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

A splitting approach for the fully nonlinear and weakly dispersive Green-Naghdi model

The fully nonlinear and weakly dispersive Green-Naghdi model for shallow water waves of large amplitude is studied. The original model is first recast under a new formulation more suitable for numerical resolution. An hybrid finite volume and finite difference splitting approach is then proposed. The hyperbolic part of the equations is handled with a high-order finite volume scheme allowing for breaking waves and dry areas. The dispersive part is treated with a classical finite difference approach. Extensive numerical validations are then performed in one horizontal dimension, relying both on analytical solutions and experimental data. The results show that our approach gives a good account of all the processes of wave transformation in coastal areas: shoaling, wave breaking and run-up

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

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

Fundamental movement skills are more than run, throw and catch: The role of stability skills.

Introduction In motor development literature fundamental movement skills are divided into three constructs: locomotive, object control and stability skills. Most fundamental movement skills research has focused on children's competency in locomotor and object control skills. The first aim of this study was to validate a test battery to assess the construct of stability skills, in children aged 6 to 10 (M age = 8.2, SD = 1.2). Secondly we assessed how the stability skills construct fitted into a model of fundamental movement skill. Method The Delphi method was used to select the stability skill battery. Confirmatory factor analysis (CFA) was used to assess if the skills loaded onto the same construct and a new model of FMS was developed using structural equation modelling. Results Three postural control tasks were selected (the log roll, rock and back support) because they had good face and content validity. These skills also demonstrated good predictive validity with gymnasts scoring significantly better than children without gymnastic training and children from a high SES school performing better than those from a mid and low SES schools and the mid SES children scored better than the low SES children (all p < .05). Inter rater reliability tests were excellent for all three skills (ICC = 0.81, 0.87, 0.87) as was test retest reliability (ICC 0.87-0.95). CFA provided good construct validity, and structural equation modelling revealed stability skills to be an independent factor in an overall FMS model which included locomotor (r = .88), object control (r = .76) and stability skills (r = .81). Discussion This study provides a rationale for the inclusion of stability skills in FMS assessment. The stability skills could be used alongside other FMS assessment tools to provide a holistic assessment of children's fundamental movement skills. Copyright

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

Hematopoietic stem cell (HSC) aging has become a concern in chemotherapy of older patients. Humoral and paracrine signals from the bone marrow (BM) hematopoietic microenvironment (HM) control HSC activity during regenerative hematopoiesis. Connexin-43 (Cx43), a connexin constituent of gap junctions (GJs) is expressed in HSCs, down-regulated during differentiation, and postulated to be a self-renewal gene. Our studies, however, reveal that hematopoietic-specific Cx43 deficiency does not result in significant long-term competitive repopulation deficiency. Instead, hematopoietic Cx43 (H-Cx43) deficiency delays hematopoietic recovery after myeloablation with 5-fluorouracil (5-FU). 5-FU-treated H-Cx43-deficient HSC and progenitors (HSC/P) cells display decreased survival and fail to enter the cell cycle to proliferate. Cell cycle quiescence is associated with down-regulation of cyclin D1, up-regulation of the cyclin-dependent kinase inhibitors, p21cip1. and p16INK4a, and Forkhead transcriptional factor 1 (Foxo1), and activation of p38 mitogen-activated protein kinase (MAPK), indicating that H-Cx43-deficient HSCs are prone to senescence. The mechanism of increased senescence in H-Cx43-deficient HSC/P cells depends on their inability to transfer reactive oxygen species (ROS) to the HM, leading to accumulation of ROS within HSCs. In vivo antioxidant administration prevents the defective hematopoietic regeneration, as well as exogenous expression of Cx43 in HSC/P cells. Furthermore, ROS transfer from HSC/P cells to BM stromal cells is also rescued by reexpression of Cx43 in HSC/P. Finally, the deficiency of Cx43 in the HM phenocopies the hematopoietic defect in vivo. These results indicate that Cx43 exerts a protective role and regulates the HSC/P ROS content through ROS transfer to the HM, resulting in HSC protection during stress hematopoietic regeneration