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Fixing nitrogen (N2 ) by electrosynthesis method has become a promising way to ammonia (NH3 ) production, nevertheless, developing electrocatalysts combining long-term stable and low-cost feathers are still a great challenge to date. Using comprehensive first-principles calculations, we herein investigate the potential of a new class of two-dimensional (2D) transition metal tri-borides (TMB3 s) as nitrogen reduction reaction (NRR) electrocatalysts, and explore the effect of magnetic orders on the NRR. Our results show that the TMB3 s can sufficiently activate N2 and convert it to NH3 . Particularly, TiB3 is identified as a high-efficiency catalyst for NRR because of its low limiting potential (-0.24â V) and good suppression of the competitive hydrogen evolution reaction (HER). For the first time, we present that these TMB3 s with various magnetic states exhibit different performances in the adsorption of N2 and NRR intermediates, and minor effect on activation of N2 . Besides, VB3 , CrB3 , MnB3 , and FeB3 monolayers possess the superior capacity to suppress surface oxidation via the self-activating process, which reduces * O/* OH into * H2 O under NRR electrochemical conditions, thus favoring the N2 electroreduction. This work paves the way for finding high-performance NRR catalysts for transition metal borides and pioneering the research of magnetic states effects in NRR.
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Pyroglutamate aminopeptidase (PGP) specifically cleaves the peptide bond of pyroglutamic acid linked to the N-terminal end of a polypeptide or protein. Previous studies showed that PGP was associated with several physiological processes and diseases especially those involving inflammation. Utilizing a 'caging' strategy, we designed and synthesized a bioluminescence probe (PBL) with a limit-of-detection of 3.7 * 10-4 mU/mL. In vivo imaging in a mouse model of inflammatory liver disease revealed that the probe has excellent sensitivity and selectivity and provides a powerful tool for studying the physiological and pathological processes involving PGP.
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Modelos Animales de Enfermedad , Inflamación/diagnóstico por imagen , Sustancias Luminiscentes/química , Piroglutamil-Peptidasa I/análisis , Animales , Diagnóstico por Imagen , Inflamación/metabolismo , Sustancias Luminiscentes/síntesis química , Ratones , Estructura Molecular , Piroglutamil-Peptidasa I/metabolismoRESUMEN
Hydrogen sulfide (H2S), the third gaseous transmitter after CO and NO, is a double-edged sword in the human body. A specific concentration of H2S can attenuate myocardial ischemia-reperfusion injury by preserving mitochondrial function, in contrast, cause illness, including inflammation and stroke. There are already some probes for the real-time monitoring of the level of H2S in the biological environment. However, they have some disadvantages, such as phototoxicity, low sensitivity, and low quantum yield. In this research, by linking 4-dinitrophenyl-ether (DNP), a specific recognition group for H2S, with a chemiluminophore 1,2-dioxetane, we designed and synthesized the probe SCL-1. To tackle the barrier that the traditional chemiluminescent group has a short emission wavelength and is not easy to penetrate deep tissues, an acrylonitrile electron-withdrawing substituent was installed to the ortho-position of the 1,2-dioxanol hydroxy group. According to the same design strategy as SCL-1, the probe SCL-2 was designed with the modified chemiluminescent group. Studies have shown that SCL-2 with electron-withdrawing acrylonitrile has higher luminescence quantum yield and high sensitivity than SCL-1, realizing real-time detection of H2S in vitro and in vivo. The LOD of SCL-2 was 0.185 µM, which was the best among the currently available luminescent probes for detecting H2S. We envisage that SCL-2 may be a practical toolbox for studying the biological functions of H2S and H2S-related diseases.
