Fos co-operation with PTEN loss elicits keratoacanthoma not carcinoma due to p53/p21^WAF-induced differentiation triggered by GSK3b inactivation and reduced AKT activity

To investigate gene synergism in multistage skin carcinogenesis, the RU486-inducible cre/lox system was employed to ablate PTEN function [K14.cre/D5PTENflx] in mouse epidermis expressing activated v-fos [HK1.fos]. RU486-treated HK1.fos/D5PTENflx mice exhibited hyperplasia, hyperkeratosis and tumours that progressed to highly differentiated keratoacanthomas rather than carcinomas, due to re-expression of high p53 and p21WAF levels. Despite elevated MAP kinase activity, cyclin D1/E2 over expression and increased AKT activity forming areas of highly proliferative, papillomatous keratinocytes, increasing levels of GSK3b inactivation exceeded a threshold that induced p53/p21WAF expression to halt proliferation and accelerate differentiation, giving the hallmark keratosis of keratoacanthomas. A pivotal facet to this GSK3b-triggered mechanism centred on increasing p53 expression in basal layer keratinocytes. This reduced activated AKT expression and released inhibition of p21WAF, which accelerated keratinocyte differentiation, as indicated by unique basal layer expression of differentiation-specific keratin K1, alongside premature filaggrin and loricrin expression. Thus, fos synergism with PTEN loss elicited a benign tumour context where GSK3b-induced, p53/p21WAF expression continually switched AKT-associated proliferation into one of differentiation, preventing further progression. This putative compensatory mechanism required the critical availability of normal p53 and/or p21WAF otherwise deregulated fos, Akt and GSK3b associate with malignant progression

Synchronization and Coarsening (without SOC) in a Forest-Fire Model

We study the long-time dynamics of a forest-fire model with deterministic tree growth and instantaneous burning of entire forests by stochastic lightning strikes. Asymptotically the system organizes into a coarsening self-similar mosaic of synchronized patches within which trees regrow and burn simultaneously. We show that the average patch length grows linearly with time as t-->oo. The number density of patches of length L, N(L,t), scales as ^{-2}M(L/), and within a mean-field rate equation description we find that this scaling function decays as e^{-1/x} for x-->0, and as e^{-x} for x-->oo. In one dimension, we develop an event-driven cluster algorithm to study the asymptotic behavior of large systems. Our numerical results are consistent with mean-field predictions for patch coarsening.Comment: 5 pages, 4 figures, 2-column revtex format. To be submitted to PR

A General Buffer Scheme for the Windows Scheduling Problem

Broadcasting is an efficient alternative to unicast for delivering popular on-demand media requests. Broadcasting schemes that are based on windows scheduling algorithms provide a way to satisfy all requests with both low bandwidth and low latency. Consider a system of n pages that need to be scheduled (transmitted) on identical channels an infinite number of times. Time is slotted, and it takes one time slot to transmit each page. In the windows scheduling problem (WS) each page i, 1 ≤ i ≤ n, is associated with a request window wi. In a feasible schedule for WS, page i must be scheduled at least once in any window of wi time slots. The objective function is to minimize the number of channels required to schedule all the pages. The main contribution of this paper is the design of a general buffer scheme for the windows scheduling problem such that any algorithm for WS follows this scheme. As a result, this scheme can serve as a tool to analyze and/or exhaust all possible WS-algorithms. The buffer scheme is based on modelling the system as a nondeterministic finite state machine in which any directed cycle corresponds to a legal schedule and vice-versa. Since WS is NP-hard, w

Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid‐beta peptide levels in vivo

J Lipid Res. 2007 Apr;48(4):914-23. Epub 2007 Jan 18. Physiologically regulated transgenic ABCA1 does not reduce amyloid burden or amyloid-beta peptide levels in vivo. Hirsch-Reinshagen V, Chan JY, Wilkinson A, Tanaka T, Fan J, Ou G, Maia LF, Singaraja RR, Hayden MR, Wellington CL. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. Abstract ABCA1-deficient mice have low levels of poorly lipidated apolipoprotein E (apoE) and exhibit increased amyloid load. To test whether excess ABCA1 protects from amyloid deposition, we crossed APP/PS1 mice to ABCA1 bacterial artificial chromosome (BAC) transgenic mice. Compared with wild-type animals, the ABCA1 BAC led to a 50% increase in cortical ABCA1 protein and a 15% increase in apoE abundance, demonstrating that this BAC supports modest ABCA1 overexpression in brain. However, this was observed only in animals that do not deposit amyloid. Comparison of ABCA1/APP/PS1 mice with APP/PS1 controls revealed no differences in levels of brain ABCA1 protein, amyloid, Abeta, or apoE, despite clear retention of ABCA1 overexpression in the livers of these animals. To further investigate ABCA1 expression in the amyloid-containing brain, we then compared ABCA1 mRNA and protein levels in young and aged cortex and cerebellum of APP/PS1 and ABCA1/APP/PS1 animals. Compared with APP/PS1 controls, aged ABCA1/APP/PS1 mice exhibited increased ABCA1 mRNA, but not protein, selectively in cortex. Additionally, ABCA1 mRNA levels were not increased before amyloid deposition but were induced only in the presence of extensive Abeta and amyloid levels. These data suggest that an induction of ABCA1 expression may be associated with late-stage Alzheimer's neuropathology. PMID: 17235115 [PubMed - indexed for MEDLINE

The Effect of Shear on Phase-Ordering Dynamics with Order-Parameter-Dependent Mobility: The Large-n Limit

The effect of shear on the ordering-kinetics of a conserved order-parameter system with O(n) symmetry and order-parameter-dependent mobility \Gamma({\vec\phi}) \propto (1- {\vec\phi} ^2/n)^\alpha is studied analytically within the large-n limit. In the late stage, the structure factor becomes anisotropic and exhibits multiscaling behavior with characteristic length scales (t^{2\alpha+5}/\ln t)^{1/2(\alpha+2)} in the flow direction and (t/\ln t)^{1/2(\alpha+2)} in directions perpendicular to the flow. As in the \alpha=0 case, the structure factor in the shear-flow plane has two parallel ridges.Comment: 6 pages, 2 figure

The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease.

