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Silk sutures are common in surgeries, and silk-based textiles are widely used in clinical medicine on account of their great mechanical properties and biodegradability. However, due to the lack of biocatalytic activity, silk sutures show unsatisfactory anti-inflammatory properties and healing speed. To address this constraint, we construct clinical grade bioactive gold cluster-sutures through a heterojunction. The antioxidant activity of bioactive gold cluster-sutures is â¼160 times more than that of clinical sutures. Meanwhile, the suture displays superb reactive oxygen species (ROS) scavenging, superoxide dismutase-like (SOD-like, 5 times more than the silk suture), and catalase-like (CAT-like) activities. The clusters assemble on the surface of silk through hydrogen bonding, leading to a durable catalytic and structural stability for 15 months without decay. Subsequently, the suture significantly accelerates wound healing by exerting excellent anti-inflammatory effects, improving neovascularization and collagen deposition. Clinical grade bioactive gold clusters with high bioactivity, stability, and biocompatibility hold promise for clinical translation and pave the way for other implanted biomaterials from wound healing to intelligent textiles.
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Designing biomimetic materials with high activity and customized biological functions by mimicking the central structure of biomolecules has become an important avenue for the development of medical materials. As an essential electron carrier, the iron-sulfur (Fe-S) clusters have the advantages of simple structure and high electron transport capacity. To rationally design and accurately construct functional materials, it is crucial to clarify the electronic structure and conformational relationships of Fe-S clusters. However, due to the complex catalytic mechanism and synthetic process in vitro, it is hard to reveal the structure-activity relationship of Fe-S clusters accurately. This review introduces the main structural types of Fe-S clusters and their catalytic mechanisms first. Then, several typical structural design strategies of biomimetic Fe-S clusters are systematically introduced. Furthermore, the development of Fe-S clusters in the biocatalytic field is enumerated, including tumor treatment, antibacterial, virus inhibition and plant photoprotection. Finally, the problems and development directions of Fe-S clusters are summarized. This review aims to guide people to accurately understand and regulate the electronic structure of Fe-S at the atomic level, which is of great significance for designing biomimetic materials with specific functions and expanding their applications in biocatalysis.
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AIM: We aimed to explore the impact of DNA methylation alterations on the DNA damage response (DDR) in melanoma prognosis and immunity. MATERIAL & METHODS: Different melanoma cohorts with molecular and clinical data were included. RESULTS: Hierarchical clustering utilizing different combinations of DDR-relevant CpGs yielded distinct melanoma subtypes, which were characteristic of different prognoses, transcriptional function profiles of DDR, and immunity and immunotherapy responses but were associated with similar tumor mutation burdens. We then constructed and validated a clinically applicable 4-CpG risk-score signature for predicting survival and immunotherapy response. CONCLUSION: Our study describes the close interrelationship among DNA methylation, DDR machinery, local tumor immune status, melanoma prognosis, and immunotherapy response.
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Dano ao DNA , Metilação de DNA , Melanoma , Melanoma/genética , Melanoma/imunologia , Melanoma/mortalidade , Humanos , Prognóstico , Imunoterapia/métodos , Ilhas de CpG , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Regulação Neoplásica da Expressão Gênica/imunologia , MutaçãoRESUMO
The description and analysis of chemical bonds have been difficult following the popularization of electronic structure calculations. Although many attempts have been made from the perspective of electronic structure, the sheer volume of information in the electronic structure has left contemporary chemical bond analysis methods grappling with an inescapable "Trilemma" where the model briefness, generality, and descriptiveness (descriptive power) cannot be obtained simultaneously. To push the generality and descriptiveness to their extremes, herein a general machine learning-based framework is introduced to compact chemical bonds into a detailed residue-by-residue "genome" with matched encoding/decoding tools. The framework fuses the quantum mechanical aspects, auto feature extraction, nanostructures and/or simulations, and generative models. The encoded genomes are information-dense and decodable, where 100% generality is guaranteed. The descriptiveness of genomes appears to be broader than most known models. As a proof of concept, the realization presented in this work compacts the complete information regarding two critical chemical bonds in thiolate-protected gold nanoclusters, the S-Au and Au-Au bonds, from a Bosonic-Fermionic character perspective into 8-valued genomes. The machine learning component is trained based on 26,528 density functional theory simulated electron localization function images. With an exploration of the space span for the genome, bond polarization, hybridization, intrusion of other atoms, alignments, crystal orientation, atomic motions, and more details are observed. Furthermore, it has emerged from extensive generation tests that molecules and solids can be integrated in such a concise manner than is typically achieved with purely geometric representations. To showcase the intraclass complexity of S-Au and Au-Au bonds visually, a roadmap is plotted by summarizing and correlating the similarities of 8-value-genomes. Furthermore, genomes can be associated with realistic indices easily with a simple multilayer perception architecture as a simple calculating tool. Besides, there are 3 sets of applications, including a set of chemisorption, a set of molecular dynamical analysis, and a set of ultrafast processes, showcasing the interpretability potentials of interatomic genomes in the geometric structures, kinetic properties, and vibration characteristics of molecular systems. As the framework rose to the challenge of nanoclusters from a complicated mesoscopic family of material, the displayed generality and comprehensiveness indicate that the model may "understand" chemical bonds in a machine's way.
