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Mutations in the epidermal growth factor receptor (EGFR) are common in non-small cell lung cancer (NSCLC), particularly in never-smoker patients. However, these mutations are not always carcinogenic, and have recently been reported in histologically normal lung tissue from patients with and without lung cancer. To investigate the outcome of EGFR mutation in healthy lung stem cells, we grow murine alveolar type II organoids monoclonally in a three-dimensional Matrigel. Our experiments show that the EGFR-L858R mutation induces a change in organoid structure: mutated organoids display more 'budding', in comparison with non-mutant controls, which are nearly spherical. We perform on-lattice computational simulations, which suggest that this can be explained by the concentration of division among a small number of cells on the surface of the mutated organoids. We are currently unable to distinguish the cell-based mechanisms that lead to this spatial heterogeneity in growth, but suggest a number of future experiments which could be used to do so. We suggest that the likelihood of L858R-fuelled tumorigenesis is affected by whether the mutation arises in a spatial environment that allows the development of these surface protrusions. These data may have implications for cancer prevention strategies and for understanding NSCLC progression.
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Many amniote vertebrate species including humans can form identical twins from a single embryo, but this only occurs rarely. It has been suggested that the primitive-streak-forming embryonic region emits signals that inhibit streak formation elsewhere but the signals involved, how they are transmitted and how they act has not been elucidated. Here we show that short tracks of calcium firing activity propagate through extraembryonic tissue via gap junctions and prevent ectopic primitive streak formation in chick embryos. Cross-regulation of calcium activity and an inhibitor of primitive streak formation (Bone Morphogenetic Protein, BMP) via NF-κB and NFAT establishes a long-range BMP gradient spanning the embryo. This mechanism explains how embryos of widely different sizes can maintain positional information that determines embryo polarity. We provide evidence for similar mechanisms in two different human embryo models and in Drosophila, suggesting an ancient evolutionary origin.
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Proteínas Morfogenéticas Óseas , Calcio , Animales , Embrión de Pollo , Humanos , Calcio/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Gastrulación/fisiología , Línea Primitiva , ReproducciónRESUMEN
BACKGROUND: This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD). METHODS: JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]-12), epidermal hyperplasia (keratin-16 [KRT16]), T-helper 2 (Th2) immune response (C-C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks. RESULTS: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP-12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose-dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26. CONCLUSIONS: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate-to-severe AD.
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Biomarcadores , Dermatitis Atópica , Índice de Severidad de la Enfermedad , Piel , Sulfonamidas , Humanos , Dermatitis Atópica/tratamiento farmacológico , Femenino , Masculino , Adulto , Piel/patología , Piel/metabolismo , Piel/efectos de los fármacos , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Pirimidinas/uso terapéutico , Pirimidinas/administración & dosificación , Persona de Mediana Edad , Resultado del Tratamiento , Método Doble Ciego , Adulto JovenRESUMEN
N-type calcium channels (CaV2.2) are predominantly localized in presynaptic terminals, and are particularly important for pain transmission in the spinal cord. Furthermore, they have multiple isoforms, conferred by alternatively spliced or cassette exons, which are differentially expressed. Here, we have examined alternatively spliced exon47 variants that encode a long or short C-terminus in human CaV2.2. In the Ensembl database, all short exon47-containing transcripts were associated with the absence of exon18a, therefore, we also examined the effect of inclusion or absence of exon18a, combinatorially with the exon47 splice variants. We found that long exon47, only in the additional presence of exon18a, results in CaV2.2 currents that have a 3.6-fold greater maximum conductance than the other three combinations. In contrast, cell-surface expression of CaV2.2 in both tsA-201 cells and hippocampal neurons is increased â¼4-fold by long exon47, relative to short exon47, in either the presence or the absence of exon18a. This surprising discrepancy between trafficking and function indicates that cell-surface expression is enhanced by long exon47, independently of exon18a. However, in the presence of long exon47, exon18a mediates an additional permissive effect on CaV2.2 gating. We also investigated the single-nucleotide polymorphism in exon47 that has been linked to schizophrenia and Parkinson's disease, which we found is only non-synonymous in the short exon47 C-terminal isoform, resulting in two minor alleles. This study highlights the importance of investigating the combinatorial effects of exon inclusion, rather than each in isolation, in order to increase our understanding of calcium channel function.
