ALL blasts drive primary mesenchymal stromal cells to increase asparagine availability during asparaginase treatment

Mechanisms underlying the resistance of acute lymphoblastic leukemia (ALL) blasts to L-asparaginase are still incompletely known. Here we demonstrate that human primary bone marrow mesenchymal stromal cells (MSCs) successfully adapt to L-asparaginase and markedly protect leukemic blasts from the enzyme-dependent cytotoxicity through an amino acid tradeoff. ALL blasts synthesize and secrete glutamine, thus increasing extracellular glutamine availability for stromal cells. In turn, MSCs use glutamine, either synthesized through glutamine synthetase (GS) or imported, to produce asparagine, which is then extruded to sustain asparagine-auxotroph leukemic cells. GS inhibition prevents mesenchymal cells adaptation to L-asparaginase, lowers glutamine secretion by ALL blasts, and markedly hinders the protection exerted by MSCs on leukemic cells. The pro-survival amino acid exchange is hindered by the inhibition or silencing of the asparagine efflux transporter SNAT5, which is induced in mesenchymal cells by ALL blasts. Consistently, primary MSCs from ALL patients express higher levels of SNAT5 (P <.05), secrete more asparagine (P <.05), and protect leukemic blasts (P <.05) better than MSCs isolated from healthy donors. In conclusion, ALL blasts arrange a pro-leukemic amino acid trade-off with bone marrow mesenchymal cells, which depends on GS and SNAT5 and promotes leukemic cell survival during L-asparaginase treatment

Virtual Outcrops Building in Extreme Logistic Conditions for Data Collection, Geological Mapping, and Teaching: The Santorini's Caldera Case Study, Greece

In the present work, we test the application of boat-camera-based photogrammetry as a tool for Virtual Outcrops (VOs) building on geological mapping and data collection. We used a 20 MPX camera run by an operator who collected pictures almost continuously, keeping the camera parallel to the ground and opposite to the target during a boat survey. Our selected target was the northern part of Santorini's caldera wall, a structure of great geological interest. A total of 887 pictures were collected along a 5.5-km-long section along an almost vertical caldera outcrop. The survey was performed at a constant boat speed of about 4 m/s and a coastal approaching range of 35.8 to 296.5m. Using the Structure from Motion technique we: i) produced a successful and high-resolution 3D model of the studied area, ii) designed high-resolution VOs for two selected caldera sections, iii) investigated the regional geology, iv) collected qualitative and quantitative structural data along the vertical caldera cliff, and v) provided a new VO building approach in extreme logistic conditions

Functional consequences of low activity of transport system a for neutral amino acids in human bone marrow mesenchymal stem cells

In cultured human fibroblasts, SNAT transporters (System A) account for the accumulation of non-essential neutral amino acids, are adaptively up-regulated upon amino acid deprivation and play a major role in cell volume recovery upon hypertonic stress. No information is instead available on the expression and activity of SNAT transporters in human bone marrow mesenchymal stromal cells (MSC), although they are increasingly investigated for their staminal and immunomodulatory properties and used for several therapeutic applications. The uptake of glutamine and proline, two substrates of SNAT1 and SNAT2 transporters, was measured in primary human MSC and an MSC line. The amino acid analogue MeAIB, a specific substrate of these carriers, has been used to selectively inhibit SNAT-dependent transport of glutamine and, through its sodium-dependent transport, as an indicator of SNAT1/2 activity. SNAT1/2 expression and localization were assessed with RT-PCR and confocal microscopy, respectively. Cell volume was assessed from urea distribution space. In all these experiments, primary human fibroblasts were used as the positive control for SNAT expression and activity. Compared with fibroblasts, MSC have a lower SNAT1 expression and hardly detectable membrane localization of both SNAT1 and SNAT2. Moreover, they exhibit no sodium-dependent MeAIB uptake or MeAIB-inhibitable glutamine transport, and exhibit a lower ability to accumulate glutamine and proline than fibroblasts. MSC exhibited an only marginal increase in MeAIB transport upon amino acid starvation and did not recover cell volume after hypertonic stress. In conclusion, the activity of SNAT transporters is low in human MSC. MSC adaptation to amino acid shortage is expected to rely on intracellular synthesis, given the absence of an effective up-regulation of the SNAT transporters

