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Background: Cellular senescence, a novel hallmark of cancer, is associated with patient outcomes and tumor immunotherapy. However, at present, there is no systematic study on the use of cellular senescence-related long non-coding RNAs (CSR-lncRNAs) to predict survival in patients with osteosarcoma. In this study, we aimed to identify a CSR-lncRNAs signature and to evaluate its potential use as a survival prognostic marker and predictive tool for immune response of osteosarcoma. Methods: We downloaded a cohort of patients with osteosarcoma from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We performed differential expression and co-expression analyses to identify CSR-lncRNAs. We performed univariate and multivariate Cox regression analyses along with the random forest algorithm to identify lncRNAs significantly correlated with senescence. Subsequently, we assessed the predictive models using survival curves, receiver operating characteristic curves, nomograms, C-index, and decision curve analysis. Based on this model, patients with osteosarcoma were divided into two groups according to their risk scores. Then, using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, we compared their clinical characteristics to uncover functional differences. We further conducted immune infiltration analyses using estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE), cell-type identification by estimating relative subsets of rna transcripts (CIBERSORT), and single-sample gene set enrichment analysis for the two groups. We also evaluated the expression of the target genes of immune checkpoint inhibitors (ICIs). Results: We identified six lncRNAs that were significantly correlated with senescence and accordingly established a novel cellular senescence-related lncRNA prognostic signature incorporating these lncRNAs. The nomogram indicated that the risk model was an independent prognostic factor that could predict the survival of patients with osteosarcoma. This model demonstrated high accuracy upon validation. Further analysis revealed that patients with osteosarcoma in the low-risk group exhibited better clinical outcomes and enhanced immune infiltration. Conclusions: The six-CSR-lncRNA prognostic signature effectively predicted survival outcomes and patients in the low-risk group might have improved immune infiltration.
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Vision plays a crucial role in the survival of animals, and the visual system has particularly selectively evolved in response to the visual environment, ecological niche, and species habitats in vertebrate species. To date, a horizontal streak of retinal ganglion cell (RGC) distribution pattern is observed across mammal species. Here, we report that the giant panda's vertically oriented visual streak, combined with current evidence of the animal's forward-placed eyes, ocular structure, and retinal neural topographic distribution patterns, presents the emergence of a well-adapted binocular visual system. Our results suggest that the giant panda may use a unique way to processing binocular visual information. Results of mathematical simulation are in favor of this hypothesis. The topographic distribution properties of RGCs reported here could be essential for understanding the visual adaptation and evolution of this living fossil.
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Células Ganglionares da Retina , Ursidae , Animais , Células Ganglionares da Retina/citologia , Ursidae/anatomia & histologia , Ursidae/fisiologia , Retina/citologia , Retina/anatomia & histologiaRESUMO
Red pandas evolved from carnivores to herbivores and are unique within Carnivora. Red pandas and carnivorous mammals consume milk during the suckling period, while they consume bamboo and meat during the adult period, respectively. Red pandas and carnivorous mammal ferrets have a close phylogenetic relationship. To further investigate the molecular mechanisms of dietary changes and nutrient utilization in red pandas from suckling to adult, comparative analysis of the whole transcriptome was performed on stomach tissues from red pandas and ferrets during the suckling and adult periods. The main results are as follows: (1) we identified ncRNAs for the first time in stomach tissues of both species, and found significant expression changes of 109 lncRNAs and 106 miRNAs in red pandas and 756 lncRNAs and 109 miRNAs in ferrets between the two periods; (2) up-regulated genes related to amino acid transport regulated by lncRNA-miRNA-mRNA networks may efficiently utilize limited bamboo amino acids in adult red pandas, while up-regulated genes related to amino acid degradation regulated by lncRNAs may maintain the balance of amino acid metabolism due to larger daily intakes in adult ferrets; and (3) some up-regulated genes related to lipid digestion may contribute to the utilization of rich nutrients in milk for the rapid growth and development of suckling red pandas, while up-regulated genes associated with linoleic acid metabolism regulated by lncRNA-miRNA-mRNA networks may promote cholesterol decomposition to reduce health risks for carnivorous adult ferrets. Collectively, our study offers evidence of gene expression adaptation and ncRNA regulation in response to specific dietary changes and nutrient utilization in red pandas during suckling and adult periods.