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Neuronas , Empalme del ARN , Humanos , Neuronas/metabolismo , Canales de Calcio Tipo N/genética , Isoformas de Proteínas/genética , Exones/genéticaRESUMEN
Understanding pattern formation driven by cell-cell interactions has been a significant theme in cellular biology for many years. In particular, due to their implications within many biological contexts, lateral-inhibition mechanisms present in the Notch-Delta signalling pathway led to an extensive discussion between biologists and mathematicians. Deterministic and stochastic models have been developed as a consequence of this discussion, some of which address long-range signalling by considering cell protrusions reaching non-neighbouring cells. The dynamics of such signalling systems reveal intricate properties of the coupling terms involved in these models. In this work, we investigate the advantages and drawbacks of a single-parameter long-range signalling model across diverse scenarios. By employing linear and multi-scale analyses, we discover that pattern selection is not only partially explained but also depends on nonlinear effects that extend beyond the scope of these analytical techniques.
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Receptores Notch , Transducción de Señal , Receptores Notch/metabolismo , Transducción de Señal/fisiología , Comunicación Celular/fisiología , Diferenciación CelularRESUMEN
OBJECTIVE: The type 1 interferon (IFN) pathway is up-regulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM. METHODS: RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed up during the course of their clinical care. A previously defined 13-gene type I IFN score was modeled as a function of demographic, serologic, and clinical variables using both cross-sectional and longitudinal data. RESULTS: The pattern of type I IFN-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to systemic lupus erythematosus. The median type I IFN score was higher or lower in patients with anti-melanoma differentiation-associated protein 5 (anti-MDA-5) or anti-Mi-2 antibodies, respectively, compared to patients without these antibodies. Absolute type I IFN score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA-5 antibodies. Changes in the type I IFN score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation between changes in the type I IFN score and skin disease activity (Spearman's ρ = 0.84-0.95). CONCLUSION: The type I IFN score is independently associated with skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA-5 status revealed that the type I IFN score is strongly correlated with skin disease activity, providing support for type I IFN blockade as a therapeutic strategy for DM.
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Dermatomiositis , Interferón Tipo I , Adulto , Humanos , Estudios Transversales , Interferón Tipo I/genética , Piel/metabolismo , Helicasa Inducida por Interferón IFIH1 , AutoanticuerposRESUMEN
In this hybrid review, we have first collected and reviewed available information on the structure and function of the enigmatic cache domains in α2δ proteins. These are organized into two double cache (dCache_1) domains, and they are present in all α2δ proteins. We have also included new data on the key function of these domains with respect to amino acid and gabapentinoid binding to the universal amino acid-binding pocket, which is present in α2δ-1 and α2δ-2. We have now identified the reason why α2δ-3 and α2δ-4 do not bind gabapentinoid drugs or amino acids with bulky side chains. In relation to this, we have determined that the bulky amino acids Tryptophan and Phenylalanine prevent gabapentin from inhibiting cell surface trafficking of α2δ-1. Together, these novel data shed further light on the importance of the cache domains in α2δ proteins.
