Search Results (16)

Mitochondria possess a double-membrane envelope which is susceptible to insult by pathogenic intracellular aggregates of amyloid-forming peptides, such as the amyloid-beta (1-42) (Aβ42) peptide and the human islet amyloid polypeptide (hIAPP). The molecular composition of membranes plays a pivotal role in regulating peptide aggregation and cytotoxicity. Therefore, we hypothesized that modifying the physicochemical properties of mitochondrial model membranes with a small molecule might act as a countermeasure against the formation of, and damage by, membrane-active amyloid peptides. To investigate this, we inserted the natural ubiquinone Coenzyme Q10 (CoQ10) in model mito-mimetic lipid vesicles, and studied how they interacted with Aβ42 and hIAPP peptide monomers and oligomers. Our results demonstrate that the membrane incorporation of CoQ10 significantly attenuated fibrillization of the peptides, whilst also making the membranes more resilient against peptide-induced permeabilization. Furthermore, these protective effects were linked with the ability of CoQ10 to enhance membrane packing in the inner acyl chain region, which increased the mechanical stability of the vesicle membranes. Based on our collective observations, we propose that mitochondrial resilience against toxic biomolecules implicit in protein misfolding disorders such as Alzheimer’s disease and type-2 diabetes, could potentially be enhanced by increasing CoQ10 levels within mitochondria. Full article

Reconstructing neuronal morphology from microscopy image stacks is essential for understanding brain function and behavior. While existing methods are capable of tracking neuronal tree structures and creating membrane surface meshes, they often lack seamless processing pipelines and suffer from stitching artifacts and reconstruction inconsistencies. In this study, we propose a new approach utilizing implicit neural representation to directly extract neuronal isosurfaces from raw image stacks by modeling signed distance functions (SDFs) with multi-layer perceptrons (MLPs). Our method accurately reconstructs the tubular, tree-like topology of neurons in complex spatial configurations, yielding highly precise neuronal membrane surface meshes. Extensive quantitative and qualitative evaluations across multiple datasets demonstrate the superior reliability of our approach compared to existing methods. The proposed method achieves a volumetric reconstruction accuracy of up to 98.2% and a volumetric IoU of 0.90. Full article

The transition of peptides or proteins along a misfolding continuum from soluble functional states to pathological aggregates, to ultimately deposit as amyloid fibrils, is a process that underlies an expanding group of human diseases—collectively known as protein-misfolding disorders (PMDs). These include common and debilitating conditions, such as Alzheimer’s disease, Parkinson’s disease, and type-2 diabetes. Compelling evidence has emerged that the complex interplay between the misfolded proteins and biological membranes is a key determinant of the pathogenic mechanisms by which harmful amyloid entities are formed and exert their cytotoxicity. Most efforts thus far to develop disease-modifying treatments for PMDs have largely focused on anti-aggregation strategies: to neutralise, or prevent the formation of, toxic amyloid species. Herein, we review the critical role of the phospholipid membrane in mediating and enabling amyloid pathogenicity. We consequently propose that the development of small molecules, which have the potential to uniquely modify the physicochemical properties of the membrane and make it more resilient against damage by misfolded proteins, could provide a novel therapeutic approach in PMDs. By way of an example, natural compounds shown to intercalate into lipid bilayers and inhibit amyloid–lipid interactions, such as the aminosterols, squalamine and trodusquamine, cholesterol, ubiquinone, and select polyphenols, are discussed. Such a strategy would provide a novel approach to counter a wide range of toxic biomolecules implicit in numerous human amyloid pathologies. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-β (Aβ) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes a sequence of cleavages, referred as trimming, performed by γ-secretase. Here, we investigated conformational changes in a series of β-amyloid substrates (from less and more amyloidogenic pathways) in the active site of presenilin-1, the catalytic subunit of γ-secretase. The substrates are trimmed every three residues, finally leading to Aβ₄₀ and Aβ₄₂, which are the major components of amyloid plaques. To study conformational changes, we employed all-atom molecular dynamics simulations, while for unfolding, we used steered molecular dynamics simulations in an implicit membrane-water environment to accelerate changes. We have found substantial differences in the flexibility of extended C-terminal parts between more and less amyloidogenic pathway substrates. We also propose that the positively charged residues of presenilin-1 may facilitate the stretching and unfolding of substrates. The calculated forces and work/energy of pulling were exceptionally high for Aβ₄₀, indicating why trimming of this substrate is so infrequent. Full article

