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Global climate change is accompanied by carbon dioxide (CO2) enrichment and high temperature (HT) stress; however, how plants adapt to the combined environments and the underlying mechanisms remain largely unclear. In this study, we show that elevated CO2 alleviated plant sensitivity to HT stress, with significantly increased apoplastic glucose (Glc) levels in tomato (Solanum lycopersicum) leaves. Exogenous Glc treatment enhanced tomato resilience to HT stress under ambient CO2 conditions. Cell-based biolayer interferometry, subcellular localization, and Split-luciferase assays revealed that Glc bound to the tomato regulator of G protein signaling 1 (RGS1) and induced RGS1 endocytosis and thereby RGS1-G protein α subunit (GPA1) dissociation in a concentration-dependent manner. Using rgs1 and gpa1 mutants, we found that RGS1 negatively regulated thermotolerance and was required for elevated CO2-Glc-induced thermotolerance. GPA1 positively regulated the elevated CO2-Glc-induced thermotolerance. A combined transcriptome and chlorophyll fluorescence parameter analysis further revealed that GPA1 integrated photosynthesis- and photoprotection-related mechanisms to regulate thermotolerance. These results demonstrate that Glc-RGS1-GPA1 signaling plays a crucial role in the elevated CO2-induced thermotolerance in tomato. This information enhances our understanding of the Glc-G protein signaling function in stress resilience in response to global climate change and will be helpful for genetic engineering approaches to improve plant resilience.
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Dióxido de Carbono , Glucose , Transdução de Sinais , Solanum lycopersicum , Solanum lycopersicum/genética , Solanum lycopersicum/fisiologia , Solanum lycopersicum/metabolismo , Dióxido de Carbono/metabolismo , Glucose/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Temperatura Alta , Regulação da Expressão Gênica de Plantas , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/genética , Fotossíntese , Folhas de Planta/metabolismo , Folhas de Planta/fisiologia , Proteínas RGS/metabolismo , Proteínas RGS/genética , Termotolerância/fisiologiaRESUMO
Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, and its risk increases with aging. Yet comprehensive insights into the complex mechanisms are largely unknown. Here, we found that anti-aging molecule Sirt6 was highly expressed in RGCs. Deleting Sirt6 globally or specifically in RGCs led to progressive RGC loss and optic nerve degeneration during aging, despite normal intraocular pressure (IOP), resembling a phenotype of normal-tension glaucoma. These detrimental effects were potentially mediated by accelerated RGC senescence through Caveolin-1 upregulation and by the induction of mitochondrial dysfunction. In mouse models of high-tension glaucoma, Sirt6 level was decreased after IOP elevation. Genetic overexpression of Sirt6 globally or specifically in RGCs significantly attenuated high tension-induced degeneration of RGCs and their axons, whereas partial or RGC-specific Sirt6 deletion accelerated RGC loss. Importantly, therapeutically targeting Sirt6 with pharmacological activator or AAV2-mediated gene delivery ameliorated high IOP-induced RGC degeneration. Together, our studies reveal a critical role of Sirt6 in preventing RGC and optic nerve degeneration during aging and glaucoma, setting the stage for further exploration of Sirt6 activation as a potential therapy for glaucoma.
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Envelhecimento , Modelos Animais de Doenças , Glaucoma , Nervo Óptico , Células Ganglionares da Retina , Sirtuínas , Animais , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Camundongos , Sirtuínas/metabolismo , Sirtuínas/genética , Glaucoma/metabolismo , Glaucoma/genética , Glaucoma/patologia , Glaucoma/etiologia , Nervo Óptico/metabolismo , Nervo Óptico/patologia , Envelhecimento/metabolismo , Envelhecimento/genética , Pressão Intraocular , Humanos , Axônios/metabolismo , Axônios/patologia , Camundongos Knockout , Degeneração Neural/metabolismoRESUMO
Sodium-ion batteries (SIBs) are experiencing a large-scale renaissance to supplement or replace expensive lithium-ion batteries (LIBs) and low energy density lead-acid batteries in electrical energy storage systems and other applications. In this case, layered oxide materials have become one of the most popular cathode candidates for SIBs because of their low cost and comparatively facile synthesis method. However, the intrinsic shortcomings of layered oxide cathodes, which severely limit their commercialization process, urgently need to be addressed. In this review, inherent challenges associated with layered oxide cathodes for SIBs, such as their irreversible multiphase transition, poor air stability, and low energy density, are systematically summarized and discussed, together with strategies to overcome these dilemmas through bulk phase modulation, surface/interface modification, functional structure manipulation, and cationic and anionic redox optimization. Emphasis is placed on investigating variations in the chemical composition and structural configuration of layered oxide cathodes and how they affect the electrochemical behavior of the cathodes to illustrate how these issues can be addressed. The summary of failure mechanisms and corresponding modification strategies of layered oxide cathodes presented herein provides a valuable reference for scientific and practical issues related to the development of SIBs.
