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1.
Nature ; 629(8014): 1100-1108, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38778103

RESUMO

The rich variety of behaviours observed in animals arises through the interplay between sensory processing and motor control. To understand these sensorimotor transformations, it is useful to build models that predict not only neural responses to sensory input1-5 but also how each neuron causally contributes to behaviour6,7. Here we demonstrate a novel modelling approach to identify a one-to-one mapping between internal units in a deep neural network and real neurons by predicting the behavioural changes that arise from systematic perturbations of more than a dozen neuronal cell types. A key ingredient that we introduce is 'knockout training', which involves perturbing the network during training to match the perturbations of the real neurons during behavioural experiments. We apply this approach to model the sensorimotor transformations of Drosophila melanogaster males during a complex, visually guided social behaviour8-11. The visual projection neurons at the interface between the optic lobe and central brain form a set of discrete channels12, and prior work indicates that each channel encodes a specific visual feature to drive a particular behaviour13,14. Our model reaches a different conclusion: combinations of visual projection neurons, including those involved in non-social behaviours, drive male interactions with the female, forming a rich population code for behaviour. Overall, our framework consolidates behavioural effects elicited from various neural perturbations into a single, unified model, providing a map from stimulus to neuronal cell type to behaviour, and enabling future incorporation of wiring diagrams of the brain15 into the model.


Assuntos
Encéfalo , Drosophila melanogaster , Modelos Neurológicos , Neurônios , Lobo Óptico de Animais não Mamíferos , Comportamento Social , Percepção Visual , Animais , Feminino , Masculino , Drosophila melanogaster/fisiologia , Drosophila melanogaster/citologia , Neurônios/classificação , Neurônios/citologia , Neurônios/fisiologia , Lobo Óptico de Animais não Mamíferos/citologia , Lobo Óptico de Animais não Mamíferos/fisiologia , Percepção Visual/fisiologia , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Encéfalo/citologia , Encéfalo/fisiologia
2.
J Theor Biol ; 386: 105-14, 2015 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-26408335

RESUMO

In this paper, using the intrinsically disordered oncoprotein Myc as an example, we present a mathematical model to help explain how protein oscillatory dynamics can influence state switching. Earlier studies have demonstrated that, while Myc overexpression can facilitate state switching and transform a normal cell into a cancer phenotype, its downregulation can reverse state-switching. A fundamental aspect of the model is that a Myc threshold determines cell fate in cells expressing p53. We demonstrate that a non-cooperative positive feedback loop coupled with Myc sequestration at multiple binding sites can generate bistable Myc levels. Normal quiescent cells with Myc levels below the threshold can respond to mitogenic signals to activate the cyclin/cdk oscillator for limited cell divisions but the p53/Mdm2 oscillator remains nonfunctional. In response to stress, the p53/Mdm2 oscillator is activated in pulses that are critical to DNA repair. But if stress causes Myc levels to cross the threshold, Myc inactivates the p53/Mdm2 oscillator, abrogates p53 pulses, and pushes the cyclin/cdk oscillator into overdrive sustaining unchecked proliferation seen in cancer. However, if Myc is downregulated, the cyclin/cdk oscillator is inactivated and the p53/Mdm2 oscillator is reset and the cancer phenotype is reversed.


Assuntos
Relógios Biológicos/fisiologia , Transformação Celular Neoplásica/metabolismo , Modelos Biológicos , Proteínas Proto-Oncogênicas c-myc/fisiologia , Ciclinas/metabolismo , Retroalimentação Fisiológica/fisiologia , Humanos , Fenótipo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo
3.
PLoS One ; 10(5): e0126729, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25974317

RESUMO

BACKGROUND: Intrinsically disordered proteins (IDPs) lack a stable tertiary structure in isolation. Remarkably, however, a substantial portion of IDPs undergo disorder-to-order transitions upon binding to their cognate partners. Structural flexibility and binding plasticity enable IDPs to interact with a broad range of partners. However, the broader network properties that could provide additional insights into the functional role of IDPs are not known. RESULTS: Here, we report the first comprehensive survey of network properties of IDP-induced sub-networks in multiple species from yeast to human. Our results show that IDPs exhibit greater-than-expected modularity and are connected to the rest of the protein interaction network (PIN) via proteins that exhibit the highest betweenness centrality and connect to fewer-than-expected IDP communities, suggesting that they form critical communication links from IDP modules to the rest of the PIN. Moreover, we found that IDPs are enriched at the top level of regulatory hierarchy. CONCLUSION: Overall, our analyses reveal coherent and remarkably conserved IDP-centric network properties, namely, modularity in IDP-induced network and a layer of critical nodes connecting IDPs with the rest of the PIN.


Assuntos
Proteínas Intrinsicamente Desordenadas/metabolismo , Redes e Vias Metabólicas , Animais , Análise por Conglomerados , Bases de Dados de Proteínas , Drosophila/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Evolução Molecular , Humanos , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/genética , Camundongos , Pressão Osmótica , Mapas de Interação de Proteínas , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
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