RESUMO
Mer tyrosine kinase (MerTK) has been found to regulate the secretion of inflammatory factors and exert immunosuppressive effects, but its role in gout remains unclear. In this study, we aimed to clarify the immnue effects of MerTK in gout. MerTK in synovium or serum of gout patients was determined by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and real-time quantitative polymerase chain reaction (RT-qPCR). In monosodium urate (MSU)-induced gout mice, the effect of MerTK inhibitor (UNC2250) on inflammation and polarization was also assessed. After inhibition, knockdown or overexpression of MerTK, inflammatory response and polarization level in THP1-derived macrophages were evaluated by RT-qPCR and flow cytometry. Regulation of MerTK inhibitors on mitochondrial function and downstream pathway in THP1-derived macrophages were detected. MerTK in synovium and serum of gout patients were increased. MerTK inhibitor stimulated the inflammation and M1 polarization in MSU-induced gout mice. MerTK inhibition, knock-down, or overexpression affected inflammatory response, polarization and mitochondrial function in vitro in gout model. The PI3K/Akt/GSK-3ß pathway was identified to reduce after MerTK inhibition and the relevant results were as expected, validated by knock-down or overexpressing MerTK. In conclusion, MerTK was detected to increase in both gout patients and model. MerTK influenced inflammatory response and polarization markers through PI3K/Akt/GSK-3ß pathway. Interfering MerTK/PI3K/Akt/GSK-3ß axis may provide a new therapeutic target for gout.
RESUMO
BACKGROUND: Myocardial ischemia-reperfusion(I/R)injury constitute the fundamental pathophysiology of acute myocardial infarction (AMI). Ischemic heart releases macrophage migration inhibitory factor (MIF), which activates MIF- AMPK signaling pathway. Depression is a significant risk factor for AMI. In a state of depression, peripheral expression of cannabinoid receptor 2 (CNR2) genes was downregulated. AIMS: We investigated the mechanism by which depression exacerbates myocardial I/R injury through the CNR2 and MIF-AMPK signaling pathways. METHODS: We established mouse models of depression and myocardial I/R. Left ventricular function was assessed using cardiac ultrasound and TTC staining. The protein levels of myocardial CNR2, MIF, AMPK, and ACC were determined by Western blot, while the expression level of CNR2 was measured using RT-qPCR. Additionally, MIF content in peripheral blood was quantified using ELISA. RESULTS: After I/R, the expression level of CNR2 was found to be lower in the depression group, leading to a deterioration in left heart function. Depressed mice exhibited lower secretion of MIF, accompanied by a decrease in the activation of the MIF-AMPK signaling pathway. However, injection of CNR2 agonist JWH133 prior to ischemia increased the activation of the MIF-AMPK signaling pathway, while CNR2 inhibitor AM630 decreased the activation. LIMITATIONS: Further research is needed to investigate the specific neuroendocrine mechanism affecting myocardial CNR2 expression in depression. And these experimental conclusions require further verification at the cellular level. CONCLUSIONS: The activation of CNR2 in myocardium following I/R is impeded by depression, thereby exacerbating myocardial I/R injury through attenuation of the MIF-AMPK signaling pathway activation.
RESUMO
OBJECTIVE: To investigate the effects of selinexor, a inhibitor of nuclear export protein 1 (XPO1) on the proliferation inhibition and apoptosis of Kasumi-1 cells in acute myeloid leukemia (AML). METHODS: MTS method was used to detect the inhibitory effect of different concentrations of selinexor on the proliferation of Kasumi-1 cells at different time points. The apoptosis rate and cell cycle changes after treatment with different concentration of selinexor were detected by flow cytometry. RESULTS: Selinexor inhibited the growth of Kasumi-1 cells at different time points in a concentration-dependent manner (r 24 h=0.7592, r 48 h=0.9456, and r 72 h=0.9425). Selinexor inhibited Kasumi-1 cells growth in a time-dependent manner (r =0.9057 in 2.5 µmol/L group, r =0.9897 in 5 µmol/L group and r =0.9994 in 10 µmol/L group). Selinexor could induce apoptosis of Kasumi-1 cells in a dose-dependent manner (r =0.9732), and the apoptosis of Kasumi-1 cells was more obvious with the increase of drug concentration. The proportion of G0/G1 phase was significantly increased and the proportion of S phase was significantly decreased after the treatment of Kasumi-1 cells by selinexor. With the increase of drug concentration, the proportion of Kasumi-1 cells cycle arrest in G0/G1 phase was increased and the cell synthesis was decreased. CONCLUSION: Selinexor can promote the death of tumor cells by inhibiting Kasumi-1 cells proliferation, inducing apoptosis and blocking cell cycle.
