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The original version of this article, published on 08 April 2019, unfortunately contained a mistake. The following correction has therefore been made in the original: The caption of Fig. 2 is wrong. The corrected version is given below.
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OBJECTIVE: To evaluate simplified intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) for liver lesion characterisation at 3.0 T and to compare it with 1.5 T. METHODS: 3.0-T DWI data from a respiratory-gated MRI sequence with b = 0, 50, 250, and 800 s/mm2 were analysed in 116 lesions (78 patients) and 27 healthy livers. Apparent diffusion coefficient ADC = ADC(0,800) and IVIM-based parameters D1' = ADC(50,800), D2' = ADC(250,800), f1' = f(0,50,800), f2' = f(0,250,800), D*' = D*(0,50,250,800), ADClow = ADC(0,50), and ADCdiff = ADClow-D2' were calculated voxel-wise and analysed on per-patient basis. Results were compared with those of 173 lesions (110 patients) and 40 healthy livers at 1.5 T. RESULTS: Focal nodular hyperplasias were best discriminated from all other lesions by f1' and haemangiomas by D1' with an area under the curve (AUC) of 0.993 and 1.000, respectively. For discrimination between malignant and benign lesions, ADC was best suited (AUC of 0.968). The combination of D1' and f1' correctly identified more lesions as malignant or benign than the ADC (99.1% vs 88.8%). Discriminatory power for differentiating malignant from benign lesions tended to be higher at 3.0 T than at 1.5 T. CONCLUSION: Simplified IVIM is suitable for lesion characterisation at 3.0 T with a trend of superior diagnostic accuracy for discriminating malignant from benign lesions compared with 1.5 T. KEY POINTS: ⢠Simplified IVIM is also suitable for liver lesion characterisation at 3.0 T. ⢠Excellent accuracy was reached for discriminating malignant from benign lesions. ⢠The acquisition of only three b-values (0, 50, 800 s/mm 2 ) is required.
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Algoritmos , Imagen de Difusión por Resonancia Magnética/métodos , Hiperplasia Nodular Focal/diagnóstico , Hemangioma/diagnóstico , Neoplasias Hepáticas/diagnóstico , Hígado/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
OBJECTIVE: The objective of this study was to evaluate a simplified intravoxel incoherent motion (IVIM) approach of diffusion-weighted imaging (DWI) with four b-values for liver lesion characterisation at 1.5 T. METHODS: DWI data from a respiratory-gated MRI sequence with b = 0, 50, 250, 800 s/mm2 were retrospectively analysed in 173 lesions and 40 healthy livers. The apparent diffusion coefficient ADC = ADC(0,800) and IVIM-based parameters D1' = ADC(50,800), D2' =ADC(250,800), f1', f2', D*', ADClow = ADC(0,50), and ADCdiff=ADClow-D2' were calculated voxel-wise without fitting procedures. Differences between lesion groups were investigated. RESULTS: Focal nodular hyperplasias were best discriminated from all other lesions by f1' with an area under the curve (AUC) of 0.989. Haemangiomas were best discriminated by D1' (AUC of 0.994). For discrimination between malignant and benign lesions, ADC(0,800) and D1' were best suited (AUC of 0.915 and 0.858, respectively). Discriminatory power was further increased by using a combination of D1' and f1'. CONCLUSION: IVIM parameters D and f approximated from three b-values provided more discriminatory power between liver lesions than ADC determined from two b-values. The use of b = 0, 50, 800 s/mm2 was superior to that of b = 0, 250, 800 s/mm2. The acquisition of four instead of three b-values has no further benefit for lesion characterisation. KEY POINTS: ⢠Diffusion and perfusion characteristics are assessable with only three b-values. ⢠Association of b = 0, 50, 800 s/mm2is superior to b = 0, 250, 800 s/mm2. ⢠A fourth acquired b-value has no benefit for differential diagnosis. ⢠For liver lesion characterisation, simplified IVIM analysis is superior to ADC determination. ⢠Simplified IVIM approach guarantees numerically stable, voxel-wise results and short acquisition times.
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Imagen de Difusión por Resonancia Magnética/métodos , Hepatopatías/diagnóstico por imagen , Hígado/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Diagnóstico Diferencial , Femenino , Hiperplasia Nodular Focal/diagnóstico por imagen , Hemangioma/diagnóstico por imagen , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Movimiento (Física) , Estudios RetrospectivosRESUMEN
Neuronal PAS domain protein 2 (NPAS2) is a transcription factor expressed primarily in the mammalian forebrain. NPAS2 is highly related in primary amino acid sequence to Clock, a transcription factor expressed in the suprachiasmatic nucleus that heterodimerizes with BMAL1 and regulates circadian rhythm. To investigate the biological role of NPAS2, we prepared a neuroblastoma cell line capable of conditional induction of the NPAS2:BMAL1 heterodimer and identified putative target genes by representational difference analysis, DNA microarrays, and Northern blotting. Coinduction of NPAS2 and BMAL1 activated transcription of the endogenous Per1, Per2, and Cry1 genes, which encode negatively activating components of the circadian regulatory apparatus, and repressed transcription of the endogenous BMAL1 gene. Analysis of the frontal cortex of wild-type mice kept in a 24-hour light-dark cycle revealed that Per1, Per2, and Cry1 mRNA levels were elevated during darkness and reduced during light, whereas BMAL1 mRNA displayed the opposite pattern. In situ hybridization assays of mice kept in constant darkness revealed that Per2 mRNA abundance did not oscillate as a function of the circadian cycle in NPAS2-deficient mice. Thus, NPAS2 likely functions as part of a molecular clock operative in the mammalian forebrain.
