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Plastic pellets, the pre-production form of many plastic products, undergo oxidation and photodegradation upon exposure to oxygen and sunlight, resulting in visible color changes. This study examines the impact of environmental aging on the mechanical interactions between pellet-derived microplastics and lipid bilayers, a critical component of biological membranes. Polyethylene pellets were collected from La Pineda beach near Tarragona, Spain, and categorized by chemical composition and yellowing index, an indicator of aging. The hydrophilicity of these pellets was assessed using contact angle measurements. Microplastics were produced by grinding and filtering these pellets and subsequently dispersed around a free-standing lipid bilayer within a 3D microfluidic chip to investigate their interactions. Our results reveal that aged microplastics exhibit a significantly increased adhesive interaction with lipid bilayers, leading to greater bilayer stretching. Theoretical modeling indicates a linear relationship between the adhesive interaction and the contact angle of the pellets, reflecting their hydrophilicity. These findings emphasize the increased mechanical impact of aged microplastics on biological membranes, which raises concerns about their potential toxicological effects on living organisms. This study highlights the importance of understanding the interactions between environmentally aged microplastics and biological systems to assess their risks, as these may differ significantly from pristine microplastics often studied under laboratory conditions. [ABSTRACT FROM AUTHOR]

The transport of particles through channels holds immense significance in physics, chemistry, and biological sciences. For instance, the motion of solutes through biological membranes is facilitated by specialized proteins that create water-filled channels. Valuable insights can be obtained by studying the transition paths of particles through a channel and gathering information on their lifetimes inside the channel as well as their exit probabilities. In a similar vein, we consider a one-dimensional model of channel-facilitated transport where a diffusive particle is subject to attractive interactions with the walls of the channel. We study the statistics of conditional and unconditional escape times in the presence of resetting—an intermittent dynamics that brings the particle back to its initial coordinate stochastically. We determine analytically the physical conditions under which such a resetting mechanism becomes beneficial for the faster escape of the particles from the channel, thus enhancing transport. Our theory has been verified with the aid of Brownian dynamics simulations for various interaction strengths and extents. The overall results presented herein highlight the scope of resetting-based strategies to be universally promising for complex transport processes of single or long molecules through biological membranes. [ABSTRACT FROM AUTHOR]

Biological cell membranes are primarily comprised of a diverse lipid bilayer with multiple phospholipid (lipid) types, each of which is comprised of a hydrophilic headgroup and two hydrophobic hydrocarbon tails. The lipid type determines the molecular structure of head and tail groups, which can affect membrane mechanics at nanoscale and subsequently cell viability under mechanical loading. Hence, using molecular dynamics simulations, the current study investigated seven membrane phospholipids and the effect of their structural differences on physical deformation, mechanoporation damage, and mechanical failure of the membranes under tension. The inspected phospholipids showed similar yield stresses and strains, as well as pore evolution and damage, but significantly different failure strains. In general, failure occurred at a lower strain for lipids with a larger equilibrium area per lipid. The obtained results suggest that larger headgroup structure, greater degree of unsaturation, and tail-length asymmetry influenced the phospholipids' ability to pack against each other, increased the fluidity and equilibrium area per lipid of the membrane, and resulted in lower failure strain. Overall, this study provides insights on how different phospholipid structures affect membrane physical responses at the molecular level and serves as a reference for future studies of more complex membrane systems with intricate biophysical properties. [ABSTRACT FROM AUTHOR]

Cholesterol (Chol) plays a crucial role in shaping the intricate physicochemical attributes of biomembranes, exerting a considerable influence on water molecules proximal to the membrane interface. In this study, we conducted molecular dynamics simulations on the bilayers of two lipid species, dipalmitoylphosphatidylcholine (DPPC) and palmitoyl sphingomyelin; they are distinct with respect to the structures of the hydrogen-bond (H-bond) acceptors. Our investigation focuses on the dynamic properties and H-bonds of water molecules in the lipid-membrane systems, with a particular emphasis on the influence of Chol at varying temperatures. Notably, in the gel phase at 303 K, the presence of Chol extends the lifetimes of H-bonds of the oxygen atoms acting as H-bond acceptors within DPPC with water molecules by a factor of 1.5–2.5. In the liquid-crystalline phase at 323 K, on the other hand, H-bonding dynamics with lipid membranes remain largely unaffected by Chol. This observed shift in H-bonding states serves as a crucial key to unraveling the subtle control mechanisms governing water dynamics in lipid-membrane systems. [ABSTRACT FROM AUTHOR]

Biological lipid membranes are generally asymmetric, not only with respect to the composition of the two membrane leaflets but also with respect to the state of mechanical stress on the two sides. Computer simulations of such asymmetric membranes pose unique challenges with respect to the choice of boundary conditions and ensemble in which such simulations are to be carried out. Here, we demonstrate an alternative to the usual choice of fully periodic boundary conditions: The membrane is only periodic in one direction, with free edges running parallel to the single direction of periodicity. In order to maintain bilayer asymmetry under these conditions, nanoscale "sticky tapes" are adhered to the membrane edges in order to prevent lipid flip-flop across the otherwise open edge. In such semi-periodic simulations, the bilayer is free to choose both its area and mean curvature, allowing for minimization of the bilayer elastic free energy. We implement these principles in a highly coarse-grained model and show how even the simplest examples of such simulations can reveal useful membrane elastic properties, such as the location of the monolayer neutral surface. [ABSTRACT FROM AUTHOR]

This retrospective case series investigated the clinical and radiographic outcomes in 19 intrabony defects treated with periodontal regenerative therapy utilizing a combined approach. Placing an amnion-chorion membrane (ACM) as a biologic modifier on the root surface of the periodontally diseased tooth, combined with bone substitutes and an additional ACM as a barrier membrane, the treated sites were examined 8 to 24 months after the therapy. The preoperative (baseline) mean probing pocket depth (PPD) was 7.21 ± 1.08 mm, and the mean clinical attachment level (CAL) was 7.68 ± 1.49 mm. A mean PPD reduction of 4.05 ± 1.22 mm, CAL gain of 3.68 ± 1.34 mm, and 73.91% ± 22.02% of bone fill were recorded postoperatively. Without any adverse events, root-surface application of ACM as a biologic material in periodontal regenerative therapy could be a safe and cost-effective approach. [ABSTRACT FROM AUTHOR]

iSoLF is a coarse-grained (CG) model for lipid molecules with the implicit-solvent approximation used in molecular dynamics (MD) simulations of biological membranes. Using the original iSoLF (iSoLFv1), MD simulations of lipid bilayers consisting of either POPC or DPPC and these bilayers, including membrane proteins, can be performed. Here, we improve the original model, explicitly treating the electrostatic interactions between different lipid molecules and adding CG particle types. As a result, the available lipid types increase to 30. To parameterize the potential functions of the new model, we performed all-atom MD simulations of each lipid at three different temperatures using the CHARMM36 force field and the modified TIP3P model. Then, we parameterized both the bonded and non-bonded interactions to fit the area per lipid and the membrane thickness of each lipid bilayer by using the multistate Boltzmann Inversion method. The final model reproduces the area per lipid and the membrane thickness of each lipid bilayer at the three temperatures. We also examined the applicability of the new model, iSoLFv2, to simulate the phase behaviors of mixtures of DOPC and DPPC at different concentrations. The simulation results with iSoLFv2 are consistent with those using Dry Martini and Martini 3, although iSoLFv2 requires much fewer computations. iSoLFv2 has been implemented in the GENESIS MD software and is publicly available. [ABSTRACT FROM AUTHOR]

