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Tripartite motif-containing protein 59 (TRIM59) is a biomarker for multiple tumors with crucial roles. However, the specific role of TRIM59 in germ cells remains largely unknown. Here, we investigated the effects and underlying regulatory mechanisms of TRIM59 on germ cells using the mouse spermatogonial cell line GC-1. Our results demonstrated that TRIM59 promoted proliferation and inhibited apoptosis of GC-1 cells. Mechanistically, TRIM59 maintained GC-1 cell behaviors through ubiquitination of AXIN1 to activate ß-catenin signaling. Furthermore, activation of ß-catenin signaling reversed the effects mediated by Trim59 knockdown in GC-1 cells. Collectively, our study revealed a major role and regulatory mechanism of TRIM59 in GC-1 cells, which sheds new light on the molecular pathogenesis of defects in spermatogenesis and may provide therapeutic targets for treatment of male infertility.
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BACKGROUND: Antiviral drugs show significant efficacy in non-severe COVID-19 cases, yet there remains a subset of moderate COVID-19 patients whose pneumonia continues to progress post a complete course of treatment. Plasma-activated water (PAW) possesses anti-SARS-CoV-2 properties. To explore the potential of PAW in improving pneumonia in COVID-19 patients following antiviral treatment failure, we conducted this study. METHODS: This was a randomized, controlled trial. Moderate COVID-19 patients with antiviral treatment failure were randomly assigned to the experimental group or the control group. They inhaled nebulized PAW or saline respectively. This was done twice daily for four consecutive days. We assessed improvement in chest CT on day 5, the rate of symptom resolution within 10 days, and safety. RESULTS: A total of 23 participants were included, with 11 receiving PAW and 12 receiving saline. The baseline characteristics of both groups were comparable. The experimental group showed a higher improvement rate in chest CT on day 5 (81.8% vs. 33.3%, p = 0.036). The cumulative disappearance rate of cough within 10 days was higher in the experimental group. Within 28 days, 4 patients in each group progressed to severe illness, and no patients died. No adverse reactions were reported from inhaling nebulized PAW. CONCLUSION: This pilot trial preliminarily confirmed that nebulized inhalation of PAW can alleviate pneumonia in moderate COVID-19 patients with antiviral treatment failure, with no adverse reactions observed. This still needs to be verified by large-scale studies. TRIAL REGISTRATION: Chinese Clinical Trial Registry; No.: ChiCTR2300078706 (retrospectively registered, 12/15/2023); URL: www.chictr.org.cn .
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Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Nebulizadores e Vaporizadores , SARS-CoV-2 , Falha de Tratamento , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Projetos Piloto , Administração por Inalação , Antivirais/uso terapêutico , Antivirais/administração & dosagem , Idoso , Água , Adulto , Resultado do TratamentoRESUMO
Accurate and efficient prediction of polymers properties is crucial for polymer design. Recently, data-driven artificial intelligence (AI) models have demonstrated great promise in polymers property analysis. Even with the great progresses, a pivotal challenge in all the AI-driven models remains to be the effective representation of molecules. Here we introduce Multi-Cover Persistence (MCP)-based molecular representation and featurization for the first time. Our MCP-based polymer descriptors are combined with machine learning models, in particular, Gradient Boosting Tree (GBT) models, for polymers property prediction. Different from all previous molecular representation, polymer molecular structure and interactions are represented as MCP, which utilizes Delaunay slices at different dimensions and Rhomboid tiling to characterize the complicated geometric and topological information within the data. Statistic features from the generated persistent barcodes are used as polymer descriptors, and further combined with GBT model. Our model has been extensively validated on polymer benchmark datasets. It has been found that our models can outperform traditional fingerprint-based models and has similar accuracy with geometric deep learning models. In particular, our model tends to be more effective on large-sized monomer structures, demonstrating the great potential of MCP in characterizing more complicated polymer data. This work underscores the potential of MCP in polymer informatics, presenting a novel perspective on molecular representation and its application in polymer science.
