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1.
Br J Anaesth ; 123(4): 488-496, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31383363

RESUMO

BACKGROUND: General anaesthetics affect loss of consciousness by disrupting information-passing and integration within thalamo-cortical (TC) networks. Feedback cortical connections that carry internally generated signals such as expectation and attention appear more sensitive to anaesthesia than feedforward signals. However, direct evidence for this effect in non-primary cortex is lacking. In addition, direct comparisons between TC core and matrix, and between cortico-cortical (CC) feedforward and feedback responses have not been reported. METHODS: We investigated the disruption of synaptic responses by isoflurane of four distinct afferent pathways to non-primary neocortex. We independently activated TC core and matrix and reciprocal CC (feedforward and feedback) pathways using optogenetic techniques, and compared the relative sensitivity of synaptic responses to isoflurane. RESULTS: Under control conditions, activation of axon terminals of all pathways evoked postsynaptic currents (recorded extracellularly) and postsynaptic potentials in pyramidal neurones. CC feedback responses were substantially more sensitive to isoflurane (0 to 0.53 mM) compared with TC core, TC matrix, or CC feedforward pathways. CONCLUSION: Differential sensitivity of CC feedback synaptic responses to isoflurane in a clinically relevant range suggests a role for disruption of these afferents in the hypnotic effects of anaesthetic agents.


Assuntos
Anestésicos Inalatórios/farmacologia , Retroalimentação Fisiológica/efeitos dos fármacos , Isoflurano/farmacologia , Neocórtex/efeitos dos fármacos , Animais , Camundongos , Modelos Animais
2.
Nat Commun ; 10(1): 3097, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308381

RESUMO

Dopaminergic neurons in the brain of the Drosophila larva play a key role in mediating reward information to the mushroom bodies during appetitive olfactory learning and memory. Using optogenetic activation of Kenyon cells we provide evidence that recurrent signaling exists between Kenyon cells and dopaminergic neurons of the primary protocerebral anterior (pPAM) cluster. Optogenetic activation of Kenyon cells paired with odor stimulation is sufficient to induce appetitive memory. Simultaneous impairment of the dopaminergic pPAM neurons abolishes appetitive memory expression. Thus, we argue that dopaminergic pPAM neurons mediate reward information to the Kenyon cells, and in turn receive feedback from Kenyon cells. We further show that this feedback signaling is dependent on short neuropeptide F, but not on acetylcholine known to be important for odor-shock memories in adult flies. Our data suggest that recurrent signaling routes within the larval mushroom body circuitry may represent a mechanism subserving memory stabilization.


Assuntos
Encéfalo/fisiologia , Neurônios Dopaminérgicos/fisiologia , Drosophila melanogaster/fisiologia , Memória/fisiologia , Corpos Pedunculados/fisiologia , Recompensa , Acetilcolina/metabolismo , Animais , Apetite/fisiologia , Encéfalo/citologia , Condicionamento Clássico , Retroalimentação Fisiológica , Larva , Modelos Psicológicos , Corpos Pedunculados/citologia , Vias Neurais/fisiologia , Neuropeptídeos/metabolismo , Odorantes , Percepção Olfatória/fisiologia , Optogenética
3.
Phys Rev Lett ; 122(20): 208102, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31172757

RESUMO

Growth in confined spaces can drive cellular populations through a jamming transition from a fluidlike state to a solidlike state. Experiments have found that jammed budding yeast populations can build up extreme compressive pressures (over 1 MPa), which in turn feed back onto cellular physiology by slowing or even stalling cell growth. Using numerical simulations, we investigate how this feedback impacts the mechanical properties of model jammed cell populations. We find that feedback directs growth toward poorly coordinated regions, resulting in an excess number of cell-cell contacts that rigidify cell packings. Cell packings possess anomalously large shear and bulk moduli that depend sensitively on the strength of feedback. These results demonstrate that mechanical feedback on the single-cell level is a simple mechanism by which living systems may tune their population-level mechanical properties.