Piezoelectric nanomaterials for wireless neuromodulation is a promising alternative to traditional electrical stimulation. However, the low‐avidity between piezoelectric nanomaterials and cellular membranes leads to low efficiency of electrical signal transmission, which requires high‐intensity thresholds of ultrasound stimulation (US). Here, lead‐free piezoelectric (K,Na)NbO3 (KNN) nanoparticles (NPs) with cholesterol coating (KNNC) are presented, in which Cholesterol can be accommodated in the membrane and make them append on the plasma membrane. Compared to non‐modified nanoparticles, cell‐anchored KNNC NPs highly resist convective washout owing to high affinity of cholesterol to biological membranes, which enables highly efficient wireless electrical stimulation to activate cell impulses under low‐intensity ultrasound. Meanwhile, after perfusion washing, the KNNC NPs distributed around the cells are washed away, while part of KNNC NPs remain on the surface of cell membrane still can induce significant Ca2+ influx under US, similar to the group without washing, indicating the KNNC NPs appended on the cell play a major role in wireless electrical stimulation. Furthermore, the highly efficient electrical transmission of KNNC enables neural differentiation of stem cells in regulating synaptic plasticity by modulating Ca2+ influx, demonstrating that KNNC NPs offer a perspective toward minimally invasive wireless neuromodulation therapies for neurological diseases. [ABSTRACT FROM AUTHOR]

ABC transporters are a diverse superfamily of membrane protein complexes that utilize the binding/hydrolysis of ATP to power substrate movement across biological membranes or perform mechanical work. In bacteria, these transporters play essential roles in biochemical processes ranging from nutrient uptake and protein secretion to antibiotic resistance and cell-wall remodeling. Analysis of the complete genome sequence of the Gram-positive organism Bacillus subtilis has previously revealed that ABC transporters comprise the largest family of proteins across the entire genome. Despite the widespread presence of these transporters in B. subtilis, relatively few experimental structures of ABC transporters from this organism have been determined. Here we leverage the power of AlphaFold-Multimer to predict the 3-dimensional structure of all potential ABC transporter complexes that have been identified from bioinformatic analysis of the B. subtilis genome. We further classify the ABC transporters into discrete classes based on their predicted architecture and the presence or absence of distinct protein domains. The 3-dimensional structure predictions presented here serve as a template to understand the structural and functional diversity of ABC transporter systems in B. subtilis and illuminate areas in which further experimental structural validation is warranted. [ABSTRACT FROM AUTHOR]

Quantifying small molecule uptake across a biological membrane of a target cell is crucial for the development of efficacious and selective drugs. However, current methods to obtaining such data are not trivial. Herein, we present an accessible, higher-throughput (20 minutes), 1H NMR spectroscopy assay, which enables the quantification of small molecule phospholipid passive membrane permeation and membrane adhesion parameters. [ABSTRACT FROM AUTHOR]

Nano- and micro-sized vesicular and colloidal structures mediate cell–cell communication. They are important players in the physiology of plants, animals, and humans, and are a subject of increasing interest. We investigated the effect of three surfactants, N-cetylpyridinium chloride (CPC), sodium dodecyl sulfate (SDS), and Triton X-100 (TX100), and two anionic polyelectrolytes, sodium polystyrene sulfonate (NaPSS) and sodium polymethacrylate (NaPMA), on nanoliposomes. In addition, the effect of SDS and TX100 on selected biological membranes (erythrocytes and microalgae) was investigated. The liposomes were produced by extrusion and evaluated by microcalorimetry and light scattering, based on the total intensity of the scattered light (Itot), hydrodynamic radius (Rh), radius of gyration (Rg), shape parameter p (=Rh/Rg,0), and polydispersity index. The EPs shed from erythrocytes and microalgae Dunaliella tertiolecta and Phaeodactylum tricornutum were visualized by scanning electron microscopy (SEM) and analyzed by flow cytometry (FCM). The Rh and Itot values in POPC liposome suspensions with added CPC, SDS, and TX100 were roughly constant up to the respective critical micelle concentrations (CMCs) of the surfactants. At higher compound concentrations, Itot dropped towards zero, whereas Rh increased to values higher than in pure POPC suspensions (Rh ≈ 60–70 nm), indicating the disintegration of liposomes and formation of larger particles, i.e., various POPC–S aggregates. Nanoliposomes were stable upon the addition of NaPSS and NaPMA, as indicated by the constant Rh and Itot values. The interaction of CPC, SDS, or TX100 with liposomes was exothermic, while there were no measurable heat effects with NaPSS or NaPMA. The SDS and TX100 increased the number density of EPs several-fold in erythrocyte suspensions and up to 30-fold in the conditioned media of Dunaliella tertiolecta at the expense of the number density of cells, which decreased to less than 5% in erythrocytes and several-fold in Dunaliella tertiolecta. The SDS and TX100 did not affect the number density of the microalgae Phaeodactylum tricornutum, while the number density of EPs was lower in the conditioned media than in the control, but increased several-fold in a concentration-dependent manner. Our results indicate that amphiphilic molecules need to be organized in nanosized particles to match the local curvature of the membrane for facilitated uptake. To pursue this hypothesis, other surfactants and biological membranes should be studied in the future for more general conclusions. [ABSTRACT FROM AUTHOR]

Objective: Nowadays, the use of SiO2-based nanoparticles in the treatment of ocular diseases has significantly increased. Nanoparticles (NPs) can easily penetrate biological membranes and interact with membrane components such as ion channels. SiO2 nanoparticles (SiO2 NPs) are one of the most common used NPs in health field. There are limited studies determining the effects of SiO2 NPs on the retinal cells. In this study, it was aimed to investigate the effect of SiO2 NPs on transient receptor potential canonical 1 (TRPC1) expression and intracellular basal calcium concentration in retinal pigment epithelial (RPE) cells. Methods: Cultured hARPE 19 cells were divided into four groups as control, 50 µg/mL SiO2, 100 µg/mL SiO2, and 150 µg/mL SiO2. All groups except control were incubated for 24 h with SiO2 NPs. Subsequently, the expression level of TRPC1 was assessed utilizing the real-time polymerase chain reaction (PCR) method. Basal intracellular calcium concentration [Ca2+]i was measured using confocal microscopy. Results and Discussion: Relative TRPC1 gene expression levels and basal [Ca2+]i decreased significantly in the SiO2 dose groups compared to control group. There was a significant correlation of relative channel expression level and basal [Ca2+]i. Conclusions: Our results show that SiO2 NPs reduce the expression of TRPC1 channels, leading to a decrease in basal [Ca2+]i. The decrease in [Ca2+]i is likely to affect calcium-related physiological processes in RPE cells. However, more investigations are required regarding this subject. [ABSTRACT FROM AUTHOR]

[Display omitted] • Actin cytoskeleton is involved in a variety of cellular processes. • Dynamic changes in actin act as key regulators of cellular signaling. • Actin reorganization on signaling is rarely explored due to lack of suitable assay. • Quantitation of F-actin by high magnification imaging and image reconstruction. • Actin quantitation is applied in a range of processes: signaling to pathogen entry. The actin cytoskeleton is involved in a large number of cellular signaling events in addition to providing structural integrity to the cell. Actin polymerization is a key event during cellular signaling. Although the role of actin cytoskeleton in cellular processes such as trafficking and motility has been extensively studied, the reorganization of the actin cytoskeleton upon signaling has been rarely explored due to lack of suitable assays. Keeping in mind this lacuna, we developed a confocal microscopy based approach that relies on high magnification imaging of cellular F-actin, followed by image reconstruction using commercially available software. In this review, we discuss the context and relevance of actin quantitation, followed by a detailed hands-on approach of the methodology involved with specific points on troubleshooting and useful precautions. In the latter part of the review, we elucidate the method by discussing applications of actin quantitation from our work in several important problems in contemporary membrane biology ranging from pathogen entry into host cells, to GPCR signaling and membrane-cytoskeleton interaction. We envision that future discovery of cell-permeable novel fluorescent probes, in combination with genetically encoded actin-binding reporters, would allow real-time visualization of actin cytoskeleton dynamics to gain deeper insights into active cellular processes in health and disease. [ABSTRACT FROM AUTHOR]

