RESUMEN
Impairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by over 40 specificity-determining regulatory "B" subunits that compete for assembly and activation of heterogeneous PP2A heterotrimers. Here, we reveal how a small molecule, DT-061, specifically stabilizes the B56α-PP2A holoenzyme in a fully assembled, active state to dephosphorylate selective substrates, such as its well-known oncogenic target, c-Myc. Our 3.6 Å structure identifies molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme and highlight inherent mechanisms of PP2A complex assembly. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for therapeutic targeting, and aid in the development of phosphatase-based therapeutics tailored against disease specific phospho-protein targets.
Asunto(s)
Proteína Fosfatasa 2/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Activadores de Enzimas/metabolismo , Células HEK293 , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Complejos Multiproteicos/metabolismo , Proteína Fosfatasa 2/química , Subunidades de ProteínaRESUMEN
Nucleotide analog inhibitors, including broad-spectrum remdesivir and favipiravir, have shown promise in in vitro assays and some clinical studies for COVID-19 treatment, this despite an incomplete mechanistic understanding of the viral RNA-dependent RNA polymerase nsp12 drug interactions. Here, we examine the molecular basis of SARS-CoV-2 RNA replication by determining the cryo-EM structures of the stalled pre- and post- translocated polymerase complexes. Compared with the apo complex, the structures show notable structural rearrangements happening to nsp12 and its co-factors nsp7 and nsp8 to accommodate the nucleic acid, whereas there are highly conserved residues in nsp12, positioning the template and primer for an in-line attack on the incoming nucleotide. Furthermore, we investigate the inhibition mechanism of the triphosphate metabolite of remdesivir through structural and kinetic analyses. A transition model from the nsp7-nsp8 hexadecameric primase complex to the nsp12-nsp7-nsp8 polymerase complex is also proposed to provide clues for the understanding of the coronavirus transcription and replication machinery.
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Betacoronavirus/química , Betacoronavirus/enzimología , ARN Polimerasa Dependiente del ARN/química , Proteínas no Estructurales Virales/química , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/química , Adenosina Monofosfato/metabolismo , Adenosina Monofosfato/farmacología , Alanina/análogos & derivados , Alanina/química , Alanina/metabolismo , Alanina/farmacología , Antivirales/química , Antivirales/metabolismo , Antivirales/farmacología , Dominio Catalítico , ARN Polimerasa Dependiente de ARN de Coronavirus , Microscopía por Crioelectrón , Modelos Químicos , Modelos Moleculares , ARN Viral/metabolismo , SARS-CoV-2 , Transcripción Genética , Replicación ViralRESUMEN
The ubiquitin E3 ligase substrate adapter cereblon (CRBN) is a target of thalidomide and lenalidomide1, therapeutic agents used in the treatment of haematopoietic malignancies2-4 and as ligands for targeted protein degradation5-7. These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN remains unknown. Here we report that C-terminal cyclic imides, post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are physiological degrons on substrates for CRBN. Dipeptides bearing the C-terminal cyclic imide degron substitute for thalidomide when embedded within bifunctional chemical degraders. Addition of the degron to the C terminus of proteins induces CRBN-dependent ubiquitination and degradation in vitro and in cells. C-terminal cyclic imides form adventitiously on physiologically relevant timescales throughout the human proteome to afford a degron that is endogenously recognized and removed by CRBN. The discovery of the C-terminal cyclic imide degron defines a regulatory process that may affect the physiological function and therapeutic engagement of CRBN.
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Imidas , Proteolisis , Complejos de Ubiquitina-Proteína Ligasa , Humanos , Asparagina/química , Dipéptidos/farmacología , Glutamina/química , Imidas/química , Imidas/metabolismo , Lenalidomida/farmacología , Ligandos , Péptido Hidrolasas/metabolismo , Proteolisis/efectos de los fármacos , Proteoma/metabolismo , Talidomida/farmacología , Ubiquitinación/efectos de los fármacos , Secuencias de Aminoácidos , CiclizaciónRESUMEN
A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1-4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 µM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.
