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Transcription factors (TFs) activate enhancers to drive cell-specific gene programs in response to signals, but our understanding of enhancer assembly during signaling events is incomplete. Here, we show that androgen receptor (AR) forms condensates through multivalent interactions mediated by its N-terminal intrinsically disordered region (IDR) to orchestrate enhancer assembly in response to androgen signaling. AR IDR can be substituted by IDRs from selective proteins for AR condensation capacity and its function on enhancers. Expansion of the poly(Q) track within AR IDR results in a higher AR condensation propensity as measured by multiple methods, including live-cell single-molecule microscopy. Either weakening or strengthening AR condensation propensity impairs its heterotypic multivalent interactions with other enhancer components and diminishes its transcriptional activity. Our work reveals the requirement of an optimal level of AR condensation in mediating enhancer assembly and suggests that alteration of the fine-tuned multivalent IDR-IDR interactions might underlie AR-related human pathologies.
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Elementos de Facilitación Genéticos , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Hormonas , Transducción de SeñalRESUMEN
Aberrant energy status contributes to multiple metabolic diseases, including obesity, diabetes, and cancer, but the underlying mechanism remains elusive. Here, we report that ketogenic-diet-induced changes in energy status enhance the efficacy of anti-CTLA-4 immunotherapy by decreasing PD-L1 protein levels and increasing expression of type-I interferon (IFN) and antigen presentation genes. Mechanistically, energy deprivation activates AMP-activated protein kinase (AMPK), which in turn, phosphorylates PD-L1 on Ser283, thereby disrupting its interaction with CMTM4 and subsequently triggering PD-L1 degradation. In addition, AMPK phosphorylates EZH2, which disrupts PRC2 function, leading to enhanced IFNs and antigen presentation gene expression. Through these mechanisms, AMPK agonists or ketogenic diets enhance the efficacy of anti-CTLA-4 immunotherapy and improve the overall survival rate in syngeneic mouse tumor models. Our findings reveal a pivotal role for AMPK in regulating the immune response to immune-checkpoint blockade and advocate for combining ketogenic diets or AMPK agonists with anti-CTLA4 immunotherapy to combat cancer.
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Proteínas Quinasas Activadas por AMP/genética , Antígeno B7-H1/genética , Neoplasias de la Mama/genética , Antígeno CTLA-4/genética , Neoplasias Colorrectales/genética , Inhibidores de Puntos de Control Inmunológico , Proteínas Quinasas Activadas por AMP/inmunología , Aloinjertos , Animales , Anticuerpos Neutralizantes/farmacología , Antineoplásicos/farmacología , Antígeno B7-H1/inmunología , Compuestos de Bifenilo/farmacología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Línea Celular Tumoral , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/terapia , Dieta Cetogénica/métodos , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia/métodos , Proteínas con Dominio MARVEL/genética , Proteínas con Dominio MARVEL/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Pironas/farmacología , Transducción de Señal , Análisis de Supervivencia , Tiofenos/farmacologíaRESUMEN
Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.
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Proteínas Portadoras , Polaridad Celular , Proteínas de la Membrana , Columna Vertebral , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/embriología , Humanos , Ratones , Polaridad Celular/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Columna Vertebral/anomalías , Columna Vertebral/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Escoliosis/genética , Escoliosis/congénito , Escoliosis/metabolismo , Vía de Señalización Wnt/genética , Predisposición Genética a la Enfermedad , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , FemeninoRESUMEN
Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts. Pathologically, immunohistochemical analyses uncovered a positive correlation between AMPK activity and pT311-EZH2, and higher pT311-EZH2 correlates with better survival in both ovarian and breast cancer patients. Our finding suggests that AMPK agonists might be promising sensitizers for EZH2-targeting cancer therapies.