While the permeation mechanism of solute (e.g., ions and glucose) through biological membrane has been studied extensively, the mechanical role of water transport in intracellular phenomena has not received much attention. In the present study, to investigate the effect of water permeation on the intracellular pressure response, a novel permeation flux model through a biological membrane is developed by incorporating the coupling permeabilities (between water and ion fluxes) as the water-ion interaction in the ion channels. The proposed model is applied to a two-dimensional permeation problem of water and ions in a closed cell separated by a thin membrane. The permeation flux model reproduces the typical time response of intracellular pressure to action potentials with reasonable agreement with experimental results in the literature, indicating that the pressure response can be characterized by the following three parameters: water permeability, the mass ratio of water and ion, and the ratio of the permeation fluxes of water and ion. In particular, the permeation flux ratio plays an essential role in intracellular phenomena; depending on the value of the permeation flux ratio, the time lag between the action potential and the pressure response is 0.1 times smaller than that expected by the previous researchers, indicating that water transport associated with ions may trigger a pressure response. This study demonstrates the importance of water permeation in intracellular mechanical response through coupling of the fluid motion and electric fields. [ABSTRACT FROM AUTHOR]

In this review, we discuss recent reproductive organ-on-a-chip (OoC) experiments that encompass multiple target areas of investigation, including model fabrication strategies, transport mechanisms, and immunology. We highlight fetal membrane and placental biology, OoC history and background, and the designs of reproductive OoC platforms. Reproductive OoC designs include fetal membrane models such as the Fetal Membrane-on-a-chip (FMOC) and others, placental models such as the placenta on-a-chip, and full reproductive tract models such as EVATAR. Diverse fabrication strategies and the integration of multiple model materials are explored. OoC samples can be analyzed with many analytical techniques, including mass spectrometry, fluorescence microscopy, ELISAs, impedance spectroscopy, and electrochemical techniques. The future of reproductive OoC models is a promising technology for advancing preterm birth (PTB) research, pharmacology studies, and fertility technologies. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the components of the cell-free supernatant (CFS) derived from a novel strain of psychrophilic Lactobacillus, Dellaglioa algida, and to further elucidate the impact of this CFS on various cellular processes. Specifically, we sought to understand its effects on the cell membrane, protein and DNA release, protease activity, and metabolites of Pseudomonas fluorescens and Pseudomonas fragi, thereby clarifying the antibacterial mechanism involved. The CFS components were analyzed using Gas Chromatography–Mass Spectrometry (GC-MS), the Coomassie Brilliant Blue method, and the phenol–sulfuric acid method. The inhibitory effect of the CFS on Pseudomonas fluorescens and Pseudomonas fragi was assessed using the ethidium bromide (EB) assay, Oxford cup assay, and ultramicroassay. Additionally, we analyzed the metabolites produced by Pseudomonas fluorescens and Pseudomonas fragi when treated with the CFS. The findings reveal that the CFS of Dellaglioa algida contains 94 volatile components, with protein and sugar concentrations of 32.857 ± 0.9705 mg/mL and 98.250 ± 4.210 mg/L, respectively. The CFS induces varying degrees of damage to the cell membranes of both Pseudomonas fluorescens and Pseudomonas fragi, leading to the release of intracellular proteins and DNA. Furthermore, the CFS reduced the protease activity and metabolic capacity of Pseudomonas fluorescens and Pseudomonas fragi. These results enhance our understanding of the mechanism by which psychrophilic Dellaglioa algida inhibits Pseudomonas fluorescens and Pseudomonas fragi, confirming that its inhibitory effect predominantly occurs through damage to the biological cell membranes of Pseudomonas. Dellaglioa algida is a newly identified cold-adapted inhibitor of Pseudomonas, indicating that its CFS is an effective microbial inhibitor in cold environments. This discovery suggests potential applications in inhibiting the growth and reproduction of Pseudomonas fluorescens and Pseudomonas fragi in food, pharmaceuticals, perfumes, and other chemicals, providing a valuable new reference for industrial preservation. [ABSTRACT FROM AUTHOR]

Nanotube porins form transmembrane nanomaterial-derived scaffolds that mimic the geometry and functionality of biological membrane channels. We report synthesis, transport properties, and osmotic energy harvesting performance of another member of the nanotube porin family: boron nitride nanotube porins (BNNTPs). Cryo-transmission electron microscopy imaging, liposome transport assays, and DNA translocation experiments show that BNNTPs reconstitute into lipid membranes to form functional channels of ~2-nm diameter. Ion transport studies reveal ion conductance characteristics of individual BNNTPs, which show an unusual C1/4 scaling with ion concentration and pronounced pH sensitivity. Reversal potential measurements indicate that BNNTPs have strong cation selectivity at neutral pH, attributable to the high negative charge on the channel. BNNTPs also deliver very large power density up to 12 kW/m2 in the osmotic gradient transport experiments at neutral pH, surpassing that of other BNNT-based devices by two orders of magnitude under similar conditions. Our results suggest that BNNTPs are a promising platform for mass transport and osmotic power generation. [ABSTRACT FROM AUTHOR]

Glycophosphatidylinositol (GPI) anchors are the predominant glycoconjugate in Plasmodium parasites, enabling modified proteins to associate with biological membranes. GPI biosynthesis commences with donation of a mannose residue held by dolichol-phosphate at the endoplasmic reticulum membrane. In Plasmodium dolichols are derived from isoprenoid precursors synthesised in the Plasmodium apicoplast, a relict plastid organelle of prokaryotic origin. We found that treatment of Plasmodium parasites with apicoplast inhibitors decreases the synthesis of isoprenoid and GPI intermediates resulting in GPI-anchored proteins becoming untethered from their normal membrane association. Even when other isoprenoids were chemically rescued, GPI depletion led to an arrest in schizont stage parasites, which had defects in segmentation and egress. In those daughter parasites (merozoites) that did form, proteins that would normally be GPI-anchored were mislocalised, and when these merozoites were artificially released they were able to attach to but not invade new red blood cells. Our data provides further evidence for the importance of GPI biosynthesis during the asexual cycle of P. falciparum, and indicates that GPI biosynthesis, and by extension egress and invasion, is dependent on isoprenoids synthesised in the apicoplast. Author summary: The plastid apicoplast organelle of the malaria parasite Plasmodium falciparum has long been recognised as a drug target. However, the downstream metabolic pathways have not been fully elucidated. In this study we inhibited apicoplast function in blood-stage P. falciparum and, following the depletion of essential apicoplast-derived isoprenoids, we observed that levels of the polyisoprenoid alcohol, dolichol-phosphate, were also depleted. This led to a block in the synthesis of glycophosphatidylinositols (GPIs), which are abundant plasma membrane glycolipids and serve as membrane anchors for major surface proteins. Severe parasite impairments followed with incomplete membrane segmentation of their daughter merozoites, which could subsequently neither egress nor reinvade host red blood cells. Our data implicates dolichol as an essential parasite metabolite, dependent on normal apicoplast function, and reveals novel roles for GPI anchored proteins. The widespread phenotype following disrupted dolichol synthesis supports aspects of GPI biosynthesis as potential future drug targets. [ABSTRACT FROM AUTHOR]

