Release Mechanism Research Articles

Exploring Hydrogel Nanoparticle Systems for Enhanced Ocular Drug Delivery.

Drug delivery to the ocular system is affected by anatomical factors like the corneal epithelium, blinking reflex, aqueous blood barrier, and retinal blood barrier, which lead to quick removal from the site and inefficient drug delivery. Developing a drug delivery mechanism that targets specific eye tissue is a major hurdle for researchers. Our study examines the challenges of drug absorption in these pathways. Hydrogels have been researched as a suitable delivery method to overcome some obstacles. These are developed alone or in conjunction with other technologies, such as nanoparticles. Many polymer hydrogel nanoparticle systems utilizing both natural and synthetic polymers have been created and investigated; each has pros and cons. The complex release mechanism of encapsulated agents from hydrogel nanoparticles depends on three key factors: hydrogel matrix swelling, drug-matrix chemical interactions, and drug diffusion. This mechanism exists regardless of the type of polymer. This study provides an overview of the classification of hydrogels, release mechanisms, and the role of controlled release systems in pharmaceutical applications. Additionally, it highlights the integration of nanotechnology in ocular disease therapy, focusing on different types of nanoparticles, including nanosuspensions, nanoemulsions, and pharmaceutical nanoparticles. Finally, the review discusses current commercial formulations for ocular drug delivery and recent advancements in non-invasive techniques. The objective is to present a comprehensive overview of the possibilities for enhancing ocular medication delivery through hydrogel nanoparticle systems.

Modeling bacterial transport and fate: Insight into the cascading consequences of soil water repellency and contrasting hydraulic conditions

The mechanisms governing bacteria transport and fate rely on their hydrophobicity and the wettability of porous media across a wide range of soil moisture conditions, extending from extreme dryness to highly saturated states. However, it largely remains unknown how transport, retention, and release mechanisms change in natural soil systems in such conditions. We thus optimized our previously published unique transport data for hydrophilic Escherichia coli (E. coli) and hydrophobic Rhodococcus erythropolis (R. erythropolis) bacteria, and bromide (Br−) in two distinct wettable and water-repellent soils at column scale. The soils were initially dry, followed by injecting influents in two pulses followed by a flushing step under saturated flow conditions for six pore volumes. We conducted simulations for each pulse separately and simultaneously for soils. There were differences in hydraulic properties of the soils due to their contrasting wetting characteristic in separate and simultaneously modeling of each pulse affecting Br− and bacteria transport fate. Bacteria attachment was the dominant retention mechanism in both soils in these conditions. Notably, the 82.4 min−1 attachment rate in wettable soil was almost 10× greater than in the water-repellent soil and it governed optimization of bacteria die-off. Physicochemical detachment and physical release unraveled the effect of bacteria size and hydrophobicity interacting with soil wettability. The smaller and hydrophobic R. erythropolis detached more easily while hydrophilic E. coli released; the rates were enhanced by soil water repellency. Further research is needed to reveal the effects of surface wettability properties on bacteria survival especially at the nanoscale.

Nanotechnology in Malaria Treatment: Targeted Drug Delivery Systems and Future Applications

Malaria continued to be a major global health challenge, particularly in regions with high disease burden, despite advancements in treatment options such as Artemisinin-based Combination Therapies (ACTs). The emergence of nanotechnology offered a transformative approach to malaria treatment, with its potential to improve drug delivery, bioavailability, and therapeutic outcomes. This review examined the current applications and advancements in nanotechnology for malaria treatment, focusing on the use of nanocarriers like liposomes, polymeric nanoparticles, and solid lipid nanoparticles. These systems enhanced the efficacy of antimalarial drugs by enabling targeted delivery to malaria-infected cells, overcoming drug resistance, and offering controlled release mechanisms. The review also explored emerging strategies such as combination therapies, personalized nanomedicine, responsive nanoparticles, and vaccine delivery systems. While nanotechnology holds great promise, challenges including safety, scalability, regulatory hurdles, and cost were addressed. Future directions suggest innovations such as smart nanocarriers, personalized treatments, and enhanced diagnostic integration. Methodologically, this review synthesized data from recent preclinical and clinical research to provide a comprehensive analysis of nanotechnology’s role in advancing malaria treatment. Global collaboration and interdisciplinary research will be pivotal in realizing the full potential of nanotechnology in combating malaria. Keywords: Nanotechnology, malaria treatment, drug delivery systems, liposomes, nanoparticles, targeted therapy, drug resistance

