Generation of multi-modal dialogue for a net environment

In this paper an architecture and special purpose markup language for simulated affective face-to-face communication is presented. In systems based on this architecture, users will be able to watch embodied conversational agents interact with each other in virtual locations on the internet. The markup language, or Rich Representation Language (RRL), has been designed to provide an integrated representation of speech, gesture, posture and facial animation

Die filling process simulation using discrete element method (DEM)

Powder compaction and sintering are important techniques for the mass production of geometrically complex parts. Powder is poured from a reservoir into the feeding shoe, which then passes the cavity one or more times thereby delivering powder into it. The powder is then compressed to create a relatively brittle green body. Finally, the green body is ejected from the cavity and sintered in a furnace where thermal activation below the melting point produces a fully dense structure. Necks form and grow between adjacent grains thereby eliminating the porosity of the part. In general, a consistent and uniform die filling process is always desirable. Heterogeneity during die filling can propagate through the subsequent processes and finally lead to serious product defects, such as cracking, low strength, distortion and shrinkage [1]. Capillary cohesion is known to influence strongly the strength and flow properties of granular materials. At low levels of water content, the water forms a discontinuous phase composed of interparticle bridges that are unevenly distributed in the bulk (the pendular state) [2]. For powder filling process these capillary forces may have strong influence in the particle dynamics and subsequent packing. An approach using discrete element method (DEM) simulation is proposed to reproduce die filling process and investigate process characteristics that affect final sand cake shape and may lead to in-homogeneities in powder during the filling process. Also an experimental apparatus able to reproduce the die filling process was built to validate numerical model. A coarse grain model is also necessary to reduce the model size (reduce the number of particles)

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: Role of endothelin-A receptor-activated ABCB1 expression

Genomically amplified fibroblast growth factor receptor 1 (FGFR1) is an oncogenic driver in defined lung cancer subgroups and predicts sensibility against FGFR1 inhibitors in this patient cohort. The FGFR inhibitor nintedanib has recently been approved for treatment of lung adenocarcinoma and is currently evaluated for small cell lung cancer (SCLC). However, tumor recurrence due to development of nintedanib resistance might occur. Hence, we aimed at characterizing the molecular mechanisms underlying acquired nintedanib resistance in FGFR1-driven lung cancer. Chronic nintedanib exposure of the FGFR1-driven SCLC cell line DMS114 (DMS114/ NIN) but not of two NSCLC cell lines induced massive overexpression of the multidrug-resistance transporter ABCB1. Indeed, we proved nintedanib to be both substrate and modulator of ABCB1-mediated efflux. Importantly, the oncogenic FGFR1 signaling axis remained active in DMS114/NIN cells while bioinformatic analyses suggested hyperactivation of the endothelin-A receptor (ETAR) signaling axis. Indeed, ETAR inhibition resensitized DMS114/NIN cells against nintedanib by downregulation of ABCB1 expression. PKC and downstream NFκB were identified as major downstream players in ETAR-mediated ABCB1 hyperactivation. Summarizing, ABCB1 needs to be considered as a factor underlying nintedanib resistance. Combination approaches with ETAR antagonists or switching to non-ABCB1 substrate FGFR inhibitors represent innovative strategies to manage nintedanib resistance in lung cancer

A novel EGFR inhibitor acts as potent tool for hypoxia-activated prodrug systems and exerts strong synergistic activity with VEGFR inhibition in vitro and in vivo

Small-molecule EGFR inhibitors have distinctly improved the overall survival especially in EGFR-mutated lung cancer. However, their use is often limited by severe adverse effects and rapid resistance development. To overcome these limitations, a hypoxia-activatable Co(III)-based prodrug (KP2334) was recently synthesized releasing the new EGFR inhibitor KP2187 in a highly tumor-specific manner only in hypoxic areas of the tumor. However, the chemical modifications in KP2187 necessary for cobalt chelation could potentially interfere with its EGFR-binding ability. Consequently, in this study, the biological activity and EGFR inhibition potential of KP2187 was compared to clinically approved EGFR inhibitors. In general, the activity as well as EGFR binding (shown in docking studies) was very similar to erlotinib and gefitinib (while other EGFR-inhibitory drugs behaved different) indicating no interference of the chelating moiety with the EGFR binding. Moreover, KP2187 significantly inhibited cancer cell proliferation as well as EGFR pathway activation in vitro and in vivo. Finally, KP2187 proved to be highly synergistic with VEGFR inhibitors such as sunitinib. This indicates that KP2187releasing hypoxia-activated prodrug systems are promising candidates to overcome the clinically observed enhanced toxicity of EGFR-VEGFR inhibitor combination therapies

