Characterization of G protein-coupled estrogen receptor (GPER) in breast epithelial proliferation and morphogenesis

Estrogen (17β-estradiol, E2) plays an important role in regulating an array of functions in both male and female reproductive physiology. In the mammary gland, E2-induced proliferation, ductal outgrowth and subsequent branching morphogenesis is required for proper development of the breast. In males, E2 is required for proper testicular development, spermatogenesis, and sperm maturation in the epididymis, but can also negatively regulate these functions with inappropriate exposure. The effects of E2 in these organs have long been attributed to classical estrogen receptors (ERα and ERβ), due to the observed effects in ER-/- mice; however, GPER is abundantly expressed in male and female reproductive organs, including the breast, testes and epididymis, and there is increasing evidence that GPER contributes to E2-induced functions in these tissues. For this study, we were interested in the contribution of GPER to E2-induced processes in 1) the breast; proliferation and morphogenesis, 2) the testes; regulation of spermatogenesis and morphology, and 3) the epididymis; specifically morphological regulation. Since proliferation and morphogenesis in the mammary gland are under tight E2 control and GPER is able mediated E2-induced proliferation in breast cancer cells, we were interested to see if GPER mediates E2-induced proliferation and morphogenesis in breast epithelial cells (MCF10A cell line) and in human breast tissue. E2 and G-1 stimulation in human breast tissue led to significant increase in proliferation measured by Ki-67 staining, and led to distinct morphological changes including an E2-induced increase in epithelial height in alveolar structures and a G-1-induced increase in luminal area after seven days in culture. E2-and G-1 also stimulated proliferation in MCF10A cells and this is dependent on epidermal growth factor receptor (EGFR) transactivation and mitogen activated protein kinase (MAPK) activation. Other observations in chapter 3, including a G-1-induced reduction in E-cadherin protein expression (breast tissue) and a G-1-induced increase in focal adhesion kinase (FAK) activation (MCF10A cells) suggest that regulation of GPER-mediated morphological changes involves regulation of cell-cell adhesion proteins. To determine the contribution of GPER to E2-induced spermatogenesis and morphology in male reproductive organs, we subcutaneously implanted C57BL/6 male mice with 21-day release E2 and G-1 pellets, and then investigated morphological effects on the testes and epididymis. G-1 had no effect on spermatogenesis or testicular morphology (unlike estrogen which impairs proper testicular morphology and abolishes spermatogenesis); however, G-1 treatment significantly increased the luminal area of epithelial structures in the epididymis. We have demonstrated in this study that while GPER doesnt mediate the entirety of estrogen\u27s effect in female and male reproductive physiology, GPER-contributes to E2-induced proliferation in the mammary gland and to the regulation of morphogenesis of epithelial structures in the breast and the epididymis

Planning and costing for the acceleration of actions for nutrition: experiences of countries in the Movement for Scaling Up Nutrition

This report is a synthesis of work undertaken by countries in the movement for Scaling Up Nutrition (SUN). The costed nutrition plans for 20 countries are analysed, looking at the assumptions made, the priority areas and targets which were set and the methods used, to determine whether they are responsive to the identified needs. It provides a basis for identifying priority areas for investment in each country, exploring answers to the questions - Are plans aligned with evidence-based recommendations? Is responsibility going beyond health sector? Which other sectors are engaged? What is the balance between specific nutrition interventions, nutrition-sensitive approaches and governance? What are the opportunities for non-Government stakeholders? Each country’s data is presented in a 2 page summary, outlining the scale of malnutrition, the distribution of programmes between specific, sensitive and governance and an outline of the costs, priorities and funding gaps. The plans themselves all have different strengths and weaknesses. This heterogeneity is inevitable, if only because countries have different interlinked sets of nutrition problems as this report clearly shows. But countries also have different sets of nutrition capacities. Importantly, the heterogeneity of the plans is a strength, not a weakness. As Lawrence Haddad concludes, “the plans serve as the most credible basis for investments to accelerate the reduction of undernutrition. They should be analysed, used, improved and backed

Asymptotic Scaling, Casimir Scaling, and Center Vortices

We report on two recent developments in the center vortex theory of confinement: (i) the asymptotic scaling of the vortex density, as measured in Monte Carlo simulations; and (ii) an explanation of Casimir scaling and the adjoint string tension, in terms of the center vortex mechanism.Comment: LATTICE98(confine), 3 pages, 3 figure

