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Single-atom catalysts (SACs) are appealing for carbon dioxide (CO2) electroreduction with the utmost advantages; however, their preparation is still challenging because of the complicated procedure. Here, a novel Ni-based single-atom catalyst (Ni-BB-BD) is constructed from raw materials, [BMIM]BF4, [BMIM]DCN, and NiCl2·6H2O, directly without any precursor by only one-step pyrolysis. Ni-BB-BD achieves a maximum carbon monoxide Faradaic efficiency (FECO) of 96.5% at -0.8 V vs RHE, as well as long-term stability over 16 h. High current density up to -170.6 mA cm-2 at -1.0 V vs RHE is achieved in the flow cell along with a CO selectivity of 97.7%. It is identified that [BMIM]BF4 is the nitrogen source, while [BMIM]DCN is mainly taken as the carbon source. Theoretical studies have revealed that the rich nitrogen content, especially for the uncoordinated nitrogen, plays a critical role in lowering rate-limiting barrier height. This work develops a facile and effective strategy to prepare the SACs.
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PURPOSE: Total knee arthroplasty is the main method for the treatment of advanced haemophilic knee arthritis. Due to the particularity of hemophilia, the blood management plan is the focus of the perioperative period for haemophilia patients. This study aimed to investigate the clinical effect and safety of intra-articular injection of tranexamic acid in patients with haemophilia. METHODS: This is a retrospective study. According to whether tranexamic acid is used or not, patients are divided into tranexamic acid group (n=30) and non-tranexamic acid group (n=29). Total blood loss, intraoperative blood loss, complete blood count, total amount of coagulation factor VIII (FVIII) usage, coagulation biomarkers, inflammatory biomarkers, knee range of motion, knee joint function, pain status, complication rate, and patient satisfaction were assessed and compared at a mean follow-up of 16 months. RESULTS: Injecting tranexamic acid into the knee joint cavity can effectively reduce the hidden blood loss and total blood loss (P<0.001), and reduce the patient's early postoperative inflammation biomarkers, pain status, and limb swelling. Therefore, the patient can obtain a better range of motion following total knee arthroplasty. In the long run, in terms of joint function and surgical satisfaction, there are no statistically significant differences. In addition, there are no statistically significant differences between the two groups of patients in terms of the total amount of FVIII usage, length of stay, and hospitalization expenses. CONCLUSION: In patients with haemophilia, intra-articular injection of tranexamic acid during total knee arthroplasty can effectively reduce postoperative blood loss, early postoperative inflammation levels, pain and limb swelling, and enable patients to receive higher-quality rehabilitation exercises to get better joint function. Previous studies on TKA in haemophilic patients have already demonstrated the efficacy of intra-articular injections of TXA in reducing postoperative blood loss. Our study confirms this efficacy.
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Antifibrinolíticos , Artritis , Artroplastia de Reemplazo de Rodilla , Hemofilia A , Ácido Tranexámico , Humanos , Ácido Tranexámico/uso terapéutico , Artroplastia de Reemplazo de Rodilla/efectos adversos , Artroplastia de Reemplazo de Rodilla/métodos , Estudios Retrospectivos , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Antifibrinolíticos/uso terapéutico , Pérdida de Sangre Quirúrgica/prevención & control , Hemorragia Posoperatoria/etiología , Inyecciones Intraarticulares , Inflamación/complicaciones , Biomarcadores , DolorRESUMEN
Thermally activated delayed fluorescence (TADF) emitters with a high horizontal orientation are highly essential for improving the external quantum efficiency (EQE) of organic light-emitting diodes; however, pivotal molecular design strategies to improve the horizontal orientation of solution processable TADF emitters are still scarce and challenging. Herein, a phenyl bridge is adopted to connect the double TADF units, and a dimerized TADF dendrimer, D4CzBNPh-SF, is successfully constructed. Compared to counterpart with single TADF unit, the proof-of-the-concept molecule not only exhibits an improved horizontal dipole ratio (78%) due to the π-delocalization-induced extended molecular conjugation, but also displays a faster reversed intersystem crossing rate constant (6.08×106 s-1) and a high photoluminescence quantum yield of 95% in neat film. Consequently, the non-doped solution-processed device with D4CzBNPh-SF as the emitter, achieves an ultra-high maximum EQE of 32.6%, which remains at 26.6% under a luminance of 1000 cd/m2. Furthermore, using D4CzBNPh-SF as a sensitizer, the TADF-sensitized fluorescence device exhibits a high maximum EQE of 30.7% at a luminance of 575 cd/m2 and a full width at half maximum of 36 nm.
