Three Dimensional Visualization and Fractal Analysis of Mosaic Patches in Rat Chimeras: Cell Assortment in Liver, Adrenal Cortex and Cornea

The production of organ parenchyma in a rapid and reproducible manner is critical to normal development. In chimeras produced by the combination of genetically distinguishable tissues, mosaic patterns of cells derived from the combined genotypes can be visualized. These patterns comprise patches of contiguously similar genotypes and are different in different organs but similar in a given organ from individual to individual. Thus, the processes that produce the patterns are regulated and conserved. We have previously established that mosaic patches in multiple tissues are fractal, consistent with an iterative, recursive growth model with simple stereotypical division rules. Fractal dimensions of various tissues are consistent with algorithmic models in which changing a single variable (e.g. daughter cell placement after division) switches the mosaic pattern from islands to stripes of cells. Here we show that the spiral pattern previously observed in mouse cornea can also be visualized in rat chimeras. While it is generally held that the pattern is induced by stem cell division dynamics, there is an unexplained discrepancy in the speed of cellular migration and the emergence of the pattern. We demonstrate in chimeric rat corneas both island and striped patterns exist depending on the age of the animal. The patches that comprise the pattern are fractal, and the fractal dimension changes with the age of the animal and indicates the constraint in patch complexity as the spiral pattern emerges. The spiral patterns are consistent with a loxodrome. Such data are likely to be relevant to growth and cell division in organ systems and will help in understanding how organ parenchyma are generated and maintained from multipotent stem cell populations located in specific topographical locations within the organ. Ultimately, understanding algorithmic growth is likely to be essential in achieving organ regeneration in vivo or in vitro from stem cell populations

One-year treatment with mometasone furoate in chronic obstructive pulmonary disease

Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing

Dynamic modeling of mean-reverting spreads for statistical arbitrage

Statistical arbitrage strategies, such as pairs trading and its generalizations, rely on the construction of mean-reverting spreads enjoying a certain degree of predictability. Gaussian linear state-space processes have recently been proposed as a model for such spreads under the assumption that the observed process is a noisy realization of some hidden states. Real-time estimation of the unobserved spread process can reveal temporary market inefficiencies which can then be exploited to generate excess returns. Building on previous work, we embrace the state-space framework for modeling spread processes and extend this methodology along three different directions. First, we introduce time-dependency in the model parameters, which allows for quick adaptation to changes in the data generating process. Second, we provide an on-line estimation algorithm that can be constantly run in real-time. Being computationally fast, the algorithm is particularly suitable for building aggressive trading strategies based on high-frequency data and may be used as a monitoring device for mean-reversion. Finally, our framework naturally provides informative uncertainty measures of all the estimated parameters. Experimental results based on Monte Carlo simulations and historical equity data are discussed, including a co-integration relationship involving two exchange-traded funds.Comment: 34 pages, 6 figures. Submitte

Molecular motors robustly drive active gels to a critically connected state

Living systems often exhibit internal driving: active, molecular processes drive nonequilibrium phenomena such as metabolism or migration. Active gels constitute a fascinating class of internally driven matter, where molecular motors exert localized stresses inside polymer networks. There is evidence that network crosslinking is required to allow motors to induce macroscopic contraction. Yet a quantitative understanding of how network connectivity enables contraction is lacking. Here we show experimentally that myosin motors contract crosslinked actin polymer networks to clusters with a scale-free size distribution. This critical behavior occurs over an unexpectedly broad range of crosslink concentrations. To understand this robustness, we develop a quantitative model of contractile networks that takes into account network restructuring: motors reduce connectivity by forcing crosslinks to unbind. Paradoxically, to coordinate global contractions, motor activity should be low. Otherwise, motors drive initially well-connected networks to a critical state where ruptures form across the entire network.Comment: Main text: 21 pages, 5 figures. Supplementary Information: 13 pages, 8 figure

Advances in estimation by the item sum technique using auxiliary information in complex surveys

To collect sensitive data, survey statisticians have designed many strategies to reduce nonresponse rates and social desirability response bias. In recent years, the item count technique (ICT) has gained considerable popularity and credibility as an alternative mode of indirect questioning survey, and several variants of this technique have been proposed as new needs and challenges arise. The item sum technique (IST), which was introduced by Chaudhuri and Christofides (2013) and Trappmann et al. (2014), is one such variant, used to estimate the mean of a sensitive quantitative variable. In this approach, sampled units are asked to respond to a two-list of items containing a sensitive question related to the study variable and various innocuous, nonsensitive, questions. To the best of our knowledge, very few theoretical and applied papers have addressed the IST. In this article, therefore, we present certain methodological advances as a contribution to appraising the use of the IST in real-world surveys. In particular, we employ a generic sampling design to examine the problem of how to improve the estimates of the sensitive mean when auxiliary information on the population under study is available and is used at the design and estimation stages. A Horvitz-Thompson type estimator and a calibration type estimator are proposed and their efficiency is evaluated by means of an extensive simulation study. Using simulation experiments, we show that estimates obtained by the IST are nearly equivalent to those obtained using “true data” and that in general they outperform the estimates provided by a competitive randomized response method. Moreover, the variance estimation may be considered satisfactory. These results open up new perspectives for academics, researchers and survey practitioners, and could justify the use of the IST as a valid alternative to traditional direct questioning survey modes.Ministerio de Economía y Competitividad of SpainMinisterio de Educacion, Cultura y Deporteproject PRIN-SURWE