The promoting effect of Fe on the immobilization of heavy metals in MSWI FA–lead–zinc tailings-based backfill materials under field application: Dynamic simulation leaching and immobilization mechanisms

Currently, research on solid waste-based backfill materials containing municipal solid waste incineration fly ash (MSWI FA) was primarily concentrated at the laboratory stage, with insufficient studies on their leaching safety and heavy metal immobilization mechanisms under field application. This study demonstrated that MLBM (Binder weight ratio: MSWI FA: steel slag (SS): blast furnace slag (BFS): flue gas desulfurized gypsum (FGDG): coal fly ash (CFA) = 10 %:33.6 %:33.6 %:12.8 %:20 %; binder-to-lead–zinc tailings (LZT) ratio was 1:8; mass concentration was 60 %) exhibited excellent leaching safety in actual backfilling. The study found that MLBM posed no risk of heavy metal and anion leaching under various leaching standards. Furthermore, MLBM showed no risk of harmful element leaching within a simulated percolation period of 100 years. The release mechanisms of Pb, As, Zn, and Cr in MLBM were diffusion, diffusion, flushing, and dissolution, respectively. The immobilization efficiency of Pb, Zn, Cr, As, Cl−, and SO42− positively correlated with the pH value (pH>7.5). The immobilization mechanism included: 1) Formation of insoluble heavy metal compounds. In the MLBM system (The pH ranged from 7.89 to 8.87), Fe(III) (Fe(OH)3(aq) and Fe(OH)4−) contributed to the immobilization of Pb2+ and SO42− and oxidized As(III) (H2AsO3−) and Cr(III) (Cr(OH)3(aq)), forming As(V) (HAsO42−) and Cr(VI) (CrO42−), respectively. 2) Adsorption. The negatively charged surface of C–(A)–S–H gel could immobilize Zn2+ and Pb2+ through adsorption, and the ionic forms of Pb(II) and Zn(II) were PbOH+ and ZnOH+, respectively. This study provided theoretical support for the leaching safety and immobilization mechanisms of solid waste-based backfill materials containing MSWI FA in field applications.

Development and evaluation of ibuprofen-loaded chitosan nanoparticles for pulmonary therapy

Lung injuries are increasingly prevalent due to various diseases causing alveolar damage, potentially leading to respiratory disorders. This study employed an incubation method to develop nano-encapsulated ibuprofen within a chitosan matrix for targeted pulmonary therapy. The encapsulation was successful without altering the molecular structure of chitosan, and a 500 mg dose was identified as optimal through lung tissue cell viability and histological analysis. The controlled release mechanism of this formulation ensures targeted delivery to the lungs, reducing inflammation and promoting alveolar regeneration. This approach highlights the importance of dose optimization and presents a promising strategy to enhance the efficacy and safety of pulmonary treatments.

Novel biopolymeric chitosan-urea-based core-shell hydrogel for use in sustainable agriculture