Assuntos
Apoptose , Proliferação de Células , Hidrazinas , Leucemia Mieloide Aguda , Triazóis , Hidrazinas/farmacologia , Triazóis/farmacologia , Apoptose/efeitos dos fármacos , Humanos , Proliferação de Células/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Linhagem Celular Tumoral , Ciclo Celular/efeitos dos fármacos , Proteína Exportina 1 , CarioferinasRESUMO
Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFß pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy.
Assuntos
Neoplasias Colorretais , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Instabilidade de Microssatélites , Mutação , Transcriptoma , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Humanos , Transcriptoma/genética , Prognóstico , Genoma Humano/genética , Variações do Número de Cópias de DNA/genética , Masculino , Feminino , Estudos de Coortes , Células Estromais/metabolismo , Células Estromais/patologiaRESUMO
OBJECTIVES: Photoangiolytic lasers have yielded significant innovation in laryngeal surgery in the last 25 years. After the discontinuation of the potassium titanyl phosphate (KTP) laser, a novel 445-nm blue laser was developed. The optimal balance between a laser's desired tissue effects and collateral tissue damage is a major determinant of laser selection in microlaryngeal surgery. The shell-less incubation system for the chick chorioallantoic membrane (CAM) simulates the microvasculature of the human vocal fold and is useful for testing effects of laser settings and in simulated surgery. The aim of this study is to compare the tissue effects of the KTP and blue lasers using the shell-less CAM model. METHODS: The shell-less incubation system contains: polymethylpentene film (used as a culture vessel), calcium lactate and distilled water supplementations. By using this system, the chick chorioallantoic membrane (CAM) can be fully exposed with a good field for surgery simulation. The effects of the 2 lasers (532 nm KTP and 445 nm blue) were quantified at clinically relevant energy settings and laser distances from target. Measures included imaging real-time vascular reactions in the CAM model, post-procedure histologic analysis of CAM tissue and temperature changes. RESULTS: Vessel coagulation and rupture rates were less common with the blue laser compared with the KTP laser. Histologic analysis demonstrated less tissue disruption with the blue laser. Temperature changes were less with the blue laser. CONCLUSION: In this CAM model with specific conditions, the blue laser reveals less tissue damage than the KTP laser. Suitable working distance and power setting of the laser are necessary for desired tissue effects.Level of Evidence: Level 3.
RESUMO
Psychoactive substances, including morphine and methamphetamine, have been shown to interact with the classic innate immune receptor Toll-like receptor 4 (TLR4) and its partner protein myeloid differentiation protein 2 (MD2) in a nonenantioselective manner. (-)-Nicotine, the primary alkaloid in tobacco and a key component of highly addictive cigarettes, targets the TLR4/MD2, influencing TLR4 signaling pathways. Existing as two enantiomers, the stereoselective recognition of nicotine by TLR4/MD2 in the context of the innate immune response remains unclear. In this study, we synthesized (+)-nicotine and investigated its effects alongside (-)-nicotine on lipopolysaccharide (LPS)-induced TLR4 signaling. (-)-Nicotine dose-dependently inhibited proinflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and cyclooxygenase-2 (COX-2). In contrast, (+)-nicotine showed no such inhibitory effects. Molecular dynamics simulations revealed that (-)-nicotine exhibited a stronger affinity with the TLR4 coreceptor MD2 than (+)-nicotine. Additionally, in silico simulations revealed that both nicotine enantiomers initially attach to the entrance of the MD2 cavity, creating a metastable state before they fully enter the cavity. In the metastable state, (-)-nicotine established more stable interactions with the surrounding residues at the entrance of the MD2 cavity compared to those of (+)-nicotine. This highlights the crucial role of the MD2 cavity entrance in the chiral recognition of nicotine. These findings provide valuable insights into the distinct interactions between nicotine enantiomers and the TLR4 coreceptor MD2, underscoring the enantioselective effect of nicotine on modulating TLR4 signaling.
