Characterization of E2F1's oncogenic, apoptotic and tumor-suppressive activities utilizing the K5 mouse model

Though E2F1 is deregulated in most human cancers by mutations of the p16-cyclin D-Rb pathway, it also exhibits tumor suppressive activity. A transgenic mouse model overexpressing E2F1 under the control of the bovine keratin 5 (K5) promoter exhibits epidermal hyperplasia and spontaneously develops tumors in the skin and other epithelial tissues after one year of age. In a p53-deficient background, aberrant apoptosis in K5 E2F1 transgenic epidermis is reduced and tumorigenesis is accelerated. In sharp contrast, K5 E2F1 transgenic mice are resistant to papilloma formation in the DMBA/TPA two-stage carcinogenesis protocol. K5 E2F4 and K5 DP1 transgenic mice were also characterized and both display epidermal hyperplasia but do not develop spontaneous tumors even in cooperation with p53 deficiency. These transgenic mice do not have increased levels of apoptosis in their skin and are more susceptible to papilloma formation in the two-stage carcinogenesis model. These studies show that deregulated proliferation does not necessarily lead to tumor formation and that the ability to suppress skin carcinogenesis is unique to E2F1. E2F1 can also suppress skin carcinogenesis when okadaic acid is used as the tumor promoter and when a pre-initiated mouse model is used, demonstrating that E2F1's tumor suppressive activity is not specific for TPA and occurs at the promotion stage. E2F1 was thought to induce p53-dependent apoptosis through upregulation of p19ARF tumor suppressor, which inhibits mdm2-mediated p53 degradation. Consistent with in vitro studies, the overexpression of E2F1 in mouse skin results in the transcriptional activation of the p19ARF and the accumulation of p53. Inactivation of either p19ARF or p53 restores the sensitivity of K5 E2F1 transgenic mice to DMBA/TPA carcinogenesis, demonstrating that an intact p19ARF-p53 pathway is necessary for E2F1 to suppress carcinogenesis. Surprisingly, while p53 is required for E2F1 to induce apoptosis in mouse skin, p19ARF is not, and inactivation of p19ARF actually enhances E2F1-induced apoptosis and proliferation in transgenic epidermis. This indicates that ARF is important for E2F1-induced tumor suppression but not apoptosis. Senescence is another potential mechanism of tumor suppression that involves p53 and p19ARF. K5 E2F1 transgenic mice initiated with DMBA and treated with TPA show an increased number of senescence cells in their epidermis. These experiments demonstrate that E2F1's unique tumor suppressive activity in two-stage skin carcinogenesis can be genetically separated from E2F1-induced apoptosis and suggest that senescence utilizing the p19ARF-p53 pathway plays a role in tumor suppression by E2F1. ^

Repeatability and Two-Dimensionality of Model Scale Sloshing Impacts

Canonical test cases for sloshing wave impact problems are pre-sented and discussed. In these cases the experimental setup has been simpli?ed seeking the highest feasible repeatability; a rectangular tank subjected to harmonic roll motion has been the tested con?guration. Both lateral and roof impacts have been studied, since both cases are relevant in sloshing assessment and show speci?c dynamics. An analysis of the impact pressure of the ?rst four impact events is provided in all cases. It has been found that not in all cases a Gaussian ?tting of each individual peak is feasible. The tests have been conducted with both water and oil in order to obtain high and moderate Reynolds number data; the latter may be useful as simpler test cases to assess the capabilities of CFD codes in simulating sloshing impacts. The re-peatability of impact pressure values increases dramatically when using oil. In addition, a study of the two-dimensionality of the problem using a tank con?guration that can be adjusted to 4 di?erent thicknesses has been carried out. Though the kinemat-ics of the free surface does not change signi cantly in some of the cases, the impact pressure values of the ?rst impact events changes substantially from the small to the large aspect ratios thus meaning that attention has to be paid to this issue when reference data is used for validation of 2D and 3D CFD codes.

Assessment of the requirement management process using a two-stage questionnaire

This research advocates the idea that although requirements management process is not carried out in many organizations there is some people within the organization that perform some requirements management practices. However, these practices are usually not documented and as consequence are not spread across the organization. This paper proposes an assessment methodology based on a two-stage questionnaire to identify which practices of the requirements management process are performed but not documented, which practices require to be prioritized and which are not implemented due to bad management or unawareness. In order to validate the assessment methodology, the questionnaire was applied to an industrial case study.

Determining practices achievement in the requirement management process using a two-stage questionnaire

This paper aims to obtain a baseline snapshot of the requirement management process using a two-stage questionnaire to identify both performed and non-performed CMMI practices. The questionnaire proposed in this paper may help with the assessment of the requirement management process, provide useful information related to the current state of the process, and indicate those practices that require immediate attention with the aim of begin a Software Process Improvement program.

A proposed two-stage two-tether scientific mission at Jupiter

A two-stage mission to place a spacecraft (SC) below the Jovian radiation belts, using a spinning bare tether with plasma contactors at both ends to provide propulsion and power,is proposed. Capture by Lorentz drag on the tether, at the periapsis of a barely hyperbolic equatorial orbit, is followed by a sequence of orbits at near-constant periapsis, drag finally bringing the SC down to a circular orbit below the halo ring. Although increasing both tether heating and bowing, retrograde motion can substantially reduce accumulated dose as compared with prograde motion, at equal tether-to-SC mass ratio. In the second stage,the tether is cut to a segment one order of magnitude smaller, with a single plasma contactor, making the SC to slowly spiral inward over severalmonths while generating large onboard power, which would allow multiple scientific applications, including in situ study of Jovian grains, auroral sounding of upper atmosphere, and space- and time-resolved observations of surface and subsurface.