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Cannabidiol (CBD), the most predominant cannabinoid, may cause addiction and liver damage. In this study, we synthesized a CBD hapten containing the carboxyl group of the spacer arm by derivatizing CBD. A highly specific and sensitive monoclonal antibody (mAb) was prepared with a half-maximal inhibitory concentration of 2.03 ng mL-1 and a limit of detection of 0.32 ng mL-1. MAb was highly specific for CBD. We developed an immunochromatographic assay (ICA) for the detection of CBD in functional beverages with a visible limit of detection of 100 ng mL-1 and a cut-off of 1000 ng mL-1. Compared with HPLC, ICA is more efficient and accurate and can be used for the rapid on-site detection of CBD in samples.
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Cannabidiol , Nanopartículas del Metal , Oro/química , Límite de Detección , Nanopartículas del Metal/química , Bebidas , Anticuerpos MonoclonalesRESUMEN
Protein-protein interactions (PPIs) are essential for various biological processes and diseases. However, most existing computational methods for identifying PPI modulators require either target structure or reference modulators, which restricts their applicability to novel PPI targets. To address this challenge, we propose MultiPPIMI, a sequence-based deep learning framework that predicts the interaction between any given PPI target and modulator. MultiPPIMI integrates multimodal representations of PPI targets and modulators and uses a bilinear attention network to capture intermolecular interactions. Experimental results on our curated benchmark data set show that MultiPPIMI achieves an average AUROC of 0.837 in three cold-start scenarios and an AUROC of 0.994 in the random-split scenario. Furthermore, the case study shows that MultiPPIMI can assist molecular docking simulations in screening inhibitors of Keap1/Nrf2 PPI interactions. We believe that the proposed method provides a promising way to screen PPI-targeted modulators.
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Aprendizaje Profundo , Mapeo de Interacción de Proteínas , Mapeo de Interacción de Proteínas/métodos , Simulación del Acoplamiento Molecular , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2RESUMEN
Previous functional magnetic resonance imaging (fMRI) studies have showed obesity (OB)-related alterations in intrinsic functional connectivity (FC) within and between different resting-state networks (RSNs). However, few studies have examined dynamic functional connectivity (DFC). Thus, we employed resting-state fMRI with independent component analysis (ICA) and DFC analysis to investigate the alterations in FC within and between RSNs in 56 individuals with OB and 46 normal-weight (NW) controls. ICA identified six RSNs, including basal ganglia (BG), salience network (SN), right executive control network/left executive control network, and anterior default-mode network (aDMN)/posterior default-mode network. The DFC analysis identified four FC states. OB compared with NW had more occurrences and a longer mean dwell time (MDT) in state 2 (positive connectivity of BG with other RSN) and also had higher FC of BG-SN in other states. Body mass index was positively correlated with MDT and FCs of BG-aDMN (state 2) and BG-SN (state 4). DFC analysis within more refined nodes of RSNs showed that OB had more occurrences and a longer MDT in state 1 in which caudate had positive connections with the other network nodes. The findings suggest an association between caudate-related and BG-related positive FC in OB, which was not revealed by traditional FC analysis, highlighting the utility of adding DFC to the more conventional methods.
