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ARH3/ADPRHL2 and PARG are the primary enzymes reversing ADP-ribosylation in vertebrates, yet their functions in vivo remain unclear. ARH3 is the only hydrolase able to remove serine-linked mono(ADP-ribose) (MAR) but is much less efficient than PARG against poly(ADP-ribose) (PAR) chains in vitro. Here, by using ARH3-deficient cells, we demonstrate that endogenous MARylation persists on chromatin throughout the cell cycle, including mitosis, and is surprisingly well tolerated. Conversely, persistent PARylation is highly toxic and has distinct physiological effects, in particular on active transcription histone marks such as H3K9ac and H3K27ac. Furthermore, we reveal a synthetic lethal interaction between ARH3 and PARG and identify loss of ARH3 as a mechanism of PARP inhibitor resistance, both of which can be exploited in cancer therapy. Finally, we extend our findings to neurodegeneration, suggesting that patients with inherited ARH3 deficiency suffer from stress-induced pathogenic increase in PARylation that can be mitigated by PARP inhibition.
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Glicósido Hidrolasas/metabolismo , Poli ADP Ribosilación/fisiología , ADP-Ribosilación , Adenosina Difosfato Ribosa/metabolismo , Línea Celular Tumoral , Cromatina , ADN , Daño del ADN , Fibroblastos/metabolismo , Glicósido Hidrolasas/genética , Glicósido Hidrolasas/fisiología , Células HEK293 , Células HeLa , Humanos , Poli Adenosina Difosfato Ribosa/metabolismo , Cultivo Primario de CélulasRESUMEN
Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers.
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Ensamble y Desensamble de Cromatina , ADN Helicasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentales/metabolismo , Nucleosomas/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Animales , ADN Helicasas/genética , Replicación del ADN/efectos de los fármacos , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Proteínas de Unión al ADN/genética , Recombinación Homóloga/efectos de los fármacos , Ratones , Ratones Noqueados , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Neoplasias Experimentales/genética , Nucleosomas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Poli(ADP-Ribosa) Polimerasas/genéticaRESUMEN
PARP-catalysed ADP-ribosylation (ADPr) is important in regulating various cellular pathways. Until recently, PARP-dependent mono-ADP-ribosylation has been poorly understood due to the lack of sensitive detection methods. Here, we utilised an improved antibody to detect mono-ADP-ribosylation. We visualised endogenous interferon (IFN)-induced ADP-ribosylation and show that PARP14 is a major enzyme responsible for this modification. Fittingly, this signalling is reversed by the macrodomain from SARS-CoV-2 (Mac1), providing a possible mechanism by which Mac1 counteracts the activity of antiviral PARPs. Our data also elucidate a major role of PARP9 and its binding partner, the E3 ubiquitin ligase DTX3L, in regulating PARP14 activity through protein-protein interactions and by the hydrolytic activity of PARP9 macrodomain 1. Finally, we also present the first visualisation of ADPr-dependent ubiquitylation in the IFN response. These approaches should further advance our understanding of IFN-induced ADPr and ubiquitin signalling processes and could shed light on how different pathogens avoid such defence pathways.
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ADP-Ribosilación , Interferones , Poli(ADP-Ribosa) Polimerasas , Ubiquitina-Proteína Ligasas , Humanos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Poli(ADP-Ribosa) Polimerasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Interferones/metabolismo , Ubiquitinación , Células HEK293 , SARS-CoV-2/metabolismo , Transducción de Señal , COVID-19/virología , COVID-19/metabolismo , Proteínas de NeoplasiasRESUMEN
The anti-cancer drug target poly(ADP-ribose) polymerase 1 (PARP1) and its close homologue, PARP2, are early responders to DNA damage in human cells1,2. After binding to genomic lesions, these enzymes use NAD+ to modify numerous proteins with mono- and poly(ADP-ribose) signals that are important for the subsequent decompaction of chromatin and the recruitment of repair factors3,4. These post-translational modifications are predominantly serine-linked and require the accessory factor HPF1, which is specific for the DNA damage response and switches the amino acid specificity of PARP1 and PARP2 from aspartate or glutamate to serine residues5-10. Here we report a co-structure of HPF1 bound to the catalytic domain of PARP2 that, in combination with NMR and biochemical data, reveals a composite active site formed by residues from HPF1 and PARP1 or PARP2 . The assembly of this catalytic centre is essential for the addition of ADP-ribose moieties after DNA damage in human cells. In response to DNA damage and occupancy of the NAD+-binding site, the interaction of HPF1 with PARP1 or PARP2 is enhanced by allosteric networks that operate within the PARP proteins, providing an additional level of regulation in the induction of the DNA damage response. As HPF1 forms a joint active site with PARP1 or PARP2, our data implicate HPF1 as an important determinant of the response to clinical PARP inhibitors.
