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Obesity has shown a global epidemic trend. The high-lipid state caused by obesity can maintain the heart in a prolonged low-grade inflammatory state and cause ventricular remodeling, leading to a series of pathologies, such as hypertrophy, fibrosis, and apoptosis, which eventually develop into obese cardiomyopathy. Therefore, prolonged low-grade inflammation plays a crucial role in the progression of obese cardiomyopathy, making inflammation regulation an essential strategy for treating this disease. Cyy-272, an indazole derivative, is an anti-inflammatory compound independently synthesized by our laboratory. Our previous studies revealed that Cyy-272 can exert anti-inflammatory effects by inhibiting the phosphorylation and activation of C-Jun N-terminal kinase (JNK), thereby alleviating lipopolysaccharide (LPS)-induced acute lung injury (ALI). The current study aimed to evaluate the potential of Cyy-272 to mitigate the occurrence and progression of obese cardiomyopathy through the inhibition of the JNK signaling pathway. Our results indicate that the compound Cyy-272 has encouraging therapeutic effects on obesity-induced cardiac injury. It significantly inhibits inflammation in cardiomyocytes and heart tissues induced by high lipid concentrations, further alleviating the resulting hypertrophy, fibrosis, and apoptosis. Mechanistically, the protective effect of Cyy-272 on obese cardiomyopathy can be attributed to its direct inhibition of JNK protein phosphorylation. In conclusion, we identified a novel compound, Cyy-272, capable of alleviating obese cardiomyopathy and confirmed that its effect is achieved through direct inhibition of JNK.
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Cardiomiopatias , Indazóis , Proteínas Quinases JNK Ativadas por Mitógeno , Obesidade , Animais , Obesidade/tratamento farmacológico , Obesidade/complicações , Cardiomiopatias/tratamento farmacológico , Indazóis/farmacologia , Indazóis/uso terapêutico , Indazóis/química , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Masculino , Apoptose/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos , Fibrose , Anti-Inflamatórios/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacosRESUMO
The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus-cell binding and virus-cell fusion, respectively4-6. Notably, Tmeff1-/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.
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Fatores de Restrição Antivirais , Encéfalo , Herpes Simples , Herpesvirus Humano 1 , Proteínas de Membrana , Neurônios , Internalização do Vírus , Replicação Viral , Animais , Feminino , Humanos , Masculino , Camundongos , Fatores de Restrição Antivirais/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/virologia , Morte Celular , Sistemas CRISPR-Cas/genética , Herpes Simples/imunologia , Herpes Simples/metabolismo , Herpes Simples/virologia , Herpesvirus Humano 1/crescimento & desenvolvimento , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 1/fisiologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Neurônios/virologia , Neurônios/metabolismo , Carga Viral , Nectinas/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Miosina não Muscular Tipo IIB/metabolismo , Interferon Tipo I , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/prevenção & controle , Doenças Neuroinflamatórias/virologiaRESUMO
As large-scale, high-proportion, and efficient distribution transformers surge into the grids, anti-short circuit capability testing of transformer windings in efficient distribution seems necessary and prominent. To deeply explore the influence of progressively short-circuit shock impulses on the core winding deformation of efficient power transformers, a finite element theoretical model was built by referring to a three-phase three-winding 3D wound core transformer with a model of S20-MRL-400/10-NX2. The distributions of internal equivalent force and total deformation of the 3D wound core transformer along different paths under progressively short-circuit shock impulses varying from 60% to 120% were investigated. Results show that the equivalent stress and total deformation change rate reach their maximum as the short-circuit current increases from 60% to 80%, and the maximum and average variation rate for the equivalent stress reach 177.75% and 177.43%, while the maximum and average variation rate for the total deformation corresponds to 178.30% and 177.45%, respectively. Meanwhile, the maximum equivalent stress and maximum total deformation reach 29.81 MPa and 38.70 µm, respectively, as the applied short-circuit current increased to 120%. In light of the above observations, the optimization and deployment of wireless sensor nodes was suggested. Therefore, a distributed monitoring system was developed for acquiring the vibration status of the windings in a 3D wound core transformer, which is a beneficial supplement to the traditional short-circuit reactance detection methods for an efficient grid access spot-check of distribution transformers.