Assuntos
Modelos Biológicos , Saccharomycetales/fisiologia , Fenômenos Biomecânicos , Retroalimentação Fisiológica , Saccharomycetales/crescimento & desenvolvimento , Saccharomycetales/metabolismo
4.
Nat Commun ; 10(1): 2418, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160574

RESUMO

In transcriptional regulatory networks (TRNs), a canonical 3-node feed-forward loop (FFL) is hypothesized to evolve to filter out short spurious signals. We test this adaptive hypothesis against a novel null evolutionary model. Our mutational model captures the intrinsically high prevalence of weak affinity transcription factor binding sites. We also capture stochasticity and delays in gene expression that distort external signals and intrinsically generate noise. Functional FFLs evolve readily under selection for the hypothesized function but not in negative controls. Interestingly, a 4-node "diamond" motif also emerges as a short spurious signal filter. The diamond uses expression dynamics rather than path length to provide fast and slow pathways. When there is no idealized external spurious signal to filter out, but only internally generated noise, only the diamond and not the FFL evolves. While our results support the adaptive hypothesis, we also show that non-adaptive factors, including the intrinsic expression dynamics, matter.


Assuntos
Regulação da Expressão Gênica/fisiologia , Redes Reguladoras de Genes/fisiologia , RNA Mensageiro/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Adaptação Fisiológica , Retroalimentação Fisiológica , Modelos Genéticos , Modelos Teóricos , Saccharomyces cerevisiae
5.
Nature ; 571(7764): 211-218, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207603

RESUMO

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Epistasia Genética , Proteínas de Homeodomínio/metabolismo , Transcrição Genética , Animais , Calcineurina/metabolismo , Sinalização do Cálcio , Retroalimentação Fisiológica , Feminino , Regulação da Expressão Gênica/imunologia , Genótipo , Memória Imunológica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Evasão Tumoral
6.
Nat Commun ; 10(1): 2572, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189917

RESUMO

Activation of G-protein coupled receptors elevates cAMP levels promoting dissociation of protein kinase A (PKA) holoenzymes and release of catalytic subunits (PKAc). This results in PKAc-mediated phosphorylation of compartmentalized substrates that control central aspects of cell physiology. The mechanism of PKAc activation and signaling have been largely characterized. However, the modes of PKAc inactivation by regulated proteolysis were unknown. Here, we identify a regulatory mechanism that precisely tunes PKAc stability and downstream signaling. Following agonist stimulation, the recruitment of the chaperone-bound E3 ligase CHIP promotes ubiquitylation and proteolysis of PKAc, thus attenuating cAMP signaling. Genetic inactivation of CHIP or pharmacological inhibition of HSP70 enhances PKAc signaling and sustains hippocampal long-term potentiation. Interestingly, primary fibroblasts from autosomal recessive spinocerebellar ataxia 16 (SCAR16) patients carrying germline inactivating mutations of CHIP show a dramatic dysregulation of PKA signaling. This suggests the existence of a negative feedback mechanism for restricting hormonally controlled PKA activities.


Assuntos
Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Retroalimentação Fisiológica/fisiologia , Chaperonas Moleculares/metabolismo , Ataxias Espinocerebelares/patologia , Animais , Retroalimentação Fisiológica/efeitos dos fármacos , Fibroblastos , Células HEK293 , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Hipocampo/patologia , Holoenzimas/metabolismo , Humanos , Leupeptinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Cultura Primária de Células , Ligação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Nucleosídeos de Purina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ataxias Espinocerebelares/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia
7.
Nat Commun ; 10(1): 2766, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235692

