Extending the applicability of the dose addition model to the assessment of chemical mixtures of partial agonists by using a novel toxic unit extrapolation method

This article has been made available through the Brunel Open Access Publishing Fund.Dose addition, a commonly used concept in toxicology for the prediction of chemical mixture effects, cannot readily be applied to mixtures of partial agonists with differing maximal effects. Due to its mathematical features, effect levels that exceed the maximal effect of the least efficacious compound present in the mixture, cannot be calculated. This poses problems when dealing with mixtures likely to be encountered in realistic assessment situations where chemicals often show differing maximal effects. To overcome this limitation, we developed a pragmatic solution that extrapolates the toxic units of partial agonists to effect levels beyond their maximal efficacy. We extrapolated different additivity expectations that reflect theoretically possible extremes and validated this approach with a mixture of 21 estrogenic chemicals in the E-Screen. This assay measures the proliferation of human epithelial breast cancers. We found that the dose-response curves of the estrogenic agents exhibited widely varying shapes, slopes and maximal effects, which made it necessary to extrapolate mixture responses above 14% proliferation. Our toxic unit extrapolation approach predicted all mixture responses accurately. It extends the applicability of dose addition to combinations of agents with differing saturating effects and removes an important bottleneck that has severely hampered the use of dose addition in the past. © 2014 Scholze et al

Visual processing of human body and non-body distractors in natural scenes

Several studies have shown that human bodies may preferentially attract attention over other objects (Ro et al., 2007; Downing et al., 2004). We have previously shown that participants took longer to decide that a natural scene contained a target when a distractor human body also appeared with the scene than when the body did not appear. However, this slowing was also demonstrated with other distractor objects (i.e. lamps; Kroll, Dunn, Howard & Baguley, 2013). Here we used an irrelevant singleton paradigm in which we manipulated the presence or absence of different target (grandfather clock or chair) and distractor (bodies: colour full-body/silhouette/colour headless body, lamp: colour/silhouette) combinations independently of one another. The task was to detect a target in either the presence or absence of a task irrelevant distractor. Human body distractors once again slowed search for targets, but only when they were maximally different from the target (i.e. non-analogous), and when contextual detail (i.e. non-silhouette and head present) was available. Non-body distractors also slowed search for the target. However, there was no difference between the distractor bodies and non-bodies in terms of their ability to slow target search. These results, therefore, provide no evidence for human bodies attracting attention over other objects, at least within natural scenes

Value Iteration for Long-run Average Reward in Markov Decision Processes

Markov decision processes (MDPs) are standard models for probabilistic systems with non-deterministic behaviours. Long-run average rewards provide a mathematically elegant formalism for expressing long term performance. Value iteration (VI) is one of the simplest and most efficient algorithmic approaches to MDPs with other properties, such as reachability objectives. Unfortunately, a naive extension of VI does not work for MDPs with long-run average rewards, as there is no known stopping criterion. In this work our contributions are threefold. (1) We refute a conjecture related to stopping criteria for MDPs with long-run average rewards. (2) We present two practical algorithms for MDPs with long-run average rewards based on VI. First, we show that a combination of applying VI locally for each maximal end-component (MEC) and VI for reachability objectives can provide approximation guarantees. Second, extending the above approach with a simulation-guided on-demand variant of VI, we present an anytime algorithm that is able to deal with very large models. (3) Finally, we present experimental results showing that our methods significantly outperform the standard approaches on several benchmarks

Does BCR/ABL1 positive Acute Myeloid Leukaemia Exist?