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Aprendizado de Máquina , Polímeros , Polímeros/química , AlgoritmosRESUMO
Continuous cropping is a common obstacle limiting the high quality and yield of Lycium barbarum ï¼wolfberryï¼. To clarify the response of soil characteristics of the wolfberry root zone to continuous cropping years, we systematically determined the physicochemical properties and pesticide residues of soils in the wolfberry root zone with different continuous cropping years. In addition, soil bacterial and fungal communities were characterized using high-throughput sequencing technology. The results were as followsï¼ The content of total salt and imidacloprid in the root zone of wolfberry increased with increasing years of continuous cropping. Compared to that with 2 and 9 years, the total salt content in the root zone of wolfberry with 15 years of continuous cropping increased by 51.97% and 54.33%, respectively, and the imidacloprid content increased by 39.58% and 36.61%, respectively. Alkaline nitrogen and available potassium showed an increasing and then decreasing trend. Compared to that with 2 and 15 years, alkaline nitrogen and available potassium in the root-soil of wolfberry with 9 years of continuous cropping increased by 16.94%-28.09% and 18.31%-18.34%, respectively. The diversity and abundance of bacterial communities and the abundance of fungal communities were higher in the root-soil of wolfberry with 9 years of continuous cropping compared to that with 15 years of continuous cropping. In addition, the increase in continuous cropping years also increased the accumulation of harmful plant pathogens such as Pseudomonas, Arthrobacter, Actinomucor, and Trichoderma in the root zone of L. barbarum. Soil total salinity, organic matter, alkaline hydrolyzable nitrogen, and available potassium were the main factors influencing the distribution of bacterial communities. Soil alkaline hydrolyzable nitrogen, available potassium, and ammonium nitrogen were the main factors influencing the distribution of fungal communities. In addition, the soil bacteria in the root zone of L. barbarum were dominated by metabolic functionsï¼ in particular, amino acid metabolism, energy metabolism, and nucleotide metabolism were most abundant in the root soil of wolfberry with 9 years of continuous cropping, whereas the highest abundance of functional genes related to membrane translocation was found in the root-soil of wolfberry with 15 years of continuous cropping. The soil fungi were all dominated by saprophytic trophic types, followed by pathogenic cross-nutrients in the root zone of L. barbarum. In conclusion, long-term continuous cropping induced changes in the soil microenvironment in the root zone of L. barbarum, increased soil residues of harmful pesticides and the enrichment of plant pathogens, and reduced the diversity of soil bacterial and fungal communities. Therefore, it is necessary to control the rate of application of soil nutrients and pesticides in the management of L. barbarum and to carry out deep ploughing and deep tilling in good time, and the turnover of old plants in the cultivation of L. barbarum.
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Lycium , Resíduos de Praguicidas , Raízes de Plantas , Microbiologia do Solo , Solo , Lycium/crescimento & desenvolvimento , Solo/química , Resíduos de Praguicidas/análise , Raízes de Plantas/microbiologia , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Agricultura/métodos , Bactérias/classificação , Bactérias/metabolismo , Bactérias/crescimento & desenvolvimento , Neonicotinoides , Microbiota , Nitrocompostos , Fungos/classificação , Fungos/crescimento & desenvolvimento , Fungos/metabolismo , Produção Agrícola/métodos , Poluentes do Solo/metabolismo , Poluentes do Solo/análiseRESUMO
Drug-drug interaction (DDI) can trigger many adverse effects in patients and has emerged as a threat to medicine and public health. Therefore, it is important to predict potential drug interactions since it can provide combination strategies of drugs for systematic and effective treatment. Existing deep learning-based methods often rely on DDI functional networks, or use them as an important part of the model information source. However, it is difficult to discover the interactions of a new drug. To address the above limitations, we propose a geometric molecular graph representation learning model (Mol-DDI) for DDI prediction based on the basic assumption that structure determines function. Mol-DDI only considers the covalent and non-covalent bond information of molecules, then it uses the pre-training idea of large-scale models to learn drug molecular representations and predict drug interactions during the fine-tuning process. Experimental results show that the Mol-DDI model outperforms others on the three datasets and performs better in predicting new drug interaction experiments.
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Testicular aging manifests as impaired spermatogenesis and morphological alterations in Drosophila. Nonetheless, the comprehensive molecular regulatory framework remains largely undisclosed. This investigation illustrates the impact of copper overload on testicular aging and underscores the interplay between copper overload and lncRNA. Copper overload triggers Cuproptosis through the mitochondrial TCA cycle, facilitating intracellular interactions with Ferroptosis, thereby governing testicular aging. Dysfunction of lncRNA:CR43306 also contributes to testicular aging in Drosophila, emphasizing the significance of lncRNA:CR43306 as a novel aging-associated lncRNA. Moreover, copper overload exacerbates spermatid differentiation defects mediated by lncRNA:CR43306 deficiency through oxidative stress, copper, and iron transport. Therapeutically, Ferrostatin-1 and Resveratrol emerge as potential remedies for addressing testicular aging. This study offers perspectives on the regulatory mechanisms involving copper overload and lncRNA:CR43306 deficiency in the context of testicular aging.