RESUMO

A major challenge in biology is that genetically identical cells in the same environment can display gene expression stochasticity (noise), which contributes to bet-hedging, drug tolerance, and cell-fate switching. The magnitude and timescales of stochastic fluctuations can depend on the gene regulatory network. Currently, it is unclear how gene expression noise of specific networks impacts the evolution of drug resistance in mammalian cells. Answering this question requires adjusting network noise independently from mean expression. Here, we develop positive and negative feedback-based synthetic gene circuits to decouple noise from the mean for Puromycin resistance gene expression in Chinese Hamster Ovary cells. In low Puromycin concentrations, the high-noise, positive-feedback network delays long-term adaptation, whereas it facilitates adaptation under high Puromycin concentration. Accordingly, the low-noise, negative-feedback circuit can maintain resistance by acquiring mutations while the positive-feedback circuit remains mutation-free and regains drug sensitivity. These findings may have profound implications for chemotherapeutic inefficiency and cancer relapse.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Modelos Genéticos , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Células CHO , Simulação por Computador , Cricetulus , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Retroalimentação Fisiológica , Regulação da Expressão Gênica/genética , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Puromicina/farmacologia , Puromicina/uso terapêutico , Processos Estocásticos
8.
Nat Commun ; 10(1): 2654, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201326

RESUMO

Animal locomotion requires spatiotemporally coordinated contraction of muscles throughout the body. Here, we investigate how contractions of antagonistic groups of muscles are intersegmentally coordinated during bidirectional crawling of Drosophila larvae. We identify two pairs of higher-order premotor excitatory interneurons present in each abdominal neuromere that intersegmentally provide feedback to the adjacent neuromere during motor propagation. The two feedback neuron pairs are differentially active during either forward or backward locomotion but commonly target a group of premotor interneurons that together provide excitatory inputs to transverse muscles and inhibitory inputs to the antagonistic longitudinal muscles. Inhibition of either feedback neuron pair compromises contraction of transverse muscles in a direction-specific manner. Our results suggest that the intersegmental feedback neurons coordinate contraction of synergistic muscles by acting as delay circuits representing the phase lag between segments. The identified circuit architecture also shows how bidirectional motor networks could be economically embedded in the nervous system.


Assuntos
Retroalimentação Fisiológica , Locomoção/fisiologia , Rede Nervosa/fisiologia , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Interneurônios/fisiologia , Larva/fisiologia , Microscopia Eletrônica , Modelos Animais , Contração Muscular/fisiologia , Músculos/inervação , Músculos/fisiologia , Optogenética
9.
Methods Mol Biol ; 1975: 3-35, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062303

RESUMO

Agent-based modelling (ABM) offers a framework to realistically couple subcellular signaling pathways to cellular behavior and macroscopic tissue organization. However, these models have been previously inaccessible to many systems biologists due to the difficulties with formulating and simulating multi-scale behavior. In this chapter, a review of the Compucell3D framework is presented along with a general workflow for transitioning from a well-mixed ODE model to an ABM. These techniques are demonstrated through a case study on the simulation of a Notch-Delta Positive Feedback, Lateral Inhibition (PFLI) gene circuit in the intestinal crypts. Specifically, techniques for gene circuit-driven hypothesis formation, geometry construction, selection of simulation parameters, and simulation quantification are presented.


Assuntos
Simulação por Computador , Intestinos/citologia , Modelos Biológicos , Nicho de Células-Tronco , Diferenciação Celular , Retroalimentação Fisiológica , Humanos , Transdução de Sinais , Análise Espaço-Temporal , Análise de Sistemas
10.
Plant Sci ; 283: 247-255, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31128695

RESUMO

Chrysanthemums require continuous short-days (SD) for anthesis. FTL3 (FLOWERING LOCUS T-like 3), a floral promoter expressed in chrysanthemum leaf, forms a complex with its interacting partner FDL1 to induce floral meristem identity gene AFL1. We explored the FTL3 induction mechanism during SD repeats in Chrysanthemum seticuspe. CsFTL3 expression was not immediately induced by a shift from long-day (LD) to SD, but gradually increased until the capitulum development stage under repeated SDs. Overexpression of CsFTL3 transgene increased endogenous leaf CsFTL3 induction under SD but not LD. Overexpression of CsFDL1 promoted anthesis and increased CsAFL1 and CsFTL3 expression under SD. Loss-of-function of CsFDL1 by RNAi resulted in delayed anthesis and downregulation of leaf CsAFL1 and CsFTL3, indicating the necessity of CsFDL1 for CsFTL3 induction. Overexpression of an antagonistic protein of CsFTL3 or CsFDL1 inhibited leaf CsFTL3 induction. CsFTL3 expression was positively regulated during SDs by a feedback mechanism involving the CsFTL3-CsFDL1 complex. Furthermore, flowering was accomplished by feedback with high levels of CsFTL3 induction under repeated SDs.