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ADP-Ribosilación , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Daño del ADN , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/química , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Poli(ADP-Ribosa) Polimerasas/química , Poli(ADP-Ribosa) Polimerasas/metabolismo , Regulación Alostérica , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Biocatálisis , Proteínas Portadoras/genética , Dominio Catalítico , Células HEK293 , Humanos , Modelos Moleculares , Mutación , NAD/metabolismo , Resonancia Magnética Nuclear Biomolecular , Proteínas Nucleares/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Anémonas de MarRESUMEN
Although ubiquitylation had traditionally been considered limited to proteins, the discovery of non-proteinaceous substrates (e.g. lipopolysaccharides and adenosine diphosphate ribose (ADPr)) challenged this perspective. Our recent study showed that DTX2 E3 ligase efficiently ubiquitylates ADPr. Here, we show that the ADPr ubiquitylation activity is also present in another DELTEX family member, DTX3L, analysed both as an isolated catalytic fragment and the full-length PARP9:DTX3L complex, suggesting that it is a general feature of the DELTEX family. Since structural predictions show that DTX3L possesses single-stranded nucleic acids binding ability and given the fact that nucleic acids have recently emerged as substrates for ADP-ribosylation, we asked whether DELTEX E3s might catalyse ubiquitylation of an ADPr moiety linked to nucleic acids. Indeed, we show that DTX3L and DTX2 are capable of ubiquitylating ADP-ribosylated DNA and RNA synthesized by PARPs, including PARP14. Furthermore, we demonstrate that the Ub-ADPr-nucleic acids conjugate can be reversed by two groups of hydrolases, which remove either the whole adduct (e.g. SARS-CoV-2 Mac1 or PARP14 macrodomain 1) or just the Ub (e.g. SARS-CoV-2 PLpro). Overall, this study reveals ADPr ubiquitylation as a general function of the DELTEX family E3s and presents the evidence of reversible ubiquitylation of ADP-ribosylated nucleic acids.
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ADP-Ribosilación , Ácidos Nucleicos , Ubiquitina-Proteína Ligasas , Adenosina Difosfato Ribosa/metabolismo , Ácidos Nucleicos/metabolismo , Ácido Ocadaico/análogos & derivados , Proteínas/genética , Ubiquitina-Proteína Ligasas/metabolismo , HumanosRESUMEN
Lipid homeostasis is essential for normal cellular functions and dysregulation of lipid metabolism is highly correlated with human diseases including neurodegenerative diseases. In the ubiquitin-dependent autophagic degradation pathway, Troyer syndrome-related protein Spartin activates and recruits HECT-type E3 Itch to lipid droplets (LDs) to regulate their turnover. In this study, we find that Spartin promotes the formation of Itch condensates independent of LDs. Spartin activates Itch through its multiple PPAY-motif platform generated by self-oligomerization, which targets the WW12 domains of Itch and releases the autoinhibition of the ligase. Spartin-induced activation and subsequent autoubiquitination of Itch lead to liquid-liquid phase separation (LLPS) of the poly-, but not oligo-, ubiquitinated Itch together with Spartin and E2 both in vitro and in living cells. LLPS-mediated condensation of the reaction components further accelerates the generation of polyubiquitin chains, thus forming a positive feedback loop. Such Itch-Spartin condensates actively promote the autophagy-dependent turnover of LDs. Moreover, we show that the catalytic HECT domain of Itch is sufficient to interact and phase separate with poly-, but not oligo-ubiquitin chains. HECT domains from other HECT E3 ligases also exhibit LLPS-mediated the promotion of ligase activity. Therefore, LLPS and ubiquitination are mutually interdependent and LLPS promotes the ligase activity of the HECT family E3 ligases.