A stochastic model updating method for parameter variability quantification based on response surface models and Monte Carlo simulation

Stochastic model updating must be considered for quantifying uncertainties inherently existing in real-world engineering structures. By this means the statistical properties,instead of deterministic values, of structural parameters can be sought indicating the parameter variability. However, the implementation of stochastic model updating is much more complicated than that of deterministic methods particularly in the aspects of theoretical complexity and low computational efficiency. This study attempts to propose a simple and cost-efficient method by decomposing a stochastic updating process into a series of deterministic ones with the aid of response surface models and Monte Carlo simulation. The response surface models are used as surrogates for original FE models in the interest of programming simplification, fast response computation and easy inverse optimization. Monte Carlo simulation is adopted for generating samples from the assumed or measured probability distributions of responses. Each sample corresponds to an individual deterministic inverse process predicting the deterministic values of parameters. Then the parameter means and variances can be statistically estimated based on all the parameter predictions by running all the samples. Meanwhile, the analysis of variance approach is employed for the evaluation of parameter variability significance. The proposed method has been demonstrated firstly on a numerical beam and then a set of nominally identical steel plates tested in the laboratory. It is found that compared with the existing stochastic model updating methods, the proposed method presents similar accuracy while its primary merits consist in its simple implementation and cost efficiency in response computation and inverse optimization.

Competitive exclusion in a two-especies chemotasis model

We consider a mathematical model for the spatio-temporal evolution of two biological species in a competitive situation. Besides diffusing, both species move toward higher concentrations of a chemical substance which is produced by themselves. The resulting system consists of two parabolic equations with Lotka–Volterra-type kinetic terms and chemotactic cross-diffusion, along with an elliptic equation describing the behavior of the chemical. We study the question in how far the phenomenon of competitive exclusion occurs in such a context. We identify parameter regimes for which indeed one of the species dies out asymptotically, whereas the other reaches its carrying capacity in the large time limit.

On a two species chemotaxis model with slow chemical diffucion.

In this paper we consider a system of three parabolic equations modeling the behavior of two biological species moving attracted by a chemical factor. The chemical substance verifies a parabolic equation with slow diffusion. The system contains second order terms in the first two equations modeling the chemotactic effects. We apply an iterative method to obtain the global existence of solutions using that the total mass of the biological species is conserved. The stability of the homogeneous steady states is studied by using an energy method. A final example is presented to illustrate the theoretical results.

Human Search for a Target on a Textured Background is Consistent with a Stochastic Model

This research was supported by the James S. McDonnell Foundation (ARH). Early version was supported by EPSRC grants EP/F02553X/1 and EP/D059364/1.

Inactive conformation of the serpin α1-antichymotrypsin indicates two-stage insertion of the reactive loop: Implications for inhibitory function and conformational disease

The serpins are a family of proteinase inhibitors that play a central role in the control of proteolytic cascades. Their inhibitory mechanism depends on the intramolecular insertion of the reactive loop into β-sheet A after cleavage by the target proteinase. Point mutations within the protein can allow aberrant conformational transitions characterized by β-strand exchange between the reactive loop of one molecule and β-sheet A of another. These loop-sheet polymers result in diseases as varied as cirrhosis, emphysema, angio-oedema, and thrombosis, and we recently have shown that they underlie an early-onset dementia. We report here the biochemical characteristics and crystal structure of a naturally occurring variant (Leu-55–Pro) of the plasma serpin α1-antichymotrypsin trapped as an inactive intermediate. The structure demonstrates a serpin configuration with partial insertion of the reactive loop into β-sheet A. The lower part of the sheet is filled by the last turn of F-helix and the loop that links it to s3A. This conformation matches that of proposed intermediates on the pathway to complex and polymer formation in the serpins. In particular, this intermediate, along with the latent and polymerized conformations, explains the loss of activity of plasma α1-antichymotrypsin associated with chronic obstructive pulmonary disease in patients with the Leu-55–Pro mutation.

A three-stage DEA model to evaluate learning-teaching technical efficiency: Key performance indicators and contextual variables

This study evaluates the technical efficiency of the learning-teaching process in higher education using a three-stage procedure that offers advances in comparison to previous studies and improves the quality of the results. First, it utilizes a multiple stage Data Envelopment Analysis (DEA) with contextual variables. Second, the levels of super efficiency are calculated in order to prioritize the efficiency units. And finally, through sensitivity analysis, the contribution of each key performance indicator (KPI) is established with respect to the efficiency levels without omission of variables. The analytical data was collected from a survey completed by 633 tourism students during the 2011/12, 2012/13 and 2013/14 academic course years. The results suggest that level of satisfaction with the course, diversity of materials and satisfaction with the teacher were the most important factors affecting teaching performance. Furthermore, the effect of the contextual variables was found to be significant.

A stochastic model for prisoner's dilemma.

Includes bibliography.

HIVEL2D : a two-dimensional flow model for high-velocity channels /

At head of title: "Repair, Evaluation, Maintenance, and Rehabilitation Research Program."