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Orbital observations suggest that Mars underwent a recent 'ice age' (roughly 0.4-2.1 million years ago), during which a latitude-dependent ice-dust mantle (LDM)1,2 was emplaced. A subsequent decrease in obliquity amplitude resulted in the emergence of an 'interglacial period'1,3 during which the lowermost latitude LDM ice4-6 was etched and removed, returning it to the polar cap. These observations are consistent with polar cap stratigraphy1,7, but lower- to mid-latitude in situ surface observations in support of a glacial-interglacial transition that can be reconciled with mesoscale and global atmospheric circulation models8 is lacking. Here we present a suite of measurements obtained by the Zhurong rover during its traverse across the southern LDM region in Utopia Planitia, Mars. We find evidence for a stratigraphic sequence involving initial barchan dune formation, indicative of north-easterly winds, cementation of dune sediments, followed by their erosion by north-westerly winds, eroding the barchan dunes and producing distinctive longitudinal dunes, with the transition in wind regime consistent with the end of the ice age. The results are compatible with the Martian polar stratigraphic record and will help improve our understanding of the ancient climate history of Mars9.
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Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1-7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.
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Dermatite Atópica , PPAR gama , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Camundongos , Obesidade/metabolismo , PPAR gama/agonistas , PPAR gama/metabolismo , Medicina de Precisão , Análise de Sequência de RNA , Células Th2/metabolismoRESUMO
MicroRNAs (miRNAs) exert powerful effects on immunological function by tuning networks of target genes that orchestrate cell activity. We sought to identify miRNAs and miRNA-regulated pathways that control the type 2 helper T cell (TH2 cell) responses that drive pathogenic inflammation in asthma. Profiling miRNA expression in human airway-infiltrating T cells revealed elevated expression of the miRNA miR-19a in asthma. Modulating miR-19 activity altered TH2 cytokine production in both human and mouse T cells, and TH2 cell responses were markedly impaired in cells lacking the entire miR-17â¼92 cluster. miR-19 promoted TH2 cytokine production and amplified inflammatory signaling by direct targeting of the inositol phosphatase PTEN, the signaling inhibitor SOCS1 and the deubiquitinase A20. Thus, upregulation of miR-19a in asthma may be an indicator and a cause of increased TH2 cytokine production in the airways.
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Asma/imunologia , Citocinas/biossíntese , MicroRNAs/imunologia , Células Th2/imunologia , Animais , Asma/genética , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Ensaios Clínicos como Assunto , Citometria de Fluxo , Ensaios de Triagem em Larga Escala , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase Multiplex , Células Th2/metabolismo , Regulação para CimaRESUMO
Over 60 years of spacecraft exploration has revealed that the Earth's Moon is characterized by a lunar crust1 dominated by the mineral plagioclase, overlying a more mafic (richer in iron and magnesium) mantle of uncertain composition. Both crust and mantle formed during the earliest stages of lunar evolution when late-stage accretional energy caused a molten rock (magma) ocean, flotation of the light plagioclase, sinking of the denser iron-rich minerals, such as olivine and pyroxene, and eventually solidification2. Very large impact craters can potentially penetrate through the crust and sample the lunar mantle. The largest of these craters is the approximately 2,500-kilometre-diameter South Pole-Aitken (SPA) basin3 on the lunar far side. Evidence obtained from orbiting spacecraft shows that the floor of the SPA basin is rich in mafic minerals4, but their mantle origin is controversial and their in situ geologic settings are poorly known. China's Chang'E-4 lunar far-side lander recently touched down in the Von Kármán crater5,6 to explore the floor of the huge SPA basin and deployed its rover, Yutu-2. Here we report on the initial spectral observations of the Visible and Near Infrared Spectrometer (VNIS)7 onboard Yutu-2, which we interpret to represent the presence of low-calcium (ortho)pyroxene and olivine, materials that may originate from the lunar mantle. Geological context6 suggests that these materials were excavated from below the SPA floor by the nearby 72-km-diameter Finsen impact crater event, and transported to the landing site. Continued exploration by Yutu-2 will target these materials on the floor of the Von Kármán crater to understand their geologic context, origin and abundance, and to assess the possibility of sample-return scenarios.