Eukaryotic cells are characterized by multiple chemically distinct compartments, one of the most notable being the nucleus. Within these compartments, there is a continuous exchange of information, chemicals, and signaling molecules, essential for coordinating and regulating cellular activities. One of the main goals of bottom-up synthetic biology is to enhance the complexity of synthetic cells by establishing functional compartmentalization. There is a need to mimic autonomous signaling between compartments, which in living cells, is often regulated at the genetic level within the nucleus. This advancement is key to unlocking the potential of synthetic cells as cell models and as microdevices in biotechnology. However, a technological bottleneck exists preventing the creation of synthetic cells with a defined nucleus-like compartment capable of genetically programmed intercompartment signaling events. Here, we present an approach for creating synthetic cells with distinct nucleus-like compartments that can encapsulate different biochemical mixtures in discrete compartments. Our system enables in situ protein expression of membrane proteins, enabling autonomous chemical communication between nuclear and cytoplasmic compartments, leading to downstream activation of enzymatic pathways within the cell. [ABSTRACT FROM AUTHOR]

Although ammonium is the preferred nitrogen source for microbes and plants, in animal cells it is a toxic product of nitrogen metabolism that needs to be excreted. Thus, ammonium movement across biological membranes, whether for uptake or excretion, is a fundamental and ubiquitous biological process catalysed by the superfamily of the Amt/Mep/Rh transporters. A remarkable feature of the Amt/Mep/Rh family is that they are ubiquitous and, despite sharing low amino acid sequence identity, are highly structurally conserved. Despite sharing a common structure, these proteins have become involved in a diverse range of physiological process spanning all domains of life, with reports describing their involvement in diverse biological processes being published regularly. In this context, we exhaustively present their range of biological roles across the domains of life and after explore current hypotheses concerning their evolution to help to understand how and why the conserved structure fulfils diverse physiological functions. [ABSTRACT FROM AUTHOR]

The crucial molecular factors that shape the interfaces of lipid-binding proteins with their target ligands and surfaces remain unknown due to the complex makeup of biological membranes. Cholesterol, the major modulator of bilayer structure in mammalian cell membranes, is recognized by various proteins, including the well-studied cholesterol-dependent cytolysins. Here, we use in vitro evolution to investigate the molecular adaptations that preserve the cholesterol specificity of perfringolysin O, the prototypical cholesterol-dependent cytolysin from Clostridium perfringens. We identify variants with altered membrane-binding interfaces whose cholesterol-specific activity exceeds that of the wild-type perfringolysin O. These novel variants represent alternative evolutionary outcomes and have mutations at conserved positions that can only accumulate when epistatic constraints are alleviated. Our results improve the current understanding of the biochemical malleability of the surface of a lipid-binding protein. [ABSTRACT FROM AUTHOR]

Membrane transport proteins undergo multistep conformational changes to fulfill the transport of substrates across biological membranes. Substrate release and uptake are the most important events of these multistep reactions that accompany significant conformational changes. Thus, their relevant structural intermediates should be identified to better understand the molecular mechanism. However, their identifications have not been achieved for most transporters due to the difficulty of detecting the intermediates. Herein, we report the success of these identifications for a light-driven chloride transporter halorhodopsin (HR). We compared the time course of two flash-induced signals during a single transport cycle. One is a potential change of Cl−-selective membrane, which enabled us to detect tiny Cl−-concentration changes due to the Cl− release and the subsequent Cl−-uptake reactions by HR. The other is the absorbance change of HR reflecting the sequential formations and decays of structural intermediates. Their comparison revealed not only the intermediates associated with the key reactions but also the presence of two additional Cl−-binding sites on the Cl−-transport pathways. The subsequent mutation studies identified one of the sites locating the protein surface on the releasing side. Thus, this determination also clarified the Cl−-transport pathway from the initial binding site until the release to the medium. [ABSTRACT FROM AUTHOR]

Cyclopropane fatty acid synthases (CFAS) catalyze the conversion of unsaturated fatty acids to cyclopropane fatty acids (CFAs) within bacterial membranes. This modification alters the biophysical properties of membranes and has been correlated with virulence in several human pathogens. Despite the central role played by CFAS enzymes in regulating bacterial stress responses, the mechanistic properties of the CFAS enzyme family and the consequences of CFA biosynthesis remain largely uncharacterized in most bacteria. We report the first characterization of the CFAS enzyme from Pseudomonas aeruginosa (PA), an opportunistic human pathogen with complex membrane biology that is frequently associated with antimicrobial resistance and high tolerance to various external stressors. We demonstrate that CFAs are produced by a single enzyme in PA and that cfas gene expression is upregulated during the transition to stationary phase and in response to oxidative stress. Analysis of PA lipid extracts reveal a massive increase in CFA production as PA cells enter stationary phase and help define the optimal membrane composition for in vitro assays. The purified PA-CFAS enzyme forms a stable homodimer and preferentially modifies phosphatidylglycerol lipid substrates and membranes with a higher content of unsaturated acyl chains. Bioinformatic analysis across bacterial phyla shows highly divergent amino acid sequences within the lipid-binding domain of CFAS enzymes, perhaps suggesting distinct membrane-binding properties among different orthologs. This work lays an important foundation for further characterization of CFAS in P. aeruginosa and for examining the functional differences between CFAS enzymes from different bacteria. [ABSTRACT FROM AUTHOR]

Lyotropic liquid crystals (LLCs) have garnered attention as a promising nanocarrier delivery system for enhancing skin permeation owing to their unique structural properties, such as improved drug loading and controlled drug release and versatility. LLCs are greatly explored for topical drug delivery owing to their strong bio-adhesive nature and structural similarity to the biological membranes when applied topically, which improves skin retention and permeation of the drugs. This review explores the functionality of structural design, especially the optimization of micellar systems, hexagonal and lamellar phases, and bicontinuous cubic and sponge phases, to achieve efficient skin permeation of therapeutic loaded LLCs. Furthermore, customization of surfactant to achieve skin compatibility and permeation is explored along with incorporating molecular modifications, functionalization, and the influence of surfactant hydrophilic–lipophilic balance. Additionally, the review illuminates the impact of LLCs curvature and the engineering of ordered and disordered phases for optimal drug release. Emerging advanced techniques such as surface modification with various ligands, stimuli-responsive LLCs for on-demand drug release, and combination therapies with multifunctional LLCs for synergistic effects that can promote targeted and site-specific drug delivery have also been discussed. The detailed findings have been discussed in this review with appropriate case studies. Challenges and future perspectives in designing and formulating LLCs for skin permeation are addressed to ignite future research. The knowledge and advancements presented in this review pave the way for developing next-generation LLCs-based systems, enabling enhanced permeation through the skin and opening new possibilities in the treatment of various dermatological conditions. [ABSTRACT FROM AUTHOR]

Bisphenols are a group of endocrine-disrupting chemicals used worldwide for the production of plastics and resins. Bisphenol A (BPA), the main bisphenol, exhibits many unwanted effects. BPA has, currently, been replaced with bisphenol F (BPF) and bisphenol S (BPS) in many applications in the hope that these molecules have a lesser effect on metabolism than BPA. Since bisphenols tend to partition into the lipid phase, their place of choice would be the cellular membrane. In this paper, I carried out molecular dynamics simulations to compare the localization and interactions of BPA, BPF, and BPS in a complex membrane. This study suggests that bisphenols tend to be placed at the membrane interface, they have no preferred orientation inside the membrane, they can be in the monomer or aggregated state, and they affect the biophysical properties of the membrane lipids. The properties of bisphenols can be attributed, at least in part, to their membranotropic effects and to the modulation of the biophysical membrane properties. The data support that both BPF and BPS, behaving in the same way in the membrane as BPA and with the same capacity to accumulate in the biological membrane, are not safe alternatives to BPA. [ABSTRACT FROM AUTHOR]