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Colorantes Fluorescentes/química , Compuestos Heterocíclicos con 1 Anillo/química , Sulfuro de Hidrógeno/análisis , Colorantes Fluorescentes/síntesis química , Compuestos Heterocíclicos con 1 Anillo/síntesis química , Humanos , Estructura MolecularRESUMEN
A series of novel fluorescent agonists were well developed herein with turn-on switch for α1-adrenergic receptors (α1-ARs) by conjugating the environment-sensitive fluorophore 4-chloro-7-nitrobenzoxadiazole with phenylephrine. Overall, these probes exhibited efficient binding and apparent fluorescence intensity changes (up to 10-fold) upon binding with α1-ARs. Moreover, these probes have been successfully applied for selectively imaging α1-ARs in the living cells. The dynamic process of α1-ARs internalization was traced successfully with these newly designed fluorescent agonists. Fluorescence polarization assay demonstrated specific interactions between these probes and α1-ARs. With these new probes, a bioluminescence resonance energy transfer binding assay has been well established and applied to the high-throughput screening of unlabeled α1-ARs agonist and antagonist. It is expected that these environment-sensitive fluorescent turn-on agonists may provide useful new tools in studying pharmacology and physiology of α1-ARs during drug discovery.
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Agonistas de Receptores Adrenérgicos alfa 1/química , Agonistas de Receptores Adrenérgicos alfa 1/farmacología , Ensayos Analíticos de Alto Rendimiento/métodos , Receptores Adrenérgicos alfa 1/metabolismo , Agonistas de Receptores Adrenérgicos alfa 1/metabolismo , Unión Competitiva , Calcio/metabolismo , Fluorescencia , Polarización de Fluorescencia , Colorantes Fluorescentes/química , Células HEK293 , Humanos , Luminiscencia , Imagen Molecular/métodos , Nitrocompuestos/química , Oxadiazoles/química , Fenilefrina/químicaRESUMEN
Fibroblast activation protein-α (FAP), as a crucial member of cell surface glycoprotein, highly expresses in reactive fibroblasts of tumors and several fibrosis diseases. It is a potential target for drug design and also reported as a prodrug strategy to increase the therapeutic window of some anticancer agents. In this work, we developed the first bioluminogenic probe for FAP with a limit-of-detection of 0.254 ng/mL, which could be applied to evaluate the FAP inhibitors in vitro. The experiments of transgenic mice and tumor-bearing nude mice validated our probe 1 could reflect the endogenous FAP level in vivo. Furthermore, this probe was successfully used to reflect FAP up-regulation in the lung homogenates of the bleomycin-induced idiopathic pulmonary fibrosis mice.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico por imagen , Diagnóstico por Imagen/métodos , Gelatinasas/genética , Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Proteínas de la Membrana/genética , Sondas Moleculares/farmacocinética , Serina Endopeptidasas/genética , Animales , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Bleomicina/administración & dosificación , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Endopeptidasas , Inhibidores Enzimáticos/farmacología , Fibroblastos/enzimología , Gelatinasas/antagonistas & inhibidores , Gelatinasas/metabolismo , Expresión Génica , Xenoinjertos , Humanos , Fibrosis Pulmonar Idiopática/enzimología , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/patología , Límite de Detección , Mediciones Luminiscentes , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/metabolismo , Ratones , Ratones Desnudos , Ratones Transgénicos , Sondas Moleculares/síntesis química , Serina Endopeptidasas/metabolismoRESUMEN
Pantetheinase, a glycosylphosphatidylinositol (GPI) anchored enzyme, overexpresses in intestine, liver, and kidney with various biological functions such as its linkage to the inflammation and some metabolic diseases. It can hydrolyze pantetheine to cysteamine, an antioxidant, and pantothenic acid (Vitamin B5) that is an essential component of coenzyme A (CoA). Until now, very few analytic methods were developed for this enzyme, hampering the further investigation of its biological functions. In this work, we report the design, synthesis, and biological examination of a highly sensitive bioluminogenic probe for pantetheinase with a limit of detection of 1.14 ng/mL. Furthermore, animal experiments validated that our probe can be applied to detect the endogenous pantetheinase activity. To the best of our knowledge, this is the first bioluminogenic probe achieving the detection of pantetheinase level in vivo.