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Envelhecimento , Cobre , Ferroptose , Estresse Oxidativo , RNA Longo não Codificante , Testículo , Animais , Masculino , RNA Longo não Codificante/genética , Testículo/metabolismo , Ferroptose/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Cobre/metabolismo , Cobre/deficiência , Espermatogênese/genética , Ferro/metabolismo , Drosophila/genética , Drosophila/metabolismo , Drosophila melanogaster/genéticaRESUMO
Hot-carrier transistors are a class of devices that leverage the excess kinetic energy of carriers. Unlike regular transistors, which rely on steady-state carrier transport, hot-carrier transistors modulate carriers to high-energy states, resulting in enhanced device speed and functionality. These characteristics are essential for applications that demand rapid switching and high-frequency operations, such as advanced telecommunications and cutting-edge computing technologies1-5. However, the traditional mechanisms of hot-carrier generation are either carrier injection6-11 or acceleration12,13, which limit device performance in terms of power consumption and negative differential resistance14-17. Mixed-dimensional devices, which combine bulk and low-dimensional materials, can offer different mechanisms for hot-carrier generation by leveraging the diverse potential barriers formed by energy-band combinations18-21. Here we report a hot-emitter transistor based on double mixed-dimensional graphene/germanium Schottky junctions that uses stimulated emission of heated carriers to achieve a subthreshold swing lower than 1 millivolt per decade beyond the Boltzmann limit and a negative differential resistance with a peak-to-valley current ratio greater than 100 at room temperature. Multi-valued logic with a high inverter gain and reconfigurable logic states are further demonstrated. This work reports a multifunctional hot-emitter transistor with significant potential for low-power and negative-differential-resistance applications, marking a promising advancement for the post-Moore era.
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Adding corrosion inhibitors is considered to be a cost-effective way to inhibit metal corrosion. In this study, we report the synthesis of a bi-mannich base corrosion inhibitor (BMT) with an impressive inhibition efficiency on carbon steel in H2S and HCl co-existing solution. At the BMT concentration of 9 ppm, the inhibition efficiency (η) of 96.9%, 97.6% and 98.0% were determined by weight loss, potentiodynamic polarization and electrochemical impedance spectroscopy, respectively. The adsorption of BMT on the carbon steel surface follows the Langmuir adsorption isotherm, and the calculated free energy indicates that the adsorption is a spontaneous process. This research also delves into understanding the adsorption behavior and corrosion inhibition mechanism of BMT on carbon steel surfaces through quantum chemistry calculations. The results of this study provide guidance for the application of BMT as a corrosion inhibitor in sour and acid environments.
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Irrigation practices and groundwater levels are critical factors contributing to soil salinization in arid and semi-arid regions. However, the impact of soil salinization resulting from Yellow River water irrigation and recharge on microbial communities and their functions in the Huinong District has not been thoroughly documented. In this study, high-throughput sequencing technology was employed to analyze the diversity, composition, and structure of bacterial and fungal communities across a gradient of salinized soils. The results indicated that the alpha diversity of bacterial communities was significantly higher in slightly saline soils compared to highly saline soils. Soil salinization notably influenced the composition of both bacterial and fungal communities. Highly salinized soils were enriched with bacterial taxa such as Halomonas, Salinimicrobium, Pseudomonas, Solibacillus, and Kocuria, as well as fungal taxa including Emericellopsis, Alternaria, and Podospora. In these highly saline soils, bacterial taxa associated with iron respiration, sulfur respiration, and hydrocarbon degradation were more prevalent, whereas fungal taxa linked to functions such as soil animal pathogens, arbuscular mycorrhizal symbiosis, endophytes, dung saprotrophy, leaf saprotrophy, soil saprotrophy, fungal parasitism, and plant pathogenicity were less abundant. Random forest analysis identified nine bacterial and eighteen fungal taxa as potential biomarkers for salinity discrimination in saline soils. Symbiotic network analysis further revealed that soil salinization pressure reduced the overall complexity and stability of bacterial and fungal communities. Additionally, bacterial community assembly showed a tendency shift from stochastic to deterministic processes in response to increasing salinity, while fungal community assembly remained dominated by deterministic processes. provide robust evidence that soil salinity is a major inhibitor of soil biogeochemical processes in the Huinong District and plays a critical role in shaping bacterial and fungal communities, their symbiotic networks, and their assembly processes.