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RAD18, an important ubiquitin E3 ligase, plays a dual role in translesion DNA synthesis (TLS) and homologous recombination (HR) repair. However, whether and how the regulatory mechanism of O-linked N-acetylglucosamine (O-GlcNAc) modification governing RAD18 and its function during these processes remains unknown. Here, we report that human RAD18, can undergo O-GlcNAcylation at Ser130/Ser164/Thr468, which is important for optimal RAD18 accumulation at DNA damage sites. Mechanistically, abrogation of RAD18 O-GlcNAcylation limits CDC7-dependent RAD18 Ser434 phosphorylation, which in turn significantly reduces damage-induced PCNA monoubiquitination, impairs Polη focus formation and enhances UV sensitivity. Moreover, the ubiquitin and RAD51C binding ability of RAD18 at DNA double-strand breaks (DSBs) is O-GlcNAcylation-dependent. O-GlcNAcylated RAD18 promotes the binding of RAD51 to damaged DNA during HR and decreases CPT hypersensitivity. Our findings demonstrate a novel role of RAD18 O-GlcNAcylation in TLS and HR regulation, establishing a new rationale to improve chemotherapeutic treatment.
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Acetilglucosamina , Proteínas de Ligação a DNA , Antígeno Nuclear de Célula em Proliferação , Rad51 Recombinase , Reparo de DNA por Recombinação , Ubiquitina-Proteína Ligases , Humanos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Ubiquitina-Proteína Ligases/metabolismo , Acetilglucosamina/metabolismo , Rad51 Recombinase/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fosforilação , Replicação do DNA , Ubiquitinação , Quebras de DNA de Cadeia Dupla , DNA Polimerase Dirigida por DNA/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Dano ao DNA , DNA/metabolismo , Células HEK293 , Raios Ultravioleta , Ligação Proteica , Glicosilação , Síntese de DNA TranslesãoRESUMO
CD8+ T cells have great roles in tumor suppression and elimination of various tumors including hepatocellular carcinoma (HCC). Nonetheless, potential prognostic roles of CD8+ T cell-related genes (CD8Gs) in HCC remains unknown. In our study, 416 CD8Gs were identified in HCC, which were enriched in inflammatory and immune signaling pathways. Using The Cancer Genome Atlas dataset, a 5-CD8Gs risk model (KLRB1, FYN, IL2RG, FCER1G, and DGKZ) was constructed, which was verified in International Cancer Genome Consortium and gene expression omnibus datasets. Furthermore, we found that overall survival was independently correlated with the CD8Gs signature, and it was associated with immune- and cancer-related signaling pathways and immune cells infiltration. Finally, drug sensitivity data indicated that 10 chemotherapeutic drugs held promise as therapeutics for HCC patients with high-risk. In conclusion, multi-databases analysis showed that 5-CD8Gs and their signature could be an indicator to predict candidate drugs for HCC therapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Prognóstico , Neoplasias Hepáticas/genética , Linfócitos T CD8-Positivos , BiomarcadoresRESUMO
Temozolomide (TMZ) resistance presents a significant challenge in the treatment of gliomas. Although lysine demethylase 4A (KDM4A) has been implicated in various cancer-related processes, its role in TMZ resistance remains unclear. This study aims to elucidate the contribution of KDM4A to TMZ resistance in glioma cells and its potential implications for glioma prognosis. We assessed the expression of KDM4A in glioma cells (T98G and U251MG) using qRT-PCR and Western blot assays. To explore the role of KDM4A in TMZ resistance, we transfected siRNA targeting KDM4A into drug-resistant glioma cells. Cell viability was assessed using the CCK-8 assay and the TMZ IC50 value was determined. ChIP assays were conducted to investigate KDM4A, H3K9me3, and H3K36me3 enrichment on the promoters of ROCK2 and HUWE1. Co-immunoprecipitation confirmed the interaction between HUWE1 and ROCK2, and we examined the levels of ROCK2 ubiquitination following MG132 treatment. Notably, T98G cells exhibited greater resistance to TMZ than U251MG cells, and KDM4A displayed high expression in T98G cells. Inhibiting KDM4A resulted in decreased cell viability and a reduction in the TMZ IC50 value. Mechanistically, KDM4A promoted ROCK2 transcription by modulating H3K9me3 levels. Moreover, disruption of the interaction between HUWE1 and ROCK2 led to reduced ROCK2 ubiquitination. Inhibition of HUWE1 or overexpression of ROCK2 counteracted the sensitization effect of si-KDM4A on TMZ responsiveness in T98G cells. Our findings highlight KDM4A's role in enhancing TMZ resistance in glioma cells by modulating ROCK2 and HUWE1 transcription and expression through H3K9me3 and H3K36me3 removal.