Assuntos
Chrysanthemum/crescimento & desenvolvimento , Flores/crescimento & desenvolvimento , Proteínas de Plantas/fisiologia , Chrysanthemum/metabolismo , Chrysanthemum/fisiologia , Retroalimentação Fisiológica , Flores/metabolismo , Flores/fisiologia , Técnicas de Silenciamento de Genes , Fotoperíodo , Folhas de Planta/metabolismo , Folhas de Planta/fisiologia , Regiões Promotoras Genéticas/fisiologia , Transcriptoma
11.
Nat Commun ; 10(1): 1931, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036804

RESUMO

Polycomb group (PcG) proteins play critical roles in the epigenetic inheritance of cell fate. The Polycomb Repressive Complexes PRC1 and PRC2 catalyse distinct chromatin modifications to enforce gene silencing, but how transcriptional repression is propagated through mitotic cell divisions remains a key unresolved question. Using reversible tethering of PcG proteins to ectopic sites in mouse embryonic stem cells, here we show that PRC1 can trigger transcriptional repression and Polycomb-dependent chromatin modifications. We find that canonical PRC1 (cPRC1), but not variant PRC1, maintains gene silencing through cell division upon reversal of tethering. Propagation of gene repression is sustained by cis-acting histone modifications, PRC2-mediated H3K27me3 and cPRC1-mediated H2AK119ub1, promoting a sequence-independent feedback mechanism for PcG protein recruitment. Thus, the distinct PRC1 complexes present in vertebrates can differentially regulate epigenetic maintenance of gene silencing, potentially enabling dynamic heritable responses to complex stimuli. Our findings reveal how PcG repression is potentially inherited in vertebrates.


Assuntos
Cromatina/metabolismo , Epigênese Genética , Inativação Gênica , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 2/genética , Processamento de Proteína Pós-Traducional , Animais , Linhagem Celular , Cromatina/química , Retroalimentação Fisiológica , Histonas/genética , Histonas/metabolismo , Padrões de Herança , Camundongos , Mitose , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Transcrição Genética
12.
BMC Bioinformatics ; 20(Suppl 4): 119, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999858

RESUMO

BACKGROUND: The search for molecular biomarkers of early-onset colorectal cancer (CRC) is an important but still quite challenging and unsolved task. Detection of CpG methylation in human DNA obtained from blood or stool has been proposed as a promising approach to a noninvasive early diagnosis of CRC. Thousands of abnormally methylated CpG positions in CRC genomes are often located in non-coding parts of genes. Novel bioinformatic methods are thus urgently needed for multi-omics data analysis to reveal causative biomarkers with a potential driver role in early stages of cancer. METHODS: We have developed a method for finding potential causal relationships between epigenetic changes (DNA methylations) in gene regulatory regions that affect transcription factor binding sites (TFBS) and gene expression changes. This method also considers the topology of the involved signal transduction pathways and searches for positive feedback loops that may cause the carcinogenic aberrations in gene expression. We call this method "Walking pathways", since it searches for potential rewiring mechanisms in cancer pathways due to dynamic changes in the DNA methylation status of important gene regulatory regions ("epigenomic walking"). RESULTS: In this paper, we analysed an extensive collection of full genome gene-expression data (RNA-seq) and DNA methylation data of genomic CpG islands (using Illumina methylation arrays) generated from a sample of tumor and normal gut epithelial tissues of 300 patients with colorectal cancer (at different stages of the disease) (data generated in the EU-supported SysCol project). Identification of potential epigenetic biomarkers of DNA methylation was performed using the fully automatic multi-omics analysis web service "My Genome Enhancer" (MGE) (my-genome-enhancer.com). MGE uses the database on gene regulation TRANSFAC®, the signal transduction pathways database TRANSPATH®, and software that employs AI (artificial intelligence) methods for the analysis of cancer-specific enhancers. CONCLUSIONS: The identified biomarkers underwent experimental testing on an independent set of blood samples from patients with colorectal cancer. As a result, using advanced methods of statistics and machine learning, a minimum set of 6 biomarkers was selected, which together achieve the best cancer detection potential. The markers include hypermethylated positions in regulatory regions of the following genes: CALCA, ENO1, MYC, PDX1, TCF7, ZNF43.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Metilação de DNA/genética , Retroalimentação Fisiológica , Transdução de Sinais/genética , Sítios de Ligação/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Ilhas de CpG/genética , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores de Transcrição/metabolismo
13.
Nat Commun ; 10(1): 1530, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30948783

