Therapeutic potential of p53 restoration in spontaneous tumors

Over 80% of p53 mutations found in human cancers are p53 missense mutations. Recent studies have shown that p53 restoration leads to tumor regression in mice with p53 deletions, but the therapeutic efficacy of p53 restoration in tumors containing p53 missense mutations has not been evaluated. Since p53 mutant such as p53R172H has gain-of-function activities and dominant-negative effect that repress wild type p53, the activity of restored wild-type p53 might be compromised by the mutant p53 in tumors. We hypothesized that p53 restoration in tumors with the p53R172H mutation may be less therapeutically effective as p53 restoration in tumors null for p53. I tested this hypothesis by comparison of the therapeutic outcomes of p53 restoration in mice with spontaneous tumors that either lacked p53 or contained the p53R172H mutation. While p53 restoration causes tumor regression in mice lacking p53, the same p53 restoration halts tumor progression in mice with the p53R172H mutation. This phenotypic difference suggests a dominant-negative activity of the mutant p53. Moreover, I showed that the mutant p53 only inhibits part of the activity of the restored wild-type p53 and that the remaining wild-type activity still causes a delay in tumor progression. We conclude that p53 restoration has therapeutic potential in p53R172H tumors via suppression of tumor progression. This knowledge is of critical importance for p53 targeted cancer therapy because many patients with cancers harbor p53 missense mutations rather p53-null mutations. Since p53R172H mutation represents one of the most frequent and potent p53 missense mutations observed in human cancers, the current findings implicates that p53 restoration may be therapeutically important not only in human cancers characterized by loss of p53 alleles but also in those in which p53 missense mutations play an important pathogenetic role. ^

Functional activation of p53 induces apoptosis in the absence of MDM2

The p53 tumor suppressor gene product is negatively regulated by the product of its downstream target, mdm2. The mdm2 oncogene abrogates p53 transactivation function. Amplification of mdm2 occurs in 36% of human sarcomas, which often retain p53 in wild type form, suggesting that overexpression of mdm2 in tumors results in p53 inactivation. Thus, the relationship of p53 to mdm2 is important in tumorigenesis. The deletion of mdm2 in the mouse results in embryonic lethality by 5.5 days post coitum. Embryonic lethality of the mdm2 null embryos was overcome by simultaneous loss of the p53 tumor suppressor, which substantiates the importance of the negative regulatory function of MDM2 on p53 function in vivo. These data suggest that the loss of MDM2 function allowed the constitutively active p53 protein to induce either a complete G1 arrest or the p53-dependent apoptotic pathway, resulting in the death of the mdm2−/− embryos.^ The present study examines the hypothesis that the absence of mdm2 induces apoptosis due to p53 activation. Viability of the p53−/−mdm2−/− mice has allowed establishment of mouse embryo fibroblasts (MEFs) and a detailed examination of the properties of these cells. To introduce p53 into this system, and essentially recreate a mdm2 null cell, a temperature sensitive p53 (tsp53) point mutant (A135V) was used, which exhibits a nonfunctional, mutant conformation at 39°C and wild type, functional conformation at 32°C. Infected pools of p53−/− and p53−/−mdm2−/− MEFs with the tsp53 gene were established and single-cell clonal populations expressing tsp53 were selected. Shifting the cells from 39°C to 32°C caused p53−/−mdm2 −/− lines expressing tsp53 to undergo up to 80% apoptosis, which did not occur in the p53−/− lines expressing tsp53 nor the parental lines lacking p53 expression. Furthermore, the amount of p53 present in the clonal population determined the extent of apoptosis. Tsp53 is transcriptionally active in this system, however, it discriminates among different target promoters and does not induce the apoptosis effector targets bax or Fas/Apo1. ^ In summary, this study indicates that the presence or absence of mdm2 is the determining factor for the ability of p53 to trigger apoptosis in this system. The loss of mdm2 promotes p53-dependent apoptosis in MEFs in a cell cycle and dose-dependent manner. p53 is differentially phosphorylated in the presence and absence of mdm2, but does not induce the apoptosis effectors, bax or Fas/ Apo1. ^

