RAB5A IN THE CONTROL OF MAMMARY EPITHELIAL MORPHOGENESIS AND MOTILITY

Endocytosis has been originally considered as a fundamental mechanism involved in the internalization of nutrients and membrane-bound molecules into the cell. However, recent studies demonstrate that endocytosis is a more complex network that regulates the delivery of specific time- and space-resolved signals to the cell. The small GTPase RAB5A, a master regulator of endocytosis, is emerging as a key player in tumor progression and metastatic dissemination. Consistently, the expression of RAB5A has been shown to promote a tumor mesenchymal invasive program and to correlate with the metastatic potential of different tumors. In Drosophila, however, loss-of-function mutant of RAB5 transforms imaginal disc epithelia into highly proliferative tissues, pointing to a tumor suppressor function of RAB5. To dissect the complex role of this GTPase in tumor development, we investigated the impact of RAB5A deregulation on MCF-10A, an immortalized non-transformed mammary epithelial cell line that forms hollow acinar-like spheroids recapitulating the morphogenesis of the human mammary gland, when cultured on 3D reconstituted basement membrane. We generated stable and inducible MCF-10A cells expressing either RAB5A WT or its dominant negative form (RAB5AS34N). We found that the expression of RAB5AS34N is sufficient to sustain MCF-10A cells proliferation in the absence of EGF. We identified Amphiregulin, a known EGFR ligand, as the secreted diffusible factor responsible for EGF-independent proliferation. Conversely, the expression of RAB5A WT delayed cell 15 cycle progression of cells grown in 2D, albeit it promoted the formation of hyper- proliferative acini when these cells were grown in 3D, without affecting acini morphological architecture or polarity establishment. Thus, RAB5A may either be implicated in growth factor independent growth, or may promote proliferation in 3D. Both clinical data and in vitro studies showed that RAB5A is required for invasion and metastasis formation, suggesting its involvement in tumor progression. In particular, the overexpression of RAB5A has been shown to be predictive of aggressive behavior and metastatic ability in human breast cancer. To further explore this function, we investigated the role of RAB5A in MCF-10A cells motility. We demonstrated that RAB5A expression does not affect single cell migration, but specifically enhances collective locomotion, the typical motility mode frequently observed in invasive cancer of epithelial origin, such as breast carcinoma. Indeed, RAB5A expression promotes increased speed and coordination of the epithelial cell sheet motility, related both to the increase in the area and persistence of migratory protrusions in cells at the leading front, and possibly to a tightening of cell-to- cell contacts, which improves cohesiveness of the migrating epithelial sheet. In conclusion, our data suggest a temporally distinct dual role of RAB5A in tumor development. On one hand, RAB5A may exploit a tumor suppressor function controlling epithelial tissue morphogenesis and homeostasis, which impairment may induce tumor initiation. On the other hand, RAB5A promotes not only a mesenchymal program of individual cell invasion, as previously shown by our group, but also it enhances coordinated collective epithelial migration, thus promoting cancer progression and dissemination

A murine model of cerebral cavernous malformations with acute hemorrhage

Cavernomas are multi-lumen and blood-filled vascular malformations which form in the brain and the spinal cord. They lead to hemorrhage, epileptic seizures, neurological deficits, and paresthesia. An effective medical treatment is still lacking, and the available murine models for cavernomas have several limitations for preclinical studies. These include disease phenotypes that differ from human diseases, such as restriction of the lesions to the cerebellum, and absence of acute hemorrhage. Additional limitations of current murine models include rapid development of lesions, which are lethal before the first month of age. Here, we have characterized a murine model that recapitulates features of the human disease: lesions develop after weaning throughout the entire CNS, including the spinal cord, and undergo acute hemorrhage. This provides a preclinical model to develop new drugs for treatment of acute hemorrhage in the brain and spinal cord, as an unmet medical emergency for patients with cavernomas

From Megabits to CPU Ticks: Enriching a Demand Trace in the Age of MEC

All the content consumed by mobile users, be it a web page or a live stream, undergoes some processing along the way; as an example, web pages and videos are transcoded to fit each device’s screen. The recent multi-access edge computing (MEC) paradigm envisions performing such processing within the cellular network, as opposed to resorting to a cloud server on the Internet. Designing a MEC network, i.e., placing and dimensioning the computational facilities therein, requires information on how much computational power is required to produce the contents needed by the users. However, real-world demand traces only contain information on how much data is downloaded. In this paper, we demonstrate how to enrich demand traces with information about the computational power needed to process the different types of content, and we show the substantial benefit that can be obtained from using such enriched traces for the design of MEC-based networks.This work is supported by the European Commission through the H2020 projects 5G-TRANSFORMER (Project ID 761536) and 5G-EVE (Project ID 815074)

The exploration of eastern Mediterranean deep hypersaline anoxic basins with MODUS: a significant example of technology spin-off from the Geostar Program

