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

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

Mesh shape and anisotropic elements : theory and practice

The relationship between the shape of finite elements in unstructured meshes and the error that results in the numerical solution is of increasing importance as finite elements are used to solve problems with highly anisotropic and, often, very complex solutions. This issue is explored in terms of a priori and a posteriori error estimates, and through consideration of the practical issues associated with assessing element shape quality and implementing an adaptive finite element solver

Phase evolution of Na2O–Al2O3–SiO2–H2O gels in synthetic aluminosilicate binders

This study demonstrates the production of stoichiometrically controlled alkali-aluminosilicate gels (‘geopolymers’) via alkali-activation of high-purity synthetic amorphous aluminosilicate powders. This method provides for the first time a process by which the chemistry of aluminosilicate-based cementitious materials may be accurately simulated by pure synthetic systems, allowing elucidation of physicochemical phenomena controlling alkali-aluminosilicate gel formation which has until now been impeded by the inability to isolate and control key variables. Phase evolution and nanostructural development of these materials are examined using advanced characterisation techniques, including solid state MAS NMR spectroscopy probing 29Si, 27Al and 23Na nuclei. Gel stoichiometry and the reaction kinetics which control phase evolution are shown to be strongly dependent on the chemical composition of the reaction mix, while the main reaction product is a Na2O–Al2O3–SiO2–H2O type gel comprised of aluminium and silicon tetrahedra linked via oxygen bridges, with sodium taking on a charge balancing function. The alkali-aluminosilicate gels produced in this study constitute a chemically simplified model system which provides a novel research tool for the study of phase evolution and microstructural development in these systems. Novel insight of physicochemical phenomena governing geopolymer gel formation suggests that intricate control over time-dependent geopolymer physical properties can be attained through a careful precursor mix design. Chemical composition of the main N–A–S–H type gel reaction product as well as the reaction kinetics governing its formation are closely related to the Si/Al ratio of the precursor, with increased Al content leading to an increased rate of reaction and a decreased Si/Al ratio in the N–A–S–H type gel. This has significant implications for geopolymer mix design for industrial applications

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

Characterizing oxygen atoms in perovskite and pyrochlore oxides using ADF-STEM at a resolution of a few tens of picometers

We present an aberration corrected scanning transmission electron microscopy (ac-STEM) analysis of perovskite (LaFeO3) and pyrochlore (Yb2Ti2O7 and Pr2Zr2O7) oxides and demonstrate that both the shape and contrast of visible atomic columns in annular dark-field (ADF) images are sensitive to the presence of nearby atoms of low atomic number (e.g. oxygen). We show that point defects (e.g. oxygen vacancies), which are invisible – or difficult to observe due to limited sensitivity – in x-ray and neutron diffraction measurements, are the origin of the complex magnetic ground state of pyrochlore oxides. In addition, we present a method by which light atoms can be resolved in the quantitative ADF-STEM images. Using this method, we resolved oxygen atoms in perovskite and pyrochlore oxides and propose this method to be suitable for other materials containing both light and heavy elements

Thermal performance of calcium-rich alkali-activated materials: A microstructural and mechanical study

The effects of Si/Al, Na/Al and water/solids ratios on thermal performance of alkali-activated materials (AAM) based on fly ash-slag blends are investigated. Higher Na/Al decreased compressive strength but increased post-heated strength retention and mass loss while reducing cracking at 1000 °C. Lower Si/Al resulted in lowest initial strength but highest thermal stability, with an increase in strength after exposure to 1000 °C, while a high degree of cracking was observed at higher Si/Al ratio. The effect of w/s on thermal performance was subtle. Computed tomography analysis showed for the first time thermally induced expansion of pores which reduced surface cracking via water vapour pressure release. Thermal performance of alkali-activated materials (AAM) is significantly better than Portland cement (PC) of the same compressive strength because of the very low bound water content. The porosity, pore connectivity and number of pores of the AAM were considerably higher than those in the PC binder

RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation

Hematopoietic stem cells (HSCs) sustain lifelong production of all blood cell types through finely balanced divisions leading to self-renewal and differentiation. Although several genes influencing HSC self-renewal have been identified, to date no gene has been described that, when activated, enhances HSC self-renewal and, when activated, promotes HSC differentiation. We observe that the retinoic acid receptor (RAR)γ is selectively expressed in primitive hematopoietic precursors and that the bone marrow of RARγ knockout mice exhibit markedly reduced numbers of HSCs associated with increased numbers of more mature progenitor cells compared with wild-type mice. In contrast, RARα is widely expressed in hematopoietic cells, but RARα knockout mice do not exhibit any HSC or progenitor abnormalities. Primitive hematopoietic precursors overexpressing RARα differentiate predominantly to granulocytes in short-term culture, whereas those overexpressing RARγ exhibit a much more undifferentiated phenotype. Furthermore, loss of RARγ abrogated the potentiating effects of all-trans retinoic acid on the maintenance of HSCs in ex vivo culture. Finally, pharmacological activation of RARγ ex vivo promotes HSC self-renewal, as demonstrated by serial transplant studies. We conclude that the RARs have distinct roles in hematopoiesis and that RARγ is a critical physiological and pharmacological regulator of the balance between HSC self-renewal and differentiation