Development and characterisation of in vitro human oral mucosal equivalents derived from immortalised oral keratinocytes.

Tissue engineered oral mucosal equivalents (OME) are being increasingly used to measure toxicity, drug delivery, and to model oral diseases. Current OME are mainly comprised of normal oral keratinocytes (NOK) cultured on top of a normal oral fibroblasts (NOF)-containing matrix. However, the commercial supply of NOK is limited, restricting widespread use of these mucosal models. In addition, NOK suffer from poor longevity and donor-to-donor variability. Therefore, we constructed, characterised and tested the functionality of oral mucosal equivalents based on commercial TERT2-immortalised oral keratinocytes (FNB6) in order to produce a more readily available alternative to NOK-based OME. FNB6 OME cultured at an air-to-liquid interface for 14 days exhibited expression of differentiation markers cytokeratin 13 in the suprabasal layers and cytokeratin 14 in basal layer of the epithelium. Proliferating cells were restricted to the basal epithelium and there was immuno-positive expression of E-cadherin confirming the presence of established cell-to-cell contacts. The histology and expression of these structural markers paralleled those observed in the normal oral mucosa and NOK-based models. Upon stimulation with TNFα & IL-1, FNB6 OME displayed a similar global gene expression profile to NOK-based OME with increased expression of many common pro-inflammatory molecules such as chemokines (CXCL8), cytokines (IL-6) and adhesion molecules (ICAM-1) when analysed by gene array and qPCR. Similarly, pathway analysis showed that both FNB6 and NOK models initiated similar intracellular signalling upon stimulation. Gene expression in FNB6 OME was more consistent than NOK-based OME that suffered from donor variation in response to stimuli. Mucosal equivalents based on immortalised FNB6 cells are accessible, reproducible and will provide an alternative animal experimental system for studying mucosal drug delivery systems, host-pathogen interactions and drug-induced toxicity

High-Resolution Continuum Imaging at 1.3 and 0.7 cm of the W3 IRS 5 Region

High-resolution images of the hypercompact HII regions (HCHII) in W3 IRS 5 taken with the Very Large Array (VLA) at 1.3 and 0.7 cm are presented. Four HCHII regions were detected with sufficient signal-to-noise ratios to allow the determination of relevant parameters such as source position, size and flux density. The sources are slightly extended in our ~0.2 arcsecond beams; the deconvolved radii are less than 240 AU. A comparison of our data with VLA images taken at epoch 1989.1 shows proper motions for sources IRS 5a and IRS 5f. Between 1989.1 and 2002.5, we find a proper motion of 210 mas at a position angle of 12 deg for IRS 5f and a proper motion of 190 mas at a position angle of 50 deg for IRS 5a. At the assumed distance to W3 IRS 5, 1.83 +/- 0.14 kpc, these offsets translate to proper motions of ~135 km/s and ~122 km/s$ respectively. These sources are either shock ionized gas in an outflow or ionized gas ejected from high mass stars. We find no change in the positions of IRS 5d1/d2 and IRS 5b; and we show through a comparison with archival NICMOS 2.2 micron images that these two radio sources coincide with the infrared double constituting W3 IRS 5. These sources contain B or perhaps O stars. The flux densities of the four sources have changed compared to the epoch 1989.1 results. In our epoch 2002.5 data, none of the spectral indicies obtained from flux densities at 1.3 and 0.7 cm are consistent with optically thin free-free emission; IRS 5d1/d2 shows the largest increase in flux density from 1.3 cm to 0.7 cm. This may be an indication of free-free optical depth within an ionized wind, a photoevaporating disk, or an accretion flow. It is less likely that this increase is caused by dust emission at 0.7 cm.Comment: 13 pages, 3 figures To be published in The Astrophysical Journa

An S-shaped arc in the galaxy cluster RXJ0054.0-2823

The center of the galaxy cluster RX J0054.0-2823 at z = 0.292 is a dynamically active region which includes an interacting system of three galaxies surrounded by a large halo of intra-cluster light. We report here the discovery of an S-shaped feature of total length 11 arcsec in the central region of this cluster and discuss its physical nature. We test the gravitational lensing assumption by doing a mass modelling of the central part of the galaxy cluster. We very naturally reproduce position and form of this S-shape feature as a gravitationally lensed background object at redshift between 0.5 and 1.0. We conclude that the lensing nature is the very probable explanation for this S-shaped arc; the ultimate proof will be the spectroscopic confirmation by measuring the high redshift of this elongated feature with surface brightness V~24mag/arcsec2.Comment: 6 pages, accepted for publication in A&

