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Fibrosis can develop in most organs and causes organ failure. The most common type of lung fibrosis is known as idiopathic pulmonary fibrosis, in which fibrosis starts at the lung periphery and then progresses toward the lung center, eventually causing respiratory failure. Little is known about the mechanisms underlying the pathogenesis and periphery-to-center progression of the disease. Here we discovered that loss of Cdc42 function in alveolar stem cells (AT2 cells) causes periphery-to-center progressive lung fibrosis. We further show that Cdc42-null AT2 cells in both post-pneumonectomy and untreated aged mice cannot regenerate new alveoli, resulting in sustained exposure of AT2 cells to elevated mechanical tension. We demonstrate that elevated mechanical tension activates a TGF-ß signaling loop in AT2 cells, which drives the periphery-to-center progression of lung fibrosis. Our study establishes a direct mechanistic link between impaired alveolar regeneration, mechanical tension, and progressive lung fibrosis.
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Células-Tronco Adultas/metabolismo , Fibrose Pulmonar Idiopática/etiologia , Alvéolos Pulmonares/metabolismo , Células-Tronco Adultas/patologia , Idoso , Células Epiteliais Alveolares/patologia , Animais , Fenômenos Biomecânicos/fisiologia , Feminino , Fibrose/patologia , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Alvéolos Pulmonares/patologia , Regeneração , Transdução de Sinais , Células-Tronco/patologia , Estresse Mecânico , Estresse Fisiológico/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Proteína cdc42 de Ligação ao GTP/genética , Proteína cdc42 de Ligação ao GTP/metabolismoRESUMO
Although the locus coeruleus (LC) is recognized as a crucial modulator for attention and perception by releasing norepinephrine into various cortical regions, the impact of LC-noradrenergic (NE) modulation on auditory discrimination behavior remains elusive. In this study, we firstly recorded local field potential (LFP) and single-unit activity (SUA) in multiple cortical regions associated with auditory-motor processing, including the auditory cortex (AC), posterior parietal cortex (PPC), secondary motor cortex (M2), anterior cingulate cortex (ACC), prefrontal cortex (PFC), and orbitofrontal cortex (OFC), in response to optogenetic activation (40Hz and 0.5s) of the LC-NE neurons in awake mice (male). We found that phasic LC stimulation induced a persistent high gamma oscillations (50 - 80Hz) in the OFC. Phasic activation of LC-NE neurons also resulted in a corresponding increase in NE levels in the OFC, accompanied by a pupillary dilation response. Furthermore, when mice were performing a Go/No-go auditory discrimination task, we optogeneticaly activated the neural projections from LC to OFC, and revealed a shortened latency in behavioral responses to sound stimuli and an increased false alarm rate. These impulsive behavioral responses may be associated with the gamma neural activity in the OFC. These findings have broadened our understanding of the neural mechanisms involved in the role of LC in auditory-motor processing.Significance Statement The locus coeruleus (LC) plays a vital role in mediating behaviors related to perception, but the underlying mechanisms remain unclear. Using optogenetic techniques, we selectively activated the neural projections from the norepinephrine (NE) neurons of LC to the orbitofrontal cortex (OFC). We found that phasical activation of LC neurons increased NE levels in the OFC and induced a gamma band neuronal activity, while also shortening the reaction latency of mice in auditory discrimination tasks, but at the cost of increased false alarm rates. These results reveal a neural mechanism involving the LC in auditory-motor processing, providing a new perspective for understanding attention and perception.
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BACKGROUND: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases. METHODS: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms. RESULTS: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH. CONCLUSIONS: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.
