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EGFR activates phosphatidylinositide 3-kinase (PI3K), but the mechanism underlying this activation is not completely understood. We demonstrated here that EGFR activation resulted in lysine acetyltransferase 5 (KAT5)-mediated K395 acetylation of the platelet isoform of phosphofructokinase 1 (PFKP) and subsequent translocation of PFKP to the plasma membrane, where the PFKP was phosphorylated at Y64 by EGFR. Phosphorylated PFKP binds to the N-terminal SH2 domain of p85α, which is distinct from binding of Gab1 to the C-terminal SH2 domain of p85α, and recruited p85α to the plasma membrane resulting in PI3K activation. PI3K-dependent AKT activation results in enhanced phosphofructokinase 2 (PFK2) phosphorylation and production of fructose-2,6-bisphosphate, which in turn promotes PFK1 activation. PFKP Y64 phosphorylation-enhanced PI3K/AKT-dependent PFK1 activation and GLUT1 expression promoted the Warburg effect, tumor cell proliferation, and brain tumorigenesis. These findings underscore the instrumental role of PFKP in PI3K activation and enhanced glycolysis through PI3K/AKT-dependent positive-feedback regulation.
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Neoplasias Encefálicas/enzimología , Glioblastoma/enzimología , Glucólisis , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfofructoquinasa-1 Tipo C/metabolismo , Acetilación , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase Ia , Activación Enzimática , Receptores ErbB/genética , Receptores ErbB/metabolismo , Retroalimentación Fisiológica , Fructosadifosfatos/metabolismo , Glioblastoma/genética , Glioblastoma/patología , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Lisina Acetiltransferasa 5/genética , Lisina Acetiltransferasa 5/metabolismo , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/genética , Fosfofructoquinasa-1 Tipo C/genética , Fosfofructoquinasa-2/genética , Fosfofructoquinasa-2/metabolismo , Fosforilación , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Dominios Homologos srcRESUMEN
BACKGROUND: CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). OBJECTIVES: This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. METHODS: The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array. RESULTS: This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+ T cells to immune stimulation. CONCLUSIONS: Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.
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Inmunodeficiencia Variable Común , Intrones , Lectinas Tipo C , Proteínas de Transporte de Monosacáridos , Humanos , Lectinas Tipo C/genética , Intrones/genética , Proteínas de Transporte de Monosacáridos/genética , Inmunodeficiencia Variable Común/genética , Inmunodeficiencia Variable Común/inmunología , Polimorfismo de Nucleótido Simple , Regulación de la Expresión Génica , Femenino , Masculino , Transducción de Señal/genética , Linfocitos T CD4-Positivos/inmunología , AdultoRESUMEN
BACKGROUND: The genetic architecture of juvenile idiopathic arthritis (JIA) remains only partially comprehended. There is a clear imperative for continued endeavors to uncover insights into the underlying causes of JIA. METHODS: This study encompassed a comprehensive spectrum of endeavors, including conducting a JIA GWAS meta-analysis that incorporated data from 4,550 JIA cases and 18 446 controls. We employed in silico and genome-editing approaches to prioritize target genes. To investigate pleiotropic effects, we conducted phenome-wide association studies. Cell-type enrichment analyses were performed by integrating bulk and single-cell sequencing data. Finally, we delved into potential druggable targets for JIA. RESULTS: Fourteen genome-wide significant non-HLA loci were identified including four novel loci, each exhibiting pleiotropic associations with other autoimmune diseases or musculoskeletal traits. We uncovered strong genetic correlation between JIA and bone mineral density (BMD) traits at 52 genomic regions, including three GWAS loci for JIA. Candidate genes with immune functions were captured by in silico analyses at each novel locus, with additional findings identified through our experimental approach. Cell-type enrichment analysis revealed 21 specific immune cell types crucial for affected organs in JIA, indicating their potential contribution to the disease. Finally, 24 known or candidate druggable target genes were prioritized. CONCLUSIONS: Our identification of four novel JIA associated genes, CD247, RHOH, COLEC10 and IRF8, broadens novel potential drug repositioning opportunities. We established a new genetic link between COLEC10, TNFRSF11B and JIA/BMD. Additionally, the identification of RHOH underscores its role in positive thymocyte selection, thereby illuminating a critical facet of JIA's underlying biological mechanisms.