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Betacoronavirus/química , Cisteína Endopeptidasas/química , Descubrimiento de Drogas/métodos , Modelos Moleculares , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/química , Antivirales/química , Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , COVID-19 , Células Cultivadas/virología , Proteasas 3C de Coronavirus , Infecciones por Coronavirus/enzimología , Infecciones por Coronavirus/virología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Pandemias , Neumonía Viral/enzimología , Neumonía Viral/virología , Inhibidores de Proteasas/farmacología , Estructura Terciaria de Proteína , SARS-CoV-2RESUMEN
Adenomatous polyposis coli (APC) and Axin are core components of the ß-catenin destruction complex. How APC's function is regulated and whether Wnt signaling influences the direct APC-Axin interaction to inhibit the ß-catenin destruction complex is not clear. Through a CRISPR screen of ß-catenin stability, we have identified ICAT, a polypeptide previously known to block ß-catenin-TCF interaction, as a natural inhibitor of APC. ICAT blocks ß-catenin-APC interaction and prevents ß-catenin-mediated APC-Axin interaction, enhancing stabilization of ß-catenin in cells harboring truncated APC or stimulated with Wnt, but not in cells deprived of a Wnt signal. Using ICAT as a tool to disengage ß-catenin-mediated APC-Axin interaction, we demonstrate that Wnt quickly inhibits the direct interaction between APC and Axin. Our study highlights an important scaffolding function of ß-catenin in the assembly of the destruction complex and suggests Wnt-inhibited APC-Axin interaction as a mechanism of Wnt-dependent inhibition of the destruction complex.
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Proteína de la Poliposis Adenomatosa del Colon/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Dominios y Motivos de Interacción de Proteínas/genética , beta Catenina/genética , Proteínas Adaptadoras Transductoras de Señales , Proteína de la Poliposis Adenomatosa del Colon/antagonistas & inhibidores , Proteína Axina/genética , Humanos , Estabilidad Proteica , Proteína 1 Similar al Factor de Transcripción 7/genética , Vía de Señalización Wnt/genéticaRESUMEN
Wnt/ß-catenin signaling is activated when extracellular Wnt ligands bind Frizzled (FZD) receptors at the cell membrane. Wnts bind FZD cysteine-rich domains (CRDs) with high affinity through a palmitoylated N-terminal "thumb" and a disulfide-stabilized C-terminal "index finger," yet how these binding events trigger receptor activation and intracellular signaling remains unclear. Here we report the crystal structure of the Frizzled-4 (FZD4) CRD in complex with palmitoleic acid, which reveals a CRD tetramer consisting of two cross-braced CRD dimers. Each dimer is stabilized by interactions of one hydrophobic palmitoleic acid tail with two CRD palmitoleoyl-binding grooves oriented end to end, suggesting that the Wnt palmitoleoyl group stimulates CRD-CRD interaction. Using bioluminescence resonance energy transfer (BRET) in live cells, we show that WNT5A stimulates dimerization of membrane-anchored FZD4 CRDs and oligomerization of full-length FZD4, which requires the integrity of CRD palmitoleoyl-binding residues. These results suggest that FZD receptors may form signalosomes in response to Wnt binding through the CRDs and that the Wnt palmitoleoyl group is important in promoting these interactions. These results complement our understanding of lipoprotein receptor-related proteins 5 and 6 (LRP5/6), Dishevelled, and Axin signalosome assembly and provide a more complete model for Wnt signalosome assembly both intracellularly and at the membrane.
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Cisteína/química , Ácidos Grasos Monoinsaturados/química , Receptores Frizzled/química , Proteína Wnt-5a/metabolismo , Cristalografía por Rayos X , Cisteína/metabolismo , Ácidos Grasos Monoinsaturados/metabolismo , Receptores Frizzled/metabolismo , Células HEK293 , Humanos , Modelos Moleculares , Unión Proteica , Multimerización de Proteína , Estructura Terciaria de Proteína , Transducción de Señal , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
The Wnt/ß-catenin signaling pathway plays essential roles in embryonic development and adult tissue homeostasis. Axin is a concentration-limiting factor responsible for the formation of the ß-catenin destruction complex. Wnt signaling itself promotes the degradation of Axin. However, the underlying molecular mechanism and biological relevance of this targeting of Axin have not been elucidated. Here, we identify SIAH1/2 (SIAH) as the E3 ligase mediating Wnt-induced Axin degradation. SIAH proteins promote the ubiquitination and proteasomal degradation of Axin through interacting with a VxP motif in the GSK3-binding domain of Axin, and this function of SIAH is counteracted by GSK3 binding to Axin. Structural analysis reveals that the Axin segment responsible for SIAH binding is also involved in GSK3 binding but adopts distinct conformations in Axin/SIAH and Axin/GSK3 complexes. Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination and attenuates Wnt-induced ß-catenin stabilization. Our data suggest that Wnt-induced dissociation of the Axin/GSK3 complex allows SIAH to interact with Axin not associated with GSK3 and promote its degradation and that SIAH-mediated Axin degradation represents an important feed-forward mechanism to achieve sustained Wnt/ß-catenin signaling.