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Plasmid-mediated conjugation is a common mechanism for most bacteria to transfer antibiotic resistance genes (ARGs). The conjugative transfer of ARGs is emerging as a major threat to human beings. Although several transfer-related factors are known to regulate this process, small RNAs (sRNAs)-based regulatory roles remain to be clarified. Here, the Hfq-binding sRNA GadY in donor strain Escherichia coli (E. coli) SM10λπ was identified as a new regulator for bacterial conjugation. Two conjugation models established in our previous studies were used, which SM10λπ carrying a chromosomally integrated IncP-1α plasmid RP4 and a mobilizable plasmid pUCP24T served as donor cells, and P. aeruginosa PAO1 or E. coli EC600 as the recipients. GadY was found to promote SM10λπ-PAO1 conjugation by base-pairing with its target mRNA SdiA, an orphan LuxR-type receptor that responds to exogenous N-acylated homoserine lactones (AHLs). However, SM10λπ-EC600 conjugation was not affected due to EC600 lacking AHLs synthase. It indicates that the effects of GadY on conjugation depended on AHLs-SdiA signalling. Further study found GadY bound SdiA to negatively regulate the global RP4 repressors KorA and KorB. When under ciprofloxacin or levofloxacin treatment, GadY expression in donor strain was enhanced, and it positively regulated quinolone-induced SM10λπ-PAO1 conjugation. Thus, our study provides a novel role for sRNA GadY in regulating plasmid-mediated conjugation, which helps us better understand bacterial conjugation to counter antibiotic resistance.
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Conjugação Genética , Proteínas de Escherichia coli , Escherichia coli , Plasmídeos , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Plasmídeos/genética , Regulação Bacteriana da Expressão Gênica , Transativadores/genética , Transativadores/metabolismo , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/metabolismo , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/metabolismo , Antibacterianos/farmacologia , Fator Proteico 1 do Hospedeiro/genética , Fator Proteico 1 do Hospedeiro/metabolismoRESUMO
Background: The judgment of the division point of the bile duct has always been one of the difficulties of laparoscopic left lateral sectionectomy (LLLS). The purpose of this study was to assess the effects of indocyanine green (ICG) fluorescence cholangiography during LLLS on the occurrence of biliary complications in both donors and recipients. The optimal dose and injection time of ICG were also investigated. Methods: This is a retrospective cohort study. From October 2016 to December 2022, the clinical data of 103 donors who underwent LLLS and relevant recipients were retrospectively analyzed. According to whether ICG fluorescence cholangiography was used, they were divided into a non-ICG group (n=46) and an ICG group (n=57). Biliary complications were observed and the optimal dose and injection time of ICG were explored. Results: Three donors in the non-ICG group suffered from bile leakage. Four grafts had multiple bile duct openings and biliary complications were observed in the relevant recipients who received these grafts in the non-ICG group. Two recipients had bile leakage, and the other two had biliary stenosis. There was no biliary complications both in donors and recipients in the ICG group. The fluorescence intensity of the liver was 108.1±17.6 at a dose of 0.004 mg/kg 90 minutes after injection, significantly weaker than that at 0.05 mg/kg 30 minutes (200.3±17.6, P=0.001) and 90 minutes after injection (140.2±15.4, P=0.001). The fluorescence intensity contrast value at a dose of 0.004 mg/kg was stronger than that at 0.05 mg/kg, both measured 90 minutes after injection (0.098±0.032 vs. 0.078±0.022, P=0.021). Conclusions: ICG fluorescence cholangiography is safe and feasible in LLLS. It reduces biliary complications in both donors and recipients. The optimal ICG dose was 0.004 mg/kg, and 90 minutes after injection was the best observation time. ICG fluorescence cholangiography is recommended for routine use in LLLS.