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Millions of patients suffer from silicosis, but it remains an uncurable disease due to its unclear pathogenic mechanisms. Though the Nlrp3 inflammasome is involved in silicosis pathogenesis, inhibition of its classic downstream factors, Caspase-1 and Gsdmd, fails to block pyroptosis and cytokine release. To clarify the molecular mechanism of silicosis pathogenesis for new therapy, we examined samples from silicosis patients and genetic mouse models. We discovered an alternative pyroptotic pathway which requires cleavage of Gsdme by Caspases-3/8 in addition to Caspase-1/Gsdmd. Consistently, Gsdmd-/-Gsdme-/- mice showed markedly attenuated silicosis pathology, and Gsdmd-/-Gsdme-/- macrophages were resistant to silica-induced pyroptosis. Furthermore, we found that in addition to Caspase 1, Caspase-8 cleaved IL-1ß in silicosis, explaining why Caspase-1-/- mice also suffered from silicosis. Finally, we found that inhibitors of Caspase-1, -3, -8 or an FDA approved drug, dimethyl fumarate, could dramatically alleviate silicosis pathology through blocking cleavage of Gsdmd and Gsdme. This study highlights that Caspase-1/Gsdmd and Caspase-3/8/Gsdme-dependent pyroptosis is essential for the development of silicosis, implicating new potential targets and drug for silicosis treatment.
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Silicose , Camundongos , Animais , Caspase 8 , Caspase 1/genética , Caspase 3/genética , Silicose/tratamento farmacológico , Silicose/genética , Piroptose/genéticaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic options. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here, we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2) was increased in the lungs of patients with pulmonary fibrosis and mice with bleomycin (BLM)-induced pulmonary fibrosis. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix deposition of fibroblasts, whereas overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis after BLM treatment was observed in GOLM1-knock-in mice, whereas BLM-treated Golm1-knockout mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and extracellular matrix production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through the GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent a novel therapeutic strategy for treating pulmonary fibrosis.
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Fibrose Pulmonar Idiopática , Animais , Humanos , Camundongos , Bleomicina , Matriz Extracelular , Fibroblastos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Proteínas de Membrana/genética , Camundongos Knockout , Regulação para CimaRESUMO
Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in the central nervous system, yet their role in vestibular compensation remains elusive. To address this knowledge gap, we employed unilateral labyrinthectomy (UL) in rats to establish animal models of peripheral vestibular dysfunction. Utilizing ribonucleic acid sequencing (RNA-seq), we comprehensively analysed the expression profiles of genes dysregulated in the medial vestibular nucleus (MVN) of these rats at distinct time points: 4 h, 4 days, and 14 days post-UL. Through trans-target prediction analysis integrating differentially co-expressed messenger RNAs (mRNAs) and lncRNAs, we constructed lncRNA-mRNA regulatory networks. Validation of selected mRNAs and lncRNAs was performed using RT-qPCR. Our RNA-seq analysis revealed significant aberrant expression of 3054 lncRNAs and 1135 mRNAs compared to control samples. By applying weighted gene co-expression network analysis (WGCNA), we identified 11 co-expressed modules encompassing all genes. Notably, within the MEmagenta module, we observed an initial upregulation of differentially expressed genes (DEGs) at 4 h, followed by downregulation at 4- and 14-days post-UL. Our findings indicated that 3068 lncRNAs positively regulated 1259 DEGs, while 1482 lncRNAs negatively regulated 433 DEGs in the MVN. The RT-qPCR results corroborated the RNA-seq data, validating our findings. This study offers novel insights into the lncRNA-mRNA expression landscape during vestibular compensation, paving the way for further exploration of lncRNA functions in this context.
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Perfilação da Expressão Gênica , Redes Reguladoras de Genes , RNA Longo não Codificante , RNA Mensageiro , Núcleos Vestibulares , Vestíbulo do Labirinto , Animais , Núcleos Vestibulares/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Masculino , Vestíbulo do Labirinto/cirurgia , Vestíbulo do Labirinto/metabolismo , Regulação da Expressão Gênica , Ratos Sprague-Dawley , Transcriptoma/genéticaRESUMO
Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin-proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues.