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O3-type layered oxides have been extensively studied as cathode materials for sodium-ion batteries due to their high reversible capacity and high initial sodium content, but they suffer from complex phase transitions and an unstable structure during sodium intercalation/deintercalation. Herein, we synthesize a high-entropy O3-type layered transition metal oxide, NaNi0.3Cu0.05Fe0.1Mn0.3Mg0.05Ti0.2O2 (NCFMMT), by simultaneously doping Cu, Mg, and Ti into its transition metal layers, which greatly increase structural entropy, thereby reducing formation energy and enhancing structural stability. The high-entropy NCFMMT cathode exhibits significantly improved cycling stability (capacity retention of 81.4% at 1C after 250 cycles and 86.8% at 5C after 500 cycles) compared to pristine NaNi0.3Fe0.4Mn0.3O2 (71% after 100 cycles at 1C), as well as remarkable air stability. Finally, the NCFMMT//hard carbon full-cell batteries deliver a high initial capacity of 103 mAh g-1 at 1C, with 83.8 mAh g-1 maintained after 300 cycles (capacity retention of 81.4%).
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BACKGROUND: Surgical site infection (SSI) is a common and costly complication in spinal surgery. Identifying risk factors and preventive strategies is crucial for reducing SSIs. GPT-4 has evolved from a simple text-based tool to a sophisticated multimodal data expert, invaluable for clinicians. This study explored GPT-4's applications in SSI management across various clinical scenarios. METHODS: GPT-4 was employed in various clinical scenarios related to SSIs in spinal surgery. Researchers designed specific questions for GPT-4 to generate tailored responses. Six evaluators assessed these responses for logic and accuracy using a 5-point Likert scale. Inter-rater consistency was measured with Fleiss' kappa, and radar charts visualized GPT-4's performance. RESULTS: The inter-rater consistency, measured by Fleiss' kappa, ranged from 0.62 to 0.83. The overall average scores for logic and accuracy were 24.27±0.4 and 24.46±0.25 on 5-point Likert scale. Radar charts showed GPT-4's consistently high performance across various criteria. GPT-4 demonstrated high proficiency in creating personalized treatment plans tailored to diverse clinical patient records and offered interactive patient education. It significantly improved SSI management strategies, infection prediction models, and identified emerging research trends. However, it had limitations in fine-tuning antibiotic treatments and customizing patient education materials. CONCLUSIONS: GPT-4 represents a significant advancement in managing SSIs in spinal surgery, promoting patient-centered care and precision medicine. Despite some limitations in antibiotic customization and patient education, GPT-4's continuous learning, attention to data privacy and security, collaboration with healthcare professionals, and patient acceptance of AI recommendations suggest its potential to revolutionize SSI management, requiring further development and clinical integration.
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The glycosaminoglycan hyaluronan (HA) plays an important role in tumor progression. However, its biological and clinical significance in papillary thyroid cancer (PTC) remains unknown. Immunohistochemistry was performed to examine HA expression in tissues from PTC patients. Two PTC cell lines were treated with HA synthesized inhibitor against HA production to assess its function. Serum HA levels from 107 PTC patients, 30 Hashimoto thyroiditis patients, and 45 normal controls (NC) were measured by chemiluminescence immunoassay. HA levels in fine needle aspiration (FNA) washouts obtained from thyroid nodules and lymph nodes (LNs) were measured by chemiluminescence immunoassay. Area under the curve (AUC) was computed to evaluate HA's clinical value. HA was highly expressed in PTC. Reducing HA production significantly inhibited PTC cell proliferation and invasion. Importantly, serum HA levels in PTC were significantly higher than those in NCs and Hashimoto thyroiditis and allowed distinguishing of thyroid cancers from NCs with high accuracy (AUC = 0.782). Moreover, elevated serum HA levels in PTC correlate with LN metastasis. HA levels in FNA washouts from PTC patients were significantly higher than those in benign controls, with a high AUC value (0.8644) for distinguishing PTC from benign controls. Furthermore, HA levels in FNA washouts from metastatic LN were significantly higher than those in nonmetastatic LN, with a high AUC value (0.8007) for distinguishing metastatic LNs from nonmetastatic LNs. HA levels in serum and FNA washout exhibited a potential significance for PTC diagnosis and an indicator for LN metastasis in patients with PTC.
