On-lattice agent-based simulation of populations of cells within the open-source chaste framework

Over the years, agent-based models have been developed that combine cell division and reinforced random walks of cells on a regular lattice, reaction-diffusion equations for nutrients and growth factors and ordinary differential equations (ODEs) for the subcellular networks regulating the cell cycle. When linked to a vascular layer, this multiple scale model framework has been applied to tumour growth and therapy. Here we report on the creation of an agent-based multiscale environment amalgamating the characteristics of these models within a Virtual Pysiological Human (VPH) Exemplar Project. This project enables re-use, integration, expansion and sharing of the model and relevant data. The agent-based and reactiondiffusion parts of the multiscale model have been implemented and are available for download as part of the latest public release of Chaste (“Cancer, Heart and Soft Tissue Environment”), (http://www.cs.ox.ac.uk/chaste/) version 3.1, part of the VPH Toolkit (http://toolkit.vph-noe.eu/). The environment functionalities are verified against the original models, in addition to extra validation of all aspects of the code. In this work, we present the details of the implementation of the agent-based environment, including the system description, the conceptual model, the development of the simulation model and the processes of verification and validation of the simulation results. We explore the potential use of the environment by presenting exemplar applications of the “what if” scenarios that can easily be studied in the environment. These examples relate to tumour growth, cellular competition for resources and tumour responses to hypoxia. We conclude our work by summarising the future steps for the expansion of the current system

Expansion of the ligand knowledge base for chelating P,P-donor ligands (LKB-PP)

[Image: see text] We have expanded the ligand knowledge base for bidentate P,P- and P,N-donor ligands (LKB-PP, Organometallics2008, 27, 1372–1383) by 208 ligands and introduced an additional steric descriptor (nHe(8)). This expanded knowledge base now captures information on 334 bidentate ligands and has been processed with principal component analysis (PCA) of the descriptors to produce a detailed map of bidentate ligand space, which better captures ligand variation and has been used for the analysis of ligand properties

Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy

Autophagy is a cell-protective and degradative process that recycles damaged and long-lived cellular components. Cancer cells are thought to take advantage of autophagy to help them to cope with the stress of tumorigenesis; thus targeting autophagy is an attractive therapeutic approach. However, there are currently no specific inhibitors of autophagy. ULK1, a serine/threonine protein kinase, is essential for the initial stages of autophagy, and here we report that two compounds, MRT67307 and MRT68921, potently inhibit ULK1 and ULK2 in vitro and block autophagy in cells. Using a drug-resistant ULK1 mutant, we show that the autophagy-inhibiting capacity of the compounds is specifically through ULK1. ULK1 inhibition results in accumulation of stalled early autophagosomal structures, indicating a role for ULK1 in the maturation of autophagosomes as well as initiation

Biotic factors limit the invasion of the plague pathogen ( <i>Yersinia pestis</i> ) in novel geographical settings

Aim: The distribution of Yersinia pestis, the pathogen that causes plague in humans, is reliant upon transmission between host species; however, the degree to which host species distributions dictate the distribution of Y. pestis, compared with limitations imposed by the environmental niche of Y. pestis per se, is debated. We test whether the present-day environmental niche of Y. pestis differs between its native range and an invaded range and whether biotic factors (host distributions) can explain observed discrepancies. Location: North America and Central Asia. Major taxa studied: Yersinia pestis. Methods: We use environmental niche models to determine whether the current climatic niche of Y. pestis differs between its native range in Asia and its invaded range in North America. We then test whether the inclusion of information on the distribution of host species improves the ability of models to capture the North American niche. We use geographical null models to guard against spurious correlations arising from spatially autocorrelated occurrence points. Results: The current climatic niche of Y. pestis differs between its native and invaded regions. The Asian niche overpredicted the distribution of Y. pestis across North America. Including biotic factors along with the native climatic niche increased niche overlap between the native and invaded models, and models containing only biotic factors performed better than the native climatic niche alone. Geographical null models confirmed that the increased niche overlap through inclusion of biotic factors did not, with a couple of exceptions, arise solely from spatially autocorrelated occurrences. Main conclusions: The current climatic niche in Central Asia differs from the current climatic niche in North America. Inclusion of biotic factors improved the fit of models to the Y. pestis distribution data in its invaded region better than climate variables alone. This highlights the importance of host species when investigating zoonotic disease introductions and suggests that climatic variables alone are insufficient to predict disease distribution in novel environments