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Enzimas Desubiquitinantes , Neoplasias , Complexo de Endopeptidases do Proteassoma , Ubiquitinação , Humanos , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Complexo de Endopeptidases do Proteassoma/metabolismo , Enzimas Desubiquitinantes/metabolismo , Proteólise , Ubiquitina/metabolismo , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Processamento de Proteína Pós-Traducional , Terapia de Alvo Molecular , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Previous studies on the intricate interactions between plants and microorganisms have revealed that fungal volatile compounds (VCs) can affect plant growth and development. However, the precise mechanisms underlying these actions remain to be delineated. In this study, we discovered that VCs from the soilborne fungus Tolypocladium inflatum GT22 enhance the growth of Arabidopsis. Remarkably, priming Arabidopsis with GT22 VCs caused the plant to display an enhanced immune response and mitigated the detrimental effects of both pathogenic infections and copper stress. Transcriptomic analyses of Arabidopsis seedlings treated with GT22 VCs for 3, 24 and 48 h revealed that 90, 83 and 137 genes were differentially expressed, respectively. The responsive genes are known to be involved in growth, hormone regulation, defense mechanisms and signaling pathways. Furthermore, we observed the induction of genes related to innate immunity, hypoxia, salicylic acid biosynthesis and camalexin biosynthesis by GT22 VCs. Among the VCs emitted by GT22, exposure of Arabidopsis seedlings to limonene promoted plant growth and attenuated copper stress. Thus, limonene appears to be a key mediator of the interaction between GT22 and plants. Overall, our findings provide evidence that fungal VCs can promote plant growth and enhance both biotic and abiotic tolerance. As such, our study suggests that exposure of seedlings to T. inflatum GT22 VCs may be a means of improving crop productivity. This study describes a beneficial interaction between T. inflatun GT22 and Arabidopsis. Our investigation of microorganism function in terms of VC activities allowed us to overcome the limitations of traditional microbial application methods. The importance of this study lies in the discovery of T. inflatun GT22 as a beneficial microorganism. This soilborne fungus emits VCs with plant growth-promoting effects and the ability to alleviate both copper and pathogenic stress. Furthermore, our study offers a valuable approach to tracking the activities of fungal VC components via transcriptomic analysis and sheds light on the mechanisms through which VCs promote plant growth and induce resistance. This research significantly advances our knowledge of VC applications and provides an example for further investigations within this field.
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Arabidopsis , Hypocreales , Arabidopsis/genética , Cobre/farmacologia , Cobre/metabolismo , Limoneno/metabolismo , Limoneno/farmacologia , Hypocreales/metabolismo , Plantas/metabolismo , Plântula/metabolismo , Regulação da Expressão Gênica de PlantasRESUMO
BACKGROUND: Previous studies have linked adolescent motherhood to adverse neurodevelopmental outcomes in offspring, yet the sex-specific effect and underlying mechanisms remain unclear. METHODS: This study included 6952 children aged 9-11 from the Adolescent Brain Cognitive Development study. The exposed group consisted of children of mothers < 20 years at the time of birth, while the unexposed group was composed of children of mothers aged 20-35 at birth. We employed a generalized linear mixed model to investigate the associations of adolescent motherhood with cognitive, behavioral, and autistic-like traits in offspring. We applied an inverse-probability-weighted marginal structural model to examine the potential mediating factors including adverse perinatal outcomes, family conflict, and brain structure alterations. RESULTS: Our results revealed that children of adolescent mothers had significantly lower cognitive scores (ß, - 2.11, 95% CI, - 2.90 to - 1.31), increased externalizing problems in male offspring (mean ratio, 1.28, 95% CI, 1.08 to 1.52), and elevated internalizing problems (mean ratio, 1.14, 95% CI, 0.99 to 1.33) and autistic-like traits (mean ratio, 1.22, 95% CI, 1.01 to 1.47) in female. A stressful family environment mediated ~ 70% of the association with internalizing problems in females, ~ 30% with autistic-like traits in females, and ~ 20% with externalizing problems in males. Despite observable brain morphometric changes related to adolescent motherhood, these did not act as mediating factors in our analysis, after adjusting for family environment. No elevated rate of adverse perinatal outcomes was observed in the offspring of adolescent mothers in this study. CONCLUSIONS: Our results reveal distinct sex-specific neurodevelopmental outcomes impacts of being born to adolescent mothers, with a substantial mediating effect of family environment on behavioral outcomes. These findings highlight the importance of developing sex-tailored interventions and support the hypothesis that family environment significantly impacts the neurodevelopmental consequences of adolescent motherhood.