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Accumulating evidence underscores the pivotal role of envelope proteins in viral secondary envelopment. However, the intricate molecular mechanisms governing this phenomenon remain elusive. To shed light on these mechanisms, we investigated a Golgi-retained gD of EHV-1 (gDEHV-1), distinguishing it from its counterparts in Herpes Simplex Virus-1 (HSV-1) and Pseudorabies Virus (PRV). To unravel the specific sequences responsible for the Golgi retention phenotype, we employed a gene truncation and replacement strategy. The results suggested that Golgi retention signals in gDEHV-1 exhibiting a multi-domain character. The extracellular domain of gDEHV-1 was identified as an endoplasmic reticulum (ER)-resident domain, the transmembrane domain and cytoplasmic tail (TM-CT) of gDEHV-1 were integral in facilitating the protein's residence within the Golgi complex. Deletion or replacement of either of these dual domains consistently resulted in the mutant gDEHV-1 being retained in an ER-like structure. Moreover, (TM-CT)EHV-1 demonstrated a preference for binding to endomembranes, inducing the generation of a substantial number of vesicles, potentially originate from the Golgi complex or the ER-Golgi intermediate compartment. In conclusion, our findings provide insights into the intricate molecular mechanisms governing the Golgi retention of gDEHV-1, facilitating the comprehension of the processes underlying viral secondary envelopment.
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Herpesvirus Equídeo 1 , Proteínas do Envelope Viral , Animais , Cavalos , Proteínas do Envelope Viral/química , Herpesvirus Equídeo 1/metabolismo , Complexo de Golgi/metabolismo , Retículo Endoplasmático/metabolismo , Domínios ProteicosRESUMO
Metal-organic frameworks (MOFs) show potential application in many domains, in which photochromic MOFs (PMOFs) have received enormous attention. Researchers mainly utilize photoactive ligands to build PMOFs. Recently, the mixed electron donating and accepting ligands strategies have also been used to construct PMOFs driven by the electron transfer between nonphotochromic moieties. However, the potential interligand competition inhibits the formation of PMOFs. Therefore, the exploration of single-ligand-guided assembly is conductive for building PMOFs. Considering the existing electron accepting and donating role of pyridyl and carboxyl, the pyridinecarboxyate derived from the fusion of pyridyl and carboxyl units may serve as single ligand to yield PMOFs. In this work, the coordination assembly of bipyridinedicarboxylate (2,2'-bipyridine-4,4'-dicarboxylic acid, H2bpdc; 1,10-phenanthroline-2,9-dicarboxylic acid, H2pda) and LaCl3 generate two PMOFs, [La(bpdc)(H2O)Cl] (1) and [La(pda)(H2O)2Cl]·2H2O (2). Both complexes feature dinuclear lanthanum as building blocks with differences in the connecting number of likers, in which 1 has (4,8)-connected topology and 2 exhibits sql topology. Their structural differences result in the diversities of photoresponsive functionalities. Compared with reported PMOFs built from photoactive ligands and mixed ligands, this study provides new available categories of single ligand for generating PMOFs and tuning the structure and photoresponsive properties via ligand substitution and external photostimulus.
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Conversion from natural lands to cropland, primarily driven by agricultural expansion, could significantly alter soil microbiome worldwide; however, influences of forest-to-cropland conversion on microbial hierarchical interactions and ecosystem multifunctionality have not been fully understood. Here, we examined the effects of forest-to-cropland conversion on intratrophic and cross-trophic microbial interactions and soil ecosystem multifunctionality and further disclosed their underlying drivers at a national scale, using Illumina sequencing combined with high-throughput quantitative PCR techniques. The forest-to-cropland conversion significantly changed the structure of soil microbiome (including prokaryotic, fungal, and protistan communities) while it did not affect its alpha diversity. Both intrakingdom and interkingdom microbial networks revealed that the intratrophic and cross-trophic microbial interaction patterns generally tended to be more modular to resist environmental disturbance introduced from forest-to-cropland conversion, but this was insufficient for the cross-trophic interactions to maintain stability; hence, the protistan predation behaviors were still disturbed under such conversion. Moreover, key soil microbial clusters were declined during the forest-to-cropland conversion mainly because of the increased soil total phosphorus level, and this drove a great degradation of the ecosystem multifunctionality (by 207%) in cropland soils. Overall, these findings comprehensively implied the negative effects of forest-to-cropland conversion on the agroecosystem, from microbial hierarchical interactions to ecosystem multifunctionality.