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Ubiquitina-Proteína Ligasas , Ubiquitina , Humanos , Retroalimentación , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Ubiquitina/metabolismoRESUMEN
AlphaFold2 and related computational tools have greatly aided studies of structural biology through their ability to accurately predict protein structures. In the present work, we explored AF2 structural models of the 17 canonical members of the human PARP protein family and supplemented this analysis with new experiments and an overview of recent published data. PARP proteins are typically involved in the modification of proteins and nucleic acids through mono or poly(ADP-ribosyl)ation, but this function can be modulated by the presence of various auxiliary protein domains. Our analysis provides a comprehensive view of the structured domains and long intrinsically disordered regions within human PARPs, offering a revised basis for understanding the function of these proteins. Among other functional insights, the study provides a model of PARP1 domain dynamics in the DNA-free and DNA-bound states and enhances the connection between ADP-ribosylation and RNA biology and between ADP-ribosylation and ubiquitin-like modifications by predicting putative RNA-binding domains and E2-related RWD domains in certain PARPs. In line with the bioinformatic analysis, we demonstrate for the first time PARP14's RNA-binding capability and RNA ADP-ribosylation activity in vitro. While our insights align with existing experimental data and are probably accurate, they need further validation through experiments.
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Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas , Humanos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Dominios Proteicos , ADP-Ribosilación , ARN/metabolismoRESUMEN
The permeability of the highly selective blood-brain barrier (BBB) to anticancer drugs and the difficulties in defining deep tumor boundaries often reduce the effectiveness of glioma treatment. Thus, exploring the combination of multiple treatment modalities under the guidance of second-generation near-infrared (NIR-II) window fluorescence (FL) imaging is considered a strategic approach in glioma theranostics. Herein, a hybrid X-ray-activated nanoprodrug was developed to precisely visualize the structural features of glioma microvasculature and delineate the boundary of glioma for synergistic chemo-radiotherapy. The nanoprodrug comprised down-converted nanoparticle (DCNP) coated with X-ray sensitive poly(Se-Se/DOX-co-acrylic acid) and targeted Angiopep-2 peptide (DCNP@P(Se-DOX)@ANG). Because of its ultrasmall size and the presence of DOX, the nanoprodrug could easily cross BBB to precisely monitor and localize glioblastoma via intracranial NIR-II FL imaging and synergistically administer antiglioblastoma chemo-radiotherapy through specific X-ray-induced DOX release and radiosensitization. This study provides a novel and effective strategy for glioblastoma imaging and chemo-radiotherapy.
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Glioblastoma , Glioma , Nanopartículas , Nitrofenoles , Humanos , Glioblastoma/patología , Rayos X , Línea Celular Tumoral , Glioma/tratamiento farmacológico , Nanopartículas/química , Quimioradioterapia , DoxorrubicinaRESUMEN
Water, being abundant and readily accessible, gains widespread usage as proton source in many catalysis and energy conversion technologies, including applications like reversible protonic ceramic cells (R-PCCs). Revealing the influence of water on the electrode surface and reaction kinetics is critical for further improving their electrochemical performance. Herein, a hydrophilic air-electrode PrBa0.875Cs0.125Co2O5+δ is developed for R-PCC, which demonstrates a remarkable peak power density of 1058 mW cm-2 in fuel cell mode and a current density of 1354 mA cm-2 under 1.3 V in electrolyzing steam at 650 °C. For the first time on R-PCC, surface protons' behavior in response to external voltages is captured using in situ FTIR characterizations. Further, it is shown that contrary to the bulk proton uptake process that is thought to follow hydrogenation reactions and lead to cation reductions. The air-electrode presents enriched surface protons occurring through oxidizing surface cations, as confirmed by depth-profiling XPS results. H/D isotope exchange experiments and subsequent electrochemical characterization analyses reveal that the presence of protons enhances surface reactions. This study fills the knowledge gap between water-containing atmospheres and electrochemical performance by providing insights into the surface properties of the material. These new findings provide guidance for future electrode design and optimization.