Assuntos
Carcinoma Papilar , Ácido Hialurônico , Metástase Linfática , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Ácido Hialurônico/sangue , Ácido Hialurônico/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/diagnóstico , Adulto , Carcinoma Papilar/metabolismo , Carcinoma Papilar/diagnóstico , Linhagem Celular Tumoral , Carcinoma/metabolismo , Carcinoma/diagnóstico , Carcinoma/patologia , Linfonodos/patologia , Linfonodos/metabolismo , Doença de Hashimoto/metabolismo , Doença de Hashimoto/sangue , Doença de Hashimoto/patologia , Doença de Hashimoto/diagnóstico , Biópsia por Agulha Fina , Idoso , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/sangue , Proliferação de CélulasRESUMO
Irritable bowel syndrome (IBS), which is characterized by chronic abdominal pain, has a high global prevalence. The anterior cingulate cortex (ACC), which is a pivotal region involved in pain processing, should be further investigated regarding its role in the regulation of visceral sensitivity and mental disorders. A C57BL/6J mouse model for IBS was established using chronic acute combining stress (CACS). IBS-like symptoms were assessed using behavioral tests, intestinal motility measurements, and abdominal withdrawal reflex scores. Fluoro-Gold retrograde tracing and immunohistochemistry techniques were employed to investigate the projection of ACC gamma-aminobutyric acid-producing (GABAergic) neurons to the lateral hypothalamus area (LHA). Chemogenetic approaches enabled the selective activation or inhibition of the ACC-LHA GABAergic pathway. Enzyme-linked immunosorbent assay (ELISA) and western blot analyses were conducted to determine the expression of histamine, 5-hydroxytryptamine (5-HT), and transient receptor potential vanilloid 4 (TRPV4). Our findings suggest that CACS induced IBS-like symptoms in mice. The GABA type A receptors (GABAAR) within LHA played a regulatory role in modulating IBS-like symptoms. The chemogenetic activation of ACC-LHA GABAergic neurons elicited anxiety-like behaviors, intestinal dysfunction, and visceral hypersensitivity in normal mice; however, these effects were effectively reversed by the administration of the GABAAR antagonist Bicuculline. Conversely, the chemogenetic inhibition of ACC-LHA GABAergic neurons alleviated anxiety-like behaviors, intestinal dysfunction, and visceral hypersensitivity in the mouse model for IBS. These results highlight the crucial involvement of the ACC-LHA GABAergic pathway in modulating anxiety-like behaviors, intestinal motility alterations, and visceral hypersensitivity, suggesting a potential therapeutic strategy for alleviating IBS-like symptoms.
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Sevoflurane, the predominant pediatric anesthetic, has been linked to neurotoxicity in young mice, although the underlying mechanisms remain unclear. This study focuses on investigating the impact of neonatal sevoflurane exposure on cell-type-specific alterations in the prefrontal cortex (PFC) of young mice. Neonatal mice were subjected to either control treatment (60% oxygen balanced with nitrogen) or sevoflurane anesthesia (3% sevoflurane in 60% oxygen balanced with nitrogen) for 2 hours on postnatal days (PNDs) 6, 8, and 10. Behavioral tests and single-nucleus RNA sequencing (snRNA-seq) of the PFC were conducted from PNDs 31 to 37. Mechanistic exploration included clustering analysis, identification of differentially expressed genes (DEGs), enrichment analyses, single-cell trajectory analysis, and genome-wide association studies (GWAS). Sevoflurane anesthesia resulted in sociability and cognition impairments in mice. Novel specific marker genes identified 8 distinct cell types in the PFC. Most DEGs between the control and sevoflurane groups were unique to specific cell types. Re-defining 15 glutamatergic neuron subclusters based on layer identity revealed their altered expression profiles. Notably, sevoflurane disrupted the trajectory from oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). Validation of disease-relevant candidate genes across the main cell types demonstrated their association with social dysfunction and working memory impairment. Behavioral results and snRNA-seq collectively elucidated the cellular atlas in the PFC of young male mice, providing a foundation for further mechanistic studies on developmental neurotoxicity induced by anesthesia.