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Mapeo Encefálico , Encéfalo , Ganglios Basales/diagnóstico por imagen , Mapeo Encefálico/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Vías Nerviosas/diagnóstico por imagen , Obesidad/diagnóstico por imagenRESUMEN
OBJECTIVE: Brain imaging studies have shown insula-related functional and structural abnormalities in patients with obesity. Laparoscopic sleeve gastrectomy is currently an effective procedure for treating obesity, which promotes acute recovery of brain functional and structural abnormalities in obese patients. The aim of this study was to investigate the long-term impact of laparoscopic sleeve gastrectomy on insula-related structural and functional connectivity. METHODS: Diffusion tensor imaging and resting-state functional magnetic resonance imaging were employed to investigate laparoscopic sleeve gastrectomy-induced changes in insula-related structural connectivity and corresponding resting-state functional connectivity in 25 obese patients prior to (PreLSG) and 12 months post-surgery (PostLSG12). RESULTS: Results showed significant increases in fractional anisotropy and axial diffusivity between the right insula and anterior cingulate cortex, and higher fractional anisotropy of left insula-putamen, left insula-caudate and anterior cingulate cortex-right posterior cingulate cortex/precuneus at PostLSG12 compared with PreLSG. There were significant negative correlations between axial diffusivity of right insula-anterior cingulate cortex and body mass index, and fractional anisotropy of right insula-anterior cingulate cortex with scores on external eating at PostLSG12. Anxiety and depressive status ratings were negatively correlated with fractional anisotropy of left insula-putamen at PostLSG12. In addition, there was a significant decrease in resting-state functional connectivity between left insula and left caudate. CONCLUSIONS: These findings demonstrate long-term changes in insula-related structural and functional connectivity abnormalities promoted by laparoscopic sleeve gastrectomy, which highlight its strong association with long-term weight loss and improvement in eating behaviors.
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Imagen de Difusión Tensora , Laparoscopía , Gastrectomía , Humanos , Imagen por Resonancia Magnética/métodos , Obesidad/diagnóstico por imagen , Obesidad/cirugíaRESUMEN
BACKGROUND: Total knee arthroplasty is the leading way to treat hemophilia arthritis. At present, there is a lack of research on the influencing factors of blood loss in total knee arthroplasty for hemophilia arthritis. This study comprehensively explores the definite factors affecting the hidden blood loss in total knee arthroplasty for hemophilia patients. MATERIALS AND METHODS: Ninety-two hemophilia A patients who underwent total knee arthroplasty in our center were included. Demographics, laboratory data, surgical data, and complications were collected. The Gross equation and Sehat equation were used to calculate the estimated value of hidden blood loss. Multivariate linear regression analysis was used to determine the influencing factors of hidden blood loss. RESULT: The hidden blood loss of hemophilia A patients undergoing total knee arthroplasty was 1069.51 ± 341.99 mL, and the age was positively correlated with the hidden blood loss (P < 0.001), while tranexamic acid, FVIII prophylaxis, and incremental invivo recovery were negatively correlated with the hidden blood loss (P < 0.001, P = 0.008, P = 0.017). CONCLUSION: Elderly patients have a greater risk of blood loss, and additional preventive measures can be appropriately added. Intraoperative intra-articular injection of tranexamic acid is recommended to reduce hidden blood loss, FVIII prophylaxis is recommended for every patient. We recommend that all HA patients measure the incremental invivo recovery and develop a personalized infusion regimen of coagulation factor.
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Antifibrinolíticos , Artritis , Artroplastia de Reemplazo de Rodilla , Hemofilia A , Ácido Tranexámico , Anciano , Antifibrinolíticos/efectos adversos , Artritis/etiología , Artritis/cirugía , Artroplastia de Reemplazo de Rodilla/efectos adversos , Pérdida de Sangre Quirúrgica/prevención & control , Transfusión Sanguínea , Hemofilia A/complicaciones , Hemofilia A/tratamiento farmacológico , Humanos , Hemorragia Posoperatoria/prevención & control , Ácido Tranexámico/uso terapéuticoRESUMEN
Coptis chinensis Franch. has been extensively used in traditional Chinese medicine. The chemical structure of oxyepiberberine, as an alkaloid isolated from Coptis chinensis Franch., has been previously studied. However, anti-cancer effects and underlying mechanisms of oxyepiberberine need to be explored. This study aimed to investigate the anti-cancer effects and underlying mechanisms of oxyepiberberine on LS-1034 human colon cancer cells. The anti-proliferative effects of six derivatives of oxyepiberberine on colon cancer cells were assessed. Among six derivatives, oxyepiberberine showed the greatest anti-proliferative effect on LS-1034 cells with an IC50 value of 1.36 µM. Oxyepiberberine also induced apoptosis and inhibited migration of LS-1034 cells in a concentration-dependent manner. Importantly, oxyepiberberine was identified as a potent tubulin polymerization inhibitor. The tubulin polymerization inhibitory effects of oxyepiberberine in a concentration-dependent manner with an IC50 value of 1.26 µM were observed. A xenograft mouse model of colon cancer showed that oxyepiberberine could suppress tumor growth without an obvious toxicity. Conclusion Oxyepiberberine was found as a novel tubulin polymerization inhibitor, and it could be a promising agent to treat colon cancer.