Agricultural sustainability is a major issue in recent times, deficiency of water as well as insufficient fertilizer to the crop is a main reason for it. This work is focused on core-shell hydrogel aiming to overcome the agricultural issues of water as well as deficiency of fertilizer to the plant. The core-shell hydrogel was prepared by incorporating urea in κ-carrageenan to be part of the controlled release mechanism of the core of the hydrogel. Chitosan was used for the shell structure to prepare over the core and cross-linked by the cations of the salts. The prepared hydrogel was termed as Chitosan-κ-carrageenan-Urea (CK-CU). Four different types of hydrogels were prepared with the different compositions named as CK-CU 2, CK-CU 5, CK-CU 7.5 and CK-CU 10 as varying with the ratio of 2 %, 5 %, 7.5 % and 10 % of urea respectively. The core-shell morphology structure was verified with Scanning electron microscopy (SEM) in which the complete coverage of the κ-carrageenan core by a consistent chitosan shell has been verified. Fourier transform infrared spectroscopy (FTIR) was utilized to confirm the composition of the hydrogel. Thermo-gravimetric analysis (TGA) was also performed for checking the thermal endurance of the hydrogel. The release rate of the urea was determined under Ultraviolet Visible spectroscopy. The swelling index, dewatering, and urea release rate of optimized CK-CU 10 hydrogel were found to 121 %, 21.22 %, and 70.4 % respectively. The developed Core-Shell hydrogel exhibits significant promise as a vehicle for fertilizer and as a soil conditioner in agricultural applications especially in arid and semi-arid areas.

Analyzing Fusion Pore Dynamics and Counting the Number of Acetylcholine Molecules Released by Exocytosis.

Acetylcholine (ACh) is a critical neurotransmitter influencing various neurophysiological functions. Despite its significance, quantitative methods with adequate spatiotemporal resolution for recording a single exocytotic ACh efflux are lacking. In this study, we introduce an ultrafast amperometric ACh biosensor that enables 50 kHz electrochemical recording of spontaneous single exocytosis events at axon terminals of differentiated cholinergic human SH-SY5Y neuroblastoma cells with sub-millisecond temporal resolution. Characterization of the recorded amperometric traces revealed seven distinct current spike types, each displaying variations in shape, time scale, and ACh quantities released. This finding suggests that exocytotic release is governed by complex fusion pore dynamics in these cells. The absolute number of ACh molecules released during exocytosis was quantified by calibrating the sensor through the electroanalysis of liposomes preloaded with varying ACh concentrations. Notably, the largest quantal release involving approximately 8000 ACh molecules likely represents full exocytosis, while a smaller release of 5000 ACh molecules may indicate partial exocytosis. Following a local administration of bafilomycin A1, a V-ATPase inhibitor, the cholinergic cells exhibited both a larger quantity of ACh released and a higher frequency of exocytosis events. Therefore, this ACh sensor provides a means to monitor minute amounts of ACh and investigate regulatory release mechanisms at the single-cell level, which is vital for understanding healthy brain function and pathologies and optimizing drug treatment for disorders.

Cell-membrane coated nanoparticles: Role of machine learning and applications in diagnosis and therapy

The advancement of biomedical technologies has introduced a promising approach for targeted drug delivery—utilizing nano and microscale systems. These compounds provide the potential for precise drug delivery to specific tissues, enhancing diagnostic accuracy and therapeutic efficacy, thereby minimizing off-target effects and improving site-specific accumulation. They enable controlled release of therapeutic agents, reducing the systemic toxicity often associated with conventional drugs. This review particularly highlights the critical role of cell membrane-decorated nanocompounds (CDCs), which represent a significant innovation in this field. Artificial Intelligence (AI) plays a pivotal role in enhancing the precision of CDCs, utilizing advanced algorithms to predict optimal delivery routes and release mechanisms. Moreover, AI-driven analytics are instrumental in the real-time monitoring and adjustment of drug release rates, ensuring maximum efficacy and patient safety. This review delves into the applications of CDCs, exploring their characterization, drug delivery potential, and future prospects, with a specific focus on how cell membrane coatings can revolutionize the landscape of drug delivery. Furthermore, the integration of AI in these processes is emphasized, particularly in how it can significantly impact future therapeutic strategies.

The Mechanism of Arsenic Release in Contaminated Paddy Soil with Added Biochar: The Role of Dissolved Organic Matter, Fe, and Bacteria.

