Neural Induction, Neural Fate Stabilization, and Neural Stem Cells

The promise of stem cell therapy is expected to greatly benefit the treatment of neurodegenerative diseases. An underlying biological reason for the progressive functional losses associated with these diseases is the extremely low natural rate of self-repair in the nervous system. Although the mature CNS harbors a limited number of self-renewing stem cells, these make a significant contribution to only a few areas of brain. Therefore, it is particularly important to understand how to manipulate embryonic stem cells and adult neural stem cells so their descendants can repopulate and functionally repair damaged brain regions. A large knowledge base has been gathered about the normal processes of neural development. The time has come for this information to be applied to the problems of obtaining sufficient, neurally committed stem cells for clinical use. In this article we review the process of neural induction, by which the embryonic ectodermal cells are directed to form the neural plate, and the process of neural�fate stabilization, by which neural plate cells expand in number and consolidate their neural fate. We will present the current knowledge of the transcription factors and signaling molecules that are known to be involved in these processes. We will discuss how these factors may be relevant to manipulating embryonic stem cells to express a neural fate and to produce large numbers of neurally committed, yet undifferentiated, stem cells for transplantation therapies

Evaluating the use of Apo-neocarzinostatin as a cell penetrating protein.

Protein-ligand complex neocarzinostatin (NCS) is a small, thermostable protein-ligand complex that is able to deliver its ligand cargo into live mammalian cells where it induces DNA damage. Apo-NCS is able to functionally display complementarity determining regions loops, and has been hypothesised to act as a cell-penetrating protein, which would make it an ideal scaffold for cell targeting, and subsequent intracellular delivery of small-molecule drugs. In order to evaluate apo-NCS as a cell penetrating protein, we have evaluated the efficiency of its internalisation into live HeLa cells using matrix-assisted laser-desorption ionization-time-of-flight mass spectrometry and fluorescence microscopy. Following incubation of cells with apo-NCS, we observed no evidence of internalisation

Discrete and fuzzy dynamical genetic programming in the XCSF learning classifier system

A number of representation schemes have been presented for use within learning classifier systems, ranging from binary encodings to neural networks. This paper presents results from an investigation into using discrete and fuzzy dynamical system representations within the XCSF learning classifier system. In particular, asynchronous random Boolean networks are used to represent the traditional condition-action production system rules in the discrete case and asynchronous fuzzy logic networks in the continuous-valued case. It is shown possible to use self-adaptive, open-ended evolution to design an ensemble of such dynamical systems within XCSF to solve a number of well-known test problems

Ozone depletion events observed in the high latitude surface layer during the TOPSE aircraft program

During the Tropospheric Ozone Production about the Spring Equinox (TOPSE) aircraft program, ozone depletion events (ODEs) in the high latitude surface layer were investigated using lidar and in situ instruments. Flight legs of 100 km or longer distance were flown 32 times at 30 m altitude over a variety of regions north of 58° between early February and late May 2000. ODEs were found on each flight over the Arctic Ocean but their occurrence was rare at more southern latitudes. However, large area events with depletion to over 2 km altitude in one case were found as far south as Baffin Bay and Hudson Bay and as late as 22 May. There is good evidence that these more southern events did not form in situ but were the result of export of ozone‐depleted air from the surface layer of the Arctic Ocean. Surprisingly, relatively intact transport of ODEs occurred over distances of 900–2000 km and in some cases over rough terrain. Accumulation of constituents in the frozen surface over the dark winter period cannot be a strong prerequisite of ozone depletion since latitudes south of the Arctic Ocean would also experience a long dark period. Some process unique to the Arctic Ocean surface or its coastal regions remains unidentified for the release of ozone‐depleting halogens. There was no correspondence between coarse surface features such as solid ice/snow, open leads, or polynyas with the occurrence of or intensity of ozone depletion over the Arctic or subarctic regions. Depletion events also occurred in the absence of long‐range transport of relatively fresh “pollution” within the high latitude surface layer, at least in spring 2000. Direct measurements of halogen radicals were not made. However, the flights do provide detailed information on the vertical structure of the surface layer and, during the constant 30 m altitude legs, measurements of a variety of constituents including hydroxyl and peroxy radicals. A summary of the behavior of these constituents is made. The measurements were consistent with a source of formaldehyde from the snow/ice surface. Median NOx in the surface layer was 15 pptv or less, suggesting that surface emissions were substantially converted to reservoir constituents by 30 m altitude and that ozone production rates were small (0.15–1.5 ppbv/d) at this altitude. Peroxyacetylnitrate (PAN) was by far the major constituent of NOy in the surface layer independent of the ozone mixing ratio

