Release Pathway Research Articles

Sustainable fragrance release wax oil coating for wood substrate based on peppermint essential oil microcapsules

At present, odorous emissions from wood products are the main leading cause of perceived discomfort in indoor environments. The source control is the most effective way to reduce odorous emissions. Herein, this study aims to investigate the impact of peppermint essential oil microcapsules on the unpleasant odor emissions from wax oil coated wood products. In this paper, peppermint essential oil microcapsules were added to wax oil to endow wax oil-coated wood with continuous fragrance release. The results showed that the microcapsules prepared by the complex coacervation method with gelatin and gum arabic as the wall materials and peppermint essential oil as the core material had significant fragrance slow-release ability and improved thermal stability. Adding microcapsules to wood wax oil at a mass ratio of 10% has no significant effect on the quality of the paint film, but the presence of amino groups in the wall material of the microcapsules causes a significant color change of the finished wood. The release of aromatic odors in wax oil-coated wood is significantly prolonged. The main odorant compounds released in the early stage were terpenes with herbal, woody and balsamic flavor characteristics. The odor compounds released at a later stage are mainly alkanes, and the odor is expressed as waxy, herbal and woody. The dispersion of microcapsules in wood wax oil leads to changes in the pore structure of the wood wax oil finish material, which provides multiple pathways for the slow release of odor compounds.

Mechanistic Insight into Acceptorless Dehydrogenation of Methanol to Syngas Catalyzed by MACHO-Type Ruthenium and Manganese Complexes: A DFT Study.

The acceptorless dehydrogenation of methanol to produce carbon monoxide (CO) and dihydrogen (H2) mediated by MACHO-type 1-Ru and 1-Mn complexes was theoretically investigated via density functional theory calculations. The 1-Ru-catalyzed process involves the formation of active species 4-Ru through a methanol-bridged H2 release pathway. Methanol dehydrogenation by 4-Ru yields formaldehyde and 1-Ru, followed by H2 release to regenerate 4-Ru (rate-determining step, ΔG‡ = 32.5 kcal/mol). Formaldehyde further reacts with methanol via nucleophilic attack of the MeO- ligand in the Ru complex (ΔG‡ = 9.6 kcal/mol), which is more favorable than the traditional methanol-to-formaldehyde nucleophilic attack (ΔG‡ = 33.8 kcal/mol) due to the higher nucleophilicity of MeO-. CO is ultimately produced through the methyl formate decarbonylation reaction. Accelerated H2 release in the early reaction stage compared to CO results from the initial methanol dehydrogenation and condensation of formaldehyde with methanol. In contrast, CO generation occurs later via methyl formate decarbonylation. The 1-Mn-catalyzed reaction has reduced efficiency compared to 1-Ru for the higher Gibbs energy barrier (ΔG‡ = 34.1 kcal/mol) of the rate-determining step. Excess NaOtBu promotes the reaction of CO and methanol, forming methyl formate, significantly reducing the CO/H2 ratio as the catalyst amount decreases. These findings deepen our understanding of the methanol-to-syngas transformation and can drive progress in this field.

An ROS-Responsive Donor That Self-Reports Its H2S Delivery by Forming a Benzoxazole-Based Fluorophore.

Hydrogen sulfide (H2S), an endogenous signaling molecule, is known to play a pivotal role in neuroprotection, vasodilation, and hormonal regulation. To further explore the biological effects of H2S, refined donors that facilitate its biological delivery, especially under specific (patho) physiological conditions, are needed. In the present study, we demonstrate that ortho-substituted, aryl boronate esters provide two unique and distinct pathways for H2S release from thioamide-based donors: Lewis acid-facilitated hydrolysis and reactive oxygen species (ROS)-induced oxidation/cyclization. Through a detailed structure-activity relationship study, donors that resist hydrolysis and release H2S solely via the latter mechanism were identified, which have the added benefit of providing a potentially useful heterocycle as the lone byproduct of this novel chemistry. To highlight this, we developed an ROS-activated donor (QH642) that simultaneously synthesizes a benzoxazole-based fluorophore en route to its H2S delivery. A distinct advantage of this design over earlier self-reporting donors is that fluorophore formation is possible only if H2S has been discharged from the donor. This key feature eliminates the potential for false positives and provides a more accurate depiction of reaction progress and donor delivery of H2S, including in complex cellular environments.