Assuntos
Anestésicos Inalatórios , Córtex Pré-Frontal , Sevoflurano , Animais , Sevoflurano/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Camundongos , Anestésicos Inalatórios/toxicidade , Masculino , Animais Recém-Nascidos , Feminino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Estudo de Associação Genômica AmplaRESUMO
BACKGROUND: Sunitinib has emerged as the primary treatment for advanced or metastatic clear cell renal cell carcinoma (ccRCC) due to its significant improvement in patients' average survival time. However, drug resistance and adverse effects of sunitinib pose challenges to its clinical benefits. METHODS: The differentially expressed genes (DEGs) associated with sunitinib sensitivity and resistance in ccRCC were investigated. Cell counting kit-8, plate colony formation, flow cytometry and subcutaneous xenograft tumor model assays were employed to explore the effects of PDZK1 on ccRCC. Further research on the molecular mechanism was conducted through western blot, co-immunoprecipitation, immunofluorescence co-localization and immunohistochemical staining. RESULTS: We elucidated that PDZK1 is significantly downregulated in sunitinib-resistant ccRCC specimens, and PDZK1 negatively regulates the phosphorylation of PDGFR-ß and the activation of its downstream pathways through interaction with PDGFR-ß. The dysregulated low levels of PDZK1 contribute to inadequate inhibition of cell proliferation, tumor growth, and insensitivity to sunitinib treatment. Notably, our preclinical investigations showed that miR-15b antagomirs enhance sunitinib cytotoxic effects against ccRCC cells by upregulating PDZK1 levels, suggesting their potential in overcoming sunitinib resistance. CONCLUSIONS: Our findings establish the miR-15b/PDZK1/PDGFR-ß axis as a promising therapeutic target and a novel predictor for ccRCC patients' response to sunitinib treatment.
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Carcinoma de Células Renais , Resistencia a Medicamentos Antineoplásicos , Neoplasias Renais , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Sunitinibe , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Humanos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Animais , Resistencia a Medicamentos Antineoplásicos/genética , Camundongos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , MicroRNAs/genética , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos Nus , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismoRESUMO
Lung cancer poses a significant threat globally, especially in China. This puts higher demands on the treatment methods and drugs for lung cancer. Natural plants provide valuable resources for the development of anti-cancer drugs. Hederagenin (Hed) is a triterpenoid compound extracted from ivy leaves and has anti-tumor activity against multifarious cancers, including lung cancer. However, the regulatory mechanism of Hed in lung cancer remains unclear. In this study, we used Hed to treat lung cancer cells, and observed the effect of Hed on cell proliferation (including CCK-8 and colony formation experiments), apoptosis (including flow cytometry and apoptosis gene detection (BAX and Bcl-2)). The results showed that Hed induced lung cancer cell death (inhibiting proliferation and promoting apoptosis). Next, we performed bioinformatics analysis of the expression profile GSE186218 and found that Hed treatment significantly increased the expression of CHAC1 gene. CHAC1 is a ferroptosis-inducing gene. RT-qPCR detection of lung cancer clinical tissues and related cell lines also showed that CHAC1 was lowly expressed in lung cancer. Therefore, we knocked down and overexpressed CHAC1 in lung cancer cells, respectively. Subsequently, cell phenotype experiments showed that down-regulating CHAC1 expression inhibited lung cancer cell death (promoting proliferation and inhibiting apoptosis); on the contrary, up-regulating CHAC1 expression promoted lung cancer cell death. To further verify that Hed exerts anti-tumor effects in lung cancer by promoting CHAC1 expression, we performed functional rescue experiments. The results showed that down-regulating CHAC1 expression reversed the promoting effect of Hed on lung cancer cell death. Mechanistically, in vitro and in vivo experiments jointly demonstrated that Hed exerts anti-cancer effects by promoting CHAC1-induced ferroptosis. In summary, our study further enriches the regulatory mechanism of Hed in lung cancer.
