Signal transduction, regulation, and developmental logic of EGFR signalling in C. elegans

RTKs-mediated signaling systems and the pathways with which they interact (e.g., those initiated by G protein-mediated signaling) involve a highly cooperative network that sense a large number of cellular inputs and then integrate, amplify, and process this information to orchestrate an appropriate set of cellular responses. The responses include virtually all aspects of cell function, from the most fundamental (proliferation, differentiation) to the most specialized (movement, metabolism, chemosensation). The basic tenets of RTK signaling system seem rather well established. Yet, new pathways and even new molecular players continue to be discovered. Although we believe that many of the essential modules of RTK signaling system are rather well understood, we have relatively little knowledge of the extent of interaction among these modules and their overall quantitative importance.

My research has encompassed the study of both positive and negative signaling by RTKs in C. elegans. I identified the C. elegans S0S-1 gene and showed that it is necessary for multiple RAS-mediated developmental signals. In addition, I demonstrated that there is a SOS-1-independent signaling during RAS-mediated vulval differentiation. By assessing signal outputs from various triple mutants, I have concluded that this SOS-1-independent signaling is not mediated by PTP-2/SHP-2 or the removal of inhibition by GAP-1/ RasGAP and it is not under regulation by SLI-1/Cb1. I speculate that there is either another exchange factor for RASor an as yet unidentified signaling pathway operating during RAS-mediated vulval induction in C. elegans.

In an attempt to uncover the molecular mechanisms of negative regulation of EGFR signaling by SLI-1/Cb1, I and two other colleagues codiscovered that RING finger domain of SLI-1 is partially dispensable for activity. This structure-function analysis shows that there is an ubiquitin protein ligase-independent activity for SLI-1 in regulating EGFR signaling. Further, we identified an inhibitory tyrosine of LET-23/ EGFR requiring sli-1(+)for its effects: removal of this tyrosine closely mimics loss of sli-1 but not loss of other negative regulator function.

By comparative analysis of two RTK pathways with similar signaling mechanisms, I have found that clr-1, a previously identified negative regulator of egl-15 mediated FGFR signaling, is also involved in let-23 EGFR signaling. The success of this approach promises a similar reciprocal test and could potentially extend to the study of other signaling pathways with similar signaling logic.

Finally, by correlating the developmental expression of lin-3 EGF to let-23 EGFR signaling activity, I demonstrated the existence of reciprocal EGF signaling in coordinating the morphogenesis of epithelia. This developmental logic of EGF signaling could provide a basis to understand a universal mechanism for organogenesis.

Aristotelian predicables, universality and realism: the logic of comparison in topics as denying the view that Aristotle was a realist

Aristotle is reportedly held to have been a Moderate Realist in that he would maintain that a concept derives from an act of grasping a mind-independent universal object that exists somehow inside of the many different things which the concept is predicated of. As far as a universal is independent of mind, it would stand for the proper object of a concept that subsumes a given number of things as its own instantiations. But we claim that Aristotle rejected such a view and instead did perceive and comprehend universality as a feature of thought rather than as a feature of reality in its own right. As showed in the chapters of Topics regarding the so-called logic of comparison (with the support of Albert the Great’s commentary), each predicate can be more or less consistent with the attribute of the subject of which it may be predicated. Both essential and accidental attributes assume a definite degree of being related to the degree of belonging to substance. Unlike particular things, the universality of a concept is to be understood always in comparison with another concept according to a hierarchy of predicates in terms of universality degree arranged by comparative terms such as ‘more’, ‘less’, and ‘likewise’. What is really mind-independent are the truth conditions which make a universal true when exclusively referring to a set of things identically meant by the same predicate whose universality is given by the place occupied in the hierarchy of predicates.

The logic of ADHD : a brief review of fallacious reasoning

This paper has two central purposes: the first is to survey some of the more important examples of fallacious argument, and the second is to examine the frequent use of these fallacies in support of the psychological construct: Attention Deficit Hyperactivity Disorder (ADHD). The paper divides 12 familiar fallacies into three different categories—material, psychological and logical—and contends that advocates of ADHD often seem to employ these fallacies to support their position. It is suggested that all researchers, whether into ADHD or otherwise, need to pay much closer attention to the construction of their arguments if they are not to make truth claims unsupported by satisfactory evidence, form or logic.