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ConspectusOptical imaging and photoacoustic (PA) imaging have become essential tools to investigate physiological or pathological processes at the molecular level in vivo. The detection of variations at the molecular level in vivo is particularly important owing to the rapid progression of diseases. However, most studies have mainly focused on plain qualitative molecular imaging and detection, which is characterized by the absence of a reference signal in one-channel responsive imaging. To overcome the limitation and quantitatively detect molecules in situ, this Account reviews the recent contributions of our group to the quantitative imaging field in the form of ratiometric optical and PA imaging in vivo in the second near-infrared window (NIR-II, 950-1700 nm).In this Account, we present recent advances that our group has made in ratiometric imaging probe design and biomedical applications by constructing probes based on ratiometric optical imaging and ratiometric PA imaging. First, we highlight the design strategies of ratiometric optical probes that were based on organic ratiometric molecular probes, radio-activated organic ratiometric probes, and hybrid organic-inorganic assembled ratiometric probes. Subsequently, the design strategies of the ratiometric NIR-II optical nanoprobes with activated bioluminescence resonance energy transfer (BRET), Förster resonance energy transfer (FRET), and nonradiative energy transfer (NRET) effects provide a reliable tool to achieve the ratiometric detection of endogenous signaling molecules and thereby apply it to the monitoring and evaluation of the efficacy of photodynamic therapy, radiotherapy, and immunotherapy to guide the treatment process. In addition, we systematically introduce the functional design principles of ratiometric PA imaging probes based on core-shell nanoprobes, core-satellite nanoprobes, and universal hybrid nanoprobes, where we have established that reference signal and sensing signal can be obtained from the random assortment of plasmonic components and organic semiconducting molecules using a phase separation strategy. On these insights, we discuss the rational and detailed biomedical applications of ratiometric PA imaging probes which include accurate quantitative detection of disease-related molecules in inflammation or tumors in real time. In these champion implementations of ratiometric PA imaging probes, different diagnostic modules have been linked through compound modification with activation characteristics (e.g., pH, redox, enzyme, hypoxia). Finally, we present the challenges and perspectives for ratiometric probes based on optical imaging and PA imaging for multitarget design and future clinical translation. We believe that the upcoming generations of ratiometric imaging probes would have promising potential applications in the precise diagnosis of diseases. Finally, this Account may stimulate innovative studies in the design of ratiometric imaging probes and exploration of their clinical applications.
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Neoplasias , Técnicas Fotoacústicas , Humanos , Técnicas Fotoacústicas/métodos , Sondas Moleculares , Neoplasias/diagnóstico por imagen , Transferencia Resonante de Energía de Fluorescencia , Imagen Óptica , Colorantes Fluorescentes/químicaRESUMEN
Low-cost, highly efficient thermoelectric thin-film materials are becoming increasingly popular as miniaturization progresses. Mg3Sb2 has great potential due to its low cost and high performance. However, the fabrication of Mg3Sb2 thin films with high power factors poses a certain challenge. In this work, we propose a general approach to prepare Mg3Sb2 thin films with excellent thermoelectric properties. Using a two-step thermal evaporation and rapid annealing process, (001)-oriented Mg3Sb2 thin films are fabricated on c-plane-oriented Al2O3 substrates. The structure of the film orientation is optimized by controlling the film thickness, which modulates the thermoelectric performance. The power factor of the Mg3Sb2 at 500 nm (14 µW·m-1·K-2) would increase to 169 µW·m-1·K-2 with Ag doping (Mg3Ag0.02Sb2) at room temperature. This work provides a new strategy for developing high-performance thermoelectric thin films at room temperature.
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Aiming at the problems of long reaction time and the risk of explosion polymerization of acrylate resin, a small amount of ferrocene (Fc) is added to the existing dibenzoyl peroxide (BPO)/N,N-dimethylaniline (DMA) initiators, and the compound redox initiators (BPO/DMA/ (Fc)) are proposed for acrylate resin polymerization at room temperature. The effect of the content of Fc in the resin on the reaction efficiency and the molding quality of products is researched, and the initiation mechanism of the compound redox initiators is analyzed. It is found that with the addition of Fc, the reaction time of the resin can be shortened by 68% at maximum, the heat release temperature of the resin can be reduced by 40% at maximum, the molecular weight of the reaction products can be increased by 74% at maximum, the tensile and bending properties of the resin castings are increased by 23% and 35% at maximum, respectively, and the bending strength and bending modulus are increased by 57% and 27% at maximum, respectively. The compound redox initiators proposed in this paper can improve the molding efficiency and quality of the product, lay a foundation for the application of acrylic resin in the field of pultrusion molding, perfusion molding, and other in situ molding of thermoplastic composites.