The migrasome, an organelle recently discovered in migrating cells, facilitates intercellular communication and plays crucial roles in various physiological and pathological conditions. The formation of migrasomes is governed by a tightly regulated process that progresses through three distinct stages: nucleation, maturation, and expansion. This process is regulated by essential molecules such as sphingomyelin lsynthase 2 (SMS2), phosphatidylinositol-4-phosphate 5-kinase type I α (PIP5K1α), integrins, and tetraspanins. The formation of migrasomes is propelled by the assembly of membrane microdomains, driven by the dynamic interaction between biochemical reactions and the physical properties of the membrane at migrasome formation sites. Migrasomes, newly identified organelles, play crucial roles in intercellular communication, contributing to organ development and angiogenesis. These vesicles, forming on retraction fibers of migrating cells, showcase a sophisticated architecture. Recent research reveals that migrasome biogenesis is a complicated and highly regulated process. This review summarizes the mechanisms governing migrasome formation, proposing a model in which biogenesis is understood through the lens of membrane microdomain assembly. It underscores the critical interplay between biochemistry and biophysics. The biogenesis unfolds in three distinct stages: nucleation, maturation, and expansion, each characterized by unique morphological, biochemical, and biophysical features. We also explore the broader implications of migrasome research in membrane biology and outline key unanswered questions that represent important directions for future investigation. [ABSTRACT FROM AUTHOR]

Treatment of schizophrenia with currently available drugs is often ineffective or results in several adverse reactions. In previous studies focusing on the search for new antipsychotic drugs, we designed and obtained a series of dopamine D2 and serotonin 5-HT1A and 5-HT2A receptor ligands that were pharmacologically evaluated and showed promising antipsychotic activity. Evaluation of ADMET parameters is an important issue in drug development and should be performed at its early stage to avoid developing molecules with poor pharmacokinetics, that are unlikely to enter the market. For this reason, in this work we focused on the assessment of physicochemical parameters of selected compounds from the series we obtained to assess their drug-like potential. The results of thermal analysis showed that most of the tested compounds are thermally stable above 200 °C, with one compound stable up to 190 °C. Permeability through biological membranes assessed in the parallel artificial membrane permeability assay indicated that all tested compounds effectively migrate through biological membranes by means of passive diffusion. The solubility of the tested compounds was determined in PBS, reflecting physiological pH, and 0.01 M HCl, indicating their low to moderate solubility in PBS, which was significantly improved in acidic environment. The lipophilicity of the studied compounds expressed as LogD falls within the range of 1.84–2.80, what suggest that they would show good oral absorption and the ability to cross lipid barriers. The studies were supplemented with in silico prediction of ADMET parameters, which also indicate the probable high drug-likeness of the tested compounds. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, was shown to be expressed 100–1000 fold higher in prostate adenocarcinoma as compared to normal prostate epithelium. Given the enzymatic function of PSMA with the presence of an internalization triggering motif, various Glu-urea-Lys-based inhibitors have been developed and, amongst others, radiolabeled with positron emitters for targeted positron emission tomography imaging such as 68Ga-PSMA-HBED-CC Glu-urea-Lys(Ahx) as well as with beta and alpha-emitting radioisotopes for targeted therapy, e.g., 177Lu-PSMA-617. In this paper, we review and discuss the potential implications for targeted imaging and therapy of altered PSMA-glycosylation, of PSMA-driven activation of the P13K/Akt/mTOR, of the evolution over time and the relationship with androgen signaling and changes in DNA methylation of PSMA, and of androgen deprivation therapy (ADT) in prostate carcinoma. [ABSTRACT FROM AUTHOR]

Stimulus-responsive materials hold significant promise for antitumor applications due to their variable structures and physical properties. In this paper, a series of peptides with a responsive viologen derivative, Pep-CnV (n = 1, 2, 3) were designed and synthesized. The process and mechanism of the interaction were studied and discussed. An ultraviolet–visible (UV) spectrophotometer and fluorescence spectrophotometer were used to study their redox responsiveness. Additionally, their secondary structures were measured by Circular Dichroism (CD) in the presence or absence of the reductant, Na2SO3. DPPC and DPPG liposomes were prepared to mimic normal and tumor cell membranes. The interaction between Pep-CnV and biomembranes was investigated by the measurements of surface tension and cargo leakage. Results proved Pep-CnV was more likely to interact with the DPPG liposome and destroy its biomembrane under the stimulus of the reductant. And the destruction increased with the length of the hydrophobic tail chain. Pep-CnV showed its potential as an intelligent antitumor agent. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. Milk contains abundant polar lipids, which are vital constituents of biological membranes. These polar lipids are present in the human diet as phospholipids and sphingolipids. Nevertheless, the limited focus has been on the attributes and role of camel milk polar lipids (MPL). In this study, camel MPL were isolated, and the composition of their lipidome was determined using ultra-high-performance liquid chromatography-tandem MS. This study characterized a total of 333 polar lipids, which encompassed glycerophospholipids and sphingolipids. Camel milk is rich in polar lipids, mainly phosphatidylethanolamine, sphingomyelin, and phosphatidylcholine. The results indicated that MPL intervention relieved the clinical symptoms and colon tissue damage in mice with dextran sulfate sodium-induced colitis, along with suppressing the expression of proinflammatory cytokines. Moreover, the administration of MPL partially alleviated mouse gut microbiota dysbiosis by increasing the abundance of probiotics (such as Lachnospiraceae_NK4A136_group and Muribaculaceae) and decreasing the number of harmful bacteria (such as Bacteroides and Parabacteroides). This study was conducted to investigate the potent protective effects of MPL in camel milk treatments on a mouse model of colitis and provided new ideas for the application of camel milk. [Display omitted] [ABSTRACT FROM AUTHOR]

Lamellarity and shape are important factors in the formation of vesicles and determine their role in biological systems and pharmaceutical applications. Cardiolipin (CL) is a major lipid in many biological membranes and exerts a great influence on their structural organization due to its particular structure and physico-chemical properties. Here, we used small-angle X-ray and neutron scattering to study the effects of CL with different acyl chain lengths and saturations (CL 14:0 , CL 18:1 , CL 18:2) on vesicle morphology and lamellarity in membrane models containing mixtures of phosphatidylcholine and phosphatidylethanolamine with different acyl chain lengths and saturations (C 14:0 and C 18:1). Measurements were performed in the presence of Phosphate Buffer Saline (PBS), at 37 °C, to better reflect physiological conditions, which resulted in strong effects on vesicle morphology, depending on the type and amount of CL used. The presence of small quantities of CL (from 2.5%) reduced inter-membrane correlations and increased perturbation of the membrane, an effect which is enhanced in the presence of matched shorter saturated acyl chains, and mainly unilamellar vesicles (ULV) are formed. In extruded vesicles, employed for SANS experiments, flattened vesicles are observed partly due to the hypertonic effect of PBS, but also influenced by the type of CL added. Our experimental data from SAXS and SANS revealed a strong dependence on CL content in shaping the membrane microstructure, with an apparent optimum in the PC:CL mixture in terms of promoting reduced correlations, preferred curvature and elongation. However, the use of PBS caused distinct differences from previously published studies in water in terms of vesicle shape, and highlights the need to investigate vesicle formation under physiological conditions in order to be able to draw conclusions about membrane formation in biological systems. [ABSTRACT FROM AUTHOR]

