Minor Pathway Research Articles

In Vitro Metabolism of Slowly Cleared G Protein-Coupled Receptor 139 Agonist TAK-041 Using Rat, Dog, Monkey, and Human Hepatocyte Models (HepatoPac): Correlation with In Vivo Metabolism.

Hepatic metabolism of low-clearance compound TAK-041 was studied in two different in vitro model systems using rat, dog, monkey, and human suspended cryopreserved hepatocytes and HepatoPac micropatterned coculture model primary hepatocytes. The aim of this work was to investigate the most appropriate system to assess the biotransformation of TAK-041, determine any notable species difference in the rate and in the extent of its metabolic pathways, and establish correlation with in vivo metabolism. TAK-041 exhibited very low turnover in suspended cryopreserved hepatocyte suspensions for all species, with no metabolites observed in human hepatocytes. However, incubations conducted for up to 14 days in the HepatoPac model resulted in more robust metabolic turnover. The major biotransformation pathways of TAK-041 proceed via hydroxylation on the benzene ring fused to the oxotriazine moiety and subsequent sulfate, glucuronide, and glutathione conjugation reactions. The glutathione conjugate of TAK-041 undergoes further downstream metabolism to produce the cysteine S-conjugate, which then undergoes N-acetylation to mercapturic acid and/or conversion to β-lyase-derived thiol metabolites. The minor biotransformation pathways include novel ring closure and hydrolysis, hydroxylation, oxidative N-dealkylation, and subsequent reduction. The HepatoPac model shows a notable species difference in the rate and in the extent of metabolic pathways of TAK-041, with dogs having the fastest metabolic clearance and humans the slowest. Furthermore, the model shows its suitability for establishing correlation with in vivo metabolism of low-turnover and extensively metabolized compounds such as TAK-041, displaying an extensive and unusual downstream sequential β-lyase-derived thiol metabolism in preclinical species and human. SIGNIFICANCE STATEMENT: This study investigated the most appropriate in vitro system to assess the biotransformation of the low-turnover and extensively metabolized compound TAK-041, determine any notable species difference in the rate and in the extent of its metabolic pathways, and establish correlation with in vivo metabolism. The HepatoPac model was identified and showed its suitability for species comparison and establishing correlation, with in vivo metabolism displaying an extensive and unusual downstream sequential β-lyase-derived thiol metabolism in preclinical species and human.

Toxicological responses of BEAS-2B cells to repeated exposures to benzene, toluene, m-xylene, and mesitylene using air-liquid interface method.

In order to reduce exposure to toxic chemicals, the European REACH regulation (1907/2006) recommends substituting toxic molecules with compounds that are less harmful to human health and the environment. Toluene is one of the most frequently used solvents in industries despite its toxicity. The objective of this study is to better understand and compare the toxicity of toluene and its homologues in a bronchial cell model. Thus, human bronchial BEAS-2B cells were exposed to steams of toluene, m-xylene, mesitylene (1,3,5-trimethylbenzene), and benzene (20 and 100ppm). Exposure was carried out using an air-liquid interface (ALI) system (Vitrocell) during 1h/day for 1, 3, or 5days. Cytotoxicity, xenobiotic metabolism enzyme gene expression, and inflammatory response were evaluated following cell exposures. BEAS-2B cell exposure to toluene and its homologues revealed the involvement of major (CYP2E1) and minor metabolic pathways (CYP1A1). A late induction of genes (EPHX1, DHDH, ALDH2, and ALDH3B1) was measured from Day 3 and can be linked to the formation of metabolites. An increase in the secretion level of inflammatory markers (TNF-α, IL-6, IL-8, MCP-1, and GM-CSF) was also observed. In parallel, regulation between inflammatory mediators and the expression of transmembrane glycoprotein mucin MUC1 was also studied. This in vitro approach with ALI system points out the relevance of conducting repeated exposures to detect potential late effects. The difference recorded after cell exposure to toluene and its homologues highlights the importance of substitution principle.

Human splice factors contribute to latent HIV infection in primary cell models and blood CD4+ T cells from ART-treated individuals.

