Role of tumor-derived extracellular vesicles in immunosuppression in malignant melanoma patients

Das Ziel dieser Studie war es die Rolle von extrazellulären Vesikeln (EVs) bei der Umwandlung von zirkulierenden CD14+ Monozyten in monozytäre myeloide suppressor Zellen (M-MDSCs) zu untersuchen. Dabei wurden EVs aus humanen Melanomzelllinien, sowie Plasma von Melanompatienten isoliert. Wir haben gezeigt, dass EVs von HT-144 Zellen (HT-144 EVs) Bcl-2 in CD14+ Monozyten hochregulierten (auf mRNA -und Proteinebene) und dieses eine anti-apoptotische Wirkung hatten. Darüber hinaus zeigten CD14+ Monozyten ein verstärktes Entzündungsprofil, sowie eine verstärkte Migration nach der Stimulation mit HT-144 EVs. Nach der Behandlung der Monozyten mit EVs aus HT-144 und SK-MEL-28 Zellen, wurde ein Hochregulation von PD-L1 und eine herunter Regulierung von HLA-DR auf Monozyten beobachtet. Dieser Phänotyp bestätigte die Konvertierung von klassischen Monozyten zu M-MDSCs. Die stimulierten Monozyten zeigten eine starke immunsuppressive Aktivität, da diese die Proliferation von CD8+ T Zellen, sowie deren Produktion von IFN-ү unterdrückten. Die Hochregulation von PD-L1 wurde über den Toll-like-Rezeptor (TLR)2 und TLR4 Signalweg induziert, wobei TLR4 eine dominantere Rolle spielte. Der Signalweg aktivierte NF-κB, was zur Hochregulation von PD-L1 führte. Die Blockade von TLR4 mittels TLR4-blockierenden Antikörpern, sowie NF-κB mit NF-κB Inhibitoren verringerte die PD-L1 Expression signifikant. Des Weiteren fanden wir, dass auf EVs von Melanomzelllinien HSP86 exprimiert wurde. Der Vergleich von HSP86+ EVs mit HSP86low/- EVs verdeutlichte die Bedeutung von der HSP86 vermittelten PD-L1 Expression und der immunsuppressiven Aktivität. Zudem haben wir die Expression von HSP86 in Plasma EVs von Melanompatienten getestet, welche eine Anti-PD-1 Therapie erhielten. Wir haben gezeigt, dass EVs von Nicht-Respondern die PD-L1 Expression hochregulierten und eine immunsuppressive Aktivität in zirkulierenden Monozyten induzierten. Diese EVs zeigten zusätzlich eine deutlich höhere Expression von HSP86 im Vergleich zu EVs von Respondern. Schließlich untersuchten wir PBMCs von 30 Melanompatienten vor und nach einer Anti-PD-1 Behandlung. Wir fanden eine signifikante Abnahme der PD-L1-Expression in zirkulierenden Monozyten von Respondern im Vergleich zum Status beim Beginn der Therapie. Darüber hinaus zeigten Patienten mit niedrigerer PD-L1 Expression auf zirkulierenden Monozyten besseres progressionsfreies Überleben. Zusammengefasst demonstrieren unsere Ergebnisse eine bedeutende Rolle von Tumor-EVs bei der Umwandlung von zirkulierender Monozyten in M-MDSCs. Des Weiteren konnten wir zeigen, dass die PD-L1 Expression auf Monozyten bei Melanompatienten, welche sich einer Anti-PD-1 Therapie unterziehen, eine entscheidende Rolle bei der Vorhersage des Therapieerfolgs hat

R&D modes and firm performance in high-tech companies: A research based on cross-boundary ambidexterity and network structures

This paper draws on the cross-boundary ambidexterity theory to propose that four different R&D modes impact firm performance differently and that cooperative network structure moderates the above relationships. The theoretical model is tested by using financial and patent data of 587 high-tech firms for 10 consecutive years in China. We find that different R&D modes have different impacts on a firm’s financial and innovative performance, and network structure plays different moderating roles. Practically, this work guides high-tech enterprises to optimize their resource allocation, select the most appropriate R&D mode, and establish efficient cooperative networks