MiR-455-5p promotes pathological cardiac remodeling via suppression of PRMT1-mediated Notch signaling pathway

Pathological cardiac remodeling plays an essential role in the progression of cardiovascular diseases, and numerous microRNAs have been reported to participate in pathological cardiac remodeling. However, the potential role of microRNA-455-5p (miR-455-5p) in this process remains to be elucidated. In the present study, we focused on clarifying the function and searching the direct target of miR-455-5p, as well as exploring its underlying mechanisms in pathological cardiac remodeling. We found that overexpression of miR-455-5p by transfection of miR-455-5p mimic in vitro or tail vain injection of miR-455-5p agomir in vivo provoked cardiac remodeling, whereas genetic knockdown of miR-455-5p attenuated the isoprenaline-induced cardiac remodeling. Besides, miR-455-5p directly targeted to 3’-untranslated region of protein arginine methyltransferase 1 (PRMT1) and subsequently downregulated PRMT1 level. Furthermore, we found that PRMT1 protected against cardiac hypertrophy and fibrosis in vitro. Mechanistically, miR-455-5p induced cardiac remodeling by downregulating PRMT1-induced asymmetric di-methylation on R1748, R1750, R1751 and R1752 of Notch1, resulting in suppression of recruitment of Presenilin, Notch1 cleavage, NICD releasing and Notch signaling pathway. Finally, circulating miR-455-5p was positively correlated with parameters of left ventricular wall thickening. Taken together, miR-455-5p plays a provocative role in cardiac remodeling via inactivation of the PRMT1-mediated Notch signaling pathway, suggesting miR-455-5p/PRMT1/Notch1 signaling axis as potential therapeutic targets for pathological cardiac remodeling.

Revealing concealed cardioprotection by platelet Mfsd2b-released S1P in human and murine myocardial infarction

Abstract Background/Introduction Platelet activation on ruptured or eroded atherosclerotic lesions leads to thrombus formation and ischemic events. Hence, platelet inhibition is the cornerstone of primary and secondary prevention in patients with cardiovascular disease. Recently, non-canonical effects of platelets in multiple disease processes were revealed. However, others have demonstrated the opposite: a protective and regenerative role of platelets during myocardial healing. Sphingosine-1-phosphate (S1P) is an important bioactive lipid released from platelets upon activation and has potent cardioprotective properties in AMI when acutely administered or kept constitutively high due to pharmacological or genetic inhibition of its degradation. In humans, S1P levels in plasma are dynamically regulated during AMI. Purpose We hypothesized that platelets may be an important source of the S1P burst during AMI and that platelet-derived S1P is relevant for the extent of myocardial damage due to AMI. Methods We have addressed these questions in experimental AMI in mice lacking components of the S1P synthesis, release and signaling pathways. In additon, we conducted a hypothesis generating, prospective, monocentric, time-series, translational analysis in 127 patients with ST-elevation myocardial infarction (STEMI) to analyze the association between S1P plasma concentration and infarct size. Results Injection of cell-free supernatant of activated platelets (SNT+) prior AMI in mice led to decreased infarct size after 24 h of reperfusion as compared to supernatant of non-activated platelets (SNT-). This reduction of infarct size by SNT+ was associated with reduced neutrophil accumulation and reduced apoptosis after AMI. S1P-concentrations in SNT+ was 25% higher as compared to SNT-. S1P concentrations in SNT- of mice lacking Sphingosinkinase-1 (SphK1) were 70% lower and did not increase in SNT+. Accordingly, SNT+ of SphK1- deficient platelets failed to reduce infarct size. Deficiency of platelet S1P exporter Mfsd2b shows increased infarct size during in vivo AMI compared to littermate controls. SNT+ of WT mice led to improved outcome after ischemia in a model of Langendorff-perfused hearts. This was blunted by inhibition of S1P receptor 1 and genetic cardiomyocyte deficiency of S1PR1. Platelet S1P release during activation was reduced by P2Y12 inhibition but preserved during GPIIb/IIIa (tirofiban) inhibition. This translated to blunted cardioprotection by SNT+ of cangrelor treated platelets but sustained cardioprotection during tirofiban treatment. Plasma S1P concentrations was associated with cardiovascular death and infarct size in patients with ST-elevation myocardial infarction. Conclusion We have identified the mechanisms underlying platelet-associated cardioprotection and finally, revealed the importance of platelet-released S1P on admission in patients with ST-elevation myocardial infarction (STEMI) regarding to infarct size and long-term prognosis.