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BACKGROUND: The management of chronic wounds presents a challenge for surgeons. In this pilot study, the authors established a novel auto-grafting approach for chronic wounds and evaluated its efficacy. PURPOSE: The objective of this pilot study was to observe the clinical efficacy of granulation-embedded skin grafting for the treatment of chronic wounds at high altitudes. METHODS: The data of 45 patients with chronic wounds were obtained from the medical records of the Yushu People's Hospital. Patients were divided into stamp skin-grafting and granulation-embedded skin-grafting groups. Skin graft survival rate, wound coverage rate, and wound-healing time were observed and recorded. The length of hospital stay and 1% total body surface area (TBSA) treatment cost were compared. RESULTS: Significant differences were noted in skin graft survival rate (94% ± 3% vs 86% ± 3%, P < .01), wound coverage rate on postoperative day 7 (61% ± 16% vs 54% ± 18%, P < .01), and wound-healing times (23 ± 2.52 days vs 31 ± 3.61 days, P < .05). The length of hospital stay and 1% TBSA treatment cost were significantly reduced in the granulation-embedded skin grafting group (P < .05). CONCLUSIONS: Granulation-embedded skin grafting can improve the healing of chronic wounds at high altitudes. These findings provide a new approach to the clinical treatment of chronic wounds.
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Altitude , Transplante de Pele , Transplante Autólogo , Cicatrização , Humanos , Transplante de Pele/métodos , Transplante de Pele/estatística & dados numéricos , Projetos Piloto , Cicatrização/fisiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Transplante Autólogo/métodos , Transplante Autólogo/estatística & dados numéricos , Tecido de Granulação/fisiopatologia , Adulto , Doença Crônica , Ferimentos e Lesões/fisiopatologia , Ferimentos e Lesões/cirurgia , Ferimentos e Lesões/terapia , Tempo de Internação/estatística & dados numéricos , Sobrevivência de Enxerto/fisiologiaRESUMO
In recent years, polymyxin has been used as a last-resort therapy for carbapenem-resistant bacterial infections. The emergence of heteroresistance (HR) to polymyxin hampers the efficacy of polymyxin treatment by amplifying resistant subpopulation. However, the mechanisms behind polymyxin HR remain unclear. Small noncoding RNAs (sRNAs) play an important role in regulating drug resistance. The purpose of this study was to investigate the effects and mechanisms of sRNA on polymyxin B (PB)-HR in carbapenem-resistant Klebsiella pneumoniae. In this study, a novel sRNA PhaS was identified by transcriptome sequencing. PhaS expression was elevated in the PB heteroresistant subpopulation. Overexpression and deletion of PhaS were constructed in three carbapenem-resistant K. pneumoniae strains. Population analysis profiling, growth curve, and time-killing curve analysis showed that PhaS enhanced PB-HR. In addition, we verified that PhaS directly targeted phoP through the green fluorescent protein reporter system. PhaS promoted the expression of phoP, thereby encouraging the expression of downstream genes pmrD and arnT. This upregulation of arnT promoted the 4-amino-4-deoxyL-arabinosaccharide (L-Ara4N) modification of lipid A in PhaS overexpressing strains, thus enhancing PB-HR. Further, within the promoter region of PhaS, specific PhoP recognition sites were identified. ONPG assays and RT-qPCR analysis confirmed that PhaS expression was positively modulated by PhoP and thus up-regulated by PB stimulation. To sum up, a novel sRNA enhancing PB-HR was identified and a positive feedback regulatory pathway of sRNA-PhoP/Q was demonstrated in the study. This helps to provide a more comprehensive and clear understanding of the underlying mechanisms behind polymyxin HR in carbapenem-resistant K. pneumoniae.
