Egr-1 Activation by Cancer-Derived Extracellular Vesicles Promotes Endothelial Cell Migration via ERK1/2 and JNK Signaling Pathways

Various mammalian cells, including cancer cells, shed extracellular vesicles (EVs), also known as exosomes and microvesicles, into surrounding tissues. These EVs play roles in tumor growth and metastasis by promoting angiogenesis. However, the detailed mechanism of how cancer-derived EVs elicit endothelial cell activation remains unknown. Here, we provide evidence that early growth response-1 (Egr-1) activation in endothelial cells is involved in the angiogenic activity of colorectal cancer cell-derived EVs. Both RNA interference-mediated downregulation of Egr-1 and ERK1/2 or JNK inhibitor significantly blocked EV-mediated Egr-1 activation and endothelial cell migration. Furthermore, lipid raft-mediated endocytosis inhibitor effectively blocked endothelial Egr-1 activation and migration induced by cancer-derived EVs. Our results suggest that Egr-1 activation in endothelial cells may be a key mechanism involved in the angiogenic activity of cancer-derived EVs. These findings will improve our understanding regarding the proangiogenic activities of EVs in diverse pathological conditions including cancer, cardiovascular diseases, and neurodegenerative diseases.open11617sciescopu

Performance Evaluation of Individual Aircraft Based Advisory Concept for Surface Management

Surface operations at airports in the US are based on tactical operations, where departure aircraft primarily queue up and wait at the departure runways. NASA's Spot And Runway Departure Advisor (SARDA) tool was developed to address these inefficiencies through Air Traffic Control Tower advisories. The SARDA system is being updated to include collaborative gate hold, either tactically or strategically. This paper presents the results of the human-in-the-loop evaluation of the tactical gate hold version of SARDA in a 360 degree simulated tower setting. The simulations were conducted for the east side of the Dallas/Fort Worth airport. The new system provides gate hold, ground controller and local controller advisories based on a single scheduler. Simulations were conducted with SARDA on and off, the off case reflecting current day operations with no gate hold. Scenarios based on medium (1.2x current levels) and heavy (1.5x current levels) traffic were explored. Data collected from the simulation was analyzed for runway usage, delay for departures and arrivals, and fuel consumption. Further, Traffic Management Initiatives were introduced for a subset of the aircraft. Results indicated that runway usage did not change with the use of SARDA, i.e., there was no loss in runway throughput as compared to baseline. Taxiing delay was significantly reduced with the use of advisory by 45% in medium scenarios and 60% in heavy. Arrival delay was unaffected by the use of advisory. Total fuel consumption was also reduced by 23% in medium traffic and 33% in heavy. TMI compliance appeared unaffected by the advisor

Performance Evaluation of SARDA: An Individual Aircraft-Based Advisory Concept for Surface Management

Surface operations at airports in the US are based on tactical operations, where departure aircraft primarily queue up and wait at the departure runways. NASAs Spot And Runway Departure Advisor (SARDA) tool was developed to address these inefficiencies through Air Traffic Control Tower advisories. The SARDA system is being updated to include collaborative gate hold, either tactically or strategically. This paper presents the results of the human-in-the-loop evaluation of the tactical gate hold version of SARDA in a 360 degree simulated tower setting. The simulations were conducted for the east side of the Dallas-Fort Worth airport. The new system provides gate hold, ground controller and local controller advisories based on a single scheduler. Simulations were conducted with SARDA on and off, the off case reflecting current day operations with no gate hold. Scenarios based on medium (1.2x current levels) and heavy (1.5x current levels) traffic were explored. Data collected from the simulation was analyzed for runway usage, delay for departures and arrivals, and fuel consumption. Further, Traffic Management Initiatives were introduced for a subset of the aircraft. Results indicated that runway usage did not change with the use of SARDA, i.e., there was no loss in runway throughput as compared to baseline. Taxiing delay was significantly reduced with the use of advisory by 45 in medium scenarios and 60 in heavy. Arrival delay was unaffected by the use of advisory. Total fuel consumption was also reduced by 23 in medium traffic and 33 in heavy. TMI compliance appeared unaffected by the advisory

Usability Evaluation of Spot and Runway Departure Advisor (SARDA) Concept in Dallas/Fort Worth Airport Tower Simulation

Spot and Runway Departure Advisor (SARDA) is a proposed decision-support tool for air traffic control tower controllers for reducing taxi delay and optimizing the departure sequence. In the present study, the tool's usability was evaluated to ensure that its claimed performance benefits are not being realized at the cost of increasing the work burden on controllers. For the evaluation, workload ratings and questionnaire responses collected during a human-in-the-loop simulation experiment were analyzed to assess the SARDA advisories' effects on the controllers' ratings on cognitive resources (e.g., workload, spare attention) and satisfaction. The results showed that SARDA reduced the controllers' workload and increased their spare attention. It also made workload and attention levels less susceptible to the effects of increases in the traffic load. The questionnaire responses suggested that the controllers generally were satisfied with the ease of use of the tool and the objectives of the SARDA concept, but with some caution. To gain more trust from controllers, the the reasoning behind advisories may need to be made more transparent to them