Rescue of embryonic lethality in mdmx null mice by loss of p53 suggests a non-overlapping pathway with MDM2 to regulate p53

The tumor suppressor p53 is mutated in over 50% of human sporadic tumors originating from diverse tissues. p53 responds to DNA damage and cell stress by activating the transcription of a variety of target genes, the protein products of which then initiate either growth arrest or apoptosis. ^ A p53 target with a particularly intriguing function is the oncogene MDM2. MDM2 functions, in part, by binding to and inhibiting p53's activity. Overexpression of MDM2, by gene amplification, has been found in 30% of human sarcomas harboring a wild type p53, indicating that an increase in MDM2 levels is sufficient for p53 inactivation. Mice carrying a homozygous null allele for mdm2 exhibit an early embryonic lethality that is completely rescued in a p53-null background. These data indicate that MDM2's only critical function in early mouse embryogenesis is the negative regulation of p53. ^ The mdmx gene is the first additional member of the mdm2 gene family to be isolated. MDMX, like MDM2, contains a RING-finger domain, ATP binding domain and a p53 binding domain, which retains the ability to bind and inhibit p53 transactivation in vitro. However, mdmx does not appear to be transcriptionally regulated by p53. We have cloned and characterized the murine mdmx genomic locus from a mouse 129 genomic library. The mdmx gene contains 11 exons, spans approximately 37 Kb of DNA, and is located on mouse chromosome 1. The genomic organization of the mdmx gene is identical to that of mdm2 except at the 5′ end of the gene near the p53 responsive element. Northern expression analysis of mdmx transcripts during mouse embryogenesis and in adult tissues revealed constitutive and ubiquitous expression throughout adult tissues and embryonic development. To determine the in vivo function of MDMX, mice carrying a null allele of mdmx have been generated. Mdmx homozygous null mice are early embryonic lethal. Mdmx null mice do not develop beyond 9.5 dpc and can be discerned by gross dissection as early as 7.5 dpc. Utilizing TUNEL and BrdU assays on 7.5 dpc histological sections we have determined that the mutant embryos are dying due to increased levels of growth arrest, but not apoptosis. Surprisingly, Mdmx homozygous null mice are viable in a p53 null background, indicating that MDMX is also very important in the negative regulation of p53. ^

Sampling sites, sampled birds and plants of young larch plantations in Tokachi district, eastern Hokkaido, northern Japan, 2011

Models and data used to describe species-area relationships confound sampling with ecological process as they fail to acknowledge that estimates of species richness arise due to sampling. This compromises our ability to make ecological inferences from and about species-area relationships. We develop and illustrate hierarchical community models of abundance and frequency to estimate species richness. The models we propose separate sampling from ecological processes by explicitly accounting for the fact that sampled patches are seldom completely covered by sampling plots and that individuals present in the sampling plots are imperfectly detected. We propose a multispecies abundance model in which community assembly is treated as the summation of an ensemble of species-level Poisson processes and estimate patch-level species richness as a derived parameter. We use sampling process models appropriate for specific survey methods. We propose a multispecies frequency model that treats the number of plots in which a species occurs as a binomial process. We illustrate these models using data collected in surveys of early-successional bird species and plants in young forest plantation patches. Results indicate that only mature forest plant species deviated from the constant density hypothesis, but the null model suggested that the deviations were too small to alter the form of species-area relationships. Nevertheless, results from simulations clearly show that the aggregate pattern of individual species density-area relationships and occurrence probability-area relationships can alter the form of species-area relationships. The plant community model estimated that only half of the species present in the regional species pool were encountered during the survey. The modeling framework we propose explicitly accounts for sampling processes so that ecological processes can be examined free of sampling artefacts. Our modeling approach is extensible and could be applied to a variety of study designs and allows the inclusion of additional environmental covariates.

