Valutazione delle prestazioni di algoritmi di elaborazione delle interrogazioni su una rete Peer-to-Peer

Vengono valutate le prestazioni di due algoritmi di elaborazione delle interrogazioni verso sorgenti informative dotate di tassonomia, attestate sui nodi di una rete Peer-to-Peer (P2P) e collegate le une alle altre da relazioni di sussunzione tra i rispettivi termini. Tali relazioni fanno sì che una interrogazione a una peer coinvolga altre peer, rendendone la valutazione un processo distribuito. Dopo una descrizione delle caratteristiche della rete e dell’ implementazione degli algoritmi, è stato affrontato il problema della valutazione delle loro prestazioni. A questo scopo è stato realizzato un simulatore che è stato successivamente utilizzato per eseguire un certo numero di esperimenti. Attraverso l’analisi dei risultati di tali esperimenti, è stato possibile evidenziare pregi e difetti di ciascun algoritmo, quindi pervenendo alla identificazione dell’algoritmo con le migliori prestazioni

Bone Marrow Endosteal Mesenchymal Progenitors Depend on HIF Factors for Maintenance and Regulation of Hematopoiesis

Summary Maintenance and differentiation of hematopoietic stem cells (HSCs) is regulated through cell-autonomous and non-cell-autonomous mechanisms within specialized bone marrow microenvironments. Recent evidence demonstrates that signaling by HIF-1α contributes to cell-autonomous regulation of HSC maintenance. By investigating the role of HIF factors in bone marrow mesenchymal progenitors, we found that murine endosteal mesenchymal progenitors express high levels of HIF-1α and HIF-2α and proliferate preferentially in hypoxic conditions ex vivo. Inactivation of either HIF-1α or HIF-2α dramatically affects their phenotype, propagation, and differentiation. Also, downregulation of HIF factors provokes an increase in interferon-responsive genes and triggers expansion and differentiation of hematopoietic progenitors by a STAT1-mediated mechanism. Interestingly, in conditions of demand-driven hematopoiesis HIF factors are specifically downregulated in mesenchymal progenitors in vivo. In conclusion, our findings indicate that HIF factors also regulate hematopoiesis non-cell-autonomously by preventing activation of a latent program in mesenchymal progenitors that promotes hematopoiesis

Gas migration along fault systems and through the vadose zone in the Latera caldera (central Italy): Implications for CO2 geological storage

A clear and detailed understanding of gas migration mechanisms from depth to ground surface is fundamental to choose the best locations for C02 geological storage sites, to engineer them so that they do not leak, and to select the most appropriate monitoring strategy and tools to guarantee public safety. Natural test sites (or "natural analogues") provide the best opportunity to study migration mechanisms, as they incorporate such issues as scale, long-time system evolution, and interacting variables that cannot be adequately addressed with laboratory studies or computer models. To this end the present work examines the migration to surface of deep, naturally produced C02 along various buried and exposed faults in the Latera caldera (central Italy) by integrating structural geology and near-surface gas geochemistry surveys. Results show how gas migration is channelled along discrete, high -permeability pathways within the faults, with release typically occurring from spatially restricted gas vents. Size, distribution, and strength of these vents appear to be controlled by the evolution and deformation style of the fault, which is in turn linked to the rheology of the lithological units cut by the fault. As such gas migration can change drastically along strike. Gas migration in the vadose zone around these vents is also discussed, focussing on how the physical-chemical characteristics of various species (C02, CH4, and He) control their spatial distribution and eventual release to the atmosphere. (c) 2008 Elsevier Ltd. All rights reserved

po 040 development of a tunable form of interferon alpha for in vivo cancer gene therapy