Theoretical elucidation of the structure, bonding, and reactivity of the CaMn4Ox clusters in the whole Kok cycle for water oxidation embedded in the oxygen evolving center of photosystem II. New molecular and quantum insights into the mechanism of the O-O bond formation.

This paper reviews our historical developments of broken-symmetry (BS) and beyond BS methods that are applicable for theoretical investigations of metalloenzymes such as OEC in PSII. The BS hybrid DFT (HDFT) calculations starting from high-resolution (HR) XRD structure in the most stable S1 state have been performed to elucidate structure and bonding of whole possible intermediates of the CaMn4Ox cluster (1) in the Si (i = 0 ~ 4) states of the Kok cycle. The large-scale HDFT/MM computations starting from HR XRD have been performed to elucidate biomolecular system structures which are crucial for examination of possible water inlet and proton release pathways for water oxidation in OEC of PSII. DLPNO CCSD(T0) computations have been performed for elucidation of scope and reliability of relative energies among the intermediates by HDFT. These computations combined with EXAFS, XRD, XFEL, and EPR experimental results have elucidated the structure, bonding, and reactivity of the key intermediates, which are indispensable for understanding and explanation of the mechanism of water oxidation in OEC of PSII. Interplay between theory and experiments have elucidated important roles of four degrees of freedom, spin, charge, orbital, and nuclear motion for understanding and explanation of the chemical reactivity of 1 embedded in protein matrix, indicating the participations of the Ca(H2O)n ion and tyrosine(Yz)-O radical as a one-electron acceptor for the O-O bond formation. The Ca-assisted Yz-coupled O-O bond formation mechanisms for water oxidation are consistent with recent XES and very recent time-resolved SFX XFEL and FTIR results.

Aberrant Expressions of PSMD14 in Tumor Tissue are the Potential Prognostic Biomarkers for Hepatocellular Carcinoma after Curative Resection.

Hepatocellular carcinoma (HCC) has a high mortality rate, with curative resection being the primary treatment. However, HCC patients have a large possibility of recurrence within 5 years after curative resection. Thus, identifying biomarkers to predict recurrence is crucial. In our study, we analyzed data from CCLE, GEO, and TCGA, identifying eight oncogenes associated with HCC. Subsequently, the expression of 8 genes was tested in 5 cases of tumor tissues and the adjacent non-tumor tissues. Then ATP6AP1, PSMD14 and HSP90AB1 were selected to verify the expression in 63 cases of tumor tissues and the adjacent non-tumor tissues. The results showed that ATP6AP1, PSMD14, HSP90AB1 were generally highly expressed in tumor tissues. A five-year follow-up of the 63 clinical cases, combined with Kaplan-Meier Plotter's relapse-free survival (RFS) analysis, found a significant correlation between PSMD14 expression and recurrence in HCC patients. Subsequently, we analyzed the PSMD14 mutations and found that the PSMD14 gene mutations can lead to a shorter disease-free survival time for HCC patients. The results of enrichment analysis indicated that the differentially expressed genes related to PSMD14 are mainly enriched in the signal release pathway. In conclusion, our research showed that PSMD14 might be related to recurrence in HCC patients, and the expression of PSMD14 in tumor tissue might be a potential prognostic biomarker after tumor resection in HCC patients.

Experimental and density functional theory study on role of calcium in NO reduction by NH3 on char surface during ammonia co-firing with pulverized coal

As a carbon-free energy, NH3 has attracted increasing attention from scholars. Ammonia-coal co-firing, as a technology for ammonia energy utilization, has great application potential. However, the NOx generated during ammonia combustion cannot be ignored due to the N element in NH3. At present, the reaction mechanism of NH3 and NO on char, together with the influence mechanism of mineral Ca, in the combustion reduction zone during ammonia-coal co-firing is still unclear. In this study, the effects of Ca on the NO reduction with NH3 on the char surface have been investigated in the high-temperature reaction system. The NO reduction efficiency and the evolutions of char structural characteristics during the reaction processes were analyzed for both demineralized coal char and CaCl2-loaded coal char. The reaction mechanism was also investigated at the molecular level using density functional theory (DFT) to clarify NO reduction and CO release pathways with and without Ca. The DFT results showed that during NO reduction on char surface, NNH group formation and CO desorption are crucial steps in the presence of NH3. Ca plays a catalytic role in NO reduction reaction, which affects NO reduction by NH3 on char surface in two ways. On the one hand, Ca facilitates the reduction of NO to N2 by lowering the energy barrier for NNH group formation (20.98 kJ/mol) and N2 release (93.70 kJ/mol). On the other hand, the formation of Ca–O–C structure increases the energy barrier for CO release from char surface (377.25 kJ/mol), which is unfavorable for NO reduction. The experimental results showed that between 1300 °C and 1500 °C, Ca increases the NO reduction efficiency by 5 %, promoting NO reduction, because Ca lowers the energy barrier of the rate-determining step, thus accelerating the reaction. At this temperature, the inhibition effect of Ca on CO release is not obvious. However, between 1000 °C and 1300 °C, Ca exhibits an inhibition effect on NO reduction. This is because Ca significantly inhibits CO release. At this temperature, the formation rate of NNH species is relatively slow, and NO reduction is influenced by homogeneous reduction. This study aims to provide fundamental information for exploring the application potential of ammonia coal co-firing in industrial furnaces.