The addition of biochar inevitably modifies the acidity (pH), redox potential (Eh), and dissolved organic matter (DOM) level in the soil. These alterations also have coupled effects on the cycling of iron (Fe) and the composition of bacterial communities, thereby impacting the speciation and availability of arsenic (As) in the soil. This study explored the potential mechanisms through which biochar affects As in paddy soil during flooded cultivation with different pyrolysis temperature biochars (300 °C, 400 °C, and 500 °C) added. The results revealed that the TAs concentration increased in the initial 15 days of soil cultivation with SBC300 or SBC400 addition because increasing the concentration of DOM induced the mobility of As though the formation of As-DOM complexes. Meanwhile, biochar addition elevated the pH, decreased the Eh, and promoted the transformation of specific adsorbed As (A-As) and amorphous iron oxide-bound As (Amo-Fe-As) to supernatant As through enhancing the reductive dissolution of Fe(oxy)(hydr)oxides. Moreover, the biochar altered the relative abundance of As (V)-reducing bacteria (such as Firmicutes) and As (III)-oxidizing bacteria (such as Chloroflex), thereby affecting As speciation. However, these mechanistic effects varied depending on the pyrolysis temperature of the biochar. The microbial composition of SBC300 and SBC400 were similar, with both containing larger populations of Enterobacteriaceae (AsRB) and pseudomonas (FeRB) compared to CK and SBC500. It was proposed that lower pyrolysis temperatures (300 °C and 400 °C) are more favorable for the dissolution of Fe(oxy)(hydr)oxides and the reduction of As (V). However, the biochar from the higher pyrolysis temperature (500 °C) showed environmental impacts akin to the control group (CK). This study demonstrated potential mechanisms of biochar's effect on As and the role of pyrolysis temperature.

Investigation on fatigue performance and residual stress release mechanism of split sleeve cold expansion holes of heterogeneous 7050-T7451 aluminum alloy

7050-T7451 aluminum alloy is widely applied in aircraft structural components due to good properties, these components majority connected with hole structures. However, stress concentration occurs around structural holes during application, which leads to fatigue cracking and ultimately resulting in low fatigue performance of these parts. The residual stress generated by cold expansion can provide sufficient strength to prevent fatigue crack initiation. However, this protective effect is lost when the residual stress is released during fatigue. Consequently, it is crucial to investigate the release of residual stress in hole structures during the fatigue process. In this work, the residual stress release process and microstructure evolution under to different cyclic loads were investigated. The back stress induced by the heterogeneous structure on residual stress release and the effect of heterogeneous structure on crack propagation were discussed. The findings indicate that the back stress generated by GNDs of heterogeneous structures can resist the applied load in early stages, delay residual stress release. As the cycle number increases, potential mechanisms for the release of residual stress include dislocation annihilation, dislocation rearrangement, and dislocation shearing. The heterogeneous grain structure with high tortuosity and the deflection and branching of cracks can reduce the driving force of crack growth.

Inulin extracted from burdock root (Arctiumlappa L.) incorporated alginate/chitosan hydrogel beads for probiotics encapsulation

Burdock root is a reliable source of inulin, a prebiotic with potential benefits for probiotic encapsulation. This study aimed to extract inulin from burdock roots and assess its physicochemical properties and functional groups in comparison to standard inulin. The focus was on evaluating the effectiveness of inulin combined with alginate and coated with chitosan as an encapsulating material for probiotics. The extracted inulin was found to be a light brown powder with a high inulin content of 78.54 %. FTIR analysis confirmed the successful extraction of inulin and highlighted its prebiotic potential. When combined with alginate, the inulin formed dense bead structures that significantly enhanced encapsulation efficiency (∼88 %) and improved probiotic viability (>6 log CFU/g) during simulated gastrointestinal transit, outperforming pristine alginate beads. The beads demonstrated a gradual probiotic release within 3 h under simulated intestinal conditions, following the Korsmeyer–Peppas release mechanism. Storage experiments showed that the beads containing extracted inulin maintained probiotic levels above 7.6 log CFU/g after 28 days. Incorporating inulin extracted from burdock root into alginate-based encapsulation systems could significantly improve probiotic survival and provide a potential method for targeted probiotic delivery to the intestine. This approach offers a promising strategy for enhancing the effectiveness of probiotics through improved protection and controlled release.