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Small-conductance Ca2+-activated K+ channels (SK, KCa2) are gated solely by intracellular microdomain Ca2+. The channel has emerged as a therapeutic target for cardiac arrhythmias. Calmodulin (CaM) interacts with the CaM binding domain (CaMBD) of the SK channels, serving as the obligatory Ca2+ sensor to gate the channels. In heterologous expression systems, phosphatidylinositol 4,5-bisphosphate (PIP2) coordinates with CaM in regulating SK channels. However, the roles and mechanisms of PIP2 in regulating SK channels in cardiomyocytes remain unknown. Here, optogenetics, magnetic nanoparticles, combined with Rosetta structural modeling, and molecular dynamics (MD) simulations revealed the atomistic mechanisms of how PIP2 works in concert with Ca2+-CaM in the SK channel activation. Our computational study affords evidence for the critical role of the amino acid residue R395 in the S6 transmembrane segment, which is localized in propinquity to the intracellular hydrophobic gate. This residue forms a salt bridge with residue E398 in the S6 transmembrane segment from the adjacent subunit. Both R395 and E398 are conserved in all known isoforms of SK channels. Our findings suggest that the binding of PIP2 to R395 residue disrupts the R395:E398 salt bridge, increasing the flexibility of the transmembrane segment S6 and the activation of the channel. Importantly, our findings serve as a platform for testing of structural-based drug designs for therapeutic inhibitors and activators of the SK channel family. The study is timely since inhibitors of SK channels are currently in clinical trials to treat atrial arrhythmias.
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Calmodulina , Simulação de Dinâmica Molecular , Fosfatidilinositol 4,5-Difosfato , Canais de Potássio Ativados por Cálcio de Condutância Baixa , Fosfatidilinositol 4,5-Difosfato/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Baixa/química , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Animais , Calmodulina/metabolismo , Calmodulina/química , Humanos , Ativação do Canal Iônico , Cálcio/metabolismo , Ligação Proteica , Miócitos Cardíacos/metabolismoRESUMO
Strain engineering plays an important role in tuning electronic structure and improving catalytic capability of biocatalyst, but it is still challenging to modify the atomic-scale strain for specific enzyme-like reactions. Here, we systematically design Pt single atom (Pt1), several Pt atoms (Ptn) and atomically-resolved Pt clusters (Ptc) on PdAu biocatalysts to investigate the correlation between atomic strain and enzyme-like catalytic activity by experimental technology and in-depth Density Functional Theory calculations. It is found that Ptc on PdAu (Ptc-PA) with reasonable atomic strain upshifts the d-band center and exposes high potential surface, indicating the sufficient active sites to achieve superior biocatalytic performances. Besides, the Pd shell and Au core serve as storage layers providing abundant energetic charge carriers. The Ptc-PA exhibits a prominent peroxidase (POD)-like activity with the catalytic efficiency (Kcat/Km) of 1.50 × 109 mM-1 min-1, about four orders of magnitude higher than natural horseradish peroxidase (HRP), while catalase (CAT)-like and superoxide dismutase (SOD)-like activities of Ptc-PA are also comparable to those of natural enzymes. Biological experiments demonstrate that the detection limit of the Ptc-PA-based catalytic detection system exceeds that of visual inspection by 132-fold in clinical cancer diagnosis. Besides, Ptc-PA can reduce multi-organ acute inflammatory damage and mitigate oxidative stress disorder.