CoForTips Congo basin forests: tipping points for biodiversity conservation and resilience. Final Report (La modélisation des changements d’utilisation des terres dans les pays d’Afrique Centrale 2000-2030)

L'utilisation des terres est un facteur crucial pour le développement économique et l'environnement. Ainsi une terre dédiée à l’agriculture permettra une production régulière qui sera bénéfique pour satisfaire les besoins alimentaires des populations alentour et potentiellement, pour l’économie dans son ensemble. Par contre, les terres agricoles ont un contenu carbone bien inférieur à une terre forestière et sont généralement pauvres en biodiversité. Les terres peuvent être utilisées de différentes manières afin de répondre à différents objectifs et il peut être potentiellement difficile de satisfaire tous ces objectifs à la fois, donnant lieu à des choix difficiles lors de la conception des politiques. Les pays membres de la Commission des forêts d'Afrique centrale (COMIFAC) ont identifié l’initiative pour la réduction des émissions issues de la déforestation et de la dégradation forestière et l'amélioration des stocks de carbone (REDD+) comme un enjeu majeur dans la dernière revision du Plan de Convergence pour la Gestion Durable des Forêts, aux côtés de la conservation et de l’utilisation durable de la diversité biologique et de la réduction des impacts du changement climatique. Cette étude a pour objectif d’identifier les zones soumises aux pressions de conversion les plus fortes dans le futur et les conséquences en termes de production agricole, d’émissions de gaz à effet de serre (GES) et de risque de perte de biodiversité, avec pour but d’accompagner les institutions impliquées dans la REDD+ ainsi que dans la planification des Stratégies Nationales et Plans d’Action pour la Biodiversité dans les pays de la COMIFAC

Probing the Solution Structure of IκB Kinase (IKK) Subunit γ and Its Interaction with Kaposi Sarcoma-associated Herpes Virus Flice-interacting Protein and IKK Subunit β by EPR Spectroscopy.

Viral flice-interacting protein (vFLIP), encoded by the oncogenic Kaposi sarcoma-associated herpes virus (KSHV), constitutively activates the canonical nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway. This is achieved through subversion of the IκB kinase (IKK) complex (or signalosome), which involves a physical interaction between vFLIP and the modulatory subunit IKKγ. Although this interaction has been examined both in vivo and in vitro, the mechanism by which vFLIP activates the kinase remains to be determined. Because IKKγ functions as a scaffold, recruiting both vFLIP and the IKKα/β subunits, it has been proposed that binding of vFLIP could trigger a structural rearrangement in IKKγ conducive to activation. To investigate this hypothesis we engineered a series of mutants along the length of the IKKγ molecule that could be individually modified with nitroxide spin labels. Subsequent distance measurements using electron paramagnetic resonance spectroscopy combined with molecular modeling and molecular dynamics simulations revealed that IKKγ is a parallel coiled-coil whose response to binding of vFLIP or IKKβ is localized twisting/stiffening and not large-scale rearrangements. The coiled-coil comprises N- and C-terminal regions with distinct registers accommodated by a twist: this structural motif is exploited by vFLIP, allowing it to bind and subsequently activate the NF-κB pathway. In vivo assays confirm that NF-κB activation by vFLIP only requires the N-terminal region up to the transition between the registers, which is located directly C-terminal of the vFLIP binding site

Modelling Land Use Changes in the Republic of Congo 2000-2030 . A report by the REDD-PAC project.

This study is intended to assist institutions involved in REDD+ and the planning of National Strategies and Action plans for Biodiversity in the Republic of Congo by attempting to identify the areas under the greatest conversion pressures in the future and the consequences in terms of agricultural production, greenhouse gas emissions and biodiversity loss.Cette étude essaye d’identifier les zones soumises aux pressions de conversion les plus fortes dans le futur et les conséquences en termes de production agricole, d’émissions de gaz à effet de serre et de risque de perte de biodiversité. L’objectif du projet REDD-PAC est d’accompagner les institutions impliquées dans la REDD+ ainsi que dans la planification de la Stratégie Nationale et du Plan d’Action pour la Biodiversité en République du Congo