Secreted signals, known as morphogens, provide the positional information that organizes gene expression and cellular differentiation in many developing tissues. In the vertebrate neural tube, Sonic ...Hedgehog (Shh) acts as a morphogen to control the pattern of neuronal subtype specification. Using an in vivo reporter of Shh signaling, mouse genetics, and systems modeling, we show that a spatially and temporally changing gradient of Shh signaling is interpreted by the regulatory logic of a downstream transcriptional network. The design of the network, which links three transcription factors to Shh signaling, is responsible for differential spatial and temporal gene expression. In addition, the network renders cells insensitive to fluctuations in signaling and confers hysteresis—memory of the signal. Our findings reveal that morphogen interpretation is an emergent property of the architecture of a transcriptional network that provides robustness and reliability to tissue patterning.
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► Shh morphogen produces a dynamic gradient of Gli activity in the neural tube ► The dynamics of Gli activity are interpreted by a downstream transcriptional network ► The regulatory logic of the network explains both spatial and temporal gene responses ► The network confers hysteresis and robustness to fluctuations in signaling
The vertebrate neural tube is patterned by a Sonic Hedgehog signaling network consisting of three transcription factors. The design of this network confers memory to the signal and robustness to fluctuations in signal intensity, revealing that morphogen interpretation is an emergent property of network architecture.
Could power distance, which is the extent that inequality is expected and accepted, explain why some countries and consumers are more likely to engage in prosocial behavior, including donations of ...both money and time? This research proposes that higher power distance results in weaker perceptions of responsibility to aid others, which decreases charitable behavior. Both correlational and causal evidence is provided in a series of five studies that examine country-level power distance as well as individual and temporarily salient power distance belief. Consistent with the mediating role of perceived responsibility, results reveal that uncontrollable needs and communal relationship norms are boundary conditions that overcome the negative effect of power distance on charitable behavior. These results explain differences in charitable giving across cultures and provide implications for nonprofit organizations soliciting donations.
During tissue development, patterns of gene expression determine the spatial arrangement of cell types. In many cases, gradients of secreted signalling molecules-morphogens-guide this process by ...controlling downstream transcriptional networks. A mechanism commonly used in these networks to convert the continuous information provided by the gradient into discrete transitions between adjacent cell types is the genetic toggle switch, composed of cross-repressing transcriptional determinants. Previous analyses have emphasised the steady state output of these mechanisms. Here, we explore the dynamics of the toggle switch and use exact numerical simulations of the kinetic reactions, the corresponding Chemical Langevin Equation, and Minimum Action Path theory to establish a framework for studying the effect of gene expression noise on patterning time and boundary position. This provides insight into the time scale, gene expression trajectories and directionality of stochastic switching events between cell states. Taking gene expression noise into account predicts that the final boundary position of a morphogen-induced toggle switch, although robust to changes in the details of the noise, is distinct from that of the deterministic system. Moreover, the dramatic increase in patterning time close to the boundary predicted from the deterministic case is substantially reduced. The resulting stochastic switching introduces differences in patterning time along the morphogen gradient that result in a patterning wave propagating away from the morphogen source with a velocity determined by the intrinsic noise. The wave sharpens and slows as it advances and may never reach steady state in a biologically relevant time. This could explain experimentally observed dynamics of pattern formation. Together the analysis reveals the importance of dynamical transients for understanding morphogen-driven transcriptional networks and indicates that gene expression noise can qualitatively alter developmental patterning.
The use of celebrity endorsements varies across countries; does their effectiveness similarly vary across cultures? The authors propose that power distance beliefs (PDB), a cultural orientation ...related to the extent to which people expect and accept differences in power, moderate the effects of celebrity endorsements. A positive effect of celebrity endorsers on evaluations of advertising should be more potent with greater PDB; source expertise and trustworthiness likely underlie this effect. To test the hypotheses, the authors use moderated mediation analyses, with corrections for measurement error and endogeneity of the mediators (source expertise and trustworthiness). The results of three studies, using both manipulated and measured PDB for respondents in different countries and with a variety of endorsers, demonstrate that PDB determine the effectiveness of celebrity endorsements on attitudes toward the advertisement and the brand. In support of the moderated mediation model, perceptions of source expertise and trust mediate the effect of celebrity endorsements, conditional on PDB. The results hold for nondurables but do not generalize to durable products.