New Experimental Limits on Macroscopic Forces Below 100 Microns

Results of an experimental search for new macroscopic forces with Yukawa range between 5 and 500 microns are presented. The experiment uses 1 kHz mechanical oscillators as test masses with a stiff conducting shield between them to suppress backgrounds. No signal is observed above the instrumental thermal noise after 22 hours of integration time. These results provide the strongest limits to date between 10 and 100 microns, improve on previous limits by as much as three orders of magnitude, and rule out half of the remaining parameter space for predictions of string-inspired models with low-energy supersymmetry breaking. New forces of four times gravitational strength or greater are excluded at the 95% confidence level for interaction ranges between 200 and 500 microns.Comment: 25 Pages, 7 Figures: Minor Correction

Analysis of the CD1 Antigen Presenting System in Humanized SCID Mice

CD1 molecules are glycoproteins that present lipids and glycolipids for recognition by T cells. CD1-dependent immune activation has been implicated in a wide range of immune responses, however, our understanding of the role of this pathway in human disease remains limited because of species differences between humans and other mammals: whereas humans express five different CD1 gene products (CD1a, CD1b, CD1c, CD1d, and CD1e), muroid rodents express only one CD1 isoform (CD1d). Here we report that immune deficient mice engrafted with human fetal thymus, liver, and CD34+ hematopoietic stem cells develop a functional human CD1 compartment. CD1a, b, c, and d isoforms were highly expressed by human thymocytes, and CD1a+ cells with a dendritic morphology were present in the thymic medulla. CD1+ cells were also detected in spleen, liver, and lungs. APCs from spleen and liver were capable of presenting bacterial glycolipids to human CD1-restricted T cells. ELISpot analyses of splenocytes demonstrated the presence of CD1-reactive IFN-γ producing cells. CD1d tetramer staining directly identified human iNKT cells in spleen and liver samples from engrafted mice, and injection of the glycolipid antigen α-GalCer resulted in rapid elevation of human IFN-γ and IL-4 levels in the blood indicating that the human iNKT cells are biologically active in vivo. Together, these results demonstrate that the human CD1 system is present and functionally competent in this humanized mouse model. Thus, this system provides a new opportunity to study the role of CD1-related immune activation in infections to human-specific pathogens

Early development of the malleus and incus in humans.

It is widely accepted by developmental biologists that the malleus and incus of the mammalian middle ear are first pharyngeal arch derivatives, a contention based originally on classical embryology that has now been backed up by molecular evidence from rodent models. However, it has been claimed in several studies of human ossicular development that the manubrium of the malleus and long process of the incus are actually derived from the second arch. This 'dual-arch' interpretation is commonly presented in otolaryngology textbooks, and it has been used by clinicians to explain the aetiology of certain congenital abnormalities of the human middle ear. In order to re-examine the origins of the human malleus and incus, we made three-dimensional reconstructions of the pharyngeal region of human embryos from 7 to 28 mm crown-rump length, based on serial histological sections from the Boyd Collection. We considered the positions of the developing ossicles relative to the pharyngeal pouches and clefts, and the facial and chorda tympani nerves. Confirming observations from previous studies, the primary union between first pharyngeal pouch and first cleft found in our youngest specimens was later lost, the external meatus developing rostroventral to this position. The mesenchyme of the first and second arches in these early embryos seemed to be continuous, but the boundaries of the developing ossicles proved to be very hard to determine at this stage. When first distinguishable, the indications were that both the manubrium of the malleus and the long process of the incus were emerging within the first pharyngeal arch. We therefore conclude that the histological evidence, on balance, favours the 'classical' notion that the human malleus and incus are first-arch structures. The embryological basis of congenital ossicular abnormalities should be reconsidered in this light.This is the author accepted manuscript. The final version is available from Wiley via https://doi.org/10.1111/joa.1252

Evaluation of absorbent materials for use as ad hoc dry decontaminants during mass casualty incidents as part of the UK’s Initial Operational Response (IOR)

Copyright: © 2017 Kassouf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The UK's Initial Operational Response (IOR) is a revised process for the medical management of mass casualties potentially contaminated with hazardous materials. A critical element of the IOR is the introduction of immediate, on-scene disrobing and decontamination of casualties to limit the adverse health effects of exposure. Ad hoc cleansing of the skin with dry absorbent materials has previously been identified as a potential means of facilitating emergency decontamination. The purpose of this study was to evaluate the in vitro oil and water absorbency of a range of materials commonly found in the domestic and clinical environments and to determine the effectiveness of a small, but representative selection of such materials in skin decontamination, using an established ex vivo model. Five contaminants were used in the study: methyl salicylate, parathion, diethyl malonate, phorate and potassium cyanide. In vitro measurements of water and oil absorbency did not correlate with ex vivo measurements of skin decontamination. When measured ex vivo, dry decontamination was consistently more effective than a standard wet decontamination method ("rinse-wipe-rinse") for removing liquid contaminants. However, dry decontamination was ineffective against particulate contamination. Collectively, these data confirm that absorbent materials such as wound dressings and tissue paper provide an effective, generic capability for emergency removal of liquid contaminants from the skin surface, but that wet decontamination should be used for non-liquid contaminants.Peer reviewedFinal Published versio