Axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC

Objective: The dysregulation of the axon guidance pathway is common in pancreatic ductal adenocarcinoma (PDAC), yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in supporting PDAC progression. Design: We integrated bulk and single-cell transcriptomic datasets of human PDAC with in situ hybridisation analyses of patients’ tissues to evaluate SEMA3A expression in molecular subtypes of PDAC. Gain and loss of function experiments in PDAC cell lines and organoids were performed to dissect how SEMA3A contributes to define a biologically aggressive phenotype. Results: In PDAC tissues, SEMA3A is expressed by stromal elements and selectively enriched in basal-like/squamous epithelial cells. Accordingly, expression of SEMA3A in PDAC cells is induced by both cell-intrinsic and cell-extrinsic determinants of the basal-like phenotype. In vitro, SEMA3A promotes cell migration as well as anoikis resistance. At the molecular level, these phenotypes are associated with increased focal adhesion kinase signalling through canonical SEMA3A-NRP1 axis. SEMA3A provides mouse PDAC cells with greater metastatic competence and favours intratumoural infiltration of tumour-associated macrophages and reduced density of T cells. Mechanistically, SEMA3A functions as chemoattractant for macrophages and skews their polarisation towards an M2-like phenotype. In SEMA3Ahigh tumours, depletion of macrophages results in greater intratumour infiltration by CD8+T cells and better control of the disease from antitumour treatment. Conclusions: Here, we show that SEMA3A is a stress-sensitive locus that promotes the malignant phenotype of basal-like PDAC through both cell-intrinsic and cell-extrinsic mechanisms

Further Development of an Analytical Model for Helicopter Main Rotor Wake-Tail Interactions

Simulation of aerodynamic and flight mechanic characteristics is essential to predict helicopter flight behaviour. One of the most important features is certainly the interactions between the main rotor wake and different helicopter components. This Master Thesis focuses on an analytical model able to predict and evaluate main rotor wake interactions with tailboom, empennage and fenestron. This was implemented in a more general flight mechanical simulation code. The first version was created in a former master thesis by Airbus Helicopters. Further development have been requested in order to have a better estimation of computed quantities in trimmed conditions for a higher range of speeds. The previous model, indeed, was suitable only for hover and low velocity steady forward flight. For this purpose, has been fundamental a better estimation of lateral forces and of wake geometry. Researches about influence of different factors have been conducted and new physical models considering fin and fenestron interactions and wake distortion have been derived and implemented. Two main variables have been considered as quality indicators: mast moment and fenestron blade pitch. Nevertheless, other quantities like forces and velocities have always been taken into account as well. Computed results have been compared with flight test data in order to verify the reliability of the improved simulation model. Moreover, CFD analysis have been used to clearly understand the wake behaviour

NATO AVT-365 Lecture Series: Rotorcraft Flight Simulation Model Fidelity Improvement and Assessment

Slides and Educational Notes for the Lecture Series NATO AVT-365 which presents results from the working group AVT-296 with the same titl