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Proteínas Quinasas Activadas por AMP/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Animales , Carcinogénesis/genética , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Metilación de ADN , Proteínas de Unión al ADN/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/fisiología , Epigénesis Genética , Femenino , Histonas/metabolismo , Humanos , Ratones , Proteínas de Neoplasias , Proteínas Nucleares/metabolismo , Oncogenes , Neoplasias Ováricas/metabolismo , Fosforilación , Complejo Represivo Polycomb 2/metabolismo , Complejo Represivo Polycomb 2/fisiología , Factores de Transcripción , Regulación hacia ArribaRESUMEN
MOTIVATION: Random forests (RFs) can deal with a large number of variables, achieve reasonable prediction scores, and yield highly interpretable feature importance values. As such, RFs are appropriate models for feature selection and further dimension reduction. However, RFs are often not appropriate for correlated datasets due to their mode of selecting individual features for splitting. Addressing correlation relationships in high-dimensional datasets is imperative for reducing the number of variables that are assigned high importance, hence making the dimension reduction most efficient. Here, we propose the LAtent VAriable Stochastic Ensemble of Trees (LAVASET) method that derives latent variables based on the distance characteristics of each feature and aims to incorporate the correlation factor in the splitting step. RESULTS: Without compromising on performance in the majority of examples, LAVASET outperforms RF by accurately determining feature importance across all correlated variables and ensuring proper distribution of importance values. LAVASET yields mostly non-inferior prediction accuracies to traditional RFs when tested in simulated and real 1D datasets, as well as more complex and high-dimensional 3D datatypes. Unlike traditional RFs, LAVASET is unaffected by single 'important' noisy features (false positives), as it considers the local neighbourhood. LAVASET, therefore, highlights neighbourhoods of features, reflecting real signals that collectively impact the model's predictive ability. AVAILABILITY AND IMPLEMENTATION: LAVASET is freely available as a standalone package from https://github.com/melkasapi/LAVASET.
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Drugs that block the activity of the methyltransferase EZH2 are in clinical development for the treatment of non-Hodgkin lymphomas harboring EZH2 gain-of-function mutations that enhance its polycomb repressive function. We have previously reported that EZH2 can act as a transcriptional activator in castration-resistant prostate cancer (CRPC). Now we show that EZH2 inhibitors can also block the transactivation activity of EZH2 and inhibit the growth of CRPC cells. Gene expression and epigenomics profiling of cells treated with EZH2 inhibitors demonstrated that in addition to derepressing gene expression, these compounds also robustly down-regulate a set of DNA damage repair (DDR) genes, especially those involved in the base excision repair (BER) pathway. Methylation of the pioneer factor FOXA1 by EZH2 contributes to the activation of these genes, and interaction with the transcriptional coactivator P300 via the transactivation domain on EZH2 directly turns on the transcription. In addition, CRISPR-Cas9-mediated knockout screens in the presence of EZH2 inhibitors identified these BER genes as the determinants that underlie the growth-inhibitory effect of EZH2 inhibitors. Interrogation of public data from diverse types of solid tumors expressing wild-type EZH2 demonstrated that expression of DDR genes is significantly correlated with EZH2 dependency and cellular sensitivity to EZH2 inhibitors. Consistent with these findings, treatment of CRPC cells with EZH2 inhibitors dramatically enhances their sensitivity to genotoxic stress. These studies reveal a previously unappreciated mechanism of action of EZH2 inhibitors and provide a mechanistic basis for potential combination cancer therapies.
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Daño del ADN/genética , Daño del ADN/fisiología , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Activación Transcripcional , Sistemas CRISPR-Cas , Línea Celular Tumoral , Reparación del ADN/genética , Reparación del ADN/fisiología , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Técnicas de Inactivación de Genes , Factor Nuclear 3-alfa del Hepatocito/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismoRESUMEN
BACKGROUND & AIMS: Sodium taurocholate cotransporting polypeptide (NTCP) has been identified as the cellular receptor for hepatitis B virus (HBV). However, hepatocytes expressing NTCP exhibit varying susceptibilities to HBV infection. This study aimed to investigate whether other host factors modulate the process of HBV infection. METHODS: Liver biopsy samples obtained from children with hepatitis B were used for single-cell sequencing and susceptibility analysis. Primary human hepatocytes, HepG2-NTCP cells, and human liver chimeric mice were used to analyze the effect of candidate host factors on HBV infection. RESULTS: Single-cell sequencing and susceptibility analysis revealed a positive correlation between neuropilin-1 (NRP1) expression and HBV infection. In the HBV-infected cell model, NRP1 overexpression before HBV inoculation significantly enhanced viral attachment and internalization, and promoted viral infection in the presence of NTCP. Mechanistic studies indicated that NRP1 formed a complex with LHBs and NTCP. The NRP1 b domain mediated its interaction with conserved arginine residues at positions 88 and 92 in the preS1 domain of the HBV envelope protein LHBs. This NRP1-preS1 interaction subsequently promoted the binding of preS1 to NTCP, facilitating viral infection. Moreover, disruption of the NRP1-preS1 interaction by the NRP1 antagonist EG00229 significantly attenuated the binding affinity between NTCP and preS1, thereby inhibiting HBV infection both in vitro and in vivo. CONCLUSIONS: Our findings indicate that NRP1 is a novel host factor for HBV infection, which interacts with preS1 and NTCP to modulate HBV entry into hepatocytes. IMPACT AND IMPLICATIONS: HBV infection is a global public health problem, but the understanding of the early infection process of HBV remains limited. Through single-cell sequencing, we identified a novel host factor, NRP1, which modulates HBV entry by interacting with HBV preS1 and NTCP. Moreover, antagonists targeting NRP1 can inhibit HBV infection both in vitro and in vivo. This study could further advance our comprehension of the early infection process of HBV.