In this study, a novel gas-extruded membrane bearing was developed, and an optimization algorithm was applied to solve a Reynolds equation that describes the load-bearing characteristics of this bearing. This was effective in improving the solution rate of the Reynolds equation, significantly reducing the difficulty of obtaining a solution, avoiding high programming difficulty, and achieving a high solution accuracy. Through a comparative analysis, the error in the accuracy of the alternating implicit difference method was addressed, and the traditional finite element method for solving the same model was verified, with an average error of 2% reached to verify its applicability. The algorithm was also used to analyze the load-bearing capacity of the gas-extruded membrane bearing. This revealed not only a positive correlation of the average load-bearing capacity of the gas-extruded membrane bearing with the frequency and amplitude of vibration but also a negative correlation with radial clearance, with the cut-off frequency reaching 19 Khz. The load-bearing capacity of the gas-extruded membrane bearing proposed in this paper reached 1.28 N, which indicated an error of 3.28% with the theoretical approach. To sum up, this research provides an important reference for the design and manufacture of novel gas-extruded membrane bearings. Full article

In this article, we present a finite element method for studying the dynamic behavior of deformable vesicles, which mimic red blood cells, in a non-Newtonian Casson fluid. The fluid membrane, represented by an implicit level-set function, adheres to the Canham–Helfrich model and maintains surface inextensibility constraint through penalty. We propose a two-step time integration scheme that incorporates higher-order accuracy by using an asymmetric composition of discrete flow based on the second-order backward difference formula, followed by a projection onto the real axis. Our framework incorporates variable time steps generated by an appropriate adaptation criterion. We validate our model through numerical simulations against existing experimental and numerical results in the case of purely Newtonian flow. Furthermore, we provide preliminary results demonstrating the influence of the non-Newtonian fluid model on membrane regimes. Full article

Flexoelectric liquid crystalline membranes immersed in asymmetric viscoelastic media is a material system model with physiological applications such as outer hair cells (OHCs), where membrane oscillations generate bulk flow. Motivated by this physiological process, here we extend our previous work by characterizing the force transmission output of our model in addition to viscoelastic fluid flow, since solid–fluid interactions are an essential feature of confined physiological flow and flow in immersed elastic structures. In this work, the rigidity of the confinement results in a passive force reception, while more complete solid–fluid interactions will be considered in the future. A significant contribution of this work is a new asymmetry linear viscoelastic electro-rheological model and the obtained implicit relation between force transmission and flow generation and how this relation is modulated by electric field frequency and the material properties of the device. Maximal force and flow are found at resonant frequencies of asymmetry viscoelastic bulk phases, flexoelectric and dispersion mechanisms through the elastic and Womersley numbers. Full article

The insertion of proteins into membranes is crucial for understanding their function in many biological processes. In this work, we present UNILIPID, a universal implicit lipid-protein description as a methodology for dealing with implicit membranes. UNILIPID is independent of the scale of representation and can be applied at the level of all atoms, coarse-grained particles down to the level of a single bead per amino acid. We provide example implementations for these scales and demonstrate the versatility of our approach by accurately reflecting the free energy of transfer for each amino acid. In addition to single membranes, we describe the analytical implementation of double membranes and show that UNILIPID is well suited for modeling at multiple scales. We generalize to membranes of arbitrary shape. With UNILIPID, we provide a methodological framework for a simple and general parameterization tuned to reproduce a selected reference hydrophobicity scale. The software we provide along with the methodological description is optimized for specific user features such as real-time response, live visual analysis, and virtual reality experiences. Full article