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Alcaloides de Berberina/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/patología , Moduladores de Tubulina/farmacología , Animales , Línea Celular Tumoral , Coptis chinensis , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The functional role of procyanidins (PC) in PM2.5-induced cardiovascular diseases (CVD) is largely unexplored. This study aimed to explore the protective effect of PC against PM2.5-induced vascular smooth muscle cells (VSMCs) apoptosis and underlying mechanisms. Sprague Dawley rats were pretreated with three doses of PC (50, 100, and 200 mg/kg) and exposed to 10 mg/kg PM2.5 by intratracheal instillation three times a week. VSMCs were exposed to 5, 10, and 20 µM PC before the addition of 100 µg/mL PM2.5. In vivo, the PM2.5 exposure induced apoptosis in the thoracic aorta of rats. The PM2.5 exposure significantly elevated the reactive oxygen species (ROS) and malondialdehyde (MDA) levels and decreased the superoxide dismutase activity. Also, PC supplementation increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), and its downstream antioxidant genes, i.e., NAD(P)H dehydrogenase (quinine) 1 and heme oxygenase 1, attenuated oxidative stress and vascular apoptosis. In vitro, PM2.5 induced cytotoxicity in VSMCs in a dose-dependent manner. Besides, PC abolished the PM2.5-induced cytotoxicity by activating the Nrf2 signal pathway, alleviating oxidative stress, and decreasing apoptosis. In conclusion, this work is the first study to demonstrate that PC can suppress the PM2.5-induced VSMCs apoptosis via the activation of the Nrf2 signal pathway.
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Factor 2 Relacionado con NF-E2 , Proantocianidinas , Animales , Apoptosis , Músculo Liso Vascular/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Material Particulado/metabolismo , Material Particulado/toxicidad , Proantocianidinas/farmacología , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
Human dipeptidyl-peptidase III (hDPP III) is capable of specifically cleaving dipeptides from the N-terminal of small peptides with biological activity such as angiotensin II (Ang II, DRVYIHPF), and participates in blood pressure regulation, pain modulation, and the development of cancers in human biological activities. In this study, 500 ns molecular dynamics simulations were performed on free-hDPP III (PDB code: 5E33), hDPP III-Ang II (PDB code: 5E2Q), and hDPP III-IVYPW (PDB code: 5E3C) to explore how these two peptides affect the catalytic efficiency of enzymes in terms of the binding mode and the conformational changes. Our results indicate that in the case of the hDPP III-Ang II complex, subsite S1 became small and hydrophobic, which might be propitious for the nucleophile to attack the substrate. The structures of the most stable conformations of the three systems revealed that Arg421-Lys423 could form an α-helix with the presence of Ang II, but only part of the α-helix was produced in hDPP III-IVYPW. As the hinge structure in hDPP III, the conformational changes that took place in the Arg421-Lys423 residue could lead to the changes in the shape and space of the catalytic subsites, which might allow water to function as a nucleophile to attack the substrate. Our results may provide new clues to enable the design of new inhibitors for hDPP III in the future.
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Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Sitios de Unión , Catálisis , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Unión Proteica , Conformación Proteica , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A tert-butyl hydroperoxide (TBHP)-mediated coupling of sulfonylhydrazides with thiols catalyzed by CuBr2 to afford thiosulfonates via a radical process is described.
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Cathepsin S, a papain-like cysteine peptidase, is an important regulator and signaling molecule with diverse biological actions in addition to immune presentation. However, our understanding of its structure and properties remains limited. Herein, a full-length cathepsin Sa from yellow catfish was cloned and named PfCTSSa. It contained 1366 bp, including a 981 bp ORF flanked by a 123 bp 5'-untranslated region (UTR) and a 262 bp 3'-UTR. This ORF encoded a 36.5 kD cysteine protease with the deduced amino acid sequence having a 76% sequence identity with Ictalurus punctatus ctssa. Additionally, PfCTSSa was found to be a paralog of cathepsin S since it generated a new cluster with cathepsin Sa in the phylogenic tree. Furthermore, PfCTSSa was found to contain more N-glycosylation sites than cathepsin S. The recombinant PfCTSSa was overexpressed in E. coli BL21 (DE3) and appeared to have the strongest activity at pH 8.5 and 35 °C in a concentration-dependent manner, with activity further affected by metal ions and detergents. Moreover, PfCTSSa mRNA was highly expressed in classic and mucosal immune tissues, although constitutively distributed in all of the examined tissues. Yellow catfish were then challenged with inactivated Aeromonas hydrophila and PfCTSSa was remarkably increased in the head kidney, liver and spleen when compared to the PBS control. Collectively, these results indicate that PfCTSSa is a paralog of cathepsin S and functions in the yellow catfish immune response.