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Antibacterianos , Proteínas de Bactérias , Carbapenêmicos , Regulação Bacteriana da Expressão Gênica , Klebsiella pneumoniae , Polimixina B , Pequeno RNA não Traduzido , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efeitos dos fármacos , Polimixina B/farmacologia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Carbapenêmicos/farmacologia , Pequeno RNA não Traduzido/genética , Testes de Sensibilidade Microbiana , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/tratamento farmacológico , Humanos , RNA Bacteriano/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Farmacorresistência Bacteriana/genéticaRESUMO
Borgs are huge extrachromosomal elements (ECE) of anaerobic methane-consuming "Candidatus Methanoperedens" archaea. Here, we used nanopore sequencing to validate published complete genomes curated from short reads and to reconstruct new genomes. 13 complete and four near-complete linear genomes share 40 genes that define a largely syntenous genome backbone. We use these conserved genes to identify new Borgs from peatland soil and to delineate Borg phylogeny, revealing two major clades. Remarkably, Borg genes encoding nanowire-like electron-transferring cytochromes and cell surface proteins are more highly expressed than those of host Methanoperedens, indicating that Borgs augment the Methanoperedens activity in situ. We reconstructed the first complete 4.00 Mbp genome for a Methanoperedens that is inferred to be a Borg host and predicted its methylation motifs, which differ from pervasive TC and CC methylation motifs of the Borgs. Thus, methylation may enable Methanoperedens to distinguish their genomes from those of Borgs. Very high Borg to Methanoperedens ratios and structural predictions suggest that Borgs may be capable of encapsulation. The findings clearly define Borgs as a distinct class of ECE with shared genomic signatures, establish their diversification from a common ancestor with genetic inheritance, and raise the possibility of periodic existence outside of host cells.
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Genoma Arqueal , Metano , Filogenia , Metano/metabolismo , Oxirredução , Archaea/genética , Archaea/metabolismo , Sequenciamento por Nanoporos/métodos , Metilação de DNA , Microbiologia do SoloRESUMO
Drug-drug interaction (DDI) is the combined effects of multiple drugs taken together, which can either enhance or reduce each other's efficacy. Thus, drug interaction analysis plays an important role in improving treatment effectiveness and patient safety. It has become a new challenge to use computational methods to accelerate drug interaction time and reduce its cost-effectiveness. The existing methods often do not fully explore the relationship between the structural information and the functional information of drug molecules, resulting in low prediction accuracy for drug interactions, poor generalization, and other issues. In this paper, we propose a novel method, which is a deep graph contrastive learning model for drug-drug interaction prediction (DeepGCL for brevity). DeepGCL incorporates a contrastive learning component to enhance the consistency of information between different views (molecular structure and interaction network), which means that the DeepGCL model predicts drug interactions by integrating molecular structure features and interaction network topology features. Experimental results show that DeepGCL achieves better performance than other methods in all datasets. Moreover, we conducted many experiments to analyze the necessity of each component of the model and the robustness of the model, which also showed promising results. The source code of DeepGCL is freely available at https://github.com/jzysj/DeepGCL.
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Interações Medicamentosas , Aprendizado Profundo , HumanosRESUMO
Intervertebral disk degeneration (IDD) is a significant cause of low back pain, characterized by excessive senescence and apoptosis of nucleus pulposus cells (NPCs). However, the precise mechanisms behind this senescence and apoptosis remain unclear. This study aimed to investigate the role of T-box transcription factor T (Tbxt) in IDD both in vitro and in vivo, using a hydrogen peroxide (H2O2)-induced NPCs senescence and apoptosis model, as well as a rat acupuncture IDD model. First, the expression of p16 and cleaved-caspase 3 significantly increased in degenerated human NPCs, accompanied by a decrease in Tbxt expression. Knockdown of Tbxt exacerbated senescence and apoptosis in the H2O2-induced NPCs degeneration model. Conversely, upregulation of Tbxt alleviated these effects induced by H2O2. Mechanistically, bioinformatic analysis revealed that the direct downstream target genes of Tbxt were highly enriched in autophagy-related pathways, and overexpression of Tbxt significantly activated autophagy in NPCs. Moreover, the administration of the autophagy inhibitor, 3-methyladenine, impeded the impact of Tbxt on the processes of senescence and apoptosis in NPCs. Further investigation revealed that Tbxt enhances autophagy by facilitating the transcription of ATG7 through its interaction with a specific motif within the promoter region. In conclusion, this study suggests that Tbxt mitigates H2O2-induced senescence and apoptosis of NPCs by activating ATG7-mediated autophagy.NEW & NOTEWORTHY This study investigates the role of Tbxt in IDD. The results demonstrate that knockdown of Tbxt exacerbates H2O2-induced senescence and apoptosis in NPCs and IDD, whereas upregulation of Tbxt significantly protects against IDD both in vivo and in vitro. Mechanistically, in the nucleus, Tbxt enhances the transcription of ATG7, leading to increased expression of ATG7 protein levels. This, in turn, promotes elevated autophagy levels, ultimately alleviating IDD.