Microstructure characteristics for improved thermal shock reliability of sintered Ag[sbnd]Al paste in SiC power module

To meet the harsh thermal shock (−50–250 °C) requirements of power device packaging, a novel sintered Ag-based die attach material based on the sustained release effect of Al was proposed. In this study, Al particles with natural core-shell structure covered with Al2O3 layer were selected as the ideal doping-phase, and micron Al particles doped sintered Ag composite paste (AgAl) was prepared. First, the microstructural evolution of sintered AgAl joints during thermal shock was studied. The results showed that Al particles effectively suppressed the cracks generation, which attributed to the sustained release effect of Al element. To clarify sustained release mechanism of Al, the interfaces evolution between Ag and Al particles was investigated. In the initial stage, Al was covered by the Al2O3 layer, preventing inter-diffusion between Ag and Al. As the thermal shock proceeds, the Al2O3 film was fractured, achieving direct contact between metal Al and Ag. Diffusion thus takes place. For the sintered Ag5Al joint, the shear strength was 17.3 MPa after 1000 cycles, which is 1.57 times that of pure sintered Ag joint. These results indicate the successful development of low-cost, high-reliability die attachment materials for use in harsh thermal shock environments.

Hydrogen production mechanism and catalytic productivity of Ni-X@g-C3N4 (X = precious and non-precious promoter metals) catalysts from KBH4 hydrolysis under stress loading and atmospheric pressure: Experimental analysis and molecular dynamics approach

In this study, the pressure effect of Ni-based catalysts added a second promoter metal to increase of catalyst performance supported a graphite carbon nitride (g-C3N4) monolayer on hydrogen release mechanisms from potassium boron hydride (KBH4) hydrolysis was investigated using molecular dynamics (MD) method based on tight-binding density functional theory (DFT). The use of the various promoters, such as transition metals (X = Cu, Ta and W) and noble metals (X = Pd, Pt and Rh) with applying a high external pressure was investigated to understand the role on catalytic performance of the Ni-based catalysts under stress loading. The g-C3N4 monolayer doped with Ni-X nano-catalysts was used for efficient H2 release from KBH4 hydrolysis. The computational results show that the number of H2 shows more increment with MD time for NiW and NiRh catalysts than other NiTa and NiCu (transition metals) and NiPd and NiPt (noble metals) under 0 GPa pressure. On the other hand, a notable increase in H2 amount is seen only NiCu and NiRh catalysts under 50 GPa. Also, the mechanism of the H2 production reaction from KBH4 hydrolysis of g-C3N4 doped NiCo catalysts was clarified. High-performance cost metal catalysts such as NiCo was investigated as both experimentally and modeling under atmospheric pressure to enhance its commercial application value. Some experimental applications and analyzes were also performed to measure the accuracy of the modeling for the relevant molecular groups in the system.

Unveiling the release mechanism of potentially toxic elements from Pb/Zn smelter contaminated soils under the coupled effects of freeze–thaw and acidification: Insights from mineralogical analysis

Most Pb/Zn smelter contaminated sites in China are often encountered natural phenomenon known as freeze–thaw (F–T) cycles and acid rain. However, the coupled effects of F–T cycles and acidification on the release behavior of potentially toxic elements (PTEs) from soils remains unclear. A mechanistic study on PTEs release from soils was conducted by revealing the physicochemical weathering characteristics of minerals under F–T cycles combined with acidification. The results from F–T test indicated that among F–T parameters, F–T frequency were the more important factors influencing PTEs release, with the corresponding contribution ranges of 21.20–94.40 %. As pH decreased, the leaching concentrations of As, Cd, Cu, Mn, Pb and Zn did not increase under the same F–T frequency. As F–T frequency increased, the leaching concentrations of these studied PTEs also did not increase under the same pH condition. Microstructure characteristics revealed that the soils were a complex system with multi–mineral aggregates, which had experienced complex physicochemical weathering after F–T combined with acidification treatment. Combined with geochemical modeling results, PTEs release was found to be mainly influenced by the microstructure damage and proton corrosion of minerals, while little affected by their precipitation and dissolution. The mutual coupling relationships of mineral weathering and PTEs release were conducive to the better understanding of the migration behavior of PTEs in contaminated sites under complex environment scenarios. The present study results would provide theoretical instruction and technical support for the longevity evaluation of multi–metal stabilization remediation.