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Background: Osteosarcoma is the most common primary malignant bone tumor, but its pathogenesis remains unclear. Ubiquitin-specific processing peptidase 22 (USP22) is reported to be highly expressed and associated with tumor malignancy and prognosis in cancers. However, the role and mechanism of USP22 in osteosarcoma is not fully understood. This study aims to investigate the function and potential mechanism of USP22 in osteosarcoma using bioinformatics analysis combined with experimental validation. Methods: We first integrated transcriptomic datasets and clinical information of osteosarcoma from GEO and TCGA databases to assess the expression and prognostic value of USP22 in osteosarcoma. Then, differential expression analysis and weighted gene co-expression network analysis (WGCNA) were conducted to identify USP22-related co-expressed genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the biological functions and signaling pathways of USP22 co-expressed genes. To validate the accuracy of bioinformatics analyses, we downregulated USP22 expression in osteosarcoma cell line Sao-2 using siRNA and assessed its effect on cell proliferation, migration, invasion, apoptosis, and regulation of key signaling pathways. Results: We found that USP22 was highly expressed in osteosarcoma tissues and correlated with poor prognosis in osteosarcoma patients. USP22 also showed potential as a diagnostic marker for osteosarcoma. In addition, 344 USP22-related co-expressed genes were identified, mainly involved in signaling pathways such as glycolysis, oxidative phosphorylation, spliceosome, thermogenesis, and cell cycle. The in vitro experiments confirmed the accuracy and reliability of bioinformatics analyses. We found that downregulation of USP22 could inhibit Sao-2 cell proliferation, migration, invasion, and induce apoptosis. Furthermore, downregulation of USP22 significantly reduced aerobic glycolysis levels in Sao-2 cells and inhibited the expression of key enzymes and transporters in aerobic glycolysis pathways such as HK2, PKM2, and GLUT1. Conclusions: USP22 plays a critical role in the occurrence, development, and prognosis of osteosarcoma. USP22 could influence Sao-2 cell proliferation, apoptosis, migration, and invasion by regulating the glycolysis pathway, thereby promoting osteosarcoma progression. Therefore, USP22 may be a potential therapeutic target for the treatment of osteosarcoma.
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Neoplasias Ósseas , Proliferação de Células , Biologia Computacional , Glicólise , Osteossarcoma , Ubiquitina Tiolesterase , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Humanos , Glicólise/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Proliferação de Células/genética , Prognóstico , Regulação Neoplásica da Expressão Gênica , Apoptose/genética , Movimento Celular/genética , Transdução de Sinais/genéticaRESUMO
Osteosarcoma (OS) is a malignant bone sarcoma arising from mesenchymal stem cells. The biological role of Acyl-CoA synthetase long-chain family member 4 (ACSL4), recently identified as an oncogene in numerous tumor types, remains largely unclear in OS. In this study, we investigated the expression of ACSL4 in OS tissues using immunohistochemistry staining (IHC) staining of a human tissue microarray and in OS cells by qPCR assay. Our findings revealed a significant up-regulation of ACSL4 in both OS tissues and cells. To further understand its biological effects, we conducted a series of loss-of-function experiments using ACSL4-depleted MNNG/HOS and U-2OS cell lines, focusing on OS cell proliferation, migration, and apoptosis in vitro. Our results demonstrated that ACSL4 knockdown remarkably suppressed OS cell proliferation, arrested cells in the G2 phase, induced cell apoptosis, and inhibited cell migration. Additionally, a subcutaneous xenograft mice model was established to validate the in vivo impact of ACSL4, revealing ACSL4 silencing impaired tumor growth in the OS xenograft mice. Additionally, we discovered that ACSL4 could regulate the phosphorylation level of Smad2 through cooperative interactions, and treatment with a TGF-ß inhibitor weakened the promoting effects of ACSL4 overexpression. In short, ACSL4 regulated OS progression by modulating TGF-ß/Smad2 signaling pathway. These findings underscore ACSL4 as a promising therapeutic target for OS patients and contribute novel insights into the pathogenesis of OS.