Herein, we propose an analytical approach based on intermolecular fluorescent resonant energy transfer (FRET) pairs for the visualization of specific enzyme activity in model biomembranes and in living cells. Cell visualizations with fluorescent confocal laser microscopy usually rely on fluorescent probes, such as Fluorescein isothiocyanate (FITC), Alexa488, Tetramethylrhodamine isothiocyanate (TRITC) and many others. However, for more specific tasks, such as the detection of certain enzymatic activity inside the living cell, the toolbox is quite limited. In the case of enzyme-hydrolases for example, the choice is limited to organic molecules comprising a fluorescent dye (typically, 4-methylumbelliferone (MUmb) or 7-amino-4-methylcoumarin (AMC) derivatives) and a fluorescence quencher, bound via an enzyme-sensitive linker—so that when the linker is degraded, the fluorescent signal increases. Unfortunately, both MUmb and AMC are quenched and have a relatively low quantum yield in cells, and their excitation and emission ranges overlap with that of intracellular fluorophores, often producing a strong background noise. R6G, on the other hand, has excellent quantum yield apart from intracellular fluorophores, but there are no efficient quenchers that could be chemically linked to R6G. Herein, we show that R6G is able to form intermolecular FRET pairs with MUmb or AMC, with the latter serving as fluorescence donors. This yields a combination of R6G's excellent fluorescence properties with a possibility to use an enzyme-sensitive linker in MUTMAC or AMC derivatives. This phenomenon was initially discovered in a model system, reversed micelles, where the donor, the acceptor, and the enzyme are forced to be in close proximity to each other, so that proximity could serve as an explanation for the intermolecular FRET effect. Surprisingly enough, the phenomenon has been reproduced in living cells. Moreover, we were able to create working intermolecular donor–acceptor FRET pairs for several different enzymes, including chymotrypsin, phosphatase, and asparaginase. This appears counterintuitive, as besides the overlap of the emission spectra of the donor and the absorption spectra of the acceptor, there are other criteria for the FRET effect, including the convergence of two fluorophores at a distance of about 1–10 nm, and the orientation of their dipoles at a certain angle, which is difficult to imagine in a bulk system like a living cell. We hypothesize that FRET-enabling donor–acceptor interaction may be taking place at the inner surface of the lipid bilayer, to which both donor and acceptor molecules would likely have an affinity. This hypothesis would require a more detailed investigation. Therefore, we have shown that the method suggested has good potential in the visualization of enzyme functioning inside living cells, which is often a challenging task. Shifting of the fluorescence signal to the long-wavelength region would increase the signal selectivity, making it easily distinguishable from autofluorescence. [ABSTRACT FROM AUTHOR]

Mitochondria are essential organelles known to serve broad functions, including in cellular metabolism, calcium buffering, signaling pathways and the regulation of apoptotic cell death. Maintaining the integrity of the outer (OMM) and inner mitochondrial membranes (IMM) is vital for mitochondrial health. Cardiolipin (CL), a unique dimeric glycerophospholipid, is the signature lipid of energy‐converting membranes. It plays a significant role in maintaining mitochondrial architecture and function, stabilizing protein complexes and facilitating efficient oxidative phosphorylation (OXPHOS) whilst regulating cytochrome c release from mitochondria. CL is especially enriched in the IMM and at sites of contact between the OMM and IMM. Disorders of protein misfolding, such as Alzheimer's and Parkinson's diseases, involve amyloidogenic peptides like amyloid‐β, tau and α‐synuclein, which form metastable toxic oligomeric species that interact with biological membranes. Electrophysiological studies have shown that these oligomers form ion‐conducting nanopores in membranes mimicking the IMM's phospholipid composition. Poration of mitochondrial membranes disrupts the ionic balance, causing osmotic swelling, loss of the voltage potential across the IMM, release of pro‐apoptogenic factors, and leads to cell death. The interaction between CL and amyloid oligomers appears to favour their membrane insertion and pore formation, directly implicating CL in amyloid toxicity. Additionally, pore formation in mitochondrial membranes is not limited to amyloid proteins and peptides; other biological peptides, as diverse as the pro‐apoptotic Bcl‐2 family members, gasdermin proteins, cobra venom cardiotoxins and bacterial pathogenic toxins, have all been described to punch holes in mitochondria, contributing to cell death processes. Collectively, these findings underscore the vulnerability of mitochondria and the involvement of CL in various pathogenic mechanisms, emphasizing the need for further research on targeting CL‐amyloid interactions to mitigate mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

RAS GTPases associate with the biological membrane where they function as molecular switches to regulate cell growth. Recent studies indicate that RAS proteins oligomerize on membranes, and disrupting these assemblies represents an alternative therapeutic strategy. However, conflicting reports on RAS assemblies, ranging in size from dimers to nanoclusters, have brought to the fore key questions regarding the stoichiometry and parameters that influence oligomerization. Here, we probe three isoforms of RAS [Kirsten Rat Sarcoma viral oncogene (KRAS), Harvey Rat Sarcoma viral oncogene (HRAS), and Neuroblastoma oncogene (NRAS)] directly from membranes using mass spectrometry. We show that KRAS on membranes in the inactive state (GDP-bound) is monomeric but forms dimers in the active state (GTP-bound). We demonstrate that the small molecule BI2852 can induce dimerization of KRAS, whereas the binding of effector proteins disrupts dimerization. We also show that RAS dimerization is dependent on lipid composition and reveal that oligomerization of NRAS is regulated by palmitoylation. By monitoring the intrinsic GTPase activity of RAS, we capture the emergence of a dimer containing either mixed nucleotides or GDP on membranes. We find that the interaction of RAS with the catalytic domain of Son of Sevenless (SOScat) is influenced by membrane composition. We also capture the activation and monomer to dimer conversion of KRAS by SOScat. These results not only reveal the stoichiometry of RAS assemblies on membranes but also uncover the impact of critical factors on oligomerization, encompassing regulation by nucleotides, lipids, and palmitoylation. [ABSTRACT FROM AUTHOR]

Biological membranes consist of a lipid bilayer in which integral membrane proteins are embedded. Based on the compositional complexity of the lipid species found in membranes, and on their specific and selective interactions with membrane proteins, we recently suggested that membrane bilayers can be best described as "finely-tuned molecular machines." We now discuss one such set of lipid-protein interactions by describing a negative feedback mechanism operating in the de novo sphingolipid biosynthetic pathway, which occurs in the membrane of the endoplasmic reticulum, and describe the atomic interactions between the first enzyme in the pathway, namely serine palmitoyl transferase, and the product of the fourth enzyme in the pathway, ceramide. We explore how hydrogen-bonding and hydrophobic interactions formed between Asn13 and Phe63 in the serine palmitoyl transferase complex and ceramide can influence the ceramide content of the endoplasmic reticulum. This example of finely-tuned biochemical interactions raises intriguing mechanistic questions about how sphingolipids and their biosynthetic enzymes could have evolved, particularly in light of their metabolic co-dependence. [ABSTRACT FROM AUTHOR]

Early diagnosis is crucial for enhancing the survival rate of renal cell cancer patients, and exosomes present potential advantages in this area. Their small size, high mobility, and lipid bilayer structure enable exosomes to cross biological membranes easily, protecting the bioactive cargo within from degradation. Exosomes significantly influence the invasion and metastasis of RCC, and they also contribute to tumor drug resistance and immune evasion. [ABSTRACT FROM AUTHOR]

Many years ago, asbestos fibers were banned and replaced by synthetic vitreous fibers because of their carcinogenicity. However, the toxicity of the latter fibers is still under debate, especially when it concerns the early fiber interactions with biological cell membranes. Here, we aimed to investigate the effects of a synthetic vitreous fiber named FAV173 on the Xenopus laevis oocyte membrane, the cell model we have already used to characterize the effect of crocidolite asbestos fiber exposure. Using an electrophysiological approach, we found that, similarly to crocidolite asbestos, FAV173 was able to stimulate a chloride outward current evoked by step membrane depolarizations, that was blocked by the potent and specific TMEM16A channel antagonist Ani9. Exposure to FAV173 fibers also altered the oocyte cell membrane microvilli morphology similarly to crocidolite fibers, most likely as a consequence of the TMEM16A protein interaction with actin. However, FAV173 only partially mimicked the crocidolite fibers effects, even at higher fiber suspension concentrations. As expected, the crocidolite fibers' effect was more similar to that induced by the co-treatment with (Fe3+ + H2O2), since the iron content of asbestos fibers is known to trigger reactive oxygen species (ROS) production. Taken together, our findings suggest that FAV173 may be less harmful that crocidolite but not ineffective in altering cell membrane properties. [ABSTRACT FROM AUTHOR]