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Apoptose , Proteína 7 Relacionada à Autofagia , Autofagia , Senescência Celular , Degeneração do Disco Intervertebral , Núcleo Pulposo , Ratos Sprague-Dawley , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Autofagia/efeitos dos fármacos , Degeneração do Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Proteína 7 Relacionada à Autofagia/genética , Animais , Senescência Celular/efeitos dos fármacos , Humanos , Ratos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Peróxido de Hidrogênio/toxicidade , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/metabolismo , Células CultivadasRESUMO
BACKGROUND: The axillary lymph-node metastatic burden is closely associated with treatment decisions and prognosis in breast cancer patients. This study aimed to explore the value of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT)-based radiomics in combination with ultrasound and clinical pathological features for predicting axillary lymph-node metastatic burden in breast cancer. METHODS: A retrospective analysis was conducted and involved 124 patients with pathologically confirmed early-stage breast cancer who had undergone 18F-FDG PET/CT examination. The ultrasound, PET/CT, and clinical pathological features of all patients were analysed, and radiomic features from PET images were extracted to establish a multi-parameter predictive model. RESULTS: The ultrasound lymph-node positivity rate and PET lymph-node positivity rate in the high nodal burden group were significantly higher than those in the low nodal burden group (χ2 = 19.867, p < 0.001; χ2 = 33.025, p < 0.001). There was a statistically significant difference in the PET-based radiomics score (RS) for predicting axillary lymph-node burden between the high and low lymph-node burden groups. (-1.04 ± 0.41 vs. -1.47 ± 0.41, t = -4.775, p < 0.001). The ultrasound lymph-node positivity (US_LNM) (odds ratio [OR] = 3.264, 95% confidence interval [CI] = 1.022-10.423), PET lymph-node positivity (PET_LNM) (OR = 14.242, 95% CI = 2.960-68.524), and RS (OR = 5.244, 95% CI = 3.16-20.896) are all independent factors associated with high lymph-node burden (p < 0.05). The area under the curve (AUC) of the multi-parameter (MultiP) model was 0.895, which was superior to those of US_LNM, PET_LNM, and RS models (AUC = 0.703, 0.814, 0.773, respectively), with statistically significant differences (Z = 2.888, 3.208, 3.804, respectively; p = 0.004, 0.002, < 0.001, respectively). Decision curve analysis indicated that the MultiP model provided a higher net benefit for all patients. CONCLUSION: A MultiP model based on PET-based radiomics was able to effectively predict axillary lymph-node metastatic burden in breast cancer. TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov (registration number: NCT05826197) on May 7, 2023.
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Axila , Neoplasias da Mama , Fluordesoxiglucose F18 , Linfonodos , Metástase Linfática , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Pessoa de Meia-Idade , Metástase Linfática/diagnóstico por imagem , Estudos Retrospectivos , Adulto , Idoso , Linfonodos/patologia , Linfonodos/diagnóstico por imagem , Compostos Radiofarmacêuticos , Prognóstico , Estadiamento de Neoplasias , RadiômicaRESUMO
Metabolic dysfunction of the extracellular matrix (ECM) is one of the primary causes of intervertebral disc degeneration (IVDD). Previous studies have demonstrated that the transcription factor Brachyury (Bry) has the potential to promote the synthesis of collagen II and aggrecan, while the specific mechanism is still unknown. In this study, we used a lipopolysaccharide (LPS)-induced model of nucleus pulposus cell (NPC) degeneration and a rat acupuncture IVDD model to elucidate the precise mechanism through which Bry affects collagen II and aggrecan synthesis in vitro and in vivo. First, we confirmed Bry expression decreased in degenerated human nucleus pulposus (NP) cells (NPCs). Knockdown of Bry exacerbated the decrease in collagen II and aggrecan expression in the lipopolysaccharide (LPS)-induced NPCs degeneration in vitro model. Bioinformatic analysis indicated that Smad3 may participate in the regulatory pathway of ECM synthesis regulated by Bry. Chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter gene assays demonstrated that Bry enhances the transcription of Smad3 by interacting with a specific motif on the promoter region. In addition, Western blot and reverse transcription-qPCR assays demonstrated that Smad3 positively regulates the expression of aggrecan and collagen II in NPCs. The following rescue experiments revealed that Bry-mediated regulation of ECM synthesis is partially dependent on Smad3 phosphorylation. Finally, the findings from the in vivo rat acupuncture-induced IVDD model were consistent with those obtained from in vitro assays. In conclusion, this study reveals that Bry positively regulates the synthesis of collagen II and aggrecan in NP through transcriptional activation of Smad3.NEW & NOTEWORTHY Mechanically, in the nucleus, Bry enhances the transcription of Smad3, leading to increased expression of Smad3 protein levels; in the cytoplasm, elevated substrate levels further lead to an increase in the phosphorylation of Smad3, thereby regulating collagen II and aggrecan expression. Further in vivo experiments provide additional evidence that Bry can alleviate IVDD through this mechanism.