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Amidohidrolasas/análisis , Sustancias Luminiscentes/química , Mediciones Luminiscentes/métodos , Imagen Óptica/métodos , Ácido Pantoténico/análogos & derivados , Inanición , Amidohidrolasas/metabolismo , Animales , Línea Celular , Proteínas Ligadas a GPI/análisis , Proteínas Ligadas a GPI/metabolismo , Humanos , Ratones Endogámicos C57BL , Ratones Transgénicos , Regulación hacia ArribaRESUMEN
As a kind of biologically important reactive oxygen species (ROS), hypochlorite (ClO-) plays a crucial role in many physiological processes. As such, endogenous ClO- is a powerful antibacterial agent during pathogen invasion. Nonetheless, excessive endogenous ClO- could pose a health threat to mammalian animals including humans. However, the detection of endogenous ClO- by bioluminescence probes in vivo remains a considerable challenge. Herein, based on a caged strategy, we developed a turn-on bioluminescent probe 1 for the highly selective detection of ClO-in vitro and imaging endogenous ClO- in a mouse inflammation model. We anticipate that such a probe could help us understand the role of endogenous ClO- in a variety of physiological and pathological processes.
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Luciferina de Luciérnaga/análogos & derivados , Ácido Hipocloroso/análisis , Ácido Hipocloroso/metabolismo , Sustancias Luminiscentes/química , Animales , Línea Celular Tumoral , Luciferina de Luciérnaga/síntesis química , Luciferina de Luciérnaga/toxicidad , Humanos , Inflamación/inducido químicamente , Inflamación/diagnóstico por imagen , Luciferasas/química , Sustancias Luminiscentes/síntesis química , Sustancias Luminiscentes/toxicidad , Masculino , Ratones , ZimosanRESUMEN
Tyrosinase, a copper-containing enzyme existing widely in plants, animals and microorganisms, usually serves as an important biomarker in melanoma, and is also related to hyperpigmentation of the skin, melasma, age spots and albinism. At present, only one bioluminescent probe has been applied to image tyrosinase in cells. Thus, it's of great significance to develop a new bioluminescent probe that can detect tyrosinase in living cells and in live animals. In the current work, we report a new BL probe, TyrBP-3, which not detect tyrosinase in vitro and in living cells, but can also visualize the level of tyrosinase activity in tumors of living animals. In summary, TyrBP-3 is the first bioluminescent probe that can image tyrosinase on a cellular level. Hence, we anticipate that TyrBP-3 can be a good tool to monitor tyrosinase in complex biosystems in the future.
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Luciferina de Luciérnaga/análogos & derivados , Sustancias Luminiscentes/química , Monofenol Monooxigenasa/análisis , Aminación , Animales , Línea Celular , Femenino , Mediciones Luminiscentes/métodos , Ratones Endogámicos C57BL , Imagen Óptica/métodosRESUMEN
To detect γ-Glutamyl Transpeptidase (GGT) activity in vitro and in vivo, a bioluminescence probe with high sensitivity and specificity was well designed and synthesized. This probe can be recognized by GGT and release strong bioluminescence with its further reaction with luciferase. The performance of this probe was demonstrated in vitro and in cells. Finally, we applied the probe for detection of GGT activity in xenograft model.
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Sustancias Luminiscentes/química , Neoplasias Ováricas/metabolismo , gamma-Glutamiltransferasa/análisis , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Sustancias Luminiscentes/administración & dosificación , Sustancias Luminiscentes/farmacología , Mediciones Luminiscentes , Ratones , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Relación Estructura-Actividad , gamma-Glutamiltransferasa/metabolismoRESUMEN
Hypoxia is a pathogenic characteristic of solid tumors owing to absent or abnormal vasculature in the tumor microenvironment and essential in tumor progression, angiogenesis, metastasis, invasion and resistance to immune system and therapy. In hypoxic environments, CYP450 enzymes are more efficient than in normoxia. Herein, based on the reductive capacity of CYP450 enzymes/NADPH system, we managed to cage aminoluciferin developing a reaction-based bioluminescent probe as well as an imaging method for the hypoxia detection. Exhibiting enhanced about 3-fold total flux in big (1.2 cm-diameter) tumors, Hypoxia BioLuminescent probe (HBL) can afford potential utility for in cellulo and in vivo hypoxia imaging in tumor model mice.