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Neoplasias Encefálicas , Glioma , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Histonas/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Glioma/genética , Metilação , Resistencia a Medicamentos Antineoplásicos/genética , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismoRESUMO
BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is considered an efficient and life-saving treatment for neonatal severe acute respiratory distress syndrome (ARDS). Bedside lung ultrasound (LUS) is an attractive and feasible method for evaluating neonatal ARDS. OBJECTIVE: To evaluate the value of LUS score at veno-arterial (V-A) ECMO withdrawal in neonatal patients with severe acute ARDS. METHODS: A retrospective preliminary study was conducted in our cardiac intensive care unit from June 2021 to June 2022. Eight severe ARDS neonates who received V-A ECMO were enroled in this study. LUS was measured daily during ECMO and when weaning off ECMO. The relationships between the LUS score and ECMO parameters (blood flow and the sweep gas of FiO2) were assessed. RESULTS: (1) There was a significant improvement in LUS score by ECMO treatment. And, various diagnostic signs of lung ultrasound were detected during ECMO, including pulmonary edema (7 neonates) and lung consolidation (4 neonates), followed by pleural effusion (1 neonate) and bilateral white lung (1 neonate). (2) A total of 12 trials for weaning off ECMO were carried out, of which four failed, but all eight neonates finally succeeded in passing the weaning trial. LUS score of 21 or less was defined as a cut-off value for predicting ECMO weaning success. During ECMO treatment, LUS score was positively correlated with ECMO blood flow (r = 0.866, P < 0.05). CONCLUSIONS: LUS can be used to evaluate the various lung diagnostic signs in ARDS neonatal patients during ECMO treatment, and the LUS score under ECMO treatment decreases over time. The reduction in LUS score is associated with lower ECMO blood flow. LUS score is regarded as a predictor of ECMO weaning success.
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Oxigenação por Membrana Extracorpórea , Síndrome do Desconforto Respiratório do Recém-Nascido , Síndrome do Desconforto Respiratório , Recém-Nascido , Humanos , Oxigenação por Membrana Extracorpórea/métodos , Estudos Retrospectivos , Pulmão/diagnóstico por imagem , Síndrome do Desconforto Respiratório do Recém-Nascido/diagnóstico por imagem , Síndrome do Desconforto Respiratório do Recém-Nascido/terapia , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Síndrome do Desconforto Respiratório/terapiaRESUMO
Haze seriously affects the visual quality of road inspection images and contaminates the discrimination of key road objects, which thus hinders the execution of road inspection work. The basic assumptions of the classical dark-channel prior are not suitable for road images containing light-colored lane lines and vehicles, while typical deep dehazing networks lack physical model interpretability, and they focus on global dehazing effects, neglecting the preservation of object features. For this reason, this paper proposes a Dark-Channel Soft-Constrained and Object-Perception-Enhanced Deep Dehazing Network (DCSC-OPE-Net) for the information recovery of road inspection images. The network is divided into two modules: a dark-channel soft-constrained dehazing module and a near-view object-perception-enhanced module. Unlike the traditional dark-channel algorithms that impose strong constraints on dark pixels, a dark-channel soft-constrained loss function is constructed to ensure that the features of light-colored vehicles and lane lines are effectively maintained. To avoid resolution loss due to patch-based dark-channel processing for image dehazing, a resolution enhancement module is used to strengthen the contrast of the dehazed image. To autonomously perceive and enhance key road features to support road inspection, edge enhancement loss combined with a transmission map is embedded into the network to autonomously discover near-view objects and enhance their key features. The experiments utilize public datasets and real road inspection datasets to validate the performance of the proposed DCSC-OPE-Net compared with typical networks using dehazing evaluation metrics and road object recognition metrics. The experimental results demonstrate that the proposed DCSC-OPE-Net can obtain the best dehazing performance, with an NIQE score of 4.5 and a BRISQUE score of 18.67, and obtain the best road object recognition results (i.e., 83.67%) among the comparison methods.