A nanocomposite film containing highly polarizable inclusions in a fluid background is explored when an external electric field is applied perpendicular to the planar film. For small electric fields, the induced dipole moments of the inclusions are all polarized in field direction, resulting in a mutual repulsion between the inclusions. Here we show that this becomes qualitatively different for high fields: the total system self-organizes into a state which contains both polarizations, parallel and antiparallel to the external field such that a fraction of the inclusions is counter-polarized to the electric field direction. We attribute this unexpected counter-polarization to the presence of neighboring dipoles which are highly polarized and locally revert the direction of the total electric field. Since dipoles with opposite moments are attractive, the system shows a wealth of novel equilibrium structures for varied inclusion density and electric field strength. These include fluids and solids with homogeneous polarizations as well as equilibrium clusters and demixed states with two different polarization signatures. Based on computer simulations of an linearized polarization model, our results can guide the control of nanocomposites for various applications, including sensing external fields, directing light within plasmonic materials, and controlling the functionality of biological membranes. [ABSTRACT FROM AUTHOR]

In this article, we introduce a mesoscale continuum model for membranes made of two different types of amphiphilic lipids. The model extends work by Peletier and the second author (Arch. Ration. Mech. Anal. 193, 2009) for the one‐phase case. We present a mathematical analysis of the asymptotic reduction to the macroscale when a key length parameter becomes arbitrarily small. We identify two main contributions in the energy: one that can be connected to bending of the overall structure and a second that describes the cost of the internal phase separations. We prove the Γ$$ \Gamma $$‐convergence towards a perimeter functional for the phase separation energy and construct, in two dimensions, recovery sequences for the convergence of the full energy towards a 2D reduction of the Jülicher–Lipowsky bending energy with a line tension contribution for phase separated hypersurfaces. [ABSTRACT FROM AUTHOR]

Biological‐machine interface (BMI) devices represent a significant step toward adaptive and cognitive technologies. However, current BMI devices emphasize the analysis of electrophysiology and often overlook the chemical information of neurotransmitters in the process of signaling between neurons. To bridge this gap, a light‐gated artificial postsynaptic membrane (APM) is introduced, capable of reading dopamine (DA) released from rat pheochromocytoma cells and regulate neural signal transmission. Like the biological postsynaptic membrane, the APM is a porous membrane functionalized by DA‐specific aptamers and azobenzene (Azo) molecules in different regions. Azo molecules act as a light‐responsive trigger that controls DA release, while DA‐specific aptamers capture DA, which converts its concentration information into an ionic current signal. By light‐enhanced responses to DA exocytosis from rat pheochromocytoma (PC12) cells, the APM confirms its ability to communicate with biological systems, which lays the foundation for developing biological‐machine interaction systems with more advanced functionalities. [ABSTRACT FROM AUTHOR]

Rechargeable aqueous Zn-ion batteries have been deemed a promising energy storage device. However, the dendrite growth and side reactions have hindered their practical application. Herein, inspired by the ultrafluidic and K+ ion-sieving flux through enzyme-gated potassium channels (KcsA) in biological plasma membranes, a metal-organic-framework (MOF-5) grafted with –ClO4 groups (MOF-ClO4) as functional enzymes is fabricated to mimic the ultrafluidic lipid-bilayer structure for gating Zn2+ 'on' and anions 'off' states. The MOF-ClO4 achieved perfect Zn2+/SO42− selectivity (∼10), enhanced Zn2+ transfer number (⁠|${{t}_{{\rm{Z}}{{{\rm{n}}}^{2 + }}}} = 0.88$|⁠) and the ultrafluidic Zn2+ flux (1.9 × 10−3 vs. 1.67 mmol m−2 s−1 for KcsA). The symmetric cells based on MOF-ClO4 achieve a lifespan of over 5400 h at 10 mA cm−2/20 mAh cm−2. Specifically, the performance of the PMCl-Zn//V2O5 pouch cell keeps 81% capacity after 2000 cycles at 1 A g−1. The regulated ion transport, by learning from a biological plasma membrane, opens a new avenue towards ultralong lifespan aqueous batteries. [ABSTRACT FROM AUTHOR]

The major energy-producing reactions of biochemistry occur at biological membranes. Computational protein design now provides the opportunity to elucidate the underlying principles of these processes and to construct bioenergetic pathways on our own terms. Here, we review recent achievements in this endeavour of 'synthetic bioenergetics', with a particular focus on new enabling tools that facilitate the computational design of bio-compatible de novo integral membrane proteins. We use recent examples to showcase some of the key computational approaches in current use and highlight that the overall philosophy of 'surface-swapping' -- the replacement of solvent-facing residues with amino acids bearing lipid-soluble hydrophobic sidechains -- is a promising avenue in membrane protein design. We conclude by highlighting outstanding design challenges and the emerging role of AI in sequence design and structure ideation. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are one of the leading causes of death worldwide. Despite significant advances in current drug therapies, issues such as poor drug targeting and severe side effects persist. In recent years, nanomedicine has been extensively applied in the research and treatment of CVDs. Among these, biomembrane-modified biomimetic nanodrug delivery systems (BNDSs) have emerged as a research focus due to their unique biocompatibility and efficient drug delivery capabilities. By modifying with biological membranes, BNDSs can effectively reduce recognition and clearance by the immune system, enhance biocompatibility and circulation time in vivo, and improve drug targeting. This review first provides an overview of the classification and pathological mechanisms of CVDs, then systematically summarizes the research progress of BNDSs in the treatment of CVDs, discussing their design principles, functional characteristics, and clinical application potential. Finally, it highlights the issues and challenges faced in the clinical translation of BNDSs. [ABSTRACT FROM AUTHOR]

Alamethicin, a peptide consisted of 20 amino acid residues, has been known to function as an antibiotic. The peptides self-associate in biological membranes, form an ion channel, and then induce cell death by leaking intracellular contents through a transmembrane pore of an ion channel. We investigated conformation and its thermal stability of alamethicin-A6 and -U6 in ethanol using proton nuclear magnetic resonance (NMR) spectroscopy; alamethicin-A6 and -U6 have the amino acid sequences of UPUAUAQUVUGLUPVUUQQO and UPUAUUQUVUGLUPVUUQQO, respectively, where U and O represent α-aminoisobutyric acid and phenylalaninol, respectively. As indicated by the under bars in the sequences, only the residue 6 differs between the alamethicins. We show that the alamethicins in ethanol form helix conformation in the region of the residues 2–11 and a non-regular conformation in the regions of the N- and C-termini, and that the helices are maintained up to 66 °C at least. Conformations in the region of the residues 12–18 of the alamethicins, however, are not well identified due to the lack of NMR data. In addition, we demonstrate that the amide proton chemical shift temperature coefficients' method, which is known as an indicator for intramolecular hydrogen bonds in peptides and proteins in aqueous solutions, can be also applied to the alamethicins in ethanol. Further, we show that the conformation around the C-terminus of alamethicin-A6 is restrained by intramolecular hydrogen bonds, whereas that of alamethicin-U6 is either restrained or unrestrained by intramolecular hydrogen bonds; the alamethicin-U6 molecules having the restrained and unrestrained conformations coexist in ethanol. We discuss the two types of conformations using a model chain consisting of particles linked by rigid bonds called as the free jointed chain. [ABSTRACT FROM AUTHOR]

