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.

p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation

p53 is the central member of a critical tumor suppressor pathway in virtually all tumor types, where it is silenced mainly by missense mutations. In melanoma, p53 predominantly remains wild type, thus its role has been neglected. To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the 'high-p53'Mdm4+/- mouse to the well-established TP-ras0/+ murine melanoma progression model. After treatment with the carcinogen dimethylbenzanthracene (DMBA), TP-ras0/+ mice on the Mdm4+/- background developed fewer tumors with a delay in the age of onset of melanomas compared to TP-ras0/+ mice. Furthermore, we observed a dramatic decrease in tumor growth, lack of metastasis with increased survival of TP-ras0/+: Mdm4+/- mice. Thus, p53 effectively prevented the conversion of small benign tumors to malignant and metastatic melanoma. p53 activation in cultured primary melanocyte and melanoma cell lines using Nutlin-3, a specific Mdm2 antagonist, supported these findings. Moreover, global gene expression and network analysis of Nutlin-3-treated primary human melanocytes indicated that cell cycle regulation through the p21WAF1/CIP1 signaling network may be the key anti-melanomagenic activity of p53.

The influence of sensitivity to reward and punishment, propensity for sensation seeking, depression, and anxiety on the risky behaviour of novice drivers : a path model

Young novice drivers are significantly more likely to be killed or injured in car crashes than older, experienced drivers. Graduated driver licensing (GDL), which allows the novice to gain driving experience under less-risky circumstances, has resulted in reduced crash incidence; however, the driver's psychological traits are ignored. This paper explores the relationships between gender, age, anxiety, depression, sensitivity to reward and punishment, sensation-seeking propensity, and risky driving. Participants were 761 young drivers aged 17–24 (M= 19.00, SD= 1.56) with a Provisional (intermediate) driver's licence who completed an online survey comprising socio-demographic questions, the Impulsive Sensation Seeking Scale, Kessler's Psychological Distress Scale, the Sensitivity to Punishment and Sensitivity to Reward Questionnaire, and the Behaviour of Young Novice Drivers Scale. Path analysis revealed depression, reward sensitivity, and sensation-seeking propensity predicted the self-reported risky behaviour of the young novice drivers. Gender was a moderator; and the anxiety level of female drivers also influenced their risky driving. Interventions do not directly consider the role of rewards and sensation seeking, or the young person's mental health. An approach that does take these variables into account may contribute to improved road safety outcomes for both young and older road users.

Phenomenological modeling of cell-to-cell and beat-to-beat variability in isolated Guinea Pig ventricular myocytes

Experimental action potential (AP) recordings in isolated ventricular myoctes display significant temporal beat-to-beat variability in morphology and duration. Furthermore, significant cell-to-cell differences in AP also exist even for isolated cells originating from the same region of the same heart. However, current mathematical models of ventricular AP fail to replicate the temporal and cell-to-cell variability in AP observed experimentally. In this study, we propose a novel mathematical framework for the development of phenomenological AP models capable of capturing cell-to-cell and temporal variabilty in cardiac APs. A novel stochastic phenomenological model of the AP is developed, based on the deterministic Bueno-Orovio/Fentonmodel. Experimental recordings of AP are fit to the model to produce AP models of individual cells from the apex and the base of the guinea-pig ventricles. Our results show that the phenomenological model is able to capture the considerable differences in AP recorded from isolated cells originating from the location. We demonstrate the closeness of fit to the available experimental data which may be achieved using a phenomenological model, and also demonstrate the ability of the stochastic form of the model to capture the observed beat-to-beat variablity in action potential duration.

Bispectral and trispectral characterization of transition to chaos in the Duffing oscillator

Higher-order spectral (bispectral and trispectral) analyses of numerical solutions of the Duffing equation with a cubic stiffness are used to isolate the coupling between the triads and quartets, respectively, of nonlinearly interacting Fourier components of the system. The Duffing oscillator follows a period-doubling intermittency catastrophic route to chaos. For period-doubled limit cycles, higher-order spectra indicate that both quadratic and cubic nonlinear interactions are important to the dynamics. However, when the Duffing oscillator becomes chaotic, global behavior of the cubic nonlinearity becomes dominant and quadratic nonlinear interactions are weak, while cubic interactions remain strong. As the nonlinearity of the system is increased, the number of excited Fourier components increases, eventually leading to broad-band power spectra for chaos. The corresponding higher-order spectra indicate that although some individual nonlinear interactions weaken as nonlinearity increases, the number of nonlinearly interacting Fourier modes increases. Trispectra indicate that the cubic interactions gradually evolve from encompassing a few quartets of Fourier components for period-1 motion to encompassing many quartets for chaos. For chaos, all the components within the energetic part of the power spectrum are cubically (but not quadratically) coupled to each other.