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Proteína Axina/metabolismo , Proteínas Nucleares/metabolismo , Transducción de Señal , Ubiquitina-Proteína Ligasas/metabolismo , Secuencia de Aminoácidos , Proteína Axina/química , Proteína Axina/genética , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Regulación de la Expresión Génica , Células HEK293 , Humanos , Proteínas Nucleares/química , Proteínas Nucleares/genética , Osteosarcoma/genética , Osteosarcoma/metabolismo , Conformación Proteica , Proteolisis , Homología de Secuencia , Células Tumorales Cultivadas , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
Chronic cerebral ischemia (CCI) is a common neurological disorder, characterized by progressive cognitive impairment. Acupoint catgut embedding (ACE) represents a modern acupuncture form that has shown neuroprotective effects; nevertheless, its effects on CCI and the mechanisms remain largely unknown. Here, we aimed to explore the therapeutic action of ACE in CCI-induced cognitive impairment and its mechanisms. The cognitive function of CCI rats was determined using Morris water maze test, and histopathological changes in the brain were assessed through hematoxylin-eosin (HE) staining. To further explore the molecular mechanisms, the expression levels of oxidative stress markers and the Ang II/AT1R/NOX axis-associated molecules in the hippocampus were evaluated using enzyme-linked immunosorbent assay (ELISA), western blotting, and immunohistochemistry. Here, we observed that ACE treatment alleviated cognitive dysfunction and histopathological injury in CCI rats. Intriguingly, candesartan (an AT1R blocker) enhanced the beneficial effects of ACE on ameliorating cognitive impairment in CCI rats. Mechanistically, ACE treatment blocked the Ang II/AT1R/NOX pathway and subsequently suppressed oxidative stress, thus mitigating cognitive impairment in CCI. Our findings first reveal that ACE treatment could suppress cognitive impairment in CCI, which might be partly due to the suppression of Ang II/AT1R/NOX axis.
Asunto(s)
Puntos de Acupuntura , Angiotensina II , Isquemia Encefálica , Disfunción Cognitiva , Estrés Oxidativo , Receptor de Angiotensina Tipo 1 , Animales , Masculino , Ratas , Terapia por Acupuntura/métodos , Angiotensina II/metabolismo , Isquemia Encefálica/metabolismo , Catgut , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/metabolismoRESUMEN
Designing catalysts to proceed with catalytic reactions along the desired reaction pathways, e.g., CO2 methanation, has received much attention but remains a huge challenge. This work reports one Ru1Ni single-atom alloy (SAA) catalyst (Ru1Ni/SiO2) prepared via a galvanic replacement reaction between RuCl3 and Ni nanoparticles (NPs) derived from the reduction of Ni phyllosilicate (Ni-ph). Ru1Ni/SiO2 achieved much improved selectivity toward hydrogenation of CO2 to CH4 and catalytic activity (Turnover frequency (TOF) value: 40.00 × 10-3 s-1), much higher than those of Ni/SiO2 (TOF value: 4.40 × 10-3 s-1) and most reported Ni-based catalysts (TOF value: 1.03 × 10-3-11.00 × 10-3 s-1). Experimental studies verify that Ru single atoms are anchored onto the Ni NPs surface via the Ru1-Ni coordination accompanied by electron transfer from Ru1 to Ni. Both in situ experiments and theoretical calculations confirm that the interface sites of Ru1Ni-SAA are the intrinsic active sites, which promote the direct dissociation of CO2 and lower the energy barrier for the hydrogenation of CO* intermediate, thereby directing and enhancing the CO2 hydrogenation to CH4.