(1) Background: We developed an algorithm to perform interactive molecular simulations (IMS) of protein alignment in membranes, allowing on-the-fly monitoring and manipulation of such molecular systems at various scales. (2) Methods: UnityMol, an advanced molecular visualization software; MDDriver, a socket for data communication; and BioSpring, a Spring network simulation engine, were extended to perform IMS. These components are designed to easily communicate with each other, adapt to other molecular simulation software, and provide a development framework for adding new interaction models to simulate biological phenomena such as protein alignment in the membrane at a fast enough rate for real-time experiments. (3) Results: We describe in detail the integration of an implicit membrane model for Integral Membrane Protein And Lipid Association (IMPALA) into our IMS framework. Our implementation can cover multiple levels of representation, and the degrees of freedom can be tuned to optimize the experience. We explain the validation of this model in an interactive and exhaustive search mode. (4) Conclusions: Protein positioning in model membranes can now be performed interactively in real time. Full article

Purpose: The purpose of this study was to determine the effect of brilliant blue G (BBG) staining of the inner limiting membrane (ILM) on macular function. Method: Fourteen eyes of 14 patients consisting of 9 men and 5 women who underwent vitreous surgery with ILM peeling were studied. The mean age of the patients was 68.8 ± 9.14 years. Three eyes had a macular hole and eleven eyes had an epiretinal membrane. The ILM was made more visible by spraying 0.25% BBG into the vitreous cavity. The macular function was assessed by recording intraoperative focal macular electroretinograms (iFMERGs) before and after the intravitreal spraying of the BBG dye. The iFMERGs were recorded three times after core vitrectomy. The first recording was performed before the BBG injection (Phase 1, baseline), the second recording was performed after the spraying of the BBG and washing out the excess BBG (Phase 2), and the third recording was performed after the ILM peeling (Phase 3). All recordings were performed after 5 min of light-adaptation and stabilization of the intraocular conditions. The iFMERGs were recorded twice at each phase. The implicit times and amplitudes of the a- and b-wave, the PhNR, and the d-wave were measured. Wilcoxon signed-rank test were used to determine the significance of differences of the findings at Phase 2 vs. Phase 1 and Phase 3 vs. Phase 1. A p value < 0.05 was taken to be statistically significant. Results: The average implicit times of the a-wave, b-wave, PhNR, and d-wave were not significantly different in Phase 1, 2, and 3. The average a-wave, b-wave, PhNR, and d-wave amplitudes at Phase 1 did not differ significantly from that at Phase 2 and at Phase 3. Conclusions: The results indicated that the intravitreal injection of BBG does not alter the physiology of the macula, and we conclude that BBG is safe. We also conclude that iFMERGs can be used to monitor the macular function safely during intraocular surgery. Full article

The detection of low gas concentrations from the soil surface demands expensive high-precision devices to estimate nitrous oxide (N₂O) flux. As the prevalence of N₂O concentration in the soil atmosphere is higher than its surface, the present study aimed to simulate N₂O surface flux (CF) from soil gas measured in a soil-interred silicone diffusion cell using a low-cost device. The methodological steps included the determination of the diffusion coefficient of silicone membrane (D_slcn), the measurement of the temporal variations in the N₂O gas in the soil (C_si) and on the surface (MF), and the development of a simulation process for predicting CF. Two experiments varying the procedure and periods of soil moisture saturation in each fertilized soil sample were conducted to detect C_si and MF. Using D_slcn and C_si, the variations in the soil gas (C_soil) were predicted by solving the diffusion equation using the implicit finite difference analysis method. Similarly, using six soil gas diffusivity models, the CF values were simulated from C_soil. For both experiments, statistical tests confirmed the good agreement of CF with MF for soil gas diffusivity models 4 and 5. We suggest that the tested simulation method is appropriate for predicting N₂O surface emissions. Full article