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Proliferação de Células , Ferroptose , Neoplasias Pulmonares , Ácido Oleanólico , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células A549 , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Bacterial wilt caused by Ralstonia solanacearum severely affects peanut (Arachis hypogaea L.) yields. The breeding of resistant cultivars is an efficient means of controlling plant diseases. Therefore, identification of resistance genes effective against bacterial wilt is a matter of urgency. The lack of a reference genome for a resistant genotype severely hinders the process of identification of resistance genes in peanut. In addition, limited information is available on disease resistance-related pathways in peanut. RESULTS: Full-length transcriptome data were used to generate wilt-resistant and -susceptible transcript pools. In total, 253,869 transcripts were retained to form a reference transcriptome for RNA-sequencing data analysis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of differentially expressed genes revealed the plant-pathogen interaction pathway to be the main resistance-related pathway for peanut to prevent bacterial invasion and calcium plays an important role in this pathway. Glutathione metabolism was enriched in wilt-susceptible genotypes, which would promote glutathione synthesis in the early stages of pathogen invasion. Based on our previous quantitative trait locus (QTL) mapping results, the genes arahy.V6I7WA and arahy.MXY2PU, which encode nucleotide-binding site-leucine-rich repeat receptor proteins, were indicated to be associated with resistance to bacterial wilt. CONCLUSIONS: This study identified several pathways associated with resistance to bacterial wilt and identified candidate genes for bacterial wilt resistance in a major QTL region. These findings lay a foundation for investigation of the mechanism of resistance to bacterial wilt in peanut.
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Arachis , Ralstonia solanacearum , Arachis/genética , Arachis/microbiologia , Transcriptoma , Ralstonia solanacearum/fisiologia , Melhoramento Vegetal , Resistência à Doença/genética , Glutationa/genética , Doenças das Plantas/genética , Doenças das Plantas/microbiologiaRESUMO
Developing low-cost and highly efficient bifunctional catalysts for both the oxygen evolution reaction (OER) and the hydrogen evolution reaction (HER) is a challenging problem in electrochemical overall water splitting. Here, iron, tungsten dual-doped nickel sulfide catalyst (Fe/W-Ni3S2) is synthesized on the nickel foam, and it exhibits excellent OER and HER performance. As a result, the water electrolyze based on Fe/W-Ni3S2 bifunctional catalyst illustrates 10 mA cm-2 at 1.69 V (without iR-compensation) and highly durable overall water splitting over 100 h tested under 500 mA cm-2. Experimental results and DFT calculations indicate that the synergistic interaction between Fe doping and Ni vacancy induced by W leaching during the in situ oxidation process can maximize exposed OER active sites on the reconstructed NiOOH species for accelerating OER kinetics, while the Fe/W dual-doping optimizes the electronic structure of Fe/W-Ni3S2 and the binding strength of intermediates for boosting HER. This study unlocks the different promoting mechanisms of incorporating Fe and W for boosting the OER and HER activity of Ni3S2 for water splitting, which provides significant guidance for designing high-performance bifunctional catalysts for overall water splitting.
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Increasing studies suggest that the biased retention of stress-related transcription factors (TFs) after whole-genome duplications (WGDs) could rewire gene transcriptional networks, facilitating plant adaptation to challenging environments. However, the role of posttranscriptional factors (e.g. RNA-binding proteins, RBPs) following WGDs has been largely ignored. Uncovering thousands of RBPs in 21 representative angiosperm species, we integrate genomic, transcriptomic, regulatomic, and paleotemperature datasets to unravel their evolutionary trajectories and roles in adapting to challenging environments. We reveal functional enrichments of RBP genes in stress responses and identify their convergent retention across diverse angiosperms from independent WGDs, coinciding with global cooling periods. Numerous RBP duplicates derived from WGDs are then identified as cold-induced. A significant overlap of 29 orthogroups between WGD-derived and cold-induced RBP genes across diverse angiosperms highlights a correlation between WGD and cold stress. Notably, we unveil an orthogroup (Glycine-rich RNA-binding Proteins 7/8, GRP7/8) and relevant TF duplicates (CCA1/LHY, RVE4/8, CBF2/4, etc.), co-retained in different angiosperms post-WGDs. Finally, we illustrate their roles in rewiring circadian and cold-regulatory networks at both transcriptional and posttranscriptional levels during global cooling. Altogether, we underline the adaptive evolution of RBPs in angiosperms after WGDs during global cooling, improving our understanding of plants surviving periods of environmental turmoil.