A mathematical investigation into the uptake kinetics of nanoparticles in vitro

Nanoparticles have the potential to increase the efficacy of anticancer drugs whilst reducing off-target side effects. However, there remain uncertainties regarding the cellular uptake kinetics of nanoparticles which could have implications for nanoparticle design and delivery. Polymersomes are nanoparticle candidates for cancer therapy which encapsulate chemotherapy drugs. Here we develop a mathematical model to simulate the uptake of polymersomes via endocytosis, a process by which polymersomes bind to the cell surface before becoming internalised by the cell where they then break down, releasing their contents which could include chemotherapy drugs. We focus on two in vitro configurations relevant to the testing and development of cancer therapies: a well-mixed culture model and a tumour spheroid setup. Our mathematical model of the well-mixed culture model comprises a set of coupled ordinary differential equations for the unbound and bound polymersomes and associated binding dynamics. Using a singular perturbation analysis we identify an optimal number of ligands on the polymersome surface which maximises internalised polymersomes and thus intracellular chemotherapy drug concentration. In our mathematical model of the spheroid, a multiphase system of partial differential equations is developed to describe the spatial and temporal distribution of bound and unbound polymersomes via advection and diffusion, alongside oxygen, tumour growth, cell proliferation and viability. Consistent with experimental observations, the model predicts the evolution of oxygen gradients leading to a necrotic core. We investigate the impact of two different internalisation functions on spheroid growth, a constant and a bond dependent function. It was found that the constant function yields faster uptake and therefore chemotherapy delivery. We also show how various parameters, such as spheroid permeability, lead to travelling wave or steady-state solutions

Topology of structure in the Sloan Digital Sky Survey: model testing

We measure the three-dimensional topology of large-scale structure in the Sloan Digital Sky Survey (SDSS). This allows the genus statistic to be measured with unprecedented statistical accuracy. The sample size is now sufficiently large to allow the topology to be an important tool for testing galaxy formation models. For comparison, we make mock SDSS samples using several state-of-the-art N-body simulations: the Millennium run of Springel et al. (2005)(10 billion particles), Kim & Park (2006) CDM models (1.1 billion particles), and Cen & Ostriker (2006) hydrodynamic code models (8.6 billion cell hydro mesh). Each of these simulations uses a different method for modeling galaxy formation. The SDSS data show a genus curve that is broadly characteristic of that produced by Gaussian random phase initial conditions. Thus the data strongly support the standard model of inflation where Gaussian random phase initial conditions are produced by random quantum fluctuations in the early universe. But on top of this general shape there are measurable differences produced by non-linear gravitational effects (cf. Matsubara 1994), and biasing connected with galaxy formation. The N-body simulations have been tuned to reproduce the power spectrum and multiplicity function but not topology, so topology is an acid test for these models. The data show a ``meatball'' shift (only partly due to the Sloan Great Wall of Galaxies; this shift also appears in a sub-sample not containing the Wall) which differs at the 2.5\sigma level from the results of the Millennium run and the Kim & Park dark halo models, even including the effects of cosmic variance.Comment: 13 Apj pages, 7 figures High-resolution stereo graphic available at http://www.astro.princeton.edu/~dclayh/stereo50.ep

Curvature of the Universe and Observed Gravitational Lens Image Separations Versus Redshift

In a flat, k=0 cosmology with galaxies that approximate singular isothermal spheres, gravitational lens image separations should be uncorrelated with source redshift. But in an open k=-1 cosmology such gravitational lens image separations become smaller with increasing source redshift. The observed separations do become smaller with increasing source redshift but the effect is even stronger than that expected in an Omega=0 cosmology. The observations are thus not compatible with the "standard" gravitational lensing statistics model in a flat universe. We try various open and flat cosmologies, galaxy mass profiles, galaxy merging and evolution models, and lensing aided by clusters to explain the correlation. We find the data is not compatible with any of these possibilities within the 95% confidence limit, leaving us with a puzzle. If we regard the observed result as a statistical fluke, it is worth noting that we are about twice as likely to observe it in an open universe (with 0<Omega<0.4) as we are to observe it in a flat one. Finally, the existence of an observed multiple image lens system with a source at z=4.5 places a lower limit on the deceleration parameter: q_0 > -2.0.Comment: 21 pages, 4 figures, AASTeX

1934: Abilene Christian College Bible Lectures - Full Text

INTRODUCTION The theme for the Lectures for 1934, “The New Testament Church in History,” is a very timely one and follows naturally the theme of the 1933 Lectures, “The Church We Read About in the New Testament.” There is no subject that is so vital in our work as Christians today as a proper understanding of the great spiritual kingdom of our Savior, the church which was built by Jesus Christ. It is a hard lesson to teach because all people are so dull of hearing concerning things spiritual. Just as Nicodemus marveled when the Christ told him of the spiritual kingdom so do people today wonder and marvel when they are told that there is only one great church, the spiritual kingdom of our Lord and Savior Jesus Christ, and that all the saved of earth belong to that church and that belonging to anything else profits little, and is unnecessary. Not only are numbers of denominational churches and people who have no religious affiliation ignorant of the true meaning of the church, but even those who claim to be members of the one body are lacking in understanding concerning the kingdom of Christ. It is therefore the purpose of the Abilene College Lectures last year, this year and next year to arouse a greater interest in the study and the teaching of this very vital matter. In this particular volume much valuable information is brought together on the trials and struggles of the church from its foundations to the present. The speakers have made careful preparation on their subjects and have given lessons that should prove helpful to all who desire to have a better understanding of the church. Our prayer is that these Lectures may be read by many and that they may do much good in the name of the Christ. Jas. F. Cox,President, Abilene Christian College. Nov. 6, 1934

