A Bayesian model predicts the response of axons to molecular gradients

Axon guidance by molecular gradients plays a crucial role in wiring up the nervous system. However, the mechanisms axons use to detect gradients are largely unknown. We first develop a Bayesian “ideal observer” analysis of gradient detection by axons, based on the hypothesis that a principal constraint on gradient detection is intrinsic receptor binding noise. Second, from this model, we derive an equation predicting how the degree of response of an axon to a gradient should vary with gradient steepness and absolute concentration. Third, we confirm this prediction quantitatively by performing the first systematic experimental analysis of how axonal response varies with both these quantities. These experiments demonstrate a degree of sensitivity much higher than previously reported for any chemotacting system. Together, these results reveal both the quantitative constraints that must be satisfied for effective axonal guidance and the computational principles that may be used by the underlying signal transduction pathways, and allow predictions for the degree of response of axons to gradients in a wide variety of in vivo and in vitro settings.

Margin-adaptive model selection in statistical learning

A classical condition for fast learning rates is the margin condition, first introduced by Mammen and Tsybakov. We tackle in this paper the problem of adaptivity to this condition in the context of model selection, in a general learning framework. Actually, we consider a weaker version of this condition that allows one to take into account that learning within a small model can be much easier than within a large one. Requiring this “strong margin adaptivity” makes the model selection problem more challenging. We first prove, in a general framework, that some penalization procedures (including local Rademacher complexities) exhibit this adaptivity when the models are nested. Contrary to previous results, this holds with penalties that only depend on the data. Our second main result is that strong margin adaptivity is not always possible when the models are not nested: for every model selection procedure (even a randomized one), there is a problem for which it does not demonstrate strong margin adaptivity.

The Bayesian conditional independence model for measurement error: applications in ecology

The measurement error model is a well established statistical method for regression problems in medical sciences, although rarely used in ecological studies. While the situations in which it is appropriate may be less common in ecology, there are instances in which there may be benefits in its use for prediction and estimation of parameters of interest. We have chosen to explore this topic using a conditional independence model in a Bayesian framework using a Gibbs sampler, as this gives a great deal of flexibility, allowing us to analyse a number of different models without losing generality. Using simulations and two examples, we show how the conditional independence model can be used in ecology, and when it is appropriate.

Towards a CRM and SCM Benefits Measurement Model

Organizations invest heavily in Customer Relationship Management (CRM) and Supply Chain Management (SCM) systems, and their related infrastructure, presumably expecting positive benefits to the organization. Assessing the benefits of such systems is an important aspect of managing such systems. Given the substantial differences between CRM and SCM systems with traditional intra-organizational applications, existing Information Systems benefits measurement models and frameworks are ill-suited to gauge CRM and SCM benefits. This paper reports the preliminary findings of a research that seeks to develop a measurement model to assess benefits of CRM and SCM applications. The a-priori benefits measurement model is developed reviewing the 55 academic studies and 40 practitioner papers. The review of related literature yielded 606 benefits, which were later synthesized into 74 mutually exclusive benefit measures of CRM and SCM applications arranged under five dimensions.

Theorising a model for teaching and assessing reflective learning in higher education

The importance of reflection in higher education, and across disciplinary fields is widely recognised; it is generally included in university graduate attributes, professional standards and program objectives. Furthermore, reflection is commonly embedded into assessment requirements in higher education subjects, often without necessary scaffolding or clear expectations for students. Despite the rhetoric around the importance of reflection for ongoing learning, there is scant literature on any systematic, developmental approach to teaching reflective learning across higher education programs/courses. Given that professional or academic reflection is not intuitive, and requires specific pedagogic intervention to do well, a program/course-wide approach is essential. This paper draws on current literature to theorise a new, transferable and customisable model for teaching and assessing reflective learning across higher education, which foregrounds and explains the pedagogic field of higher education as a multi-dimensional space. We argue that explicit and strategic pedagogic intervention, supported by dynamic resources, is necessary for successful, broad-scale approaches to reflection in higher education.

Melanoma mouse model implicates metabotropic glutamate signaling in melanocytic neoplasia

To gain insight into melanoma pathogenesis, we characterized an insertional mouse mutant, TG3, that is predisposed to develop multiple melanomas. Physical mapping identified multiple tandem insertions of the transgene into intron 3 of Grm1 (encoding metabotropic glutamate receptor 1) with concomitant deletion of 70 kb of intronic sequence. To assess whether this insertional mutagenesis event results in alteration of transcriptional regulation, we analyzed Grm1 and two flanking genes for aberrant expression in melanomas from TG3 mice. We observed aberrant expression of only Grm1. Although we did not detect its expression in normal mouse melanocytes, Grm1 was ectopically expressed in the melanomas from TG3 mice. To confirm the involvement of Grm1 in melanocytic neoplasia, we created an additional transgenic line with Grm1 expression driven by the dopachrome tautomerase promoter. Similar to the original TG3, the Tg(Grm1)EPv line was susceptible to melanoma. In contrast to human melanoma, these transgenic mice had a generalized hyperproliferation of melanocytes with limited transformation to fully malignant metastasis. We detected expression of GRM1 in a number of human melanoma biopsies and cell lines but not in benign nevi and melanocytes. This study provides compelling evidence for the importance of metabotropic glutamate signaling in melanocytic neoplasia.

Exploring the parameter space of a rabbit ventricular action potential model to investigate the effect of variation on action potential and calcium transients

Computational models for cardiomyocyte action potentials (AP) often make use of a large parameter set. This parameter set can contain some elements that are fitted to experimental data independently of any other element, some elements that are derived concurrently with other elements to match experimental data, and some elements that are derived purely from phenomenological fitting to produce the desired AP output. Furthermore, models can make use of several different data sets, not always derived for the same conditions or even the same species. It is consequently uncertain whether the parameter set for a given model is physiologically accurate. Furthermore, it is only recently that the possibility of degeneracy in parameter values in producing a given simulation output has started to be addressed. In this study, we examine the effects of varying two parameters (the L-type calcium current (I(CaL)) and the delayed rectifier potassium current (I(Ks))) in a computational model of a rabbit ventricular cardiomyocyte AP on both the membrane potential (V(m)) and calcium (Ca(2+)) transient. It will subsequently be determined if there is degeneracy in this model to these parameter values, which will have important implications on the stability of these models to cell-to-cell parameter variation, and also whether the current methodology for generating parameter values is flawed. The accuracy of AP duration (APD) as an indicator of AP shape will also be assessed.