RESUMEN
Groundwater contamination by 1,2,3-trichloropropane (TCP) poses a unique challenge due to its human toxicity and recalcitrance to degradation. Previous work suggests that nitrogenous functional groups of pyrogenic carbonaceous matter (PCM), such as biochar, are important in accelerating contaminant dechlorination by sulfide. However, the reaction mechanism is unclear due, in part, to PCM's structural complexity. Herein, PCM-like polymers (PLPs) with controlled placement of nitrogenous functional groups [i.e., quaternary ammonium (QA), pyridine, and pyridinium cations (py+)] were employed as model systems to investigate PCM-enhanced TCP degradation by sulfide. Our results suggest that both PLP-QA and PLP-py+ were highly effective in facilitating TCP dechlorination by sulfide with half-lives of 16.91 ± 1.17 and 0.98 ± 0.15 days, respectively, and the reactivity increased with surface nitrogenous group density. A two-step process was proposed for TCP dechlorination, which is initiated by reductive ß-elimination, followed by nucleophilic substitution by surface-bound sulfur nucleophiles. The TCP degradation kinetics were not significantly affected by cocontaminants (i.e., 1,1,1-trichloroethane or trichloroethylene), but were slowed by natural organic matter. Our results show that PLPs containing certain nitrogen functional groups can facilitate the rapid and complete degradation of TCP by sulfide, suggesting that similarly functionalized PCM might form the basis for a novel process for the remediation of TCP-contaminated groundwater.
Asunto(s)
Polímeros , Sulfuros , Sulfuros/química , Polímeros/química , Agua Subterránea/química , Contaminantes Químicos del Agua/química , Carbono/química , Propano/análogos & derivadosRESUMEN
Selective catalytic reduction using CO as a reducing agent (CO-SCR) has exhibited its application potential in coal-fired, steel, and other industrial sectors. In comparison to NH3-SCR, CO-SCR can achieve synergistic control of CO and NO pollutants, making it a powerful denitrification technology that treats waste with waste. Unfortunately, the competitive adsorption of O2 and NO on CO-SCR catalysts inhibits efficient conversion of NOx under O2-containing conditions. In this work, we obtained two Ir sites with different electron densities, Ir1 single atoms in the oxidized Irδ+ state and Ir0 nanoparticles in the metallic state, by controlled pretreatment of the Ir/ZSM-5 catalyst with H2 at 200 °C. The coexistence of Ir1 single atoms and Ir0 nanoparticles on ZSM-5 creates a synergistic effect, which facilitates the reduction of NO through CO in the presence of O2, following the Langmuir-Hinshelwood mechanism. The ONNO dimer is formed on the Ir1 single atom sites and then spills over to the neighboring Ir0 nanoparticles for subsequent reduction to N2 by CO. Specifically, this tandem reaction enables 83% NO conversion and 100% CO conversion on an Ir-based catalyst at 250 °C under 3% O2.
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Monóxido de Carbono , Catálisis , Monóxido de Carbono/química , Óxido Nítrico/química , Oxidación-Reducción , AdsorciónRESUMEN
This study investigated the reaction pathway of 2,4-dinitroanisole (DNAN) on the pyrogenic carbonaceous matter (PCM) to assess the scope and mechanism of PCM-facilitated surface hydrolysis. DNAN degradation was observed at pH 11.5 and 25 °C with a model PCM, graphite, whereas no significant decay occurred without graphite. Experiments were performed at pH 11.5 due to the lack of DNAN decay at pH below 11.0, which was consistent with previous studies. Graphite exhibited a 1.78-fold enhancement toward DNAN decay at 65 °C and pH 11.5 relative to homogeneous solution by lowering the activation energy for DNAN hydrolysis by 54.3 ± 3.9%. This is supported by our results from the computational modeling using Car-Parrinello simulations by ab initio molecular dynamics/molecular mechanics (AIMD/MM) and DFT free energy simulations, which suggest that PCM effectively lowered the reaction barriers by approximately 8 kcal mol-1 compared to a homogeneous solution. Quaternary ammonium (QA)-modified activated carbon performed the best among several PCMs by reducing DNAN half-life from 185 to 2.5 days at pH 11.5 and 25 °C while maintaining its reactivity over 10 consecutive additions of DNAN. We propose that PCM can affect the thermodynamics and kinetics of hydrolysis reactions by confining the reaction species near PCM surfaces, thus making them less accessible to solvent molecules and creating an environment with a weaker dielectric constant that favors nucleophilic substitution reactions. Nitrite formation during DNAN decay confirmed a denitration pathway, whereas demethylation, the preferred pathway in homogeneous solution, produces 2,4-dinitrophenol (DNP). Denitration catalyzed by PCM is advantageous to demethylation because nitrite is less toxic than DNAN and DNP. These findings provide critical insights for reactive adsorbent design that has broad implications for catalyst design and pollutant abatement.