A significant example of technological spin-off from the GEOSTAR project is represented by the special-purpose instrumented module, based on the deep-sea ROV MODUS, which was developed in the framework of the EU-sponsored project BIODEEP. The goal to be achieved has been defined as the exploration, through real-time video images, measurements and accurate video-guided sampling, of the deep hypersaline anoxic basins of the eastern Mediterranean Sea at water depths well exceeding 3000 meters. Due to their peculiar characteristics, these basins are one of the most extreme environments on Earth and represent a site of utmost interest for their geochemical and microbial resources. The paper presents the strategies and the main results achieved during the two cruises carried out within the BIODEEP project

Support of Safety Services through Vehicular Communications: The Intersection Collision Avoidance Use Case

Cooperative systems are based on the periodical exchange of standardized information, thanks to which vehicles can advertise their presence, position and the direction they are moving to, and execute sophisticated C-ITS applications that can detect potentially dangerous situations and properly react. The technological pillar, which must enable a Vehicular ad Hoc Network (VANET), is now being debated: the candidates are the traditional WiFi-based approach and the upcoming cellular one. The application effectiveness, however, depends not only on the technology, but also on how fast it is adopted and becomes widespread, i.e., the so-called technology Penetration Rate (PR). In this paper, simulation is used to evaluate the Intersection Collision Avoidance (ICA) application for both candidate technologies, and evaluated as a function of the technology PR.This work was partially supported by FCA through the DiVe project, by the C.A.R.S. center at Politecnico di Torino, and by the H2020 5G-TRANSFORMER project (Project ID 761536

Particle fluxes in the deep Eastern Mediterranean basins: the role of ocean vertical velocities

This paper analyzes the relationship between deep sedimentary fluxes and ocean current vertical velocities in an offshore area of the Ionian Sea, the deepest basin of the Eastern Mediterranean Sea. Sediment trap data are collected at 500 m and 2800 m depth in two successive moorings covering the period September 1999–May 2001. A tight coupling is observed between the upper and deep traps and the estimated particle sinking rates are more than 200 m day−1. The current vertical velocity field is computed from a 1/16°×1/16° Ocean General Circulation Model simulation and from the wind stress curl. Current vertical velocities are larger and more variable than Ekman vertical velocities, yet the general patterns are alike. Current vertical velocities are generally smaller than 1 m day−1: we therefore exclude a direct effect of downward velocities in determining high sedimentation rates. However we find that upward velocities in the subsurface layers of the water column are positively correlated with deep particle fluxes. We thus hypothesize that upwelling would produce an increase in upper ocean nutrient levels – thus stimulating primary production and grazing – a few weeks before an enhanced vertical flux is found in the sediment traps. High particle sedimentation rates may be attained by means of rapidly sinking fecal pellets produced by gelatinous macro-zooplankton. Other sedimentation mechanisms, such as dust deposition, are also considered in explaining large pulses of deep particle fluxes. The fast sinking rates estimated in this study might be an evidence of the efficiency of the biological pump in sequestering organic carbon from the surface layers of the deep Eastern Mediterranean basins

Cooperative Localization Enhancement through GNSS Raw Data in Vehicular Networks

The evolution and integration of communication networks and positioning technologies are evolving at a fast pace in the framework of vehicular systems. The mutual dependency of such two capabilities can enable several new cooperative paradigms, whose adoption is however slowed down by the lack of suitable open protocols, especially related to the positioning and navigation domain. In light of this, the paper introduces a novel vehicular message type, namely the Cooperative Enhancement Message (CEM), and an associated open protocol to enable the sharing of Global Navigation Satellite Systems (GNSS) raw measurements among connected vehicles. The proposed CEM aims at extending existent approaches such as Cooperative Awareness Messages (CAM) and Collective Perception Messages (CPM) by complementing their paradigms with a cooperative enhancement of the localization accuracy, precision, and integrity proposed by state-of-the-art solutions. Besides the definition of CEMs and a related protocol, a validation of the approach is proposed through a novel simulation framework. A preliminary analysis of the network performance is presented in the case where CEM and CAM transmissions coexist and are concurrently used to support cooperative vehicle applications

Particle fluxes in the deep Eastern Mediterranean basins: the role of ocean vertical velocities

This paper analyzes the relationship between deep sedimentary fluxes and ocean current vertical velocities in an offshore area of the Ionian Sea, the deepest basin of the Eastern Mediterranean Sea. Sediment trap data are collected at 500 m and 2800 m depth in two successive moorings covering the period September 1999 – May 2001. A tight coupling is observed between the upper and deep traps and the deduced particle settling rates are larger than 200 m/day. The current vertical velocity field is computed from a high resolution Ocean General Circulation Model (OGCM) simulation and from the wind stress curl. Values are generally smaller than 1 m/day: we therefore exclude a direct effect of downward vertical velocities in determining sedimentation rates. However we find that upward vertical velocities in the subsurface layers of the water column are significantly correlated with deep particle fluxes. We thus hypothesize that upwelling would produce an increase in upper ocean nutrient levels - thus stimulating primary productivity and grazing - a few weeks before an enhanced vertical flux is found in the sediment traps. The role of ocean vertical velocities on deep particle fluxes would therefore be indirect. High particle sedimentation rates may be attained by means of rapidly sinking fecal pellets produced by gelatinous macro-zooplankton organisms. Other sedimentation mechanisms, such as dust deposition, are also taken into account in explaining large pulses of deep particle fluxes