Assuntos
Antígeno 96 de Linfócito , Simulação de Dinâmica Molecular , Nicotina , Transdução de Sinais , Receptor 4 Toll-Like , Receptor 4 Toll-Like/metabolismo , Nicotina/farmacologia , Nicotina/química , Nicotina/análogos & derivados , Nicotina/metabolismo , Antígeno 96 de Linfócito/metabolismo , Antígeno 96 de Linfócito/química , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Humanos , Lipopolissacarídeos/farmacologia , Simulação de Acoplamento Molecular , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/químicaRESUMO
Medical imaging is indispensable for accurate diagnosis and effective treatment, with modalities like MRI and CT providing diverse yet complementary information. Traditional image fusion methods, while essential in consolidating information from multiple modalities, often suffer from poor image quality and loss of crucial details due to inadequate handling of semantic information and limited feature extraction capabilities. This paper introduces a novel medical image fusion technique leveraging unsupervised image segmentation to enhance the semantic understanding of the fusion process. The proposed method, named DUSMIF, employs a multi-branch, multi-scale deep learning architecture that integrates advanced attention mechanisms to refine the feature extraction and fusion processes. An innovative approach that utilizes unsupervised image segmentation to extract semantic information is introduced, which is then integrated into the fusion process. This not only enhances the semantic relevance of the fused images but also improves the overall fusion quality. The paper proposes a sophisticated network structure that extracts and fuses features at multiple scales and across multiple branches. This structure is designed to capture a comprehensive range of image details and contextual information, significantly improving the fusion outcomes. Multiple attention mechanisms are incorporated to selectively emphasize important features and integrate them effectively across different modalities and scales. This approach ensures that the fused images maintain high quality and detail fidelity. A joint loss function combining content loss, structural similarity loss, and semantic loss is formulated. This function not only guides the network in preserving image brightness and texture but also ensures that the fused image closely resembles the source images in both content and structure. The proposed method demonstrates superior performance over existing fusion techniques in objective assessments and subjective evaluations, confirming its effectiveness in enhancing the diagnostic utility of fused medical images.
Assuntos
Imageamento por Ressonância Magnética , Imagem Multimodal , Redes Neurais de Computação , Semântica , Humanos , Imagem Multimodal/métodos , Imageamento por Ressonância Magnética/métodos , Processamento de Imagem Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Aprendizado Profundo , AlgoritmosRESUMO
Surface sediment samples were collected from the surrounding sea areas of the two largest tourist islands in Sanya City, China, to compare and assess the sources, distribution, and ecological risks of 16 polycyclic aromatic hydrocarbons (PAHs). The total PAHs concentrations ranged from 31.16 to 163.3 ng/g, with an average concentration of 102.46 ng/g, which is still lower than the levels detected in most other sediment studies worldwide. PAHs from coal combustion (Flu, Pyr, Fl, Phe) showed positive correlations with TOC, Silt, and Clay, indicating that these PAHs are easily adsorbed in muddy and silty sediments. Sanya Bay is primarily composed of mud and silt, whereas Haitang Bay is mainly sandy. This corresponds to the significantly higher concentrations of Fl, Phe, and Pyr in Sanya Bay compared to Haitang Bay. The main industrial activities in the study area are related to power and heat production and supply. The results indicate that the primary sources of sediment PAHs are high-temperature combustion during heavy industrial production, followed by maritime transportation and petroleum sources. Overall, the PAHs pollution levels in the study area range from slight to moderate. Sediment quality assessments show that only Ace and Phe have higher individual risk values. Six stations in Sanya Bay have higher adverse impact risks, while in Haitang Bay, only HT07 poses a high risk to biological impact. These two areas require enhanced monitoring and pollution source control.