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Despite the recent advances in this field, there are limited methods for translating organoid-based study results to clinical response. The goal of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model to facilitate the translation, using oxaliplatin and irinotecan treatments with colorectal cancer (CRC) as examples. The PK models were developed using qualified oxaliplatin and irinotecan PK data from the literature. The PD models were developed based on antitumor efficacy data of SN-38 and oxaliplatin evaluated in vitro using tumor organoids. To predict the clinical response, translational scaling of the models was established by incorporating predicted ultrafiltration platinum in plasma or SN-38 in tumors to PD models as the driver of efficacy. The final PK/PD model can predict PK profiles and responses following treatments with oxaliplatin or irinotecan. After generation of virtual patient cohorts, this model simulated their tumor shrinkages following treatments, which were used in analyzing the efficacies of the two treatments. Consistent with the published clinical trials, the model simulation suggested similar patient responses following the treatments of oxaliplatin and irinotecan with regards to the probabilities of progression-free survival (HR = 1.05, 95%CI [0.97;1.15]) and the objective response rate (OR = 1.15, 95%CI [1.00;1.32]). This proposed translational PK/PD modeling approach provides a significant tool for predicting clinical responses of different agents, which may help decision-making in drug development and guide clinical trial design.
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OBJECTIVES: To focus on evaluating the clinical influence of metoprolol on sepsis-induced cardiomyopathy (SICM). METHODS: A total of 90 patients with SICM was enrolled from December 2018 to February 2021 and divided into 2 groups according to the use of metoprolol during hospitalization in Suzhou Municipal Hospital in Suzhou, China. We compared them with the cardiac function, sequential organ failure assessment score, and clinical outcomes. RESULTS: Between the 2 groups, the oxygenation indices and Glasgow coma scale in the metoprolol group were higher on the first day of treatment, with Glasgow coma scale higher on the third day of treatment. However, the doses of norepinephrine in patients with metoprolol showed no significant differences with the control group. The all-causemortality at 28 days in the metoprolol group was lower, and the time of removing from ventilator support as well as the number of failured organs also significantly differed between the 2 groups. CONCLUSION: Metoprolol can reduce the 28-day mortality and shorten the duration of mechanical ventilation in SICM. It can also reduce the number of organ failures and improve the oxygenation index and Glasgow coma scale of these patients. Meanwhile, metoprolol did not affect the norepinephrine dose in patients with SICM.
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Cardiomiopatias , Sepse , Humanos , Metoprolol/uso terapêutico , Estudos Retrospectivos , Sepse/complicações , Sepse/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Norepinefrina/uso terapêuticoRESUMO
Overhead transmission lines are important lifelines in power systems, and the research and application of their intelligent patrol technology is one of the key technologies for building smart grids. The main reason for the low detection performance of fittings is the wide range of some fittings' scale and large geometric changes. In this paper, we propose a fittings detection method based on multi-scale geometric transformation and attention-masking mechanism. Firstly, we design a multi-view geometric transformation enhancement strategy, which models geometric transformation as a combination of multiple homomorphic images to obtain image features from multiple views. Then, we introduce an efficient multiscale feature fusion method to improve the detection performance of the model for targets with different scales. Finally, we introduce an attention-masking mechanism to reduce the computational burden of model-learning multiscale features, thereby further improving model performance. In this paper, experiments have been conducted on different datasets, and the experimental results show that the proposed method greatly improves the detection accuracy of transmission line fittings.
