Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis

Cerebellar neuronal progenitors undergo a series of divisions before irreversibly exiting the cell cycle and differentiating into neurons. Dysfunction of this process underlies many neurological diseases including ataxia and the most common pediatric brain tumor, medulloblastoma. To better define the pathways controlling the most abundant neuronal cells in the mammalian cerebellum, cerebellar granule cell progenitors (GCPs), we performed RNA-sequencing of GCPs exiting the cell cycle. Time-series modeling of GCP cell cycle exit identified downregulation of activity of the epigenetic reader protein Brd4. Brd4 binding to the Gli1 locus is controlled by Casein Kinase 1δ (CK1 δ)-dependent phosphorylation during GCP proliferation, and decreases during GCP cell cycle exit. Importantly, conditional deletion of Brd4 in vivo in the developing cerebellum induces cerebellar morphological deficits and ataxia. These studies define an essential role for Brd4 in cerebellar granule cell neurogenesis and are critical for designing clinical trials utilizing Brd4 inhibitors in neurological indications

Toward Sensor Modular Autonomy for Persistent Land Intelligence Surveillance and Reconnaissance (ISR)

Currently, most land Intelligence, Surveillance and Reconnaissance (ISR) assets (e.g. EO/IR cameras) are simply data collectors. Understanding, decision making and sensor control are performed by the human operators, involving high cognitive load. Any automation in the system has traditionally involved bespoke design of centralised systems that are highly specific for the assets/targets/environment under consideration, resulting in complex, non-flexible systems that exhibit poor interoperability. We address a concept of Autonomous Sensor Modules (ASMs) for land ISR, where these modules have the ability to make low-level decisions on their own in order to fulfil a higher-level objective, and plug in, with the minimum of preconfiguration, to a High Level Decision Making Module (HLDMM) through a middleware integration layer. The dual requisites of autonomy and interoperability create challenges around information fusion and asset management in an autonomous hierarchical system, which are addressed in this work. This paper presents the results of a demonstration system, known as Sensing for Asset Protection with Integrated Electronic Networked Technology (SAPIENT), which was shown in realistic base protection scenarios with live sensors and targets. The SAPIENT system performed sensor cueing, intelligent fusion, sensor tasking, target hand-off and compensation for compromised sensors, without human control, and enabled rapid integration of ISR assets at the time of system deployment, rather than at design-time. Potential benefits include rapid interoperability for coalition operations, situation understanding with low operator cognitive burden and autonomous sensor management in heterogenous sensor systems

Dynamics of tournaments: the soccer case

A random walk-like model is considered to discuss statistical aspects of tournaments. The model is applied to soccer leagues with emphasis on the scores. This competitive system was computationally simulated and the results are compared with empirical data from the English, the German and the Spanish leagues and showed a good agreement with them. The present approach enabled us to characterize a diffusion where the scores are not normally distributed, having a short and asymmetric tail extending towards more positive values. We argue that this non-Gaussian behavior is related with the difference between the teams and with the asymmetry of the scores system. In addition, we compared two tournament systems: the all-play-all and the elimination tournaments.Comment: To appear in EPJ

Statistics of the contact network in frictional and frictionless granular packings

Simulated granular packings with different particle friction coefficient mu are examined. The distribution of the particle-particle and particle-wall normal and tangential contact forces P(f) are computed and compared with existing experimental data. Here f equivalent to F/F-bar is the contact force F normalized by the average value F-bar. P(f) exhibits exponential-like decay at large forces, a plateau/peak near f = 1, with additional features at forces smaller than the average that depend on mu. Computations of the force-force spatial distribution function and the contact point radial distribution function indicate that correlations between forces are only weakly dependent on friction and decay rapidly beyond approximately three particle diameters. Distributions of the particle-particle contact angles show that the contact network is not isotropic and only weakly dependent on friction. High force-bearing structures, or force chains, do not play a dominant role in these three dimensional, unloaded packings.Comment: 11 pages, 13 figures, submitted to PR

Control of inflammation by stromal Hedgehog pathway activation restrains colitis

Inflammation disrupts tissue architecture and function, thereby contributing to the pathogenesis of diverse diseases; the signals that promote or restrict tissue inflammation thus represent potential targets for therapeutic intervention. Here, we report that genetic or pharmacologic Hedgehog pathway inhibition intensifies colon inflammation (colitis) in mice. Conversely, genetic augmentation of Hedgehog response and systemic small-molecule Hedgehog pathway activation potently ameliorate colitis and restrain initiation and progression of colitis-induced adenocarcinoma. Within the colon, the Hedgehog protein signal does not act directly on the epithelium itself, but on underlying stromal cells to induce expression of IL-10, an immune-modulatory cytokine long known to suppress inflammatory intestinal damage. IL-10 function is required for the full protective effect of small-molecule Hedgehog pathway activation in colitis; this pharmacologic augmentation of Hedgehog pathway activity and stromal IL-10 expression are associated with increased presence of CD4(+) Foxp3(+) regulatory T cells. We thus identify stromal cells as cellular coordinators of colon inflammation and suggest their pharmacologic manipulation as a potential means to treat colitis.11138Ysciescopu