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Bladder cancer (BC) occurrence and progression are accompanied by alterations in microRNAs (miRNAs) expression levels. Simultaneous detection of multiple miRNAs contributes to the accuracy and reliability of the BC diagnosis. In this work, wrinkled silica nanoparticles (WSNs) were applied as the microreactor for multiplex miRNAs analysis without enzymes or nucleic acid amplification. Conjugated on the surface of WSNs, the S9.6 antibody was adopted as the universal module for binding DNA/miRNA duplexes, regardless of their sequence. Furthermore, single-stranded DNA (ssDNA) was labeled with quantum dots (QDs) for identifying a given miRNA to form QDs-ssDNA/miRNA, which enabled the specific capture of the corresponding QDs on the wrinkled surface of WSNs. Based on the detection of fluorescence signals that were ultimately focused on WSNs, target miRNAs could be sensitively identified to a femtomolar level (5 fM) with a wide dynamic range of up to 6 orders of magnitude. The proposed strategy achieved high specificity to obviously distinguish single-base mutation sequences and possessed multiplex assay capability. Moreover, the assay exhibited excellent practicability in the multiplex detection of miRNAs in clinical serum specimens.
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Técnicas Biosensibles , MicroARNs , Puntos Cuánticos , Neoplasias de la Vejiga Urinaria , Humanos , MicroARNs/análisis , Reproducibilidad de los Resultados , ADN , ADN de Cadena Simple , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
Photodynamic therapy (PDT) is extensively investigated for tumor therapy in the clinic. However, the efficacy of PDT is severely limited by the tissue penetrability of light, short effective half-life and radius of reactive oxygen species (ROS), and the weak immunostimulatory effect. In this study, a glutathione (GSH)-activatable nano-photosensitizer is developed to load with arachidonic acid (AA) and camouflage by erythrocyte membrane, which serves as a laser-ignited lipid peroxidation nanoamplifier (MAR). The photosensitive effect of MAR is recovered accompanied by the degradation in the tumor microenvironment and triggers the peroxidation of AA upon laser excitation. Interestingly, it aggravates the propagation of ferroptosis among cancer cells by driving the continuous lipid peroxidation chain reactions with the participation of the degradation products, ferrous ions (Fe2+), and AA. Consequently, even the deep-seated tumor cells without illumination also undergo ferroptosis owing to the propagation of ferroptotic signal. Moreover, the residual tumor cells undergoing ferroptosis still maintain high immunogenicity after PDT, thus continuously triggering sufficient tumor-associated antigens (TAAs) release to remarkably promote the anti-tumor immune response. Therefore, this study will provide a novel "all-in-one" nano-photosensitizer that not only amplifies the damaging effect and expands the effective range of PDT but also improves the immunostimulatory effect after PDT.
