D-optimal designs for multiarm trials with dropouts.

Multiarm trials with follow-up on participants are commonly implemented to assess treatment effects on a population over the course of the studies. Dropout is an unavoidable issue especially when the duration of the multiarm study is long. Its impact is often ignored at the design stage, which may lead to less accurate statistical conclusions. We develop an optimal design framework for trials with repeated measurements, which takes potential dropouts into account, and we provide designs for linear mixed models where the presence of dropouts is noninformative and dependent on design variables. Our framework is illustrated through redesigning a clinical trial on Alzheimer's disease, whereby the benefits of our designs compared with standard designs are demonstrated through simulations.Grant codes MR∕N028171∕ and MC_UP_1302∕

Apology and forgiveness evolve to resolve failures in cooperative agreements

Making agreements on how to behave has been shown to be an evolutionarily viable strategy in one-shot social dilemmas. However, in many situations agreements aim to establish long-term mutually beneficial interactions. Our analytical and numerical results reveal for the first time under which conditions revenge, apology and forgiveness can evolve and deal with mistakes within ongoing agreements in the context of the Iterated Prisoners Dilemma. We show that, when the agreement fails, participants prefer to take revenge by defecting in the subsisting encounters. Incorporating costly apology and forgiveness reveals that, even when mistakes are frequent, there exists a sincerity threshold for which mistakes will not lead to the destruction of the agreement, inducing even higher levels of cooperation. In short, even when to err is human, revenge, apology and forgiveness are evolutionarily viable strategies which play an important role in inducing cooperation in repeated dilemmas.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Generosity Pays in the Presence of Direct Reciprocity: A Comprehensive Study of 2×2 Repeated Games

By applying a technique previously developed to study ecosystem assembly [Capitán et al., Phys. Rev. Lett. 103, 168101 (2009)] we study the evolutionary stable strategies of iterated 22 games. We focus on memory-one strategies, whose probability to play a given action depends on the actions of both players in the previous time step. We find the asymptotically stable populations resulting from all possible invasions of any known stable population. The results of this invasion process are interpreted as transitions between different populations that occur with a certain probability. Thus the whole process can be described as a Markov chain whose states are the different stable populations. With this approach we are able to study the whole space of symmetric 22 games, characterizing the most probable results of evolution for the different classes of games. Our analysis includes quasi-stationary mixed equilibria that are relevant as very long-lived metastable states and is compared to the predictions of a fixation probability analysis. We confirm earlier results on the success of the Pavlov strategy in a wide range of parameters for the iterated Prisoner's Dilemma, but find that as the temptation to defect grows there are many other possible successful strategies. Other regions of the diagram reflect the equilibria structure of the underlying one-shot game, albeit often some non-expected strategies arise as well. We thus provide a thorough analysis of iterated 22 games from which we are able to extract some general conclusions. Our most relevant finding is that a great deal of the payoff parameter range can still be understood by focusing on win-stay, lose-shift strategies, and that very ambitious ones, aspiring to obtaining always a high payoff, are never evolutionary stable

The emergence of waves in random discrete systems

Essential criteria for the emergence of wave-like manifestations occurring in an entirely discrete system are identified using a simple model for the movement of particles through a network. The dynamics are entirely stochastic and memoryless involving a birth-death-migration process. The requirements are that the network should have at least three nodes, that migration should have a directional bias, and that the particle dynamics have a non-local dependence. Well defined bifurcations mark transitions between amorphous, wave-like and collapsed states with an intermittent regime between the latter two

Synergy between intention recognition and commitments in cooperation dilemmas

Commitments have been shown to promote cooperation if, on the one hand, they can be sufficiently enforced, and on the other hand, the cost of arranging them is justified with respect to the benefits of cooperation. When either of these constraints is not met it leads to the prevalence of commitment free-riders, such as those who commit only when someone else pays to arrange the commitments. Here, we show how intention recognition may circumvent such weakness of costly commitments. We describe an evolutionary model, in the context of the one-shot Prisoner's Dilemma, showing that if players first predict the intentions of their co-player and propose a commitment only when they are not confident enough about their prediction, the chances of reaching mutual cooperation are largely enhanced. We find that an advantageous synergy between intention recognition and costly commitments depends strongly on the confidence and accuracy of intention recognition. In general, we observe an intermediate level of confidence threshold leading to the highest evolutionary advantage, showing that neither unconditional use of commitment nor intention recognition can perform optimally. Rather, our results show that arranging commitments is not always desirable, but that they may be also unavoidable depending on the strength of the dilemma.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Generosity motivated by acceptance - evolutionary analysis of an anticipation game

We here present both experimental and theoretical results for an Anticipation Game, a two-stage game wherein the standard Dictator Game is played after a matching phase wherein receivers use the past actions of dictators to decide whether to interact with them. The experimental results for three different treatments show that partner choice induces dictators to adjust their donations towards the expectations of the receivers, giving significantly more than expected in the standard Dictator Game. Adding noise to the dictators' reputation lowers the donations, underlining that their actions are determined by the knowledge provided to receivers. Secondly, we show that the recently proposed stochastic evolutionary model where payoff only weakly drives evolution and individuals can make mistakes requires some adaptations to explain the experimental results. We observe that the model fails in reproducing the heterogeneous strategy distributions. We show here that by explicitly modelling the dictators' probability of acceptance by receivers and introducing a parameter that reflects the dictators' capacity to anticipate future gains produces a closer fit to the aforementioned strategy distributions. This new parameter has the important advantage that it explains where the dictators' generosity comes from, revealing that anticipating future acceptance is the key to success.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

