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1.
Int J Mol Sci ; 21(22)2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33187258

RESUMO

Adrenocortical carcinoma (ACC) is a rare but deadly cancer for which few treatments exist. Here, we have undertaken a targeted bioinformatics study of The Cancer Genome Atlas (TCGA) ACC dataset focusing on the 30 genes encoding the γ-aminobutyric acid (GABA) system-an under-studied, evolutionarily-conserved system that is an emerging potential player in cancer progression. Our analysis identified a subset of ACC patients whose tumors expressed a distinct GABA system transcriptome. Transcript levels of ABAT (encoding a key GABA shunt enzyme), were upregulated in over 40% of tumors, and this correlated with several favorable clinical outcomes including patient survival; while enrichment and ontology analysis implicated two cancer-related biological pathways involved in metastasis and immune response. The phenotype associated with ABAT upregulation revealed a potential metabolic heterogeneity among ACC tumors associated with enhanced mitochondrial metabolism. Furthermore, many GABAA receptor subunit-encoding transcripts were expressed, including two (GABRB2 and GABRD) prognostic for patient survival. Transcripts encoding GABAB receptor subunits and GABA transporters were also ubiquitously expressed. The GABA system transcriptome of ACC tumors is largely mirrored in the ACC NCI-H295R cell line, suggesting that this cell line may be appropriate for future functional studies investigating the role of the GABA system in ACC cell growth phenotypes and metabolism.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Expressão Gênica/genética , Ácido gama-Aminobutírico/genética , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Biologia Computacional/métodos , Humanos , Mitocôndrias/genética , Mitocôndrias/patologia , Prognóstico , Receptores de GABA-A/genética , Receptores de GABA-B/genética , Transcriptoma/genética , Regulação para Cima/genética
2.
Nat Methods ; 16(8): 763-770, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308547

RESUMO

Current techniques for monitoring GABA (γ-aminobutyric acid), the primary inhibitory neurotransmitter in vertebrates, cannot follow transients in intact neural circuits. To develop a GABA sensor, we applied the design principles used to create the fluorescent glutamate receptor iGluSnFR. We used a protein derived from a previously unsequenced Pseudomonas fluorescens strain and performed structure-guided mutagenesis and library screening to obtain intensity-based GABA sensing fluorescence reporter (iGABASnFR) variants. iGABASnFR is genetically encoded, detects GABA release evoked by electric stimulation of afferent fibers in acute brain slices and produces readily detectable fluorescence increases in vivo in mice and zebrafish. We applied iGABASnFR to track mitochondrial GABA content and its modulation by an anticonvulsant, swimming-evoked, GABA-mediated transmission in zebrafish cerebellum, GABA release events during interictal spikes and seizures in awake mice, and found that GABA-mediated tone decreases during isoflurane anesthesia.


Assuntos
Técnicas Biossensoriais/métodos , Encéfalo/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/metabolismo , Imagem Molecular/métodos , Neurônios/metabolismo , Ácido gama-Aminobutírico/metabolismo , Anestesia , Animais , Animais Geneticamente Modificados , Feminino , Proteínas de Fluorescência Verde/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Convulsões/metabolismo , Convulsões/patologia , Peixe-Zebra
3.
J Forensic Sci ; 57(4): 1051-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22309221

RESUMO

The potential application of mRNA for the identification of biological fluids using molecular techniques has been a recent development in forensic serology. Constitutively expressed housekeeping genes can assess the amount of mRNA recovered from a sample, establish its suitability for downstream applications, and provide a reference point to corroborate the identity of the fluid. qPCR was utilized to compare the expression levels of housekeeping genes from forensic-like body fluid stains to establish the most appropriate assessment of human mRNA quantity prior to profiling. Although variability was observed between fluids and individuals, results indicated that beta-2 microglobulin exhibited the highest expression for all body fluids examined and across donors. A one-way analysis of variance was performed for housekeeping gene variability between donors (at the α, 0.05, significance level), and the results indicated significant differences for semen, vaginal secretions, and menstrual blood.


Assuntos
Perfilação da Expressão Gênica , RNA Mensageiro/metabolismo , Actinas/genética , Adulto , Análise de Variância , Análise Química do Sangue , Muco do Colo Uterino/química , Ciclofilina A/genética , Feminino , Genética Forense , Expressão Gênica , Gliceraldeído 3-Fosfato/genética , Humanos , Masculino , Menstruação , Pessoa de Meia-Idade , Fosfoglicerato Quinase/genética , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Ribossômicas/genética , Saliva/química , Sêmen/química , Microglobulina beta-2/genética
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