It is unclear what mechanisms govern latent HIV infection in vivo or in primary cell models. To investigate these questions, we compared the HIV and cellular transcription profile in three primary cell models and peripheral CD4+ T cells from HIV-infected ART-suppressed individuals using RT-ddPCR and RNA-seq. All primary cell models recapitulated the block to HIV multiple splicing seen in cells from ART-suppressed individuals, suggesting that this may be a key feature of HIV latency in primary CD4+ T cells. Blocks to HIV transcriptional initiation and elongation were observed more variably among models. A common set of 234 cellular genes, including members of the minor spliceosome pathway, was differentially expressed between unstimulated and activated cells from primary cell models and ART-suppressed individuals, suggesting these genes may play a role in the blocks to HIV transcription and splicing underlying latent infection. These genes may represent new targets for therapies designed to reactivate or silence latently-infected cells.

A continuous-flow catalytic process with natural hematite-alginate beads for effective water decontamination and disinfection: Peroxymonosulfate activation leading to dominant sulfate radical and minor non-radical pathways

A natural, ferruginous material, Hormuz Red Soil (HRS), was used as a catalyst for decontamination and disinfection via PMS activation. The HRS was fully characterized (morphological, structural, chemical properties) and was mainly comprised of α-Fe2O3. Complete degradation and 88.6% mineralization of Diclofenac (DCF) was achieved in the HRS/PMS process (10 mg/L HRS, 75 mg/L PMS) within 8 min at neutral pH, while sulfate and chloride did not inhibit the process. E. coli and Enterococcus sp. were rapidly inactivated in shorter timeframe than DCF. The rapid purification was attributed to SO4∙-, less to 1O2 and almost insignificant HO∙ participation; the degradation mechanisms and transformation pathways were fully elucidated by scavenging tests/EPR, and LC/MS, respectively. Considering potential applications, HRS was supported on alginate beads (HRSB), maintaining high activity and high reusability (x5 reuse). Finally, a continuous-flow, packed-bed process with HRSB/PMS was assessed, where DCF degradation and mineralization was reached within 2 min HRT.

C-Src is Activated by the EGF Receptor in a Pathway that Mediates JNK and ERK Activation by Gonadotropin-Releasing Hormone in COS7 Cells.

The key participants in G-protein-coupled receptor (GPCR) signaling are the mitogen-activated protein kinase (MAPK) signaling cascades. The mechanisms involved in the activation of the above cascades by GPCRs are not fully elucidated. The prototypical GPCR is the receptor for gonadotropin-releasing hormone (GnRHR), which serves as a key regulator of the reproductive system. Here, we expressed GnRHR in COS7 cells and found that GnRHR transmits its signals to MAPKs mainly via Gαi and the EGF receptor, without the involvement of Hb-EGF or PKCs. The main pathway that leads to JNK activation downstream of the EGF receptor involves a sequential activation of c-Src and PI3K. ERK activation by GnRHR is mediated by the EGF receptor, which activates Ras either directly or via c-Src. Beside the main pathway, the dissociated Gβγ and β-arrestin may initiate additional (albeit minor) pathways that lead to MAPK activation in the transfected COS7 cells. The pathways detected are significantly different from those in other GnRHR-bearing cells, indicating that GnRH can utilize various signaling mechanisms for MAPK activation. The unique pathway elucidated here, in which c-Src and PI3K are sequentially activated downstream of the EGF receptor, may serve as a prototype of signaling mechanisms by GnRHR and additional GPCRs in various cell types.

Identification and Reactivity of s-cis,s-cis-Dihydroxycarbene, a New [CH2O2] Intermediate.

We report the first preparation of the s-cis,s-cis conformer of dihydroxycarbene (1cc) by means of pyrolysis of oxalic acid, isolation of the lower-energy s-trans,s-trans (1tt) and s-cis,s-trans (1ct) product conformers at cryogenic temperatures in a N2 matrix, and subsequent narrow-band near-infrared (NIR) laser excitation to give 1cc. Carbene 1cc converts quickly to 1ct via quantum-mechanical tunneling with an effective half-life of 22 min at 3 K. The potential energy surface features around 1 were pinpointed by convergent focal point analysis targeting the AE-CCSDT(Q)/CBS level of electronic structure theory. Computations of the tunneling kinetics confirm the time scale of the 1cc → 1ct rotamerization and suggest that direct 1cc → H2 + CO2 decomposition may also be a minor pathway. The intriguing latter possibility cannot be confirmed spectroscopically, but hints of it may be present in the measured kinetic profiles.