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A new multifunctional proportional control triaxial stress loading apparatus is presented in this study, which can apply an output force on coal rock to simulate the conditions of triaxial stress loading, aiming at solving the problems of excessive consideration of static indices in the design and the incompleteness of the simulation and test verification system for the test parts at the performance analysis stage. This apparatus mainly combines the configuration of a triaxial stress loading system which can meet the stress loading requirements under different operating conditions, with the effective integration of multiple pressure loading operations based on the electrohydraulic proportional control method. In this context, a pressure and position combined control strategy based on the sliding mode is proposed to control the vertical and longitudinal loading hydraulic cylinders. Then, a co-simulation mode including the triaxial stress loading hydraulic system is established to verify the control strategy, system response characteristics and selection of the controller parameters. Furthermore, a multifunctional stress loading experimental platform is developed, and the stress loading characteristics with the proposed strategy are tested and analyzed. The results show that the triaxial stress loading hydraulic system can meet the response characteristics, the fluctuating deviation of the constant loading test can be restricted to 8.5%, the tracking error of the variable loading test is small, the minimum response time of instantaneous loading can reach 2.8 s, and the stress loading effect is noticeable. The experimental platform fully indicates that the stress loading system with the state perception and processing method as the core can meet a variety of verification indices of constant, variable and instantaneous loading tests. This research provides technical support for the smooth, synchronous control and intelligent operation of various types of hydraulic actuator machines.
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Dopamine is a key neurotransmitter in the signaling cascade controlling ocular refractive development, but the exact role and site of action of dopamine D1 receptors (D1Rs) involved in myopia remains unclear. Here, we determine whether retinal D1Rs exclusively mediate the effects of endogenous dopamine and systemically delivered D1R agonist or antagonist in the mouse form deprivation myopia (FDM) model. Male C57BL/6 mice subjected to unilateral FDM or unobstructed vision were divided into the following four groups: one noninjected and three groups that received intraperitoneal injections of a vehicle, D1R agonist SKF38393 (18 and 59 nmol/g), or D1R antagonist SCH39166 (0.1 and 1 nmol/g). The effects of these drugs on FDM were further assessed in Drd1-knock-out (Drd1-KO), retina-specific conditional Drd1-KO (Drd1-CKO) mice, and corresponding wild-type littermates. In the visually unobstructed group, neither SKF38393 nor SCH39166 affected normal refractive development, whereas myopia development was attenuated by SKF38393 and enhanced by SCH39166 injections. In Drd1-KO or Drd1-CKO mice, however, these drugs had no effect on FDM development, suggesting that activation of retinal D1Rs is pertinent to myopia suppression by the D1R agonist. Interestingly, the development of myopia was unchanged by either Drd1-KO or Drd1-CKO, and neither SKF38393 nor SCH39166 injections, nor Drd1-KO, affected the retinal or vitreal dopamine and the dopamine metabolite DOPAC levels. Effects on axial length were less marked than effects on refraction. Therefore, activation of D1Rs, specifically retinal D1Rs, inhibits myopia development in mice. These results also suggest that multiple dopamine D1R mechanisms play roles in emmetropization and myopia development.SIGNIFICANCE STATEMENT While dopamine is recognized as a "stop" signal that inhibits myopia development (myopization), the location of the dopamine D1 receptors (D1Rs) that mediate this action remains to be addressed. Answers to this key question are critical for understanding how dopaminergic systems regulate ocular growth and refraction. We report here the results of our study showing that D1Rs are essential for controlling ocular growth and myopia development in mice, and for identifying the retina as the site of action for dopaminergic control via D1Rs. These findings highlight the importance of intrinsic retinal dopaminergic mechanisms for the regulation of ocular growth and suggest specific avenues for exploring the retinal mechanisms involved in the dopaminergic control of emmetropization and myopization.