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The co-occurrence and familial clustering of neurodevelopmental disorders and immune disorders suggest shared genetic risk factors. Based on genome-wide association summary statistics from five neurodevelopmental disorders and four immune disorders, we conducted genome-wide, local genetic correlation and polygenic overlap analysis. We further performed a cross-trait GWAS meta-analysis. Pleotropic loci shared between the two categories of diseases were mapped to candidate genes using multiple algorithms and approaches. Significant genetic correlations were observed between neurodevelopmental disorders and immune disorders, including both positive and negative correlations. Neurodevelopmental disorders exhibited higher polygenicity compared to immune disorders. Around 50%-90% of genetic variants of the immune disorders were shared with neurodevelopmental disorders. The cross-trait meta-analysis revealed 154 genome-wide significant loci, including 8 novel pleiotropic loci. Significant associations were observed for 30 loci with both types of diseases. Pathway analysis on the candidate genes at these loci revealed common pathways shared by the two types of diseases, including neural signaling, inflammatory response, and PI3K-Akt signaling pathway. In addition, 26 of the 30 lead SNPs were associated with blood cell traits. Neurodevelopmental disorders exhibit complex polygenic architecture, with a subset of individuals being at a heightened genetic risk for both neurodevelopmental and immune disorders. The identification of pleiotropic loci has important implications for exploring opportunities for drug repurposing, enabling more accurate patient stratification, and advancing genomics-informed precision in the medical field of neurodevelopmental disorders.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades del Sistema Inmune , Herencia Multifactorial , Trastornos del Neurodesarrollo , Polimorfismo de Nucleótido Simple , Humanos , Trastornos del Neurodesarrollo/genética , Enfermedades del Sistema Inmune/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Herencia Multifactorial/genéticaRESUMEN
Functional abnormalities of default mode network (DMN) have been well documented in major depressive disorder (MDD). However, the association of DMN functional reorganization with antidepressant treatment and gene expression is unclear. Moreover, whether the functional interactions of DMN could predict treatment efficacy is also unknown. Here, we investigated the link of treatment response with functional alterations of DMN and gene expression with a comparably large sample including 46 individuals with MDD before and after electroconvulsive therapy (ECT) and 46 age- and sex-matched healthy controls. Static and dynamic functional connectivity (dFC) analyses showed increased intrinsic/static but decreased dynamic functional couplings of inter- and intra-subsystems and between nodes of DMN. The changes of static functional connections of DMN were spatially correlated with brain gene expression profiles. Moreover, static and dFC of the DMN before treatment as features could predict depressive symptom improvement following ECT. Taken together, these results shed light on the underlying neural and genetic basis of antidepressant effect of ECT and the intrinsic functional connectivity of DMN have the potential to serve as prognostic biomarkers to guide accurate personalized treatment.
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Trastorno Depresivo Mayor , Terapia Electroconvulsiva , Humanos , Trastorno Depresivo Mayor/terapia , Trastorno Depresivo Mayor/tratamiento farmacológico , Red en Modo Predeterminado , Depresión , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Antidepresivos/uso terapéutico , Vías Nerviosas/diagnóstico por imagenRESUMEN
The steerability of a quantum state can be detected by steering inequalities. The linear steering inequalities show that more steerable states can be discovered with the increase of measurements. In order to detect more steerable states in two-photon systems, we first theoretically derive an optimized steering criterion based on infinity measurements for an arbitrary two-qubit state. The steering criterion is only determined by the spin correlation matrix of the state, and do not require infinity measurements. Then, we prepared the Werner-like states in two-photon systems, and measure their spin correlation matrices. Finally, we apply three steering criteria, which include our steering criterion, the three-measurement steering criterion and the geometric Bell-like inequality, to distinguish the steerability of these states. The results show that our steering criterion can detect the most steerable states under the same experimental conditions. Thus, our work provides a valuable reference for detecting the steerability of quantum states.