RESUMO

Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood. The pediatric cancer neuroblastoma includes adrenergic (ADRN) and mesenchymal (MES) tumor cell types, which differ in phenotype, super-enhancers (SEs) and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we unravel how a NOTCH3 intracellular domain reprogrammed the ADRN transcriptional landscape towards a MES state. A transcriptional feed-forward circuitry of NOTCH-family transcription factors amplifies the NOTCH signaling levels, explaining the swift transition between two semi-stable cellular states. This transition induces genome-wide remodeling of the H3K27ac landscape and a switch from ADRN SEs to MES SEs. Once established, the NOTCH feed-forward loop maintains the induced MES state. In vivo reprogramming of ADRN cells shows that MES and ADRN cells are equally oncogenic. Our results elucidate a swift transdifferentiation between two semi-stable epigenetic cellular states.


Assuntos
Neurônios Adrenérgicos/patologia , Reprogramação Celular/genética , Células-Tronco Mesenquimais/patologia , Neuroblastoma/patologia , Receptor Notch3/fisiologia , Neurônios Adrenérgicos/metabolismo , Linhagem Celular Tumoral , Epigênese Genética , Retroalimentação Fisiológica , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Células-Tronco Mesenquimais/metabolismo , Neuroblastoma/metabolismo , Receptor Notch3/genética , Receptor Notch3/metabolismo
14.
Phys Rev E ; 99(2-1): 022422, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30934371

RESUMO

We map a class of well-mixed stochastic models of biochemical feedback in steady state to the mean-field Ising model near the critical point. The mapping provides an effective temperature, magnetic field, order parameter, and heat capacity that can be extracted from biological data without fitting or knowledge of the underlying molecular details. We demonstrate this procedure on fluorescence data from mouse T cells, which reveals distinctions between how the cells respond to different drugs. We also show that the heat capacity allows inference of the absolute molecule number from fluorescence intensity. We explain this result in terms of the underlying fluctuations, and we demonstrate the generality of our work.


Assuntos
Retroalimentação Fisiológica , Modelos Imunológicos , Linfócitos T/imunologia , Linfócitos T/metabolismo
15.
Int J Mol Sci ; 20(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934732

RESUMO

The human diploid cell line Medical Research Council -5 (MRC-5) is commonly utilized for vaccine development. Although a rabies vaccine developed in cultured MRC-5 cells exists, the poor susceptibility of MRC-5 cells to the rabies virus (RABV) infection limits the potential yield of this vaccine. The underlying mechanism of MRC-5 cell resistance to RABV infection remains unknown. In this study, we demonstrate that viral infection increased exosomal release from MRC-5 cells; conversely, blocking exosome release promoted RABV infection in MRC-5 cells. Additionally, RABV infection up-regulated microRNA (miR)-423-5p expression in exosomes, resulting in feedback inhibition of RABV replication by abrogating the inhibitory effect of suppressor of cytokine signaling 3 (SOCS3) on type I interferon (IFN) signaling. Furthermore, intercellular delivery of miR-423-5p by exosomes inhibited RABV replication in MRC-5 cells. We also show that RABV infection increased IFN-ß production in MRC-5 cells and that blocking the type I IFN receptor promoted RABV infection. In conclusion, MRC-5 cells were protected from RABV infection by the intercellular delivery of exosomal miR-423-5p and the up-regulation of IFN-ß. These findings reveal novel antiviral mechanisms in MRC-5 cells against RABV infection. miR-423-5p, exosomes, and IFN signaling pathways may therefore be potential targets for improving MRC-5 cell-based rabies vaccine production.