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Aminas , Canales de Calcio , Canales de Calcio/metabolismo , Gabapentina/metabolismo , Aminas/metabolismo , Aminas/farmacología , Membrana Celular/metabolismoRESUMEN
Evolutionary game theory (EGT) is a branch of mathematics which considers populations of individuals interacting with each other to receive pay-offs. An individual's pay-off is dependent on the strategy of its opponent(s) as well as on its own, and the higher its pay-off, the higher its reproductive fitness. Its offspring generally inherit its interaction strategy, subject to random mutation. Over time, the composition of the population shifts as different strategies spread or are driven extinct. In the last 25 years there has been a flood of interest in applying EGT to cancer modelling, with the aim of explaining how cancerous mutations spread through healthy tissue and how intercellular cooperation persists in tumour-cell populations. This review traces this body of work from theoretical analyses of well-mixed infinite populations through to more realistic spatial models of the development of cooperation between epithelial cells. We also consider work in which EGT has been used to make experimental predictions about the evolution of cancer, and discuss work that remains to be done before EGT can make large-scale contributions to clinical treatment and patient outcomes.
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Teoría del Juego , Neoplasias , Evolución Biológica , Conducta Cooperativa , Humanos , MutaciónRESUMEN
It has been proposed that environmental stress acted as a selection pressure on the evolution of human cooperation. Through agent-based evolutionary modelling, mathematical analysis, and human experimental data we illuminate the mechanisms by which the environment influences cooperative success and decision making in a Stag Hunt game. The modelling and mathematical results show that only cooperative foraging phenotypes survive the harshest of environments but pay a penalty for miscoordination in favourable environments. When agents are allowed to coordinate their hunting intentions by communicating, cooperative phenotypes outcompete those who pursue individual strategies in almost all environmental and payoff scenarios examined. Data from human participants show flexible decision-making in face of cooperative uncertainty, favouring high-risk, high-reward strategy when environments are harsher and starvation is imminent. Converging lines of evidence from the three approaches indicate a significant role for environmental variability in human cooperative dynamics and the species-unique cognition designed to support it.
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BACKGROUND: In vertebrate cells, the Golgi functional subunits, mini-stacks, are linked into a tri-dimensional network. How this "ribbon" architecture relates to Golgi functions remains unclear. Are all connections between mini-stacks equal? Is the local structure of the ribbon of functional importance? These are difficult questions to address, without a quantifiable readout of the output of ribbon-embedded mini-stacks. Endothelial cells produce secretory granules, the Weibel-Palade bodies (WPB), whose von Willebrand Factor (VWF) cargo is central to hemostasis. The Golgi apparatus controls WPB size at both mini-stack and ribbon levels. Mini-stack dimensions delimit the size of VWF "boluses" whilst the ribbon architecture allows their linear co-packaging, thereby generating WPBs of different lengths. This Golgi/WPB size relationship suits mathematical analysis. RESULTS: WPB lengths were quantized as multiples of the bolus size and mathematical modeling simulated the effects of different Golgi ribbon organizations on WPB size, to be compared with the ground truth of experimental data. An initial simple model, with the Golgi as a single long ribbon composed of linearly interlinked mini-stacks, was refined to a collection of mini-ribbons and then to a mixture of mini-stack dimers plus long ribbon segments. Complementing these models with cell culture experiments led to novel findings. Firstly, one-bolus sized WPBs are secreted faster than larger secretory granules. Secondly, microtubule depolymerization unlinks the Golgi into equal proportions of mini-stack monomers and dimers. Kinetics of binding/unbinding of mini-stack monomers underpinning the presence of stable dimers was then simulated. Assuming that stable mini-stack dimers and monomers persist within the ribbon resulted in a final model that predicts a "breathing" arrangement of the Golgi, where monomer and dimer mini-stacks within longer structures undergo continuous linking/unlinking, consistent with experimentally observed WPB size distributions. CONCLUSIONS: Hypothetical Golgi organizations were validated against a quantifiable secretory output. The best-fitting Golgi model, accounting for stable mini-stack dimers, is consistent with a highly dynamic ribbon structure, capable of rapid rearrangement. Our modeling exercise therefore predicts that at the fine-grained level the Golgi ribbon is more complex than generally thought. Future experiments will confirm whether such a ribbon organization is endothelial-specific or a general feature of vertebrate cells.