Assuntos
Monitoramento Ambiental , Sedimentos Geológicos , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , Hidrocarbonetos Policíclicos Aromáticos/análise , Sedimentos Geológicos/química , Medição de Risco , Poluentes Químicos da Água/análise , China , IlhasRESUMO
Coupling hydrazine oxidation reaction (HzOR) with hydrogen evolution reaction (HER) has been widely concerned for high efficiency of green hydrogen preparation with low energy consumption. However, the lacking of bifunctional electrodes with ampere-level performance severely limits its industrialization. Herein, we put forward an efficient active site anchored strategy for MnCo2O4 nanosheet arrays on nickel foam (NF) by introducing Pt species (denoted as Pt-MnCo2O4/NF), which is standing for excellent bifunctional electrodes. The Pt-MnCo2O4/NF delivers ultralow potentials of -195 mV and 350 mV at 1000 mA cm-2 as well as robust stability for HzOR and HER, respectively. The study of in-situ Raman and reaction kinetics reveal that the formation of key adsorbed *NH2 and *N2H4 intermediates and the rapidly oxidization of intermediates with a fast interfacial charge transfer on Pt-MnCo2O4/NF. Remarkably, the Pt-MnCo2O4/NF assembled two-electrode hydrazine assisted water electrolyzer realizes current density of 100 mA cm-2 and 1000 mA cm-2 at 0.16 V and 0.62 V with over 80 h stability. This work provides a promising way to design efficient electrodes for energy-saving H2 generation under ampere-level current density.
RESUMO
Antisense oligonucleotides (ASOs) are molecules used to regulate RNA expression by targeting specific RNA sequences. One specific type of ASO, known as neutralized DNA (nDNA), contains site-specific methyl phosphotriester (MPTE) linkages on the phosphate backbone, changing the negatively charged DNA phosphodiester into a neutralized MPTE with designed locations. While nDNA has previously been employed as a sensitive nucleotide sequencing probe for the PCR, the potential of nDNA in intracellular RNA regulation and gene therapy remains underexplored. Our study aims to evaluate the regulatory capacity of nDNA as an ASO probe in cellular gene expression. We demonstrated that by tuning MPTE locations, partially and intermediately methylated nDNA loaded onto mesoporous silica nanoparticles (MSNs) can effectively knock down the intracellular miRNA, subsequently resulting in downstream mRNA regulation in colorectal cancer cell HCT116. Additionally, the nDNA ASO-loaded MSNs exhibit superior efficacy in reducing miR-21 levels over 72 hours compared to the efficacy of canonical DNA ASO-loaded MSNs. The reduction in the miR-21 level subsequently resulted in the enhanced mRNA levels of tumour-suppressing genes PTEN and PDCD4. Our findings underscore the potential of nDNA in gene therapies, especially in cancer treatment via a fine-tuned methylation location.
Assuntos
DNA , MicroRNAs , Nanopartículas , Dióxido de Silício , Dióxido de Silício/química , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Nanopartículas/química , DNA/química , Porosidade , Células HCT116 , Fosfatos/química , Tamanho da Partícula , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , Propriedades de Superfície , Proteínas de Ligação a RNA/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genéticaRESUMO
Although the use of Doxorubicin (Dox) is extensive in the treatment of malignant tumor, the toxic effects of Dox on the heart can cause myocardial injury. Therefore, it is necessary to find an alternative drug to alleviate the Dox-induced cardiotoxicity. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin, which is an active ingredient of Artemisia annua. The study investigates the effects of DHA on doxorubicin-induced cardiotoxicity and ferroptosis, which are related to the activation of Nrf2 and the regulation of autophagy. Different concentrations of DHA were administered by gavage for 4 weeks in mice. H9c2 cells were pretreated with different concentrations of DHA for 24 h in vitro. The mechanism of DHA treatment was explored through echocardiography, biochemical analysis, real-time quantitative PCR, western blotting analysis, ROS/DHE staining, immunohistochemistry, and immunofluorescence. In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes. In vitro, DHA attenuated oxidative stress and cardiomyocyte ferroptosis, activated Nrf2, promoted clearance of autophagosomes, and reduced lysosomal destruction. The changes of ferroptosis and Nrf2 depend on selective degradation of keap1 and recovery of lysosome. We found for the first time that DHA could protect the heart from the toxic effects of Dox-induced cardiotoxicity. In addition, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.