Quantum-like Representation of Extensive Form Games: Wine Testing Game

We consider an application of the mathematical formalism of quantum mechanics (QM) outside physics, namely, to game theory. We present a simple game between macroscopic players, say Alice and Bob (or in a more complex form - Alice, Bob and Cecilia), which can be represented in the quantum-like (QL) way -- by using a complex probability amplitude (game's ``wave function'') and noncommutative operators. The crucial point is that games under consideration are so called extensive form games. Here the order of actions of players is important, such a game can be represented by the tree of actions. The QL probabilistic behavior of players is a consequence of incomplete information which is available to e.g. Bob about the previous action of Alice. In general one could not construct a classical probability space underlying a QL-game. This can happen even in a QL-game with two players. In a QL-game with three players Bell's inequality can be violated. The most natural probabilistic description is given by so called contextual probability theory completed by the frequency definition of probability

Accounting for extinction dynamics unifies the geological and biological histories of Indo-Australian Archipelago

Acknowledgements The manuscript was improved by the constructive feedback from anonymous reviewers. We thank University of Aberdeen High Performance Computing. We thank the authors of the revisited studies who kindly granted us access to their datasets.Peer reviewe

Clinical characteristics and outcome of dogs with presumed primary renal lymphoma

Objectives: To characterise the presentation, clinicopathologic data and outcome of 29 dogs with presumed primary renal lymphoma. Materials and methods: Retrospective analysis of medical records of dogs with suspected primary renal lymphoma from 11 institutions. Results: All dogs were substage b, and lethargy and gastrointestinal signs were common presenting complaints, as were azotaemia (n=25; 86%) and erythrocytosis (n=15; 51%) on biochemical testing. Ultrasonography typically revealed bilateral renal lesions (n=23; 79%), renomegaly (n=22; 76%) and abdominal lymphadenopathy (n=14; 48%). Chemotherapy was the only treatment in 23 dogs, of which 11 responded, all considered partial responses. For all dogs the median progression-free survival and median overall survival times were 10 days (range: 1 to 126) and 12 days (range: 1 to 212), respectively, and for dogs that responded to chemotherapy 41 days (range: 10 to 126) and 47 days (range: 10 to 212), respectively. Clinical significance: Primary renal lymphoma in dogs appears to be associated with a poor prognosis and short-lived response to chemotherapy

Fauxcurrence: simulating multi-species occurrences for null models in species distribution modelling and biogeography

The work was funded by Newton Fund (UK)/NERC (UK)/RISTEKDIKTI (Indonesia) grants awarded to JT, BJ, ACA, ASTP, CG-R, GB and LTL (grant no.: NE/S006923/1, NE/S006893/1, 2488/IT3.L1/PN/2020 and 3982/IT3.L1/PN/2020). GB and CG-R are funded by Royal Society Univ. Research Fellowships (UF160614 and UF150571 respectively).Peer reviewedPublisher PD

Evaluation Research and Institutional Pressures: Challenges in Public-Nonprofit Contracting

This article examines the connection between program evaluation research and decision-making by public managers. Drawing on neo-institutional theory, a framework is presented for diagnosing the pressures and conditions that lead alternatively toward or away the rational use of evaluation research. Three cases of public-nonprofit contracting for the delivery of major programs are presented to clarify the way coercive, mimetic, and normative pressures interfere with a sound connection being made between research and implementation. The article concludes by considering how public managers can respond to the isomorphic pressures in their environment that make it hard to act on data relating to program performance.This publication is Hauser Center Working Paper No. 23. The Hauser Center Working Paper Series was launched during the summer of 2000. The Series enables the Hauser Center to share with a broad audience important works-in-progress written by Hauser Center scholars and researchers