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Transtorno Autístico , Encéfalo , Cognição , Comportamento Problema , Humanos , Feminino , Masculino , Criança , Encéfalo/crescimento & desenvolvimento , Adolescente , Cognição/fisiologia , Conflito Familiar , Mães , Adulto , Gravidez , Adulto Jovem , Gravidez na Adolescência , Fatores SexuaisRESUMO
Hydroxides are the archetype of layered crystals with metal-oxygen (M-O) octahedron units, which have been widely investigated as oxygen evolution reaction (OER) catalysts. However, the better crystallinity of hydroxide materials, the more perfect octahedral symmetry and atomic ordering, resulting in the less exposed metal sites and limited electrocatalytic activity. Herein, a glassy state hydroxide material featuring with short-range order and long-range disorder structure is developed to achieve high intrinsic activity for OER. Specifically, a rapid freezing point precipitation method is utilized to fabricate amorphous multi-component hydroxide. Owing to the freezing-point crystallization environment and chaotic M-O (M = Ni/Fe/Co/Mn/Cr etc.) structures, the as-fabricated NiFeCoMnCr hydroxide exhibit a highly-disordered glassy structure, as-confirmed by X-ray/electron diffraction, enthalpic response, and pair distribution function analysis. The as-achieved glassy-state hydroxide materials display a low OER overpotential of 269 mV at 20 mA cm-2 with a small Tafel slope of 33.3 mV dec-1, outperform the benchmark noble-metal RuO2 catalyst (341 mV, 84.9 mV dec-1) . Operando Raman and density functional theory studies reveal that the glassy state hydroxide converted into disordered active oxyhydroxide phase with optimized oxygen intermediates adsorption under low OER overpotentials, thus boosting the intrinsic electrocatalytic activity.
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BACKGROUND: COVID-19 lockdowns increased the risk of mental health problems, especially for children with autism spectrum disorder (ASD). However, despite its importance, little is known about the protective factors for ASD children during the lockdowns. METHODS: Based on the Shanghai Autism Early Developmental Cohort, 188 ASD children with two visits before and after the strict Omicron lockdown were included; 85 children were lockdown-free, while 52 and 51 children were under the longer and the shorter durations of strict lockdown, respectively. We tested the association of the lockdown group with the clinical improvement and also the modulation effects of parent/family-related factors on this association by linear regression/mixed-effect models. Within the social brain structures, we examined the voxel-wise interaction between the grey matter volume and the identified modulation effects. RESULTS: Compared with the lockdown-free group, the ASD children experienced the longer duration of strict lockdown had less clinical improvement (ß = 0.49, 95% confidence interval (CI) [0.19-0.79], p = 0.001) and this difference was greatest for social cognition (2.62 [0.94-4.30], p = 0.002). We found that this association was modulated by parental agreeableness in a protective way (-0.11 [-0.17 to -0.05], p = 0.002). This protective effect was enhanced in the ASD children with larger grey matter volumes in the brain's mentalizing network, including the temporal pole, the medial superior frontal gyrus, and the superior temporal gyrus. CONCLUSIONS: This longitudinal neuroimaging cohort study identified that the parental agreeableness interacting with the ASD children's social brain development reduced the negative impact on clinical symptoms during the strict lockdown.
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Transtorno do Espectro Autista , Transtorno Autístico , COVID-19 , Criança , Humanos , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/psicologia , Estudos de Coortes , Fatores de Proteção , COVID-19/prevenção & controle , Controle de Doenças Transmissíveis , China/epidemiologiaRESUMO
Auditory gating (AG) is an adaptive mechanism for filtering out redundant acoustic stimuli to protect the brain against information overload. AG deficits have been found in many mental illnesses, including schizophrenia (SZ). However, the neural correlates of AG remain poorly understood. Here, we found that the posterior parietal cortex (PPC) shows an intermediate level of AG in auditory thalamocortical circuits, with a laminar profile in which the strongest AG is in the granular layer. Furthermore, AG of the PPC was decreased and increased by optogenetic inactivation of the medial dorsal thalamic nucleus (MD) and auditory cortex (AC), respectively. Optogenetically activating the axons from the MD and AC drove neural activities in the PPC without an obvious AG. These results indicated that AG in the PPC is determined by the integrated signal streams from the MD and AC in a bottom-up manner. We also found that a mouse model of SZ (postnatal administration of noncompetitive N-methyl-d-aspartate receptor antagonist) presented an AG deficit in the PPC, which may be inherited from the dysfunction of MD. Together, our findings reveal a neural circuit underlying the generation of AG in the PPC and its involvement in the AG deficit of SZ.