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Biocatálise , Catalase , Ouro , Platina , Platina/química , Ouro/química , Humanos , Catalase/química , Catalase/metabolismo , Paládio/química , Peroxidase do Rábano Silvestre/química , Peroxidase do Rábano Silvestre/metabolismo , Superóxido Dismutase/química , Superóxido Dismutase/metabolismo , Catálise , Teoria da Densidade Funcional , Nanopartículas Metálicas/químicaRESUMO
Currently, pulmonary complications such as lung infections during the perioperative period are still the main cause of prolonged hospitalization and death in patients with lung injury due to the lack of effective drugs. Clusterzyme, a kind of artificial enzyme with a high enzyme-like activity and safety profile, exhibits good effects on reducing oxidative stress and immunomodulation. Here, we present the functionalized patches that is administered on the lung airways and rescues the injured organ via clusterzymes. The long-term antioxidant capacity of the patches significantly ameliorated lipopolysaccharide-induced lung function impairment with a significant reduction in lung goblet cell metaplasia and oxidative stress. The inflammatory factors such as cytokines interleukin-1ß, interleukin-6, and tumor necrosis factor-α levels decreased by 50%, while the mtDNA copy number increased by 50% and ATP production increased by 100%. Mice lung function was significantly improved, suggesting that the patches can rescue lung injury by modulating oxidative stress and immune responses as well as protecting the mitochondria, providing an avenue for effective intervention of lung injury.
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Pneumonia involves complex immunological and pathological processes leading to pulmonary dysfunction, which can be life-threatening yet lacks effective specialized medications. Natural enzymes can be used as biological agents for the treatment of oxidative stress-related diseases, but limiting to catalytic and environmental stability as well as high cost. Herein, an artificial enzyme, gold nanoclusters (Au NCs) with excellent stability, bioactivity, and renal clearance can be used as the next-generation biological agents for acute lung injury (ALI) and allergic lung disease (ALD). The Au25 clusters can mimic catalase (CAT) and glutathione peroxidase (GPx), and the Km of Au24Er1 with H2O2 reaches 1.28 mM, about 22 times higher than natural CAT (≈28.8 mM). The clusters inhibit the oxidative stress in the mitochondria and promote the synthesis of adenosine triphosphate (ATP). The molecular mechanism shows that the TLR4/MyD88/NF-κB pathway and M1 macrophage-mediated inflammatory response are suppressed in ALI and the Th1/Th2 imbalance in ovalbumin (OVA)-induced ALD is rescued. Further, the clusters can notably improve lung function in both ALI and ALD models which paves the way for immunomodulation and intervention for lung injury and can be used as a substitute for natural enzymes and potential biopharmaceuticals in the treatment of various types of pneumonia.
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BACKGROUND: AGTPBP1 is a cytosolic carboxypeptidase that cleaves poly-glutamic acids from the C terminus or side chains of α/ß tubulins. Although its dysregulated expression has been linked to the development of non-small cell lung cancer, the specific roles and mechanisms of AGTPBP1 in pancreatic cancer (PC) have yet to be fully understood. In this study, we examined the role of AGTPBP1 on PC in vitro and in vivo. METHODS: Immunohistochemistry was used to examine the expression of AGTPBP1 in PC and non-cancerous tissues. Additionally, we assessed the malignant behaviors of PC cells following siRNA-mediated AGTPBP1 knockdown both in vitro and in vivo. RNA sequencing and bioinformatics analysis were performed to identify the differentially expressed genes regulated by AGTPBP1. RESULTS: We determined that AGTPBP1 was overexpressed in PC tissues and the higher expression of AGTPBP1 was closely related to the location of tumors. AGTPBP1 inhibition can significantly decrease cell progression in vivo and in vitro. Moreover, the knockdown of AGTPBP1 inhibited the expression of ERK1/2, P-ERK1/2, MYLK, and TUBB4B proteins via the ERK signaling pathway. CONCLUSION: Our research indicates that AGTPBP1 may be a putative therapeutic target for PC.