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Dopamina , Miopia , Masculino , Camundongos , Animais , Dopamina/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Camundongos Endogâmicos C57BL , Miopia/genética , Miopia/metabolismo , Retina/metabolismo , Receptores de Dopamina D1/metabolismoRESUMO
Reprogramming of metabolic genes and subsequent alterations in metabolic phenotypes occur widely in malignant tumours, including glioblastoma (GBM). FOXM1 is a potent transcription factor that plays an oncogenic role by regulating the expression of many genes. As a SET domain containing protein, SET7 is a protein lysine methyltransferase which monomethylates histone proteins and other proteins. The epigenetic modification of histones regulates gene expressions by epigenetically modifying promoters of DNAs and inter vening in tumor development. Activation of FASN increased de novo fatty acid (FA) synthesis, a hallmark of cancer cells. Here, we report that FOXM1 may directly promote the transcription of SET7 and activate SET7-H3K4me1-FASN axis, which results in the maintenance of de novo FA synthesis.
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The foliar disease, which is the primary complex disease of Pseudostellaria heterophylla, can be caused by multiple co-infecting pathogens, resulting in a significant reduction in yield. However, there is a lack of research on the relationship between co-infection of various pathogens and the response of resistance-related genes in P. heterophylla. Through the use of 18S rDNA sequencing and pathogenicity testing, it has been determined that Fusarium oxysporum, Alternaria alternata, Arcopilus aureus, Botrytis cinerea, Nemania diffusa, Whalleya microplaca, and Cladosporium cladosporioides are co-infecting pathogens responsible for foliar diseases in P. heterophylla. Furthermore, the qRT-PCR analysis revealed that F. oxysporum, A. alternata, B. cinerea, A. aureus, N. diffusa, Schizophyllum commune, C. cladosporioides, and Coprinellus xanthothrix upregulated ten, two, three, four, seven, thirteen, five, one, and six resistance-related genes, respectively. These findings suggest that a total of 22 resistance-related genes were implicated in the response to diverse fungi, and the magnitude and frequency of induction of resistance-related genes varied considerably among the different fungi. The aforementioned gene associated with resistance was found to be implicated in the response to multiple fungi, including PhPRP1, PhBDRN15, PhBDRN11, and PhBDRN3, which were found to be involved in the resistance response to nine, five, four, and four fungi, respectively. The findings indicate that the PhPRP1, PhBDRN15, PhBDRN11, and PhBDRN3 genes exhibit a broad-spectrum resistance to various fungi. Furthermore, the avirulence fungi C. xanthothrix, which is known to affect P. heterophylla, was found to prime a wide range of resistance responses in P. heterophylla, thereby enhancing its disease resistance. This study provided insight into the management strategies for foliar diseases of P. heterophylla and new genetic materials for disease-resistant breeding.
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Coinfecção , Humanos , DNA Ribossômico , Resistência à DoençaRESUMO
BACKGROUND: Glioblastoma (GBM) preferred to infiltrate into white matter (WM) beyond the recognizable tumor margin. OBJECTIVE: To investigate whether fiber density (FD) and structural brain connectome can provide meaningful information about WM destruction and glioma cell infiltration. METHODS: GBM cases were collected based on inclusion criteria, and baseline information and preoperative MRI results were obtained. GBM lesions were automatically segmented into necrosis, contrast-enhanced tumor, and edema areas. We obtained the FD map to compute the FD and lnFD values in each subarea and reconstructed the structural brain connectome to obtain the topological metrics in each subarea. We also divided the edema area into a nonenhanced tumor (NET) area and a normal WM area based on the contralesional lnFD value in the edema area, and computed the NET ratio. RESULTS: Twenty-five GBM cases were included in this retrospective study. The FD/lnFD value and topological metrics (aCp, aLp, aEg, aEloc, and ar) were significantly correlated with GBM subareas, which represented the extent of WM destruction and glioma cell infiltration. The FD/lnFD values and topological parameters were correlated with the NET ratio. In particular, the lnFD value in the edema area was correlated with the NET ratio (coefficient, 0.92). Therefore, a larger lnFD value indicates more severe glioma infiltration in the edema area and suggests an extended resection for better clinical outcomes. CONCLUSION: The FD and structural brain connectome in this study provide a new insight into glioma infiltration and a different consideration of their clinical application in neuro-oncology.