Discrete cilia modelling with singularity distributions

We discuss in detail techniques for modelling flows due to finite and infinite arrays of beating cilia. An efficient technique, based on concepts from previous ‘singularity models’ is described, that is accurate in both near and far-fields. Cilia are modelled as curved slender ellipsoidal bodies by distributing Stokeslet and potential source dipole singularities along their centrelines, leading to an integral equation that can be solved using a simple and efficient discretisation. The computed velocity on the cilium surface is found to compare favourably with the boundary condition. We then present results for two topics of current interest in biology. 1) We present the first theoretical results showing the mechanism by which rotating embryonic nodal cilia produce a leftward flow by a ‘posterior tilt,’ and track particle motion in an array of three simulated nodal cilia. We find that, contrary to recent suggestions, there is no continuous layer of negative fluid transport close to the ciliated boundary. The mean leftward particle transport is found to be just over 1 μm/s, within experimentally measured ranges. We also discuss the accuracy of models that represent the action of cilia by steady rotlet arrays, in particular, confirming the importance of image systems in the boundary in establishing the far-field fluid transport. Future modelling may lead to understanding of the mechanisms by which morphogen gradients or mechanosensing cilia convert a directional flow to asymmetric gene expression. 2) We develop a more complex and detailed model of flow patterns in the periciliary layer of the airway surface liquid. Our results confirm that shear flow of the mucous layer drives a significant volume of periciliary liquid in the direction of mucus transport even during the recovery stroke of the cilia. Finally, we discuss the advantages and disadvantages of the singularity technique and outline future theoretical and experimental developments required to apply this technique to various other biological problems, particularly in the reproductive system

Higher dimensional dust collapse with a cosmological constant

The general solution of the Einstein equation for higher dimensional (HD) spherically symmetric collapse of inhomogeneous dust in presence of a cosmological term, i.e., exact interior solutions of the Einstein field equations is presented for the HD Tolman-Bondi metrics imbedded in a de Sitter background. The solution is then matched to exterior HD Scwarschild-de Sitter. A brief discussion on the causal structure singularities and horizons is provided. It turns out that the collapse proceed in the same way as in the Minkowski background, i.e., the strong curvature naked singularities form and that the higher dimensions seem to favor black holes rather than naked singularities.Comment: 7 Pages, no figure

Theory of Two-Dimensional Quantum Heisenberg Antiferromagnets with a Nearly Critical Ground State

We present the general theory of clean, two-dimensional, quantum Heisenberg antiferromagnets which are close to the zero-temperature quantum transition between ground states with and without long-range N\'{e}el order. For N\'{e}el-ordered states, `nearly-critical' means that the ground state spin-stiffness, $\rho_s$, satisfies $\rho_s \ll J$, where $J$ is the nearest-neighbor exchange constant, while `nearly-critical' quantum-disordered ground states have a energy-gap, $\Delta$, towards excitations with spin-1, which satisfies $\Delta \ll J$. Under these circumstances, we show that the wavevector/frequency-dependent uniform and staggered spin susceptibilities, and the specific heat, are completely universal functions of just three thermodynamic parameters. Explicit results for the universal scaling functions are obtained by a $1/N$ expansion on the $O(N)$ quantum non-linear sigma model, and by Monte Carlo simulations. These calculations lead to a variety of testable predictions for neutron scattering, NMR, and magnetization measurements. Our results are in good agreement with a number of numerical simulations and experiments on undoped and lightly-doped $La_{2-\delta} Sr_{\delta}Cu O_4$.Comment: 81 pages, REVTEX 3.0, smaller updated version, YCTP-xxx

Understanding preventive behaviors among mid-Western African-American men: a pilot qualitative study of prostate screening

http://dx.doi.org/10.1016/j.jomh.2011.03.00

Shrinking a large dataset to identify variables associated with increased risk of Plasmodium falciparum infection in Western Kenya

Large datasets are often not amenable to analysis using traditional single-step approaches. Here, our general objective was to apply imputation techniques, principal component analysis (PCA), elastic net and generalized linear models to a large dataset in a systematic approach to extract the most meaningful predictors for a health outcome. We extracted predictors for Plasmodium falciparum infection, from a large covariate dataset while facing limited numbers of observations, using data from the People, Animals, and their Zoonoses (PAZ) project to demonstrate these techniques: data collected from 415 homesteads in western Kenya, contained over 1500 variables that describe the health, environment, and social factors of the humans, livestock, and the homesteads in which they reside. The wide, sparse dataset was simplified to 42 predictors of P. falciparum malaria infection and wealth rankings were produced for all homesteads. The 42 predictors make biological sense and are supported by previous studies. This systematic data-mining approach we used would make many large datasets more manageable and informative for decision-making processes and health policy prioritization