Endosomal Trafficking and Exosomal Secretion Of EGFRvIII

The epidermal growth factor receptor (EGFR) variant three (EGFRvIII) mutation is linked with approximately one third of Glioblastoma Multiforme (GBM) tumors and is associated with poor patient prognosis. Persistent signaling due to a lack of the EGFR ectodomain and inefficient degradation have been suggested to underlie the tumorgenic properties of EGFRvIII. I observed that, like the parental EGFR, EGFRvIII is internalized into the intraluminal vesicles of late endosomes / multivesicular bodies (MVBs) but does not follow the canonical pathway by which wild-type EGFR is degraded following MVB fusion with lysosomes. I determined that EGFRvIII is secreted on exosomes, the intraluminal vesicles that are secreted upon MVB fusion with the plasma membrane. This suggested that EGFRvIII is localized in a subset of MVBs that preferentially fuse with the plasma membrane rather than with lysosomes which may account for its decreased degradation. Astrocytes are a component of the GBM tumor microenvironment with whom tumor cells interact in a paracrine manner. I examined the effect of EGFRvIII-containing exosomes derived from GBM cells on astrocytes and observed that EGFRvIII containing exosomes induce changes in astrocytes that mimic reactive astrogliosis including an increase in glial fibrillary acidic protein (GFAP) and altered astrocyte morphology. These results reveal novel aspects of the endocytic trafficking of EGFRvIII that underlie its reduced degradation and the mechanism by which it is packaged into exosomes for secretion. Moreover, I show that EGFRvIII secretion on exosomes can facilitate changes in the tumor microenvironment to enable tumor growth

Numerical Welding Simulation as a Basis for Structural Integrity Assessment of Structures: Microstructure and Residual Stresses

The importance of welding process modeling is specifically related to the role of the induced welding residual stresses and distortions on the structural behavior of the components under service load. In the absence of reliable information on the magnitude and distribution of residual stresses, it is generally assumed that residual stresses are as high as the yield strength of the material that could lead to overconservatism in design and consequently economic challenges. The more exact the microstructure and residual stress or strain fields is predicted, the better one can judge the risk of structural damage, for example, the formation of fatigue cracks or initiation of failure. In this chapter, the application of finite element approach to the calculation of welding residual stresses is described through three different case studies. SYSWELD has been used for welding simulation. Residual stress measurements are carried out to determine the distribution of residual stresses in three orthogonal directions, on the surface and in the bulk of the material. The numerical results are compared directly with the measured data. The overall aim is to evaluate the use of finite element approach in the accurate calculation of residual stress states for use in the structural integrity assessments

Long-time convergence of an Adaptive Biasing Force method: the bi-channel case

International audienceWe present convergence results for an adaptive algorithm to compute free energies, namely the adaptive biasing force (ABF) method. The free energy is the effective potential associated to a so-called reaction coordinate (RC). Computing free energy differences remains an important challenge in molecular dynamics due to the presence of meta-stable regions in the potential energy surface. The ABF method uses an on-the-fly estimate of the free energy to bias dynamics and overcome metastability. Using entropy arguments and logarithmic Sobolev inequalities, previous results have shown that the rate of convergence of the ABF method is limited by the metastable features of the canonical measures conditioned to being at fixed values of the RC. In this paper, we present an improvement on the existing results, in the presence of such metastabilities, which is a generic case encountered in practice. More precisely, we study the so-called bi-channel case, where two channels along the RC direction exist between an initial and final state, the channels being separated from each other by a region of very low probability. With hypotheses made on 'channel-dependent' conditional measures, we show on a bi-channel model that we introduce, that the convergence of the ABF method is in fact not limited by metastabilities in directions orthogonal to the RC under two crucial assumptions: (i) exchange between the two channels is possible for some values of the RC and (ii) the free energy is a good bias in each channel

Exploring Adaptive MCTS with TD Learning in miniXCOM

In recent years, Monte Carlo tree search (MCTS) has achieved widespread adoption within the game community. Its use in conjunction with deep reinforcement learning has produced success stories in many applications. While these approaches have been implemented in various games, from simple board games to more complicated video games such as StarCraft, the use of deep neural networks requires a substantial training period. In this work, we explore on-line adaptivity in MCTS without requiring pre-training. We present MCTS-TD, an adaptive MCTS algorithm improved with temporal difference learning. We demonstrate our new approach on the game miniXCOM, a simplified version of XCOM, a popular commercial franchise consisting of several turn-based tactical games, and show how adaptivity in MCTS-TD allows for improved performances against opponents.Comment: 7 page

A case of intractable infectious keratitis and subsequent flap necrosis after laser in situ keratomileusis