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Neoplasias Encefálicas , Conectoma , Glioblastoma , Glioma , Humanos , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Estudos Retrospectivos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Glioma/diagnóstico por imagem , Glioma/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Edema/patologiaRESUMO
BACKGROUND: It is inevitable to change the function or expression of genes during the environmental adaption of species. Both the giant panda (Ailuropoda melanoleuca) and red panda (Ailurus fulgens) belong to Carnivora and have developed similar adaptations to the same dietary switch to bamboos at the morphological and genomic levels. However, the genetic adaptation at the gene expression level is unclear. Therefore, we aimed to examine the gene expression patterns of giant and red panda convergent specialized bamboo-diets. We examined differences in liver and pancreas transcriptomes between the two panda species and other non-herbivorous species. RESULTS: The clustering and PCA plots suggested that the specialized bamboo diet may drive similar expression shifts in these two species of pandas. Therefore, we focused on shared liver and pancreas DEGs (differentially expressed genes) in the giant and red panda relative to other non-herbivorous species. Genetic convergence occurred at multiple levels spanning carbohydrate metabolism, lipid metabolism, and lysine degradation. The shared adaptive convergence DEGs in both organs probably be an evolutionary response to the high carbohydrate, low lipid and lysine bamboo diet. Convergent expression of those nutrient metabolism-related genes in both pandas was an intricate process and subjected to multi-level regulation, including DNA methylation and transcription factor. A large number of lysine degradation and lipid metabolism related genes were hypermethylated in promoter regions in the red panda. Most genes related to carbohydrate metabolism had reduced DNA methylation with increased mRNA expression in giant pandas. Unlike the red panda, the core gene of the lysine degradation pathway (AASS) doesn't exhibit hypermethylation modification in the giant panda, and dual-luciferase reporter assay showed that transcription factor, NR3C1, functions as a transcriptional activator in AASS transcription through the binding to AASS promoter region. CONCLUSIONS: Our results revealed the adaptive expressions and regulations of the metabolism-related genes responding to the unique nutrients in bamboo food and provided data accumulation and research hints for the future revelation of complex mechanism of two pandas underlying convergent adaptation to a specialized bamboo diet.
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Ailuridae , Dieta , Ursidae , Animais , Dieta/veterinária , Expressão Gênica , Lisina/metabolismo , Ursidae/genética , Ursidae/metabolismo , Ailuridae/genética , Ailuridae/metabolismoRESUMO
Naked cuticle homolog 1 (NKD1), which is expressed at low levels in many tumors, is considered an inhibitor of the Wnt/ß-catenin pathway, but it is highly expressed in colon cancer and can promote colon cancer cell proliferation. miRNAs are involved in the occurrence and progression of many tumors. However, miRNAs that can regulate NKD1 and the mechanisms by which NKD1 regulates tumor progression remain ambiguous. This research aims to reveal the potential regulatory network of NKD1 in colon cancer. miRNA data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed by bioinformatics to screen for potential miRNAs targeting NKD1. Let-7b-5p was found to inhibit proliferation, migration, and invasion of colon cancer cells targeting NKD1. Further studies suggested that let-7b-5p can modulate Wnt signaling activity, and the nuclear accumulation of ß-catenin was significantly restrained by let-7b-5p through targeting NKD1. Moreover, NKD1 could prohibit the expression of the APC protein. Further studies manifested that NKD1 bound to APC and promoted the ubiquitination degradation of APC through restraining the expression of the deubiquitinating enzyme USP15 and blocking the combination between USP15 and APC. Functionally, NKD1 enhanced the proliferation and migration of colon cancer cells by inhibiting APC expression. This research revealed a novel mechanism by which the let-7b-5p-NKD1-APC-ß-catenin signaling pathway inhibited colon cancer cell progression.