Cross-sectional associations between sleep duration, sedentary time, physical activity, and adiposity indicators among Canadian preschool-aged children using compositional analyses

Abstract Background Sleep duration, sedentary behaviour, and physical activity are three co-dependent behaviours that fall on the movement/non-movement intensity continuum. Compositional data analyses provide an appropriate method for analyzing the association between co-dependent movement behaviour data and health indicators. The objectives of this study were to examine: (1) the combined associations of the composition of time spent in sleep, sedentary behaviour, light-intensity physical activity (LPA), and moderate- to vigorous-intensity physical activity (MVPA) with adiposity indicators; and (2) the association of the time spent in sleep, sedentary behaviour, LPA, or MVPA with adiposity indicators relative to the time spent in the other behaviours in a representative sample of Canadian preschool-aged children. Methods Participants were 552 children aged 3 to 4 years from cycles 2 and 3 of the Canadian Health Measures Survey. Sedentary time, LPA, and MVPA were measured with Actical accelerometers (Philips Respironics, Bend, OR USA), and sleep duration was parental reported. Adiposity indicators included waist circumference (WC) and body mass index (BMI) z-scores based on World Health Organization growth standards. Compositional data analyses were used to examine the cross-sectional associations. Results The composition of movement behaviours was significantly associated with BMI z-scores (p = 0.006) but not with WC (p = 0.718). Further, the time spent in sleep (BMI z-score: γ sleep  = −0.72; p = 0.138; WC: γ sleep  = −1.95; p = 0.285), sedentary behaviour (BMI z-score: γ SB  = 0.19; p = 0.624; WC: γ SB  = 0.87; p = 0.614), LPA (BMI z-score: γ LPA  = 0.62; p = 0.213, WC: γ LPA  = 0.23; p = 0.902), or MVPA (BMI z-score: γ MVPA  = −0.09; p = 0.733, WC: γ MVPA  = 0.08; p = 0.288) relative to the other behaviours was not significantly associated with the adiposity indicators. Conclusions This study is the first to use compositional analyses when examining associations of co-dependent sleep duration, sedentary time, and physical activity behaviours with adiposity indicators in preschool-aged children. The overall composition of movement behaviours appears important for healthy BMI z-scores in preschool-aged children. Future research is needed to determine the optimal movement behaviour composition that should be promoted in this age group

Activity of immunoproteasome inhibitor ONX-0914 in acute lymphoblastic leukemia expressing MLL–AF4 fusion protein

Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL–AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Many of these toxicities are caused by on-target inhibition of proteasomes in non-lymphoid tissues (e.g., heart muscle, gut, testicles). We found that MLL–AF4 cells express high levels of lymphoid tissue-specific immunoproteasomes and are sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914, even in the presence of stromal cells. Inhibition of multiple active sites of the immunoproteasomes was required to achieve cytotoxicity against ALL. ONX-0914, an inhibitor of LMP7 (ß5i) and LMP2 (ß1i) sites of the immunoproteasome, and LU-102, inhibitor of proteasome ß2 sites, exhibited synergistic cytotoxicity. Treatment with ONX-0914 significantly delayed the growth of orthotopic ALL xenograft tumors in mice. T-cell ALL lines were also sensitive to pharmacologically relevant concentrations of ONX-0914. This study provides a strong rationale for testing clinical stage immunoproteasome inhibitors KZ-616 and M3258 in ALL

A new view of electrochemistry at highly oriented pyrolytic graphite

Major new insights on electrochemical processes at graphite electrodes are reported, following extensive investigations of two of the most studied redox couples, Fe(CN)64–/3– and Ru(NH3)63+/2+. Experiments have been carried out on five different grades of highly oriented pyrolytic graphite (HOPG) that vary in step-edge height and surface coverage. Significantly, the same electrochemical characteristic is observed on all surfaces, independent of surface quality: initial cyclic voltammetry (CV) is close to reversible on freshly cleaved surfaces (>400 measurements for Fe(CN)64–/3– and >100 for Ru(NH3)63+/2+), in marked contrast to previous studies that have found very slow electron transfer (ET) kinetics, with an interpretation that ET only occurs at step edges. Significantly, high spatial resolution electrochemical imaging with scanning electrochemical cell microscopy, on the highest quality mechanically cleaved HOPG, demonstrates definitively that the pristine basal surface supports fast ET, and that ET is not confined to step edges. However, the history of the HOPG surface strongly influences the electrochemical behavior. Thus, Fe(CN)64–/3– shows markedly diminished ET kinetics with either extended exposure of the HOPG surface to the ambient environment or repeated CV measurements. In situ atomic force microscopy (AFM) reveals that the deterioration in apparent ET kinetics is coupled with the deposition of material on the HOPG electrode, while conducting-AFM highlights that, after cleaving, the local surface conductivity of HOPG deteriorates significantly with time. These observations and new insights are not only important for graphite, but have significant implications for electrochemistry at related carbon materials such as graphene and carbon nanotubes