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Acrilatos , Resinas Acrílicas , Polimerizacion , Temperatura , Oxidación-Reducción , Ensayo de MaterialesRESUMEN
A novel construction strategy is introduced for an ultrasensitive dynamic light scattering (DLS) immunosensor targeting alpha fetoprotein (AFP). This approach relies on a self-assembled heptamer fusion protein (A1-C4bpα), incorporating the dual functions of multivalent recognition and crosslinking aggregation amplification due to the presence of seven AFP-specific A1 nanobodies on the A1-C4bpα heptamer. Leveraging antibody-functionalized magnetic nanoparticles for target AFP capture and DLS signal output, the proposed heptamer-assisted DLS immunosensor offers high sensitivity, strong specificity, and ease of operation. Under the optimized conditions, the designed DLS immunosensor demonstrates excellent linear detection of AFP in the concentration range 0.06 ng mL-1 to 512 ng mL-1, with a detection limit of 15 pg mL-1. The selectivity, accuracy, precision, practicability, and reliability of this newly developed method were further validated through an assay of AFP levels in spiked and actual human serum samples. This work introduces a novel approach for constructing ultrasensitive DLS immunosensors, easily extendable to the sensitive determination of other targets via simply replacing the nanobody sequence, holding great promise in various applications, particularly in disease diagnosis.
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Dispersión Dinámica de Luz , Límite de Detección , alfa-Fetoproteínas , alfa-Fetoproteínas/análisis , alfa-Fetoproteínas/inmunología , Humanos , Inmunoensayo/métodos , Anticuerpos Inmovilizados/inmunología , Técnicas Biosensibles/métodos , Anticuerpos de Dominio Único/química , Anticuerpos de Dominio Único/inmunología , Nanopartículas de Magnetita/químicaRESUMEN
Neijiang (NJ) and Yacha (YC) are two indigenous pig breeds in the Sichuan basin of China, displaying higher resistance to diseases, lower lean ratio, and slower growth rate than the commercial Western pig breed Yorkshire (YS). The molecular mechanisms underlying the differences in growth and development between these pig breeds are still unknown. In the present study, five pigs from NJ, YC, and YS breeds were subjected to the whole genome resequencing, and then the differential single-nucleotide polymorphisms (SNPs) were screened using a 10-kb window sliding in 1-kb step using the Fst method. Finally, 48,924, 48,543, and 46,228 nonsynonymous single-nucleotide polymorphism loci (nsSNPs) were identified between NJ and YS, NJ and YC, and YC and YS, which highly or moderately affected 2,490, 800, and 444 genes, respectively. Moreover, three nsSNPs were detected in the genes of acetyl-CoA acetyltransferase 1 (ACAT1) insulin-like growth factor 2 receptor (IGF2R), insulin-like growth factor 2 and mRNA-binding protein 3 (IGF2BP3), which potentially affected the transformation of acetyl-CoA to acetoacetyl-CoA and the normal functions of the insulin signaling pathways. Moreover, serous determinations revealed significantly lower acetyl-CoA content in YC than in YS, supporting that ACAT1 might be a reason explaining the differences in growth and development between YC and YS breeds. Contents of phosphatidylcholine (PC) and phosphatidic acid (PA) significantly differed between the pig breeds, suggesting that glycerophospholipid metabolism might be another reason for the differences between Chinese and Western pig breeds. Overall, these results might contribute basic information to understand the genetic differences determining the phenotypical traits in pigs.
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Porcinos , Animales , Acetilcoenzima A , Genoma , Polimorfismo de Nucleótido Simple , Porcinos/genética , Porcinos/crecimiento & desarrolloRESUMEN
In situ thermal desorption (ISTD) provides an efficient solution to remediation of soil and groundwater contaminated with nonaqueous phase liquids (NAPLs). Establishing a relationship between the subsurface temperature rise and NAPL removal is significant to reduce energy consumption of ISTD. However, the co-boiling phenomenon between NAPL and water poses a great challenge in developing this relationship due to the nonequilibrium heat and mass transport effects. We performed a systematic experimental investigation into the local temperature rise patterns at different distances from a NAPL pool and under different degrees of superheat by selecting four representative NAPLs (i.e., trichloroethylene, tetrachlorethylene, n-hexane, and n-octane) according to their density and boiling point relative to water. The patterns of temperature rise indicated that the underground temperature field can be divided into three zones: the zone of local thermal equilibrium, the nonequilibrium zone affected by co-boiling, and the zone unaffected by co-boiling. We developed a pattern-recognition-based approach, which considers the effects of local heat and mass transport to establish a qualitative correlation between the temperature rise and NAPL removal. Our results give deeper insights into the understanding of subsurface temperatures in ISTD practice, which can serve as the guideline for more accurate and sustainable remediation.
