A Genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology

We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org

Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer

Colorectal cancer is initiated in colonic crypts. A succession of genetic mutations or epigenetic changes can lead to homeostasis in the crypt being overcome, and subsequent unbounded growth. We consider the dynamics of a single colorectal crypt by using a compartmental approach [Tomlinson IPM, Bodmer WF (1995) Proc Natl Acad Sci USA 92: 11130-11134], which accounts for populations of stem cells, differential cells, and transit cells. That original model made the simplifying assumptions that each cell popuation divides synchronously, but we relax these assumptions by adopting an age-structured approach that models asynchronous cell division, and by using a continuum model. We discuss two mechanims that could regulate the growth of cell numbers and maintain the equilibrium that is normally observed in the crypt. The first will always maintain an equilibrium for all parameter values, whereas the second can allow unbounded proliferation if the net per capita growth rates are large enough. Results show that an increase in cell renewal, which is equivalent to a failure of programmed cell death or of differentiation, can lead to the growth of cancers. The second model can be used to explain the long lag phases in tumor growth, during which news, higher equilibria are reached, before unlimited growth in cell number ensues

Multiphoton microfabrication of conducting polymer-based biomaterials

We report the application of multiphoton microfabrication to prepare conducting polymer (CP)-based biomaterials that were capable of drug delivery and interacting with brain tissue ex vivo, thereby highlighting the potential of multiphoton lithography to prepare electroactive biomaterials which may function as implantable neural biointerfaces (e.g. electrodes)

Toward semiclassical theory of quantum level correlations of generic chaotic systems

In the present work we study the two-point correlation function $R(\epsilon)$ of the quantum mechanical spectrum of a classically chaotic system. Recently this quantity has been computed for chaotic and for disordered systems using periodic orbit theory and field theory. In this work we present an independent derivation, which is based on periodic orbit theory. The main ingredient in our approach is the use of the spectral zeta function and its autocorrelation function $C(\epsilon)$. The relation between $R(\epsilon)$ and $C(\epsilon)$ is constructed by making use of a probabilistic reasoning similar to that which has been used for the derivation of Hardy -- Littlewood conjecture. We then convert the symmetry properties of the function $C(\epsilon)$ into relations between the so-called diagonal and the off-diagonal parts of $R(\epsilon)$. Our results are valid for generic systems with broken time reversal symmetry, and with non-commensurable periods of the periodic orbits.Comment: 15 pages(twocolumn format), LaTeX, EPSF, (figures included

Superconducting Gap and Strong In-Plane Anisotropy in Untwinned YBa2Cu3O7-d

With significantly improved sample quality and instrumental resolution, we clearly identify in the (pi,0) ARPES spectra from YBa2Cu3O6.993, in the superconducting state, the long-sought `peak-dip-hump' structure. This advance allows us to investigate the large a-b anisotropy of the in-plane electronic structure including, in particular, a 50% difference in the magnitude of the superconducting gap that scales with the energy position of the hump feature. This anisotropy, likely induced by the presence of the CuO chains, raises serious questions about attempts to quantitatively explain the YBa2Cu3O7-d data from various experiments using models based on a perfectly square lattice.Comment: Phys. Rev. Lett., in press. Revtex, 4 pages, 4 postscript figures embedded in the tex

Change management: The case of the elite sport performance team

The effective and efficient implementation of change is often required for both successful performance and management survival across a host of contemporary domains. However, although of major theoretical and practical significance, research to date has overlooked the application of change management (hereafter CM) knowledge to the elite sport performance team environment. Considering that the success of ‘off-field’ sports businesses are largely dependent on the performances of their ‘on-field’ team, this article explores the application of current CM theorizing to this specific setting and the challenges facing its utility. Accordingly, we identify the need and importance of developing theory specific to this area, with practical application in both sport and business, through examination of current knowledge and identification of the domain's unique, dynamic and contested properties. Markers of successful change are then suggested to guide initial enquiry before the article concludes with proposed lines of research which may act to provide a valid and comprehensive theoretical account of CM to optimize the research and practice of those working in the field

Plaque contact and unimpaired Trem2 is required for the microglial response to amyloid pathology

Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia-touching plaques, neighboring plaques, and far from plaques in an aged Alzheimer’s mouse model with late plaque development. In 18-month-old APPNL-F/NL-F knockin mice, with and without the Alzheimer’s disease risk mutation Trem2R47H/R47H, we report that expression of 38/55 PIGs have plaque-induced microglial upregulation, with a subset only upregulating in microglia directly contacting plaques. For seven PIGs, including Trem2, this upregulation is prevented in APPNL-F/NL-FTrem2R47H/R47H mice. These TREM2-dependent genes are all involved in phagocytic and degradative processes that we show correspond to a decrease in phagocytic markers and an increase in the density of small plaques in Trem2-mutated mice. Furthermore, despite the R47H mutation preventing increased Trem2 gene expression, TREM2 protein levels and microglial density are still marginally increased on plaques. Hence, both microglial contact with plaques and functioning TREM2 are necessary for microglia to respond appropriately to amyloid patholog

Upregulation of Trem2 expression occurs exclusively on microglial contact with plaques

Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia touching plaques, neighboring plaques, and far from plaques in 18-month-old APPNLF/NLF knock-in mice with and without the Alzheimer’s disease risk mutation Trem2R47H/R47H. We report that, in AppNLF/NLF mice, expression of 35/55 PIGs, is exclusively upregulated in microglia that are touching plaques. In 7 PIGs including Trem2 this upregulation is prevented by the Trem2R47H/R47H mutation. Unlike in young mice, knockin of the Trem2R47H/R47H mutation does not significantly decrease the Trem2 expression but decreases protein levels by 20% in the absence of plaques. On plaques, despite the mutation preventing increased gene expression, TREM2 protein levels increased by 1.6-fold (compared to 3-fold with Trem2WT/WT) and microglial density increased 20-fold compared to 30-fold. Hence microglia must touch plaques before Trem2 gene expression is increased but small changes in protein expression can increase microglia density without a change in gene expression

Extremal-point Densities of Interface Fluctuations

We introduce and investigate the stochastic dynamics of the density of local extrema (minima and maxima) of non-equilibrium surface fluctuations. We give a number of exact, analytic results for interface fluctuations described by linear Langevin equations, and for on-lattice, solid-on-solid surface growth models. We show that in spite of the non-universal character of the quantities studied, their behavior against the variation of the microscopic length scales can present generic features, characteristic to the macroscopic observables of the system. The quantities investigated here present us with tools that give an entirely un-orthodox approach to the dynamics of surface morphologies: a statistical analysis from the short wavelength end of the Fourier decomposition spectrum. In addition to surface growth applications, our results can be used to solve the asymptotic scalability problem of massively parallel algorithms for discrete event simulations, which are extensively used in Monte-Carlo type simulations on parallel architectures.Comment: 30 pages, 5 ps figure