Assuntos
Resistência à Doença , Exossomos/metabolismo , Técnicas de Transferência de Genes , MicroRNAs/administração & dosagem , Vírus da Raiva/fisiologia , Raiva/genética , Raiva/virologia , Sequência de Bases , Linhagem Celular , Exossomos/ultraestrutura , Retroalimentação Fisiológica , Humanos , Interferon beta/metabolismo , Raiva/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Regulação para Cima , Replicação Viral
16.
Molecules ; 24(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018591

RESUMO

Sonic hedgehog (Shh) signaling plays a tumor-promoting role in many epithelial cancers. Cancer cells produce soluble a Shh that signals to distant stromal cells that express the receptor Patched (Ptc). These receiving cells respond by producing other soluble factors that promote cancer cell growth, generating a positive feedback loop. To interfere with reinforced Shh signaling, we examined the potential of defined heparin and heparan sulfate (HS) polysaccharides to block Shh solubilization and Ptc receptor binding. We confirm in vitro and in vivo that proteolytic cleavage of the N-terminal Cardin-Weintraub (CW) amino acid motif is a prerequisite for Shh solubilization and function. Consistent with the established binding of soluble heparin or HS to the Shh CW target motif, both polysaccharides impaired proteolytic Shh processing and release from source cells. We also show that HS and heparin bind to, and block, another set of basic amino acids required for unimpaired Shh binding to Ptc receptors on receiving cells. Both modes of Shh activity downregulation depend more on HS size and overall charge than on specific HS sulfation modifications. We conclude that heparin oligosaccharide interference in the physiological roles of HS in Shh release and reception may be used to expand the field of investigation to pharmaceutical intervention of tumor-promoting Shh functions.


Assuntos
Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas Hedgehog/química , Heparina/farmacologia , Heparitina Sulfato/farmacologia , Receptor Patched-1/genética , Receptores de Superfície Celular/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação , Ligação Competitiva , Linhagem Celular Tumoral , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Embrião não Mamífero , Retroalimentação Fisiológica , Regulação da Expressão Gênica no Desenvolvimento , Células HeLa , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Heparina/química , Heparitina Sulfato/química , Humanos , Modelos Moleculares , Receptor Patched-1/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Solubilidade , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
17.
Math Biosci Eng ; 16(3): 1392-1413, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30947426

RESUMO

Cell polarity refers to spatial di erences in the shape and structure of cells, which leads to the generation of diverse cell types playing di erent roles in biological processes. Cell polarization usually involves the localization of some specific signaling molecules to a proper location of the cell membrane. Recent studies proposed that delayed negative feedback may be important for maintaining the robustness of cell polarization and the observed oscillating behavior of signaling cluster. However, the fundamental mechanisms for achieving cell polarization under negative feedback remain controversial. In this paper, we formulate the cell polarization system as a non-local reaction di usion equation with positive and delayed negative feedback loops. Through the Turing stability analysis, we identify the parameter conditions, including the range of the time delay constant, for achieving cell polarization without any inhomogeneous spatial cues. Also, our numerical results support that by controlling the length of the time delay in negative feedback and the magnitude of positive feedback, the oscillating behavior of signaling cluster can be observed in our simulations.


Assuntos
Membrana Celular/fisiologia , Polaridade Celular , Simulação por Computador , Saccharomyces cerevisiae/fisiologia , Transdução de Sinais , Retroalimentação Fisiológica , Modelos Lineares , Modelos Biológicos , Saccharomyces cerevisiae/genética
18.
Bull Exp Biol Med ; 166(6): 709-713, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31020579

RESUMO

An original concept of a two-stage mechanism of positive reinforcement is proposed. The first stage, "virtual" reinforcement, is formed in parallel with the action result acceptor when the result is still not achieved. At this stage, the importance of the planned result and the probability of its achievement are assessed. The greater are these indices, the stronger is "virtual" reinforcement. Hypothetically, the "virtual" reinforcement is mediated by dopamine release from nerve terminals in the mesencephalon. The "real" reinforcement (the second stage) occurs after achievement of the result. Probably, an important role in the mechanisms of the "real" reinforcement is given to endogenous opioids, cannabinoids, and GABA. Based on the advanced hypothesis on interaction between the central and peripheral subdivisions of the corresponding neurochemical systems, the review focuses on possibility of pharmacological intervention into the mechanisms of positive reinforcement by modifying activity of the peripheral opioid and dopamine receptors with the ligands that cannot cross blood-brain barrier.