SARDA: An Integrated Concept for Airport Surface Operations Management

The Spot and Runway Departure Advisor (SARDA) is an integrated decision support tool for airlines and air traffic control tower enabling surface collaborative decision making (CDM) and departure metering in order to enhance efficiency of surface operations at congested airports. The presentation describes the concept and architecture of the SARDA as a CDM tool, and the results from a human-in-the-loop simulation of the tool conducted in 2012 at the FutureFlight Central, the tower simulation facility. Also, presented is the current activities and future plan for SARDA development. The presentation was given at the meeting with the FAA senior advisor of the Surface Operations Office

C5 Extract Induces Apoptosis in B16F10 Murine Melanoma Cells through Extrinsic and Intrinsic Apoptotic Pathways and Sub-G1 Phase Arrest

Purpose: To investigate the anti-cancer activities of C5 extract (C5E), a new herbal preparation from Korea, on B16F10 cells.Methods: The anti-proliferative effects of C5E were assessed by culturing B16F10 cells in the presence or absence of C5E. Cell cycle progression was analyzed by PI staining using flow cytometry. The quantities of apoptosis-inducing proteins were measured by Western blot.Results: C5E inhibited the proliferation of B16F10 cells but not human keratinocytes. C5E induced S phase arrest by interfering with cell regulatory factors such as cyclins B1, D1, D3, and E, and cyclindependent kinase 2, in B16F10 cells. Furthermore, immunoblot analysis confirmed that treatment with C5E induced apoptosis and cleaved caspase-3, poly (ADP-ribose) polymerase, via extrinsic pathway, whereas Bcl-2 expression was down-regulated. In addition, the suppression of cell proliferation by C5E is through down-regulation of p-Akt, up-regulation of phosphatase and tensin homolog protein expression via phosphoinositol 3 kinase survival signaling pathways in B16F10 cells. The combined cytotoxic effects of C5E and vinblastine generated 10 % increase in activity in contrast to the sum of the inhibitory effects of the individual agents.Conclusion: C5E shows promising anti-cancer activity and can be a useful adjuvant with vinblastine in combination therapeutic treatment of skin cancer.Keywords: Melanoma, Apoptosis, Anti-cancer, p53, Vinblastine, Cell cycle arrest, Caspas

A Concept and Implementation of Optimized Operations of Airport Surface Traffic

This paper presents a new concept of optimized surface operations at busy airports to improve the efficiency of taxi operations, as well as reduce environmental impacts. The suggested system architecture consists of the integration of two decoupled optimization algorithms. The Spot Release Planner provides sequence and timing advisories to tower controllers for releasing departure aircraft into the movement area to reduce taxi delay while achieving maximum throughput. The Runway Scheduler provides take-off sequence and arrival runway crossing sequence to the controllers to maximize the runway usage. The description of a prototype implementation of this integrated decision support tool for the airport control tower controllers is also provided. The prototype decision support tool was evaluated through a human-in-the-loop experiment, where both the Spot Release Planner and Runway Scheduler provided advisories to the Ground and Local Controllers. Initial results indicate the average number of stops made by each departure aircraft in the departure runway queue was reduced by more than half when the controllers were using the advisories, which resulted in reduced taxi times in the departure queue

A Genome-Wide Knockout Screen in Human Macrophages Identified Host Factors Modulating Salmonella Infection.

A genome-scale CRISPR knockout library screen of THP-1 human macrophages was performed to identify loss-of-function mutations conferring resistance to Salmonella uptake. The screen identified 183 candidate genes, from which 14 representative genes involved in actin dynamics (ACTR3, ARPC4, CAPZB, TOR3A, CYFIP2, CTTN, and NHLRC2), glycosaminoglycan metabolism (B3GNT1), receptor signaling (PDGFB and CD27), lipid raft formation (CLTCL1), calcium transport (ATP2A2 and ITPR3), and cholesterol metabolism (HMGCR) were analyzed further. For some of these pathways, known chemical inhibitors could replicate the Salmonella resistance phenotype, indicating their potential as targets for host-directed therapy. The screen indicated a role for the relatively uncharacterized gene NHLRC2 in both Salmonella invasion and macrophage differentiation. Upon differentiation, NHLRC2 mutant macrophages were hyperinflammatory and did not exhibit characteristics typical of macrophages, including atypical morphology and inability to interact and phagocytose bacteria/particles. Immunoprecipitation confirmed an interaction of NHLRC2 with FRYL, EIF2AK2, and KLHL13.IMPORTANCESalmonella exploits macrophages to gain access to the lymphatic system and bloodstream to lead to local and potentially systemic infections. With an increasing number of antibiotic-resistant isolates identified in humans, Salmonella infections have become major threats to public health. Therefore, there is an urgent need to identify alternative approaches to anti-infective therapy, including host-directed therapies. In this study, we used a simple genome-wide screen to identify 183 candidate host factors in macrophages that can confer resistance to Salmonella infection. These factors may be potential therapeutic targets against Salmonella infections