The BCR/ABL1 fusion gene, usually carried by the Philadelphia chromosome (Ph) resulting from t(9;22)(q34;q11) or variants, is pathognomonic for chronic myeloid leukaemia (CML). It is also occasionally found in acute lymphoblastic leukaemia (ALL) mostly in adults and rarely in de novo acute myeloid leukaemia (AML). Array Comparative Genomic Hybridization (aCGH) was used to study six Ph(+)AML, three bi-lineage and four Ph(+)ALL searching for specific genomic profiles. Surprisingly, loss of the IKZF1 and/or CDKN2A genes, the hallmark of Ph(+)ALL, were recurrent findings in Ph(+)AML and accompanied cryptic deletions within the immunoglobulin and T cell receptor genes. The latter two losses have been shown to be part of 'hot spot' genome imbalances associated with BCR/ABL1 positive pre-B lymphoid phenotype in CML and Ph(+)ALL. We applied Significance Analysis of Microarrays (SAM) to data from the 'hot spot' regions to the Ph(+)AML and a further 40 BCR/ABL1(+) samples looking for differentiating features. After exclusion of the most dominant markers, SAM identified aberrations unique to de novo Ph(+)AML that involved relevant genes. While the biological and clinical significance of this specific genome signature remains to be uncovered, the unique loss within the immunoglobulin genes provides a simple test to enable the differentiation of clinically similar de novo Ph(+) AML and myeloid blast crisis of CML. © 2013 John Wiley & Sons Ltd and Crown

A 19-SNP coronary heart disease gene score profile in subjects with type 2 diabetes: the coronary heart disease risk in type 2 diabetes (CoRDia study) study baseline characteristics

Background: The coronary risk in diabetes (CoRDia) trial (n = 211) compares the effectiveness of usual diabetes care with a self-management intervention (SMI), with and without personalised risk information (including genetics), on clinical and behavioural outcomes. Here we present an assessment of randomisation, the cardiac risk genotyping assay, and the genetic characteristics of the recruits. / Methods: Ten-year coronary heart disease (CHD) risk was calculated using the UKPDS score. Genetic CHD risk was determined by genotyping 19 single nucleotide polymorphisms (SNPs) using Randox’s Cardiac Risk Prediction Array and calculating a gene score (GS). Accuracy of the array was assessed by genotyping a subset of pre-genotyped samples (n = 185). / Results: Overall, 10-year CHD risk ranged from 2–72 % but did not differ between the randomisation groups (p = 0.13). The array results were 99.8 % concordant with the pre-determined genotypes. The GS did not differ between the Caucasian participants in the CoRDia SMI plus risk group (n = 66) (p = 0.80) and a sample of UK healthy men (n = 1360). The GS was also associated with LDL-cholesterol (p = 0.05) and family history (p = 0.03) in a sample of UK healthy men (n = 1360). / Conclusions: CHD risk is high in this group of T2D subjects. The risk array is an accurate genotyping assay, and is suitable for estimating an individual’s genetic CHD risk. / Trial registration: This study has been registered at ClinicalTrials.gov; registration identifier NCT0189178

The developmental dynamics of terrorist organizations

We identify robust statistical patterns in the frequency and severity of violent attacks by terrorist organizations as they grow and age. Using group-level static and dynamic analyses of terrorist events worldwide from 1968-2008 and a simulation model of organizational dynamics, we show that the production of violent events tends to accelerate with increasing size and experience. This coupling of frequency, experience and size arises from a fundamental positive feedback loop in which attacks lead to growth which leads to increased production of new attacks. In contrast, event severity is independent of both size and experience. Thus larger, more experienced organizations are more deadly because they attack more frequently, not because their attacks are more deadly, and large events are equally likely to come from large and small organizations. These results hold across political ideologies and time, suggesting that the frequency and severity of terrorism may be constrained by fundamental processes.Comment: 28 pages, 8 figures, 4 tables, supplementary materia

Edible crabs “Go West”: migrations and incubation cycle of Cancer pagurus revealed by electronic tags

Crustaceans are key components of marine ecosystems which, like other exploited marine taxa, show seasonable patterns of distribution and activity, with consequences for their availability to capture by targeted fisheries. Despite concerns over the sustainability of crab fisheries worldwide, difficulties in observing crabs’ behaviour over their annual cycles, and the timings and durations of reproduction, remain poorly understood. From the release of 128 mature female edible crabs tagged with electronic data storage tags (DSTs), we demonstrate predominantly westward migration in the English Channel. Eastern Channel crabs migrated further than western Channel crabs, while crabs released outside the Channel showed little or no migration. Individual migrations were punctuated by a 7-month hiatus, when crabs remained stationary, coincident with the main period of crab spawning and egg incubation. Incubation commenced earlier in the west, from late October onwards, and brooding locations, determined using tidal geolocation, occurred throughout the species range. With an overall return rate of 34%, our results demonstrate that previous reluctance to tag crabs with relatively high-cost DSTs for fear of loss following moulting is unfounded, and that DSTs can generate precise information with regards life-history metrics that would be unachievable using other conventional means

