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Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active ...pharmaceutical ingredients – ranging from small molecule drugs to proteins and nucleic acids – these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility.
This work aims to provide insights into the drug-phospholipid interaction by combining molecular dynamic simulations and thermodynamic modelling techniques. In particular, we have made a connection between the structural properties of the drug-phospholipid system and the physicochemical performance of the drug-loaded liposomal nanoformulations. We have considered two prototypical drugs, felodipine (FEL) and naproxen (NPX), and one model hydrogenated soy phosphatidylcholine (HSPC) bilayer membrane. Molecular dynamic simulations revealed which regions within the phospholipid bilayers are most and least favoured by the drug molecules. NPX tends to reside at the water-phospholipid interface and is characterized by a lower free energy barrier for bilayer membrane permeation. Meanwhile, FEL prefers to sit within the hydrophobic tails of the phospholipids and is characterized by a higher free energy barrier for membrane permeation. Flory-Huggins thermodynamic modelling, small angle X-ray scattering, dynamic light scattering, TEM, and drug release studies of these liposomal nanoformulations confirmed this drug-phospholipid structural difference. The naproxen-phospholipid system has a lower free energy barrier for permeation, higher drug miscibility with the bilayer, larger liposomal nanoparticle size, and faster drug release in the aqueous medium than felodipine. We suggest that this combination of molecular dynamics and thermodynamics approach may offer a new tool for designing and developing lipid-based nanocarriers for unmet medical applications.
Ciguatoxins (CTXs) and gambierones are ladder-shaped polyethers associated with ciguatera poisoning and Gambierdiscus spp. Several of these compounds contain carbonyl or hemiketal groups, which have ...the potential to exchange with 18O-labeled water under acidic conditions. The effects of solvent composition and acid on the rate of exchange and on the stability of the labels at various pH values were assessed to optimize the incorporation of 18O into Caribbean ciguatoxin-1 and -2 (C-CTX1/2), gambierone, and 44-methylgambierone. LC−HRMS results showed that 18O-labeling occurred at the hydroxy group of the hemiketal at C-56 in C-CTX1/2, and at the hydroxy group of the hemiketal at C-4 and the ketone at C-40 in gambierones. Labeling occurred very rapidly (complete in <30 min) for C-CTX1/2, and more slowly (complete in ca. 16 h) for both gambierones. Labeled C-CTX1/2 was reduced with sodium borohydride to produce 18O-labeled C-CTX3/4. The incorporated 18O labels in the gambierones and C-CTXs were retained in aqueous solvent mixtures under neutral conditions in a short-term stability study, demonstrating that these 18O-labeled toxins have the potential to be used in isotope dilution and metabolism studies.
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•Methodologies developed for 18O exchange with H218O to produce labeled C-CTX1/2 and gambierones.•Borohydride reduction of 18OC-CTX1/2 produced stable 18OC-CTX3/4.•pH stability suggested 18O-labeled CTXs and gambierones maintained under neutral conditions.
We investigate the dynamics of a dilute suspension of hydrodynamically interacting motile or immotile stress-generating swimmers or particles as they invade a surrounding viscous fluid. Colonies of ...aligned pusher particles are shown to elongate in the direction of particle orientation and undergo a cascade of transverse concentration instabilities, governed at small times by an equation that also describes the Saffman-Taylor instability in a Hele-Shaw cell, or the Rayleigh-Taylor instability in a two-dimensional flow through a porous medium. Thin sheets of aligned pusher particles are always unstable, while sheets of aligned puller particles can either be stable (immotile particles), or unstable (motile particles) with a growth rate that is nonmonotonic in the force dipole strength. We also prove a surprising "no-flow theorem": a distribution initially isotropic in orientation loses isotropy immediately but in such a way that results in no fluid flow everywhere and for all time.
Many types of cells require the ability to pinpoint the location of an external stimulus from the arrival of diffusing signaling molecules at cell-surface receptors. How does the organization (number ...and spatial configuration) of these receptors shape the limit of a cell's ability to infer the source location? In the idealized scenario of a spherical cell, we apply asymptotic analysis to compute splitting probabilities between individual receptors and formulate an information-theoretic framework to quantify the role of receptor organization. Clustered configurations of receptors provide an advantage in detecting sources aligned with the clusters, suggesting a possible multiscale mechanism for single-cell source inference.