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Ecossistema , Florestas , Microbiologia do Solo , Microbiota , Agricultura , Solo , Produtos AgrícolasRESUMO
Oligodendrocytes (OLs) are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system (CNS). Demyelination is a common feature of many neurological diseases such as multiple sclerosis (MS) and leukodystrophies. Although spontaneous remyelination can happen after myelin injury, nevertheless, it is often insufficient and may lead to aggravated neurodegeneration and neurological disabilities. Our previous study has discovered that MEK/ERK pathway negatively regulates OPC-to-OL differentiation and remyelination in mouse models. To facilitate possible clinical evaluation, here we investigate several MEK inhibitors which have been approved by FDA for cancer therapies in both mouse and human OPC-to-OL differentiation systems. Trametinib, the first FDA approved MEK inhibitor, displays the best effect in stimulating OL generation in vitro among the four MEK inhibitors examined. Trametinib also significantly enhances remyelination in both MOG-induced EAE model and LPC-induced focal demyelination model. More exciting, trametinib facilitates the generation of MBP+ OLs from human embryonic stem cells (ESCs)-derived OPCs. Mechanism study indicates that trametinib promotes OL generation by reducing E2F1 nuclear translocation and subsequent transcriptional activity. In summary, our studies indicate a similar inhibitory role of MEK/ERK in human and mouse OL generation. Targeting the MEK/ERK pathway might help to develop new therapies or repurpose existing drugs for demyelinating diseases.
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Cardiomyocytes are terminal differentiated cells and have limited ability to proliferate or regenerate. Condition like myocardial infarction causes massive death of cardiomyocytes and is the leading cause of death. Previous studies have demonstrated that cardiac fibroblasts can be induced to transdifferentiate into cardiomyocytes in vitro and in vivo by forced expression of cardiac transcription factors and microRNAs. Our previous study have demonstrated that full chemical cocktails could also induce fibroblast to cardiomyocyte transdifferentiation both in vitro and in vivo. With the development of tissue clearing techniques, it is possible to visualize the reprogramming at the whole-organ level. In this study, we investigated the effect of the chemical cocktail CRFVPTM in inducing in situ fibroblast to cardiomyocyte transdifferentiation with two strains of genetic tracing mice, and the reprogramming was observed at whole-heart level with CUBIC tissue clearing technique and 3D imaging. In addition, single-cell RNA sequencing (scRNA-seq) confirmed the generation of cardiomyocytes from cardiac fibroblasts which carries the tracing marker. Our study confirms the use of small molecule cocktails in inducing in situ fibroblast to cardiomyocyte reprogramming at the whole-heart level and proof-of-conceptly providing a new source of naturally incorporated cardiomyocytes to help heart regeneration.
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A Co3Mn-LDHs and carbon nanotube (Co3Mn-LDHs/CNT) composite catalyst was constructed for permonosulfate (PMS) activation and degrading sulfamethoxazole (SMX) under Vis light irradiation. The introduction of CNTs into Co3Mn-LDHs facilitate the exciton dissociation and carrier migration, and the e- and h+ were readily separated from Co3Mn-LDHs/CNT in the photocatalysis process, which promoted the production rate of reactive oxygen species (ROS), so the Co3Mn-LDHs + Vis + PMS system exhibited better activity with an SMX degradation ratio of 61.25% than those of Co3Mn-LDHs + Vis system (42.30%) and Co3Mn-LDHs + PMS system (48.30%). After 10 cycles, the degradation rate of SMX only decreased by 7.16%, indicating the good reusability of the Co3Mn-LDHs/CNTs catalyst. The results of electron paramagnetic resonance (EPR) analysis and radical quenching experiments demonstrated that that the SO4â¢- played crucial role for SMX removal in Co3Mn-LDHs/CNTs + Vis + PMS system, and both e- and h+ made an important contribution to activating PMS to produce ROS. Overall, this work provided an excellent catalyst for photo-assisted PMS activation and suggested the activation mechanism for organic pollutant remediation.
