While outcomes for children with T-cell acute lymphoblastic leukemia have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor T-ALLs as well as in a subset (...) of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.Leukemia advance online publication, 30 May 2017; doi:10.1038/leu.2017.136. (shrink)

Circadian rhythms are ∼24‐h biological oscillations that enable organisms to anticipate daily environmental cycles, so that they may designate appropriate day/night functions that align with these changes. The molecular clock in animals and fungi consists of a transcription‐translation feedback loop, the plant clock is comprised of multiple interlocking feedback‐loops, and the cyanobacterial clock is driven by a phosphorylation cycle involving three main proteins. Despite the divergent core clock mechanisms across these systems, all circadian clocks are able to buffer period length (...) against changes in the ambient growth environment, such as temperature and nutrients. This defining capability, termed compensation, is critical to proper timekeeping, yet the underlying mechanism(s) remain elusive. Here we examine the known players in, and the current models for, compensation across five circadian systems. While compensation models across these systems are not yet unified, common themes exist across them, including regulation via temperature‐dependent changes in post‐translational modifications. (shrink)

The purpose of this study is to explore with more rigor and detail the role of social norms in tax compliance. This study draws on Cialdini and Trost’s (The Handbook of Social Psychology: Oxford University Press, Boston, MA, 1998) taxonomy of social norms to investigate with more specificity this potentially decisive (Alm and McKee, Managerial and Decision Economics, 19:259–275, 1998) influence on tax compliance. We test our research hypotheses regarding the direct and indirect influences of social norms using a hypothetical (...) compliance scenario with 174 experienced taxpayers as participants. Factor analysis of the social norm questions successfully identified four distinct social norm constructs, in line with Cialdini and Trost (1998). Results of the path analysis show that individuals’ standards for behavior/ethical beliefs (personal norms) as well as the expectations of close others (subjective norms) directly influence tax compliance decisions, whereas general societal expectations (injunctive norms) and other individuals’ actual behavior (descriptive norms) have an indirect influence. This shows that social norms have important direct as well as indirect influences on tax compliance behavior. We also investigate a number of attitudinal variables that may be related to social norms and taxpayer compliance. The results of this study further clarify the important role that social norms have with regard to taxpayers’ compliance behavior. (shrink)

We obtain in this paper a representation of the formulae of extensions ofL by generalized quantifiers through functors between categories of first-order structures and partial isomorphisms. The main tool in the proofs is the back-and-forth technique. As a corollary we obtain the Caicedo's version of Fraïssés theorem characterizing elementary equivalence for such languages. We also discuss informally some geometrical interpretations of our results.

DNA double‐strand breaks (DSBs) are extremely hazardous lesions for all DNA‐bearing organisms and the mechanisms of DSB repair are highly conserved. In the eukaryotic mitotic cell cycle, DSBs are often present following DNA replication while, in meiosis, hundreds of DSBs are generated as a prelude to the reshuffling of the maternally and paternally derived genomes. In both cases, the DSBs are repaired by a process called homologous recombinational repair (HRR), which utilises an intact DNA molecule as the repair template. Mitotic (...) and meiotic HRR are managed by ‘checkpoints’ that inhibit cell division until DSB repair is complete. Here we attempt to summarise the substantial recent progress in understanding the checkpoint management of HRR in mitosis (focussing mainly on mammals) and then go on to use this information as a framework for understanding the presumed checkpoint management of HRR in mammalian meiosis. BioEssays 29:974–986, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Buildings are constructed for accommodating living and industrial needs. Floor cleaning robots have been developed to cater to the demand of these buildings. Area coverage and coverage time are crucial performance factors of a floor cleaning robot. Reconfigurable tiling robots have been introduced over fixed shape robots to improve area coverage in floor cleaning applications compared to robots with fixed morphologies. However, area coverage and coverage time of a tiling robot compromised one another. This study proposes a novel concept that (...) considers the ability of a tiling robot to configure both its morphology and size according to the environment. This concept is inspired by the pleomorphism that could be seen in bacteria. In this regard, P-hTetro, a pleomorphic tiling robot that can reconfigure its morphology and size, is considered. A novel coverage strategy for realizing the size reconfiguration is also proposed. According to this strategy, the robot covers obstacle-free areas with its maximum size, while an obstacle cluster is covered after shrinking to an optimum size. The optimum size for reconfiguration is determined by the genetic algorithm based on the arrangement of the environment. The performance and behavior of the proposed P-hTetro have been compared against that of an existing tiling robot which has a fixed size. According to the statistical outcomes, a tiling robot with the ability to reconfigure its size can significantly improve the performance in the aspects of area coverage and coverage time compared to a tiling robot with no ability to reconfigure its size. (shrink)