A New Way to Explore Volcanic Areas: QR-Code-Based Virtual Geotrail at Mt. Etna Volcano, Italy

In this body of work, we showcase a historic virtual geotrail on the eastern flank of the iconic Mt. Etna volcano (Italy), along a series of outstanding geological sites and features subsequent to an important eruption that took place in 1928. A geohistoric account of such a major eruption, is of great interest, since it is the only event since 1669 to have caused the destruction of a town (Mascali) in the Etna region. Volcanologists, educators, the lay public, tourists and volcano explorers can now access a series of \u201cvirtual geostops\u201d belonging to this virtual geotrail, such that \u201cvisitors\u201d can virtually fly above these sites by scanning a QR code on the printed or electronic version of the present manuscript, as well as on the poster provided as additional material for this manuscript. The virtual geostops that comprise the virtual geotrail were developed using the structure-from-motion (SfM) photogrammetry technique from images captured by using unmanned aerial vehicles (UAVs). The main result of our work is the virtual geotrail, subdivided in two parts and composed of eight geostops, each showing outstanding examples of geological features resulting from volcanic phenomena that took place also during 1979. Our approach is designed to support classical field trips, and it can undoubtedly become complementary to traditional field teaching in earth sciences, both now and in the future

Monocyte–macrophage polarization and recruitment pathways in the tumour microenvironment of B-cell acute lymphoblastic leukaemia

B-cell acute lymphoblastic leukaemia (B-ALL) reprograms the surrounding bone marrow (BM) stroma to create a leukaemia-supportive niche. To elucidate the contribution of immune cells to the leukaemic microenvironment, we investigated the involvement of monocyte/macrophage compartments, as well as several recruitment pathways in B-ALL development. Immunohistochemistry analyses showed that CD68-expressing macrophages were increased in leukaemic BM biopsies, compared to controls and predominantly expressed the M2-like markers CD163 and CD206. Furthermore, the "non-classical" CD14+CD16++ monocyte subset, expressing high CX3CR1 levels, was significantly increased in B-ALL patients' peripheral blood. CX3CL1 was shown to be significantly upregulated in leukaemic BM plasma, thus providing an altered migratory pathway possibly guiding NC monocyte recruitment into the BM. Additionally, the monocyte/macrophage chemoattractant chemokine ligand 2 (CCL2) strongly increased in leukaemic BM plasma, possibly because of the interaction of leukaemic cells with mesenchymal stromal cells and vascular cells and due to a stimulatory effect of leukaemia-related inflammatory mediators. C5a, a macrophage chemoattractant and M2-polarizing factor, further appeared to be upregulated in the leukaemic BM, possibly as an effect of PTX3 decrease, that could unleash complement cascade activation. Overall, deregulated monocyte/macrophage compartments are part of the extensive BM microenvironment remodelling at B-ALL diagnosis and could represent valuable targets for novel treatments to be coupled with classical chemotherapy

How academics and the public experienced immersive virtual reality for geo-education

Immersive virtual reality can potentially open up interesting geological sites to students, academics and others who may not have had the opportunity to visit such sites previously. We study how users perceive the usefulness of an immersive virtual reality approach applied to Earth Sciences teaching and communication. During nine immersive virtual reality-based events held in 2018 and 2019 in various locations (Vienna in Austria, Milan and Catania in Italy, Santorini in Greece), a large number of visitors had the opportunity to navigate, in immersive mode, across geological landscapes reconstructed by cutting-edge, unmanned aerial system-based photogrammetry techniques. The reconstructed virtual geological environments are specifically chosen virtual geosites, from Santorini (Greece), the North Volcanic Zone (Iceland), and Mt. Etna (Italy). Following the user experiences, we collected 459 questionnaires, with a large spread in participant age and cultural background. We find that the majority of respondents would be willing to repeat the immersive virtual reality experience, and importantly, most of the students and Earth Science academics who took part in the navigation confirmed the usefulness of this approach for geo-education purposes