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Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by transverse myelitis and optic neuritis. The pathogenic serum IgG antibody against the aquaporin-4 (AQP4) on astrocytes triggers the activation of the complement cascade, causing astrocyte injury, followed by oligodendrocyte injury, demyelination, and neuronal loss. Complement C3 is positioned as a central player that relays upstream initiation signals to activate downstream effectors, potentially stimulating and amplifying host immune and inflammatory responses. However, whether targeting the inhibition of C3 signaling could ameliorate tissue injury, locomotor defects, and visual impairments in NMO remains to be investigated. In this study, using the targeted C3 inhibitor CR2-Crry led to a significant decrease in complement deposition and demyelination in both slice cultures and focal intracerebral injection models. Moreover, the treatment downregulated the expression of inflammatory cytokines and improved motor dysfunction in a systemic NMO mouse model. Similarly, employing serotype 2/9 adeno-associated virus (AAV2/9) to induce permanent expression of CR2-Crry resulted in a reduction in visual dysfunction by attenuating NMO-like lesions. Our findings reveal the therapeutic value of inhibiting the complement C3 signaling pathway in NMO.
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Complemento C3 , Neuromielite Óptica , Animais , Camundongos , Complemento C3/genética , Complemento C3/metabolismo , Neuromielite Óptica/patologia , Aquaporina 4/metabolismo , Transtornos da Visão/complicações , Transtornos da Visão/patologia , Astrócitos/metabolismo , Transdução de Sinais , Proteínas Recombinantes de Fusão/metabolismoRESUMO
Elaborating on the fate tendency of thifluzamide (thiazole-amide fungicide) in buckwheat based on nationwide application is vital for grain security and human health based on nationwide application. A rapid and sensitive analytical method was developed to trace thifluzamide in buckwheat matrices using an ultrahigh-performance liquid chromatography-tandem triple quadrupole mass spectrometer (UHPLC-MS/MS), with a retention time of 2.90 min and limit of quantitation (LOQ) of 0.001 mg/kg. Thifluzamide could be stably stored for 84 d in buckwheat matrices under -20 °C under dark condition. The occurrence, dissipation and terminal magnitudes of thifluzamide were reflected by the primary deposition of 0.02-0.55 mg/kg, half-lives of 12-14 d, and highest residues of 0.41 mg/kg. The long-term risks (ADI%) of thifluzamide were 37.268 %-131.658 % in registered crops, and the risks for the rural population were significantly higher than those of the urban population. The unacceptable dietary risks of thifluzamide should be continuously emphasized for children aged 2-7 with an ADI% values of 100.750 %-131.658 %. A probabilistic model was further introduced to evaluate the risk discrepancy of thifluzamide in buckwheat, showing the risks in Tartary buckwheat (Fagopyrum tararicum Gaerth) were 1.5-75.4 times than that in sweet buckwheat (Fagopyrum esculentum Moench). Despite the low risks for dietary buckwheat, the high-potential health hazards of thifluzamide should be pay more attention given the increasing applications and cumulative effects.
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Anilidas , Fagopyrum , Criança , Humanos , Fagopyrum/química , Espectrometria de Massas em Tandem , Cromatografia Líquida , TiazóisRESUMO
BACKGROUND: The differences in outcomes after aneurysmal subarachnoid hemorrhage (aSAH) between the sexes have not been concretely determined. This study aimed to evaluate the differences in epidemiology, outcomes, and risk factors between male and female patients with aSAH. METHODS: We performed a multicenter, retrospective study of patients with aSAH from 2017 to 2020. We investigated the epidemiological differences between the two sexes. Propensity score matching (PSM) was used to compare short-term outcomes between the sexes. Binary logarithmic regression was performed to investigate the odds ratio (OR) for dependent survival in patients of different sexes. RESULTS: A total of 5,407 consecutive patients with aSAH were included in this study, and the female-to-male ratio was 1.8:1. The peak incidence of aSAH occurred in the 6th and 7th decades in males and females, respectively. There were more female patients with internal carotid artery or posterior communicating artery aneurysms (53.2%), and there were more male patients with anterior cerebral artery or anterior communicating artery aneurysms (43.2%). The incidence of multiple aneurysms was greater in female patients (21.5% vs. 14.2%, P < 0.001). There was no significant difference in outcomes before and after PSM at discharge. The dependent survival risk was related only to the clinical condition on admission in women. In addition, age > 50 years (OR 1.88, 95% confidence interval 1.17-3.02; P = 0.01) and hypertension (OR 1.81, 95% confidence interval 1.25-2.61; P = 0.002) were also risk factors for male patients. CONCLUSIONS: There were more female patients with aneurysms than male patients in this study. Most aneurysm locations were different between the two groups. There was no significant difference in discharge outcomes before and after PSM. The risk factors for dependent survival were different between female and male patients.