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OBJECTIVE: To investigate whether dynamic monitoring of citrulline (Cit) has guiding value for early enteral nutrition (EN) in patients with severe gastrointestinal injury. METHODS: A observational study was conducted. A total of 76 patients with severe gastrointestinal injury admitted to different intensive care units of Suzhou Hospital Affiliated to Nanjing Medical University from February 2021 to June 2022 were enrolled. Early EN was performed in 24-48 hours after admission as recommended by the guidelines. Those who did not terminate EN after 7 days were enrolled in the early EN success group, and those who terminated EN within 7 days due to persistent feeding intolerance or deterioration of general condition were enrolled in the early EN failure group. There was no intervention during the treatment. Serum Cit levels were measured by mass spectrometry at admission, before EN starting and EN 24 hours, respectively, and the changes in Cit within EN 24 hours (ΔCit) were calculated (ΔCit = EN 24-hour Cit-Cit before EN starting). Receiver operator characteristic curve (ROC curve) was plotted to investigate the predictive value of ΔCit for early EN failure, and the optimal predictive value was calculated. Multivariate unconditional Logistic regression was used to analyze the independent risk factors for early EN failure and death at 28 days. RESULTS: Seventy-six patients were enrolled in the final analysis, of which 40 succeeded in early EN and 36 failed. There were significant differences in age, main diagnosis, acute physiology and chronic health evaluation II (APACHE II) score at admission, blood lactic acid (Lac) before EN initiation and ΔCit between the two groups. Multivariate Logistic regression analysis showed that age [odds ratio (OR) = 0.929, 95% confidence interval (95%CI) was 0.874-0.988, P = 0.018], ΔCit (OR = 2.026, 95%CI was 1.322-3.114, P = 0.001) and increased feeding rate within 48 hours (OR = 13.719, 95%CI was 1.795-104.851, P = 0.012) were independent risk factors for early EN failure in patients with severe gastrointestinal injury. ROC curve analysis showed that ΔCit had a good predictive value for early EN failure in patients with severe gastrointestinal injury [area under the ROC curve (AUC) = 0.787, 95%CI was 0.686-0.887, P < 0.001], and the optimal predictive value of ΔCit was 0.74 µmol/L (sensitivity was 65.0%, specificity was 75.0%). Combined with the optimal predictive value of ΔCit, "overfeeding" was defined as ΔCit < 0.74 µmol/L and increased feeding within 48 hours. Multivariate Logistic regression analysis showed that age (OR = 0.825, 95%CI was 0.732-0.930, P = 0.002), APACHE II score (OR = 0.696, 95%CI was 0.518-0.936, P = 0.017) and early EN failure (OR = 181.803, 95%CI was 3.916-8 439.606, P = 0.008) were independent risk factors for 28-day death in patients with severe gastrointestinal injury. The new variable "overfeeding" was also associated with an increased risk of death at 28 days (OR = 27.816, 95%CI was 1.023-755.996, P = 0.048). CONCLUSIONS: Dynamic monitoring of Cit has guiding value for early EN in patients with severe gastrointestinal injury.
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Traumatismos Abdominais , Traumatismos Torácicos , Humanos , Recém-Nascido , Nutrição Enteral , Citrulina , APACHE , CogniçãoRESUMO
Dynamic signal transduction requires the rapid assembly and disassembly of signaling complexes, often mediated by phosphoprotein binding modules. The guanylate kinase-like (GK) domain of the membrane-associated guanylate kinases (MAGUKs) is such a module orchestrating signaling at cellular junctions. The MAGI subfamily of MAGUKs contains a truncated GK domain with unknown structure and function, although they participate in diverse physiological and pathological processes. Here, we demonstrate that the truncated GK domain of MAGI2 interacts with its adjacent PDZ0 domain to form a structural supramodule capable of recognizing phosphoproteins. A conserved phosphorylation-dependent binding motif for PDZ0-GK is delineated, which leads to identification of a set of previously unknown binding partners. We explore the structure and function of the MAGI2-target complex with an inhibitory peptide derived from the consensus motif. Our work reveals an action mechanism of the cryptic MAGI GKs and broadens our understanding of the target recognition rules of phosphoprotein binding modules.