Introduction The immune system is a double-edge sword in cancer. On the one hand, it exerts immunosurveillance to eradicate transformed cells that occasionally appear in the body; on the other hand, cancer cells can recruit immune cells endowed with pro-tumorigenic activity. Our lab previously developed a strategy for targeted gene-based delivery of interferon alpha (IFNa) to tumours by tumour infiltrating monocytes/macrophages, which induces robust anti-cancer responses in several experimental models without inducing strong IFN responses in normal tissues as compared to systemic administration of recombinant IFNa. Whereas a sustained output could ensure long-term protection from tumour recurrence, it may raise concerns for long-term side effects, especially in case of cancer eradication.To overcome this issue, we are developing inducible strategies to control the amount of IFNa secreted in the tumour microenvironment. Material and methods By fusing a destabilising domain (DD) to a protein of interest (POI) the former can confer its instability to the latter. This destabilisation can be rescued in a reversible and dose dependent manner with the addition of a small molecule specifically binding to the DD. To apply this technology to our strategy we have designed and in vitro tested different fusion proteins of IFNa (DD-IFNa). We also developed improved DD-IFNa with the addition of flexible and/or cleavable linkers and selected them for their capacity to be stabilised in a dose dependent manner in presence of their specific ligand in vitro . Results and discussions Through this approach, we have identified effective fusion proteins with low basal activity and high fold induction upon ligand treatment. These novel tunable forms of IFNa are functional and their specific activity are comparable to the wild type cytokine in inducing IFN responsive genes. Based on these promising in vitro results we are now translating these new platforms in vivo to test their efficacy in inducing anti-tumour responses in melanoma, colon and glioma models of cancer. Conclusion In the perspective of clinical translation our approach can be used in the future to switch on/off the levels of IFNa in a tunable and personalised fashion for cancer eradication

Regional Seismic Characterization of Shallow Subsoil of Northern Apulia (Southern Italy)

A first-order seismic characterization of Northern Apulia (Southern Italy) has been provided by considering geological information and outcomes of a low-cost geophysical survey. In particular, 403 single-station ambient vibration measurements (HVSR techniques) distributed within the main settlements of the area have been considered to extract representative patterns deduced by Principal Component Analysis. The joint interpretation of these pieces of information allows the identification of three main domains (Gargano Promontory, Bradanic Through and Southern Apennines Fold and Thrust Belt), each characterized by specific seismic resonance phenomena. In particular, the Bradanic Through is homogeneously characterized by low frequency (< 1 Hz) resonance effects associated with relatively deep (> 100 m) seismic impedance, which is contrasting corresponding to the buried Apulian carbonate platform and/or sandy horizons located within the Plio-Pleistocene deposits. In the remaining ones, relatively high frequency (> 1 Hz) resonance phenomena are ubiquitous due to the presence of shallower impedance contrasts (< 100 m), which do not always correspond to the top of the geological bedrock. These general indications may be useful for a preliminary regional characterization of seismic response in the study area, which can be helpful for an effective planning of more detailed studies targeted to engineering purposes

Performance evaluation of a new on-demand molecular test for the rapid identification of severe acute respiratory syndrome coronavirus 2 in pediatric and adult patients

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has increased the need to identify additional rapid diagnostic tests for an accurate and early diagnosis of infection. Here, we evaluated the diagnostic performance of the cartridge-based reverse transcription polymerase chain reaction (RT-PCR) test STANDARD M10 SARS-CoV-2 (SD Biosensor Inc., Suwon, South Korea), targeting the ORF1ab and E gene of SARS-CoV-2, and which can process up to eight samples in parallel in 60 min. From January 2022 to March 2022, STANDARD (TM) M10 assay performance was compared with Xpert (R) Xpress SARS-CoV-2 (Cepheid, Sunnyvale CA) on 616 nasopharyngeal swabs from consecutive pediatric (N = 533) and adult (N = 83) patients presenting at the "Istituto di Ricovero e Cura a Carattere Scientifico" (IRCCS) Ospedate Pediatrico Bambino Gesu, Roma. The overall performance of STANDARD M10 SARS-CoV-2 was remarkably and consistently comparable to the Xpert (R) Xpress SARS-CoV-2 with an overall agreement of 98% (604/616 concordant results), and negligible differences in time-to-result (60 min vs. 50 min, respectively). When the Xpert (R) Xpress SARS-CoV-2 results were considered as the reference, STANDARD (TM) M10 SARS-CoV-2 had 96.5% sensitivity and 98.4% specificity. STANDARD M10 SARS-CoV2 can thus be safely included in diagnostic pathways because it rapidly and accurately identifies SARS-CoV-2 present in nasopharyngeal swabs