Despite the well-established role of actin polymerization as a driving mechanism for cell protrusion, upregulated actin polymerization alone does not initiate protrusions. Using a combination of ...theoretical modeling and quantitative live-cell imaging experiments, we show that local depletion of actin-membrane links is needed for protrusion initiation. Specifically, we show that the actin-membrane linker ezrin is depleted prior to protrusion onset and that perturbation of ezrin’s affinity for actin modulates protrusion frequency and efficiency. We also show how actin-membrane release works in concert with actin polymerization, leading to a comprehensive model for actin-driven shape changes. Actin-membrane release plays a similar role in protrusions driven by intracellular pressure. Thus, our findings suggest that protrusion initiation might be governed by a universal regulatory mechanism, whereas the mechanism of force generation determines the shape and expansion properties of the protrusion.
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•Actin and pressure-driven protrusions are triggered by actin-membrane detachment•Increased actin polymerization is not sufficient to initiate protrusion•Increased actin-membrane attachment reduces protrusion•Stimulated decreases in actin-membrane attachment induce protrusion
Using experiments and mathematical modeling, Welf et al. identify that plasma membrane detachment from actin is needed to initiate cell protrusion, regardless of whether actin polymerization or intracellular pressure create pushing forces. Their actin release model augments the tethered Brownian ratchet model, explaining why actin polymerization alone cannot initiate protrusion.
Benefits from mental health early interventions may not be sustained over time, and longer-term intervention programs may be required to maintain early clinical gains. However, due to the high ...intensity of face-to-face early intervention treatments, this may not be feasible. Adjunctive internet-based interventions specifically designed for youth may provide a cost-effective and engaging alternative to prevent loss of intervention benefits. However, until now online interventions have relied on human moderators to deliver therapeutic content. More sophisticated models responsive to user data are critical to inform tailored online therapy. Thus, integration of user experience with a sophisticated and cutting-edge technology to deliver content is necessary to redefine online interventions in youth mental health. This paper discusses the development of the moderated online social therapy (MOST) web application, which provides an interactive social media-based platform for recovery in mental health. We provide an overview of the system's main features and discus our current work regarding the incorporation of advanced computational and artificial intelligence methods to enhance user engagement and improve the discovery and delivery of therapy content.
Our case study is the ongoing Horyzons site (5-year randomized controlled trial for youth recovering from early psychosis), which is powered by MOST. We outline the motivation underlying the project and the web application's foundational features and interface. We discuss system innovations, including the incorporation of pertinent usage patterns as well as identifying certain limitations of the system. This leads to our current motivations and focus on using computational and artificial intelligence methods to enhance user engagement, and to further improve the system with novel mechanisms for the delivery of therapy content to users. In particular, we cover our usage of natural language analysis and chatbot technologies as strategies to tailor interventions and scale up the system.
To date, the innovative MOST system has demonstrated viability in a series of clinical research trials. Given the data-driven opportunities afforded by the software system, observed usage patterns, and the aim to deploy it on a greater scale, an important next step in its evolution is the incorporation of advanced and automated content delivery mechanisms.
Collective motion of locally interacting agents is found ubiquitously throughout nature. The inability to probe individuals has driven longstanding interest in the development of methods for ...inferring the underlying interactions. In the context of heterogeneous collectives, where the population consists of individuals driven by different interactions, existing approaches require some knowledge about the heterogeneities or underlying interactions. Here, we investigate the feasibility of identifying the identities in a heterogeneous collective without such prior knowledge. We numerically explore the behavior of a heterogeneous Vicsek model and find sufficiently long trajectories intrinsically cluster in a principal component analysis-based dimensionally reduced model-agnostic description of the data. We identify how heterogeneities in each parameter in the model (interaction radius, noise, population proportions) dictate this clustering. Finally, we show the generality of this phenomenon by finding similar behavior in a heterogeneous D'Orsogna model. Altogether, our results establish and quantify the intrinsic model-agnostic statistical disentanglement of identities in heterogeneous collectives.
•LC-HRMS detected gambierone and novel methylgambierone in Gambierdiscus silvae.•LC-HRMS/MS to tentatively identify a novel isomer of 44-methylgambierone.•Boronate gel technique developed for ...selective extraction of gambierones.•Several potential sulfated polyether metabolites identified in eluate.
