. Differences between the aggregate structures in the presence of different ions are reflected also in calorimetric experiments and supported by pH and fluorimetric measurements. Reasons for different behavior in the presence of Mg2+ ions lie in specific properties of this cation, in particular in its strong hydration and preference towards monodentate binding to carboxylate groups.

Mechanisms of microbial community structure and biofouling shifts under multivalent cations stress in membrane bioreactors.

Five lab-scale membrane bioreactors (MBRs) were continuously operated to investigate the mechanisms and linkages of the microbial community and membrane fouling with trivalent metal cations (Fe(III) and Al(III)) and bivalent metal cations (Ca(II) and Mg(II)) shock loads. COD and NH4+-N removals showed recovery trends along with treatment process in the presence of metals. Trivalent metal cations reduced trans-membrane pressure (TMP) as well as fouling rate (dTMP/dt) and extended membrane module replacement period by binding activated sludge extracellular polymeric substance (EPS) and effluent soluble microbial product (SMP) productions. Illunima sequencing of 16S rRNA gene showed that metal stress stimulated specific metal-tolerance bacteria in the MBRs. Canonical correspondence analysis indicated that EPS and SMP made different contributions to the distribution of microbial community structure in Fe(III) and Al (III) systems, respectively. Under bivalent metal conditions, microbial community shifts and Ca(II) binding bridge worked together to inhibit EPS and SMP, while filamentous bacteria stimulated by Mg(II) that mainly controlled membrane fouling. This study has shown that the comparison of tri- and bivalent metals for membrane fouling control with binding bridge and functional microorganisms can provide a strategy for practical membrane bioreactor applications.

Multivalent cations-triggered rapid shape memory sodium carboxymethyl cellulose/polyacrylamide hydrogels with tunable mechanical strength.

A novel multivalent cations-triggered shape memory hydrogels were synthesized in a one-pot method, and interpenetrating double network was formed by chemically cross-linked polyacrylamide (PAM) network and physically cross-linked sodium carboxymethyl cellulose network. The temporary shape was fixed by complexation between a native biopolymer, sodium carboxymethyl cellulose (CMC), and transition metal ions, specifically Fe3+, Ag+, Al3+, Cu2+, Ni2+, and Mg2+. In particular, CMC-Fe3+ hydrogel exhibits excellent shape fixity ratio (95%). Therefore, we chose PAM/CMC1.0-Fe3+ hydrogel as the model material and further investigated its shape recovery process. It was found that a wide range of molecules and anions could be applied to break off the temporary cross-links between CMC and Fe3+. The PAM/CMC composite hydrogels also exhibited excellent tunable mechanical properties. The mechanical properties of the composite hydrogel can be adjusted by changing the cross-linking densities. The presented strategy could enrich the construction as well as application of biopolymers based shape memory hydrogels.

Cu and Zn adsorption to a terrestrial sediment: Influence of solid-to-solution ratio.

Laboratory batch adsorption experiments are commonly used to quantify contaminant adsorption to natural sediments. The distribution coefficients (KD) determined via these experiments are often incorporated into reactive transport models to predict contaminant movement in groundwater. The solid-to-solution ratio (SSR) in most laboratory experiments is much lower in comparison to that in aquifers, therefore it is questionable if distribution coefficients thus obtained can accurately quantify contaminant adsorption in the natural environment. SSR may also influence the leaching of multivalent cations and organic matters from natural sediments, which in turn could alter contaminant adsorption. The objective of this study is to determine how SSR influences heavy metal adsorption to a heterogeneous natural sediment. Cu and Zn adsorption was examined at SSRs of 250 and 25 g/L in the pH range of 3-8 using both batch experiments and surface complexation modelling. Results indicated that Ca, Mg, and DOC leaching depended on SSR, with higher SSR generally resulting in greater leaching. Conversely, Al and Fe leaching was less dependent on SSR. Cu distribution coefficients in the low pH range (3-6) and Zn distribution coefficients across the pH range (3-8) were not very sensitive to the SSR, despite higher leached concentrations of competing cations at a higher SSR. In contrast, Cu distribution coefficients at high pH (6-8) were more SSR-dependent, likely due to formation of non-adsorbing aqueous Cu-DOC complexes. This study demonstrates that cautions must be taken when distribution coefficients measured by laboratory batch experiments are used to predict contaminant transport in aquifers.

Is amyloid-ß an innocent bystander and marker in Alzheimer's disease? Is the liability of multivalent cation homeostasis and its influence on amyloid-ß function the real mechanism?

Two decades of the amyloid-ß (Aß) hypothesis in Alzheimer's disease (AD) and the prominence of Aß-targeting strategies have yet to meet the levels of original expectation. Disappointing results in numerous Phase II/III studies have called for a re-examination of the validity of the Aß-targeting approaches as an intervention strategy in AD. The mid-life onset of chronic conditions (e.g., hypertension, diabetes, insulin intolerance, and depression nominated as risk factors for the later development of AD) points to the possibility that each condition could involve mechanisms, which while relatively modest over a short-term, could have significant accumulative effects. What may also not be fully appreciated is that a number of these conditions involve potential disturbances to multivalent cations (MC) levels through various mechanisms such as autophagy, oxidative stress, and apoptosis. Furthermore, some MCs have intimate associations with the mechanisms by which Aß pathology manifests. Considering various lines of evidence and incorporating statistical analysis on Disability-Adjusted Life Years (DALYs) data of both causes of and prevalence of multifactorial risk factors in different world regions, we propose an MC hypothesis for AD. More specifically, we suggest that MC imbalance marks many chronic conditions and because of their involvement with Aß pathology, could reflect that Aß may be a vital manifestation and marker of underlying MC imbalance. Thus, careful targeting of MC imbalance may provide an alternative or complementary interventional approach to current Aß treatment strategies.