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Sistema Enzimático del Citocromo P-450/metabolismo , Sustancias Luminiscentes/química , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Hipoxia Tumoral , Animales , Línea Celular Tumoral , Humanos , Mediciones Luminiscentes , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/metabolismo , Imagen ÓpticaRESUMEN
Sleep apnea is a common sleep disorder. Traditional testing and diagnosis heavily rely on the expertise of physicians, as well as analysis and statistical interpretation of extensive sleep testing data, resulting in time-consuming and labor-intensive processes. To address the problems of complex feature extraction, data imbalance, and low model capacity, we proposed an automatic sleep apnea classification model (CA-EfficientNet) based on the wavelet transform, a lightweight neural network, and a coordinated attention mechanism. The signal is converted into a time-frequency image by wavelet transform and put into the proposed model for classification. The effects of input time window, wavelet transform type and data balancing on the classification performance are considered, and a cost-sensitive algorithm is introduced to more accurately distinguish between normal and abnormal breathing events. PhysioNet apnea ECG database was used for training and evaluation. The 3-min Frequency B-Spline wavelets transform of ECG signal was carried out, and Dice Loss was used to train the classification model of sleep breathing. The classification accuracy was 93.44%, sensitivity was 88.9%, specificity was 96.2% and most indexes were better than other related work.
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Aprendizaje Profundo , Síndromes de la Apnea del Sueño , Apnea Obstructiva del Sueño , Humanos , Análisis de Ondículas , Apnea Obstructiva del Sueño/diagnóstico por imagen , Síndromes de la Apnea del Sueño/diagnóstico por imagen , Electrocardiografía/métodosRESUMEN
The chemical and physical properties of nanomaterials ultimately rely on their crystal structures, chemical compositions and distributions. In this paper, a series of AuCu bimetallic nanoparticles with well-defined architectures and variable compositions has been addressed to explore their thermal stability and thermally driven behavior by molecular dynamics simulations. By combination of energy and Lindemann criteria, the solid-liquid transition and its critical temperature were accurately identified. Meanwhile, atomic diffusion, bond order, and particle morphology were examined to shed light on thermodynamic evolution of the particles. Our results reveal that composition-dependent melting point of AuCu nanoparticles significantly departs from the Vegard's law prediction. Especially, chemically disordered (ordered) alloy nanoparticles exhibited markedly low (high) melting points in comparison with their unary counterparts, which should be attributed to enhancing (decreasing) atomic diffusivity in alloys. Furthermore, core-shell structures and heterostructures demonstrated a mode transition between the ordinary melting and the two-stage melting with varying Au content. AuCu alloyed nanoparticles presented the evolution tendency of chemical ordering from disorder to order before melting and then to disorder during melting. Additionally, as the temperature increases, the shape transformation was observed in AuCu nanoparticles with heterostructure or L10 structure owing to the difference in thermal expansion coefficients of elements and/or of crystalline orientations. Our findings advance the fundamental understanding on thermodynamic behavior and stability of metallic nanoparticles, offering theoretical insights for design and application of nanosized particles with tunable properties.
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The development of nonprecious metal catalysts to meet the activity-stability balance at industrial-grade large current densities remains a challenge toward practical alkali-water electrolysis. Here, this work develops an orderly nanodendritic nickel (ND-Ni) catalyst that consists of ultrafine nanograins in chain-like conformation, which shows both excellent activity and robust stability for large current density hydrogen evolution reaction (HER) in alkaline media, superior to currently applied Raney nickel (R-Ni) catalyst in commercial alkali-water electrolyzer (AWE). The ND-Ni catalyst featured by a three-dimensional (3D) interconnecting microporous structure endows with high specific surface area and excellent conductivity and hydrophilicity, which together afford superior charge/mass transport favorable to HER kinetics at high current densities. An actual AWE with ND-Ni catalyst demonstrates durable water splitting with 1.0 A cm-2 at 1.71 V under industrial conditions and renders a record-low power consumption of 3.95 kW h Nm-3 with an energy efficiency close to 90%. The hydrogen price per gallon of gasoline equivalent (GGE) is calculated to be ≈$0.95, which is less than the target of $2.0 per GGE by 2026 from the U.S. Department of Energy. The results suggest the feasibility of ND-Ni substitute for R-Ni catalyst in commercial AWE.