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Fotoquimioterapia , Fármacos Fotosensibilizantes , Peroxidación de Lípido , Fármacos Fotosensibilizantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Glutatión/metabolismo , Línea Celular TumoralRESUMEN
Biallelic pathogenic variants in CCN6 cause progressive pseudorheumatoid dysplasia (PPD), a rare skeletal dysplasia. The predominant features include noninflammatory progressive joint stiffness and enlargement, which are not unique to this condition. Nearly 100% of the reported variants are single nucleotide variants or small indels, and missing of a second variant has been reported. Genome sequencing (GS) covers various types of variants and deep phenotyping (DP) provides detailed and precise information facilitating genetic data interpretation. The combination of GS and DP improves diagnostic yield, especially in rare and undiagnosed diseases. We identified a novel compound heterozygote involving a disease-causing copy number variant (g.112057664_112064205del) in trans with a single nucleotide variant (c.624dup(p.Cys209MetfsTer21)) in CCN6 in a pair of monozygotic twins, through the methods of GS and DP. The twins had received three nondiagnostic results before. The g.112057664_112064205del variant was missed by all the tests, and the recorded phenotypes were inaccurate or even misleading. The twins were diagnosed with PPD, ending a 13-year diagnostic odyssey. There may be other patients with PPD experiencing underdiagnosis and misdiagnosis due to inadequate genetic testing or phenotyping methods. This case highlights the critical role of GS and DP in facilitating an accurate and timely diagnosis.
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BACKGROUND: Progressive hepatitis B virus (HBV) infection can result in cirrhosis, hepatocellular cancer, and chronic hepatitis. While antiviral drugs that are now on the market are efficient in controlling HBV infection, finding a functional cure is still quite difficult. Identifying host factors involved in regulating the HBV life cycle will contribute to the development of new antiviral strategies. Zinc finger proteins have a significant function in HBV replication, according to earlier studies. Zinc finger protein 148 (ZNF148), a zinc finger transcription factor, regulates the expression of various genes by specifically binding to GC-rich sequences within promoter regions. The function of ZNF148 in HBV replication was investigated in this study. METHODS: HepG2-Na+/taurocholate cotransporting polypeptide (HepG2-NTCP) cells and Huh7 cells were used to evaluate the function of ZNF148 in vitro. Northern blotting and real-time PCR were used to quantify the amount of viral RNA. Southern blotting and real-time PCR were used to quantify the amount of viral DNA. Viral protein levels were elevated, according to the Western blot results. Dual-luciferase reporter assays were used to examine the transcriptional activity of viral promoters. ZNF148's impact on HBV in vivo was investigated using an established rcccDNA mouse model. RESULTS: ZNF148 overexpression significantly decreased the levels of HBV RNAs and HBV core DNA in HBV-infected HepG2-NTCP cells and Huh7 cells expressing prcccDNA. Silencing ZNF148 exhibited the opposite effects in both cell lines. Furthermore, ZNF148 inhibited the activity of HBV ENII/Cp and the transcriptional activity of cccDNA. Mechanistic studies revealed that ZNF148 attenuated retinoid X receptor alpha (RXRα) expression by binding to the RXRα promoter sequence. RXRα binding site mutation or RXRα overexpression abolished the suppressive effect of ZNF148 on HBV replication. The inhibitory effect of ZNF148 was also observed in the rcccDNA mouse model. CONCLUSIONS: ZNF148 inhibited HBV replication by downregulating RXRα transcription. Our findings reveal that ZNF148 may be a new target for anti-HBV strategies.
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Virus de la Hepatitis B , Hepatitis B , Animales , Humanos , Ratones , ADN Viral/genética , Células Hep G2 , Virus de la Hepatitis B/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Replicación ViralRESUMEN
Nipah virus (NiV), a bat-borne zoonotic viral pathogen with high infectivity and lethality to humans, has caused severe outbreaks in several countries of Asia during the past two decades. Because of the worldwide distribution of the NiV natural reservoir, fruit bats, and lack of effective treatments or vaccines for NiV, routine surveillance and early detection are the key measures for containing NiV outbreaks and reducing its influence. In this study, we developed two rapid, sensitive and easy-to-conduct methods, RAA-CRISPR/Cas12a-FQ and RAA-CRISPR/Cas12a-FB, for NiV detection based on a recombinase-aided amplification (RAA) assay and a CRISPR/Cas12a system by utilizing dual-labeled fluorophore-quencher or fluorophore-biotin ssDNA probes. These two methods can be completed in 45 min and 55 min and achieve a limit of detection of 10 copies per µL and 100 copies per µL of NiV N DNA, respectively. In addition, they do not cross-react with nontarget nucleic acids extracted from the pathogens causing similar symptoms to NiV, showing high specificity for NiV N DNA detection. Meanwhile, they show satisfactory performance in the detection of spiked samples from pigs and humans. Collectively, the RAA-CRISPR/Cas12a-FQ and RAA-CRISPR/Cas12a-FB methods developed by us would be promising candidates for the early detection and routine surveillance of NiV in resource-poor areas and outdoors.