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Fosfoproteínas , Guanilato Quinases/genética , Guanilato Quinases/química , Guanilato Quinases/metabolismo , Fosforilação , Sequência de Aminoácidos , Ligação Proteica , Fosfoproteínas/metabolismoRESUMO
Objective: To investigate the effect of epigallocatechin gallate (EGCG) on chondrocyte senescence and its mechanism. Methods: The chondrocytes were isolated from the articular cartilage of 4-week-old Sprague Dawley rats, and cultured with type â ¡collagenase and passaged. The cells were identified by toluidine blue staining, alcian blue staining, and immunocytochemical staining for type â ¡ collagen. The second passage (P2) cells were divided into blank control group, 10 ng/mL IL-1ß group, and 6.25, 12.5, 25.0, 50.0, 100.0, and 200.0 µmol/L EGCG+10 ng/mL IL-1ß group. The chondrocyte activity was measured with cell counting kit 8 after 24 hours of corresponding culture, and the optimal drug concentration of EGCG was selected for the subsequent experiment. The P2 chondrocytes were further divided into blank control group (group A), 10 ng/mL IL-1ß group (group B), EGCG+10 ng/mL IL-1ß group (group C), and EGCG+10 ng/mL IL-1ß+5 mmol/L 3-methyladenine (3-MA) group (group D). After cultured, the degree of cell senescence was detected by ß-galactosidase staining, the autophagy by monodansylcadaverine method, and the expression levels of chondrocyte-related genes [type â ¡ collagen, matrix metalloproteinase 3 (MMP-3), MMP-13] by real-time fluorescent quantitative PCR, the expression levels of chondrocyte-related proteins (Beclin-1, LC3, MMP-3, MMP-13, type â ¡ collagen, P16, mTOR, AKT) by Western blot. Results: The cultured cells were identified as chondrocytes. Compared with the blank control group, the cell activity of 10 ng/mL IL-1ß group significantly decreased ( P<0.05). Compared with the 10 ng/mL IL-1ß group, the cell activity of EGCG+10 ng/mL IL-1ß groups increased, and the 50.0, 100.0, and 200.0 µmol/L EGCG significantly promoted the activity of chondrocytes ( P<0.05). The 100.0 µmol/L EGCG was selected for subsequent experiments. Compared with group A, the cells in group B showed senescence changes. Compared with group B, the senescence rate of chondrocytes in group C decreased, autophagy increased, the relative expression of type â ¡ collagen mRNA increased, and relative expressions of MMP-3 and MMP-13 mRNAs decreased; the relative expressions of Beclin-1, LC3, and type â ¡ collagen proteins increased, but the relative expressions of P16, MMP-3, MMP-13, mTOR, and AKT proteins decreased; the above differences were significant ( P<0.05). Compared with group C, when 3-MA was added in group D, the senescence rate of chondrocytes increased, autophagy decreased, and the relative expressions of the target proteins and mRNAs showed an opposite trend ( P<0.05). Conclusion: EGCG regulates the autophagy of chondrocytes through the PI3K/AKT/mTOR signaling pathway and exerts anti-senescence effects.
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Condrócitos , Metaloproteinase 3 da Matriz , Ratos , Animais , Ratos Sprague-Dawley , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/farmacologia , Condrócitos/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/farmacologia , Proteína Beclina-1/metabolismo , Interleucina-1beta/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/farmacologia , RNA Mensageiro , Células CultivadasRESUMO
Vitamin B consists of a group of water-soluble micronutrients that are mainly derived from the daily diet. They serve as cofactors, mediating multiple metabolic pathways in humans. As an integrated part of human health, gut microbiota could produce, consume, and even compete for vitamin B with the host. The interplay between gut microbiota and the host might be a crucial factor affecting the absorbing processes of vitamin B. On the other hand, vitamin B supplementation or deficiency might impact the growth of specific bacteria, resulting in changes in the composition and function of gut microbiota. Together, the interplay between vitamin B and gut microbiota might systemically contribute to human health. In this review, we summarized the interactions between vitamin B and gut microbiota and tried to reveal the underlying mechanism so that we can have a better understanding of its role in human health.