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BACKGROUND: Schizophrenia is regarded as a brain network or connectome disorder that is associated with neurodevelopment. Children with early-onset schizophrenia (EOS) provide an opportunity to evaluate the neuropathology of schizophrenia at a very early stage without potential confounding factors. But dysfunction in brain networks of schizophrenia is inconsistent. PURPOSE: To identify abnormal functional connectivity (FC) in EOS patients and relationships with clinical symptoms, we aimed to reveal neuroimaging phenotypes of EOS. STUDY TYPE: Prospective, cross-sectional. POPULATION: Twenty-six female/22 male patients (age:14.3 ± 3.45 years) with first-episode EOS, 27 female/22 male age- and gender-matched healthy controls (HC) (age:14.1 ± 4.32). FIELD STRENGTH/SEQUENCE: 3-T, resting-state (rs) gradient-echo echo-planar imaging and three-dimensional magnetization-prepared rapid gradient-echo imaging. ASSESSMENT: Intelligence quotient (IQ) was measured by the Wechsler Intelligence Scale-Fourth edition for Children (WISC-IV). The clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). FC strength (FCS) from rs functional MRI (rsfMRI) was used to investigate functional integrity of global brain regions. In addition, associations between regionally altered FCS and clinical symptoms in EOS patients were examined. STATISTICAL TESTS: Two-sample t-test controlling for sample size, diagnostic method, brain volume algorithm, and age of the subjects, Bonferroni correction, Pearson's correlation analysis. A P-value <0.05 with a minimum cluster size of 50 voxels was considered statistically significant. RESULTS: Compared with HC, EOS patients had significantly lower total IQ scores (IQ:91.5 ± 16.1), increased FCS in the bilateral precuneus, left dorsolateral prefrontal cortex, left thalamus, and left parahippocampus (paraHIP), and decreased FCS in the right cerebellum posterior lobe and right superior temporal gyrus. The PANSS total score of EOS patients (PANSS total score:74.30 ± 7.23) was found to be positively correlated to FCS in the left paraHIP (r = 0.45). DATA CONCLUSION: Our study revealed that disrupted FC of brain hubs illustrate multiple abnormalities in brain networks in EOS patients. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY STAGE: 2.
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Esquizofrenia , Humanos , Masculino , Femenino , Niño , Adolescente , Esquizofrenia/diagnóstico por imagen , Mapeo Encefálico/métodos , Estudios Transversales , Estudios Prospectivos , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagenRESUMEN
As a member of the apolipoprotein C (ApoC) family with a relatively high content, ApoC3 plays a major role in the regulation of triglyceride metabolism, and plays an important role in the occurrence and development of cardiovascular diseases, glucose and lipid metabolism disorders. Nonalcoholic fatty liver disease (NAFLD) refers to the accumulation of a large amount of fat in the liver in the absence of a history of chronic alcohol consumption or other damage to the liver. A large number of previous studies have shown that there is a correlation between the gene polymorphism and high expression of ApoC3 and NAFLD. In the context of hypertriglyceridemia (HTG), this article reviews the relationship between ApoC3 and NAFLD, glucose and lipid metabolism, and islet ß cell function, showing that ApoC3 can not only inhibit lipoprotein lipase (LPL) and hepatic lipase (HL) activity, delay the decomposition of triglyceride in plasma to maintain the body's energy metabolism during fasting, but also be significantly increased under insulin resistance, prompting the liver to secrete a large amount of very low-density lipoprotein (VLDL) to induce HTG. Therefore, targeting and inhibiting ApoC3 might become a new approach to treat HTG. Increasing evidence suggests that ApoC3 does not appear to be an independent "contributor" to NAFLD. Similarly, our previous studies have shown that ApoC3 is not an independent factor triggering islet ß cell dysfunction in ApoC3 transgenic mice, but in a state of excess nutrition, HTG triggered by ApoC3 high expression may exacerbate the effects of hyperglycemia and insulin resistance on islet ß cell function, and the underlying mechanism remains to be further discussed.
