Highly porous, three-dimensional (3D) nanostructured composite adsorbents of reduced graphene oxides/Mn3O4 (RGO/Mn3O4) were fabricated by a facile method of a combination of reflux condensation and ...solvothermal reactions and systemically characterized. The as-prepared RGO/Mn3O4 possesses a mesoporous 3D structure, in which Mn3O4 nanoparticles are uniformly deposited on the surface of the reduced graphene oxide. The adsorption properties of RGO/Mn3O4 to antimonite (Sb(III)) and antimonate (Sb(V)) were investigated using batch experiments of adsorption isotherms and kinetics. Experimental results show that the RGO/Mn3O4 composite has fast liquid transport and superior adsorption capacity toward antimony (Sb) species in comparison to six recent adsorbents reported in the literature and summarized in a table in this paper. Theoretical maximum adsorption capacities of RGO/Mn3O4 toward Sb(III) and Sb(V) are 151.84 and 105.50 mg/g, respectively, modeled by Langmuir isotherms. The application of RGO/Mn3O4 was demonstrated by using drinking water spiked with Sb (320 μg/L). Fixed-bed column adsorption experiments indicate that the effective breakthrough volumes were 859 and 633 mL bed volumes (BVs) for the Sb(III) and Sb(V), respectively, until the maximum contaminant level of 5 ppb was reached, which is below the maximum limits allowed in drinking water according to the most stringent regulations. The advantages of being nontoxic, highly stable, and resistant to acid and alkali and having high adsorption capacity toward Sb(III) and Sb(V) confirm the great potential application of RGO/Mn3O4 in Sb-spiked water treatment.
► Current structures of voltage gated ion channels reviewed. ► Voltage sensor domains highlighted. ► The influence of lipids on voltage gated ion channels discussed. ► Electron crystallography ...described as a tool for studying lipid–protein interactions.
Voltage-gated ion channels are responsible for transmitting electrochemical signals in both excitable and non-excitable cells. Structural studies of voltage-gated potassium and sodium channels by X-ray crystallography have revealed atomic details on their voltage-sensor domains (VSDs) and pore domains, and were put in context of disparate mechanistic views on the voltage-driven conformational changes in these proteins. Functional investigation of voltage-gated channels in membranes, however, showcased a mechanism of lipid-dependent gating for voltage-gated channels, suggesting that the lipids play an indispensible and critical role in the proper gating of many of these channels. Structure determination of membrane-embedded voltage-gated ion channels appears to be the next frontier in fully addressing the mechanism by which the VSDs control channel opening. Currently electron crystallography is the only structural biology method in which a membrane protein of interest is crystallized within a complete lipid-bilayer mimicking the native environment of a biological membrane. At a sufficiently high resolution, an electron crystallographic structure could reveal lipids, the channel and their mutual interactions at the atomic level. Electron crystallography is therefore a promising avenue toward understanding how lipids modulate channel activation through close association with the VSDs.
A series of lanthanide-organic frameworks Ln(Himdc)(ina)(H
O)
(Ln = Eu 1a; Sm 1b; and Nd 1c, H
imdc = imidazole-4,5-dicarboxylic acid, Hina = isonicotinic acid) were synthesized under hydrothermal ...conditions. All compounds 1a-1c consist of a 3D microporous lanthanide carboxylate (Eu(COO)
) framework and uncoordinated Lewis basic pyridyl and imidazole groups hung in the channels. The luminescence investigations show that the compound 1c displays an interesting NIR luminescence property. The compound 1a exhibits a good potential as a luminescent multi-responsive sensing material for Fe
ions and Cr
O
anions.
Synaptotagmin-1 functions as a Ca ²⁺ sensor in neurotransmitter release through its two C ₂ domains (the C ₂A and C ₂B domain). The ability of synaptotagmin-1 to bridge two membranes is likely ...crucial for its function, enabling cooperation with the soluble N-ethylmaleimide sensitive factor adaptor protein receptors (SNAREs) in membrane fusion, but two bridging mechanisms have been proposed. A highly soluble synaptotagmin-1 fragment containing both domains (C ₂AB) was shown to bind simultaneously to two membranes via the Ca ²⁺-binding loops at the top of both domains and basic residues at the bottom of the C ₂B domain (direct bridging mechanism). In contrast, a longer fragment including a linker sequence (lnC ₂AB) was found to aggregate in solution and was proposed to bridge membranes through trans interactions between lnC ₂AB oligomers bound to each membrane via the Ca ²⁺-binding loops, with no contact of the bottom of the C ₂B domain with the membranes. We now show that lnC ₂AB containing impurities indeed aggregates in solution, but properly purified lnC ₂AB is highly soluble. Moreover, cryo-EM images reveal that a majority of lnC ₂AB molecules bridge membranes directly. Fluorescence spectroscopy indicates that the bottom of the C ₂B domain contacts the membrane in a sizeable population of molecules of both membrane-bound C ₂AB and membrane-bound lnC ₂AB. NMR data on nanodiscs show that a fraction of C ₂AB molecules bind to membranes with antiparallel orientations of the C ₂ domains. Together with previous studies, these results show that direct bridging constitutes the prevalent mechanism of membrane bridging by both C ₂AB and lnC ₂AB, suggesting that this mechanism underlies the function of synaptotagmin-1 in neurotransmitter release.