Talking of many things : using topical networks to study discussions in social media

This paper outlines a method for studying online activity using both qualitative and quantitative methods: topical network analysis. A topical network refers to "the collection of sites commenting on a particular event or issue, and the links between them" (Highfield, Kirchhoff, & Nicolai, 2011, p. 341). The approach is a complement for the analysis of large datasets enabling the examination and comparison of different discussions as a means of improving our understanding of the uses of social media and other forms of online communication. Developed for an analysis of political blogging, the method also has wider applications for other social media websites such as Twitter.

The logic of data-sense: Thinking through Learning Personalisation

Big Data and Learning Analytics’ promise to revolutionise educational institutions, endeavours, and actions through more and better data is now compelling. Multiple, and continually updating, data sets produce a new sense of ‘personalised learning’. A crucial attribute of the datafication, and subsequent profiling, of learner behaviour and engagement is the continual modification of the learning environment to induce greater levels of investment on the parts of each learner. The assumption is that more and better data, gathered faster and fed into ever-updating algorithms, provide more complete tools to understand, and therefore improve, learning experiences through adaptive personalisation. The argument in this paper is that Learning Personalisation names a new logistics of investment as the common ‘sense’ of the school, in which disciplinary education is ‘both disappearing and giving way to frightful continual training, to continual monitoring'.

Logic of aid in an intertemporal setting

The paper studies the welfare implications of temporary foreign aid in the context of a simple two-country model of trade. In addition to its usual effects, a transfer of income in one period is assumed to influence the preferences of the recipient country in the following period. The implied changes in the terms of trade over the two periods are consistent with a number of possible outcomes with respect to the intertemporal welfare of the donor, the recipient, and the world as a whole. Particular attention is devoted to the conditions for strict Pareto improvement and the circumstances under which temporary aid transactions are likely to occur.

Group Beliefs : Studies on the Nature and Logic of Collective Doxastic Attitudes

This thesis studies the nature and logic of collective doxastic attitudes, or what is referred to in ordinary language as "group beliefs". Beliefs and other intentional attitudes are attributed to groups and collections of people, and such attributions are used to explain and predict the actions of groups. The thesis develops an understanding of group beliefs as voluntarily adopted views or acceptances rather than as ordinary beliefs. Such an understanding can provide new answers to questions concerning collective knowledge and justification of group beliefs, and it allows developing modal logics with collective doxastic and epistemic notions. The thesis consists of six articles. The first three articles are philosophical studies concerned with the nature of group beliefs. The last three articles are logical studies that aim at developing proof-theoretical calculi for reasoning about collective doxastic attitudes.

Marketing and the Logic of Service: Value Facilitation, Value Creation and Co-creation, and Their Marketing Implications

The discussion of a service-dominant logic has made the findings of decades of service marketing research a topic of interest for marketing at large. Some fundamental aspects of the logic such as value creation and its marketing implications are more complex than they have been treated as so far and need to be further developed to serve marketing theory and practice well. Following the analysis in the present article it is argued that although customers are co-producers in service processes, according to the value-in-use notion adopted in the contemporary marketing and management literature they are fundamentally the creators of value for themselves. Furthermore, it is concluded that although by providing goods and services as input resources into customers’ consumption and value-generating processes firms are fundamentally value facilitators, interactions with customers that exist or can be created enable firms to engage themselves with their customers’ processes and thereby they become co-creators of value with their customers. As marketing implications it is observed that 1) the goal of marketing is to support customers’ value creation, 2) following a service logic and due to the existence of interactions where the firm’s and the customer’s processes merge into an integrated joint value creation process, the firm is not restricted to making value propositions only, but can directly and actively influence the customer’s value fulfilment as well and extend its marketing process to include activities during customer-firm interactions, and 3) although all goods and services are consumed as service, customers’ purchasing decisions can be expected to be dependant of whether they have the skills and interest to use a resource, such as a good, as service or want to buy extended market offerings including process-related elements. Finally, the analysis concludes with five service logic theses.

