Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance

Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.Mannu K Walia, Patricia MW Ho, Scott Taylor, Alvin JM Ng, Ankita Gupte, Alistair M Chalk, Andrew CW Zannettino, T John Martin, Carl R Walkle

Fostering collaborative research for rare genetic disease: The example of Niemann-Pick type C disease

Rare disease represents one of the most significant issues facing the medical community and health care providers worldwide, yet the majority of these disorders never emerge from their obscurity, drawing little attention from the medical community or the pharmaceutical industry. The challenge therefore is how best to mobilize rare disease stakeholders to enhance basic, translational and clinical research to advance understanding of pathogenesis and accelerate therapy development. Here we describe a rare, fatal brain disorder known as Niemann-Pick type C (NPC) and an innovative research collaborative known as Support of Accelerated Research for NPC (SOAR-NPC) which illustrates one pathway through which knowledge of a rare disease and its possible treatments are being successfully advanced. Use of the “SOAR” mechanism, we believe, offers a blueprint for similar advancement for many other rare disorders

Finite element simulation of three-dimensional free-surface flow problems

An adaptive finite element algorithm is described for the stable solution of three-dimensional free-surface-flow problems based primarily on the use of node movement. The algorithm also includes a discrete remeshing procedure which enhances its accuracy and robustness. The spatial discretisation allows an isoparametric piecewise-quadratic approximation of the domain geometry for accurate resolution of the curved free surface. The technique is illustrated through an implementation for surface-tension-dominated viscous flows modelled in terms of the Stokes equations with suitable boundary conditions on the deforming free surface. Two three-dimensional test problems are used to demonstrate the performance of the method: a liquid bridge problem and the formation of a fluid droplet

Wanted dead or alive : high diversity of macroinvertebrates associated with living and ’dead’ Posidonia oceanica matte

The Mediterranean endemic seagrass Posidonia oceanica forms beds characterised by a dense leaf canopy and a thick root-rhizome ‘matte’. Death of P. oceanica shoots leads to exposure of the underlying matte, which can persist for many years, and is termed ‘dead’ matte. Traditionally, dead matte has been regarded as a degraded habitat. To test whether this assumption was true, the motile macroinvertebrates of adjacent living (with shoots) and dead (without shoots) matte of P. oceanica were sampled in four different plots located at the same depth (5–6 m) in Mellieha Bay, Malta (central Mediterranean). The total number of species and abundance were significantly higher (ANOVA; P<0.05 and P<0.01, respectively) in the dead matte than in living P. oceanica matte, despite the presence of the foliar canopy in the latter. Multivariate analysis (MDS) clearly showed two main groups of assemblages, corresponding to the two matte types. The amphipods Leptocheirus guttatus and Maera grossimana, and the polychaete Nereis rava contributed most to the dissimilarity between the two different matte types. Several unique properties of the dead matte contributing to the unexpected higher number of species and abundance of motile macroinvertebrates associated with this habitat are discussed. The findings have important implications for the conservation of bare P. oceanica matte, which has been generally viewed as a habitat of low ecological value.peer-reviewe

Effects of Expert Testimony and Interrogation Tactics on Perceptions of Confessions

Evidence obtained through the process of interrogation is frequently undermined by what can be perceived as overzealous interrogation tactics. Although the majority of psychologically oriented tactics are legally permissible, they nonetheless contribute to innocent suspects confessing to crimes they did not commit. The present study examined the effect of expert testimony and interrogation tactics on perceptions of a confession. 182 undergraduates read a transcript of a homicide trial that varied based on interrogation tactic: implicit threat of punishment (maximization) or leniency (minimization) and expert witness testimony (presence or absence of expert testimony). Analysis indicated that the type of interrogation tactic used in obtaining the confession affected participants\u27 perceptions of the coerciveness of the interrogation process

Police interrogation practice in Slovenia

Interrogation techniques are well explored, but in Slovenia it has remained unknown what interrogation techniques are used and what the basic characteristics of suspect interrogations are. The Slovenian interrogation manual proposes some coercive interrogation techniques and neglects their weaknesses. The aim of the current study was to examine Slovenian police officers’ beliefs as to the basic characteristics of their interrogations and whether techniques proposed by the manual are used in practice to begin to provide some insight into what actually happens in such interrogations. A survey instrument was used to obtain selfreport data from a sample of criminal investigators. From 86 completed questionnaires it was found that a typical interrogation of a suspect lasts around 90 minutes and is not recorded. Interviewers typically use three interrogation techniques namely (i) conducting interrogations in isolation; (ii) identifying contradictions in the suspect’s story; and (iii) confronting the suspect with evidence. Findings suggest that some coercive interrogation techniques are used in practice (e.g. offering moral justifications, alluding to have evidence of guilt, good cop/bad cop routine, and minimization). The study is the first insight into the practices of Slovenian investigators when questioning suspects. Differences among general, white-collar and organized crime investigators are also discussed