Development of Lightweight 6 m Deployable Mesh Reflector Antenna Mechanisms Based on a Superelastic Shape Memory Alloy

This paper describes the design and experimental verification of a 6 m parabolic deployable mesh reflector antenna mechanism based on a superelastic shape memory alloy. This antenna mainly consists of a deployable primary reflector with a superelastic shape memory alloy-based hinge mechanism and a fixed-type secondary reflector mast, where a rotary-type holding and release mechanism and deployment speed control system are installed. The main feature of this antenna is the application of a superelastic shape memory alloy to the mechanism, which has the advantages of plastic deformation resistance, high damping, and fatigue resistance. A shape memory alloy is applied to the hinge mechanism of each primary reflector rib and to the rotary-type holding and release mechanism as a deployment mechanism. In addition, a superelastic shape memory alloy wire is applied to the antenna in the circumferential direction to maintain the curvature of the primary reflector. The effectiveness of the proposed mechanism design was verified through repeated deployment tests on models of the superelastic shape memory alloy-based hinge mechanism and the antenna system.

μ-Opioid Receptor Modulation of the Glutamatergic/GABAergic Midbrain Inputs to the Mouse Dorsal Hippocampus.

We used virus-mediated anterograde and retrograde tracing, optogenetic modulation, immunostaining, in situ hybridization, and patch-clamp recordings in acute brain slices to study the release mechanism and μ-opioid modulation of the dual glutamatergic/GABAergic inputs from the ventral tegmental area and supramammillary nucleus to the granule cells of the dorsal hippocampus of male and female mice. In keeping with previous reports showing that the two transmitters are released by separate active zones within the same terminals, we found that the short-term plasticity and pharmacological modulation of the glutamatergic and GABAergic currents are indistinguishable. We further found that glutamate and GABA release at these synapses are both virtually completely mediated by N- and P/Q-type calcium channels. We then investigated μ-opioid modulation of these synapses and found that activation of μ-opioid receptors (MORs) strongly inhibits the glutamate and GABA release, mostly through inhibition of presynaptic N-type channels. However, the modulation by MORs of these dual synapses is complex, as it likely includes also a disinhibition due to downmodulation of local GABAergic interneurons which make direct axo-axonic contacts with the dual glutamatergic/GABAergic terminals. We discuss how this opioid modulation may enhance LTP at the perforant path inputs, potentially contributing to reinforce memories of drug-associated contexts.

Investigation of pH-dependent Paclitaxel delivery mechanism employing Chitosan-Eudragit bioresponsive nanocarriers: a molecular dynamics simulation

Before embarking on any experimental research endeavor, it is advisable to do a mathematical computation and thoroughly examine the methodology. Despite the use of polymeric nanocarriers, the regulation of bioavailability and drug release at the disease site remains insufficient. Several effective methods have been devised to address this issue, including the creation of polymeric nanocarriers that can react to stimuli such as redox potential, temperature, pH, and light. The present study has been utilized all-atom molecular dynamics (AA-MD) and coarse-grained molecular dynamics (CG-MD) methods and illustrated the drug release mechanism, which is influenced by pH, for Chitosan-Eudragit bioresponsive nanocarriers. The aim of current work is to study the molecular mechanism and atomistic interactions of PAX delivery using a Chitosan-Eudragit carrier. The ability of Eudragit polymers to dissolve in various organic solvents employed in the process of solvent evaporation is a crucial benefit in enhancing the solubility of pharmaceuticals. This study investigated the use of Chitosan-Eudragit nanocarriers for delivering an anti-tumor drug, namely Paclitaxel (PAX). Upon analyzing several significant factors affecting the stability of the drug and nanocarrier, it has been shown that the level of stability is more significant in the neutral state than the acidic state. Furthermore, the system exhibits higher stability in the neutral state. The used Chitosan-Eudragit nanocarriers exhibit a stable structure under alkaline conditions, but undergo deformation and release their payloads under acidic conditions. It was demonstrated that the in silico analysis of anti-tumor drugs and carriers’ integration could be quantified and validated by experimental results (from previous works) at an acceptable level.Graphical abstract