Impaired mitochondrial medium-chain fatty acid oxidation drives periportal macrovesicular steatosis in sirtuin-5 knockout mice

Medium-chain triglycerides (MCT), containing C8–C12 fatty acids, are used to treat several pediatric disorders and are widely consumed as a nutritional supplement. Here, we investigated the role of the sirtuin deacylase Sirt5 in MCT metabolism by feeding Sirt5 knockout mice (Sirt5KO) high-fat diets containing either C8/C10 fatty acids or coconut oil, which is rich in C12, for five weeks. Coconut oil, but not C8/C10 feeding, induced periportal macrovesicular steatosis in Sirt5KO mice. 14C–C12 degradation was significantly reduced in Sirt5KO liver. This decrease was localized to the mitochondrial β-oxidation pathway, as Sirt5KO mice exhibited no change in peroxisomal C12 β-oxidation. Endoplasmic reticulum ω-oxidation, a minor fatty acid degradation pathway known to be stimulated by C12 accumulation, was increased in Sirt5KO liver. Mice lacking another mitochondrial C12 oxidation enzyme, long-chain acyl-CoA dehydrogenase (LCAD), also developed periportal macrovesicular steatosis when fed coconut oil, confirming that defective mitochondrial C12 oxidation is sufficient to induce the steatosis phenotype. Sirt5KO liver exhibited normal LCAD activity but reduced mitochondrial acyl-CoA synthetase activity with C12. These studies reveal a role for Sirt5 in regulating the hepatic response to MCT and may shed light into the pathogenesis of periportal steatosis, a hallmark of human pediatric non-alcoholic fatty liver disease.

Kinetics of isopropanol decomposition and reaction with H atoms from shock tube experiments and rate constant optimization using the method of uncertainty minimization using polynomial chaos expansions (MUM‐PCE)

AbstractWe have used the single‐pulse shock tube technique with postshock GC/MS product analysis to investigate the mechanism and kinetics of the unimolecular decomposition of isopropanol, a potential biofuel, and of its reaction with H atoms at 918‐1212 K and 183‐484 kPa. Experiments employed dilute mixtures in argon of isopropanol, a radical scavenger, and, for H‐atom studies, two different thermal precursors of H. Without an added H source, isopropanol decomposes in our studies predominantly by molecular dehydration. Added H atoms significantly augment decomposition, mainly by abstraction of the tertiary and primary hydrogens, reactions that, respectively, lead to acetone and propene as stable organic products. Traces of acetaldehyde were observed in some experiments above ≈ 1100 K and establish branching limits for minor decomposition pathways. To quantitatively account for secondary chemistry and optimize rate constants of interest, we employed the method of uncertainty minimization using polynomial chaos expansions (MUM‐PCE) to carry out a unified analysis of all datasets using a chemical model–based originally on JetSurF 2.0. We find: k(isopropanol → propene + H2O) = 10(13.87 ± 0.69) exp(−(33 099 ± 979) K/ T) s−1 at 979‐1212 K and 286‐484 kPa, with a factor of two uncertainty (2σ), including systematic errors. For H atom reactions, optimization yields: k(H + isopropanol → H2 + p‐C3H6OH) = 10(6.25 ± 0.42) T2.54 exp(−(3993 ± 1028) K /T) cm3 mol−1 s−1 and k(H + isopropanol → H2 + t‐C3H6OH) = 10(5.83 ± 0.37) T2.40 exp(−(1507 ± 957) K /T) cm3 mol−1 s−1 at 918‐1142 K and 183‐323 kPa. We compare our measured rate constants with estimates used in current combustion models and discuss how hydrocarbon functionalization with an OH group affects H abstraction rates.