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Aeromonas hydrophila/fisiología , Bagres/genética , Bagres/inmunología , Catepsinas/genética , Proteínas de Peces/genética , Inmunidad Innata , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Bagres/metabolismo , Catepsinas/química , Catepsinas/metabolismo , Clonación Molecular , ADN Complementario/genética , ADN Complementario/metabolismo , Escherichia coli/genética , Proteínas de Peces/química , Proteínas de Peces/metabolismo , Especificidad de Órganos , Filogenia , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alineación de Secuencia/veterinariaRESUMEN
BACKGROUND: Social anxiety, which is widely prevalent among Chinese college students, poses a significant barrier to their holistic psychological and physiological development. Although numerous cross-sectional studies have examined the relationship between rumination and social anxiety, there is still a gap in understanding their interplay over time. This longitudinal study aimed to explore and analyze the intricate interrelations between these two factors, with the ultimate goal of informing the development of effective mental health education interventions for university students. METHODS: Using the Ruminative Responses Scale (RRS) and the Interaction Anxiousness Scale (IAS), a two-stage longitudinal follow-up study of 392 college students from three universities in Henan Province was conducted over a six-month period (October 2022 to March 2023) using a cross-lagged model to explore the correlation between rumination and social anxiety. The results of the correlation analysis showed that rumination was positively associated with social anxiety at both time points (r = 0.18,0.12, p < 0.01). RESULTS: Cross-lagged regression analyses revealed that the predictive effect of the first measure (T1) rumination on the second measure (T2) rumination was statistically significant (ß = 0.32, p < 0.001). The predictive effect of T1 social anxiety on T2 social anxiety was statistically significant (ß = 0.65, p < 0.001), the predictive effect of T1 rumination on T2 social anxiety was statistically significant (ß = 0.33, p < 0.001), and the prediction of T1 social anxiety on T2 rumination was statistically significant (ß = 0.28, p < 0.001). CONCLUSION: College students' rumination and social anxiety are mutually predictive of each other, and interventions by educators in either of these areas have the potential to interrupt the vicious cycle between ruminant thinking and social anxiety.
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Depresión , Estudiantes , Humanos , Depresión/psicología , Estudios Longitudinales , Estudios Transversales , Estudios de Seguimiento , Estudiantes/psicología , Ansiedad/psicologíaRESUMEN
Gastric cancer (GC), notorious for its poor prognosis, often advances to peritoneal dissemination, a crucial determinant of detrimental outcomes. This study intricately explores the role of the TGFß-Smad-LIF axis within the tumor microenvironment in propagating peritoneal metastasis, with a specific emphasis on its molecular mechanism in instigating Neutrophil Extracellular Traps (NETs) formation and encouraging GC cellular functions. Through a blend of bioinformatics analyses, utilizing TCGA and GEO databases, and meticulous in vivo and in vitro experiments, LIF was identified as pivotally associated with GC metastasis, notably, enhancing the NETs formation through neutrophil stimulation. Mechanistically, TGF-ß was substantiated to elevate LIF expression via the activation of the Smad2/3 complex, culminating in NETs formation and consequently, propelling peritoneal metastasis of GC. This revelation uncovers a novel potential therapeutic target, promising a new avenue in managing GC and mitigating its metastatic propensities.
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Trampas Extracelulares , Neoplasias Peritoneales , Neoplasias Gástricas , Factor de Crecimiento Transformador beta , Humanos , Trampas Extracelulares/metabolismo , Neutrófilos/metabolismo , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/patología , Neoplasias Gástricas/patología , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral , Factor Inhibidor de Leucemia/metabolismo , Transducción de SeñalRESUMEN
Congenital radial head subluxation is relatively rare and may be overlooked due to mild symptoms. The diagnosis mainly relies on imaging and history. Observation is an option for those with insignificant symptoms, while surgical intervention, such as ulnar osteotomy or arthroscopy, is often required when dysfunction exists. A 30-year-old man was admitted with congenital radial head dislocation, which was treated with manipulative repositioning. During follow-up, the patient regained the original mobility of the elbow joint and had no recurrence of dislocation. In conclusion, in adults with congenital dislocation of the radial head, we recommend conservative treatment as a first step.