Background: Discussing treatment risks has become increasingly important in medical communication. Still, despite regulations, physicians must decide how much and what kind of information to present. Objective: To investigate patients’ preference for information about a small risk of a complication of colonoscopy, and whether medical and personal factors contribute to such preference. To propose a disclosure policy related to our results. Design: Vignettes study. Setting: Department of Gastroenterology, Academic Medical Centre, the Netherlands. Patients: 810 consecutive colonoscopy patients. Intervention: A home-sent (...) questionnaire containing three vignettes. Vignettes varied in the indication for colonoscopy, complication severity and level of risk. Patients were invited to indicate their wish to be informed and the importance of such information. In addition, sociodemograhic, illness-related and psychological characteristics were assessed. Main outcome measurements: Wish to be informed and importance of information. Results: Of 810 questionnaires, 68% were returned. Patients generally wished to be informed about low-risk complications, regardless of the indication for colonoscopy or the severity of the complication. The level of risk did matter, though (OR = 2.48, SE = 0.28, p = 0.001). The information was considered less important if done for population screening purposes or diagnosis of colon cancer, if the complication was less severe (bleeding) and if the risk was smaller (0.01% and 0.1%). Patients’ information preference was also related to age, mood and coping style. Limitations: Difficulty of vignettes. Conclusions: Patients generally wish to be informed about all possible risks. However, this might become uninformative. A stepwise approach is suggested. (shrink)

If self-interested behavior conflicts with the collective welfare, rules of cooperation are often installed to prevent egoistic behavior. We hypothesized that installing such rules may instigate personal moral norms of cooperation, but that they fail in doing so when installed by a leader who is self-interested rather than self-sacrificing. Three studies confirmed this and also showed that, consequently, only self-sacrificing leaders were able to install rules that increase cooperation without the need for a perfectly operating monitoring system.

Many contemporary logicians acknowledge a plurality of logical theories and accept that theory choice is in part motivated by logical evidence. However, just as there is no agreement on logical theories, there is also no consensus on what constitutes logical evidence. In this paper, I outline Jean Piaget’s psychological theory of reasoning and show how he used it to diagnose and solve one of the paradoxes of material implication. I assess Piaget’s use of psychology as a source of evidence for (...) logical theory in light of reservations raised by psychologism, and I highlight some ramifications for exceptionalism and anti-exceptionalism about logic by considering his use of psychology as logical evidence in the framework of genetic epistemology, Piaget’s research programme. I conclude that Piaget’s psychological theory of reasoning not only plausibly serves as a source of evidence for logical theory but also makes a strong case for anti-exceptionalism about logic. (shrink)

Jan Narveson has articulated a deeply held, widely shared intuition regarding what moral law has to say about bringing additional people into existence: while we are “in favour of making people happy,” we are “neutral about making happy people.” Various formulations of the Narvesonian intuition (closely related to the person-affecting intuition or restriction) have been widely criticized. This present paper outlines an off-the-beaten-path alternate construction of the intuition—the existence condition—and argues that that particular construction has the resources to avoid some (...) of those criticisms. But still other considerably more widely recognized alternate constructions have been offered as well. Thus John Broome outlines what he calls the neutrality intuition. While Broome finds the underlying intuition “strongly attractive,” he nonetheless argues that the neutrality intuition itself leads us quickly into inconsistency. Wlodek Rabinowicz disagrees. On his view, Broome’s inconsistency argument shows, not that the neutrality intuition is false, but rather that it doesn’t follow, from the fact that the outcome, or possible future or world, that includes the additional person is neither better nor worse than the (otherwise similar) world that excludes that person, that the one world is exactly as good as the other. The better view, according to Rabinowicz, is that, on occasion, and specifically when the coming into existence of additional people is at stake, the one world is incommensurate with the other. What is called the principle of trichotomy is, in other words, false. Difficulties arise, however, when we try to reject that seemingly compelling conceptual principle. This present paper concludes with the argument that the availability of the existence condition—which, together with certain other uncontroversial moral principles and a handful of conceptual principles, forms the existential approach—shows that we can maintain the most intuitive parts of neutrality intuition while avoiding both Broome’s inconsistency worry and Rabinowicz’s commitment to incommensurability. Incommensurability may be correct on other grounds—but not, this present paper argues, on the grounds provided by Broome’s inconsistency argument. (shrink)