In Vivo Metabolism of Aristolochic Acid I and II in Rats Is Influenced by Their Coexposure

The plant extract aristolochic acid (AA), containing aristolochic acid I (AAI) and II (AAII) as major components, causes aristolochic acid nephropathy and Balkan endemic nephropathy, unique renal diseases associated with upper urothelial cancer. Differences in the metabolic activation and detoxification of AAI and AAII and their effects on the metabolism of AAI/AAII mixture in the plant extract might be of great importance for an individual's susceptibility in the development of AA-mediated nephropathies and malignancies. Here, we investigated in vivo metabolism of AAI and AAII after ip administration to Wistar rats as individual compounds and as AAI/AAII mixture using high performance liquid chromatography/electrospray ionization mass spectrometry. Experimental findings were supported by theoretical calculations using density functional theory. We found that exposure to AAI/AAII mixture affected the generation of their oxidative and reductive metabolites formed during Phase I biotransformation and excreted in rat urine. Several Phase II metabolites of AAI and AAII found in the urine of exposed rats were also analyzed. Our results indicate that AAI is more efficiently metabolized in rats in vivo than AAII. Whereas AAI is predominantly oxidized during in vivo metabolism, its reduction is the minor metabolic pathway. In contrast, AAII is mainly metabolized by reduction. The oxidative reaction only occurs if aristolactam II, the major reductive metabolite of AAII, is enzymatically hydroxylated, forming aristolactam Ia. In AAI/AAII mixture, the metabolism of AAI and AAII is influenced by the presence of both AAs. For instance, the reductive metabolism of AAI is increased in the presence of AAII while the presence of AAI decreased the reductive metabolism of AAII. These results suggest that increased bioactivation of AAI in the presence of AAII also leads to increased AAI genotoxicity, which may critically impact AAI-mediated carcinogenesis. Future studies are needed to explain the underlying mechanism(s) for this phenomenon.

Hydrometeor Budget of the Meiyu Frontal Rainstorms Associated With Two Different Atmospheric Circulation Patterns

AbstractCharacteristics of hydrometeor budget and the microphysical processes responsible for heavy precipitation are studied based on the WRF model simulations of two representative Meiyu frontal rainstorms that are associated with two distinct atmospheric circulation patterns. Case 1 is characterized by the coupling of the Eastward Propagating Mesoscale Vortex (EPMV) and Meiyu front, while Case 2 is dominated by the interaction between the Low‐Level Wind Shear (LLWS) and Meiyu front. The temporal and spatial characteristics of the hydrometeor budget are validated against observations and assimilation products including those obtained during the 2018 Integrative Monsoon Frontal Rainfall Experiment (IMFRE) campaign and discussed in the context of contrasting the precipitation intensification and dissipation stage. Specifically, the ice‐dependent cloud processes, rather than the liquid‐dependent cloud processes, are predominantly responsible for the variation of precipitation. These terms include the deposition from water vapor to the ice phase hydrometeors, the accretion from cloud liquid water to the ice phase hydrometeors in the upper troposphere, and the melting of the ice phase hydrometeors into raindrops in the mid‐lower troposphere. Then three major ice cloud conversion pathways and two minor warm cloud conversion pathways for the formation of raindrops are extracted from the overall microphysical processes active in both Case 1 and Case 2. One of the key findings is that ice‐dependent cloud processes are significantly more active in the case characterized by the coupling of EPMV and Meiyu front, and this difference is at least partly explained by the differences in dynamical and thermodynamic conditions dominated by the circulation patterns.

Effect of Formaldehyde in Selective Catalytic Reduction of NOx by Ammonia (NH3-SCR) on a Commercial V2O5-WO3/TiO2 Catalyst under Model Conditions.

The impact of formaldehyde (HCHO, formed in vehicle exhaust gases by incomplete combustion of fuel) on the performance of a commercial V2O5-WO3/TiO2 catalyst in NH3-SCR of NOx under dry conditions has been analyzed in detail by catalytic tests, in situ FTIR and transient studies using temporal analysis of products (TAP). HCHO reacts preferentially with NH3 to a formamide (HCONH2) surface intermediate. This deprives NH3 partly from its desired role as a reducing agent in the SCR and diminishes NO conversion and N2 selectivity. Between 250 and 400 °C, HCONH2 decomposes by dehydration (major pathway) and decarbonylation (minor pathway) to liberate toxic HCN and CO, respectively. HCN was proven to be oxidized by lattice oxygen of the catalyst to CO2 and NO, which enters the NH3-SCR reaction.