Uniformly reweighted belief propagation for distributed Bayesian hypothesis testing

Belief propagation (BP) is a technique for distributed inference in wireless networks and is often used even when the underlying graphical model contains cycles. In this paper, we propose a uniformly reweighted BP scheme that reduces the impact of cycles by weighting messages by a constant ?edge appearance probability? rho ? 1. We apply this algorithm to distributed binary hypothesis testing problems (e.g., distributed detection) in wireless networks with Markov random field models. We demonstrate that in the considered setting the proposed method outperforms standard BP, while maintaining similar complexity. We then show that the optimal ? can be approximated as a simple function of the average node degree, and can hence be computed in a distributed fashion through a consensus algorithm.

Correlating a documentary record of historical floods with the dendrochronological dating of a wooden decking in the old mint of Segovia (Spain)

the aim of this study is to apply an integrated methodological approximation where dendrochronology and documentary analysis allow us to reconstruct the historical flood record of the Segovia Mint. Our hypothesis is that differences between the dendrochronological data of the wooden decking pieces can be related to historical floods and, therefore, they could be used as proxy-source data in future palaeoflood research.

Gas sensor based on room temperature optical properties of Surface QDs

Self-organized InGaAs QDs are intensively studied for optoelectronic applications. Several approaches are in study to reach the emission wavelengths needed for these applications. The use of antimony (Sb) in either the capping layer or into the dots is one example. However, these studies are normally focused on buried QD (BQD) where there are still different controversial theories concerning the role of Sb. Ones suggest that Sb incorporates into the dot [1], while others support the hypothesis that the Sb occupies positions surrounding the dot [2] thus helping to keep their shape during the capping growth.

Measuring the influence of Cooperative Learning and Project Based Learning on problem solvin skill.

The aim of this study is to evaluate the effects obtained after applying two active learning methodologies (cooperative learning and project based learning) to the achievement of the competence problem solving. This study was carried out at the Technical University of Madrid, where these methodologies were applied to two Operating Systems courses. The first hypothesis tested was whether the implementation of active learning methodologies favours the achievement of ?problem solving?. The second hypothesis was focused on testing if students with higher rates in problem solving competence obtain better results in their academic performance. The results indicated that active learning methodologies do not produce any significant change in the generic competence ?problem solving? during the period analysed. Concerning this, we consider that students should work with these methodologies for a longer period, besides having a specific training. Nevertheless, a close correlation between problem solving self appraisal and academic performance has been detected.

AR drone identification and navigation control at CVG-UPM

This article presents the proposal of the Computer Vision Group to the first phase of the international competition “Concurso de Ingeniería de Control 2012, Control Aut ́onomo del seguimiento de trayectorias de un vehículo cuatrirrotor”. This phase consists mainly of two parts: identifying a model and designing a trajectory controller for the AR Drone quadrotor. For the identification task, two models are proposed: a simplified model that captures only the main dynamics of the quadrotor, and a second model based on the physical laws underlying the AR Drone behavior. The trajectory controller design is based on the simplified model, whereas the physical model is used to tune the controller to attain a certain level of robust stability to model uncertainties. The controller design is simplified by the hypothesis that accurate positions sensors will be available to implement a feedback controller.

Proposal for redesigning the financial system: lessons learned from the crisis

this paper analyzes the singularities inherent to the financial industry, in relation to other businesses, and its implications to financial crises throughout history. The efficient markets hypothesis is questioned, and its impact on the deregulation of the financial system is analyzed. Finally, the causes of the current crisis are investigated, and the general lines to be addressed for the redesign of a financial system to achieve an efficient and equitable capitalism are suggested.

A novel methodology to determine the mechanical properties of amorphous materials through instrumented nanoindentation

A novel methodology based on instrumented indentation was developed to characterize the mechanical properties of amorphous materials. The approach is based on the concept of a universal postulate that assumes the existence of a characteristic indentation pressure proportional to the hardness. This hypothesis was numerically validated. This method overcomes the limitation of the conventional indentation models (pile-up effects and pressure sensitivity materials).