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Células Endoteliales , Factor de von Willebrand , Células Cultivadas , Exocitosis , Aparato de Golgi , Cuerpos de Weibel-Palade/fisiología , Factor de von Willebrand/farmacología , Factor de von Willebrand/fisiologíaRESUMEN
In many developing and regenerating systems, tissue pattern is established through gradients of informative morphogens, but we know little about how cells interpret these. Using experimental manipulation of early chick embryos, including misexpression of an inducer (VG1 or ACTIVIN) and an inhibitor (BMP4), we test two alternative models for their ability to explain how the site of primitive streak formation is positioned relative to the rest of the embryo. In one model, cells read morphogen concentrations cell-autonomously. In the other, cells sense changes in morphogen status relative to their neighbourhood. We find that only the latter model can account for the experimental results, including some counter-intuitive predictions. This mechanism (which we name the 'neighbourhood watch' model) illuminates the classic 'French Flag Problem' and how positional information is interpreted by a sheet of cells in a large developing system.
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Gastrulación , Estratos Germinativos , Animales , Embrión de Pollo , GástrulaRESUMEN
The auxiliary α2δ subunits of voltage-gated calcium (CaV) channels are key to augmenting expression and function of CaV1 and CaV2 channels, and are also important drug targets in several therapeutic areas, including neuropathic pain. The α2δ proteins are translated as preproteins encoding both α2 and δ, and post-translationally proteolyzed into α2 and δ subunits, which remain associated as a complex. In this study, we have identified ADAM17 as a key protease involved in proteolytic processing of pro-α2δ-1 and α2δ-3 subunits. We provide three lines of evidence: First, proteolytic cleavage is inhibited by chemical inhibitors of particular metalloproteases, including ADAM17. Second, proteolytic cleavage of both α2δ-1 and α2δ-3 is markedly reduced in cell lines by knockout of ADAM17 but not ADAM10. Third, proteolytic cleavage is reduced by the N-terminal active domain of TIMP-3 (N-TIMP-3), which selectively inhibits ADAM17. We have found previously that proteolytic cleavage into mature α2δ is essential for the enhancement of CaV function, and in agreement, knockout of ADAM17 inhibited the ability of α2δ-1 to enhance both CaV2.2 and CaV1.2 calcium currents. Finally, our data also indicate that the main site of proteolytic cleavage of α2δ-1 is the Golgi apparatus, although cleavage may also occur at the plasma membrane. Thus, our study identifies ADAM17 as a key protease required for proteolytic maturation of α2δ-1 and α2δ-3, and thus a potential drug target in neuropathic pain.
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Neuralgia , Inhibidor Tisular de Metaloproteinasa-3 , Humanos , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Canales de Calcio Tipo N/genética , Proteolisis , Calcio de la Dieta/metabolismo , Péptido Hidrolasas/metabolismo , Proteína ADAM17/genéticaRESUMEN
SignificanceAmino acids are the building blocks of life and important signaling molecules. Despite their common structure, no universal mechanism for amino acid recognition by cellular receptors is currently known. We discovered a simple motif, which binds amino acids in various receptor proteins from all major life-forms. In humans, this motif is found in subunits of calcium channels that are implicated in pain and neurodevelopmental disorders. Our findings suggest that γ-aminobutyric acid-derived drugs bind to the same motif in human proteins that binds natural ligands in bacterial receptors, thus enabling future improvement of important drugs.