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This study aimed to systematically evaluate the impact of evidence-based nursing (EBN) on perioperative wound infections and postoperative complications in patients undergoing surgery for liver hepatocellular carcinoma (LIHC). Randomised controlled trials (RCTs) on the application of EBN on patients receiving LIHC surgery were searched in PubMed, Web of Science, Cochrane Library, Embase, Wanfang, China Biomedical Literature Database and China National Knowledge Infrastructure from the inception of each database to September 2023. Studies were screened and evaluated by two investigators based on inclusion and exclusion criteria, and data were extracted from the final included literature. RevMan 4.0 was used for data analysis. Overall, 15 RCTs involving 1374 patients with LIHC were included, with 687 in the EBN group and 687 in the conventional care group. The analysis revealed that the incidence of wound infections (odds ratio [OR] = 0.32, 95% confidence interval [CI]: 0.18-0.56, p < 0.001) and postoperative complications (OR = 0.22, 95% CI: 0.15-0.31, p < 0.001) was significantly lower in the EBN group than in the conventional care group. The available evidence suggests that nursing strategies for EBN applied in the perioperative period in patients with LIHC receiving surgery can effectively reduce the incidence of wound infections and postoperative complications and promote postoperative recovery.
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Enfermagem Baseada em Evidências , Neoplasias Hepáticas , Humanos , Infecção da Ferida Cirúrgica/etiologia , Neoplasias Hepáticas/cirurgia , Abdome , ChinaRESUMO
Peroxisome proliferator-activated receptors (PPARs) are essential for cellular physiological processes. However, there is less research on the PPAR-related genes in lung adenocarcinoma (LUAD). Open-access data were get from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. All the analysis were conducted in the R software based on different R packages. In this study, we gauged the PPAR score employing a set of 72 PPAR-associated genes and probed the biological impact of this score on lung adenocarcinoma (LUAD). Subsequently, we established a unique signature composed of eight PPAR-related genes (ANGPTL4, ACSL3, ADIPOQ, FABP1, SLC27A1, ACOX2, PPARD and OLR1) to forecast the prognosis of LUAD. The signature's effectiveness in predicting survival was validated through the receiver operating characteristic curve in the TCGA-LUAD cohort. As per the pathway enrichment analysis, several crucial oncogenic pathways and metabolic processes were enriched in high-risk individuals. Further, we observed that these high-risk patients exhibited heightened genomic instability. Additionally, compared to the low-risk cohort, high-risk patients demonstrated diminished immune components and function. Intriguingly, high-risk patients exhibited a potential heightened sensitivity to immunotherapy and certain drugs, including Gefitinib, Afatinib, Erlotinib, IAP_5620, Sapitinib, LCL161, Lapatinib and AZD3759. The prognosis model based on eight PPAR-related genes has satisfactory prognosis prediction efficiency. Meanwhile, our results can provide direction for future studies in the relevant aspects.