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Extracellular vesicles (EVs) are an effective tool to elucidate the bioeffect of nanomedicines. To clarify the interaction between oral nanomedicines and intestinal epithelial cells, and their bioeffects on downstream cells, polystyrene nanoparticles (PS-NPs) with different sizes were used as the model nanomedicines for EVs induction. Caco-2 monolayers were selected as the model of the intestinal epithelium and DLD-1 cells as the colorectal cancer model proximal to the gastrointestinal tract. It is found that compared with small-sized (25, 50, 100 nm) PS-NPs, the large-sized (200 and 500 nm) exhibited higher co-localization with multivesicular bodies and lysosomes, and more significant reduction of lysosomal acidification in Caco-2 cells. Proteomic and western-blotting analysis showed that the EVs remodeled by large-sized PS-NPs exhibited a higher extent of protein expression changes. The in vitro and in vivo signaling pathway detection in DLD-1 cells and DLD-1 cell xenograft nude mice showed that the remodeled EVs by large-sized PS-NPs inhibited the activation of multiple signaling pathways including Notch3, EGF/EGFR, and PI3K/Akt pathways, which resulted in the inhibition of tumor cell migration. These results primarily clarify the regulation mechanisms of nanomedicines-EVs-receptor cells chain. It provides a new perspective for the rational design and bioeffect evaluation of oral drug nanomaterials and sets up the fundamental knowledge for novel tumor therapeutics in the future.
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Vesículas Extracelulares , Nanopartículas , Animales , Ratones , Humanos , Células CACO-2 , Proteómica/métodos , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Mucosa Intestinal/metabolismo , Vesículas Extracelulares/metabolismo , Nanopartículas/metabolismo , Movimiento CelularRESUMEN
BACKGROUND: Various heart diseases ultimately lead to chronic heart failure (CHF). In CHF, the inflammatory response is associated with pyroptosis, which is mediated by the NOD-like receptor protein 3 (NLRP3) inflammasome. Fu Xin decoction (FXD) is commonly used in clinical practice to treat CHF and improve inflammatory conditions. However, the specific pharmacological mechanisms of action for FXD in these processes have yet to be fully understood. PURPOSE: The objective of this study was to examine the protective mechanism of FXT against CHF, both in H9c2 cells and mice. METHOD: A CHF mouse model was established, and the effect of FXD was observed via gavage. Cardiac function was evaluated using echocardiography, while serum BNP and LDH levels were analyzed to assess the severity of CHF. Hematoxylin and eosin staining (H&E) and Masson staining were performed to evaluate myocardial pathological changes, and TdT-mediated dUTP Nick-End Labeling staining was used to detect DNA damage. Additionally, doxorubicin was utilized to induce myocardial cell injury in H9c2 cells, establishing a relevant model. CCK8 was used to observe cell viability and detect LDH levels in the cell supernatant. Subsequently, the expression of pyroptosis-related proteins was detected using immunohistochemistry, immunofluorescence, and western blotting. Finally, the pharmacological mechanism of FXD against CHF was further validated by treating H9c2 cells with an NLRP3 activator and inducing NLRP3 overexpression. RESULT: According to current research findings, echocardiography demonstrated a significant improvement of cardiac function by FXD, accompanied by reduced levels of BNP and LDH, indicating the amelioration of cardiac injury in CHF mice. FXD exhibited the ability to diminish serum CRP and MCP inflammatory markers in CHF mice. The results of HE and Masson staining analyses revealed a significant reduction in pathological damage of the heart tissue following FXD treatment. The CCK8 assay demonstrated the ability of FXD to enhance H9c2 cell viability, improve cell morphology, decrease LDH levels in the cell supernatant, and alleviate cell damage. Immunohistochemistry, Western blotting, and immunofluorescence staining substantiated the inhibitory effect of FXD on the NLRP3/caspase-1/GSDMD pyroptosis signaling pathway in both CHF and H9c2 cell injury models. Ultimately, the administration of the NLRP3 activator (Nigericin) and the overexpression of NLRP3 counteract the effects of FXD on cardiac protection and pyroptosis inhibition in vitro. CONCLUSION: FXD exhibits a cardioprotective effect, improving CHF and alleviating pyroptosis by inhibiting the NLRP3/caspase-1/GSDMD pathway.