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Carboxipeptidases , Regulação Neoplásica da Expressão Gênica , Sistema de Sinalização das MAP Quinases , Microtúbulos , Neoplasias Pancreáticas , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Carboxipeptidases/metabolismo , Carboxipeptidases/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Progressão da Doença , Microtúbulos/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , D-Ala-D-Ala Carboxipeptidase Tipo Serina/genética , D-Ala-D-Ala Carboxipeptidase Tipo Serina/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismoRESUMO
AIMS: Pulsed-field ablation (PFA) is a novel, myocardial-selective, non-thermal ablation modality used to target cardiac arrhythmias. Although prompt electrogram (EGM) signal disappearance is observed immediately after PFA application in the pulmonary veins, whether this finding results in adequate transmural lesions is unknown. The aim of this study is to check whether application repetition and catheter-tissue contact impact lesion formation during PFA. METHODS AND RESULTS: A circular loop PFA catheter was used to deliver repeated energy applications with various levels of contact force. A benchtop vegetal potato model and a beating heart ventricular myocardial model were utilized to evaluate the impact of application repetition, contact force, and catheter repositioning on contiguity and lesion depth. Lesion development occurred over 18â h in the vegetal model and over 6â h in the porcine model. Lesion formation was found to be dependent on application repetition and contact. In porcine ventricles, single and multiple stacked applications led to a lesion depth of 3.5 ± 0.7 and 4.4 ± 1.3â mm, respectively (P = 0.002). Furthermore, the greater the catheter-tissue contact, the more contiguous and deeper the lesions in the vegetal model (1.0 ± 0.9â mm with no contact vs. 5.4 ± 1.4â mm with 30â g of force; P = 0.0001). CONCLUSION: Pulsed-field ablation delivered via a circular catheter showed that both repetition and catheter contact led independently to deeper lesion formation. These findings indicate that endpoints for effective PFA are related more to PFA biophysics than to mere EGM attenuation.
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Cateteres Cardíacos , Ablação por Cateter , Desenho de Equipamento , Ablação por Cateter/métodos , Ablação por Cateter/instrumentação , Animais , Suínos , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/cirurgia , Modelos Animais , Sus scrofa , Fatores de TempoRESUMO
Breast cancer (BC) is the most common tumor worldwide and requires crucial molecular typing for treatment and prognosis assessment. Currently, approaches like pathological staining, immunohistochemistry (IHC), and immunofluorescence (IF) face limitations due to the low signal-to-background ratio (SBR) and high tumor heterogeneity, resulting in a high misdiagnosis rate. Fluorescent assay in the second near-infrared region (NIR-II, 1000-1700 nm) exhibits ultrahigh SBR owing to diminished scattering and tissue autofluorescence. Here, we present a NIR-II strategy for accurate BC molecular typing and three-dimensional (3D) visualization based on the atomically precise fluorescent Au24Pr1 clusters. Single-atom Pr doping results in 3.9-fold fluorescence enhancement and long-term photostability. The Au24Pr1 clusters possess high fluorescence centered at â¼1100 nm and the SBR on pathological section diagnosis was 4 times higher than that of NIR-I imaging. This enables high spatial resolution 3D visualization of biopsy specimens, which can surmount tissue heterogeneity for clinical diagnosis of BC.
