Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
bioRxiv ; 2023 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-36993629

RESUMO

Neural circuit function is shaped both by the cell types that comprise the circuit and the connections between those cell types 1 . Neural cell types have previously been defined by morphology 2, 3 , electrophysiology 4, 5 , transcriptomic expression 6-8 , connectivity 9-13 , or even a combination of such modalities 14-16 . More recently, the Patch-seq technique has enabled the characterization of morphology (M), electrophysiology (E), and transcriptomic (T) properties from individual cells 17-20 . Using this technique, these properties were integrated to define 28, inhibitory multimodal, MET-types in mouse primary visual cortex 21 . It is unknown how these MET-types connect within the broader cortical circuitry however. Here we show that we can predict the MET-type identity of inhibitory cells within a large-scale electron microscopy (EM) dataset and these MET-types have distinct ultrastructural features and synapse connectivity patterns. We found that EM Martinotti cells, a well defined morphological cell type 22, 23 known to be Somatostatin positive (Sst+) 24, 25 , were successfully predicted to belong to Sst+ MET-types. Each identified MET-type had distinct axon myelination patterns and synapsed onto specific excitatory targets. Our results demonstrate that morphological features can be used to link cell type identities across imaging modalities, which enables further comparison of connectivity in relation to transcriptomic or electrophysiological properties. Furthermore, our results show that MET-types have distinct connectivity patterns, supporting the use of MET-types and connectivity to meaningfully define cell types.

2.
PLoS Genet ; 11(7): e1005305, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26134322

RESUMO

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. The search for targeted treatments has been hampered by the lack of relevant animal models for the genetically diverse subsets of HCC, including the 20-40% of HCCs that are defined by activating mutations in the gene encoding ß-catenin. To address this chemotherapeutic challenge, we created and characterized transgenic zebrafish expressing hepatocyte-specific activated ß-catenin. By 2 months post fertilization (mpf), 33% of transgenic zebrafish developed HCC in their livers, and 78% and 80% of transgenic zebrafish showed HCC at 6 and 12 mpf, respectively. As expected for a malignant process, transgenic zebrafish showed significantly decreased mean adult survival compared to non-transgenic control siblings. Using this novel transgenic model, we screened for druggable pathways that mediate ß-catenin-induced liver growth and identified two c-Jun N-terminal kinase (JNK) inhibitors and two antidepressants (one tricyclic antidepressant, amitriptyline, and one selective serotonin reuptake inhibitor) that suppressed this phenotype. We further found that activated ß-catenin was associated with JNK pathway hyperactivation in zebrafish and in human HCC. In zebrafish larvae, JNK inhibition decreased liver size specifically in the presence of activated ß-catenin. The ß-catenin-specific growth-inhibitory effect of targeting JNK was conserved in human liver cancer cells. Our other class of hits, antidepressants, has been used in patient treatment for decades, raising the exciting possibility that these drugs could potentially be repurposed for cancer treatment. In support of this proposal, we found that amitriptyline decreased tumor burden in a mouse HCC model. Our studies implicate JNK inhibitors and antidepressants as potential therapeutics for ß-catenin-induced liver tumors.


Assuntos
Amitriptilina/uso terapêutico , Antidepressivos Tricíclicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , beta Catenina/metabolismo , Animais , Animais Geneticamente Modificados , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/patologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mesotelina , Camundongos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Xenopus laevis , Peixe-Zebra , beta Catenina/genética
3.
Neuroscience ; 298: 455-66, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-25934038

RESUMO

Exposure to early-life inflammation results in time-of-challenge-dependent changes in both brain and behavior. The consequences of this neural and behavioral reprogramming are most often reported in adulthood. However, the trajectory for the expression of these various changes is not well delineated, particularly between the juvenile and adult phases of development. Moreover, interventions to protect against these neurodevelopmental disruptions are rarely evaluated. Here, female Sprague-Dawley rats were housed in either environmental enrichment (EE) or standard care (SC) and their male and female offspring were administered 50 µg/kg i.p. of lipopolysaccharide (LPS) or pyrogen-free saline in a dual-administration neonatal protocol. All animals maintained their respective housing assignments from breeding until the end of the study. LPS exposure on postnatal days (P) 3 and 5 of life resulted in differential expression of emotional and cognitive disruptions and evidence of oxidative stress across development. Specifically, social behavior was reduced in neonatal-treated (n)LPS animals at adolescence (P40), but not adulthood (P70). In contrast, male nLPS rats exhibited intact spatial memory as adolescents which was impaired in later life. Moreover, these males had decreased prefrontal cortex levels of glutathione at P40, which was normalized in adult animals. Notably, EE appeared to offer some protection against the consequences of inflammation on juvenile social behavior and fully prevented reduced glutathione levels in the juvenile prefrontal cortex. Combined, these time-dependent effects provide evidence that early-life inflammation interacts with other developmental variables, specifically puberty and EE, in the expression (and prevention) of select behavioral and molecular programs.


Assuntos
Deficiências do Desenvolvimento/etiologia , Inflamação/complicações , Transtornos Mentais/etiologia , Estresse Oxidativo/fisiologia , Fatores Etários , Animais , Animais Recém-Nascidos , Corticosterona/sangue , Deficiências do Desenvolvimento/metabolismo , Progressão da Doença , Feminino , Glutationa/metabolismo , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Masculino , Comportamento Materno , Transtornos Mentais/sangue , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Comportamento Social , Estatísticas não Paramétricas , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...