Characterization of the reactivity of luciferin boronate - A probe for inflammatory oxidants with improved stability

Boronate derivatives of luciferin, containing oxidant-activated self-immolative moieties, recently have been developed for bioluminescent detection of hydrogen peroxide in animal models. Here, we report the synthesis and characterization of luciferin boronic acid pinacol ester (LBE) as a probe for detection of hydrogen peroxide, hypochlorous acid, and peroxynitrite, with improved stability and response time. HPLC analyses showed that LBE quickly hydrolyzes in phosphate buffer to luciferin boronic acid (LBA). Hydrogen peroxide oxidizes LBA slowly, with the formation of luciferase substrate, luciferin (Luc-OH), as the only product. Hypochlorite also oxidizes LBA to luciferin, but the subsequent reaction of Luc-OH with hypochlorite gives a chlorinated luciferin Luc–OH–Cl, which has a higher fluorescence quantum yield than luciferin at pH 7.4 and is also a substrate for luciferase (Takakura H, et. all. ChemBioChem 2012; 13:1424). Similar to other boronate probes, LBA is oxidized by peroxynitrite in two pathways. Luc-OH is the product of the major pathway, common for all the oxidants tested, whereas the non-fluorescent nitrated derivative, Luc-NO2, is formed in the minor pathway, specific for peroxynitrite. Formation of luciferin radical intermediate in the minor pathway has been confirmed by EPR spin trapping and mass spectrometric analyses of the spin adducts. We conclude that LBE shows potential as an improved probe for the detection of inflammatory oxidants in biological settings. Complementation of the bioluminescence measurements by HPLC or LC-MS-based identification of chlorinated and nitrated luciferin(s) will help identify the oxidants detected.

Disrupted minor intron splicing is prevalent in Mendelian disorders.

BackgroundSplicing is crucial for proper gene expression, and is predominately executed by the major spliceosome. Conversely, 722 introns in 699 human minor intron‐containing genes (MIGs) are spliced by the minor spliceosome. Splicing of these minor introns is disrupted in diseases caused by pathogenic variants in the minor spliceosome, ultimately leading to the aberrant expression of a subset of these MIGs. However, the effect of variants in minor introns and MIGs on diseases remains unexplored.MethodsVariants in MIGs and associated clinical manifestations were identified using ClinVar. The HPO database was then used to curate the related symptoms and affected organ systems. Results: We found pathogenic variants in 211 MIGs, which commonly resulted in intellectual disability, seizures and microcephaly. This revealed a subset of MIGs whose aberrant splicing may contribute to the pathogenesis of minor spliceosome‐related diseases. Moreover, we identified 51 pathogenic variants in minor intron splice sites that reduce the splice site strength and can induce alternative splicing.ConclusionThese findings highlight that disrupted minor intron splicing has a broader impact on human diseases than previously appreciated. The hope is that this knowledge will aid in the development of therapeutic strategies that incorporate the minor intron splicing pathway.

Kinetic analysis of amino acid radicals formed in H2O2-driven CuI LPMO reoxidation implicates dominant homolytic reactivity

Lytic polysaccharide monooxygenases (LPMOs) have been proposed to react with both [Formula: see text] and [Formula: see text] as cosubstrates. In this study, the [Formula: see text] reaction with reduced Hypocrea jecorina LPMO9A (CuI-HjLPMO9A) is demonstrated to be 1,000-fold faster than the [Formula: see text] reaction while producing the same oxidized oligosaccharide products. Analysis of the reactivity in the absence of polysaccharide substrate by stopped-flow absorption and rapid freeze-quench (RFQ) electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) yields two intermediates corresponding to neutral tyrosyl and tryptophanyl radicals that are formed along minor reaction pathways. The dominant reaction pathway is characterized by RFQ EPR and kinetic modeling to directly produce CuII-HjLPMO9A and indicates homolytic O-O cleavage. Both optical intermediates exhibit magnetic exchange coupling with the CuII sites reflecting facile electron transfer (ET) pathways, which may be protective against uncoupled turnover or provide an ET pathway to the active site with substrate bound. The reactivities of nonnative organic peroxide cosubstrates effectively exclude the possibility of a ping-pong mechanism.

Input and output pathways determining potassium budgets in two paddy fields subjected to countermeasures against radiocesium in Fukushima, Japan.