HIF factors cooperate with PML-RARα to promote acute promyelocytic leukemia progression and relapse

Acute promyelocytic leukemia (APL) is epitomized by the chromosomal translocation t(15;17) and the resulting oncogenic fusion protein PML-RARα. Although acting primarily as a transcriptional repressor, PML-RARα can also exert functions of transcriptional co-activation. Here, we find that PML-RARα stimulates transcription driven by HIF factors, which are critical regulators of adaptive responses to hypoxia and stem cell maintenance. Consistently, HIF-related gene signatures are upregulated in leukemic promyelocytes from APL patients compared to normal promyelocytes. Through in vitro and in vivo studies, we find that PML-RARα exploits a number of HIF-1α-regulated pro-leukemogenic functions that include cell migration, bone marrow (BM) neo-angiogenesis and self-renewal of APL blasts. Furthermore, HIF-1α levels increase upon treatment of APL cells with all-trans retinoic acid (ATRA). As a consequence, inhibiting HIF-1α in APL mouse models delays leukemia progression and exquisitely synergizes with ATRA to eliminate leukemia-initiating cells (LICs)

Pml represses tumour progression through inhibition of mTOR

The promyelocytic leukaemia gene PML is a pleiotropic tumour suppressor. We have recently demonstrated that PML opposes mTOR-HIF1α-VEGF signalling in hypoxia. To determine the relevance of PML-mTOR antagonism in tumourigenesis, we have intercrossed Pml null mice with Tsc2 heterozygous mice, which develop kidney cysts and carcinomas exhibiting mTOR upregulation. We find that combined inactivation of Pml and Tsc2 results in aberrant TORC1 activity both in pre-tumoural kidneys as well as in kidney lesions. Such increase correlates with a marked acceleration in tumour progression, impacting on both the biology and histology of kidney carcinomas. Also, Pml inactivation decreases the rate of loss of heterozygosity (LOH) for the wt Tsc2 allele. Interestingly, however, aberrant TORC1 activity does not accelerate renal cystogenesis in Tsc2/Pml mutants. Our data demonstrate that activation of mTOR is critical for tumour progression, but not for tumour initiation in the kidney

Hypoxia inducible factor-1β regulates a pro-invasive phenotype in acute monocytic leukemia

Hypoxia inducible transcription factors (HIFs) are the main regulators of adaptive responses to hypoxia and are often activated in solid tumors, but their role in leukemia is less clear. In acute myeloid leukemia (AML), in particular, controversial new findings indicate that HIF-1β can act either as an oncogene or a tumor suppressor gene, and this may depend on the stage of leukemia development and/or the AML sub-type. In this study, we find that HIF-1β promotes leukemia progression in the acute monocytic leukemia sub-type of AML through activation of an invasive phenotype. By applying a list of validated HIF-1β-target genes to different AML sub-types, we identified a HIF-1β signature that typifies acute monocytic leukemia when compared with all other AML sub-types. We validated expression of this signature in cell lines and primary cells from AML patients. Interestingly, this signature is enriched for genes that control cell motility at different levels. As a consequence, inhibiting HIF- 1β impaired leukemia cell migration, chemotaxis, invasion and transendothelial migration in vitro, and this resulted in impaired bone marrow homing and leukemia progression in vivo. Our data suggest that in acute monocytic leukemia an active HIF-1β-dependent pro-invasive pathway mediates the ability of leukemic cells to migrate and invade extramedullary sites and may be targeted to reduce leukemia dissemination