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Sistemas CRISPR-Cas , Virus Nipah , Virología , Animales , Humanos , Sistemas CRISPR-Cas/genética , ADN Viral/genética , ADN Viral/análisis , Colorantes Fluorescentes/química , Límite de Detección , Virus Nipah/genética , Virus Nipah/aislamiento & purificación , Técnicas de Amplificación de Ácido Nucleico/métodos , Virología/métodosRESUMEN
The evolution of prostate cancer from an androgen-dependent state to one that is androgen-independent marks its lethal progression. The androgen receptor (AR) is essential in both, though its function in androgen-independent cancers is poorly understood. We have defined the direct AR-dependent target genes in both androgen-dependent and -independent cancer cells by generating AR-dependent gene expression profiles and AR cistromes. In contrast to what is found in androgen-dependent cells, AR selectively upregulates M-phase cell-cycle genes in androgen-independent cells, including UBE2C, a gene that inactivates the M-phase checkpoint. We find that epigenetic marks at the UBE2C enhancer, notably histone H3K4 methylation and FoxA1 transcription factor binding, are present in androgen-independent cells and direct AR-enhancer binding and UBE2C activation. Thus, the role of AR in androgen-independent cancer cells is not to direct the androgen-dependent gene expression program without androgen, but rather to execute a distinct program resulting in androgen-independent growth.
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Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Andrógenos/metabolismo , División Celular , Línea Celular Tumoral , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Histonas/metabolismo , Humanos , Masculino , Neoplasias de la Próstata/genética , Activación Transcripcional , Enzimas Ubiquitina-Conjugadoras/metabolismoRESUMEN
BACKGROUND & AIMS: Kinesin family member 18A (KIF18A) is notable for its aberrant expression across various cancer types and its pivotal role is driving cancer progression. In this study, we aim to investigate the intricate molecular mechanisms underlying the impact of KIF18A on the progression of HCC. METHODS: Western blotting assays, a quantitative real-time PCR and immunohistochemical analyses were performed to quantitatively assess KIF18A expression in HCC tissues. We then performed genetic manipulations within HCC cells by silencing endogenous KIF18A using short hairpin RNA (shRNA) and introducing exogenous plasmids to overexpress KIF18A. We monitored cell progression, analyzed cell cycle and cell apoptosis and assessed cell migration and invasion both in vitro and in vivo. Moreover, we conducted RNA-sequencing to explore KIF18A-related signaling pathways utilizing Reactome and KEGG enrichment methods and validated these critical mediators in these pathways. RESULTS: Analysis of the TCGA-LIHC database revealed pronounced overexpression of KIF18A in HCC tissues, the finding was subsequently confirmed through the analysis of clinical samples obtained from HCC patients. Notably, silencing KIF18A in cells led to an obvious inhibition of cell proliferation, migration and invasion in vitro. Furthermore, in subcutaneous and orthotopic xenograft models, suppression of KIF18A sgnificantly redudce tumor weight and the number of lung metastatic nodules. Mechanistically, KIF18A appears to facilitate cell proliferation by upregulating MAD2 and CDK1/CyclinB1 expression levels, with the activation of SMAD2/3 signaling contributing to KIF18A-driven metastasis. CONCLUSION: Our study elucidates the molecular mechanism by which KIF18A mediates proliferation and metastasis in HCC cells, offering new insights into potential therapeutic targets.