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.
Consumer‐brand relationships can be formed based on individual‐ or group‐level connections. For example, a consumer’s relationship with a Mercedes may be based on the desire to express ...individual‐level unique identity (e.g., self‐concept connection), whereas a relationship with a local brand (e.g., Ford) may be based on a group‐level patriotic national identity (e.g., country‐of‐origin connection). We suggest that the effects of self‐concept connection and brand country‐of‐origin connection vary based on self‐construal. Results across two studies reveal that, under independent self‐construal, self‐concept connection is more important. Under interdependent self‐construal, brand country‐of‐origin connection is more important.
•I present a way of breaking down regulatory networks to find Hopf bifurcations. This helps find optimal conditions for oscillations in dynamical systems models of these networks.•In a model of ...negative auto-regulation of a gene by its dimeric protein, it is optimal for the monomer to degrade faster than the mRNA and the mRNA to degrade faster than the dimer.•Adding a weak positive feedback loop to a repressilator increases the probability of oscillations.•The optimal degradation rate of species in the sub-loop is higher than that of species outside it.•The opposite is true for a negative feedback sub-loop or a very strong positive feedback sub-loop.
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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.
Collective cell migration is a fundamental process, occurring during embryogenesis and cancer metastasis. Neural crest cells exhibit such coordinated migration, where aberrant motion can lead to ...fatality or dysfunction of the embryo. Migration involves at least two complementary mechanisms: contact inhibition of locomotion (a repulsive interaction corresponding to a directional change of migration upon contact with a reciprocating cell), and co-attraction (a mutual chemoattraction mechanism). Here, we develop and employ a parameterized discrete element model of neural crest cells, to investigate how these mechanisms contribute to long-range directional migration during development. Motion is characterized using a coherence parameter and the time taken to reach, collectively, a target location. The simulated cell group is shown to switch from a diffusive to a persistent state as the response-rate to co-attraction is increased. Furthermore, the model predicts that when co-attraction is inhibited, neural crest cells can migrate into restrictive regions. Indeed, inhibition of co-attraction in vivo and in vitro leads to cell invasion into restrictive areas, confirming the prediction of the model. This suggests that the interplay between the complementary mechanisms may contribute to guidance of the neural crest. We conclude that directional migration is a system property and does not require action of external chemoattractants.
Each year, people in the United States donate more than $200 billion to charitable causes. Despite the lack of understanding of whether and how recognition increases charitable behavior, charities ...often offer it to motivate donor action. This research focuses on how the effectiveness of recognition on charitable behavior is dependent on the joint influence of two distinct dimensions of moral identity: internalization and symbolization. Three studies examining both monetary donations and volunteering behavior show that recognition increases charitable behavior among those characterized by high moral identity symbolization and low moral identity internalization. Notably, those who show high levels of moral identity internalization are uninfluenced by recognition, regardless of their symbolization. By understanding correlates of the two dimensions of moral identity among donors, nonprofits can strategically recognize potential donors to maximize donation and volunteering behavior.
Collective cell migration is a mode of movement crucial for morphogenesis and cancer metastasis. However, little is known about how migratory cells coordinate collectively. Here we show that mutual ...cell-cell attraction (named here coattraction) is required to maintain cohesive clusters of migrating mesenchymal cells. Coattraction can counterbalance the natural tendency of cells to disperse via mechanisms such as contact inhibition and epithelial-to-mesenchymal transition. Neural crest cells are coattracted via the complement fragment C3a and its receptor C3aR, revealing an unexpected role of complement proteins in early vertebrate development. Loss of coattraction disrupts collective and coordinated movements of these cells. We propose that coattraction and contact inhibition act in concert to allow cell collectives to self-organize and respond efficiently to external signals, such as chemoattractants and repellents.
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► Neural crest (NC) cells mutually attract each other (coattraction) ► NC coattraction is mediated by the complement fragment C3a and its receptor C3aR ► Coattraction is required for the swarm-like behavior of migratory NC cells ► Coattraction and contact inhibition suffice to generate collective migration
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