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Proteína da Polipose Adenomatosa do Colo , Proteínas de Ligação ao Cálcio , Neoplasias do Colo , MicroRNAs , Via de Sinalização Wnt , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Proteína da Polipose Adenomatosa do Colo/metabolismoRESUMO
LINC00467 was reported as an oncogenic gene in different types of human cancers. In this study, we investigated the molecular mechanisms of LINC00467 in the tumorigenesis of laryngeal squamous cell cancer (LSCC). RT-qPCR was utilized to detect the mRNA expression of genes, and western blot assay was used to determine the protein levels of TNF alpha-induced protein 3 (TNFAIP3). The cell viability was detected by CCK-8 assay. Transwell assays were conducted to determine the cell migration and invasion of LSCC cells, and the cell cycle was assessed by flow cytometry. The association between paired box 5 (PAX5), LINC00467, miR-4735-3p, and TNFAIP3 was verified using ChIP, RNA pull-down, or luciferase reporter assays. In our study, we found that LINC00467 was upregulated in LSCC, and knockdown of LINC00467 suppressed cell viability and metastasis of LSCC. Besides, LINC00467 transcription could be activated by PAX5 in LSCC. Furthermore, LINC00467 acted as competitive endogenous RNA (ceRNA) for miR-4735-3p to accelerate LSCC progression. In the meantime, TNFAIP3 was identified as a downstream gene of miR-4735-3p. Finally, TNFAIP3 overexpression could overturn the effects of miR-4735-3p mimic on LSCC cellular activities. In conclusion, our results demonstrated that PAX5-induced LINC00467 facilitated LSCC progression by inhibiting miR-4735-3p to increase TNFAIP3 expression.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Laríngeas , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação para Cima , Fator de Necrose Tumoral alfa/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/patologia , Linhagem Celular Tumoral , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Male patients with prolactinomas usually present with typical hyperprolactinemia symptoms, including sexual dysfunction and infertility. However, clinical factors related to sexual dysfunction and surgical outcomes in these patients remain unclear. This study aimed to investigate the outcomes of male patients with prolactinomas after transsphenoidal surgery and the risk factors affecting sexual dysfunction. This study was conducted on 58 male patients who underwent transsphenoidal surgery for prolactinomas between May 2014 and December 2020 at the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. We evaluated the sexual function of patients before and after surgery through International Index of Erectile Function-5 scores, libido, and frequency of morning erection. Of the 58 patients, 48 (82.8%) patients had sexual intercourse preoperatively. Among those 48 patients, 41 (85.4%) patients presented with erectile dysfunction. The preoperative International Index of Erectile Function-5 scores in patients with macroprolactinomas were significantly higher than those in patients with giant prolactinomas (17.63 ± 0.91 vs 13.28 ± 1.43; P = 0.01). Postoperatively, the incidence of erectile dysfunction was 47.9%, which was significantly lower than that preoperatively (85.4%; P = 0.01). Twenty-eight (68.3%) patients demonstrated an improvement in erectile dysfunction. Tumor size and invasiveness were significantly correlated with the improvement of erectile dysfunction. Preoperative testosterone <2.3 ng ml-1 was an independent predictor of improvement in erectile dysfunction. In conclusion, our results indicated that tumor size and invasiveness were important factors affecting the improvement of sexual dysfunction in male patients with prolactinoma. The preoperative testosterone level was an independent predictor related to the improvement of erectile dysfunction.
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Disfunção Erétil , Neoplasias Hipofisárias , Prolactinoma , Disfunções Sexuais Fisiológicas , Humanos , Masculino , Prolactinoma/complicações , Prolactinoma/cirurgia , Disfunção Erétil/epidemiologia , Disfunção Erétil/etiologia , Estudos Retrospectivos , Disfunções Sexuais Fisiológicas/complicações , Testosterona , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/patologiaRESUMO
A low reproductive rate coupled with human activities has endangered the giant panda, a species endemic to southwest China. Although giant pandas feed almost exclusively on bamboo, they retain carnivorous traits and suffer from carnivorous diseases. Additionally, their immune system is susceptible to aging, resulting in a reduced ability to respond to diseases. This study aimed to determine the genes and pathways expressed differentially with age in blood tissues. The differentially expressed genes in different age groups of giant pandas were identified by RNA-seq. The elderly giant pandas had many differentially expressed genes compared with the young group (3 years old), including 548 upregulated genes and 401 downregulated genes. Further, functional enrichment revealed that innate immune upregulation and adaptive immune downregulation were observed in the elderly giant pandas compared with the young giant pandas. Meanwhile, the immune genes in the elderly giant pandas changed considerably, including genes involved in innate immunity and adaptive immunity such as PLSCR1, CLEC7A, CCL5, CCR9, and EPAS1. Time series analysis found that giant pandas store glycogen by prioritizing fat metabolism at age 11, verifying changes in the immune system. The results reported in this study will provide a foundation for further research on disease prevention and the energy metabolism of giant pandas.