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Archaea/química , Proteínas Arqueales/química , Bacterias/química , Proteínas Bacterianas/química , Proteínas de la Membrana/química , Secuencias de Aminoácidos , Archaea/metabolismo , Proteínas Arqueales/metabolismo , Bacterias/metabolismo , Proteínas Bacterianas/metabolismo , Humanos , Proteínas de la Membrana/metabolismoRESUMEN
Cancer cells obtain mutations which rely on the production of diffusible growth factors to confer a fitness benefit. These mutations can be considered cooperative, and studied as public goods games within the framework of evolutionary game theory. The population structure, benefit function and update rule all influence the evolutionary success of cooperators. We model the evolution of cooperation in epithelial cells using the Voronoi tessellation model. Unlike traditional evolutionary graph theory, this allows us to implement global updating, for which birth and death events are spatially decoupled. We compare, for a sigmoid benefit function, the conditions for cooperation to be favoured and/or beneficial for well-mixed and structured populations. We find that when population structure is combined with global updating, cooperation is more successful than if there were local updating or the population were well-mixed. Interestingly, the qualitative behaviour for the well-mixed population and the Voronoi tessellation model is remarkably similar, but the latter case requires significantly lower incentives to ensure cooperation.
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Conducta Cooperativa , Teoría del Juego , Evolución Biológica , Recuento de CélulasRESUMEN
The IL-23/T helper type 17 cell axis is a target for psoriasis. The TYK2/Janus kinase 1 inhibitor PF-06700841 will directly suppress TYK2-dependent IL-12 and IL-23 signaling and Janus kinase 1-dependent signaling in cells expressing these signaling molecules, including T cells and keratinocytes. This clinical study sought to define the inflammatory gene and cellular pathways through which PF-06700841 improves the clinical manifestations of psoriasis. Patients (n = 30) with moderate-to-severe psoriasis were randomized to once-daily 30 mg (n = 14) or 100 mg (n = 7) PF-06700841 or placebo (n = 9) for 28 days. Biopsies were taken from nonlesional and lesional skin at baseline and weeks 2 and 4. Changes in the psoriasis transcriptome and genes induced by IL-17 in keratinocytes were evaluated with microarray profiling and reverse transcriptase-PCR. Reductions in IL-17A, IL-17F, and IL-12B mRNA were observed as early as 2 weeks and approximately 70% normalization of lesional gene expression after 4 weeks. Immunohistochemistry showed significant decreases in markers of keratinocyte activation, epidermal thickness, KRT16 and Ki-67 expression, and immune cell infiltrates CD3+/CD8+ (T cells) and CD11c (dendritic cells) after 2 weeks of treatment, corresponding with improvement in histologic score. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibition of proinflammatory cytokines that require TYK2 and Janus kinase 1 for signal transduction.
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Inhibidores de Proteínas Quinasas/administración & dosificación , Psoriasis/tratamiento farmacológico , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Células Th17/efectos de los fármacos , Adulto , Biopsia , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Humanos , Subunidad p40 de la Interleucina-12/metabolismo , Interleucina-17/metabolismo , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Psoriasis/inmunología , Psoriasis/patología , Pirazoles/efectos adversos , Pirimidinas/efectos adversos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Piel/efectos de los fármacos , Piel/inmunología , Piel/patología , TYK2 Quinasa/antagonistas & inhibidores , TYK2 Quinasa/metabolismo , Células Th17/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
Cell division, movement and differentiation contribute to pattern formation in developing tissues. This is the case in the vertebrate neural tube, in which neurons differentiate in a characteristic pattern from a highly dynamic proliferating pseudostratified epithelium. To investigate how progenitor proliferation and differentiation affect cell arrangement and growth of the neural tube, we used experimental measurements to develop a mechanical model of the apical surface of the neuroepithelium that incorporates the effect of interkinetic nuclear movement and spatially varying rates of neuronal differentiation. Simulations predict that tissue growth and the shape of lineage-related clones of cells differ with the rate of differentiation. Growth is isotropic in regions of high differentiation, but dorsoventrally biased in regions of low differentiation. This is consistent with experimental observations. The absence of directional signalling in the simulations indicates that global mechanical constraints are sufficient to explain the observed differences in anisotropy. This provides insight into how the tissue growth rate affects cell dynamics and growth anisotropy and opens up possibilities to study the coupling between mechanics, pattern formation and growth in the neural tube.