An Augmented Subspace Based Adaptive Proper Orthogonal Decomposition Method for Time Dependent Partial Differential Equations

In this paper, we propose an augmented subspace based adaptive proper orthogonal decomposition (POD) method for solving the time dependent partial differential equations. By augmenting the POD subspace with some auxiliary modes, we obtain an augmented subspace. We use the difference between the approximation obtained in this augmented subspace and that obtained in the original POD subspace to construct an error indicator, by which we obtain a general framework for augmented subspace based adaptive POD method. We then provide two strategies to obtain some specific augmented subspaces, the random vector based augmented subspace and the coarse-grid approximations based augmented subspace. We apply our new method to two typical 3D advection-diffusion equations with the advection being the Kolmogorov flow and the ABC flow. Numerical results show that our method is more efficient than the existing adaptive POD methods, especially for the advection dominated models.Comment: 28 pages, 4 figures, 7 table

Synapse: Interactive Guidance by Demonstration with Trial-and-Error Support for Older Adults to Use Smartphone Apps

As smartphones are widely adopted, mobile applications (apps) are emerging to provide critical services such as food delivery and telemedicine. While bring convenience to everyday life, this trend may create barriers for older adults who tend to be less tech-savvy than young people. In-person or screen sharing support is helpful but limited by the help-givers' availability. Video tutorials can be useful but require users to switch contexts between watching the tutorial and performing the corresponding actions in the app, which is cumbersome to do on a mobile phone. Although interactive tutorials have been shown to be promising, none was designed for older adults. Furthermore, the trial-and-error approach has been shown to be beneficial for older adults, but they often lack support to use the approach. Inspired by both interactive tutorials and trial-and-error approach, we designed an app-independent mobile service, \textit{Synapse}, for help-givers to create a multimodal interactive tutorial on a smartphone and for help-receivers (e.g., older adults) to receive interactive guidance with trial-and-error support when they work on the same task. We conducted a user study with 18 older adults who were 60 and over. Our quantitative and qualitative results show that Synapse provided better support than the traditional video approach and enabled participants to feel more confident and motivated. Lastly, we present further design considerations to better support older adults with trial-and-error on smartphones

Cognitive Flexibility and Advice Network Centrality: The Moderating Role of Self-Monitoring

This study examined the role of individuals’ cognitive flexibility and self-monitoring in shaping their workplace advice network centrality. Drawing on advice network generation theory, we hypothesized a positive relationship between cognitive flexibility and advice network centrality, and a moderation effect of self-monitoring on this relationship. Then, we collected two time-points data from insurance salesmen to test the hypotheses. As predicted, cognitive flexibility was positively associated with advice network centrality. Furthermore, this positive relationship was only significant for low self-monitoring individuals, but not for high self-monitoring individuals. These findings indicated that individuals with high cognitive flexibility were more likely to have central positions in the advice network; however, this effect was attenuated as their self-monitoring increased

Boosting output performance of contact-separation mode triboelectric nanogenerators by adopting discontinuity and fringing effect: experiment and modelling studies

Triboelectric nanogenerators (TENGs) are promising self-powering supplies for a diverse range of intelligent sensing and monitoring devices, especially due to their capability of harvesting electric energy from low frequency and small-scale mechanical motions. Inspired by the fact that contact-separation mode TENGs with small contact areas harvest high electrical outputs due to fringing effect, this study employed discontinuity on the dielectric side of contact-separation mode TENGs to promote fringing electric fields for the enhancement of electrical outputs. The results reveal that the TENGs with more discontinuities show higher overall electric performance. Compared to pristine TENGs, the TENGs with cross discontinuities increased the surface charge by 50% and the power density by 114%. However, one should avoid generating discontinuities on tribonegative side of TENGs using metal blade within a positive-ion atmosphere due to the neutralization through electrically conductive metal blade. The computational simulation validated that the TENGs with discontinuities obtained higher electrical outputs, and further investigated the effect of discontinuity gap size and array distance on TENGs performance. This study has provided a promising method for the future design of TENGs using discontinuous structures.Comment: 23 pages, 8 figure