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Medicamentos Herbarios Chinos , Insuficiencia Cardíaca , Proteína con Dominio Pirina 3 de la Familia NLR , Piroptosis , Animales , Ratones , Caspasa 1/efectos de los fármacos , Caspasa 1/metabolismo , Línea Celular , Enfermedad Crónica , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Gasderminas/efectos de los fármacos , Gasderminas/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones Endogámicos C57BL , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Proteína con Dominio Pirina 3 de la Familia NLR/efectos de los fármacos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Piroptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
The electrochemical nitrogen reduction reaction (eNRR) to NH3 has become an alternative to traditional NH3 production techniques, while developing NRR catalysts with high activity and high selectivity is of great importance. In this study, we systematically investigated the potentiality of dual transition metal (TM) atom anchored electrocatalysts, TM1TM2@C9N4 (TM1, TM2 = 3(4)d TM atoms), for the NRR through the first principles high-throughput screening method. A total of 78 TM1TM2@C9N4 candidates were designed to evaluate their stability, catalytic activity, and selectivity for the NRR. Four TM1TM2@C9N4 candidates (TM1TM2 = NiRu, FeNi, TiNi, and NiZr) with an end-on N2 adsorption configuration, and two candidates (TM1TM2 = TiNi and TiFe) with a side-on adsorption configuration, were screened out with the advantage of suppressing the hydrogen evolution reaction (HER) and exhibiting high NRR activity. Moreover, the catalysts with end-on and side-on N2 adsorption configurations were determined to favor distal and consecutive reaction pathways, respectively, with favorable limiting potentials of only -0.33 V to -0.53 V. Detailed analysis showed that the N2 adsorption and activation are primarily ascribed to the strong back-donation interactions between the d-electrons of TM atoms and the anti-orbitals of an N2 molecule. Our findings pave a way for the rational design and rapid screening of highly active C9N4-based catalysts for the NRR.
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Sulfur cathodes in Li-S batteries suffer significant volumetric expansion and lack of catalytic activity for polysulfide conversion. In this study, a confined self-reduction synthetic route is developed for preparing nanocomposites using diverse metal ions (Mn2+ , Co2+ , Ni2+ , and Zn2+ )-introduced Al-MIL-96 as precursors. The Ni2+ -introduced Al-MIL-96-derived nanocomposite contains a "hardness unit", amorphous aluminum oxide framework, to restrain the volumetric expansion, and a "softness unit", Ni nanocrystals, to improve the catalytic activity. The oxygen-potential diagram theoretically explains why Ni2+ is preferentially reduced. Postmortem microstructure characterization confirms the suppressive volume expansion. The in situ ultraviolet-visible measurements are performed to probe the catalytic activity of polysulfide conversion. This study provides a new perspective for designing nanocomposites with "hardness units" and "softness units" as sulfur or other catalyst hosts.
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BACKGROUND: Vancomycin area under the curve/minimum inhibitory concentration (AUC/MIC) has been proposed as a therapeutic drug monitoring (TDM) target to dose vancomycin. It is time-consuming to estimate AUCs using traditional methods. A two-point trough-peak method is more straightforward for calculating the vancomycin AUC. However, the technique and the AUC/MIC target have not been validated in Chinese patients. AIM: To compare the clinical outcomes of vancomycin therapy in Chinese older adults (aged > 60 years) between the trough-only and the two-point peak-trough AUC TDM approaches. METHOD: The patients were divided into study and control groups according to TDM approaches. A trough-based TDM was used in the control group (target trough level 15-20 mg/L). Stanford University has provided a method to predict vancomycin AUC using peak-valley concentration alone (two-point method). A two-point trough-peak TDM approach was employed in the study group (target AUC/MIC ≥ 400). The effect of vancomycin was evaluated in terms of clinical findings, laboratory values, and bacteriologic responses. The effects of treatment and kidney functions were compared between the two groups. RESULTS: A total of 389 patients met the study inclusion criteria, and 189 were excluded based on the exclusion criteria. Of the 200 patients, 80 received the two-point TDM approach (the study group), and 120 were monitored using the trough-based approach (the control group). The average age was 69.8 ± 7.1 years. Staphylococcus aureus (34%) was the most common Gram-positive bacteria. No vancomycin-related nephrotoxicity was observed in either group. The percentages of patients with an excellent response to vancomycin therapy were significantly higher in the study group than in the control group, 90% (72/80) versus 73.3% (88/120), P = 0.0039. CONCLUSION: The two-point peak-trough method is practical for obtaining vancomycin AUC. The AUC/MIC ≥ 400 target demonstrates treatment effectiveness and safety in older Chinese patients.