Global Development and Climate Change: A Game Theory Approach

The increasing concern with climate change is one of the main issues of our time, and thus we aim to theoretically and mathematically analyse its causes. However our approach follows a different stream of thought, presenting the reasoning and decision-making processes between technical and moral solutions. We have resorted to game theory models in order to demonstrate cooperative and non-cooperative scenarios, ranging from the traditional to the evolutionary within game theory. In doing so we are able to glimpse the development of modern society and a paradigm shift regarding human control over nature and to what extent it is harmful to the sustainability of our environment and the survival of future generations. Merging different fields of knowledge, we present a theoretical-philosophical approach, combined with empirical-mathematical solutions taking into account the agent-based behaviour guided blindly by instrumental rationality

Primary central nervous system lymphoma presenting as a pure third ventricular lesion: a case report

<p>Abstract</p> <p>Introduction</p> <p>Primary central nervous system lymphomas are infrequently occurring lymphomas that account for only 0.3-1.5% of all intra-cranial neoplasms in patients without acquired immune deficiency syndrome. However, a pure third ventricle lymphoma is extremely rare. Here, we discuss the similar radiological appearances of lesions localized in the third ventricle and the importance of accurately diagnosing primary central nervous system lymphomas for favorable treatment outcomes.</p> <p>Case presentation</p> <p>A 38-year-old Caucasian man from Turkey presented with a severe headache lasting for three months that failed to respond to any medication. Both severity and duration of the symptoms increased gradually, resulting in vomiting, nausea and gait disturbance that accompanied the headache for three weeks. Neuro-imaging studies showed a lesion located solely in the third ventricle, resulting in partial obstruction of the foramen of Monro. The pre-operative diagnosis was a colloid cyst. Following the surgical procedure, the results of pathological and immunochemical assays revealed that the pre-operative diagnosis was incorrect and that the lesion was a primary central system lymphoma.</p> <p>Conclusion</p> <p>Pure third ventricle lymphomas are extremely rare and are exceptionally localized. It is important to be aware of, and to differentiate between, other possible third ventricular lesions that may mimic the same radiological appearance. Accurate diagnosis is necessary for selecting appropriate treatment modalities.</p

Putting the pieces together: Integration for forest landscape restoration implementation

© 2019 John Wiley & Sons, Ltd. The concept of forest landscape restoration (FLR) is being widely adopted around the globe by governmental, non-governmental agencies, and the private sector, all of whom see FLR as an approach that contributes to multiple global sustainability goals. Originally, FLR was designed with a clearly integrative dimension across sectors, stakeholders, space and time, and in particular across the natural and social sciences. Yet, in practice, this integration remains a challenge in many FLR efforts. Reflecting this lack of integration are the continued narrow sectoral and disciplinary approaches taken by forest restoration projects, often leading to marginalisation of the most vulnerable populations, including through land dispossessions. This article aims to assess what lessons can be learned from other associated fields of practice for FLR implementation. To do this, 35 scientists came together to review the key literature on these concepts to suggest relevant lessons and guidance for FLR. We explored the following large-scale land use frameworks or approaches: land sparing/land sharing, the landscape approach, agroecology, and socio-ecological systems. Also, to explore enabling conditions to promote integrated decision making, we reviewed the literature on understanding stakeholders and their motivations, tenure and property rights, polycentric governance, and integration of traditional and Western knowledge. We propose lessons and guidance for practitioners and policymakers on ways to improve integration in FLR planning and implementation. Our findings highlight the need for a change in decision-making processes for FLR, better understanding of stakeholder motivations and objectives for FLR, and balancing planning with flexibility to enhance social–ecological resilience.The Frank Jackson Foundatio