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Neoplasias da Mama , Imageamento Tridimensional , Humanos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Feminino , Imageamento Tridimensional/métodos , Imagem Óptica/métodos , Ouro/química , Corantes Fluorescentes/químicaRESUMO
Introduction: Tuberculosis (TB) stands as a paramount global health concern, contributing significantly to worldwide mortality rates. Effective containment of TB requires deployment of cost-efficient screening method with limited resources. To enhance the precision of resource allocation in the global fight against TB, this research proposed chest X-ray radiography (CXR) based machine learning screening algorithms with optimization, benchmarking and tuning for the best TB subclassification tasks for clinical application. Methods: This investigation delves into the development and evaluation of a robust ensemble deep learning framework, comprising 43 distinct models, tailored for the identification of active TB cases and the categorization of their clinical subtypes. The proposed framework is essentially an ensemble model with multiple feature extractors and one of three fusion strategies-voting, attention-based, or concatenation methods-in the fusion stage before a final classification. The comprised de-identified dataset contains records of 915 active TB patients alongside 1,276 healthy controls with subtype-specific information. Thus, the realizations of our framework are capable for diagnosis with subclass identification. The subclass tags include: secondary tuberculosis/tuberculous pleurisy; non-cavity/cavity; secondary tuberculosis only/secondary tuberculosis and tuberculous pleurisy; tuberculous pleurisy only/secondary tuberculosis and tuberculous pleurisy. Results: Based on the dataset and model selection and tuning, ensemble models show their capability with self-correction capability of subclass identification with rendering robust clinical predictions. The best double-CNN-extractor model with concatenation/attention fusion strategies may potentially be the successful model for subclass tasks in real application. With visualization techniques, in-depth analysis of the ensemble model's performance across different fusion strategies are verified. Discussion: The findings underscore the potential of such ensemble approaches in augmenting TB diagnostics with subclassification. Even with limited dataset, the self-correction within the ensemble models still guarantees the accuracies to some level for potential clinical decision-making processes in TB management. Ultimately, this study shows a direction for better TB screening in the future TB response strategy.
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Artificial enzymes, especially nanozymes, have attracted wide attention due to their controlled catalytic activity, selectivity, and stability. The rising Cerium-based nanozymes exhibit unique SOD-like activity, and Vanadium-based nanozymes always hold excellent GPx-like activity. However, most inflammatory diseases involve polymerase biocatalytic processes that require multi-enzyme activities. The nanocomposite can fulfill multi-enzymatic activity simultaneously, but large nanoparticles (>10 nm) cannot be excreted rapidly, leading to biosafety challenges. Herein, atomically precise Ce12V6 clusters with a size of 2.19 nm are constructed. The Ce12V6 clusters show excellent glutathione peroxidase (GPx) -like activity with a significantly lower Michaelis-Menten constant (Km, 0.0125 mM versus 0.03 mM of natural counterpart) and good activities mimic superoxide dismutase (SOD) and peroxidase (POD). The Ce12V6 clusters exhibit the ability to scavenge the ROS including O2 ·- and H2O2 via the cascade reactions of multi-enzymatic activities. Further, the Ce12V6 clusters modulate the proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) and consequently rescue the multi-organ failure in the lipopolysaccharide (LPS)-induced sepsis mouse model. With excellent biocompatibility, the Ce12V6 clusters show promise in the treatment of sepsis.
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Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 in enhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.
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BACKGROUND: The incidence of colorectal cancer (CRC) in China is steadily rising, with a high proportion of advanced-stage diagnoses. This highlights the significance of early detection and prevention measures to enhance survival rates. Fecal immunochemical testing (FIT) is a globally recommended CRC screening method; however, limited research has been conducted on its application in Hainan. AIM: To assess the efficacy and adherence of FIT screening among average-risk individuals in Hainan, while also examining the risk factors associated with positive FIT results. METHODS: This population-based cross-sectional study implemented FIT screening for CRC in 2000 asymptomatic participants aged 40-75 years from five cities and 21 community health centers in Hainan Province. The study was conducted from August 2022 to April 2023, employing a stratified sampling method to select participants. Individuals with positive FIT results subsequently underwent colonoscopy. Positive predictive values for confirmed CRC and advanced adenoma were calculated, and the relationship between relevant variables and positive FIT results was analyzed using χ 2 tests and multivariate logistic regression. RESULTS: A total of 1788 participants completed the FIT screening, with a median age of 57 years (interquartile range: 40-75). Among them, 503 (28.1%) were males, and 1285 (71.9%) were females, resulting in an 89.4% compliance rate for FIT screening. The overall positivity rate of FIT was 4.4% [79 out of 1788; 95% confidence interval (CI): 3%-5%]. The specific positivity rates for Haikou, Sanya, Orient City, Qionghai City, and Wuzhishan City were 9.6% (45 of 468; 95%CI: 8%-11%), 1.3% (6 of 445; 95%CI: 0.1%-3.1%), 2.7% (8 of 293; 95%CI: 1.2%-4.3%), 3.3% (9 of 276; 95%CI: 1.0%-6.3%), and 4.2% (11 of 406; 95%CI: 1.2%-7.3%), respectively. Significant associations were found between age, dietary habits, and positive FIT results. Out of the 79 participants with positive FIT results, 55 underwent colonoscopy, demonstrating an 82.2% compliance rate. Among them, 10 had a clean gastrointestinal tract, 43 had polyps or adenomas, and 2 were confirmed to have CRC, yielding a positive predictive value of 3.6% (95%CI: 0.9%-4.2%). Among the 43 participants with polyps or adenomas, 8 were diagnosed with advanced adenomas, resulting in an advanced adenoma rate of 14.5% (95%CI: 10.1%-17.7%). CONCLUSION: In the Hainan region, FIT screening for CRC among asymptomatic individuals at average risk is feasible and well-received.