Assuntos
Artemisininas , Autofagia , Cardiotoxicidade , Doxorrubicina , Ferroptose , Miócitos Cardíacos , Fator 2 Relacionado a NF-E2 , Artemisininas/farmacologia , Animais , Fator 2 Relacionado a NF-E2/metabolismo , Autofagia/efeitos dos fármacos , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Camundongos , Ferroptose/efeitos dos fármacos , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/metabolismo , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Linhagem Celular , RatosRESUMO
Objective: The aim was to systematically review the association between depression and frailty in the elderly. Methods: Databases such as PubMed, Web of Science, Embase, and Scopus were searched for articles on the link between the risk of depression and frailty since the creation of the databases to September 1, 2023. A pair of investigators collaboratively conducted the screening, collected data, and evaluated the potential for bias in the included studies. R software was utilized for meta-synthesis. Results: Eight cohort studies comprising 13 043 participants and 14 854 senior individuals with depression were included. The meta-analysis showed that there was a significant connection regarding frailty and the incidence of depression among the elderly (Risk Ratio [RR] = 3.26, 95% Confidence Interval [CI]: 1.68-6.32). Subgroup evaluations showed that there was no association between frailty and depression in the community-dwelling elderly (RR = 2.28, 95% CI: 0.644-8.102) and in the elderly patients with depression assessed by Center for Epidemiological Studies Depression Scale (CES-D) (RR = 5.82, 95% CI: 0.481-70.526). Conclusion: Frailty is correlated with the risk of depression in the elderly. Frailty is a contributing factor to depression in the elderly.
RESUMO
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been administered as the first-line therapy for patients with EGFR mutations in LUAD, but it is almost inevitable that resistance to EGFR-TKIs therapy eventually arises. Polyphyllin I (PPI), derived from Paris polyphylla rhizomes, has been shown to have potent anti-cancer properties in a range of human cancer types including LUAD. However, the role of PPI in gefitinib resistance and the underlying mechanism remain elusive. PURPOSE: To evaluate the antitumor impacts of PPI on gefitinib resistance cells and investigate its molecular mechanism. METHODS: CCK-8, wound healing, transwell assay, and xenograft model were performed to determine the anti-cancer effects of PPI as well as its ability to overcome gefitinib resistance. Immunoblotting, co-immunoprecipitation, phospho-RTK antibody array, qRT-PCR, and immunofluorescence were utilized to explore the mechanism by which PPI overrides gefitinib resistance. RESULTS: PPI inhibited cell survival, growth, and migration/invasion in both gefitinib-sensitive (PC9) and -resistant (PC9/GR) LUAD cells (IC50 at 2.0 µM). Significantly, treatment with PPI at 1.0 µM resensitized the resistant cells to gefitinib. Moreover, cell-derived xenograft experiments revealed that the combination of PPI and gefitinib overcame gefitinib resistance. The phospho-RTK array and immunoblotting analyses showed PPI significant inhibition of the VEGFR2/p38 pathway. In addition, molecular docking suggested the interaction between PPI and HIF-1α. Mechanistically, PPI reduced the protein expression of HIF-1α in both normoxia and hypoxia conditions by triggering HIF-1α degradation. Moreover, HIF-1α protein but not mRNA level was elevated in gefitinib-resistant LUAD. We further demonstrated that PPI considerably facilitated the binding of HIF-1α to VHL. CONCLUSIONS: We present a novel discovery demonstrating that PPI effectively counteracts gefitinib resistance in LUAD by modulating the VEGF/VEGFR2/p38 pathway. Mechanistic investigations unveil that PPI facilitates the formation of the HIF-1α /VHL complex, leading to the degradation of HIF-1α and subsequent inhibition of angiogenesis. These findings uncover a previously unidentified mechanism governing HIF-1α expression in reaction to PPI, providing a promising method for therapeutic interventions targeting EGFR-TKI resistance in LUAD.