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Apolipoproteína C-III , Glucosa , Islotes Pancreáticos , Metabolismo de los Lípidos , Enfermedad del Hígado Graso no Alcohólico , Apolipoproteína C-III/antagonistas & inhibidores , Apolipoproteína C-III/genética , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Glucosa/metabolismo , Humanos , Animales , Hipertrigliceridemia/metabolismo , Islotes Pancreáticos/metabolismoRESUMEN
Alterations in DNAs could not reveal what happened in proteins. The accumulated alterations of DNAs would change the manifestation of proteins. Therefore, as is the case in cancer liquid biopsies, deep proteome profiling will likely provide invaluable and clinically relevant information in real-time throughout all stages of cancer progression. However, due to the great complexity of proteomes in liquid biopsy samples and the limitations of proteomic technologies compared to high-plex sequencing technologies, proteomic discoveries have yet lagged behind their counterpart, genomic technologies. Therefore, novel protein technologies are in urgent demand to fulfill the goals set out for biomarker discovery in cancer liquid biopsies.Notably, conventional and innovative technologies are being rapidly developed for proteomic analysis in cancer liquid biopsies. These advances have greatly facilitated early detection, diagnosis, prognosis, and monitoring of cancer evolution, adapted or adopted in response to therapeutic interventions. In this paper, we review the high-plex proteomics technologies that are capable of measuring at least hundreds of proteins simultaneously from liquid biopsy samples, ranging from traditional technologies based on mass spectrometry (MS) and antibody/antigen arrays to innovative technologies based on aptamer, proximity extension assay (PEA), and reverse phase protein arrays (RPPA).
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Neoplasias , Proteómica , Detección Precoz del Cáncer , Humanos , Biopsia Líquida , Neoplasias/diagnóstico , Neoplasias/genética , Proteoma/metabolismo , Proteómica/métodosRESUMEN
Chemoresistance seriously hinders the treatment efficiency of human cancers, including prostate cancer (PCa). Multiple long noncoding RNAs (lncRNAs) were involved in drug resistance in PCa. We aimed to explore the function of transient receptor potential cation channel subfamily M member 2 (TRPM2) antisense RNA (TRPM2-AS) in paclitaxel (PTX) resistance in PCa. Our results showed that TRPM2-AS was increased in PTX-resistant PCa cells. TRPM2-AS knockdown accelerated cell apoptosis and inhibited cell proliferation, migration, invasion, and PTX resistance in PTX-resistant PCa cells. MiR-497-5p was bound to TRPM2-AS and its inhibition reversed the effects of TRPM2-AS knockdown on cell progression and PTX resistance in PTX-resistant PCa cells. FOXK1 was identified as a target of miR-497-5p and FOXK1 overexpression showed similar effects on cell progression and PTX resistance with miR-497-5p inhibition in PTX-resistant PCa cells. In conclusion, TRPM2-AS knockdown suppressed cell progression and PTX resistance in PTX-resistant PCa cells by miR-497-5p/FOXK1 axis.
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Resistencia a Antineoplásicos , Factores de Transcripción Forkhead , MicroARNs , Neoplasias de la Próstata , ARN Largo no Codificante , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Humanos , Masculino , MicroARNs/genética , Paclitaxel/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , ARN Largo no Codificante/genética , Canales Catiónicos TRPM/genéticaRESUMEN
Quantum entanglement, quantum steering and Bell nonlocality, as significant quantum resources in the field of quantum information science, can achieve variously valuable quantum information tasks. Among of them, quantum entanglement and Bell nonlocality are the weakest and strongest nonlocal correlations, respectively. One can capture the quantum steering and Bell nonlocality via violating steering inequality and Bell inequality, respectively. In general, the detections of quantum steering and Bell nonlocality are strictly harder than entanglement detection. Here, based on steering inequality test and quantum state tomography, we attain various nonlocal correlations and experimentally demonstrate that the estimations of quantum steering and Bell nonlocality can be realized according to the quantum entanglement of the prepared two-photon test states. The estimated efficiency of quantum steering is stronger than the one of Bell nonlocality in this scenario, i.e., more steerable two-photon test states can be verified through quantum entanglement. In addition, quantum steering and Bell nonlocality are bounded by the corresponding upper and lower bounds, and these bounds cannot be punctured by all prepared two-photon states in experiment. These results are conducive to understand the relations among these nonlocal correlations.