Multistep conformational changes leading to the gate opening of light-driven sodium pump rhodopsin

Membrane transport proteins require a gating mechanism that opens and closes the substrate transport pathway to carry out unidirectional transport. The "gating" involves large conformational changes and is achieved via multistep reactions. However, these elementary steps have not been clarified for most transporters due to the difficulty of detecting the individual steps. Here, we propose these steps for the gate opening of the bacterial Na+ pump rhodopsin, which outwardly pumps Na+ upon illumination. We herein solved an asymmetric dimer structure of Na+ pump rhodopsin from the bacterium Indibacter alkaliphilus. In one protomer, the Arg108 sidechain is oriented toward the protein center and appears to block a Na+ release pathway to the extracellular (EC) medium. In the other protomer, however, this sidechain swings to the EC side and then opens the release pathway. Assuming that the latter protomer mimics the Na+-releasing intermediate, we examined the mechanism for the swing motion of the Arg108 sidechain. On the EC surface of the first protomer, there is a characteristic cluster consisting of Glu10, Glu159, and Arg242 residues connecting three helices. In contrast, this cluster is disrupted in the second protomer. Our experimental results suggested that this disruption is a key process. The cluster disruption induces the outward movement of the Glu159-Arg242 pair and simultaneously rotates the seventh transmembrane helix. This rotation resultantly opens a space for the swing motion of the Arg108 sidechain. Thus, cluster disruption might occur during the photoreaction and then trigger sequential conformation changes leading to the gate-open state.

Unraveling the tau puzzle: a review of mechanistic targets and therapeutic interventions to prevent tau pathology in Alzheimer’s disease

Alzheimer’s disease (AD) is a prevalent neurodegenerative disease characterized by irreversible neural degeneration and cognitive decline. The prion-like propagation of the β-amyloid (Aβ) and tau proteins leads to the formation of protein plaques and, subsequently, neuronal dysfunction, contributing significantly to AD pathogenesis. Although effective AD treatments remain elusive, targeting tau protein aggregation has emerged as a promising therapeutic approach. However, recent anti-tau antibody trials have shown limited success in improving cognition, underscoring the need for a more advanced, multifaceted approach to address multiple mechanisms of tau pathology. This review examines the role of tau protein in the context of AD, with a particular focus on potential therapeutic interventions. Emphasis is placed on the modulation of tau protein expression, tau post-translational modifications and aggregation, receptor-mediated uptake and extracellular release pathways, neural inflammatory response pathways, intercellular organelle exchange, mitochondrial function, microtubule stability, and nuclear factor expression as critical intervention points. Despite the challenges faced in ongoing anti-tau clinical efforts, a comprehensive strategy targeting multiple pathways involved in tau pathology, by using either combinations of existing drugs or novel multitarget drugs, holds promise. By gaining a deeper understanding of the complex mechanisms underlying tau pathology, researchers can develop innovative therapeutic strategies to combat AD.

Transport and barrier mechanisms that regulate ciliary compartmentalization and ciliopathies.