Assuntos
Agrecanas , Matriz Extracelular , Proteínas Fetais , Regulação da Expressão Gênica , Núcleo Pulposo , Proteína Smad3 , Adulto , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Agrecanas/metabolismo , Agrecanas/genética , Células Cultivadas , Colágeno Tipo II/metabolismo , Colágeno Tipo II/genética , Matriz Extracelular/metabolismo , Proteínas Fetais/genética , Proteínas Fetais/metabolismo , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Ratos Sprague-Dawley , Proteína Smad3/metabolismo , Proteína Smad3/genética , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismoRESUMO
Background: The blood volume of intraparenchymal vessels is reported to be increased in smokers. However, the blood volume can be affected by many confounders besides tobacco exposure. This study aimed to investigate the association between cigarette smoking and pulmonary blood volume after adjusting the related factors in a large cohort of Chinese males. Methods: In this retrospective study, male participants admitted to the First Affiliated Hospital of Xi'an Jiaotong University for annual health assessment between February 2017 and February 2018 were enrolled. All subjects underwent non-contrast chest computed tomography (CT) scans, and 152 subjects underwent a review CT scan 2-3 years later. A three-dimensional approach was employed to segment the lung and intrapulmonary vessels and quantitative CT (QCT) measurements, including lung volume (LV), intrapulmonary vessel volume (IPVV), low-attenuation area <-950 Hounsfield unit (LAA-950 and LAA-950%), and mean lung density (MLD). Linear regression was used to estimate the association between IPVV and the smoking index (SI). A paired t-test was used to compare the QCT parameters between the initial and follow-up CT scans. Results: A total of 656 male participants were enrolled and classified into three subgroups: non-smokers (n=311), current smokers (n=267), and former smokers (n=78). The IPVV of current smokers (134.62±23.96 vs. 120.76±25.52 mL) and former smokers (130.79±25.13 vs. 120.76±25.52 mL) were significantly larger than that of non-smokers (P<0.05). A higher SI was associated with greater IPVV [non-standardized coefficient: 0.167, 95% confidence interval (CI): 0.086-0.248]. For current smokers, the IPVV of the follow-up scan significantly increased compared to its baseline scan (135.49±28.60 vs. 129.73±29.75 mL, t=-2.326, P=0.02), but for the non-smokers and former smokers, the IPVV of the follow-up scan did not increase or decrease compared to the baseline scan (P>0.05). Conclusions: Pulmonary vascular volumes detectable on non-contrast CT are associated with cigarette exposure, and smoking cessation may prevent pulmonary vasculature remodeling.
RESUMO
Arthropods' eyes are effective biological vision systems for object tracking and wide field of view because of their structural uniqueness; however, unlike mammalian eyes, they can hardly acquire the depth information of a static object because of their monocular cues. Therefore, most arthropods rely on motion parallax to track the object in three-dimensional (3D) space. Uniquely, the praying mantis (Mantodea) uses both compound structured eyes and a form of stereopsis and is capable of achieving object recognition in 3D space. Here, by mimicking the vision system of the praying mantis using stereoscopically coupled artificial compound eyes, we demonstrated spatiotemporal object sensing and tracking in 3D space with a wide field of view. Furthermore, to achieve a fast response with minimal latency, data storage/transportation, and power consumption, we processed the visual information at the edge of the system using a synaptic device and a federated split learning algorithm. The designed and fabricated stereoscopic artificial compound eye provides energy-efficient and accurate spatiotemporal object sensing and optical flow tracking. It exhibits a root mean square error of 0.3 centimeter, consuming only approximately 4 millijoules for sensing and tracking. These results are more than 400 times lower than conventional complementary metal-oxide semiconductor-based imaging systems. Our biomimetic imager shows the potential of integrating nature's unique design using hardware and software codesigned technology toward capabilities of edge computing and sensing.