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Coherence and steerability are two essential characteristics of quantum systems. For a two-qubit state, the first-order coherence and the maximal violation of linear steering inequality are used to operationally measure the degree of coherence and steerability, respectively. Recently, a complementary relation between first-order coherence and linear steerability has been proposed. In this paper, we report an experimental verification of the complementary relation by preparing biphoton polarization entangled states in an all-optical setup. We propose an operable method for experimental measurement of the first-order coherence and linear steerability and calculate the purity of the initial states by reconstructing the density matrices of them. The experimental results coincide with the theoretical predictions very well, which provides a valuable reference for the application of optical quantum technology.
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Despite the improvement in acute myeloid leukemia (AML) treatments, most patients had a poor prognosis and suffered from chemoresistance and disease relapse. Therefore, there is an urgent need for elucidation of mechanism(s) underlying drug resistance in AML. In the present study, we found that AML cells showed less susceptibility to adriamycin (ADR) in the presence of hypoxia, while inhibition of hypoxia-inducible factor 1α (HIF-1α) by CdCl2 can make AML cells re-susceptibile to ADR even under hypoxia. Moreover, HIF-1α is overexpressed and plays an important role in ADR-resistance maintenance in resistant AML cells. We further found hypoxia or induction of HIF-1α can significantly upregulate yes-associated protein (YAP) expression in AML cells, and resistant cells express a high level of YAP. Finally, we found that YAP may not only enhance HIF-1α stability but also promote HIF-1α's activity on the target gene pyruvate kinase M2. In conclusion, our data indicate that HIF-1α or YAP may represent a therapeutic target for overcoming resistance toward adriamycin-based chemotherapy in AML.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Hipoxia/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Antibióticos Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Factores de Transcripción/genética , Células Tumorales Cultivadas , Proteínas Señalizadoras YAPRESUMEN
Molecular analysis of tumors forms the basis for personalized cancer medicine and increasingly guides patient selection for targeted therapy. Future opportunities for personalized medicine are highlighted by the measurement of protein expression levels via immunohistochemistry, protein arrays, and other approaches; however, sample type, sample quantity, batch effects, and "time to result" are limiting factors for clinical application. Here, we present a development pipeline for a novel multiplexed DNA-labeled antibody platform which digitally quantifies protein expression from lysate samples. We implemented a rigorous validation process for each antibody and show that the platform is amenable to multiple protocols covering nitrocellulose and plate-based methods. Results are highly reproducible across technical and biological replicates, and there are no observed "batch effects" which are common for most multiplex molecular assays. Tests from basal and perturbed cancer cell lines indicate that this platform is comparable to orthogonal proteomic assays such as Reverse-Phase Protein Array, and applicable to measuring the pharmacodynamic effects of clinically-relevant cancer therapeutics. Furthermore, we demonstrate the potential clinical utility of the platform with protein profiling from breast cancer patient samples to identify molecular subtypes. Together, these findings highlight the potential of this platform for enhancing our understanding of cancer biology in a clinical translation setting.
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Anticuerpos/química , ADN/química , Neoplasias/metabolismo , Proteínas/metabolismo , Línea Celular Tumoral , Femenino , Humanos , ProteómicaAsunto(s)
Secuestro de Carbono , Carbono , Carbono/análisis , Dióxido de Carbono/análisis , Análisis de Datos , Tibet , IncertidumbreRESUMEN
Corticostriatal atrophy is a cardinal manifestation of Huntington's disease (HD). However, the mechanism(s) by which mutant huntingtin (mHTT) protein contributes to the degeneration of the corticostriatal circuit is not well understood. We recreated the corticostriatal circuit in microfluidic chambers, pairing cortical and striatal neurons from the BACHD model of HD and its WT control. There were reduced synaptic connectivity and atrophy of striatal neurons in cultures in which BACHD cortical and striatal neurons were paired. However, these changes were prevented if WT cortical neurons were paired with BACHD striatal neurons; synthesis and release of brain-derived neurotrophic factor (BDNF) from WT cortical axons were responsible. Consistent with these findings, there was a marked reduction in anterograde transport of BDNF in BACHD cortical neurons. Subunits of the cytosolic chaperonin T-complex 1 (TCP-1) ring complex (TRiC or CCT for chaperonin containing TCP-1) have been shown to reduce mHTT levels. Both CCT3 and the apical domain of CCT1 (ApiCCT1) decreased the level of mHTT in BACHD cortical neurons. In cortical axons, they normalized anterograde BDNF transport, restored retrograde BDNF transport, and normalized lysosomal transport. Importantly, treating BACHD cortical neurons with ApiCCT1 prevented BACHD striatal neuronal atrophy by enhancing release of BDNF that subsequently acts through tyrosine receptor kinase B (TrkB) receptor on striatal neurons. Our findings are evidence that TRiC reagent-mediated reductions in mHTT enhanced BDNF delivery to restore the trophic status of BACHD striatal neurons.