When agreement-accepting free-riders are a necessary evil for the evolution of cooperation

Agreements and commitments have provided a novel mechanism to promote cooperation in social dilemmas in both one-shot and repeated games. Individuals requesting others to commit to cooperate (proposers) incur a cost, while their co-players are not necessarily required to pay any, allowing them to free-ride on the proposal investment cost (acceptors). Although there is a clear complementarity in these behaviours, no dynamic evidence is currently available that proves that they coexist in different forms of commitment creation. Using a stochastic evolutionary model allowing for mixed population states, we identify non-trivial roles of acceptors as well as the importance of intention recognition in commitments. In the one-shot prisoner's dilemma, alliances between proposers and acceptors are necessary to isolate defectors when proposers do not know the acceptance intentions of the others. However, when the intentions are clear beforehand, the proposers can emerge by themselves. In repeated games with noise, the incapacity of proposers and acceptors to set up alliances makes the emergence of the first harder whenever the latter are present. As a result, acceptors will exploit proposers and take over the population when an apology-forgiveness mechanism with too low apology cost is introduced, and hence reduce the overall cooperation level.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

C-Kit Binding Properties of Hesperidin (a Major Component of KMP6) as a Potential Anti-Allergic Agent

Accumulation of mast cells can be causally related to several allergic inflammations. Stem cell factor (SCF) as a mast cell chemotaxin induces mast cell migration. To clarify a new effect of Pyeongwee-San extract (KMP6, a drug for indigestion) for the treatment of allergy, we investigated the effects of KMP6 on SCF-induced migration of rat peritoneal mast cells (RPMCs). A molecular docking simulation showed that hesperidin, a major component of KMP6, controls the SCF and c-kit binding by interaction with the active site of the c-kit. KMP6 and hesperidin significantly inhibited SCF-induced migration of RPMCs (P<0.05). The ability of the SCF to enhance morphological alteration and F-actin formation was also abolished by treatment with KMP6 or hesperidin. KMP6 and hesperidin inhibited SCF-induced p38 MAPK activation. In addition, SCF-induced inflammatory cytokine production was significantly inhibited by treatment with KMP6 or hesperidin (P<0.05). Our results show for the first time that KMP6 potently regulates SCF-induced migration, p38 MAPK activation and inflammatory cytokines production through hindrance of SCF and c-kit binding in RPMCs. Such modulation may have functional consequences during KMP6 treatment, especially mast cell-mediated allergic inflammation disorders

Incipient Cognition Solves the Spatial Reciprocity Conundrum of Cooperation

Background: From the simplest living organisms to human societies, cooperation among individuals emerges as a paradox difficult to explain and describe mathematically, although very often observed in reality. Evolutionary game theory offers an excellent toolbar to investigate this issue. Spatial structure has been one of the first mechanisms promoting cooperation; however, alone it only opens a narrow window of viability. Methodology/Principal Findings: Here we equip individuals with incipient cognitive abilities, and investigate the evolution of cooperation in a spatial world where retaliation, forgiveness, treason and mutualism may coexist, as individuals engage in Prisoner’s Dilemma games. In the model, individuals are able to distinguish their partners and act towards them based on previous interactions. We show how the simplest level of cognition, alone, can lead to the emergence of cooperation. Conclusions/Significance: Despite the incipient nature of the individuals ’ cognitive abilities, cooperation emerges for unprecedented values of the temptation to cheat, being also robust to invasion by cheaters, errors in decision making an

Sp1 Is Essential for p16(INK4a) Expression in Human Diploid Fibroblasts during Senescence

BACKGROUND: p16 (INK4a) tumor suppressor protein has been widely proposed to mediate entrance of the cells into the senescent stage. Promoter of p16 (INK4a) gene contains at least five putative GC boxes, named GC-I to V, respectively. Our previous data showed that a potential Sp1 binding site, within the promoter region from −466 to −451, acts as a positive transcription regulatory element. These results led us to examine how Sp1 and/or Sp3 act on these GC boxes during aging in cultured human diploid fibroblasts. METHODOLOGY/PRINCIPAL FINDINGS: Mutagenesis studies revealed that GC-I, II and IV, especially GC-II, are essential for p16 (INK4a) gene expression in senescent cells. Electrophoretic mobility shift assays (EMSA) and ChIP assays demonstrated that both Sp1 and Sp3 bind to these elements and the binding activity is enhanced in senescent cells. Ectopic overexpression of Sp1, but not Sp3, induced the transcription of p16 (INK4a). Both Sp1 RNAi and Mithramycin, a DNA intercalating agent that interferes with Sp1 and Sp3 binding activities, reduced p16 (INK4a) gene expression. In addition, the enhanced binding of Sp1 to p16 (INK4a) promoter during cellular senescence appeared to be the result of increased Sp1 binding affinity, not an alteration in Sp1 protein level. CONCLUSIONS/SIGNIFICANCE: All these results suggest that GC- II is the key site for Sp1 binding and increase of Sp1 binding activity rather than protein levels contributes to the induction of p16 (INK4a) expression during cell aging