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The Three-Year Action Plan for Winning the Blue Sky Defense Battle states that structural adjustments of industrial, energy, transportation, and land use are important to significantly reduce CO2 and air pollutant emissions. This co-effect is evident but has not been quantified at the city-cluster level. This study developed an emission inventory for the "2+26" cities of the Jing-Jin-Ji region and its surroundings and quantitatively analyzed the impacts of measures in the Three-Year Action Plan for Winning the Blue Sky Defense Battle on the emissions of CO2 and major air pollutants using Greenhouse Gas and Air Pollution Interactions and Synergies in the "2+26" cities model (GAINS-JJJ). The results showed that in the "2+26" cities, the emission reductions in CO2, primary PM2.5, SO2, NOx, and NH3 under policy scenario 2020 were 29.1 Mt (equivalent to 2% of the emissions in 2017), 203.8 (21%), 281.8 (27%), 485.5 (17%), and 34.3 kt (3%), respectively, relative to 2017. In terms of the cities or sectors, the higher the pollutant emissions, the higher the reduction achieved. The CO2 mitigation co-effect results showed that industrial adjustment measures, such as eliminating backward production capacity, upgrades on industrial boilers, and phasing out small and polluting factories, contributed the most to the co-effect of CO2 emission reduction, whereas NOx presented the highest co-effects, with CO2 among the different air pollutants.
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Poluentes Atmosféricos , Poluição do Ar , Gases de Efeito Estufa , Cidades , Dióxido de Carbono/análise , Poluição do Ar/prevenção & controle , Poluição do Ar/análise , Poluentes Atmosféricos/análise , Gases de Efeito Estufa/análiseRESUMO
In recent years, the flourishing of synthetic methodology studies has provided concise access to numerous molecules with new chemical space. These compounds form a large library with unique scaffolds, but their application in hit discovery is not systematically evaluated. In this work, we establish a synthetic methodology-based compound library (SMBL), integrated with compounds obtained from our synthetic researches, as well as their virtual derivatives in significantly larger scale. We screen the library and identify small-molecule inhibitors to interrupt the protein-protein interaction (PPI) of GIT1/ß-Pix complex, an unrevealed target involved in gastric cancer metastasis. The inhibitor 14-5-18 with a spiro[bicyclo[2.2.1]heptane-2,3'-indolin]-2'-one scaffold, considerably retards gastric cancer metastasis in vitro and in vivo. Since the PPI targets are considered undruggable as they are hard to target, the successful application illustrates the structural specificity of SMBL, demonstrating its potential to be utilized as compound source for more challenging targets.
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Neoplasias Gástricas , Humanos , Biblioteca Gênica , Heptanos , Restrição Física , Fatores de Troca de Nucleotídeo Guanina Rho , Mapeamento de Interação de ProteínasRESUMO
Bioaugmentation is an effective approach for removing pyrene from contaminated sites, and its performance is enhanced by a biosurfactant. To reveal the mechanisms of biosurfactant-assisted bioaugmentation, we introduced RNA stable isotope probing (RNA-SIP) in the pyrene-contaminated soils and explored the impacts of rhamnolipid on the pyrene degradation process. After 12-day degradation, residual pyrene was the lowest in the bioaugmentation treatment (7.76 ± 1.57%), followed by biosurfactant-assisted bioaugmentation (9.86 ± 2.58%) and enhanced natural attenuation (23.97 ± 1.05%). Thirteen well-known and two novel pyrene-degrading bacteria were confirmed to participate in the pyrene degradation. Pyrene degradation was accelerated in the biosurfactant-assisted bioaugmentation, manifested by the high diversity of active pyrene degraders. Our findings expand the knowledge on pyrene degrading bacteria and the mechanisms of pyrene degradation in a bioaugmentation process.
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Microbiologia do Solo , Poluentes do Solo , Bactérias/metabolismo , Biodegradação Ambiental , Isótopos/metabolismo , Pirenos/metabolismo , RNA/metabolismo , Sondas RNA/metabolismo , Solo , Poluentes do Solo/análiseRESUMO
The mechanosensory stereocilia in hair cells are organized into rows of graded height, a property crucial for auditory perception. Gpsm2-Gαi-Whirlin-Myo15-Eps8 complex at tips of the tallest stereocilia is proposed to define hair bundle row identity, although the underlying mechanism remains elusive. Here, we find that Gpsm2 could undergo phase separation. Moreover, row 1-specific Gpsm2-Gαi complex significantly promotes the formation of the five-component tip complex density (5xTCD) condensates. The 5xTCD condensates display much stronger actin-bundling ability than those without Gpsm2-Gαi, which may provide critical insights into how Gpsm2-Gαi specifies the tallest stereocilia. A deafness-associated mutation of Gpsm2 leads to impaired formation of the 5xTCD condensates and consequently reduced actin bundling, providing possible clues for etiology of hearing loss in patients with Chudley-McCullough syndrome.
