A highly potent and specific MET therapeutic protein antagonist with both ligand-dependent and ligand-independent activity

Activation of the MET oncogenic pathway has been implicated in the development of aggressive cancers that are difficult to treat with current chemotherapies. This has led to an increased interest in developing novel therapies that target the MET pathway. However, most existing drug modalities are confounded by their inability to specifically target and/or antagonize this pathway. Anticalins, a novel class of monovalent small biologics, are hypothesized to be "fit for purpose" for developing highly specific and potent antagonists of cancer pathways. Here, we describe a monovalent full MET antagonist, PRS-110, displaying efficacy in both ligand-dependent and ligand-independent cancer models. PRS-110 specifically binds to MET with high affinity and blocks hepatocyte growth factor (HGF) interaction. Phosphorylation assays show that PRS-110 efficiently inhibits HGF-mediated signaling of MET receptor and has no agonistic activity. Confocal microscopy shows that PRS-110 results in the trafficking of MET to late endosomal/lysosomal compartments in the absence of HGF. In vivo administration of PRS-110 resulted in significant, dose-dependent tumor growth inhibition in ligand-dependent (U87-MG) and ligand-independent (Caki-1) xenograft models. Analysis of MET protein levels on xenograft biopsy samples show a significant reduction in total MET following therapy with PRS-110 supporting its ligand-independent mechanism of action. Taken together, these data indicate that the MET inhibitor PRS-110 has potentially broad anticancer activity that warrants evaluation in patients.

Performance analysis of switch-and-stay combining in two-way relay systems with analog network coding and time-division broadcast protocols

In this paper, weconsider switch-and-stay combining (SSC) in two-way relay systems with two amplify-and-forward relays, one of which is activated to assist the information exchange between the two sources. The system operates in either analog network coding (ANC) protocol where the communication is only achieved with the help of the active relay or timedivision broadcast (TDBC) protocol where the direct link between two sources can be utilized to exploit more diversity gain. In both cases, we study the outage probability and bit error rate (BER) for Rayleigh fading channels. In particular, we derive closed-form lower bounds for the outage probability and the average BER, which remain tight for different fading conditions. We also present asymptotic analysis for both the outage probability and the average BER at high signalto-noise ratio. It is shown that SSC can achieve the full diversity order in two-way relay systems for both ANC and TDBC protocols with proper switching thresholds. Copyright © 2014 John Wiley & Sons, Ltd.

Dengue Virus Inhibition of Autophagic Flux and Dependency of Viral Replication on Proteasomal Degradation of the Autophagy Receptor p62

Autophagic flux involves formation of autophagosomes and their degradation by lysosomes. Autophagy can either promote or restrict viral replication. In the case of Dengue virus (DENV) several studies report that autophagy supports the viral replication cycle, and describe an increase of autophagic vesicles (AVs) following infection. However, it is unknown how autophagic flux is altered to result in increased AVs. To address this question, and gain insight into the role of autophagy during DENV infection, we established an unbiased, image-based flow cytometry approach to quantify autophagic flux under normal growth conditions and in response to activation by nutrient deprivation or the mTOR inhibitor Torin1. We found that DENV induced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Early after infection, basal and activated autophagic flux was enhanced. However, during established replication, basal and Torin1-activated autophagic flux was blocked, while autophagic flux activated by nutrient deprivation was reduced, indicating a block to AV formation and reduced AV degradation capacity. During late infection AV levels increased as a result of inefficient fusion of autophagosomes with lysosomes. Additionally, endo-lysosomal trafficking was suppressed, while lysosomal activities were increased. We further determined that DENV infection progressively reduced levels of the autophagy receptor SQSTM1/p62 via proteasomal degradation. Importantly, stable over-expression of p62 significantly suppressed DENV replication suggesting a novel role for p62 as viral restriction factor. Overall our findings indicate that in the course of DENV infection, autophagy shifts from a supporting to an anti-viral role, which is countered by DENV.

IMPORTANCE: Autophagic flux is a dynamic process starting with the formation of autophagosomes and ending with their degradation after fusion with lysosomes. Autophagy impacts the replication cycle of many viruses. However, thus far the dynamics of autophagy in case of Dengue virus (DENV) infections has not been systematically quantified. Therefore, we employed high-content, imaging-based flow cytometry to quantify autophagic flux and endo-lysosomal trafficking in response to DENV infection. We report that DENV induced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Further, lysosomal activity was increased, but endo-lysosomal trafficking was suppressed confirming the block of autophagic flux. Importantly, we provide evidence that p62, an autophagy receptor, restrict DENV replication and was specifically depleted in DENV-infected cells via increased proteasomal degradation. These results suggest that during DENV infection autophagy shifts from a pro- to an antiviral cellular process, which is counteracted by the virus.