We report on a patient in whom intractable infectious keratitis and subsequent lamellar flap necrosis necessitating flap amputation after laser in situ keratomileusis (LASIK). A 34-year-old woman undergoing LASIK complained of blurred vision and pain in the left eye. The best spectacle-corrected visual acuity was 0.01, and slit-lamp examination showed a marked presence of stromal infiltrates involving the flap and the underlying stroma in that eye. The patient was treated topically with hourly instillation of micronomicin, levofloxacin, and cefmenoxime, together with systemic administration of imipenem, but the left eye developed corneal flap necrosis. We performed surgical debridement of the diseased stroma and excised the lamellar flap. Since nontuberculous mycobacterium was detected on the surgical instruments, we then added oral clarithromycin, and substituted systemic administration of amikacin with that of imipenem. At one month after the flap removal, the visual acuity gradually improved to 0.7, but the stromal opacity of the central cornea and hyperopic shift of +3.0 diopters remained. LASIK can cause intractable keratitis, resulting in significant visual disturbance that presumably results from insufficient antisepsis of the medical instruments used for this surgery, supporting the importance of strict sterilization of these instruments

Investigating the safety climate, safety competency and role overload as predictors of safe behavior of employees in the Bidboland Gas Refining Company

Background and Aims: Safety and safe behavior are the most important issues that anyone at any level in the workplace and life should pay attention to them. Neglecting security duties may cause irreparable damages. Therefore, the present study was aimed to investigate the safety climate, safety competence and overload role as the predictors of safe behavior of Bidboland Gas Refinery employees in Khuzestan province. Materials and Methods: The present study design is a correlational predictor. The statistical population included all operational staff employed by Bidboland Gas Refining Company in 2015. Study sample consisted of 273 persons selected through stratified random sampling. Participants were first divided into two groups of safe and unsafe employees using the Safe Behaviors Scale )Salleh, 2010(, and then Safety Climate Scale )Vinodkumar & Bhasi, 2009(, Safety Competency Scale )Salleh, 2010( and Perceived Work Pressure Questionnaire )Seo, 2005( were used to measure the studied variables. Data were analyzed through discriminant analysis and using SPSS-16 software. All stages of this research were conducted ethically.Results: The results showed that safety climate (β=0.662), safety competence (β=0.558) and role overload (β=0.08) were able to predict the safe behavior and are capable of distinguishing safe employees from unsafe ones )p<0.0001(.Conclusion: According to the results of the present study, it is suggested that organizational managers should consider the variables influencing safe behavior (safety climate, safety competence and role overload) in their workplace safety behavior development programs.Keywords: Safe Behavior, Safety Climate, Safety Competency, Role Overload

Design Procedures and Finite Element Analysis of Pot Bearings

RÉSUMÉ Au Canada, les infrastructures des ponts vieillissent rapidement. En 2007, un grand nombre de ponts ont dépassé 57% de leur durée de vie, estimée à 43,3 années. Ce ratio augmenté 72% au Québec, ce qui indique qu’un bon nombre de ces ponts sont structurellement ou fonctionnellement déficient (Gagnon and Gaudreault 2011). Ce contexte met l’accent sur la nécessité de ce baser sur la performance, la rentabilité et l’optimisation des techniques de construction et l’amélioration des stratégies de rénovation. L’appui du pont est un élément essentiel de l’ensemble de la structure. Étant donné que la durée de vie d’un appui de pont est plus courte que celle du pont lui-même, un nombre considérable de déficiences dans les ponts peut être dû à un dysfonctionnement de l’appui du pont. Le type d’appui du pont qui est largement utilisé est un appui de type pot (élastomère confiné), qui a été développé en Europe au début des années 1960. Comme d’autres types d’appuis, l’appui de type pot est utilisé pour supporter une superstructure de pont et accommoder ses mouvements indépendamment des éléments de support, c’est-à-dire piles et culées (Tonias 1994).----------ABSTRACT Bridge infrastructure in Canada is aging rapidly, with a large number of bridges exceeding 57% of their service life estimated at 43.3 years in 2007 (Gagnon and Gaudreault 2011). This ratio increases to 72% in Quebec, indicating that many of these bridges are structurally or functionally deficient. This context emphasizes the need for performance-based, cost-effective and optimized construction techniques and retrofit strategies. A bridge bearing is a crucial part of the whole structure. Since the total lifetime of a bearing is much less than that of the bridge itself, considerable number of deficiencies in bridges can be due to bearing malfunction. A widely used type of bridge bearings are elastomeric pot bearings (EPBs), which are developed in Europe in the early 1960s. As other bearing types, they are used to support a bridge superstructure and accommodate its movements independently from the supporting elements, i.e. piers and abutments (Tonias 1994)