Titanium (Ti) nanoparticles (NPs) were successfully seeded on the platform of a polyacrylonitrile (PAN) ultrafiltration (UF) membrane previously coated with bio-glue (a co-deposition of dopamine hydrochloric bicarbonate buffer having undergone pyrocatechol deprotonation). The tools in vogue, especially field emission scanning electron microscopy (FESEM), energy dispersive spectroscopy (EDS), and atomic force microscopy (AFM), have made it possible to fully characterize the structure of the new organic-inorganic nanofiltration (NF) membrane, namely NF_PAN_Ti. A soft computing model has been applied to make commonplace the complex and implicit extended Nernst–Planck equations that govern the transport of ions through NF membranes. Euler’s numerical method was applied with a small step-size and the results obtained were very interesting. The filtration velocity approach of GUEROUT-ELFORD-FERRY helped to estimate the average pore size of NF_PAN_Ti to r_p = 0.538 nm. A six-day test carried out on NF_PAN_Ti demonstrated its long-term stability and showed a steady-rejection rate of 89.3% of MgCl₂ salt and permeate flux of 56 L·m⁻²·h⁻¹. The Euler’ numerical method corroborated perfectly the experimental findings since the relative error was found to be very low at 0.33% for Cl⁻ and 0.09% for Mg²⁺ (RE << 0.1). These practical prediction tools may henceforth help in the choice and calibration of next-generation NF membranes’ synthesis. Full article

In order to realize the low temperature and rapid cold start-up of a proton exchange membrane fuel cell stack, a dynamic model containing 40 single proton exchange membrane fuel cells is established to estimate the melting time of the proton exchange membrane fuel cell stack as well as to analyze the melting process of the ice by using the obtained liquid–solid boundary. The methods of proton exchange membrane electric heating and electrothermal film heating are utilized to achieve cold start-up of the proton exchange membrane fuel cell (PEMFC). The fluid simulation software fluent is used to simulate and analyze the process of melting ice. The solidification and melting model and multi-phase flow model are introduced. The pressure-implicit with splitting of operators algorithm is also adopted. The results show that both the proton exchange membrane electric heating technology and the electrothermal film heating method can achieve rapid cold start-up. The interior ice of the proton exchange membrane fuel cell stack melts first, while the first and 40th pieces melt afterwards. The ice melting time of the proton exchange membrane fuel cell stack is 32.5 s and 36.5 s with the two methods, respectively. In the end, the effect of different electrothermal film structures on cold start-up performance is studied, and three types of pore diameter electrothermal films are established. It is found that the electrothermal film with small holes melts completely first, and the electrothermal film with large holes melts completely last. Full article

Modeling and control of proton-exchange membrane fuel cells (PEMFC) has become a very popular research topic lately due to the increasing use of renewable energy. Despite this fact, most of the work in the current literature only studies standard dynamical models without taking into consideration possible parasitics such as small gas flow perturbations that could be available in the system. This paper addresses this issue by elaborating on time-scale modeling of an augmented eighteenth-order PEMFC-reformer system via singular perturbation theory. The latter captures time scales that arise in the model due to the presence of small perturbations. Specifically, a novel and efficient algorithm that helps identify the presence of different time-scales is developed. In addition, the method converts an implicit singularly perturbed model into an explicit equivalent where the time-scales are evident. Using this algorithm, a complete singularly perturbed dynamic model of the augmented eighteenth-order PEMFC-reformer system is obtained. Modeling of the PEMFC-reformer system is followed by linear quadratic regulator (LQR) design for the individual time-scales present in the system. Full article

We report the first complete description of the molecular mechanisms behind the transition of the N-methyl-d-aspartate (NMDA) receptor from the state where the transmembrane domain (TMD) and the ion channel are in the open configuration to the relaxed unliganded state where the channel is closed. Using an aggregate of nearly 1 µs of unbiased all-atom implicit membrane and solvent molecular dynamics (MD) simulations we identified distinct structural states of the NMDA receptor and revealed functionally important residues (GluN1/Glu522, GluN1/Arg695, and GluN2B/Asp786). The role of the “clamshell” motion of the ligand binding domain (LBD) lobes in the structural transition is supplemented by the observed structural similarity at the level of protein domains during the structural transition, combined with the overall large rearrangement necessary for the opening and closing of the receptor. The activated and open states of the receptor are structurally similar to the liganded crystal structure, while in the unliganded receptor the extracellular domains perform rearrangements leading to a clockwise rotation of up to 45 degrees around the longitudinal axis of the receptor, which closes the ion channel. The ligand-induced rotation of extracellular domains transferred by LBD–TMD linkers to the membrane-anchored ion channel is responsible for the opening and closing of the transmembrane ion channel, revealing the properties of NMDA receptor as a finely tuned molecular machine. Full article