Cellular feedback dynamics and multilevel regulation driven by the hippo pathway

The Hippo pathway is a dynamic cellular signalling nexus that regulates differentiation and controls cell proliferation and death. If the Hippo pathway is not precisely regulated, the functionality of the upstream kinase module is impaired, which increases nuclear localisation and activity of the central effectors, the transcriptional co-regulators YAP and TAZ. Pathological YAP and TAZ hyperactivity consequently cause cancer, fibrosis and developmental defects. The Hippo pathway controls an array of fundamental cellular processes, including adhesion, migration, mitosis, polarity and secretion of a range of biologically active components. Recent studies highlight that spatio-temporal regulation of Hippo pathway components are central to precisely controlling its context-dependent dynamic activity. Several levels of feedback are integrated into the Hippo pathway, which is further synergized with interactors outside of the pathway that directly regulate specific Hippo pathway components. Likewise, Hippo core kinases also ‘moonlight’ by phosphorylating multiple substrates beyond the Hippo pathway and thereby integrates further flexibility and robustness in the cellular decision-making process. This topic is still in its infancy but promises to reveal new fundamental insights into the cellular regulation of this therapeutically important pathway. We here highlight recent advances emphasising feedback dynamics and multilevel regulation of the Hippo pathway with a focus on mitosis and cell migration, as well as discuss potential productive future research avenues that might reveal novel insights into the overall dynamics of the pathway

The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer

Tumorigenesis is a highly complex process, involving many interrelated and cross-acting signalling pathways. One such pathway that has garnered much attention in the field of cancer research over the last decade is the Hippo signalling pathway. Consisting of two antagonistic modules, the pathway plays an integral role in both tumour suppressive and oncogenic processes, generally via regulation of a diverse set of genes involved in a range of biological functions. This review discusses the history of the pathway within the context of cancer and explores some of the most recent discoveries as to how this critical transducer of cellular signalling can influence cancer progression. A special focus is on the various recent efforts to therapeutically target the key effectors of the pathway in both preclinical and clinical settings

Vocalic Intrusions in Consonant Clusters in Child-Directed vs. Adult-Directed Speech.

In this paper, we investigate a prosodic-phonetic feature in child-directed speech within a dynamic, complex, interactive theoretical framework. We focus on vocalic intrusions, commonly occurring in Norwegian word initial consonant clusters. We analysed child-directed speech from nine Norwegian-speaking mothers to their children, aged 2;6, 4, and 6 years, and compared the incidence and duration of vocalic intrusions in initial consonant clusters in these data with those in adult-directed speech and child speech. When viewed overall, vocalic intrusion was found to be similar in incidence in child- and adult-directed speech. However, closer examination revealed differential behaviour in child-directed speech for certain conditions. Firstly, a difference emerged for one particular phonetic context: While vocalic intrusions in /Cr/ clusters are frequent in adult-directed speech, their presence is near-categorical in child-directed speech. Secondly, we found that the duration of vocalic intrusions was longer in child- than in adult-directed speech, but only when directed to 2;6-year-olds. We argue that vocalic intrusions in child-directed speech may have both a bonding as well as a didactic function, and that these may vary according to the age of the child being addressed

LF-PPL: A Low-Level First Order Probabilistic Programming Language for Non-Differentiable Models

We develop a new Low-level, First-order Probabilistic Programming Language (LF-PPL) suited for models containing a mix of continuous, discrete, and/or piecewise-continuous variables. The key success of this language and its compilation scheme is in its ability to automatically distinguish parameters the density function is discontinuous with respect to, while further providing runtime checks for boundary crossings. This enables the introduction of new inference engines that are able to exploit gradient information, while remaining efficient for models which are not everywhere differentiable. We demonstrate this ability by incorporating a discontinuous Hamiltonian Monte Carlo (DHMC) inference engine that is able to deliver automated and efficient inference for non-differentiable models. Our system is backed up by a mathematical formalism that ensures that any model expressed in this language has a density with measure zero discontinuities to maintain the validity of the inference engine.Comment: Published in the proceedings of the 22nd International Conference on Artificial Intelligence and Statistics (AISTATS

Persuasive Technology for Learning in Business Context

"Persuasive Design is a relatively new concept which employs general principles of persuasion that can be implemented in persuasive technology. This concept has been introduced by BJ Fogg in 1998, who since then has further extended it to use computers for changing attitudes and behaviour. Such principles can be applied very well in learning and teaching: in traditional human-led learning, teachers always have employed persuasion as one of the elements of teaching. Persuasive technology moves these principles into the digital domain, by focusing on technology that inherently stimulates learners to learn more quickly and effectively. This is very relevant for the area of Business Management in several aspects: Consumer Behavior, Communications, Human Resource, Marketing & Advertising, Organisational Behavior & Leadership. The persuasive principles identified by BJ Fogg are: reduction, tunnelling, tailoring, suggestion, self-monitoring, surveillance, conditioning, simulation, social signals. Also relevant is the concept of KAIROS, which means the just-in-time, at the right place provision of information/stimulus. In the EuroPLOT project (2010-2013) we have developed persuasive learning objects and tools (PLOTs) in which we have applied persuasive designs and principles. In this context, we have developed a pedagogical framework for active engagement, based on persuasive design in which the principles of persuasive learning have been formalised in a 6-step guide for persuasive learning. These principles have been embedded in two tools – PLOTmaker and PLOTLearner – which have been developed for creating persuasive learning objects. The tools provide specific capability for implementing persuasive principles at the very beginning of the design of learning objects. The feasibility of employing persuasive learning concepts with these tools has been investigated in four different case studies with groups of teachers and learners from realms with distinctly different teaching and learning practices: Business Computing, language learning, museum learning, and chemical substance handling. These case studies have involved the following learner target groups: school children, university students, tertiary students, vocational learners and adult learners. With regards to the learning context, they address archive-based learning, industrial training, and academic teaching. Alltogether, these case studies include participants from Sweden, Africa (Madagascar), Denmark, Czech Republic, and UK. One of the outcomes of this investigation was that one cannot apply a common set of persuasive designs that would be valid for general use in all situations: on the contrary, the persuasive principles are very specific to learning contexts and therefore must be specifically tailored for each situation. Two of these case studies have a direct relevance to education in the realm of Business Management: Business Computing and language learning (for International Business). In this paper we will present the first results from the evaluation of persuasive technology driven learning in these two relevant areas.