J Biol Chem. 2005 Dec 30;280(52):43243-56. Epub 2005 Oct 5. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. Hirsch-Reinshagen V, Maia LF, Burgess BL, Blain JF, Naus KE, McIsaac SA, Parkinson PF, Chan JY, Tansley GH, Hayden MR, Poirier J, Van Nostrand W, Wellington CL. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V4Z 5H5, Canada. Abstract ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required to maintain normal apoE levels and lipidation in the central nervous system. In addition, ABCA1 has been reported to modulate beta-amyloid (Abeta) production in vitro. These observations raise the possibility that ABCA1 may play a role in the pathogenesis of Alzheimer disease. Here we report that the deficiency of ABCA1 does not affect soluble or guanidine-extractable Abeta levels in Tg-SwDI/B or amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with a dramatic reduction in soluble apoE levels in brain. Although this reduction in apoE was expected to reduce the amyloid burden in vivo, we observed that the parenchymal and vascular amyloid load was increased in Tg-SwDI/B animals and was not diminished in APP/PS1 mice. Furthermore, we observed an increase in the proportion of apoE retained in the insoluble fraction, particularly in the APP/PS1 model. These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo. PMID: 16207707 [PubMed - indexed for MEDLINE

Scalar perturbation spectra from warm inflation

We present a numerical integration of the cosmological scalar perturbation equations in warm inflation. The initial conditions are provided by a discussion of the thermal fluctuations of an inflaton field and thermal radiation using a combination of thermal field theory and thermodynamics. The perturbation equations include the effects of a damping coefficient $\Gamma$ and a thermodynamic potential $V$. We give an analytic expression for the spectral index of scalar fluctuations in terms of a new slow-roll parameter constructed from $\Gamma$. A series of toy models, inspired by spontaneous symmetry breaking and a known form of the damping coefficient, lead to a spectrum with $n_s>1$ on large scales and $n_s<1$ on small scales.Comment: 12 pages, 5 figures, RevTeX 4, revised with extra figure

Possible origins of macroscopic left-right asymmetry in organisms

I consider the microscopic mechanisms by which a particular left-right (L/R) asymmetry is generated at the organism level from the microscopic handedness of cytoskeletal molecules. In light of a fundamental symmetry principle, the typical pattern-formation mechanisms of diffusion plus regulation cannot implement the "right-hand rule"; at the microscopic level, the cell's cytoskeleton of chiral filaments seems always to be involved, usually in collective states driven by polymerization forces or molecular motors. It seems particularly easy for handedness to emerge in a shear or rotation in the background of an effectively two-dimensional system, such as the cell membrane or a layer of cells, as this requires no pre-existing axis apart from the layer normal. I detail a scenario involving actin/myosin layers in snails and in C. elegans, and also one about the microtubule layer in plant cells. I also survey the other examples that I am aware of, such as the emergence of handedness such as the emergence of handedness in neurons, in eukaryote cell motility, and in non-flagellated bacteria.Comment: 42 pages, 6 figures, resubmitted to J. Stat. Phys. special issue. Major rewrite, rearranged sections/subsections, new Fig 3 + 6, new physics in Sec 2.4 and 3.4.1, added Sec 5 and subsections of Sec

Static quantities of the W boson in the SU_L(3) X U_X(1) model with right-handed neutrinos

The static electromagnetic properties of the $W$ boson, $\Delta \kappa$ and $\Delta Q$, are calculated in the SU_L(3)} \times U_X(1) model with right-handed neutrinos. The new contributions from this model arise from the gauge and scalar sectors. In the gauge sector there is a new contribution from a complex neutral gauge boson $Y^0$ and a singly-charged gauge boson $Y^\pm$. The mass of these gauge bosons, called bileptons, is expected to be in the range of a few hundreds of GeV according to the current bounds from experimental data. If the bilepton masses are of the order of 200 GeV, the size of their contribution is similar to that obtained in other weakly coupled theories. However the contributions to both $\Delta Q$ and $\Delta \kappa$ are negligible for very heavy or degenerate bileptons. As for the scalar sector, an scenario is examined in which the contribution to the $W$ form factors is identical to that of a two-Higgs-doublet model. It is found that this sector would not give large corrections to $\Delta \kappa$ and $\Delta Q$.Comment: New material included. Final version to apppear in Physical Review

Boundary Element Analysis of Thin Anisotropic Structures by a Self-regularization Scheme

In the conventional boundary element method (BEM), the presence of singular kernels in the boundary integral equation or integral identities causes serious inaccuracy of the numerical solutions when the source and field points are very close to each other. This situation occurs commonly in elastostatic analysis of thin structures. The numerical inaccuracy issue can be resolved by some regularization process. Very recently, the self-regularization scheme originally proposed by Cruse and Richardson (1996) for 2D stress analysis has been extended and modified by He and Tan (2013) to 3D elastostatics analysis of isotropic bodies. This paper deals with the extension of the technique developed by the latter authors to the elastostatics analysis of 3D thin, anisotropic structures using the self-regularized displacement boundary integral equation (BIE). The kernels of the BIE employ the double Fourier-series representations of the fundamental solutions as proposed by Shiah, Tan and Wang (2012) and Tan, Shiah and Wang (2013) recently. Numerical examples are presented to demonstrate the veracity of the scheme for BEM analysis of thin anisotropic bodies