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Carcinoma Hepatocelular , Cinesinas , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Cinesinas/genética , Cinesinas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , ARN Interferente PequeñoRESUMEN
OBJECTIVE: To investigate the efficacy and safety of mini-track, mini-nephroscopy and mini-ultrasonic probe percutaneous nephrolithotomy (3mPCNL) for the treatment of 1.5-2.5 cm kidney stones. METHODS: The perioperative data and postoperative follow-up data of a total of 25 patients with about 1.5-2.5 cm kidney stones who underwent 3mPCNL under ultrasound guidance in Peking University People's Hospital from November 2023 to January 2024 were retrospectively analyzed. During the matching period, the 25 patients with 1.5-2.5 cm kidney stones receiving standard percutaneous nephrolithotomy (sPCNL) were matched one-to-one according to the criterion that the absolute difference of the maximum diameter of stones between the two groups was less than 1 mm. The operative time, renal function changes, postoperative stone-free rate, hemoglobin changes, and complication rate of the two treatments were compared, and then the effectiveness and safety of 3mPCNL were preliminarily analyzed. RESULTS: There were no significant differences in mean age, preoperative median creatinine, preoperative mean hemoglobin, preoperative mean hematocrit, median stone maximum diameter, and median stone CT density between the 3mPCNL group and the sPCNL group. The median operation time in the 3mPCNL group was 60.0 (45.0-110.0) min, with no statistical significance compared with the sPCNL group, and all the patients underwent single-channel operations. The mean hemoglobin after operation in the 3mPCNL group was (115.3±15.5) mmol/L, and there was no significant difference between the preoperative group and the sPCNL group, and the mean hemoglobin decreased significantly between the sPCNL group and the sPCNL group [(9.5±2.2) mmol/L vs. (10.1±1.9) mmol/L]. The mean hematocrit after operation was (28.0±5.2)%, and the difference was statistically significant compared with that before operation (t=2.414, P=0.020). The mean hematocrit drop was not statistically signi-ficant compared with the sPCNL group (2.3% vs. 2.7%). The median serum creatinine in the 3mPCNL group was 74.0 (51.0-118.0) µmol/L after operation, and the difference was statistically significant compared with that before operation (Z=-2.980, P=0.005). The stone-free rate in the 3mPCNL group and the sPCNL group was 96.0% and 97.3%, respectively, and the mean hospital stay was (4.3± 1.4) d and (5.5±2.0) d, respectively, with the statistical significance (t=0.192, P=0.025). After the operation, one patient in sPCNL group had massive hemorrhage after the nephrostomy tube was removed, which was improved after selective renal artery embolization. One patient in the 3mPCNL group developed mild perirenal hematoma, which was improved after conservative treatment, and no complications were observed in the other patients. CONCLUSION: 3mPCNL in the treatment of 1.5-2.5 cm kidney stones can achieve an effective rate comparable to sPCNL, and can achieve the ideal stone-free rate in a shorter operative time with a lower rate of surgery-related complications.
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Cálculos Renales , Nefrolitotomía Percutánea , Humanos , Cálculos Renales/cirugía , Nefrolitotomía Percutánea/métodos , Nefrolitotomía Percutánea/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento , Tempo Operativo , Masculino , Femenino , Persona de Mediana EdadRESUMEN
Emotion recognition refers to the process of determining and identifying an individual's current emotional state by analyzing various signals such as voice, facial expressions, and physiological indicators etc. Using electroencephalogram (EEG) signals and virtual reality (VR) technology for emotion recognition research helps to better understand human emotional changes, enabling applications in areas such as psychological therapy, education, and training to enhance people's quality of life. However, there is a lack of comprehensive review literature summarizing the combined researches of EEG signals and VR environments for emotion recognition. Therefore, this paper summarizes and synthesizes relevant research from the past five years. Firstly, it introduces the relevant theories of VR and EEG signal emotion recognition. Secondly, it focuses on the analysis of emotion induction, feature extraction, and classification methods in emotion recognition using EEG signals within VR environments. The article concludes by summarizing the research's application directions and providing an outlook on future development trends, aiming to serve as a reference for researchers in related fields.
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Electroencefalografía , Emociones , Realidad Virtual , Humanos , Emociones/fisiología , Expresión FacialRESUMEN
Lanthanide organic frameworks (Ln-MOFs) have attracted increasing research enthusiasm as photoluminescent materials. However, limited luminescence efficiency stemming from restricted energy transfer efficiency from the organic linker to the metal center hinders their applications. Herein, a uranyl sensitization approach was proposed to boost the luminescence efficiency of Ln-MOFs in a distinct heterobimetallic uranyl-europium organic framework. The record-breaking photoluminescence quantum yield (PLQY, 92.68%) among all reported Eu-MOFs was determined to benefit from nearly 100% energy transfer efficiency between UO22+ and Eu3+. Time-dependent density functional theory and ab initio wave-function theory calculations confirmed the overlap of excited state levels between UO22+ and Eu3+, which is responsible for the efficient energy transfer process. Coupled with intrinsically strong stopping power toward X-ray of the uranium center, SCU-UEu-2 features an ultralow detection limit of 1.243 µGyair/s, outperforming the commercial scintillator LYSO (13.257 µGyair/s) and satisfying the requirement of X-ray diagnosis (below 5.5 µGyair/s) in full.