Assuntos
Adenocarcinoma de Pulmão , Diosgenina , Resistencia a Medicamentos Antineoplásicos , Gefitinibe , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias Pulmonares , Camundongos Nus , Fator A de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Gefitinibe/farmacologia , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Diosgenina/farmacologia , Diosgenina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Animais , Linhagem Celular Tumoral , Adenocarcinoma de Pulmão/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , FemininoRESUMO
Background: Mechanical thrombectomy (MT) is one of the effective treatment methods for acute ischemic stroke (AIS), which requires a period of dual antiplatelet therapy (DAPT) after endovascular treatment. This study aimed to compare the efficacy and safety of 3-month DAPT and 1-month DAPT in AIS patients receiving MT through a retrospective study. Methods: AIS patients who received MT from May 2018 to March 2023 were grouped into a 1-month group (1-M group) and a 3-month group (3-M group) according to the duration of DAPT after MT. The primary outcome was the mRS score at 90 days. Secondary outcomes included a good prognosis (mRS score of 0-2) at 90 days post-surgery, 6-month mortality, recurrence of cerebral infarction, Barthel's index, Montreal Cognitive Assessment (MoCA) score, and incidence of symptomatic intracranial hemorrhage (sICH) during hospitalization. Result: A total of 147 patients with AIS were included in the final analysis, with 78 patients in the 1-M group and 69 patients in the 3-M group. The baseline and neurological characteristics were comparable between both groups. At 3-month follow-up, a total of 61 patients had an mRS of 0-2 at 90 days, with an average mRS of 3.3 ± 0.9 for all patients. There was no statistically significant difference in the mRS between the two groups of patients at 90 days (P > 0.05). There was no statistically significant difference in the mortality rate and incidence of sICH between the two groups of patients during the 6-month follow-up period (P > 0.05), but the recurrence rate of AIS in the 3-M group was lower than that in the 1-M group (P < 0.05). The improvement of Barthel index and MoCA in patients in the 3-M group was higher than those in the 1-M group at 6 months but not statistically different (P > 0.05). Conclusion: For AIS patients undergoing mechanical thrombectomy, compared to 1-month DAPT, 3-month DAPT can reduce the recurrence rate of IS during a 6-month follow-up period, without increasing the mortality and risk of cerebral hemorrhage.
RESUMO
As industrial technology continues to advance through integration, society's demand for electricity is rapidly increasing. To meet the requirements of refined grid management and address the elevated challenges arising from the increased electrical load, this paper delves into the investigation of distribution vehicle scheduling for the practical scenario of batch rotation of smart meters. Initially, based on the practical distribution task requirements of a provincial metrology verification center, a multi-level optimization model is constructed for the batch rotation and distribution vehicle scheduling of smart meters. The primary objective is to maximize the enhancement of smart meter distribution efficiency while minimizing the overall distribution cost. Moreover, this paper introduces a refined Grey Wolf Optimization algorithm (OLC-GWO) based on Opposition-based Learning, Levy flight strategy, and Cauchy mutation to solve the model. By generating an opposite population to improve the quality of initial feasible solutions and further harnessing the global search capabilities of Levy flight and Cauchy mutation operators, the algorithm's effectiveness is enhanced. The algorithm is subjected to testing using multiple benchmark functions and its performance is compared with variants of GWO, as well as several cutting-edge intelligent optimization algorithms including Particle Swarm Optimization (PSO), Harris Hawks Optimization (HHO), and Honey Bee Algorithm (HBA). The results indicate that OLC-GWO exhibits excellent performance in terms of convergence speed and optimization capability. Finally, the improved algorithm is subjected to simulation experiments by incorporating order data from the practical distribution operations of a provincial metrology verification center. The outcomes verify the efficiency of the proposed algorithm, reinforcing the practical significance of the established model in addressing the real-world challenge of batch rotation and distribution vehicle scheduling for smart meters.
RESUMO
Cortical surface registration plays a crucial role in aligning cortical functional and anatomical features across individuals. However, conventional registration algorithms are computationally inefficient. Recently, learning-based registration algorithms have emerged as a promising solution, significantly improving processing efficiency. Nonetheless, there remains a gap in the development of a learning-based method that exceeds the state-of-the-art conventional methods simultaneously in computational efficiency, registration accuracy, and distortion control, despite the theoretically greater representational capabilities of deep learning approaches. To address the challenge, we present SUGAR, a unified unsupervised deep-learning framework for both rigid and non-rigid registration. SUGAR incorporates a U-Net-based spherical graph attention network and leverages the Euler angle representation for deformation. In addition to the similarity loss, we introduce fold and multiple distortion losses to preserve topology and minimize various types of distortions. Furthermore, we propose a data augmentation strategy specifically tailored for spherical surface registration to enhance the registration performance. Through extensive evaluation involving over 10,000 scans from 7 diverse datasets, we showed that our framework exhibits comparable or superior registration performance in accuracy, distortion, and test-retest reliability compared to conventional and learning-based methods. Additionally, SUGAR achieves remarkable sub-second processing times, offering a notable speed-up of approximately 12,000 times in registering 9,000 subjects from the UK Biobank dataset in just 32 min. This combination of high registration performance and accelerated processing time may greatly benefit large-scale neuroimaging studies.