Investigating verbal intelligence using the TF-IDF approach

In this paper we investigated differences in language use of speakers yielding different verbal intelligence when they describe the same event. The work is based on a corpus containing descriptions of a short film and verbal intelligence scores of the speakers. For analyzing the monologues and the film transcript, the number of reused words, lemmas, n-grams, cosine similarity and other features were calculated and compared to each other for different verbal intelligence groups. The results showed that the similarity of monologues of higher verbal intelligence speakers was greater than of lower and average verbal intelligence participants. A possible explanation of this phenomenon is that candidates yielding higher verbal intelligence have a better short-term memory. In this paper we also checked a hypothesis that differences in vocabulary of speakers yielding different verbal intelligence are sufficient enough for good classification results. For proving this hypothesis, the Nearest Neighbor classifier was trained using TF-IDF vocabulary measures. The maximum achieved accuracy was 92.86%.

Seismic Activity Rates in the Iberian Peninsula

Evaluating the seismic hazard requires establishing a distribution of the seismic activity rate, irrespective of the methodology used in the evaluation. In practice, how that activity rate is established tends to be the main difference between the various evaluation methods. The traditional procedure relies on a seismogenic zonation and the Gutenberg-Richter (GR) hypothesis. Competing zonations are often compared looking only at the geometry of the zones, but the resulting activity rate is affected by both geometry and the values assigned to the GR parameters. Contour plots can be used for conducting more meaningful comparisons, providing the GR parameters are suitably normalised. More recent approaches for establishing the seismic activity rate forego the use of zones and GR statistics and special attention is paid here to such procedures. The paper presents comparisons between the local activity rates that result for the complete Iberian Peninsula using kernel estimators as well as two seismogenic zonations. It is concluded that the smooth variation of the seismic activity rate produced by zoneless methods is more realistic than the stepwise changes associated with zoned approaches; moreover, the choice of zonation often has a stronger influence on the results than its fairly subjective origin would warrant. It is also observed that the activity rate derived from the kernel approach, related with the GR parameter “a”, is qualitatively consistent with the epicentres in the catalogue. Finally, when comparing alternative zonations it is not just their geometry but the distribution of activity rate that should be compared.

Novel fast random search clustering approach for mixing matrix identification in MIMO linear blind inverse problems with sparse inputs

In this paper we propose a novel fast random search clustering (RSC) algorithm for mixing matrix identification in multiple input multiple output (MIMO) linear blind inverse problems with sparse inputs. The proposed approach is based on the clustering of the observations around the directions given by the columns of the mixing matrix that occurs typically for sparse inputs. Exploiting this fact, the RSC algorithm proceeds by parameterizing the mixing matrix using hyperspherical coordinates, randomly selecting candidate basis vectors (i.e. clustering directions) from the observations, and accepting or rejecting them according to a binary hypothesis test based on the Neyman–Pearson criterion. The RSC algorithm is not tailored to any specific distribution for the sources, can deal with an arbitrary number of inputs and outputs (thus solving the difficult under-determined problem), and is applicable to both instantaneous and convolutive mixtures. Extensive simulations for synthetic and real data with different number of inputs and outputs, data size, sparsity factors of the inputs and signal to noise ratios confirm the good performance of the proposed approach under moderate/high signal to noise ratios. RESUMEN. Método de separación ciega de fuentes para señales dispersas basado en la identificación de la matriz de mezcla mediante técnicas de "clustering" aleatorio.

Diffusion of Eco-innovations: exploring the literature

In recent years, the importance of the management of eco-innovations has been growing, more in practice than in academia. However, although in the literature there are already some evidences focussed on management of eco-innovations, there is no comprehensive review on the knowledge base of diffusion of eco-innovations. This paper provides a current overview of the existing body of literature, identifying the most active scholars and relevant publications in this field, and deepening in the major disciplines and research streams. Results show that the theory of diffusion of innovations which provided the philosophical underpinnings of how innovations are diffused is not the main knowledge base to explain the diffusion of eco-innovations. Lead market hypothesis, sustainable transitions and the ecological modernization appear as the initial base of the cognitive platform that can contribute to the understanding of diffusion of eco-innovations.