Countermeasures to reduce radiocesium (134Cs and 137Cs) uptake by crops have been implemented in farmlands affected by the Fukushima nuclear accident in 2011. A widely practiced countermeasure is the application of potassium (K). Long-term soil K maintenance is a key issue due to the long physical half-life of 137Cs (30 years). Information on input and output pathways determining plant-available K budgets can provide a base for the development of maintenance strategies. Therefore, in this study we evaluated these pathways in paddy fields subjected to K fertilization as a countermeasure. We selected two fields with different soil textures and drainage conditions and quantified input and output via fertilization, irrigation, precipitation, straw return to soil, plant harvesting, surface runoff, and percolation during the cropping period in 2018. The major input pathways were fertilization, straw return, and irrigation due to a large inflow volume with spill-over irrigation. The major output pathways consisted of plant harvesting, surface runoff, and percolation. However, 85% of K in harvested plants was brought back by straw return; in practice, harvesting was a minor pathway. The K budgets during the study period were negative (−20 and −289 kg ha−1) and especially severe in clay loam soil with high output via percolation. This could probably be attributed to the low cation exchange capacity and high permeability from the low total C and clay contents. Losses via surface runoff stemmed from excessive irrigation volumes in both fields. Around 70% of the total K output via surface runoff and percolation was discharged before mid-summer drainage. Accordingly, controlling the irrigation volume during this period in addition to increasing cation exchange capacity and decreasing permeability may improve the negative budgets.

TiO2 Photocatalytic Degradation of Diclofenac: Intermediates and Total Reaction Mechanism

Diclofenac (DCF) photocatalytic degradation with TiO2-P25 illuminated with UV-A light in aqueous media was investigated. The photodegradation rate was assessed by HPLC and UV–vis spectroscopy, while the mineralization rate was obtained by total organic carbon measurements. The formation and degradation of intermediate compounds were investigated by UV–vis, IR and 1H NMR spectroscopy and GC/MS analysis. UV–vis absorbance and HPLC results indicated that DCF is completely transformed into some aromatic compounds after several hours of irradiation. TOC analysis indicated that some intermediate compounds are degraded slowly since 90% mineralization was achieved after several hours of irradiation. FT-IR studies demonstrated a rapid conversion of diclofenac into a lactam, which was converted into several aromatic compounds. GC/MS and HPLC analysis indicated that the initial photoproducts are two lactams and several aromatic anilines and phenols. 1H NMR studies indicated DCF degrades by a rather simple mechanism generating a recalcitrant intermediate acid, namely 2-hydrophenyl acetic acid which is oxidized in several steps by hydroxyl radicals. 1H NMR studies also indicated that an oxidation route via a quinone is actually a very minor pathway. Based on this and previous investigations, a total photocatalytic degradation mechanism for DCF is presented, first involving hydroxyl radical reactions to generate anilines and phenols, which were all converted into polyhydroxylated compounds and eventually into low molecular saturated and unsaturated amines and carboxylic acids. Basic studies about diclofenac photocatalytic degradation are required for future applications of this process in the removal of DCF and other structurally related pharmaceutical compounds from any water body.

Ex vivo diffusion-weighted MRI tractography of the Göttingen minipig limbic system.

The limbic system encompasses a collection of brain areas primarily involved in higher cognitive and emotional processing. Altered function in the limbic circuitry may play a major role in various psychiatric disorders. This study aims to provide a high-quality ex vivo diffusion-weighted MRI (DWI) tractographic overview of the Göttingen minipig limbic system pathways, which are currently not well described. This may facilitate future translational large animal studies. The study used previously obtained post-mortem DWI scans in 3 female Göttingen minipigs aging 11-15months. The tractography performed on the DWI data set was made using a probabilistic algorithm, and regions of interest (ROIs) were defined in accordance with a histological atlas. The investigated pathways included the fornix, mammillothalamic tract, stria terminalis, stria medullaris, habenulo-interpeduncular tract, and cingulum. All the investigated limbic connections could be visualized with a high detail yielding a comprehensive three-dimensional overview, which was emphasized by the inclusion of video material. The minipig limbic system pathways displayed using tractography closely resembled what was previously described in both human studies and neuronal tracing studies from other mammalian species. We encountered well-known inherent methodological challenges of tractography, e.g., partial volume effects and complex white matter regions, which may have contributed to derouted false-positive streamlines and the failure to visualize some of the minor limbic pathway ramifications. This underlines the importance of preexisting anatomical knowledge. Conclusively, we have, for the first time, provided an overview and substantial insight of the Göttingen minipig limbic system.