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Factor Neurotrófico Derivado del Encéfalo/genética , Chaperonina con TCP-1/genética , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Degeneraciones Espinocerebelosas/genética , Animales , Atrofia/genética , Atrofia/metabolismo , Atrofia/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Chaperonina con TCP-1/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Humanos , Proteína Huntingtina/metabolismo , Enfermedad de Huntington/tratamiento farmacológico , Enfermedad de Huntington/patología , Dispositivos Laboratorio en un Chip , Ratones , Mutación , Neuronas/metabolismo , Neuronas/patología , Receptor trkB/genética , Receptor trkB/metabolismo , Degeneraciones Espinocerebelosas/tratamiento farmacológico , Degeneraciones Espinocerebelosas/patologíaRESUMEN
Protein-protein interactions (PPIs) are useful for understanding signaling cascades, predicting protein function, associating proteins with disease and fathoming drug mechanism of action. Currently, only â¼ 10% of human PPIs may be known, and about one-third of human proteins have no known interactions. We introduce FpClass, a data mining-based method for proteome-wide PPI prediction. At an estimated false discovery rate of 60%, we predicted 250,498 PPIs among 10,531 human proteins; 10,647 PPIs involved 1,089 proteins without known interactions. We experimentally tested 233 high- and medium-confidence predictions and validated 137 interactions, including seven novel putative interactors of the tumor suppressor p53. Compared to previous PPI prediction methods, FpClass achieved better agreement with experimentally detected PPIs. We provide an online database of annotated PPI predictions (http://ophid.utoronto.ca/fpclass/) and the prediction software (http://www.cs.utoronto.ca/~juris/data/fpclass/).
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Biología Computacional/métodos , Simulación por Computador , Minería de Datos/métodos , Mapeo de Interacción de Proteínas/métodos , Humanos , Proteoma , Programas Informáticos , Proteína p53 Supresora de Tumor/fisiologíaRESUMEN
BACKGROUND: Aberrant AKT activation is prevalent across human cancer lineages, providing an important therapeutic target. AKT comprises three isoforms that mediate critical non-redundant, even opposing functions in cancer pathophysiology. Therefore, targeting specific AKT isoforms in particular cancers may be more effective than pan-AKT inhibition while avoiding disadvantages of pan-AKT inhibition. Currently, AKT isoform-specific expression and activation in cancer are not clearly characterized. METHODS: We systematically characterized AKT isoform-specific expression and activation in 211 cancer cell lines derived from different lineages and genetic backgrounds using a reverse-phase protein array platform. RESULTS: We found that phosphorylation, but not expression, of AKT1 and AKT2 was coordinated in most but not all cells. Different cancer lineages displayed differential AKT1 and AKT2 expression and phosphorylation. A PIK3CA hotspot mutation H1047R but not E545K was associated with selective activation of AKT2 but not AKT1. CONCLUSIONS: Our study identified and validated AKT isoform-specific expression and phosphorylation in certain cell lines and demonstrated that genetic changes can affect AKT isoform-specific activation. These results provide a more precise understanding of AKT isoform-specific signaling and, in addition, facilitate AKT isoform targeting for personalized cancer therapies.