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BACKGROUND: hsa_circ_0001727 (circZKSCAN1) has been reported to be a tumor-associated circRNA by sponging microRNAs. Intriguingly, we found that circZKSCAN1 encoded a secretory peptide (circZKSaa) in the liver. The present study aims to elucidate the potential role and molecular mechanism of circZKSaa in the regulation of hepatocellular carcinoma (HCC) progression. METHODS: The circRNA profiling datasets (RNA-seq data GSE143233 and GSE140202) were reanalyzed and circZKSCAN1 was selected for further study. Mass spectrometry, polysome fractionation assay, dual-luciferase reporter, and a series of experiments showed that circZKSCAN1 encodes circZKSaa. Cell proliferation, apoptosis, and tumorigenesis in nude mice were examined to investigate the functions of circZKSaa. Mechanistically, the relationship between the circZKSaa and mTOR in HCC was verified by immunoprecipitation analyses, mass spectrometry, and immunofluorescence staining analyses. RESULTS: Receiver operating characteristic (ROC) analysis demonstrated that the secretory peptide circZKSaa encoded by circZKSCAN1 might be the potential biomarker for HCC tissues. Through a series of experiments, we found that circZKSaa inhibited HCC progression and sensitize HCC cells to sorafenib. Mechanistically, we found that the sponge function of circZKSCAN1 to microRNA is weak in HCC, while overexpression of circZKSaa promoted the interaction of FBXW7 with the mammalian target of rapamycin (mTOR) to promote the ubiquitination of mTOR, thereby inhibiting the PI3K/AKT/mTOR pathway. Furthermore, we found that the high expression of cicZKSCAN1 in sorafenib-treated HCC cells was regulated by QKI-5. CONCLUSIONS: These results reveal that a novel circZKSCAN1-encoded peptide acts as a tumor suppressor on PI3K/AKT/mTOR pathway, and sensitizes HCC cells to sorafenib via ubiquitination of mTOR. These findings demonstrated that circZKSaa has the potential to serve as a therapeutic target and biomarker for HCC treatment.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Animais , Camundongos , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , Mamíferos/genética , Mamíferos/metabolismo , Camundongos Nus , MicroRNAs/genética , Peptídeos/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Circular/genética , Sirolimo , Sorafenibe , Serina-Treonina Quinases TOR/metabolismo , HumanosRESUMO
BACKGROUND: The treatment of Triple-negative breast cancer (TNBC) has always been challenging due to its heterogeneity and the absence of well-defined molecular targets. The present study aims to elucidate the role of protein-coding circRNAs in the etiology and carcinogenesis of TNBC. METHODS: CircRNA expression data in TNBC (GEO: GSE113230, GSE101123) were reanalyzed and then circCAPG was selected for further study. To identify the polypeptide-coding function of circCAPG, a series of experiments, such as Mass spectrometry and dual-luciferase reporter assays were conducted. Cell proliferation, apoptosis and metastasis parameters were determined to investigate the cancerous functions CAPG-171aa plays in both TNBC organoids and nude mice. Mechanistically, the relation between CAPG-171aa and STK38 in TNBC was verified by immunoprecipitation analyses and mass spectrometry. The interactions between SLU7 and its binding site on circCAPG were validated by RIP-qPCR experiments. RESULTS: In both TNBC clinical samples and cell lines, the expression level of circCAPG was identified to be higher compared with normal ones and positively correlated with the overall survival (n = 132) in a 10-year follow-up study, in which the area under the curve of receiver operating characteristic was 0.8723 with 100% specificity and 80% sensitivity. In addition, we found that circCAPG knockdown (KD) significantly inhibited the growth of TNBC organoids. Intriguingly, circCAPG can be translated into a polypeptide named CAPG-171aa which promotes tumor growh by disrupting the binding of serine/threonine kinase 38 (STK38) to SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) and thereby preventing MEKK2 ubiquitination and proteasomal degradation. Furthermore, we found that SLU7 Homolog- Splicing Factor (SLU7) can regulate the bio-generation of circCAPG through binding to the flanking Alu sequences of circRNA transcripts. CONCLUSIONS: circCAPG significantly enhances the proliferation and metastasis of TNBC cells by encoding a novel polypeptide CAPG-171aa and afterwards activates MEKK2-MEK1/2-ERK1/2 pathway. Additionally, the formation of circCAPG is found to be mediated by SLU7. The present study provides innovative insight into the role of protein-coding circRNAs CAPG-171aa in TNBC, and its capacity to serve as a promising prognostic biomarker and potential therapeutic target in TNBC.
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MicroRNAs , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , MicroRNAs/genética , RNA Circular/genética , Neoplasias de Mama Triplo Negativas/patologia , Camundongos Nus , Seguimentos , Proliferação de Células/genética , Peptídeos/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Fatores de Processamento de RNA/genética , Proteínas dos Microfilamentos/genética , Proteínas Nucleares/genéticaRESUMO
It is well known that exosomes could serve as anti-microbial immune factors in animals. However, despite growing evidences have shown that the homeostasis of the hemolymph microbiota was vital for immune regulation in crustaceans, the relationship between exosomes and hemolymph microbiota homeostasis during pathogenic bacteria infection has not been addressed. Here, we reported that exosomes released from Vibrio parahaemolyticus-infected mud crabs (Scylla paramamosain) could help to maintain the homeostasis of hemolymph microbiota and have a protective effect on the mortality of the host during the infection process. We further confirmed that miR-224 was densely packaged in these exosomes, resulting in the suppression of HSP70 and disruption of the HSP70-TRAF6 complex, then the released TRAF6 further interacted with Ecsit to regulate the production of mitochondrial ROS (mROS) and the expression of Anti-lipopolysaccharide factors (ALFs) in recipient hemocytes, which eventually affected hemolymph microbiota homeostasis in response to the pathogenic bacteria infection in mud crab. To the best of our knowledge, this is the first document that reports the role of exosome in the hemolymph microbiota homeostasis modulation during pathogen infection, which reveals the crosstalk between exosomal miRNAs and innate immune response in crustaceans.