Defects in normal autophagic pathways are implicated in numerous human diseases—such as neurodegenerative diseases, cancer, and cardiomyopathy—highlighting the importance of autophagy and its proper ...regulation. Herein we show that Vibrio parahaemolyticus uses the type III effector VopQ (Vibrio outer protein Q) to alter autophagic flux by manipulating the partitioning of small molecules and ions in the lysosome. This effector binds to the conserved Vo domain of the vacuolar-type H+ -ATPase and causes deacidification of the lysosomes within minutes of entering the host cell. VopQ forms a gated channel ~18 Å in diameter that facilitates outward flux of ions across lipid bilayers. The electrostatic interactions of this type 3 secretion system effector with target membranes dictate its preference for host vacuolar-type H+ -ATPase-containing membranes, indicating that its pore-forming activity is specific and not promiscuous. As seen with other effectors, VopQ is exploiting a eukaryotic mechanism, in this case manipulating lysosomal homeostasis and autophagic flux through transmembrane permeation.
Carbon quantum dots/CdS quantum dots/g-C3N4 (CDs/CdS/GCN) photocatalysts have been designed and prepared. Systematic characterization such as XRD, SEM, TEM, UV, and XPS, were done to confirm the ...composite catalysts of CDs/CdS/GCN. The simultaneous photocatalytic production of hydrogen coupled with degradation of organic contaminants (p-chlorophenol, bisphenol A, and tetracycline, called 4-NP, BPA, and TTC, respectively) was efficiently realized over the resultant CDs/CdS/GCN composites. The as-prepared 3%CDs/10%CdS/GCN exhibits high efficiency of photocatalytic hydrogen evolution from water splitting and photodegradation rates of organic pollutants in aqueous solutions of 4-NP, BPA, and TTC under visible-light illumination since the formation of interfaces between CdS quantum dots and GCN nanosheets leads to an efficient charge separation efficiency. Furthermore, as compared to that in a pure water system, the photocatalytic evolution rate of H2 over the 3%CDs/10%CdS/GCN catalyst in the presence of 4-NP solution is decreased, while the H2 evolution rates increase when BPA or TTC solution were used instead of 4-NP solution under visible-light irradiation. Consequently, 4-NP shows higher photodegradation efficiency than do BPA and TTC in the simultaneous photocatalytic oxidation and reduction system. Aiming at making clear the relationship between the photocatalytic H2 production and the photocatalytic pollutants degradation, density functional theory (DFT) calculations, and liquid chromatography mass spectrometry (LC-MS) were used for a systematic investigation. The present work reports a plausible mechanism of photodegradation of different organic contaminants with synchronous photocatalytic H2 evolution from water and the photocatalytic enhancement of the CDs/10%CdS/GCN catalysts.
Protein degradation is a promising strategy for drug development. Proteolysis-targeting chimeras (PROTACs) hijacking the E3 ligase cereblon (CRBN) exhibit enormous potential and universal degradation ...performance due to the small molecular weight of CRBN ligands. In this study, the CRBN-recruiting PROTACs were explored on the degradation of oncogenic fusion protein BCR-ABL, which drives the pathogenesis of chronic myeloid leukemia (CML). A series of novel PROTACs were synthesized by conjugating BCR-ABL inhibitor dasatinib to the CRBN ligand including pomalidomide and lenalidomide, and the extensive structure-activity relationship (SAR) studies were performed focusing on optimization of linker parameters. Therein, we uncovered that pomalidomide-based degrader 17 (SIAIS056), possessing sulfur-substituted carbon chain linker, exhibits the most potent degradative activity in vitro and favorable pharmacokinetics in vivo. Besides, degrader 17 also degrades a variety of clinically relevant resistance-conferring mutations of BCR-ABL. Furthermore, degrader 17 induces significant tumor regression against K562 xenograft tumors. Our study indicates that 17 as an efficacious BCR-ABL degrader warrants intensive investigation for the future treatment of BCR-ABL+ leukemia.
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•The extensive SAR studies identify 17 as a novel promising BCR-ABL degrader.•The lengths and compositions of linkers influence the PK properties of PROTACs.•17 effectively degrades wild type and a variety of mutations of BCR-ABL in vitro.•17 displayed favorable PK profile and robust antitumor efficacy in vivo.
In this study, we develop a new composite material of Fe-Cu/D407 composite via using nanoscale zero-valent iron (nZVI) with copper deposited on chelating resin (D407) to remove nitrate from the ...water. The experimental results show that a remarkable nitrate removal and the selectivity of N2 are 99.9% and 89.7%, respectively, under the anaerobic conditions of Cu/Fe molar ratio of 1:2, pH = 3.0. Even without of inert gas and adjusting the initial pH of the solution, the removal rate of nitrate by Fe-Cu/D407 reached to 85% and the selectivity of nitrogen reached to 55%. Meanwhile, the Fe-Cu/D407 maintained preferable removal efficiency of nitrate (100% - 92%) over a wide pH range of 3–11. In addition, the removal rate of the drinking water, lake water and wastewater from the Fe-Cu/D407 is still very high and the reactivity of Fe-Cu/D407 was relatively unaffected by the presence of dissolved ions in the waters tested. Moreover, the synergetic effect of Fe, Cu and D407 in the composite Fe-Cu/D407 were well investigated for the first time according to the analyses of TPR, XPS and EIS. The catalytic mechanism and denitrification routes were also proposed.
Proposed the reaction mechanism and denitrification routes over the Fe-Cu/D407. Display omitted
•Novel catalyst of Fe-Cu/D407 was designed and prepared.•The Fe-Cu/D407 shows excellent removal efficiency of nitrate and selectivity of N2 over a wide pH range.•Synergetic effect of Fe, Cu and D407 in the Fe-Cu/D407 was firstly investigated.•The catalytic mechanism and denitrification routes of nitrate were proposed.
The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of the MEF2C gene results in ...dilated cardiomyopathy (DCM). However, in humans, the association of MEF2C variation with DCM remains to be investigated.
The coding regions and splicing boundaries of the MEF2C gene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identified MEF2C mutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped for MEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system.
A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier's family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM.
This study indicates MEF2C as a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.
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