Primary cilia act as cell surface antennae, coordinating cellular responses to sensory inputs and signalling molecules that regulate developmental and homeostatic pathways. Cilia are therefore critical to physiological processes, and defects in ciliary components are associated with a large group of inherited pleiotropic disorders - known collectively as ciliopathies - that have a broad spectrum of phenotypes and affect many or most tissues, including the kidney. A central feature of the cilium is its compartmentalized structure, which imparts its unique molecular composition and signalling environment despite its membrane and cytosol being contiguous with those of the cell. Such compartmentalization is achieved via active transport pathways that bring protein cargoes to and from the cilium, as well as gating pathways at the ciliary base that establish diffusion barriers to protein exchange into and out of the organelle. Many ciliopathy-linked proteins, including those involved in kidney development and homeostasis, are components of the compartmentalizing machinery. New insights into the major compartmentalizing pathways at the cilium, namely, ciliary gating, intraflagellar transport, lipidated protein flagellar transport and ciliary extracellular vesicle release pathways, have improved our understanding of the mechanisms that underpin ciliary disease and associated renal disorders.

Controlled release of fishy odors in soluble dietary fiber/surimi mixture by kinetic analysis of real and simulated systems

This study aimed to investigate the effects and mechanisms of soluble dietary fiber (SDF), temperature and hydrophobicity on the release of fishy compounds from surimi by the preparation of real and simulated systems. The results of gas chromatography-mass spectrometry revealed 15 fishy compounds in silver carp surimi, and adding 2 wt% SDF to surimi was found to inhibit the release of 14 fishy compounds by 2.16–43.49%. The simulated release indicated that SDF matrices with different concentrations inhibited the release of fishy compounds by different mechanisms. The resistance to the release of fishy compounds was attributed to viscosity and chemisorption in 2 and 5 wt% SDF matrices, while chemisorption and entanglement network in 8 and 10 wt% SDF matrices. Moreover, high temperature and hydrophobicity of fishy compounds could promote their release by decreasing interfacial mass transfer resistance and H-bond interaction, respectively. Additionally, adding SDF changed the release pathway of fishy compounds in surimi, and they were released through the first pathway consisting of surimi intraparticle diffusion, SDF boundary layer diffusion and gas-liquid interfacial diffusion, or through the second pathway additionally including chemisorption and desorption. This study provides new insights into controlling the release of fishy odors in surimi products.

Proton Release Reactions in the Inward H+ Pump NsXeR.

Directional ion transport across biological membranes plays a central role in many cellular processes. Elucidating the molecular determinants for vectorial ion transport is key to understanding the functional mechanism of membrane-bound ion pumps. The extensive investigation of the light-driven proton pump bacteriorhodopsin from Halobacterium salinarum(HsBR) enabled a detailed description of outward proton transport. Although the structure of inward-directed proton pumping rhodopsins is very similar to HsBR, little is known about their protonation pathway, and hence, the molecular reasons for the vectoriality of proton translocation remain unclear. Here, we employ a combined experimental and theoretical approach to tracking protonation steps in the light-driven inward proton pump xenorhodopsin from Nanosalina sp. (NsXeR). Time-resolved infrared spectroscopy reveals the transient deprotonation of D220 concomitantly with deprotonation of the retinal Schiff base. Our molecular dynamics simulations support a proton release pathway from the retinal Schiff base via a hydrogen-bonded water wire leading to D220 that could provide a putative gating point for the proton release and with allosteric interactions to the retinal Schiff base. Our findings support the key role of D220 in mediating proton release to the cytoplasmic side and provide evidence that this residue is not the primary proton acceptor of the proton transiently released by the retinal Schiff base.

The 14C dose assessment model chain – 14C source term definition and uncertainty quantification

Abstract. Carbon-14 (14C) is an important, dose-determining contributing radionuclide in a deep geological repository for low and intermediate level radioactive waste (L/ILW). 14C is relevant for safety assessments as it can be present both as dissolved and gaseous species in the disposal facility and the host rock, and 14C-organic compounds migrate in the near field and the geosphere due to weak interaction with mineral surfaces in alkaline to near-neutral conditions. Thus, the chemical form of the 14C-bearing carbon species dictates the routes of 14C migration in the engineered barrier system of a deep geological repository and the surrounding host rock and therefore determines the long-term contribution of 14C to dose release from a repository for radioactive waste. Furthermore, 14C released from a deep repository would be subject to a certain accumulation in the biosphere, given the role of carbon as main building block of any life form on earth. The contribution will illustrate Nagra's recent progress within the 14C dose assessment model chain for a L/ILW deep geological repository to address the quantification of uncertainties. The systematic approach began by incorporating a realistic best-estimate plus uncertainty description of 14C activities within the Swiss model inventory of radioactive materials assembled specifically for the purpose of the general licence application. In this context state-of-the-art activation calculations for expected reactor and decommissioning wastes as well as extensive inquiries into origin and use of 14C within medicine, research, and industry played a key role. Uncertainties were screened for relevance and main contributing factors taken into account, differentiating between the characterisation methods of the relevant waste streams. Based on detailed knowledge of the expected activity and material inventory, release rates for the release pathways through congruent and instantaneous release processes as well as resulting chemical species could be defined with confidence. Key findings and characteristics of the 14C source term will be highlighted and discussed.