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Tratamiento Conservador , Articulación del Codo , Luxaciones Articulares , Radio (Anatomía) , Humanos , Masculino , Adulto , Articulación del Codo/cirugía , Articulación del Codo/diagnóstico por imagen , Luxaciones Articulares/congénito , Luxaciones Articulares/terapia , Luxaciones Articulares/cirugía , Luxaciones Articulares/diagnóstico por imagen , Tratamiento Conservador/métodos , Radio (Anatomía)/anomalías , Radio (Anatomía)/diagnóstico por imagen , Radio (Anatomía)/cirugía , Rango del Movimiento Articular , Resultado del Tratamiento , Manipulación Ortopédica/métodosRESUMEN
Electrochemical carbon dioxide reduction reaction (eCO2RR) to generate syngas is an appealing strategy for CO2 net reduction. However, it suffers from the inferior faradaic efficiency (FE), selectivity, and difficult modulation of hydrogen/carbon monoxide (H2/CO) ratio. To address these issues, a series of magnesium-nickel (Mg-Ni) dual atomic catalysts with different Ni contents are fabricated on the nitrogen-doped carbon matrix (MgNiX-NC DACs) by one-step pyrolysis. MgNi5-NC electrocatalyst generates 0.51-0.79 H2/CO ratios in a potential range of -0.6 to -1.0 V vs. reversible hydrogen electrode (RHE) and the total FE reaches 100 % with good stability. While a wider range of H2/CO (0.95-4.34) is achieved for MgNi3-NC electrocatalyst in the same overpotential range, which is suitable for typical downstream thermochemical reactions. Introduction of Ni species accelerates the generation of CO, however, there is much less influence on the H2 production as compared with Mg-based single atomic electrocatalyst. According to the experimental results and density functional theory (DFT) calculations, the synergistic effect between Mg and Ni achieves the satisfied results rather than each one fulfill its own duty for selective producing H2 and CO, respectively. This work introduces a feasible approach to develop atomic catalysts on main group metal for more controllable CO2RR.
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The accessory protein ORF6 of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key interferon (IFN) antagonist that strongly suppresses the production of primary IFN as well as the expression of IFN-stimulated genes. However, how host cells respond to ORF6 remains largely unknown. Our research of ORF6-binding proteins by pulldown revealed that E3 ligase components such as Cullin 4B (CUL4B), DDB1, and RBX1 are potential ORF6-interacting proteins. Further study found that the substrate recognition receptor PRPF19 interacts with CUL4B, DDB1, and RBX1 to form a CRL4B-based E3 ligase, which catalyzes ORF6 ubiquitination and subsequent degradation. Overexpression of PRPF19 promotes ORF6 degradation, releasing ORF6-mediated IFN inhibition, which inhibits SARS-CoV-2 replication. Moreover, we found that activation of CUL4B by the neddylation inducer etoposide alleviates lung lesions in a SARS-CoV-2 mouse infection model. Therefore, targeting ORF6 for degradation may be an effective therapeutic strategy against SARS-CoV-2 infection.IMPORTANCEThe cellular biological function of the ubiquitin-proteasome pathway as an important modulator for the regulation of many fundamental cellular processes has been greatly appreciated. The critical role of the ubiquitin-proteasome pathway in viral pathogenesis has become increasingly apparent. It is a powerful tool that host cells use to defend against viral infection. Some cellular proteins can function as restriction factors to limit viral infection by ubiquitin-dependent degradation. In this research, we identificated of CUL4B-DDB1-PRPF19 E3 Ubiquitin Ligase Complex can mediate proteasomal degradation of ORF6, leading to inhibition of viral replication. Moreover, the CUL4B activator etoposide alleviates disease development in a mouse infection model, suggesting that this agent or its derivatives may be used to treat infections caused by SARS-CoV-2. We believe that these results will be extremely useful for the scientific and clinic communities in their search for cues and preventive measures to combat the COVID-19 pandemic.