Syzygium jambolanum treatment improves survival in lethal sepsis induced in mice

<p>Abstract</p> <p>Background</p> <p>The leaves and the fruits from <it>Syzygium jambolanum </it>DC.(Myrtaceae), a plant known in Brazil as sweet olive or 'jambolão', have been used by native people to treat infectious diseases, diabetes, and stomachache. Since the bactericidal activity of <it>S. jambolanum </it>has been confirmed <it>in vitro</it>, the aim of this work was to evaluate the effect of the prophylactic treatment with <it>S. jambolanum </it>on the <it>in vivo </it>polymicrobial infection induced by cecal ligation and puncture (CLP) in mice.</p> <p>Methods</p> <p>C57Bl/6 mice were treated by the subcutaneous route with a hydroalcoholic extract from fresh leaves of <it>S. jambolanum </it>(HCE). After 6 h, a bacterial infection was induced in the peritoneum using the lethal CLP model. The mice were killed 12 h after the CLP induction to evaluate the cellular influx and local and systemic inflammatory mediators' production. Some animals were maintained alive to evaluate the survival rate.</p> <p>Results</p> <p>The prophylactic HCE treatment increased the mice survival, the neutrophil migration to infectious site, the spreading ability and the hydrogen peroxide release, but decreased the serum TNF and nitrite. Despite the increased migration and activation of peritoneal cells the HCE treatment did not decrease the number of CFU. The HCE treatment induced a significant decrease on the bone marrow cells number but did not alter the cell number of the spleen and lymph node.</p> <p>Conclusion</p> <p>We conclude that the treatment with <it>S. jambolanum </it>has a potent prophylactic anti-septic effect that is not associated to a direct microbicidal effect but it is associated to a recruitment of activated neutrophils to the infectious site and to a diminished systemic inflammatory response.</p

Comprehensive Assignment of Roles for Salmonella Typhimurium Genes in Intestinal Colonization of Food-Producing Animals

Chickens, pigs, and cattle are key reservoirs of Salmonella enterica, a foodborne pathogen of worldwide importance. Though a decade has elapsed since publication of the first Salmonella genome, thousands of genes remain of hypothetical or unknown function, and the basis of colonization of reservoir hosts is ill-defined. Moreover, previous surveys of the role of Salmonella genes in vivo have focused on systemic virulence in murine typhoid models, and the genetic basis of intestinal persistence and thus zoonotic transmission have received little study. We therefore screened pools of random insertion mutants of S. enterica serovar Typhimurium in chickens, pigs, and cattle by transposon-directed insertion-site sequencing (TraDIS). The identity and relative fitness in each host of 7,702 mutants was simultaneously assigned by massively parallel sequencing of transposon-flanking regions. Phenotypes were assigned to 2,715 different genes, providing a phenotype–genotype map of unprecedented resolution. The data are self-consistent in that multiple independent mutations in a given gene or pathway were observed to exert a similar fitness cost. Phenotypes were further validated by screening defined null mutants in chickens. Our data indicate that a core set of genes is required for infection of all three host species, and smaller sets of genes may mediate persistence in specific hosts. By assigning roles to thousands of Salmonella genes in key reservoir hosts, our data facilitate systems approaches to understand pathogenesis and the rational design of novel cross-protective vaccines and inhibitors. Moreover, by simultaneously assigning the genotype and phenotype of over 90% of mutants screened in complex pools, our data establish TraDIS as a powerful tool to apply rich functional annotation to microbial genomes with minimal animal use

SIV Nef Proteins Recruit the AP-2 Complex to Antagonize Tetherin and Facilitate Virion Release

Lentiviral Nef proteins have multiple functions and are important for viral pathogenesis. Recently, Nef proteins from many simian immunodefiency viruses were shown to antagonize a cellular antiviral protein, named Tetherin, that blocks release of viral particles from the cell surface. However, the mechanism by which Nef antagonizes Tetherin is unknown. Here, using related Nef proteins that differ in their ability to antagonize Tetherin, we identify three amino-acids in the C-terminal domain of Nef that are critical specifically for its ability to antagonize Tetherin. Additionally, divergent Nef proteins bind to the AP-2 clathrin adaptor complex, and we show that residues important for this interaction are required for Tetherin antagonism, downregulation of Tetherin from the cell surface and removal of Tetherin from sites of particle assembly. Accordingly, depletion of AP-2 using RNA interference impairs the ability of Nef to antagonize Tetherin, demonstrating that AP-2 recruitment is required for Nef proteins to counteract this antiviral protein

Impact of surface adhesion and sample heterogeneity on the multiscale mechanical characterisation of soft biomaterials

Funding from the Engineering and Physical Sciences Research Council (EP/L505602/1) is gratefully acknowledged