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Relojes Biológicos/fisiología , Ritmo Circadiano/fisiología , Proteínas de Drosophila , Ecdisterona/análogos & derivados , Proteínas del Ojo , Proteínas del Tejido Nervioso/metabolismo , Células Fotorreceptoras de Invertebrados , Prosencéfalo/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción ARNTL , Secuencia de Aminoácidos , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Northern Blotting , Proteínas CLOCK , Proteínas de Ciclo Celular , Línea Celular , Clonación Molecular , Criptocromos , Oscuridad , Dimerización , Ecdisterona/farmacología , Flavoproteínas/genética , Flavoproteínas/metabolismo , Regulación de la Expresión Génica , Humanos , Hibridación in Situ , Luz , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Circadianas Period , Receptores Acoplados a Proteínas G , Transactivadores/química , Transactivadores/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , Transfección , Células Tumorales CultivadasRESUMEN
Clock:BMAL1 and NPAS2:BMAL1 are heterodimeric transcription factors that control gene expression as a function of the light-dark cycle. Although built to fluctuate at or near a 24-hour cycle, the clock can be entrained by light, activity, or food. Here we show that the DNA-binding activity of the Clock:BMAL1 and NPAS2:BMAL1 heterodimers is regulated by the redox state of nicotinamide adenine dinucleotide (NAD) cofactors in a purified system. The reduced forms of the redox cofactors, NAD(H) and NADP(H), strongly enhance DNA binding of the Clock:BMAL1 and NPAS2:BMAL1 heterodimers, whereas the oxidized forms inhibit. These observations raise the possibility that food, neuronal activity, or both may entrain the circadian clock by direct modulation of cellular redox state.
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Proteínas de Unión al ADN , ADN/metabolismo , NADP/metabolismo , NAD/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores de Hidrocarburo de Aril , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción ARNTL , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Relojes Biológicos , Proteínas CLOCK , Línea Celular , Ritmo Circadiano , Dimerización , Secuencias Hélice-Asa-Hélice , Humanos , L-Lactato Deshidrogenasa/genética , L-Lactato Deshidrogenasa/metabolismo , Ratones , NAD/farmacología , NADP/farmacología , Proteínas del Tejido Nervioso/química , Oxidación-Reducción , Proteínas Recombinantes/metabolismo , Transactivadores/química , Factores de Transcripción/químicaRESUMEN
Neuronal PAS domain protein 2 (NPAS2) is a basic helix-loop-helix (bHLH) PAS domain transcription factor expressed in multiple regions of the vertebrate brain. Targeted insertion of a beta-galactosidase reporter gene (lacZ) resulted in the production of an NPAS2-lacZ fusion protein and an altered form of NPAS2 lacking the bHLH domain. The neuroanatomical expression pattern of NPAS2-lacZ was temporally and spatially coincident with formation of the mature frontal association/limbic forebrain pathway. NPAS2-deficient mice were subjected to a series of behavioral tests and were found to exhibit deficits in the long-term memory arm of the cued and contextual fear task. Thus, NPAS2 may serve a dedicated regulatory role in the acquisition of specific types of memory.
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Encéfalo/fisiología , Aprendizaje/fisiología , Memoria/fisiología , Proteínas del Tejido Nervioso/fisiología , Factores de Transcripción/fisiología , Animales , Reacción de Prevención , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Conducta Animal , Encéfalo/metabolismo , Condicionamiento Psicológico , Señales (Psicología) , Miedo , Marcación de Gen , Secuencias Hélice-Asa-Hélice , Sistema Límbico/metabolismo , Sistema Límbico/fisiología , Masculino , Ratones , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Prosencéfalo/metabolismo , Prosencéfalo/fisiología , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Tacto , Factores de Transcripción/química , Factores de Transcripción/genética , Activación Transcripcional , Transfección , beta-Galactosidasa/metabolismoRESUMEN
Aryl hydrocarbons (AHs) such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and benzo[a]pyrene activate the sequence-specific DNA-binding activity of the AH receptor. In the rat hepatocyte-derived cell line LCS7, DNA-binding activity peaked after 30 min and was then down-regulated, reaching negligible levels by 2 h. Down-regulation could be blocked, and DNA-binding activity maintained at maximum for many hours by inhibiting protein or RNA synthesis, implying that down-regulation is a mediated process requiring a labile or inducible protein. CYP1A1 transcription and in vivo DNA-protein interactions at xenobiotic response elements were down-regulated in parallel with DNA-binding activity in nuclear extracts, and these changes could also be blocked by inhibitors of protein synthesis. The correlation between AH receptor DNA-binding activity, intensity of in vivo footprints at xenobiotic response elements, and CYP1A1 transcription rate implies that down-regulation of AH receptor DNA-binding activity is important in regulating CYP1A1 transcription and that receptor is required continuously to maintain transcription. This correlation extends to the murine hepatoma cell line Hepa-1c1c7, in which slower kinetics of activation and down-regulation of CYP1A1 transcription paralleled slower activation and down-regulation of AH receptor DNA-binding activity. The difference in kinetics between cell lines also implies that AH receptor DNA-binding activity is modulated by a mechanism that may be influenced by cell-specific regulatory pathways. The above observations in conjunction with mixing experiments and comparisons of cytoplasmic and nuclear extracts indicate that down-regulation of AH receptor DNA-binding activity is probably due either to degradation or to conversion of the receptor to form that is inactive in both DNA binding and transactivation.