Haematopoietic stem cell health in sickle cell disease and its implications for stem cell therapies and secondary haematological disorders.

Gene modification of haematopoietic stem cells (HSCs) is a potentially curative approach to sickle cell disease (SCD) and offers hope for patients who are not eligible for allogeneic HSC transplantation. Current approaches require in vitro manipulation of healthy autologous HSC prior to their transplantation. However, the health and integrity of HSCs may be compromised by a variety of disease processes in SCD, and challenges have emerged in the clinical trials of gene therapy. There is also concern about increased susceptibility to haematological malignancies during long-term follow up of patients, and this raises questions about genomic stability in the stem cell compartment. In this review, we evaluate the evidence for HSC deficits in SCD and then discuss their potential causation. Finally, we suggest several questions which need to be addressed in order to progress with successful HSC manipulation for gene therapy in SCD

The Time Machine: A Simulation Approach for Stochastic Trees

In the following paper we consider a simulation technique for stochastic trees. One of the most important areas in computational genetics is the calculation and subsequent maximization of the likelihood function associated to such models. This typically consists of using importance sampling (IS) and sequential Monte Carlo (SMC) techniques. The approach proceeds by simulating the tree, backward in time from observed data, to a most recent common ancestor (MRCA). However, in many cases, the computational time and variance of estimators are often too high to make standard approaches useful. In this paper we propose to stop the simulation, subsequently yielding biased estimates of the likelihood surface. The bias is investigated from a theoretical point of view. Results from simulation studies are also given to investigate the balance between loss of accuracy, saving in computing time and variance reduction.Comment: 22 Pages, 5 Figure

Politics by other means?:STS and research in education

Science and Technology Studies (STS) has been surprisingly slow to become widely known and deployed in the field of education. Yet STS has a rich array of concepts and analytical methods to offer to studies of: knowledge practices and epistemic cultures; the interrelationship between states and knowledge; regulatory practices, governance and institutions; and classrooms, pedagogy, teaching and learning. Most importantly, it provides a fresh perspective on how power operates in ordering societies, disciplining actors and promoting ideas and practices. In this paper, we provide an introduction to STS and elaborate what it offers education scholars. Using examples from the emerging body of STS work in the field of education, and in particular from the papers in this special issue, we argue that STS is not only useful, but an exciting and generative form of critique–one that is especially suited to investigating contemporary issues in education policies and practices

DC Inclined-Plane Tracking and Erosion Test of Insulating Materials

The paper reviews previous work on the DC inclined plane test and suggests equivalent DC voltage levels in parallel to AC voltage in the ASTM inclined plane tracking and erosion test. The aim of this work is to provide a basis for standardizing the inclined plane test for DC voltage. Round robin tests done in five laboratories on five specimens of a silicone rubber material were done with the purpose of establishing appropriate ratios by which the equivalent DC voltages can be determined with respect to the corresponding AC voltages. These levels were determined as 67% and 87%, for +DC and-DC respectively, of the AC initial tracking voltage, and for practical purposes, these levels are rounded to 70 and 90%.Peer reviewed: YesNRC publication: Ye

Highly Fluorescent Pyrene-Functional Polystyrene Copolymer Nanofibers for Enhanced Sensing Performance of TNT

A pyrene-functional polystyrene copolymer was prepared via 1,3-dipolar cycloaddition reaction (Sharpless-type click recation) between azide-functional styrene copolymer and 1-ethynylpyrene. Subsequently, nanofibers of pyrene-functional polystyrene copolymer were obtained by using electrospinning technique. The nanofibers thus obtained, found to preserve their parent fluorescence nature, confirmed the avoidance of aggregation during fiber formation. The trace detection of trinitrotoluene (TNT) in water with a detection limit of 5 nM was demonstrated, which is much lower than the maximum allowable limit set by the U.S. Environmental Protection Agency. Interestingly, the sensing performance was found to be selective toward TNT in water, even in the presence of higher concentrations of toxic metal pollutants such as Cd2+, Co2+, Cu2+, and Hg2+. The enhanced sensing performance was found to be due to the enlarged contact area and intrinsic nanoporous fiber morphology. Effortlessly, the visual colorimetric sensing performance can be seen by naked eye with a color change in a response time of few seconds. Furthermore, vapor-phase detection of TNT was studied, and the results are discussed herein. In terms of practical application, electrospun nanofibrous web of pyrene-functional polystyrene copolymer has various salient features including flexibility, reproducibility, and ease of use, and visual outputs increase their value and add to their advantage. © 2015 American Chemical Society

(un)Doing standards in education with actor-network theory

Recent critiques have drawn important attention to the depoliticized consensus and empty promises embedded in network discourses of educational policy. While acceding this critique, this discussion argues that some forms of network analysis – specifically those adopting actor-network theory (ANT) approaches - actually offer useful theoretical resources for policy studies. Drawing from ANT-inspired studies of policy processes associated with educational standards, the article shows the ambivalences and contradictions as well as the possibilities that can be illuminated by ANT analysis of standards as networks. The discussion outlines the diverse network conceptions, considerations and sensibilities afforded by ANT approaches. Then it shows four phenomena that have been highlighted by ANT studies of educational standards: ordering (and rupturing) practice through ‘immutable mobiles’, local universality, tensions among networks of prescription and networks of negotiation, and different co-existing ontological forms of the same standards. The conclusion suggests starting points, drawing from these ANT-inspired network analyses, for examining policy processes associated with educational standards

In Vivo Analysis of the Notch Receptor S1 Cleavage

A ligand-independent cleavage (S1) in the extracellular domain of the mammalian Notch receptor results in what is considered to be the canonical heterodimeric form of Notch on the cell surface. The in vivo consequences and significance of this cleavage on Drosophila Notch signaling remain unclear and contradictory. We determined the cleavage site in Drosophila and examined its in vivo function by a transgenic analysis of receptors that cannot be cleaved. Our results demonstrate a correlation between loss of cleavage and loss of in vivo function of the Notch receptor, supporting the notion that S1 cleavage is an in vivo mechanism of Notch signal control

A missense mutation in Katnal1 underlies behavioural, neurological and ciliary anomalies

Microtubule severing enzymes implement a diverse range of tissue-specific molecular functions throughout development and into adulthood. Although microtubule severing is fundamental to many dynamic neural processes, little is known regarding the role of the family member Katanin p60 subunit A-like 1, KATNAL1, in central nervous system (CNS) function. Recent studies reporting that microdeletions incorporating the KATNAL1 locus in humans result in intellectual disability and microcephaly suggest that KATNAL1 may play a prominent role in the CNS; however, such associations lack the functional data required to highlight potential mechanisms which link the gene to disease symptoms. Here we identify and characterise a mouse line carrying a loss of function allele in Katnal1. We show that mutants express behavioural deficits including in circadian rhythms, sleep, anxiety and learning/memory. Furthermore, in the brains of Katnal1 mutant mice we reveal numerous morphological abnormalities and defects in neuronal migration and morphology. Furthermore we demonstrate defects in the motile cilia of the ventricular ependymal cells of mutants, suggesting a role for Katnal1 in the development of ciliary function. We believe the data we present here are the first to associate KATNAL1 with such phenotypes, demonstrating that the protein plays keys roles in a number of processes integral to the development of neuronal function and behaviour.Molecular Psychiatry advance online publication, 4 April 2017; doi:10.1038/mp.2017.54