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Magnoliopsida , Magnoliopsida/genética , Filogenia , Evolução Molecular , Genoma de Planta , Duplicação Gênica , Plantas/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
BACKGROUND: It's unclear if excess visceral adipose tissue (VAT) mass in individuals with prediabetes can be countered by adherence to a Mediterranean lifestyle (MEDLIFE). We aimed to examine VAT mass, MEDLIFE adherence, and their impact on type 2 diabetes (T2D) and diabetic microvascular complications (DMC) in individuals with prediabetes. METHODS: 11,267 individuals with prediabetes from the UK Biobank cohort were included. VAT mass was predicted using a non-linear model, and adherence to the MEDLIFE was evaluated using the 25-item MEDLIFE index, encompassing categories such as "Mediterranean food consumption," "Mediterranean dietary habits," and "Physical activity, rest, social habits, and conviviality." Both VAT and MEDLIFE were categorized into quartiles, resulting in 16 combinations. Incident cases of T2D and related DMC were identified through clinical records. Cox proportional-hazards regression models were employed to examine associations, adjusting for potential confounding factors. RESULTS: Over a median follow-up of 13.77 years, we observed 1408 incident cases of T2D and 714 cases of any DMC. High adherence to the MEDLIFE, compared to the lowest quartile, reduced a 16% risk of incident T2D (HR: 0.84, 95% CI: 0.71-0.98) and 31% for incident DMC (0.69, 0.56-0.86). Conversely, compared to the lowest quartile of VAT, the highest quartile increased the risk of T2D (5.95, 4.72-7.49) and incident any DMC (1.79, 1.36-2.35). We observed an inverse dose-response relationship between MEDLIFE and T2D/DMC, and a dose-response relationship between VAT and all outcomes (P for trend < 0.05). Restricted cubic spline analysis confirmed a nearly linear dose-response pattern across all associations. Compared to individuals with the lowest MEDLIFE quartile and highest VAT quartile, those with the lowest T2D risk had the lowest VAT and highest MEDLIFE (0.12, 0.08-0.19). High MEDLIFE was linked to reduced T2D risk across all VAT categories, except in those with the highest VAT quartile. Similar trends were seen for DMC. CONCLUSION: High adherence to MEDLIFE reduced T2D and MDC risk in individuals with prediabetes, while high VAT mass increases it, but MEDLIFE adherence may offset VAT's risk partly. The Mediterranean lifestyle's adaptability to diverse populations suggests promise for preventing T2D.
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Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Dieta Mediterrânea , Gordura Intra-Abdominal , Estado Pré-Diabético , Fatores de Proteção , Comportamento de Redução do Risco , Humanos , Estado Pré-Diabético/epidemiologia , Estado Pré-Diabético/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Gordura Intra-Abdominal/fisiopatologia , Idoso , Fatores de Risco , Medição de Risco , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/prevenção & controle , Fatores de Tempo , Incidência , Adiposidade , Reino Unido/epidemiologia , Adulto , Dieta Saudável , Exercício Físico , Estilo de Vida Saudável , Obesidade Abdominal/diagnóstico , Obesidade Abdominal/epidemiologia , Obesidade Abdominal/fisiopatologia , Estudos ProspectivosRESUMO
Sodium-oxygen batteries have been regarded as promising energy storage devices due to their low overpotential and high energy density. Its applications, however, still face formidable challenges due to the lack of understanding about the influence of electrocatalysts on the discharge products. Here, a phosphorous and nitrogen dual-doped carbon (PNDC) based cathode is synthesized to increase the electrocatalytic activity and to stabilize the NaO2 superoxide nanoparticle discharge products, leading to enhanced cycling stability when compared to the nitrogen-doped carbon (NDC). The PNDC air cathode exhibits a low overpotential (0.36 V) and long cycling stability (120 cycles). The reversible formation/decomposition and stabilization of the NaO2 discharge products are clearly proven by in-situ synchrotron X-ray diffraction and ex-situ X-ray diffraction. Based on the density functional theory calculation, the PNDC has much stronger adsorption energy (-2.85 eV) for NaO2 than that of NDC (-1.80 eV), which could efficiently stabilize the NaO2 discharge products.