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Developing biomimetic catalysts with excellent peroxidase (POD)-like activity has been a long-standing goal for researchers. Doping nonmetallic atoms with different electronegativity to boost the POD-like activity of Fe-N-C single-atom catalysts (SACs) has been successfully realized. However, the introduction of heteroatoms to regulate the coordination environment of the central Fe atom and thus influence the activation of the H2O2 molecule in the POD-like reaction has not been extensively explored. Herein, the effect of different doping sites and numbers of heteroatoms (P, S, B, and N) on the adsorption and activation of H2O2 molecules of Fe-N sites is thoroughly investigated by density functional theory (DFT) calculations. In general, alternation in the catalytic efficiency directly depends on the transfer of electrons and the geometrical shifts near the Fe-N site. First, the symmetry disruption of the Fe-N4 site by P, S, and B doping is beneficial to the activation of H2O2 due to a significant reduction in the adsorption energies. In some cases, without Fe-N4 site disruption, the configurations fail to modulate the adsorption behavior of H2O2. Second, Fe-N-P/S configurations exhibit a stronger affinity for H2O2 molecules due to the significant out-of-plane distortions induced by larger atomic radii of P and S. Moreover, the synergistic effects of Fe and doping atoms P, S, and B with weaker electronegativity than that of N atoms promote electron donation to generated oxygen-containing intermediates, thus facilitating subsequent electron transfer with other substrates. This work demonstrates the critical role of tuning the coordinating environment of Fe-N active centers by heteroatom doping and provides theoretical guidance for controlling the types by breaking the symmetry of SACs to achieve optimal POD-like catalytic activity and selectivity.
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Hepatic ischemia/reperfusion (I/R) injury is an important cause of liver function impairment following liver surgery. The ubiquitin-proteasome system (UPS) plays a crucial role in protein quality control and has substantial impact on the hepatic I/R process. Although OTU deubiquitinase 1 (OTUD1) is involved in diverse biological processes, its specific functional implications in hepatic I/R are not yet fully understood. This study demonstrates that OTUD1 alleviates oxidative stress, apoptosis, and inflammation induced by hepatic I/R injury. Mechanistically, OTUD1 deubiquitinates and activates nuclear factor erythroid 2-related factor 2 (NRF2) through its catalytic site cysteine 320 residue and ETGE motif, thereby attenuating hepatic I/R injury. Additionally, administration of a short peptide containing the ETGE motif significantly mitigates hepatic I/R injury in mice. Overall, our study elucidates the mechanism and role of OTUD1 in ameliorating hepatic I/R injury, providing a theoretical basis for potential treatment using ETGE-peptide.