Multiphase flow modeling at the component level for the Swiss deep geological repository

Abstract. In a deep geological repository for radioactive waste, anaerobic corrosion of various metals lead to the formation of hydrogen. In Switzerland, the implementor (i.e., Nagra) is commissioned to describe and evaluate safety-relevant processes related to gas that can affect the long-term evolution of low- and intermediate-level waste (L/ILW), high-level waste (HLW), and combined L/ILW and HLW repositories. Key tasks include the evaluation of gas and radionuclide release pathways and the pressure and temperature evolution in the repository using multiphase and multicomponent flow and transport models. The Swiss repository design foresees the installation of multiple seals (engineered barriers) in the repository: (i) the V1 seals next to the waste emplacement caverns and tunnels, (ii) the V2 seals located in the access tunnels toward the emplacement caverns and tunnels, and (iii) the V3 seals positioned in the shafts of the repository. These seals are designed to satisfy a wide range of requirements, including requirements related to the hydraulic evolution of the repository and the associated transport of gas, water, and radionuclides. A modeling workflow is currently being developed that integrates modeling performed both at the repository scale using site-specific models and at the component scale using semi-generic models. The repository-scale models are built to assess the thermo-hydraulic evolution in the entire repository, whereas the component-scale models allow for more detailed evaluations of the gas and water flows in key structures of the repository, such as the V1, V2, and V3 seals as well as the emplacement caverns and tunnels. This conference contribution describes the methodology and workflow developed to integrate these models, with a focus on the development and functionality of the component-scale models.

Hsa-miR-320a mediated exosome release under PD stress conditions rescue mitochondrial ROS and cell death in the recipient neuronal and glial cells.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal cell death. Emerging evidence suggest exosomes as a crucial player in the progression and pathogenesis of PD via intercellular communication between different cell types in brain. Exosome release is enhanced from dysfunctional neurons/glia (source cells) under PD stress and mediates the transfer of biomolecules between different cell types (recipient) in brain leading to unique functional outcomes. Exosome release is modulated by alterations in the autophagy and lysosomal pathways; however, the molecular factors regulating these pathways remain elusive. Micro-RNAs (miRNAs) are class of non-coding RNAs that regulate gene expression post-transcriptionally by binding target mRNA and modulate its turnover and translation; however their role in modulating exosome release is not understood. Here, we analyzed the miRNAs-mRNAs network which target cellular processes regulating exosome release. hsa-miR-320a showed the maximum mRNA targets of autophagy, lysosome, mitochondria and exosome release pathways. hsa-miR-320a regulate ATG5 levels and modulate exosome release under PD stress conditions in neuronal SH-SY5Y and glial U-87 MG cells. hsa-miR-320a modulates autophagic flux, lysosomal functions, and mitochondrial ROS in neuronal SH-SY5Y and glial U-87 MG cells. Exosomes derived from hsa-miR-320a expressing source cells under PD stress conditions were actively internalized in the recipient cells and rescued cell death and mitochondrial ROS. These results suggest that hsa-miR-320a regulates autophagy and lysosomal pathways and modulates exosome release in the source cells and derived exosomes under PD stress conditions rescue cell death and mitochondrial ROS in the recipient neuronal and glial cells.

Hybridize magnesium-iron layered double hydroxide with biopolymers to develop multiple pathways for phosphate sorption and release: A potential slow release phosphorus fertilizer