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Neoplasias/enzimología , Proteínas Proto-Oncogénicas c-akt/análisis , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I/genética , Activación Enzimática , Humanos , Mutación , Neoplasias/terapia , Fosforilación , Análisis por Matrices de Proteínas , Proteínas Proto-Oncogénicas c-akt/fisiologíaRESUMEN
Vaccination is an important approach for the control of avian viral diseases. The aim of this study was to evaluate the immune-potentiating effect of oral administration of Inonotus obliquus fermentation products (IOFP) at vaccination in chickens. In total, 120 one-day-old specific-pathogen-free chickens were randomly assigned to six groups: groups 1 to 3 were vaccinated with Newcastle disease virus (NDV) LaSota live vaccine via intranasal and eye-dropped route at seven days of age, and boosted two weeks later. Before each immunization, chickens in groups 1 and 2 were orally administered 0.8% IOFP and 0.2% astragalus polysaccharide (APS) in their diets, respectively, for seven consecutive days and group 3 was fed with commercial diet. At the same time, group 4, 5 and 6 were inoculated in the same manner with PBS and fed with commercial diet, containing 0.8% IOFP and 0.2% APS diet, respectively, as negative controls. At 0, 7, 14, 21, 28, and 35 days post-inoculation (dpi) firstly, the temporal changes in serum Newcastle disease hemagglutination inhibition (HI) and neutralizing antibody titers were determined. Meanwhile, proliferations of peripheral blood mononuclear cells (PBMCs) isolated from each group in response to concanavalin A stimulation and the expression levels of Th1-type (IFN-γ) and Th2-type (IL-4) cytokines were determined by 3-(4,5-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, and ELISA methods. On days 0, 14 and 28 after the first vaccination, the percentages of CD3+, CD3+CD8+, and CD3+CD4+ T lymphocytes were detected by flow cytometry. At 35 dpi, a challenge test was carried out and protective efficacy was determined. Results showed that oral administration of IOFP could significantly enhance ND HI and neutralizing antibody titers, proliferation of PBMCs, proportions of CD3+, CD3+CD8+, and CD3+CD4+ T lymphocytes, as well as the ratio of Th1/Th2, and all of these values were superior to those seen with APS as a positive control, and other groups. Therefore, IOFP possesses significant immune-potentiating properties in chickens and may be a more economical and convenient oral adjuvant to improve vaccination in avian species.
Asunto(s)
Basidiomycota/química , Pollos/inmunología , Fermentación , Vacunación , Vacunas Virales/administración & dosificación , Animales , Pollos/virología , Citocinas/metabolismo , Femenino , Pruebas de Inhibición de Hemaglutinación , Inmunidad Celular , Inmunidad Humoral , Enfermedad de Newcastle/inmunología , Virus de la Enfermedad de Newcastle/inmunología , Análisis de Supervivencia , Células TH1/inmunología , Células Th2/inmunología , Vacunas Virales/inmunologíaRESUMEN
BACKGROUND: In 2016, it is estimated that there will be 62,700 new cases of kidney cancer in the United States, and 14,240 patients will die from the disease. Because the incidence of kidney renal clear cell carcinoma (KIRC), the most common type of kidney cancer, is expected to continue to increase in the US, there is an urgent need to find effective diagnostic biomarkers for KIRC that could help earlier detection of and customized treatment strategies for the disease. Accordingly, in this study we systematically investigated KIRC's prognostic biomarkers for survival using the reverse phase protein array (RPPA) data and the high throughput sequencing data from The Cancer Genome Atlas (TCGA). RESULTS: With comprehensive data available in TCGA, we systematically screened protein expression based survival biomarkers in 10 major cancer types, among which KIRC presented many protein prognostic biomarkers of survival time. This is in agreement with a previous report that expression level changes (mRNAs, microRNA and protein) may have a better performance for prognosis of KIRC. In this study, we also identified 52 prognostic genes for KIRC, many of which are involved in cell-cycle and cancer signaling, as well as 15 tumor-stage-specific prognostic biomarkers. Notably, we found fewer prognostic biomarkers for early-stage than for late-stage KIRC. Four biomarkers (the RPPA protein IDs: FASN, ACC1, Cyclin_B1 and Rad51) were found to be prognostic for survival based on both protein and mRNA expression data. CONCLUSIONS: Through pan-cancer screening, we found that many protein biomarkers were prognostic for patients' survival in KIRC. Stage-specific survival biomarkers in KIRC were also identified. Our study indicated that these protein biomarkers might have potential clinical value in terms of predicting survival in KIRC patients and developing individualized treatment strategies. Importantly, we found many biomarkers in KIRC at both the mRNA expression level and the protein expression level. These biomarkers shared a significant overlap, indicating that they were technically replicable.