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COVID-19 , Ubiquitina-Proteína Ligasas , Animales , Humanos , Ratones , Proteínas Portadoras/metabolismo , Proteínas Cullin/genética , Enzimas Reparadoras del ADN/metabolismo , Etopósido , Proteínas Nucleares/metabolismo , Pandemias , Complejo de la Endopetidasa Proteasomal/metabolismo , Factores de Empalme de ARN/genética , SARS-CoV-2/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
P38/Mk2 (mitogen-activated protein kinase (MAPK)-activated protein kinase-2, also known as MAKAP kinase-2) is a member of the mitogen-activated protein kinases (MAPKs) family, and participates in inflammatory responses directly or indirectly. WIN55, 212-2 (WIN55) is a synthetic non-selective agonist of cannabinoid (CB) receptors with remarkable anti-inflammatory properties. This study was to explore the roles of WIN55 and p38/Mk2 signaling pathway in dextran sodium sulfate (DSS)-induced mouse colitis and ascertain their anti-inflammatory mechanisms. Colitis was induced in C57BL Mk2 gene homozygous deletion (Mk2-/-) and wild-type mice by replacing the drinking water with 4% DSS solution for 7 days. DSS-treated mice developed bloody stool, weight loss, and eye-visible multiple bleeding ulcers on colon mucosa. The mRNA expressions levels of TNF-α and IL-6, as well as the protein levels of p38 and its phosphorylated form (p-p38), were upregulated in the colon. The plasma levels of TNF-α, IL-6, cytokine-induced neutrophil chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), and lung myeloperoxidase (MPO) activities were raised; however, all these changes were less severe in Mk2-/- mice. After WIN55 intervention, the Mk2-/- mice recovered faster and better from the induced colitis than their wild-type counterparts. The results indicate that the Mk2 homozygous deletion in mice impedes the induction of experimental colitis by DSS, confirming the notion that p38/Mk2 is involved in this inflammatory response. WIN55 protects mice against DSS-induced colitis, in particular when the p38/Mk2 pathway is obstructed, implying that the activation of CB system, together with blocking of p38/Mk2 pathway, serves as a potential drug target for colitis treatment.
Asunto(s)
Antiinflamatorios/farmacología , Benzoxazinas/farmacología , Colitis/tratamiento farmacológico , Péptidos y Proteínas de Señalización Intracelular/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Morfolinas/farmacología , Naftalenos/farmacología , Proteínas Serina-Treonina Quinasas/genética , Análisis de Varianza , Animales , Quimiocina CCL2/sangre , Quimiocina CXCL1/sangre , Colitis/inducido químicamente , Colitis/patología , Cartilla de ADN/genética , Sulfato de Dextran/toxicidad , Ensayo de Inmunoadsorción Enzimática , Inmunohistoquímica , Interleucina-6/sangre , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Peroxidasa/metabolismo , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND: Phubbing is a commonly seen phenomenon that has emerged in recent years among groups of college students, posing a rising challenge to educators. We conduct research in which the reciprocal relationship between problematic social media use and phubbing is explored and analysed quantitatively, aiming to discover reliable theoretical support to work out an appropriate intervention on students' phubbing for students' mental health concerns. METHODS: Using the problematic social media use scale and the phubbing scale, 328 college students from four universities in Shandong Province were enrolled in a two-stage longitudinal follow-up study for 20 months from December 2019 to August 2021. A cross-lagged model was constructed to explore the reciprocal relationship between problematic social media use and phubbing. The results of correlation analysis showed that problematic social media use was positively correlated with phubbing at both time points (r = 0.51, 0.53, P < 0.01). RESULTS: The results of cross-lagged regression analysis showed that the predictive effect of pretest problematic social media use on posttest problematic social media use was statistically significant (ß = 0.24, P < 0.01). There was statistical significance in the prediction effect of pretest phubbing on posttest phubbing (ß = 0.16, P < 0.05). Pretest problematic social media use had statistical significance in predicting posttest phubbing (ß = 0.22, P < 0.01), and there was no statistical significance in the prediction of pretest phubbing on posttest problematic social media (ß = 0.16, P < 0.05). CONCLUSION: The problematic social media use of college students is closely related to phubbing, and problematic social media use can predict phubbing.