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Contaminantes del Suelo , Tricloroetileno , Contaminantes Químicos del Agua , Calor , Agua , Temperatura , Contaminantes Químicos del Agua/análisisRESUMEN
Radiotherapy (RT) is an effective and widely applied cancer treatment strategy in clinic. However, it usually suffers from radioresistance of tumor cells and severs side effects of excessive radiation dose. Therefore, it is highly significant to improve radiotherapeutic performance and monitor real-time tumor response, achieving precise and safe RT. Herein, an X-ray responsive radio-pharmaceutical molecule containing chemical radiosensitizers of diselenide and nitroimidazole (BBT-IR/Se-MN) is reported. BBT-IR/Se-MN exhibits enhanced radiotherapeutic effect via a multifaceted mechanisms and self-monitoring ROS levels in tumors during RT. Under X-ray irradiation, the diselenide produces high levels of ROS, leading to enhanced DNA damage of cancer cell. Afterwards, the nitroimidazole in the molecule inhibits the damaged DNA repair, offering a synergetic radiosensitization effect of cancer. Moreover, the probe shows low and high NIR-II fluorescence ratios in the absence and presence of ROS, which is suitable for precise and quantitative monitoring of ROS during sensitized RT. The integrated system is successfully applied for radiosensitization and the early prediction of in vitro and in vivo RT efficacy.
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Neoplasias , Fármacos Sensibilizantes a Radiaciones , Humanos , Especies Reactivas de Oxígeno , Colorantes Fluorescentes , Neoplasias/diagnóstico por imagen , Neoplasias/radioterapia , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Preparaciones Farmacéuticas , Línea Celular TumoralRESUMEN
Triple-conducting (H+ /O2- /e- ) cathodes are a vital constituent of practical protonic ceramic fuel cells. However, seeking new candidates has remained a grand challenge on account of the limited material system. Though triple conduction can be achieved by mechanically mixing powders uniformly consisting of oxygen ion-electron and proton conductors, the catalytic activity and durability are still restricted. By leveraging this fact, a highly efficient strategy to construct a triple-conductive region through surface self-assembly protonation based on the robust double-perovskite PrBaCo1.92 Zr0.08 O5+δ , is proposed. In situ exsolution of BaZrO3 -based nanoparticles growing from the host oxide under oxidizing atmosphere by liberating Ba/Zr cations from A/B-sites readily forms proton transfer channels. The surface reconstructing heterostructures improve the structural stability, reduce the thermal expansion, and accelerate the oxygen reduction catalytic activity of such nanocomposite cathodes. This design route significantly boosts electrochemical performance with maximum peak power densities of 1453 and 992 mW cm-2 at 700 and 650 °C, respectively, 86% higher than the parent PrBaCo2 O5+δ cathode, accompanied by a much improved operational durability of 140 h at 600 °C.
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Attempted preparation of a low-valent Ca(I) complex by reduction of Ca iodide precursor [LCaI(THF)]2 (1) (L = [CH3C(NAr)CHC(CH3)NCH2CH2N(CH3)2]-, Ar = 2,6-iPr2C6H3), with KC8 led to isolation of a dinuclear calcium azaallyl complex {[H2CC(NAr)CHC(CH3)(NCH2CH2N(CH3)2)]Ca(THF)}2 (2). Alternatively, reaction of 1 with KC8 in the presence of azobenzene gives an azobenzenyl calcium complex LCa(PhNNPh)(THF) (3). The electron paramagnetic resonance and UV-vis spectra of complex 3 suggest that the (PhNNPh) moiety should be regarded as a radical anion. Complex 3 can react with Me3SiN3, Me3SiCHN2, CS2, W(CO)6, elemental sulfur, and AgBr, resulting in the formation of the azido complex [LCaN3(THF)]2 (5), isonitril complex {LCa[CNN(Si(CH3)3)]}2 (6), dimeric bis(thiolate) complex {[S2CC(CMe(NAr))C(Me)NCH2CH2NMe2]Ca(DME)}2 (7), metallocyclic carbene complex {[OC(W(CO)5)N(C6H5)]Ca(THF)3}2 (8), bis(thiolate) complex {[S2C(CMe(NAr))C(Me)NCH2CH2NMe2]Ca(THF)}2 (9), and bromide complex [LCaBr(THF)]2 (10). Additional insights on the reaction process resulting in the formation of complex 7 are provided by density-functional theory studies. These results demonstrate that the (PhNNPh)â¢- radical anion can serve as a very potent one-electron donor, and 3 acts as a low-valent calcium(I) synthon.