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Córtex Auditivo , Vigília , Camundongos , Animais , Lobo Parietal/fisiologia , Tálamo , Núcleo Mediodorsal do Tálamo , Encéfalo , Córtex Auditivo/fisiologiaRESUMO
BACKGROUND: Dyslipidemia is increasingly recognized as an essential risk factor for cardiovascular diseases. However, few studies illustrated the effects of ambient temperature exposure (TE) on lipid levels in children. The study aimed to examine the association between ambient TE and lipid levels in children. METHODS: Based on a prospective cohort, a total of 2423 children (with 4466 lipids measure person-time) were collected from 2014 to 2019. The meteorological observation data and adjusted variables were collected. Mixed-effect models and generalized additive mixed model (GAMM) were applied to investigate the association between ambient TE and lipid levels. RESULTS: A significant negative association was observed between TE and low-density lipoprotein cholesterol (LDL-C) or total cholesterol (TC) levels both in all children [LDL-C, ß(95%CI) = -0.350(-0.434,-0.265), P < 0.001; TC, ß(95%CI) = -0.274(-0.389,-0.160), P < 0.001] and by different sex group. However, no significant association was found in low-density lipoprotein cholesterol (HDL-C) or triglycerides (TG) levels. The estimated optimal ambient TEs for LDL-C were 18.273 °C and 18.024 °C for girls and boys, respectively. For TC, the optimal ambient TEs were 17.949 °C and 18.024 °C, respectively. With ambient TE decreased, the risk of dyslipidemia increased for both boys [OR = 0.032(0.006,0.179), P < 0.001] and girls [OR = 0.582(0.576,0.587), P < 0.001]. CONCLUSION: This study provided a comprehensive illustration about the associations between ambient TE and lipid levels in different sex and ages from a prospective cohort study. The findings will provide evidence for the government to prevent dyslipidemia in vulnerable children through regulating TE.
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Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids' biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.
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Fibrose Pulmonar , Humanos , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Análise da Expressão Gênica de Célula Única , Metabolismo dos Lipídeos/genética , Células Endoteliais/metabolismo , Fosfolipídeos/metabolismo , Colesterol/metabolismo , FosfatidilcolinasRESUMO
Rationale: Sustained activation of lung fibroblasts and the resulting oversynthesis of the extracellular matrix are detrimental events for patients with interstitial lung diseases (ILDs). Lung biopsy is a primary evaluation technique for the fibrotic status of ILDs, and is also a major risk factor for triggering acute deterioration. Fibroblast activation protein (FAP) is a long-known surface biomarker of activated fibroblasts, but its expression pattern and diagnostic implications in ILDs are poorly defined. Objectives: The present study aims to comprehensively investigate whether the expression intensity of FAP could be used as a potential readout to estimate or measure the amounts of activated fibroblasts in ILD lungs quantitatively. Methods: FAP expression in human primary lung fibroblasts as well as in clinical lung specimens was first tested using multiple experimental methods, including real-time quantitative PCR (qPCR), Western blot, immunofluorescence staining, deep learning measurement of whole slide immunohistochemistry, as well as single-cell sequencing. In addition, FAP-targeted positron emission tomography/computed tomography imaging PET/CT was applied to various types of patients with ILD, and the correlation between the uptake of FAP tracer and pulmonary function parameters was analyzed. Measurements and Main Results: Here, it was revealed, for the first time, FAP expression was upregulated significantly in the early phase of lung fibroblast activation event in response to a low dose of profibrotic cytokine. Single-cell sequencing data further indicate that nearly all FAP-positive cells in ILD lungs were collagen-producing fibroblasts. Immunohistochemical analysis validated that FAP expression level was closely correlated with the abundance of fibroblastic foci on human lung biopsy sections from patients with ILDs. We found that the total standard uptake value (SUV) of FAP inhibitor (FAPI) PET (SUVtotal) was significantly related to lung function decline in patients with ILD. Conclusions: Our results strongly support that in vitro and in vivo detection of FAP can assess the profibrotic activity of ILDs, which may aid in early diagnosis and the selection of an appropriate therapeutic window.