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Proteínas de Artrópodes/metabolismo , Braquiúros/imunologia , Exossomos/genética , Hemolinfa/imunologia , Imunidade Inata/imunologia , MicroRNAs/genética , Vibrioses/imunologia , Animais , Proteínas de Artrópodes/genética , Braquiúros/microbiologia , Perfilação da Expressão Gênica , Hemócitos/imunologia , Hemócitos/metabolismo , Hemócitos/microbiologia , Hemolinfa/metabolismo , Hemolinfa/microbiologia , Homeostase , Microbiota , Filogenia , Vibrioses/microbiologia , Vibrio parahaemolyticus/fisiologiaRESUMO
BACKGROUND: Due to general unavailability and common side effects of tetracycline, the clinical application of bismuth quadruple therapy (BQT) is greatly limited. Whether amoxicillin can replace tetracycline in BQT remains unknown. This study aimed to compare the eradication rate, safety and compliance between amoxicillin-containing and tetracycline-containing BQT as a first-line regimen for Helicobacter pylori eradication. METHODS: This randomized trial was conducted on 404 naïve patients for H. pylori eradication. The participants were randomly assigned to 14-day amoxicillin-containing (bismuth potassium citrate 110 mg four times/day, esomeprazole 20 mg twice daily, metronidazole 400 mg four times/day and amoxicillin 500 mg four times/day) and tetracycline-containing (tetracycline 500 mg four times/day and the other three drugs used as above) BQT. Safety and compliance were assessed within 3 days after eradication. Urea breath test was performed 4-8 weeks after eradication to evaluate outcome. RESULTS: As for the eradication rates of amoxicillin-containing and tetracycline-containing BQT, the results of both intention-to-treat and per-protocol analyses showed that the difference rate of the lower limit of 95% confidence interval was above -10.0% (intention-to-treat analysis: 81.7% vs. 83.2%, with a rate difference of -1.5% [-6.3% to 9.3%]; per-protocol analysis: 89.0% vs. 91.6%, -2.6% [-4.1% to 9.3%]). The incidence of adverse events in amoxicillin-containing BQT was significantly lower than tetracycline-containing BQT (29.5% vs. 39.7%). Both groups achieved relatively good compliance (92.0% vs. 89.9%). CONCLUSION: The eradication efficacy of amoxicillin-containing BQT was non-inferior to tetracycline-containing BQT as a first-line regimen for H. pylori eradication with better safety and similar compliance.
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Infecções por Helicobacter , Helicobacter pylori , Humanos , Amoxicilina/efeitos adversos , Metronidazol/efeitos adversos , Bismuto/efeitos adversos , Esomeprazol/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Antibacterianos/efeitos adversos , Tetraciclina/efeitos adversos , Quimioterapia CombinadaRESUMO
Trained immunity has been widely observed in mammals. Its identification in red swamp crayfish (Procambarus clarkii) is important for disease resistance in the crayfish farming industry. In this study, the mortality, expression of immune genes, production of reactive oxygen species (ROS), and phagocytosis ability of haemocytes in crayfish infected by pathogens (Vibrio parahaemolyticus or white spot syndrome virus) and crayfish trained with ß-glucan or PBS (the control) were assessed when they were re-challenged by the pathogens. The results showed that the mortality of the trained and re-challenged crayfish were significantly lower than those of the untrained and challenged crayfish. Furthermore, the expression of immune genes, including Resistance (R), ALF, crustin2, and proPO, ROS levels, and phagocytosis ability of haemocytes, was significantly improved in the trained crayfish compared to that in the untrained crayfish. Interestingly, we found that the immune memory of trained crayfish lasted for at least 18 days. Together, these results indicate that crayfish develops trained immunity that can play an important role in the disease resistance. This suggests that trained immunity may be applied to improve disease resistance and crayfish production.