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Anisoles , Hidrólisis , Anisoles/química , Simulación de Dinámica Molecular , Carbono/químicaRESUMEN
BACKGROUND: Endothelial cells (ECs) can confer neuroprotection by secreting molecules. This study aimed to investigate whether DNA methylation contributes to the neuroprotective gene expression induced by hypoxia preconditioning (HPC) in ECs and to clarify that the secretion of molecules from HPC ECs may be one of the molecular mechanisms of neuroprotection. METHODS: Human microvascular endothelial cell-1 (HMEC-1) was cultured under normal conditions (C), hypoxia(H), and hypoxia preconditioning (HPC), followed by the isolation of culture medium (CM). SY5Y cell incubated with the isolated CM from HMEC-1 was exposed to oxygen-glucose deprivation (OGD). The DNA methyltransferases (DNMTs), global methylation level, miR-126 and its promotor DNA methylation level in HMEC-1 were measured. The cell viability and cell injury in SY5Y were detected. RESULTS: HPC decreased DNMTs level and global methylation level as well as increased miR-126 expression in HMEC-1. CM from HPC treated HMEC-1 also relieved SY5Y cell damage, while CM from HMEC-1 which over-expression of miR-126 can reduce injury in SY5Y under OGD condition. CONCLUSIONS: These findings indicate EC may secrete molecules, such as miR-126, to execute neuroprotection induced by HPC through regulating the expression of DNMTs.
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Hipoxia de la Célula , Metilación de ADN , Células Endoteliales , MicroARNs , Neuronas , MicroARNs/genética , MicroARNs/metabolismo , Metilación de ADN/genética , Humanos , Células Endoteliales/metabolismo , Hipoxia de la Célula/genética , Neuronas/metabolismo , Regulación hacia Arriba/genética , Supervivencia Celular/genética , Glucosa/metabolismo , Línea Celular , Oxígeno/metabolismo , Regiones Promotoras Genéticas/genéticaRESUMEN
Membrane-bound O-acyltransferases (MBOATs) are a superfamily of integral transmembrane enzymes that are found in all kingdoms of life1. In bacteria, MBOATs modify protective cell-surface polymers. In vertebrates, some MBOAT enzymes-such as acyl-coenzyme A:cholesterol acyltransferase and diacylglycerol acyltransferase 1-are responsible for lipid biosynthesis or phospholipid remodelling2,3. Other MBOATs, including porcupine, hedgehog acyltransferase and ghrelin acyltransferase, catalyse essential lipid modifications of secreted proteins such as Wnt, hedgehog and ghrelin, respectively4-10. Although many MBOAT proteins are important drug targets, little is known about their molecular architecture and functional mechanisms. Here we present crystal structures of DltB, an MBOAT responsible for the D-alanylation of cell-wall teichoic acid in Gram-positive bacteria11-16, both alone and in complex with the D-alanyl donor protein DltC. DltB contains a ring of 11 peripheral transmembrane helices, which shield a highly conserved extracellular structural funnel extending into the middle of the lipid bilayer. The conserved catalytic histidine residue is located at the bottom of this funnel and is connected to the intracellular DltC through a narrow tunnel. Mutation of either the catalytic histidine or the DltC-binding site of DltB abolishes the D-alanylation of lipoteichoic acid and sensitizes the Gram-positive bacterium Bacillus subtilis to cell-wall stress, which suggests cross-membrane catalysis involving the tunnel. Structure-guided sequence comparison among DltB and vertebrate MBOATs reveals a conserved structural core and suggests that MBOATs from different organisms have similar catalytic mechanisms. Our structures provide a template for understanding structure-function relationships in MBOATs and for developing therapeutic MBOAT inhibitors.