Stop whining and make the best of it: a cross-national comparison of response to regional disadvantage in the wine industry

Our cross-national field study of wine entrepreneurship in the “wrong” places provides some redress to the focus of the “regional advantage” literature on places that have already won and on the firms that benefit from “clusters” and other centers of industry advantage. Regional “disadvantage” is at best a shadowy afterthought to this literature. By poking around in these shadows, we help to synthesize and extend the incipient yet burgeoning literature on entrepreneurial “resourcefulness” and we contribute to the developing body of insights and theory pertinent to the numerous but often ignored firms and startups that mostly need to worry about how they will compete at all now if they are ever to have of chance of “winning” in the future. The core of our findings suggests that understandable – though contested – processes of ingenuity underlie entrepreneurial responses to regional disadvantage. Because we study entrepreneurship that from many angles simply does not make sense, we are also able to proffer a novel perspective on entrepreneurial sensemaking.

Teachers' conceptions of how to engage students through inquiry learning : foundations for STEM

The advocacy for inquiry-based learning in contemporary curricula assumes the principle that students learn in their own way by drawing on direct experience fostered by the teacher. That students should be able to discover answers themselves through active engagement with new experiences was central to the thinking of eminent educators such as Pestalozzi, Dewey and Montessori. However, even after many years of research and practice, inquiry learning as a referent for teaching still struggles to find expression in the average teachers' pedagogy. This study drew on interview data from 20 primary teachers. A phenomenographic analysis revealed three conceptions of teaching that support inquiry learning in science in the primary years of schooling: (a) The Experience-centred conception where teachers focused on providing interesting sensory experiences to students; (b) The Problem-centred conception where teachers focused on challenging students with engaging problems; and (c) The Question-centred conception where teachers focused on helping students to ask and answer their own questions. Understanding teachers' conceptions of teaching has implications for both the enactment of inquiry teaching in the classroom as well as the uptake of new teaching behaviours during professional development, with enhanced outcomes for engaging students in STEM.

Stop whining and make the best of it : a cross-national comparison of responses to regional disadvantage in the wine industry

Our cross-national field study of wine entrepreneurship in the “wrong” places provides some redress to the focus of the “regional advantage” literature on places that have already won and on the firms that benefit from “clusters” and other centers of industry advantage. Regional “disadvantage” is at best a shadowy afterthought to this literature. By poking around in these shadows, we help to synthesize and extend the incipient yet burgeoning literature on entrepreneurial “resourcefulness” and we contribute to the developing body of insights and theory pertinent to the numerous but often ignored firms and startups that mostly need to worry about how they will compete at all now if they are ever to have of chance of “winning” in the future. The core of our findings suggests that understandable – though contested – processes of ingenuity underlie entrepreneurial responses to regional disadvantage. Because we study entrepreneurship that from many angles simply does not make sense, we are also able to proffer a novel perspective on entrepreneurial sensemaking.

Investigation of barriers to entry into the design-build market in the People’s Republic of China (PRC)

Although the design-build (DB) system has been demonstrated to be an effective delivery method and has gained popularity worldwide, it has not gained the same popularity in the construction market of China. The objective of this study was, theretofore, to investigate the barriers to entry in the DB market. A total of 22 entry barriers were first identified through an open-ended questionnaire survey with 15 top construction professionals in the construction market of China. A broad questionnaire survey was further conducted to prioritize these entry barriers. Statistical analysis of responses shows that the most dominant barriers to entry into the DB market are, namely, lack of design expertise, lack of interest from owners, lack of suitable organization structure, lack of DB specialists, and lack of credit record system. Analysis of variance indicates that there is no difference of opinions among the respondent groups of academia, government departments, state-owned company, and private company, at the 5% significance level, on most of the barriers to entry. Finally, the underlying dimensions of barriers to entry in the DB market were investigated through factor analysis. The results indicate that there are six major underlying dimensions of entry barriers in DB market, which include, namely, the competence of design-builders, difficulty in project procurement, characteristics of DB projects, lack of support from public sectors, the competence of DB owners, and the immaturity of DB market. These findings are useful for both potential and incumbent design-builders to understand and analyze the DB market in China.

Reply to the discussion by Karen Johannesson on “Rare earth element geochemistry of scleractinian coral skeleton during meteoric diagenesis: a sequence through neomorphism of aragonite to calcite” by Webb et al., Sedimentology, 56, 1433-1463

Webb et al. (2009) described a late Pleistocenecoral sample wherein the diagenetic stabilization of original coral aragonite to meteoric calcite was halted more or less mid-way through the process, allowing direct comparison of pre-diagenetic and post-diagenetic microstructure and trace element distributions. Those authors found that the rare earth elements (REEs) were relatively stable during meteoric diagenesis, unlike divalent cations such as Sr,and it was thus concluded that original, in this case marine, REE distributions potentially could be preserved through the meteoric carbonate stabilization process that must have affected many, if not most, ancient limestones. Although this was not the case in the analysed sample, they noted that where such diagenesis took place in laterally transported groundwater, trace elements derived from that groundwater could be incorporated into diagenetic calcite, thus altering the initial REE distribution (Banner et al., 1988). Hence, the paper was concerned with the diagenetic behaviour of REEs in a groundwater-dominated karst system. The comment offered by Johannesson (2011) does not question those research results, but rather, seeks to clarify an interpretation made by Webb et al. (2009) of an earlier paper, Johannesson et al. (2006).