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Herein, we reported a new dynamic light scattering (DLS) immunosensing technology for the rapid and sensitive detection of glycoprotein N-terminal pro-brain natriuretic peptide (NT-proBNP). In this design, the boronate affinity recognition based on the interaction of boronic acid ligands and cis-diols was introduced to amplify the nanoparticle aggregation to enable highly sensitive DLS transduction, thereby lowering the limit of detection (LOD) of the methodology. After covalently coupling with antibodies, magnetic nanoparticles (MNPs) were employed as the nanoprobes to selectively capture trace amount of NT-proBNP from complex samples and facilitate DLS signal transduction. Meanwhile, silica nanoparticles modified with phenylboronic acid (SiO2@PBA) were designed as the crosslinking agent to bridge the aggregation of MNPs in the presence of target NT-proBNP. Owing to the multivalent and fast affinity recognition between NT-proBNP containing cis-diols and SiO2@PBA, the developed DLS immunosensor exhibited charming advantages over traditional immunoassays, including ultrahigh sensitivity with an LOD of 7.4 fg mL-1, fast response time (< 20 min), and small sample consumption (1 µL). The DLS immunosensor was further characterized with good selectivity, accuracy, precision, reproducibility, and practicability. Collectively, this work demonstrated the promising application of the designed boronate affinity amplified-DLS immunosensor for field or point-of-care testing of cis-diol-containing molecules.
Asunto(s)
Técnicas Biosensibles/métodos , Ácidos Borónicos/química , Dispersión Dinámica de Luz/métodos , Inmunoensayo/métodos , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Anticuerpos Monoclonales/química , Humanos , Límite de Detección , Nanopartículas de Magnetita/químicaRESUMEN
Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common inflammatory disease with high heterogeneity and postoperative recidivation. The IL-33/ST2 axis is known to be involved in Th2 immune responses. This study is aimed at exploring levels of serum IL-33 and soluble ST2 (sST2) in CRSwNP patients and their potential for predicting CRSwNP endotypes and postoperative recurrence. Methods: The present study recruited 149 CRSwNP patients, 80 of whom were noneosinophilic (neCRSwNP) and 69 eosinophilic (eCRSwNP), as well as 60 healthy controls (HCs). Serum samples were collected from all participants, and sST2 and IL-33 concentrations were measured using ELISA. Multivariate analysis, receiver operating characteristic (ROC) curves, and Kaplan-Meier curves were used to evaluate the value of serum sST2 and IL-33 levels in distinguishing CRSwNP endotypes and predicting postoperative recurrence. Results: The levels of serum sST2 and IL-33 in CRSwNP patients were significantly higher than those in HCs, especially in the eCRSwNP group. Increased sST2 and IL-33 levels were associated with eosinophil counts and percentages in both tissue and blood. Multivariate regression and ROC curve analysis showed that serum sST2 and IL-33 exhibited potential for distinguishing CRSwNP endotypes, and the combination of serum IL-33 and sST2 showed even more predictive power. Finally, 124 CRSwNP patients completed the entire 3-year follow-up. Multivariate analysis and Kaplan-Meier curves showed that serum sST2 and IL-33 levels were associated with recurrence; serum sST2 and IL-33 each exhibited potential for predicting postoperative recurrence, and combining serum sST2 and IL-33 exhibited better accuracy and practicability. Conclusion: Our results suggested that serum sST2 and IL-33 levels were upregulated in CRSwNP patients and related to the degree of mucosal eosinophil infiltration and postoperative recurrence. Serum sST2 and IL-33 might serve as objective biomarkers for distinguishing phenotypes and predicting recurrence in CRSwNP, and their combined use outperformed either marker alone.