Nonstoichiometric perovskite for enhanced catalytic oxidation through excess A-site cation

Perovskite oxide has been emerging as one of the efficient heterogeneous catalysts for advanced oxidation of organic contaminants in wastewater because of their structural integrity and compositional tunability. Herein, we report a new perovskite oxide, La1.15MnO3+δ with excess La, for a lowered average oxidation state of Mn cations and abundant oxygen vacancies, which can be active sites for peroxymonosulfate (PMS) activation. The La1.15MnO3+δ did exhibit improving catalytic performance as compared to LaMnO3+δ for the degradation of Rhodamine B by activating PMS. Besides, it also demonstrated high tolerance to variant water environments such as temperature, pH and impurity anions. A major non-radical activation mechanism dominated by 1O2 was further confirmed in La1.15MnO3+δ/PMS system, accompanied by a minor radical pathway. This work provides a new effective strategy to advance catalytic PMS oxidation processes by tailoring the oxidation state of B-site metals and defects of perovskite oxide through manipulating A-site cation stoichiometry.

The G3BP1-Family-USP10 Deubiquitinase Complex Rescues Ubiquitinated 40S Subunits of Ribosomes Stalled in Translation from Lysosomal Degradation.

Ribosome-associated quality control (RQC) purges aberrant mRNAs and nascent polypeptides in a multi-step molecular process initiated by the E3 ligase ZNF598 through sensing of ribosomes collided at aberrant mRNAs and monoubiquitination of distinct small ribosomal subunit proteins. We show that G3BP1-family-USP10 complexes are required for deubiquitination of RPS2, RPS3, and RPS10 to rescue modified 40S subunits from programmed degradation. Knockout of USP10 or G3BP1 family proteins increased lysosomal ribosomal degradation and perturbed ribosomal subunit stoichiometry, bothof which were rescued by a single K214R substitution of RPS3. While the majority of RPS2 and RPS3 monoubiquitination resulted from ZNF598-dependent sensing of ribosome collisions initiating RQC, another minor pathway contributed to their monoubiquitination. G3BP1 family proteins have long been considered RNA-binding proteins, however, our results identified 40S subunits and associated mRNAs as their predominant targets, a feature shared by stress granules to which G3BP1 family proteins localize under stress.

Comprehensive study of polymerization of pyrrole: A theoretical approach

Polypyrrole is a popular conducting polymer. The pyrrole polymerization involving radical cations are very fast; therefore, it is difficult for instruments to probe the reaction progress at a molecular level, leading to different mechanisms proposed previously. As such, density functional theory calculations were performed to investigate how pyrroles polymerize, and provide insights into polypyrrole electrosynthesis. From the results, the CC couplings between two radical cations of pyrrole py-Hα+, and between a radical cation of an oligomer (py)x-Hα+ and py-Hα+ generating the dimeric doubly charged product py-Hα-αα-py-Hα2+ and the oligomeric doubly charged product (py)x-Hα-αα-py-Hα2+ respectively dominate the polymerization mechanism. It is plausible that the CC coupling between py-Hα+ and a neutral pyrrole molecule py-Hα forms the dimeric singly charged product py-Hα-αα-py-Hα+, subsequently being oxidized to py-Hα-αα-py-Hα2+. Unless the singly charged product py-Hα-αα-py-Hα+ can be stabilized, it cannot participate in later deprotonation. The CC coupling between two (py)x-Hα+ to form another oligomeric doubly charged product (py)x-Hα-αα-(py)x-Hα2+ is a minor pathway. The formation of oligomeric singly charged products (py)x-Hα-αα-py-Hα+ and (py)x-Hα-αα-(py)x-Hα+ via the CC couplings between (py)x-Hα+ and py-Hα, between py-Hα+ and (py)x-Hα, and between (py)x-Hα+ and (py)x-Hα unlikely occurs. Therefore, the formation of each polypyrrole linkage involves the loss of two electrons in the main. Weak bases such as Cl− and H2O are required to take the H+ in the α position away in the two successive deprotonations of (py)x-Hα-αα-py-Hα2+ to form a neutral oligomer (py)x-αα-py. Resonance-induced stability determines how pyrrole polymerizes.