Gambierdiscus spp. are epi-benthic dinoflagellates that have been associated with ciguatera poisoning. These microalgae can have complex secondary metabolite profiles including ciguatoxins, maitotoxins, and gambierones, with varying compositions and toxicities across species and strains. Given this chemical diversity there is a need to develop selective and sensitive methods for secondary metabolite profiling. In this study, we used a cultured Caribbean strain of Gambierdiscus silvae to develop sample preparation and analysis strategies for characterizing vic-diol containing secondary metabolites. A pooled cellular extract was first screened by liquid chromatography–high-resolution mass spectrometry (LC–HRMS) for ciguatoxin-related compounds, which resulted in the confirmation of gambierone (1) and a novel isomer of 44-methylgambierone (3). Treatment of the extract with periodate confirmed that the gambierones each contained one reactive vic-diol, which was exploited for the development of a selective extraction procedure using m-aminophenylboronic acid gel and the non-aqueous binding solvent chloroform. Using this non-traditional boronate affinity procedure, LC–HRMS also revealed the presence of additional sulfated polycyclic ethers in the gambierone-containing vic-diol fraction, while pigments and other contaminants were removed. The developed tools could be applied to screen collections of Gambierdiscus and other benthic algae to provide additional chemical characterization of gambierone-related compounds. The selective extraction procedure may also prove useful as a step in the isolation of these sulfated polyethers for structural, toxicological and biotransformation studies.
A glutathione (GSH) adduct of the mycotoxin 4-deoxynivalenol (DON), together with a range of related conjugates, has recently been tentatively identified by LC-MS of DON-treated wheat spikelets. In ...this study, we prepared samples of DON conjugated at the 10- and 13-positions with GSH, Cys, CysGly, γ-GluCys and
-acetylcysteine (NAC). The mixtures of conjugates were used as standards for LC-HRMS analysis of one of the DON-treated wheat spikelet samples, as well as 19 Norwegian grain samples of spring wheat and 16 grain samples of oats that were naturally-contaminated with DON at concentrations higher than 1 mg/kg. The artificially-contaminated wheat spikelets contained conjugates of GSH, CysGly and Cys coupled at the olefinic 10-position of DON, whereas the naturally-contaminated harvest-ripe grain samples contained GSH, CysGly, Cys, and NAC coupled mainly at the 13-position on the epoxy group. The identities of the conjugates were confirmed by LC-HRMS comparison with authentic standards, oxidation to the sulfoxides with hydrogen peroxide, and examination of product-ion spectra from LC-HRMS/MS analysis. No γ-GluCys adducts of DON were detected in any of the samples. The presence of 15-
-acetyl-DON was demonstrated for the first time in Norwegian grain. The results indicate that a small but significant proportion of DON is metabolized via the GSH-conjugation pathway in plants. To our knowledge, this is the first report of in vivo conjugation of trichothecenes via their epoxy group, which has generally been viewed as unreactive. Because conjugation at the 13-position of DON and other trichothecenes has been shown to be irreversible, this type of conjugate may prove useful as a biomarker of exposure to DON and other 12,13-epoxytrichothecenes.
The time that it takes a diffusing particle to find a small target has emerged as a critical quantity in many systems in molecular and cellular biology. In this paper, we extend the theory for ...calculating this time to account for several ubiquitous biological features which have largely been ignored in the mathematics and physics literature on this problem. In particular, we allow (i) targets to diffuse on the two-dimensional boundary of the three-dimensional domain, (ii) targets to diffuse in the interior of the domain, (iii) the diffusivities of the searcher particle and the targets to stochastically fluctuate, (iv) targets to be stochastically gated, and (v) the transition times between fluctuations in diffusivity and gating to have effectively any probability distribution. In this general framework, we analytically calculate the leading order behavior of the mean first passage time and splitting probability for the searcher to reach a target as the target size decays, which is the so-called narrow escape limit. To make these extensions, we use a generalized Itô’s formula to derive a system of coupled partial differential equations which are satisfied by statistics of the process, where the size of the system and its spatial dimension can be arbitrarily large. We apply matched asymptotic analysis to this system and verify our analytical results by numerical simulation. Our results reveal several new features and generic principles of diffusive search for small targets.
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