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Diferenciación Celular/fisiología , Células-Madre Neurales/metabolismo , Tubo Neural/embriología , Neurogénesis/fisiología , Neuronas/metabolismo , Transducción de Señal/fisiología , Animales , Epitelio/embriología , Ratones , Células-Madre Neurales/citología , Tubo Neural/citología , Neuronas/citologíaRESUMEN
Voltage-gated calcium channels are exquisitely Ca2+ selective, conferred primarily by four conserved pore-loop glutamate residues contributing to the selectivity filter. There has been little previous work directly measuring whether the trafficking of calcium channels requires their ability to bind Ca2+ in the selectivity filter or to conduct Ca2+. Here, we examine trafficking of neuronal CaV2.1 and 2.2 channels with mutations in their selectivity filter and find reduced trafficking to the cell surface in cell lines. Furthermore, in hippocampal neurons, there is reduced trafficking to the somatic plasma membrane, into neurites, and to presynaptic terminals. However, the CaV2.2 selectivity filter mutants are still influenced by auxiliary α2δ subunits and, albeit to a reduced extent, by ß subunits, indicating the channels are not grossly misfolded. Our results indicate that Ca2+ binding in the pore of CaV2 channels may promote their correct trafficking, in combination with auxiliary subunits. Furthermore, physiological studies utilizing selectivity filter mutant CaV channels should be interpreted with caution.
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Sitios de Unión/fisiología , Canales de Calcio Tipo N/metabolismo , Calcio/metabolismo , Neuronas/metabolismo , Transporte de Proteínas/fisiología , Animales , Línea Celular , Membrana Celular/metabolismo , Femenino , Hipocampo/metabolismo , Humanos , Masculino , Ratones , Neuritas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
A ring oscillator is a system in which one species regulates the next, which regulates the next and so on until the last species regulates the first. In addition, the number of the regulations which are negative, and so result in a reduction in the regulated species, is odd, making the overall feedback in the loop negative. In ring oscillators, the probability of oscillations is maximised if the degradation rates of the species are equal. When there is more than one loop in the regulatory network, the dynamics can be more complicated. Here, a systematic way of organising the characteristic equation of ODE models of regulatory networks is provided. This facilitates the identification of Hopf bifurcations. It is shown that the probability of oscillations in non-ring systems is maximised for unequal degradation rates. For example, when there is a ring and a second ring employing a subset of the genes in the first ring, then the probability of oscillations is maximised when the species in the sub-ring degrade more slowly than those outside, for a negative feedback subring. When the sub-ring forms a positive feedback loop, the optimal degradation rates are larger for the species in the sub-ring, provided the positive feedback is not too strong. By contrast, optimal degradation rates are smaller for the species in the sub-ring, when the positive feedback is very strong. Adding a positive feedback loop to a repressilator increases the probability of oscillations, provided the positive feedback is not too strong, whereas adding a negative feedback loop decreases the probability of oscillations. The work is illustrated with numerical simulations of example systems: an autoregulatory gene model in which transcription is downregulated by the protein dimer and three-species and four-species gene regulatory network examples.
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Relojes Biológicos , Simulación por Computador , Redes Reguladoras de Genes , Modelos GenéticosRESUMEN
Cooperation is prevalent in nature, not only in the context of social interactions within the animal kingdom but also on the cellular level. In cancer, for example, tumour cells can cooperate by producing growth factors. The evolution of cooperation has traditionally been studied for well-mixed populations under the framework of evolutionary game theory, and more recently for structured populations using evolutionary graph theory (EGT). The population structures arising due to cellular arrangement in tissues, however, are dynamic and thus cannot be accurately represented by either of these frameworks. In this work, we compare the conditions for cooperative success in an epithelium modelled using EGT, to those in a mechanical model of an epithelium-the Voronoi tessellation (VT) model. Crucially, in this latter model, cells are able to move, and birth and death are not spatially coupled. We calculate fixation probabilities in the VT model through simulation and an approximate analytic technique and show that this leads to stronger promotion of cooperation in comparison with the EGT model.