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Fígado , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Traumatismo por Reperfusão , Animais , Humanos , Masculino , Camundongos , Apoptose , Enzimas Desubiquitinantes/metabolismo , Modelos Animais de Doenças , Fígado/metabolismo , Fígado/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Traumatismo por Reperfusão/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Proteases Específicas de Ubiquitina/genética , UbiquitinaçãoRESUMO
Sepsis, a life-threatening condition caused by a dysregulated immune response to infection, leads to systemic inflammation, immune dysfunction, and multiorgan damage. Various oxidoreductases play a very important role in balancing oxidative stress and modulating the immune response, but they are stored inconveniently, environmentally unstable, and expensive. Herein, we develop multifunctional artificial enzymes, CeO2 and Au/CeO2 nanozymes, exhibiting five distinct enzyme-like activities, namely, superoxide dismutase, catalase, glutathione peroxidase, peroxidase, and oxidase. These artificial enzymes have been used for the biocatalytic treatment of sepsis via inhibiting inflammation and modulating immune responses. These nanozymes significantly reduce reactive oxygen species and proinflammatory cytokines, achieving multiorgan protection. Notably, CeO2 and Au/CeO2 nanozymes with enzyme-mimicking activities can be particularly effective in restoring immunosuppression and maintaining homeostasis. The redox nanozyme offers a promising dual-protective strategy against sepsis-induced inflammation and organ dysfunction, paving the way for biocatalytic-based immunotherapies for sepsis and related inflammatory diseases.
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Cério , Ouro , Inflamação , Sepse , Sepse/tratamento farmacológico , Sepse/imunologia , Animais , Inflamação/tratamento farmacológico , Inflamação/imunologia , Ouro/química , Cério/química , Cério/uso terapêutico , Camundongos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Catalase/metabolismo , Catalase/química , Citocinas/metabolismoRESUMO
OBJECTIVES: To investigate the ultrasound (US) characteristics of metastatic malignancies (MM) in the major salivary glands and to assess the diagnostic value of the close relationship with the glandular capsule in identifying MM. METHODS: From January 2016 and April 2022, 122 patients with major salivary gland malignancies, including 20 patients with MM and 102 patients with primary malignancies (PM) confirmed by histopathological examination, were enrolled in this study. Their clinicopathologic and US data were recorded and analyzed. The diagnostic performance of the close relationship with the glandular capsule for differentiating MM from PM was analyzed. RESULTS: The mean age of MM were older than that of PM (59.50 ± 14.57 vs. 49.96 ± 15.73, p = 0.013). Compared with PM patients, MM were associated with a higher prevalence of local pain symptoms (p = 0.007) and abnormal facial nerve function (p < 0.001). MM were also more frequently characterized by unclear borders, rough margins, irregular shapes, heterogeneous internal echos, absence of cystic areas, presence of calcifications, close relationship with the glandular capsule, and US-reported positive cervical lymph nodes (all p < 0.05). The close relationship with the glandular capsule showed to be a good indicator in distinguishing between MM and PM, with an area under the receiver operating characteristic curve of 0.863, a sensitivity of 100%, a specificity of 72.5%, and an accuracy of 92.2%. Positive and negative predictive were calculated at 41.7% and 100%, respectively. CONCLUSIONS: The US finding of a close relationship with the glandular capsule is a highly sensitive diagnostic indicator for MM. Following this finding, US-guided needle biopsy should be recommended to further confirm the diagnosis.
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Dopamine (DA), ascorbic acid (AA), and uric acid (UA) are crucial neurochemicals, and their abnormal levels are involved in various neurological disorders. While electrodes for their detection have been developed, achieving the sensitivity required for in vivo applications remains a challenge. In this study, we proposed a synthetic Au24Cd nanoenzyme (ACNE) that significantly enhanced the electrochemical performance of metal electrodes. ACNE-modified electrodes demonstrated a remarkable 10-fold reduction in impedance compared to silver microelectrodes. Furthermore, we validated their excellent electrocatalytic activity and sensitivity using five electrochemical detection methods, including cyclic voltammetry, differential pulse voltammetry, square-wave pulse voltammetry, normal pulse voltammetry, and linear scanning voltammetry. Importantly, the stability of gold microelectrodes (Au MEs) modified with ACNEs was significantly improved, exhibiting a 30-fold enhancement compared to Au MEs. This improved performance suggests that ACNE functionalization holds great promise for developing micro-biosensors with enhanced sensitivity and stability for detecting small molecules.