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Background: Telomerase reverse transcriptase promoter (TERT-p) mutation has been frequently found, but associated with contrary prognosis, in both low-grade gliomas and glioblastomas. For the low-grade gliomas (Grades II-III), TERT-p mutant patients have a better prognosis than the wildtype patients, whereas for the GBMs (Grade IV), TERT-p mutation is related to a poor prognosis. We hypothesize that there exist high-risk patients in LGGs who share GBM-like molecular features, including TERT-p mutation, and need more intensive treatment than other LGGs. A molecular signature is needed to identify these high-risk patients for an accurate and timely treatment. Methods: Using the within-sample relative expression orderings of gene pairs, we identified the gene pairs with significantly stable REOs, respectively, in both the TERT-p mutant LGGs and GBMs but with opposite directions in the two groups. These reversely stable gene pairs were used as the molecular signature to stratify the LGGs into high-risk and low-risk groups. Results: A signature consisting of 21 gene pairs was developed, which can classify LGGs into two groups with significantly different overall survival. The high-risk group has a similar genetic mutation profile and a similar survival profile as GBMs, and these high-risk tumors may progress to a more malignant state. Conclusion: The 21 gene-pair signature based on REOs is capable of identifying high-risk patients in LGGs and guiding the clinical choice for appropriate and timely intervention.
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Presently, the treatment of four-way catalysts is important for reducing pollutant emissions from diesel engine exhaust, which is a major cause of urban haze. In this study, we prepared perovskite-type catalysts via the citric acid sol-gel method. Experiment results showed that K substitution at site A in LaMnO3 decreased the agglomeration of the catalysts effectively, increased the contact with the reaction gas, promoted the conversion of Mn3+ â Mn4+, and reduced the ignition temperature of soot. Ce substitution at the B-site in La0.5K0.5MnO3 produced a CeO2 phase and decreased the Mn4+/Mn3+ ratio to 0.49, which is conducive to improving the catalytic oxidation performance. The K and Ce co-doping had the best activation effect, which showed a low activation energy (10.87 KJ mol-1) and a high simultaneous removal rate of NO x (reaching 90% at 275 °C) and soot ignition at 250 °C under lean conditions.
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BACKGROUND: Slit diaphragm is a specialized adhesion junction between the opposing podocytes, establishing the final filtration barrier to urinary protein loss. At the cytoplasmic insertion site of each slit diaphragm there is an electron-dense and protein-rich cellular compartment that is essential for slit diaphragm integrity and signal transduction. Mutations in genes that encode components of this membrane-less compartment have been associated with glomerular diseases. However, the molecular mechanism governing formation of compartmentalized slit diaphragm assembly remains elusive. METHODS: We systematically investigated the interactions between key components at slit diaphragm, such as MAGI2, Dendrin, and CD2AP, through a combination of biochemical, biophysical, and cell biologic approaches. RESULTS: We demonstrated that MAGI2, a unique MAGUK family scaffold protein at slit diaphragm, can autonomously undergo liquid-liquid phase separation. Multivalent interactions among the MAGI2-Dendrin-CD2AP complex drive the formation of the highly dense slit diaphragm condensates at physiologic conditions. The reconstituted slit diaphragm condensates can effectively recruit Nephrin. A nephrotic syndrome-associated mutation of MAGI2 interfered with formation of the slit diaphragm condensates, thus leading to impaired enrichment of Nephrin. CONCLUSIONS: Key components at slit diaphragm (e.g., MAGI2 and its complex) can spontaneously undergo phase separation. The reconstituted slit diaphragm condensates can be enriched in adhesion molecules and cytoskeletal adaptor proteins. Therefore, the electron-dense slit diaphragm assembly might form via phase separation of core components of the slit diaphragm in podocytes.