Exosomes, are a subpopulation of extracellular vesicles, that originate from endosomes. The major role of exosomes is cellular communication (in this process exosomes display the status of the parental cell's nature, healthy or the cell suffers any pathological complication). In recent decades, research evidence highlighted that exosomes are the masterminds of cancer development and they appear as smart solutions for early diagnosis, prognosis and therapeutic (eg. stem cell, plant and immune cell‐derived exosomes) approaches. Exosomes transform the cancer liquid biopsy into a new orientation. Several biofluids (blood, plasma, serum, saliva, urine, CSF (Cerebrospinal Fluid) and cancer tissue are used for exosome‐based cancer biomarkers detection. Liquid biopsy becomes more efficient for exosomes, compared to tissue biopsy. Exosomes biocompatibility, low toxicity, and ability to cross biological membranes make it a potential tool for cancer therapeutic development. Exosome‐based cancer therapeutics introduce a cutting‐edge era of cell‐free cancer therapy. This article explores the critical role of exosomes in cancer development, progression, treatment, and clinical trials. Exosome‐based clinical trials indicate that we are close to cancer precision medicine. [ABSTRACT FROM AUTHOR]

In a landmark study, oleocanthal (OLC), a major phenolic in extra virgin olive oil (EVOO), was found to possess anti-inflammatory activity similar to ibuprofen, involving inhibition of cyclooxygenase (COX) enzymes. EVOO is a rich source of bioactive compounds including fatty acids and phenolics; however, the biological activities of only a small subset of compounds associated with Olea europaea have been explored. Here, the OliveNetTM library (consisting of over 600 compounds) was utilized to investigate olive-derived compounds as potential modulators of the arachidonic acid pathway. Our first aim was to perform enzymatic assays to evaluate the inhibitory activity of a selection of phenolic compounds and fatty acids against COX isoforms (COX-1 and COX-2) and 15-lipoxygenase (15-LOX). Olive compounds were found to inhibit COX isoforms, with minimal activity against 15-LOX. Subsequent molecular docking indicated that the olive compounds possess strong binding affinities for the active site of COX isoforms, and molecular dynamics (MD) simulations confirmed the stability of binding. Moreover, olive compounds were predicted to have favorable pharmacokinetic properties, including a readiness to cross biological membranes as highlighted by steered MD simulations and umbrella sampling. Importantly, olive compounds including OLC were identified as non-inhibitors of the human ether-à-go-go-related gene (hERG) channel based on patch clamp assays. Overall, this study extends our understanding of the bioactivity of Olea-europaea-derived compounds, many of which are now known to be, at least in part, accountable for the beneficial health effects of the Mediterranean diet. [ABSTRACT FROM AUTHOR]

Membrane intrinsic proteins (MIPs), including aquaporins (AQPs) and aquaglyceroporins (GLPs), form an ancient family of transporters for water and small solutes across biological membranes. The evolutionary history and functions of MIPs have been extensively studied in vertebrates and land plants, but their widespread presence across the eukaryotic tree of life suggests both a more complex evolutionary history and a broader set of functions than previously thought. That said, the early evolution of MIPs remains obscure. The presence of one GLP and four AQP clades across both bacteria and archaea suggests that the first eukaryotes could have possessed up to five MIPs. Here, we report on a previously unknown richness in MIP diversity across all major eukaryotic lineages, including unicellular eukaryotes, which make up the bulk of eukaryotic diversity. Three MIP clades have likely deep evolutionary origins, dating back to the last eukaryotic common ancestor (LECA), and support the presence of a complex MIP repertoire in early eukaryotes. Overall, our findings highlight the growing complexity of the reconstructed LECA genome: the dynamic evolutionary history of MIPs was set in motion when eukaryotes were in their infancy followed by radiative bursts across all main eukaryotic lineages. [ABSTRACT FROM AUTHOR]

Currently, the biomimetic approach of drawing inspiration from nature has frequently been employed in designing drug nanocarriers (NCs) of actively target various diseases, ranging from cancer to neuronal and inflammation pathologies. The cell-membrane coating can confer upon the inner nanomaterials a biological identity and the functions exhibited by the cells from which the membrane is derived. Monocyte- and macrophage-membrane-coated nanomaterials have emerged as an ideal delivery system to target inflamed vasculature. Herein, we developed two biomimetic NCs using a human-derived leukaemia monocytic cell line (THP-1), either undifferentiated or differentiated by phorbol 12-myristate 13-acetate (PMA) into adherent macrophage-like cells as membrane sources for NC coating. We employed a secondary oil-in-water nano-emulsion (SNE) as the inner core, which served as an optimal NC for high payloads of lipophilic compounds. Two different biomimetic systems were produced, combining the biomimetic features of biological membranes with the physicochemical and nano-sized characteristics of SNEs. These systems were named Monocyte NEsoSome (M-NEsoSome) and Macrophage NEsoSome (M0-NEsoSome). Their uptake ability was investigated in tumour necrosis factor alfa (TNFα)-treated human umbilical vein endothelial cells (HUVECs), selected as a model of inflamed endothelial cells. The M0 membrane coating demonstrated accelerated internalisation compared with the monocyte coating and notably surpassed the uptake rate of bare NCs. In conclusion, M0-NEsoSome NCs could be a therapeutic system for targeting inflamed endothelial cells and potentially delivering anti-inflammatory drugs in vascular inflammation. [ABSTRACT FROM AUTHOR]

Current understanding of the structure and functioning of biomembranes is impossible without determining the mechanism of formation of membrane lipid rafts. The formation of liquid-ordered and disordered phases (Lo and Ld) and lipid rafts in membranes and their simplified models is discussed. A new consideration of the processes of formation of lipid phases Lo and Ld and lipid rafts is proposed, taking into account the division of each of the glycerophospholipids into several groups. Generally accepted three-component schemes for modeling the membrane structure are critically considered. A four-component scheme is proposed, which is designed to more accurately assume the composition of lipids in the resulting Lo and Ld phases. The role of the polar head groups of phospholipids and, in particular, phosphatidylethanolamine is considered. The structure of membrane rafts and the possible absence of a clear boundary between the Lo and Ld phases are discussed. [ABSTRACT FROM AUTHOR]

Natural products include inorganic as well as organic compounds. Living organisms face constant challenges in acquiring essential metal ions and getting rid of non-essential ones with toxic actions. They employ an extracellular biochemistry in these tasks and use it to engage in a chemical warfare against invaders and competitors by either increasing or decreasing the availability of metal ions for maintaining their welfare in aquatic or terrestrial ecological niches. To control mutualistic, cambialistic or parasitic symbiosis with other organisms they use a remarkably rich suite of secreted bioactive molecules with ligand donor atoms for metal binding. This overview discusses the interactions of these extracellular natural products with a multitude of metal ions in the periodic system of the elements. It focuses mainly on metallophores and metal ionophores secreted from bacteria, fungi, and plants, but metal-carrying cofactors and other chelating agents will also be mentioned in the context of related functions and with an intent to categorize. The intracellular fate of the metal ions and the controlled pathways for the biosynthesis, secretion, uptake, biodegradation or recycling of the secreted natural products that interact with metal ions will not be covered. Metallophores make extracellular metal ions available via delivery to specific transporters and unavailable to competing organisms, especially pathogens, though some invaders have developed ways to compete efficiently for metal ions. The classic concept of siderophores, carriers of iron(III) ions, is extended here to specific and broad-band metallophores for metal ions such as copper (chalkophores), zinc (zincophores), and yet others. Metal ionophores, in contrast, transport metal ions through biological membranes. There is a wide variety of chemical structures for either metallophores or metal ionophores. Together with physicochemical investigations of metal complexation und conditions mimicking the natural environment, “omics” mining and mapping the diversity of chemotypes is an on-going effort with analytic, genetic, and bioinformatic tools and comes together in defining the metallometabolome, which combines the metabolome and the metallome. Investigations are highly multidisciplinary, include an important, but academically infrequently crossed bridge between the biosciences (biochemistry) and the earth sciences (geochemistry), define significant applications in the pharmaceutical/medical sciences regarding immune modulation and the control of virulence at the host-pathogen interface, and have implications for the nutritional/toxicological and environmental/ecological sciences. [ABSTRACT FROM AUTHOR]