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BACKGROUND: Surgical therapy is the most optimal treatment for hepatocellular carcinoma (HCC) combined with bile duct tumor thrombus (BDTT) patients. However, whether to perform bile duct resection (BDR) is still controversial. The purpose of this multicenter research is to compare the effect of BDR on the prognosis of extrahepatic BDTT patients. METHODS: We collected the data of 111 HCC patients combined with extrahepatic BDTT who underwent radical hepatectomy from June 1, 2004 to December 31, 2021. Those patients had either received hepatectomy with extrahepatic bile duct resection (BDR group) or hepatectomy without bile duct resection (NBDR group). Inverse probability of treatment weighting (IPTW) was used to reduce the potential bias between two groups and balance the influence of confounding factors in baseline data. Then compare the prognosis between the two groups of patients. Cox regression model was used for univariate and multivariate analysis to further determine the independent risk factors that influence the prognosis of HCC-BDTT patients. RESULTS: There were 38 patients in the BDR group and 73 patients in the NBDR group. Before and after IPTW, there were no statistical significance in OS, RFS and intraoperative median blood loss between the two groups (all P > 0.05). Before IPTW, the median postoperative hospital stay in the NBDR group was shorter (P = 0.046) and the grade of postoperative complications was lower than BDR group (P = 0.014). After IPTW, there was no difference in postoperative hospital stay between the two groups (P > 0.05). The complication grade in the NBDR group was still lower than that in the BDR group (P = 0.046). The univariate analysis showed that TNM stage and portal vein tumor thrombus (PVTT) were significantly correlated with OS (both P < 0.05). Preoperative AFP level, TNM stage and prognostic nutritional index (PNI) were significantly correlated with postoperative RFS (all P < 0.05). Multivariate analysis showed that tumor TNM stage was an independent risk factor for the OS rate (P = 0.014). TNM stage, PNI and AFP were independent predictors of RFS after radical hepatectomy (all P < 0.05). CONCLUSIONS: For HCC-BDTT patients, hepatocellular carcinoma resection combined with choledochotomy to remove the tumor thrombus may benefit more.
Assuntos
Ductos Biliares Extra-Hepáticos , Carcinoma Hepatocelular , Hepatectomia , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/complicações , Masculino , Feminino , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/complicações , Pessoa de Meia-Idade , Prognóstico , Ductos Biliares Extra-Hepáticos/cirurgia , Ductos Biliares Extra-Hepáticos/patologia , Trombose/cirurgia , Trombose/etiologia , Trombose/patologia , Estudos Retrospectivos , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/mortalidade , Idoso , AdultoRESUMO
Carbonyl reductases are useful for producing optically active alcohols from their corresponding prochiral ketones. Herein, we applied a computer-assisted strategy to increase the thermostability of a previously constructed carbonyl reductase, LsCRM4 (N101D/A117G/F147L/E145A), which showed an outstanding activity in the synthesis of the ticagrelor precursor (1S)-2-chloro-1-(3,4-difluorophenyl)ethanol. The stability changes introduced by mutations at the flexible sites were predicted using the computational tools FoldX, I-Mutant 3.0, and DeepDDG, which demonstrated that 12 virtually screened mutants could be thermally stable; 11 of these mutants exhibited increased thermostability. Then a superior mutant LsCRM4-V99L/D150F was screened out from the library that was constructed by iteratively combining the beneficial sites, which showed a 78% increase in activity and a 17.4°C increase in melting temperature compared to LsCRM4. Our computer-assisted design and combinatorial strategy dramatically increased the efficiency of thermostable enzyme production.
Assuntos
Oxirredutases do Álcool , Etanol , Ticagrelor , Estabilidade Enzimática , Oxirredutases do Álcool/genética , Temperatura , ComputadoresRESUMO
Pulmonary fibrosis (PF) is a progressive interstitial inflammatory disease with a high mortality rate. Patients with PF commonly experience a chronic dry cough and progressive dyspnoea for years without effective mitigation. The pathogenesis of PF is believed to be associated with dysfunctional macrophage polarization, fibroblast proliferation, and the loss of epithelial cells. Thus, it is of great importance and necessity to explore the interactions among macrophages, fibroblasts, and alveolar epithelial cells in lung fibrosis, as well as in the pro-fibrotic microenvironment. In this review, we discuss the latest studies that have investigated macrophage polarization and activation of non-immune cells in the context of PF pathogenesis and progression. Next, we discuss how profibrotic cellular crosstalk is promoted in the PF microenvironment by multiple cytokines, chemokines, and signalling pathways. And finally, we discuss the potential mechanisms of fibrogenesis development and efficient therapeutic strategies for the disease. Herein, we provide a comprehensive summary of the vital role of macrophage polarization in PF and its profibrotic crosstalk with fibroblasts and alveolar epithelial cells and suggest potential treatment strategies to target their cellular communication in the microenvironment.