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Doenças Pulmonares Intersticiais , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Fibrose , Fibroblastos/metabolismoRESUMO
BACKGROUND: Patients with airway stenosis (AS) are associated with considerable morbidity and mortality after lung transplantation (LTx). This study aims to develop and validate machine learning (ML) models to predict AS requiring clinical intervention in patients after LTx. METHODS: Patients who underwent LTx between January 2017 and December 2019 were reviewed. The conventional logistic regression (LR) model was fitted by the independent risk factors which were determined by multivariate LR. The optimal ML model was determined based on 7 feature selection methods and 8 ML algorithms. Model performance was assessed by the area under the curve (AUC) and brier score, which were internally validated by the bootstrap method. RESULTS: A total of 381 LTx patients were included, and 40 (10.5%) patients developed AS. Multivariate analysis indicated that male, pulmonary arterial hypertension, and postoperative 6-min walking test were significantly associated with AS (all P < 0.001). The conventional LR model showed performance with an AUC of 0.689 and brier score of 0.091. In total, 56 ML models were developed and the optimal ML model was the model fitted using a random forest algorithm with a determination coefficient feature selection method. The optimal model exhibited the highest AUC and brier score values of 0.760 (95% confidence interval [CI], 0.666-0.864) and 0.085 (95% CI, 0.058-0.117) among all ML models, which was superior to the conventional LR model. CONCLUSIONS: The optimal ML model, which was developed by clinical characteristics, allows for the satisfactory prediction of AS in patients after LTx.
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Transplante de Pulmão , Aprendizado de Máquina , Humanos , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Feminino , Adulto , Estudos de Casos e Controles , Constrição Patológica , Complicações Pós-Operatórias , Fatores de RiscoRESUMO
Hydrocarbon separation is an important process in the field of petrochemical industry, which provides a variety of raw materials for industrial production and a strong support for the development of national economy. However, traditional separation processes involve huge energy consumption. Adsorptive separation based on nonporous adaptive crystal (NAC) materials is considered as an attractive green alternative to traditional energy-intensive separation technologies due to its advantages of low energy consumption, high chemical and thermal stability, excellent selective adsorption and separation performance, and outstanding recyclability. Considering the exceptional potential of NAC materials for hydrocarbon separation, this review comprehensively summarizes recent advances in various supramolecular host-based NACs. Moreover, the current challenges and future directions are illustrated in detail. It is expected that this review will provide useful and timely references for researchers in this area. Based on a large number of state-of-the-art studies, the review will definitely advance the development of NAC materials for hydrocarbon separation and stimulate more interesting studies in related fields.
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Edge servers frequently manage their own offline digital twin (DT) services, in addition to caching online digital twin services. However, current research often overlooks the impact of offline caching services on memory and computation resources, which can hinder the efficiency of online service task processing on edge servers. In this study, we concentrated on service caching and task offloading within a collaborative edge computing system by emphasizing the integrated quality of service (QoS) for both online and offline edge services. We considered the resource usage of both online and offline services, along with incoming online requests. To maximize the overall QoS utility, we established an optimization objective that rewards the throughput of online services while penalizing offline services that miss their soft deadlines. We formulated this as a utility maximization problem, which was proven to be NP-hard. To tackle this complexity, we reframed the optimization problem as a Markov decision process (MDP) and introduced a joint optimization algorithm for service caching and task offloading by leveraging the deep Q-network (DQN). Comprehensive experiments revealed that our algorithm enhanced the utility by at least 14.01% compared with the baseline algorithms.
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Bergenia purpurascens is an important medicinal, edible and ornamental plant. It generally grows in high-altitude areas with complex climates. There have been no reports about how B. purpurascens survives under cold stress. Here, the B. purpurascens under low temperature were subjected to transcriptomics analysis to explore the candidate genes and pathways that involved in the cold tolerance of B. purpurascens. Compared with the control treatment, we found 9,600 up-regulated differentially expressed genes (DEGs) and 7,055 down-regulated DEGs. A significant number of DEGs were involved in the Ca2+ signaling pathway, mitogen-activated protein kinase (MAPK) cascade, plant hormone signaling pathway, and lipid metabolism. A total of 400 transcription factors were found to respond to cold stress, most of which belonged to the MYB and AP2/ERF families. Five novel genes were found to be potential candidate genes involved in the cold tolerance of B. purpurascens. The study provide insights into further investigation of the molecular mechanism of how B. purpurascens survives under cold stress.