Managing the Risk of Aggressive Dog Behavior: Investigating the Influence of Owner Threat and Efficacy Perceptions.

Aggressive behavior in pet dogs is a serious problem for dog owners across the globe, with bite injuries representing a serious risk to both people and other dogs. The effective management of aggressive behavior in dogs represents a challenging and controversial issue. Although positive reinforcement training methods are now considered to be the most effective and humane technique to manage the risk of aggression, punishment-based methods continue to be used. Unfortunately, there has been little scientific study into the various factors influencing whether dog owners choose to use positive reinforcement techniques to manage aggression in their dogs. As such, current understanding of how best to encourage and support dog owners to use these methods remains extremely limited. This article uses a survey methodology based on protection motivation theory (PMT) to investigate the factors that influence owner use of positive reinforcement methods to manage aggressive behavior, in an attempt to understand potential barriers and drivers of use. In addition, the article provides an initial exploration of the potential role of wider psychological factors, including owner emotional state, social influence, and cognitive bias. Findings show that the perceived efficacy of positive reinforcement methods and the perceived ability of owners to effectively implement the technique are both key factors predicting future intentions and current reported use. Future interventions should focus on enhancing owner confidence in the effective use of positive reinforcement techniques across multiple scenarios, as well as helping owners manage their own emotional responses when they encounter challenging situations and setbacks.

Discovery of AZD3147: a potent, selective dual inhibitor of mTORC1 and mTORC2.

High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.

Telling lies: the irrepressible truth?

Telling a lie takes longer than telling the truth but precisely why remains uncertain. We investigated two processes suggested to increase response times, namely the decision to lie and the construction of a lie response. In Experiments 1 and 2, participants were directed or chose whether to lie or tell the truth. A colored square was presented and participants had to name either the true color of the square or lie about it by claiming it was a different color. In both experiments we found that there was a greater difference between lying and telling the truth when participants were directed to lie compared to when they chose to lie. In Experiments 3 and 4, we compared response times when participants had only one possible lie option to a choice of two or three possible options. There was a greater lying latency effect when questions involved more than one possible lie response. Experiment 5 examined response choice mechanisms through the manipulation of lie plausibility. Overall, results demonstrate several distinct mechanisms that contribute to additional processing requirements when individuals tell a lie.

The molecular basis of the cooperation between EGF, FGF and eCB receptors in the regulation of neural stem cell function.

Adult neurogenesis relies on EGF and FGF receptor (EGFR/FGFR) function and endocannabinoid (eCB) signalling. Here we have used a neural stem cell (NSC) line to determine how these systems cooperate to regulate neurogenesis. The results show the EGFR to be solely responsible for maintaining PI3K activation explaining its dominant role in promoting NSC survival. The EGFR and FGFR synergistically regulate the ERK/MAPK pathway, and this explains the requirement for both for optimal cell proliferation. The eCB receptors did not contribute to activation of the PI3K or ERK/MAPK pathways, highlighting the importance of another major proliferation pathway. The EGFR plays the dominant role in maintaining the transcriptome, with significant changes in the expression of over 3500 transcripts seen within hours of inhibition or activation of this receptor. The FGFR has a more modest effect on transcription with evidence for nodal integration with EGFR signalling at the level of the ERK/MAPK pathway. A common set of transcripts are regulated by the CB1 and CB2 receptors, with cooperation between these receptors and the EGFR apparent in the regulation of a pool of transcripts, most likely representing signal integration downstream from an as yet to be identified node. Finally, a first level molecular analysis of the transcriptional response shows regulation of a number of key growth factors, growth factor receptors and GPCRs to be under the control of the EGFR.

Inhibitors of the tyrosine kinase EphB4. Part 2: structure-based discovery and optimisation of 3,5-bis substituted anilinopyrimidines.

Crystallographic studies of a range of 3-substituted anilinopyrimidine inhibitors of EphB4 have highlighted two alternative C-2 aniline conformations and this discovery has been exploited in the design of a highly potent series of 3,5-disubstituted anilinopyrimidines. The observed range of cellular activities has been rationalised on the basis of physicochemical and structural characteristics.

Inhibitors of the tyrosine kinase EphB4. Part 1: Structure-based design and optimization of a series of 2,4-bis-anilinopyrimidines.

A series of bis-anilinopyrimidines have been identified as potent inhibitors of the tyrosine kinase EphB4. Structural information from two alternative series identified from screening efforts was combined to identify the initial leads.

Neutral 5-substituted 4-anilinoquinazolines as potent, orally active inhibitors of erbB2 receptor tyrosine kinase.

Neutral 5-substituted 4-anilinoquinazolines addressed high in vivo clearance and phospholipidosis associated with previous basic compounds. A representative compound 8a inhibited tumor growth in a mouse xenograft model when co-administered with the cytochrome P450 inhibitor 1-aminobenzotriazole (ABT), and data are consistent with pharmacology primarily reflecting inhibition of erbB2 receptor tyrosine kinase.

Inhibitors of epidermal growth factor receptor tyrosine kinase: optimisation of potency and in vivo pharmacokinetics.

The structure-activity and structure-property relationships of anilinoquinazoline inhibitors of EGFR were investigated. Strategies to lower volume of distribution and shorten half-life through structure and pKa modulation are discussed.

Inhibitors of epidermal growth factor receptor tyrosine kinase: Novel C-5 substituted anilinoquinazolines designed to target the ribose pocket.

A series of novel C-5 substituted anilinoquinazolines, selected on the basis of docking experiments and overlays with ATP in the active site of EGFR tyrosine kinase, have been prepared and found to be potent inhibitors. In vivo pharmacokinetics and disease model activity are discussed.

Detecting residual cognitive function in persistent vegetative state.

Despite converging agreement about the definition of persistent vegetative state, recent reports have raised concerns about the accuracy of diagnosis in some patients, and the extent to which, in a selection of cases, residual cognitive functions may remain undetected. Objective assessment of residual cognitive function can be extremely difficult as motor responses may be minimal, inconsistent, and difficult to document in many patients, or may be undetectable in others because no cognitive output is possible. Here we describe strategies for using H(2)(15)O positron emission tomography activation studies to study covert cognitive processing in patients with a clinical diagnosis of persistent vegetative state. Three cases are described in detail. Of these, two exhibited clear and predicted regional cerebral blood flow responses during well-documented activation paradigms (face recognition and speech perception) which have been shown to produce specific, robust and reproducible activation patterns in normal volunteers. Some months after scanning, both patients made a significant recovery. In a third case, blood flow data were acquired during a speech perception task, although methodological difficulties precluded any systematic interpretation of the results. In spite of the multiple logistic and procedural problems involved, these results have major clinical and scientific implications and provide a strong basis for the systematic study of possible residual cognitive function in patients diagnosed as being in a persistent vegetative state.