A coat of many scents: Cuticular hydrocarbons in multitrophic interactions of fig wasps with ants

The fig fig wasp system of Ficus racemosa constitutes an assemblage of galler and parasitoid wasps in which tritrophic interactions occur. Since predatory ants (Oecophylla smaragdina and Technomyrmex albipes) or mostly trophobiont-tending ants (Myrmicaria brunnea) were previously shown to differentially use volatile organic compounds (VOCs) from figs as proximal cues for predation on fig wasps, we examined the response of these ants to the cuticular hydrocarbons (CHCs) of the wasps. CHC signatures of gallers were distinguished from those of parasitoids by the methyl-branched alkanes 5-methylpentacosane and 13-methylnonacosane which characterised trophic group membership. CHC profiles of wasp predator and wasp prey were congruent suggesting that parasitoids acquire CHCs from their prey; the CHC composition of the parasitoid Apocrypta sp 2 clustered with that of its galler host Apocryptophagus fusca, while the CHC profile of the parasitoid Apocryptophagus agraensis clustered with its galler prey, the fig pollinator Ceratosolen fusciceps. In behavioural assays with ants, parasitoid CHC extracts evoked greater response in all ant species compared to galler extracts, suggesting that parasitoid CHC extracts contain more elicitors of ant behaviour than those of plant feeders. CHCs of some wasp species did not elicit significant responses even in predatory ants, suggesting chemical camouflage. Contrary to earlier studies which demonstrated that predatory ants learned to associate wasp prey with specific fig VOCs, prior exposure to fig wasp CHCs did not affect the reaction of any ant species to these CHCs. (C) 2015 Elsevier Masson SAS. All rights reserved.

The logic of receptor-ligand interactions in the Notch signaling pathway

The Notch signaling pathway enables neighboring cells to coordinate developmental fates in diverse processes such as angiogenesis, neuronal differentiation, and immune system development. Although key components and interactions in the Notch pathway are known, it remains unclear how they work together to determine a cell's signaling state, defined as its quantitative ability to send and receive signals using particular Notch receptors and ligands. Recent work suggests that several aspects of the system can lead to complex signaling behaviors: First, receptors and ligands interact in two distinct ways, inhibiting each other in the same cell (in cis) while productively interacting between cells (in trans) to signal. The ability of a cell to send or receive signals depends strongly on both types of interactions. Second, mammals have multiple types of receptors and ligands, which interact with different strengths, and are frequently co-expressed in natural systems. Third, the three mammalian Fringe proteins can modify receptor-ligand interaction strengths in distinct and ligand-specific ways. Consequently, cells can exhibit non-intuitive signaling states even with relatively few components.

In order to understand what signaling states occur in natural processes, and what types of signaling behaviors they enable, this thesis puts forward a quantitative and predictive model of how the Notch signaling state is determined by the expression levels of receptors, ligands, and Fringe proteins. To specify the parameters of the model, we constructed a set of cell lines that allow control of ligand and Fringe expression level, and readout of the resulting Notch activity. We subjected these cell lines to an assay to quantitatively assess the levels of Notch ligands and receptors on the surface of individual cells. We further analyzed the dependence of these interactions on the level and type of Fringe expression. We developed a mathematical modeling framework that uses these data to predict the signaling states of individual cells from component expression levels. These methods allow us to reconstitute and analyze a diverse set of Notch signaling configurations from the bottom up, and provide a comprehensive view of the signaling repertoire of this major signaling pathway.

New parameters of many-body potentials: studying the thermal and mechanical properties of noble metals

New parameters of nearest-neighbor EAM (1N-EAM), n-th neighbor EAM (NN-EAM), and the second-moment approximation to the tight-binding (TB-SMA) potentials are obtained by fitting experimental data at different temperatures. In comparison with the available many-body potentials, our results suggest that the 1N-EAM potential with the new parameters is the best description of atomic interactions in studying the thermal expansion of noble metals. For mechanical properties, it is suggested that the elastic constants should be calculated in the experimental zero-stress states for all three potentials. Furthermore, for NNEAM and TB-SMA potentials, the calculated results approach the experimental data as the range of the atomic interaction increases from the first-neighbor to the sixth-neighbor distance.