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Aciltransferasas/química , Aciltransferasas/metabolismo , Membrana Dobles de Lípidos/metabolismo , Aciltransferasas/genética , Secuencia de Aminoácidos , Animales , Bacillus subtilis/metabolismo , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Sitios de Unión , Biocatálisis , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Pared Celular/metabolismo , Secuencia Conservada , Cristalografía por Rayos X , Histidina/genética , Histidina/metabolismo , Membrana Dobles de Lípidos/química , Lipopolisacáridos/metabolismo , Proteínas de Transporte de Membrana/química , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Modelos Moleculares , Mutación , Unión Proteica , Relación Estructura-Actividad , Ácidos Teicoicos/metabolismoRESUMEN
Carbon monoxide (CO) has recently been considered an ideal reducing agent to replace NH3 in selective catalytic reduction of NOx (NH3-SCR). This shift is particularly relevant in diesel engines, coal-fired industry, the iron and steel industry, of which generate substantial amounts of CO due to incomplete combustion. Developing high-performance catalysts remain a critical challenge for commercializing this technology. The active sites on catalyst surface play a crucial role in the various microscopic reaction steps of this reaction. This work provides a comprehensive overview and insights into the reaction mechanism of active sites on transition metal- and noble metal-based catalysts, including the types of intermediates and active sites, as well as the conversion mechanism of active molecules or atoms. In addition, the effects of factors such as O2, SO2, and alkali metals, on NO reduction by CO were discussed, and the prospects for catalyst design are proposed. It is hoped to provide theoretical guidance for the rational design of efficient CO selective catalytic denitration materials based on the structure-activity relations.
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Contaminantes Ambientales , Gases , Catálisis , Monóxido de Carbono , IndustriasRESUMEN
White matter hyperintensities (WMHs) refer to a group of diseases with numerous etiologies while oligodendrocytes remain the centerpiece in the pathogenesis of WMHs. Ring Finger Protein 216 (RNF216) encodes a ubiquitin ligase, and its mutation begets WMHs, ataxia, and cognitive decline in patients. Yet no study has revealed the function of RNF216 in oligodendroglia and WHIs before. In this study, we summarized the phenotypes of RNF216-mutation cases and explored the normal distribution of RNF216 in distinct brain regions and neuronal cells by bioinformatic analysis. Furthermore, MO3.13, a human oligodendrocyte cell line, was applied to study the function alteration after RNF216 knockdown. As a result, WMHs were the most common symptom in RNF216-mutated diseases, and RNF216 was indeed relatively enriched in corpus callosum and oligodendroglia in humans. The downregulation of RNF216 in oligodendroglia remarkably hampered cell proliferation by inhibiting the Akt pathway while having no significant effect on cell injury and oligodendrocyte maturation. Combining clinical, bioinformatical, and experimental evidence, our study implied the pivotal role of RNF216 in WMHs which might serve as a potent target in the therapy of WMHs.
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Proliferación Celular , Oligodendroglía , Ubiquitina-Proteína Ligasas , Sustancia Blanca , Humanos , Mutación con Pérdida de Función , Oligodendroglía/metabolismo , Oligodendroglía/citología , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Sustancia Blanca/metabolismo , Sustancia Blanca/patología , Sustancia Blanca/citologíaRESUMEN
Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of AKI acquired in hospital, lacking of effective interventions. In the study, we identified the renal beneficial role of 2, 2-dimethylthiazolidine hydrochloride (DMTD), a safer compound which is readily hydrolyzed to cysteamine, in the rodent model of CI-AKI. Our data showed that administration of DMTD attenuated the impaired renal function and tubular injury induced by the contrast agent. Levels of MDA, 4-hydroxynonenal, ferrous iron and morphological signs showed that contrast agent induced ferroptosis, which could be inhibited in the DMTD group. In vitro, DMTD suppressed ferroptosis induced by ioversol in the cultured tubular cells. Treatment of DMTD upregulated glutathione (GSH) and glutathione peroxidase 4 (GPX4). Moreover, we found that DMTD promoted the ubiquitin-mediated proteasomal degradation of Keap1, and thus increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistically, increase of the ubiquitylation degradation of Keap1 mediates the upregulated effect of DMTD on Nrf2. Consequently, activated Nrf2/Slc7a11 results in the increase of GSH and GPX4, and therefore leads to the inhibition of ferroptosis. Herein, we imply DMTD as a potential therapeutic agent for the treatment of CI-AKI.