Scaling and Inverse Scaling in Anisotropic Bootstrap percolation

In bootstrap percolation it is known that the critical percolation threshold tends to converge slowly to zero with increasing system size, or, inversely, the critical size diverges fast when the percolation probability goes to zero. To obtain higher-order terms (that is, sharp and sharper thresholds) for the percolation threshold in general is a hard question. In the case of two-dimensional anisotropic models, sometimes correction terms can be obtained from inversion in a relatively simple manner.Comment: Contribution to the proceedings of the 2013 EURANDOM workshop Probabilistic Cellular Automata: Theory, Applications and Future Perspectives, equation typo corrected, constant of generalisation correcte

Transform Ranking: a New Method of Fitness Scaling in Genetic Algorithms

The first systematic evaluation of the effects of six existing forms of fitness scaling in genetic algorithms is presented alongside a new method called transform ranking. Each method has been applied to stochastic universal sampling (SUS) over a fixed number of generations. The test functions chosen were the two-dimensional Schwefel and Griewank functions. The quality of the solution was improved by applying sigma scaling, linear rank scaling, nonlinear rank scaling, probabilistic nonlinear rank scaling, and transform ranking. However, this benefit was always at a computational cost. Generic linear scaling and Boltzmann scaling were each of benefit in one fitness landscape but not the other. A new fitness scaling function, transform ranking, progresses from linear to nonlinear rank scaling during the evolution process according to a transform schedule. This new form of fitness scaling was found to be one of the two methods offering the greatest improvements in the quality of search. It provided the best improvement in the quality of search for the Griewank function, and was second only to probabilistic nonlinear rank scaling for the Schwefel function. Tournament selection, by comparison, was always the computationally cheapest option but did not necessarily find the best solutions

Rural to Urban Population Density Scaling of Crime and Property Transactions in English and Welsh Parliamentary Constituencies

Urban population scaling of resource use, creativity metrics, and human behaviors has been widely studied. These studies have not looked in detail at the full range of human environments which represent a continuum from the most rural to heavily urban. We examined monthly police crime reports and property transaction values across all 573 Parliamentary Constituencies in England and Wales, finding that scaling models based on population density provided a far superior framework to traditional population scaling. We found four types of scaling: i ) non-urban scaling in which a single power law explained the relationship between the metrics and population density from the most rural to heavily urban environments, ii ) accelerated scaling in which high population density was associated with an increase in the power-law exponent, iii ) inhibited scaling where the urban environment resulted in a reduction in the power-law exponent but remained positive, and iv ) collapsed scaling where transition to the high density environment resulted in a negative scaling exponent. Urban scaling transitions, when observed, took place universally between 10 and 70 people per hectare. This study significantly refines our understanding of urban scaling, making clear that some of what has been previously ascribed to urban environments may simply be the high density portion of non-urban scaling. It also makes clear that some metrics undergo specific transitions in urban environments and these transitions can include negative scaling exponents indicative of collapse. This study gives promise of far more sophisticated scale adjusted metrics and indicates that studies of urban scaling represent a high density subsection of overall scaling relationships which continue into rural environments

Effects of gauge theory based number scaling on geometry

Effects of local availability of mathematics (LAM) and space time dependent number scaling on physics and, especially, geometry are described. LAM assumes separate mathematical systems as structures at each space time point. Extension of gauge theories to include freedom of choice of scaling for number structures, and other structures based on numbers, results in a space time dependent scaling factor based on a scalar boson field. Scaling has no effect on comparison of experimental results with one another or with theory computations. With LAM all theory expressions are elements of mathematics at some reference point. Changing the reference point introduces (external) scaling. Theory expressions with integrals or derivatives over space or time include scaling factors (internal scaling) that cannot be removed by reference point change. Line elements and path lengths, as integrals over space and/or time, show the effect of scaling on geometry. In one example, the scaling factor goes to 0 as the time goes to 0, the big bang time. All path lengths, and values of physical quantities, are crushed to 0 as $t$ goes to 0. Other examples have spherically symmetric scaling factors about some point, $x.$ In one type, a black scaling hole, the scaling factor goes to infinity as the distance, $d$, between any point $y$ and $x$ goes to 0. For scaling white holes, the scaling factor goes to 0 as $d$ goes to 0. For black scaling holes, path lengths from a reference point, $z$, to $y$ become infinite as $y$ approaches $x.$ For white holes, path lengths approach a value much less than the unscaled distance from $z$ to $x.$Comment: 22 pages, 4 figures; to appear in proceedings, Quantum information and computation XI, SPIE conference proceedings, Vol. 8749, May 1-3, Baltimore, M