Secure Switch-and-Stay Combining (SSSC) for Cognitive Relay Networks

In this paper, we study a two-phase underlay cognitive relay network, where there exists an eavesdropper who can overhear the message. The secure data transmission from the secondary source to secondary destination is assisted by two decode-and-forward (DF) relays. Although the traditional opportunistic relaying technique can choose one relay to provide the best secure performance, it needs to continuously have the channel state information (CSI) of both relays, and may result in a high relay switching rate. To overcome these limitations, a secure switch-and-stay combining (SSSC) protocol is proposed where only one out of the two relays is activated to assist the secure data transmission, and the secure relay switching occurs when the relay cannot support the secure communication any longer. This security switching is assisted by either instantaneous or statistical eavesdropping CSI. For these two cases, we study the system secure performance of SSSC protocol, by deriving the analytical secrecy outage probability as well as an asymptotic expression for the high main-to-eavesdropper ratio (MER) region. We show that SSSC can substantially reduce the system complexity while achieving or approaching the full diversity order of opportunistic relaying in the presence of the instantaneous or statistical eavesdropping CSI.

O contributo das representações numéricas básicas e da função executiva no desempenho de operações aritméticas : um estudo exploratório

Tese de mestrado, Psicologia (Secção de Cognição Social Aplicada), Universidade de Lisboa, Faculdade de Psicologia, 2014

Valuing and encouraging critical reflection in pre-service teacher education

This qualitative study was designed to investigate aspects related to valuing and encouraging critical reflection in pre-service teacher education. An examination of the place and function of practicum logbooks as used at Covenant Canadian Reformed Teachers' College, a small private college which offers pre-service teacher education formed the core of the research. An analysis of the practicum logbooks written by five student teachers during three different practicum placements was performed at two levels. First, a content analysis served to identify general and specific categories within the practice teaching contextas a learning experience. Secondly, in-depth intuitive and thematic analyses of the entries which related specifically to reflection as a learning experience gave rise to critical questions. Throughout the process, the five participants formed an active and involved group of co-researchers, adding their voices to the narrative of the learning experience. Variables such as personality type, learning style and self-directedness added a dimension which deepened and emiched the study. The result of the study suggests that practicum logbooks form a valuable base for valuing and encouraging critical reflection in pre-service teacher education. The results also suggest that not all students appear to be equally capable of critical reflection. Recognizing that teacher education exists as a continuum appears to support the findings that in their journey along this continuum, student teachers not only move from reflection-on-action to reflection-in-action, but also from content to process to premise reflection. An awareness of contributing factors such as personality type, degree of risk-taking, preferred learning style and self-directedness on the part of teacher-educators will serve to create a climate of trust in which student teachers can safely develop critical reflection, using practicum logbooks as one possible medium.

Report of the Committee on Military Affairs, on the differences that exist, between the United States and some of the individual States, respecting the relative powers of the general and state governments over the militia.--

February 28, 1815. Printed by order of the Senate of the United States.

Report of the Committee on Military Affairs, on the differences that exist, between the United States and some of the individual States, respecting the relative powers of the general and state governments over the militia

February 28, 1815. Printed by order of the Senate of the United States. Printed be Roger C. Weightman

Indenture between The Honourable Peter Russell, His Majesty’s Receiver General and William Dickson

Indenture between The Honourable Peter Russell, His Majesty’s Receiver General and William Dickson 10 acres bounded by a Port, and a Military Reserve. This document is slightly torn and taped. This does not affect the text – instrument no. 6507, Aug. 22, 1798.

The Sherman letters : correspondance between General and Senator Sherman from 1837 to 1891

UANL

Compositional hypotheses of subcompositional stability and specific perturbation change and their testing

In standard multivariate statistical analysis common hypotheses of interest concern changes in mean vectors and subvectors. In compositional data analysis it is now well established that compositional change is most readily described in terms of the simplicial operation of perturbation and that subcompositions replace the marginal concept of subvectors. To motivate the statistical developments of this paper we present two challenging compositional problems from food production processes. Against this background the relevance of perturbations and subcompositions can be clearly seen. Moreover we can identify a number of hypotheses of interest involving the specification of particular perturbations or differences between perturbations and also hypotheses of subcompositional stability. We identify the two problems as being the counterpart of the analysis of paired comparison or split plot experiments and of separate sample comparative experiments in the jargon of standard multivariate analysis. We then develop appropriate estimation and testing procedures for a complete lattice of relevant compositional hypotheses

Psychological contract breach and outcomes : Combining meta-analysis and structural equation models. 'Ruptura de contrato psicol??gico : combinando meta-an??lisis y modelos de ecuaciones estructurales'

Resumen tomado de la publicaci??n

Publicidad, medio para crear una ventaja competitiva

El caso muestra la manera en que surge una capacidad dinámica de reacción de la empresa líder del mercado en el sector automotriz en Colombia. GM Colmotores, genera estrategias para responder a los cambios, oportunidades y retos del mercado y los competidores. Así mismo se muestra la flexibilidad y evolución de la empresa que durante los últimos años siempre ha estado con la mayor porción de mercado en la industria. El desarrollo del caso permite ver como por medio de la capacidad de dirigir sus estrategias publicitarias de una manera diferente, va a crear una ventaja de diferenciación que no afecte en un margen muy alto sus costos y rendimientos crecientes. Por lo que va a tener una ventaja competitiva frente a sus competidores, adquiriendo una capacidad de respuesta, manteniéndose flexible ante los cambios tanto del entorno general y específico, como a los generados por los actores del mercado, tales como clientes, proveedores y competidores.