Assuntos
Fibrose Pulmonar , Humanos , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose , Macrófagos/metabolismo , Citocinas/metabolismo , Transdução de Sinais , Fibroblastos/metabolismoRESUMO
Acute kidney injury (AKI) is closely related to lysosomal dysfunction and ferroptosis in renal tubular epithelial cells (TECs), for which effective treatments are urgently needed. Although selenium nanoparticles (SeNPs) have emerged as promising candidates for AKI therapy, their underlying mechanisms have not been fully elucidated. Here, we investigated the effect of SeNPs on hypoxia/reoxygenation (H/R)-induced ferroptosis and lysosomal dysfunction in TECs in vitro and evaluated their efficacy in a murine model of ischemia/reperfusion (I/R)-AKI. We observed that H/R-induced ferroptosis was accompanied by lysosomal Fe2+ accumulation and dysfunction in TECs, which was ameliorated by SeNPs administration. Furthermore, SeNPs protected C57BL/6 mice against I/R-induced inflammation and ferroptosis. Mechanistically, we found that lysosomal Fe2+ accumulation and ferroptosis were associated with the excessive activation of NCOA4-mediated ferritinophagy, a process mitigated by SeNPs through the upregulation of X-box binding protein 1 (XBP1). Downregulation of XBP1 promoted ferritinophagy and partially counteracted the protective effects of SeNPs on ferroptosis inhibition in TECs. Overall, our findings revealed a novel role for SeNPs in modulating ferritinophagy, thereby improving lysosomal function and attenuating ferroptosis of TECs in I/R-AKI. These results provide evidence for the potential application of SeNPs as therapeutic agents for the prevention and treatment of AKI.
Assuntos
Ferroptose , Nanopartículas , Traumatismo por Reperfusão , Selênio , Proteína 1 de Ligação a X-Box , Animais , Humanos , Masculino , Camundongos , Injúria Renal Aguda/patologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/tratamento farmacológico , Autofagia/efeitos dos fármacos , Ferritinas/metabolismo , Ferroptose/efeitos dos fármacos , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Coativadores de Receptor Nuclear/metabolismo , Coativadores de Receptor Nuclear/genética , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Selênio/farmacologia , Selênio/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Proteína 1 de Ligação a X-Box/metabolismo , Proteína 1 de Ligação a X-Box/genéticaRESUMO
BACKGROUND: Preventing emergence delirium is a clinical goal for pediatric anesthesia, yet there is no consensus on its prevention. This study investigated the hypothesis that a continuous infusion or a single bolus of remimazolam can reduce the incidence of emergence delirium in children. METHODS: A total of 120 children aged 1 to 6 yr were randomly and equally allocated into three groups: group RC, which received a continuous infusion of remimazolam at 1 mg · kg-1 · h-1; group RB, which received a single bolus of remimazolam at 0.2 mg · kg-1 at the beginning of wound closure; and group C, which received a continuous infusion of saline at 1 ml · kg-1 · h-1 and a single bolus of saline at 0.2 ml · kg-1 at the beginning of sutures. The primary outcome was the incidence of emergence delirium assessed by the Pediatric Anesthesia Emergence Delirium scale. Secondary outcomes included the number of rescue propofol administrations in the postanesthesia care unit, recovery time, and adverse events. RESULTS: Emergence delirium was observed in 14 of 40 (35%) patients in group C, 2 of 40 (5%) patients in group RC (vs. group C, P = 0.001; risk ratio, 95% CI: 0.14, 0.04 to 0.59), and 3 of 39 (7.7%) patients in group RB (vs. group C, P = 0.003; risk ratio, 95% CI: 0.22, 0.07 to 0.71). Ten of 40 patients in group C, 2 of 40 patients in group RC (vs. group C, P = 0.012; risk ratio, 95% CI: 0.20, 0.05 to 0.86), and 2 of 39 patients in group RB (vs. group C, P = 0.014; risk ratio, 95% CI: 0.21, 0.05 to 0.88) needed rescue propofol. No differences in the recovery time and adverse effects were detected. CONCLUSIONS: Both continuous infusion and single bolus administration of remimazolam can effectively reduce the occurrence of emergence delirium in children.