Assuntos
Processamento de Imagem Assistida por Computador , Neuroimagem , Humanos , Processamento de Imagem Assistida por Computador/métodos , Reprodutibilidade dos Testes , Neuroimagem/métodos , AlgoritmosRESUMO
Disruptions in the toll-like receptor 4 (TLR4) signaling pathway are linked to chronic inflammation, neuropathic pain, and drug addiction. (+)-Naltrexone, an opioid-derived TLR4 antagonist with a (+)-isomer configuration, does not interact with classical opioid receptors and has moderate blood-brain barrier permeability. Herein, we developed a concise 10-step synthesis for (+)-naltrexone and explored its precursors, (+)-14-hydroxycodeinone (1) and (+)-14-hydroxymorphinone (3). These precursors exhibited TLR4 antagonistic activities 100 times stronger than (+)-naltrexone, particularly inhibiting the TLR4-TRIF pathway. In vivo studies showed that these precursors effectively reduced behavioral effects of morphine, like sensitization and conditioned place preference by suppressing microglial activation and TNF-α expression in the medial prefrontal cortex and ventral tegmental area. Additionally, 3 displayed a longer half-life and higher oral bioavailability than 1. Overall, this research optimized (+)-naltrexone synthesis and identified its precursors as potent TLR4 antagonists, offering potential treatments for morphine addiction.
Assuntos
Dependência de Morfina , Naltrexona , Ratos , Animais , Humanos , Naltrexona/farmacologia , Receptor 4 Toll-Like , Dependência de Morfina/tratamento farmacológico , Ratos Sprague-Dawley , Antagonistas de Entorpecentes/farmacologia , Antagonistas de Entorpecentes/uso terapêutico , Morfina/farmacologia , Analgésicos Opioides/uso terapêuticoRESUMO
Understanding how bacteria evolve resistance to phages has implications for phage-based therapies and microbial evolution. In this study, the susceptibility of 335 Salmonella isolates to the wide host range Salmonella phage BPSELC-1 was tested. Potentially significant gene sets that could confer resistance were identified using bioinformatics approaches based on phage susceptibility phenotypes; more than 90 potential antiphage defense gene sets, including those involved in lipopolysaccharide (LPS) biosynthesis, DNA replication, secretion systems, and respiratory chain, were found. The evolutionary dynamics of Salmonella resistance to phage were assessed through laboratory evolution experiments, which showed that phage-resistant mutants rapidly developed and exhibited genetic heterogeneity. Most representative Salmonella hosts (58.1% of 62) rapidly developed phage resistance within 24 h. All phage-resistant mutant clones exhibited genetic heterogeneity and observed mutations in LPS-related genes (rfaJ and rfaK) as well as other genes such as cellular respiration, transport, and cell replication-related genes. The study also identified potential trade-offs, indicating that bacteria tend to escape fitness trade-offs through multi-site mutations, all tested mutants increased sensitivity to polymyxin B, but this does not always affect their relative fitness or biofilm-forming capacity. Furthermore, complementing the rfaJ mutant gene could partially restore the phage sensitivity of phage-resistant mutants. These results provide insight into the phage resistance mechanisms of Salmonella and the complexity of bacterial evolution resulting from phage predation, which can inform future strategies for phage-based therapies and microbial evolution.
Assuntos
Bacteriófagos , Bacteriófagos/genética , Lipopolissacarídeos , Salmonella , Mutação , Fenótipo , BactériasRESUMO
In 2023, Baishideng Publishing Group (Baishideng) routinely published 47 open-access journals, including 46 English-language journals and 1 Chinese-language journal. Our successes were accomplished through the collective dedicated efforts of Baishideng staffs, Editorial Board Members, and Peer Reviewers. Among these 47 Baishideng journals, 7 are included in the Science Citation Index Expanded (SCIE) and 6 in the Emerging Sources Citation Index (ESCI). With the support of Baishideng authors, company staffs, Editorial Board Members, and Peer Reviewers, the publication work of 2023 is about to be successfully completed. This editorial summarizes the 2023 activities and accomplishments of the 13 SCIE- and ESCI-indexed Baishideng journals, outlines the Baishideng publishing policy changes and additions made this year, and highlights the unique advantages of Baishideng journals.