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Lesión Renal Aguda , Ferroptosis , Humanos , Proteína 1 Asociada A ECH Tipo Kelch , Medios de Contraste , Factor 2 Relacionado con NF-E2 , Glutatión , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & controlRESUMEN
Regarding aerosol particle-laded turbid atmospheres, full-sky background radiation polarization patterns can be adversely affected, an important factor limiting their effective near-ground observation and acquisition. We established a multiple-scattering polarization computational model and measurement system and conducted the following three tasks. (a) We thoroughly analyzed the impact of aerosol scattering characteristics on polarization distributions, calculating the degree of polarization (DOP) and angle of polarization (AOP) patterns for a more comprehensive set of atmospheric aerosol compositions and aerosol optical depth (AOD) values than calculated in previous studies. (b) We assessed the uniqueness of the DOP and AOP patterns as a function of AOD. (c) By employing a new polarized radiation acquisition system for measurements, we demonstrated that our computational models are more representative of the DOP and AOP patterns under actual atmospheric conditions. We found that under a clear sky without clouds, the impact of the AOD on the DOP was detectable. With increasing AOD, the DOP decreased, and the decreasing trend became increasingly obvious. When the AOD was above 0.3, the maximum DOP did not exceed 0.5. The AOP pattern did not change notably and remained stable, except for the contraction point at the sun position under an AOD of 2.
RESUMEN
Chemical transfer across the air-water interface is one of the most important geochemical processes of global significance. Quantifying such a process has remained extremely challenging due to the lack of suitable technologies to measure chemical diffusion across the air-water microlayer. Herein, we present a fluorescence optical system capable of visualizing the formation of the air-water microlayer with a spatial resolution of 10 µm and quantifying air-water diffusion fluxes using pyrene as a target chemical. We show for the first time that the air-water microlayer is composed of the surface microlayer in water (â¼290 ± 40 µm) and a diffusion layer in air (â¼350 ± 40 µm) with 1 µg L-1 of pyrene. The diffusion flux of pyrene across the air-water interface is derived from its high-resolution concentration profile without any pre-emptive assumption, which is 2 orders of magnitude lower than those from the conventional method. This system can be expanded to visualize diffusion dynamics of other fluorescent chemicals across the air-water interface and provides a powerful tool for furthering our understanding of air-water mass transfer of organic chemicals related to their global cycling.
Asunto(s)
Monitoreo del Ambiente , Agua , Monitoreo del Ambiente/métodos , Compuestos Orgánicos , PirenosRESUMEN
BACKGROUND: Studies on the incidence of venous thromboembolism (VTE) events in patients with interstitial lung disease (ILD) are limited and the results are inconsistent. The aim of this research was to investigate the incidence and risk factors of VTE in ILD during hospitalization. MATERIALS AND METHODS: In this retrospective, cross-sectional, observational study, a total of 5009 patients diagnosed with ILD from January 2016 to March 2022 in our hospital were retrospectively included. In ILD patients, VTE including pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) were screened from the electronic medical record system. Diagnosis of PTE and DVT were performed by CT pulmonary angiography (CTPA), CTV or ultrasound. And then the incidence and risk factors of VTE in different types of ILD were assessed. RESULTS: Among 5009 patients with ILD, VTE was detected in 129 (2.6%) patients, including 15(0.3%) patients with both PTE and DVT, 34 (0.7%) patients with PTE and 80 (1.6%) patients with DVT. 85.1% of patients with APE were in the intermediate-low risk group. The incidence of VTE in Anti-Neutrophil Cytoplasmic Antibodies -associated vasculitis related ILD (ANCA-AV-ILD), hypersensitivity pneumonitis and idiopathic pulmonary fibrosis (IPF) respectively was 7.9% and 3.6% and 3.5%. In patients with connective tissue disease-associated ILD (CTD-ILD), the incidence of VTE, DVT, PTE, combined PTE and DVT respectively was 3.0%, 2.3%, 0.4% and 0.3%. Among the various risk factors, different ILD categories, age ≥ 80 years (OR 4.178, 95% CI 2.097-8.321, P < 0.001), respiratory failure (OR 2.382, 95% CI 1.533-3.702, P < 0.001) and varicose veins (OR 3.718, 95% CI 1.066-12.964, P = 0.039) were independent risk factors of VTE. The incidence of VTE in patients with ILD increased with the length of time in hospital from 2.2% (< 7 days) to 6.4% (> 21 days). CONCLUSION: The incidence of VTE during hospitalization in ILD patients was 2.6%, with a 1.6% incidence of DVT, higher than the 0.7% incidence of PTE. Advanced age, ILD categories, respiratory failure and varicose veins as independent risk factors for the development of VTE should be closely monitored.