Assuntos
Retroalimentação Fisiológica/fisiologia , Mesencéfalo/fisiologia , Receptores Dopaminérgicos/fisiologia , Receptores Opioides/fisiologia , Reforço (Psicologia) , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Canabinoides/metabolismo , Canabinoides/farmacologia , Humanos , Mesencéfalo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Satisfação Pessoal , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologia
19.
Nat Commun ; 10(1): 1473, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931927

RESUMO

Insulin controls glucose homeostasis and cell growth through bifurcated signaling pathways. Dysregulation of insulin signaling is linked to diabetes and cancer. The spindle checkpoint controls the fidelity of chromosome segregation during mitosis. Here, we show that insulin receptor substrate 1 and 2 (IRS1/2) cooperate with spindle checkpoint proteins to promote insulin receptor (IR) endocytosis through recruiting the clathrin adaptor complex AP2 to IR. A phosphorylation switch of IRS1/2 orchestrated by extracellular signal-regulated kinase 1 and 2 (ERK1/2) and Src homology phosphatase 2 (SHP2) ensures selective internalization of activated IR. SHP2 inhibition blocks this feedback regulation and growth-promoting IR signaling, prolongs insulin action on metabolism, and improves insulin sensitivity in mice. We propose that mitotic regulators and SHP2 promote feedback inhibition of IR, thereby limiting the duration of insulin signaling. Targeting this feedback inhibition can improve insulin sensitivity.


Assuntos
Complexo 2 de Proteínas Adaptadoras/metabolismo , Retroalimentação Fisiológica , Proteínas Substratos do Receptor de Insulina/metabolismo , Insulina/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Receptor de Insulina/metabolismo , Animais , Endocitose , Células Hep G2 , Humanos , Resistência à Insulina , Pontos de Checagem da Fase M do Ciclo Celular , Camundongos , Fosforilação , Transdução de Sinais
20.
J Exp Clin Cancer Res ; 38(1): 109, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823890

RESUMO

BACKGROUND: Breast cancer is the most common cancer among women worldwide, and approximately 70% of breast cancers are hormone receptor-positive and express estrogen receptor-α (ERα) or/and progesterone receptor. ERα has been identified to promote the growth of primary breast cancer, however, it can also antagonize signaling pathways that lead to epithelial-mesenchymal transition (EMT), including transforming growth factor-ß (TGF-ß) signaling. miRNA alteration or dysfunction is involved in cancer development and progression. Although miR-1271 has identified as a tumor suppressor in various cancers, the role of miR-1271 in breast cancer is still limited. METHODS: The effect of miR-1271 on breast cancer progression was investigated both in vitro and in vivo. The EMT-related protein expression levels and localization were analyzed by western blotting and immunofluorescence, respectively. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to validate the regulation of ERα-miR-1271-SNAI2 feedback loop. RESULTS: miR-1271 suppresses breast cancer progression and EMT phenotype both in vitro and in vivo by targeting SNAI2. Estrogen reverses TGF-ß-induced EMT in a miR-1271 dependent manner. Furthermore, ERα transactivates the miR-1271 expression and is also transcriptionally repressed by SNAI2. CONCLUSIONS: Our data uncover the ERα-miR-1271-SNAI2 feedback loop and provide a mechanism to explain the TGF-ß network in breast cancer progression.


Assuntos
Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Progressão da Doença , Transição Epitelial-Mesenquimal/fisiologia , Retroalimentação Fisiológica , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Fator de Crescimento Transformador beta/metabolismo
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