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Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Humanos , Anciano , Persona de Mediana Edad , Vancomicina , Área Bajo la Curva , Antibacterianos , Infecciones Estafilocócicas/tratamiento farmacológico , Monitoreo de Drogas/métodos , Estudios RetrospectivosRESUMEN
Hepatocellular carcinoma (HCC) is a type of cancer characterized by high heterogeneity and a complex multistep progression process. Significantly-altered biomarkers for HCC need to be identified. Differentially expressed genes and weighted gene co-expression network analyses were used to identify progression-related biomarkers. LASSO-Cox regression and random forest algorithms were used to construct the progression-related prognosis (PRP) score. Three chromosomal instability-associated genes (KIF20A, TOP2A, and TTK) have been identified as progression-related biomarkers. The robustness of the PRP scores were validated using four independent cohorts. Immune status was observed using the single-sample gene set enrichment analysis (ssGSEA). Comprehensive analysis showed that the patients with high PRP score had wider genomic alterations, more malignant phenotypes, and were in a state of immunosuppression. The diagnostic models constructed via logistic regression based on the three genes showed satisfactory performances in distinguishing HCC from cirrhotic tissues or dysplastic nodules. The nomogram combining PRP scores with clinical factors had a better performance in predicting prognosis than the tumor node metastasis classification (TNM) system. We further confirmed that KIF20A, TOP2A, and TTK were highly expressed in HCC tissues than in cirrhotic tissues. Downregulation of all three genes aggravated chromosomal instabilities in HCC and suppressed HCC cells viability both in vitro and in vivo. Overall, our study highlights the important roles of chromosomal instability-associated genes during the progression of HCC and their potential clinical diagnosis and prognostic value and provides promising new ideas for developing therapeutic strategies to improve the outcomes of HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores de Tumor , Inestabilidad Cromosómica , Regulación Neoplásica de la Expresión Génica , Humanos , Cirrosis HepáticaRESUMEN
Combination therapy is frequently used in cancer treatments. Delivery of combined anticancer agents loaded in a nanocarrier would be a promising option for combination therapy. Here, we designed PEGylated nano-liposomes for co-delivery Docetaxel (Doc) and Resveratrol (Res) to evaluate antitumor efficiency of the combined drugs in prostate cancer. The average diameter of the liposomes was 99.67 nm with a spheral-like shape. Drug release studies showed that both drugs could synchronously leak from the liposomes in a sustained release behavior. Cellular uptake results demonstrated that liposomes could effectively deliver more cargos into cells than other formulations. Moreover, co-loaded liposomes with Doc/Res in a molar ratio of 1:2 exhibited significantly higher cytotoxicity than a mixed solution containing both drugs on cancer cells. In the study of caspase 3, we found that the combination of Doc and Res could significantly increase the activity of caspase 3 enzyme compared with Doc alone. Animal studies revealed that co-encapsulated Doc/Res in liposomes predominantly inhibited tumor growth in PC3 bearing Balb/c nude mice, as evidenced by a change in cell proliferation and apoptosis parameters. Importantly, little toxicities and prolonged survival time were observed in mice treated with liposome-loaded Doc/Res than control group exposed to liposome-free Doc/Res. These results provided evidence that loading of Doc/Res in a nano-liposome is an efficient delivery formulation for synergistic treating prostate cancer.