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The organic photoelectrochemical transistor (OPECT) has been proven to be a promising platform to study the rich light-matter-bio interplay toward advanced biomolecular detection, yet current OPECT is highly restrained to its intrinsic electronic amplification. Herein, this work first combines chemical amplification with electronic amplification in OPECT for dual-amplified bioanalytics with high current gain, which is exemplified by human immunoglobulin G (HIgG)-dependent sandwich immunorecognition and subsequent alkaline phosphatase (ALP)-mediated chemical redox cycling (CRC) on a metal-organic framework (MOF)-derived BiVO4/WO3 gate. The target-dependent redox cycling of ascorbic acid (AA) acting as an effective electron donor could lead to an amplified modulation against the polymer channel, as indicated by the channel current. The as-developed bioanalysis could achieve sensitive HIgG detection with a good analytical performance. This work features the dual chemical and electronic amplification for OPECT bioanalysis and is expected to stimulate further interest in the design of CRC-assisted OPECT bioassays.
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Técnicas Biosensibles , Estructuras Metalorgánicas , Humanos , Técnicas Electroquímicas , Oxidación-Reducción , Polímeros , Límite de DetecciónRESUMEN
Acellular extracellular matrices (aECM) are commonly utilized, both experimentally and clinically, in the regenerative medicine field. However, some disadvantages such as rapid degradation, poor mechanical properties, chronic inflammatory reactions and low antioxidant activity have limited their further application. In this study the feasibility of caffeic acid as a crosslinking agent in fixing small intestinal submucosa (SIS) was evaluated. The ninhydrin assay, swelling ratio and FTIR spectra indicated that caffeic acid can efficiently react with free amino groups to crosslink SIS and the highest crosslinking index reached 21.60 ± 1.37%. Moreover, the shrinkage temperature of SIS remarkably increased from 59 °C to about 80 °C and the degradation rate of CA-SIS was all lower than 6%, demonstrating their improved biostability and hydrothermal stability. Importantly, the antioxidant activity of CA-SIS ranged from 55% to 90%, statistically higher than that of native SIS (37.33 ± 2.94%). Additionally the cytotoxicity test presented that the cytotoxicity grade of CA-SIS was 1 or 0, whilst large numbers of living HUVECs were attached to the surface of the material and exhibited high cell viability. These results indicated their excellent cytocompatibility. The data of subcutaneous implant displayed that the number of inflammatory cells in 2%- and 2.5%CA-SIS groups remained at a low level (below 100 cells/field) while that of the native SIS group continued increasing, finally reaching 142.33 ± 30.92 cells/field. In conclusion, caffeic acid is a promising candidate for modifying aECM and may play a vital role in the design and fabrication of tissue engineering scaffolds.
Asunto(s)
Antioxidantes , Ácidos Cafeicos , Antioxidantes/farmacología , Estudios de Factibilidad , Ácidos Cafeicos/farmacología , Matriz ExtracelularRESUMEN
Root hair is regarded as a pivotal complementary survival tactic for mycorrhizal plant like Abies beshanzuensis when symbiosis is disrupted. Relatively little is known about the mechanism underlying root hair morphogenesis in plant species that are strongly dependent on mycorrhizal symbiosis. Many of these species are endangered, and this knowledge is critical for ensuring their survival. Here, a MYB6/bHLH13-sucrose synthase 2 (AbSUS2) module was newly identified and characterized in A. beshanzuensis using bioinformatics, histochemistry, molecular biology, and transgenesis. Functional, expression pattern, and localization analysis showed that AbSUS2 participated in sucrose synthesis and was involved in root hair initiation in A. beshanzuensis. Additionally, the major enzymatic product of AbSUS2 was found to suppress root hair initiation in vitro. Our data further showed that a complex involving the transcription factors AbMYB6 and AbbHLH13 directly interacted with the promoter of AbSUS2 and strengthened its expression, thereby inhibiting root hair initiation in response to exogenous sucrose. Our findings offer novel insights into how root hair morphogenesis is regulated in mycorrhizal plants and also provide a new strategy for the preservation of endangered mycorrhizal plant species.