The intensive use of chemical fertilizers presents a dilemma for sustaining food production or causing soil degradation and posing agricultural contamination. The reduction of phosphorus (P) fertilizer usage is particularly crucial because it is a limited resource. This situation calls for the development of efficient P fertilizers to address the impending P deficiency. Mg-Fe layered double hydroxides (LDH) with 0.5 and 2.5 M metal precursors were hybridized with chitosan (CTS) and carboxymethyl cellulose (CMC) to design alternatives of slow release P fertilizers. While phosphate (PO4) sorption capacities were in the order of Mg-Fe LDH > 2.5LDH-CTS/CMC > 0.5LDH-CTS/CMC, PO4 release from 0.5LDH-CTS exhibited a rate constant ∼2.6–7.6 times lower than that of other samples, which had not reached equilibration even after 2688 h. Fe-EXAFS data implied the greatest degree of isomorphic substitution into LDH interlayer of 0.5LDH-CTS. In addition to intercalated PO4, P-XANES data also suggested the organic-P and Fe(III)-P on 0.5LDH-CTS, causing versatile retention processes. After 2688 h of PO4 release, LDH structure gradually weathered and transformed primarily into a structure dominated by ferric (oxyhydrox)oxides. On 0.5LDH-CTS, however, 14.3% of Fe inventory was contributed by Fe(II) species. The Fe(II) domains in conjunction with the likely remaining Mg-Fe LDH structure and amorphous Mg(OH)2 provided bonding sites for PO4, serving as the key factor for the continuous PO4 release beyond 2688 h. Such extended duration of PO4 release warrants the use of LDHs hybridized with biopolymers as promising substitutes for slow release P fertilizers.

Uracil/H+ Symport by FurE Refines Aspects of the Rocking-bundle Mechanism of APC-type Transporters

Transporters mediate the uptake of solutes, metabolites and drugs across the cell membrane. The eukaryotic FurE nucleobase/H+ symporter of Aspergillus nidulans has been used as a model protein to address structure–function relationships in the APC transporter superfamily, members of which are characterized by the LeuT-fold and seem to operate by the so-called ‘rocking-bundle’ mechanism. In this study, we reveal the binding mode, translocation and release pathway of uracil/H+ by FurE using path collective variable, funnel metadynamics and rational mutational analysis. Our study reveals a stepwise, induced-fit, mechanism of ordered sequential transport of proton and uracil, which in turn suggests that FurE, functions as a multi-step gated pore, rather than employing ‘rocking’ of compact domains, as often proposed for APC transporters. Finally, our work supports that specific residues of the cytoplasmic N-tail are involved in substrate translocation, in line with their essentiality for FurE function.

Aberrant metabolite trafficking and fuel sensitivity in human pluripotent stem cell-derived islets

Pancreatic islets regulate blood glucose homeostasis through the controlled release of insulin; however, current metabolic models of glucose-sensitive insulin secretion are incomplete. A comprehensive understanding of islet metabolism is integral to studies of endocrine cell development as well as diabetic islet dysfunction. Human pluripotent stem cell-derived islets (SC-islets) are a developmentally relevant model of human islet function that have great potential in providing a cure for type 1 diabetes. Using multiple 13C-labeled metabolic fuels, we demonstrate that SC-islets show numerous divergent patterns of metabolite trafficking in proposed insulin release pathways compared with primary human islets but are still reliant on mitochondrial aerobic metabolism to derive function. Furthermore, reductive tricarboxylic acid cycle activity and glycolytic metabolite cycling occur in SC-islets, suggesting that non-canonical coupling factors are also present. In aggregate, we show that many facets of SC-islet metabolism overlap with those of primary islets, albeit with a retained immature signature.

Disulfide-Modified Mesoporous Silica Nanoparticles for Biomedical Applications

Mesoporous silica nanoparticles (MSNs) are highly porous carriers used in drug and gene delivery research for biomedical applications due to their high surface area, narrow particle size distribution, and low toxicity. Incorporating disulfide (SS) bonds into the walls of MSNs (MSN-SSs) offers a dual pathway for drug release due to the pore delivery and collapsing porous structure after cellular engulfment. This study explores the effect of embedding disulfide bonds into MSNs through various structural and biological characterization methods. Raman spectroscopy is employed to detect the SS bonds, SEM and TEM for morphology analyses, and a BET analysis to determine the required amount of SSs for achieving the largest surface area. The MSN-SSs are further loaded with doxorubicin, an anticancer drug, to assess drug release behavior under various pH conditions. The MSN-SS system demonstrated an efficient pH-responsive drug release, with over 65% of doxorubicin released under acidic conditions and over 15% released under neutral conditions. Cleaving the SS bonds using dithiothreitol increased the release to 94% in acidic conditions and 46% in neutral conditions. Biocompatibility studies were conducted using cancer cells to validate the engulfment of the nanoparticle. These results demonstrate that MSN-SS is a feasible nanocarrier for controlled-release drug delivery.