Design and Evaluation of New Gel-Based Floating Matrix Tablets Utilizing the Sublimation Technique for Gastroretentive Drug Delivery.

A gel-based floating matrix tablet was formulated and evaluated using the sublimation technique to enhance gastroretentive drug delivery. Anhydrous theophylline was employed as the active pharmaceutical ingredient, combined with sublimation agents and hydroxypropyl methylcellulose as the gel-forming polymer. The resulting tablets exhibited high porosity, immediate floatation, and sustained buoyancy for over 8 h. Optimization of the floating behavior and drug release profiles was achieved by adjusting the viscosity of and hydroxypropyl methylcellulose and the concentration of sublimation agents, specifically ammonium carbonate and menthol. These agents were selected for their effectiveness in creating a porous structure, thus reducing tablet density and enhancing floatation. Higher HPMC viscosity resulted in increased floating force, slower drug release, and improved swelling properties due to a slower erosion rate. A critical assessment of the balance between tablet porosity, mechanical strength, and drug release kinetics indicates that ammonium carbonate provided superior tablet hardness and lower friability compared to menthol, favoring a controlled release mechanism. The release dynamics of theophylline were best described by the anomalous (non-Fickian) diffusion model, suggesting a combined effect of diffusion and erosion. This research advances the development of gastroretentive drug delivery systems, highlighting the potential of sublimation-based floating matrix tablets for sustained drug release.

Vps4 substrate binding and coupled mechanisms of Vps4p substrate recruitment and release from autoinhibition.

The ESCRT pathway's AAA+ ATPase, Vps4p, remodels ESCRT-III complexes to drive membrane fission. Here, we use peptide binding assays to further the understanding of substrate specificity and the mechanism of autoinhibition. Our results reveal unexpected sequence preference to the substrate binding groove and an elegant mechanism of regulation that couples localization to substrate with release from autoinhibition.

Thrombomodulin (p.Cys537Stop) is released from cells by an unusual membrane insertion/leakage mechanism

AbstractExpression of the thrombomodulin (TM) variant c.1611C>A (p.Cys537Stop) leads to the synthesis of a protein with no cytoplasmic tail and a transmembrane domain shortened by 3 amino acids (TM536). However, little is known regarding the release mechanism and properties of TM536. Using umbilical vein endothelial cells and peripheral blood-derived endothelial colony-forming cells from a heterozygous carrier of the TM536 variant as well as overexpression cell models, we demonstrated that TM536 is released from cells by an unusual mechanism. First, TM536 is inserted into the endoplasmic reticulum (ER) membrane, then, because of the low hydrophobicity of its intramembrane domain, it escapes from it and follows the conventional secretory pathway to be released into the extracellular compartment without the involvement of proteolysis. This particular secretion mechanism yields a soluble TM536, which is poorly modified by chondroitin sulfate glycosaminoglycan compared with conventionally secreted soluble forms of TM, and therefore has a suboptimal capacity to mediate thrombin-dependent activation of protein C (PC). We also showed that TM536 cellular trafficking was altered, with retention in the early secretory pathway and increased sensitivity to ER-associated degradation. As expected, activation of ER-associated degradation increased TM536 degradation and reduced its release. The expression of TM536 at the cell surface was low, and its distribution in lipid raft-like membrane microdomains was altered, resulting in low thrombin-dependent PC activation on the cell surface.