Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma.

Background: ADAR enzymes convert adenosines to inosines within double-stranded RNAs, including microRNA (miRNA) precursors, with important consequences on miRNA retargeting and expression. ADAR2 activity is impaired in glioblastoma and its rescue has anti-tumoral effects. However, how ADAR2 activity may impact the miRNome and the progression of glioblastoma is not known. Results: By integrating deep-sequencing and array approaches with bioinformatics analyses and molecular studies, we show that ADAR2 is essential to edit a small number of mature miRNAs and to significantly modulate the expression of about 90 miRNAs in glioblastoma cells. Specifically, the rescue of ADAR2 activity in cancer cells recovers the edited miRNA population lost in glioblastoma cell lines and tissues, and rebalances expression of onco-miRNAs and tumor suppressor miRNAs to the levels observed in normal human brain. We report that the major effect of ADAR2 is to reduce the expression of a large number of miRNAs, most of which act as onco-miRNAs. ADAR2 can edit miR-222/221 and miR-21 precursors and decrease the expression of the corresponding mature onco-miRNAs in vivo and in vitro, with important effects on cell proliferation and migration. Conclusions: Our findings disclose an additional layer of complexity in miRNome regulation and provide information to better understand the impact of ADAR2 editing enzyme in glioblastoma. We propose that ADAR2 is a key factor for maintaining edited-miRNA population and balancing the expression of several essential miRNAs involved in cancer

Gateway Discovery and Selection in Mobile Hotspots

Gaining IP connectivity in mobile hotspots (e.g. public transport vehicles) through on-board local area networks and mobile gateways has recently attracted strong commercial and research interests. In this paper we propose a multi-dimensional protocol to support the process of gatewaydiscovery in mobile hotspots, and to help in selecting the best path able to satisfy the user's requirements and to guarantee a target end-to-end service quality. Our proposal is based on highly popular and almost standard protocols, such as SDPng for session description and AODV for route discovery

Anti-PD-L1 immunoconjugates for cancer therapy: Are available antibodies good carriers for toxic payload delivering?

Immune checkpoint mechanisms are important molecular cell systems that maintain tolerance toward autoantigens in order to prevent immunity-mediated accidental damage. It is well known that cancer cells may exploit these molecular and cellular mechanisms to escape recognition and elimination by immune cells. Programmed cell death protein-1 (PD-1) and its natural ligand programmed cell death ligand-1 (PD-L1) form the PD-L1/PD-1 axis, a well-known immune checkpoint mechanism, which is considered an interesting target in cancer immunotherapy. In fact, the expression of PD-L1 was found in various solid malignancies and the overactivation of PD-L1/PD-1 axis results in a poor patient survival rate. Breaking PD-L1/PD-1 axis, by blocking either the cancer side or the immune side of the axis, is currently used as anti-cancer strategy to re-establish a tumor-specific immune response. For this purpose, several blocking antibodies are now available. To date, three anti-PD-L1 antibodies have been approved by the FDA, namely atezolizumab, durvalumab and avelumab. The main advantages of anti-PD-L1 antibodies arise from the overexpression of PD-L1 antigen by a high number of tumor cells, also deriving from different tissues; this makes anti-PD-L1 antibodies potential pan-specific anti-cancer molecules. Despite the good results reported in clinical trials with anti-PD-L1 antibodies, there is a significant number of patients that do not respond to the therapy. In fact, it should be considered that, in some neoplastic patients, reduced or absent infiltration of cytotoxic T cells and natural killer cells in the tumor microenvironment or presence of other immunosuppressive molecules make immunotherapy with anti-PD-L1 blocking antibodies less effective. A strategy to improve the efficacy of antibodies is to use them as carriers for toxic payloads (toxins, drugs, enzymes, radionuclides, etc.) to form immunoconjugates. Several immunoconjugates have been already approved by FDA for treatment of malignancies. In this review, we focused on PD-L1 targeting antibodies utilized as carrier to construct immunoconjugates for the potential elimination of neoplastic cells, expressing PD-L1. A complete examination of the literature regarding anti-PD-L1 immunoconjugates is here reported, describing the results obtained in vitro and in vivo. The real potential of anti-PD-L1 antibodies as carriers for toxic payload delivery is considered and extensively discussed

Anti-persistence in the global temperature anomaly field

In this study, low-frequency variations in temperature anomaly are investigated by mapping temperature anomaly records onto random walks. We show evidence that global overturns in trends of temperature anomalies occur on decadal time-scales as part of the natural variability of the climate system. Paleoclimatic summer records in Europe and New-Zealand provide further support for these findings as they indicate that anti-persistence of temperature anomalies on decadal time-scale have occurred in the last 226 yrs. Atmospheric processes in the subtropics and mid-latitudes of the SH and interactions with the Southern Oceans seem to play an important role to moderate global variations of temperature on decadal time-scales

Sequence, structure, and binding site analysis of kirkiin in comparison with ricin and other type 2 rips

Kirkiin is a new type 2 ribosome-inactivating protein (RIP) purified from the caudex of Adenia kirkii with a cytotoxicity compared to that of stenodactylin. The high toxicity of RIPs from Adenia genus plants makes them interesting tools for biotechnology and therapeutic applications, particularly in cancer therapy. The complete amino acid sequence and 3D structure prediction of kirkiin are here reported. Gene sequence analysis revealed that kirkiin is encoded by a 1572 bp open reading frame, corresponding to 524 amino acid residues, without introns. The amino acid sequence analysis showed a high degree of identity with other Adenia RIPs. The 3D structure of kirkiin preserves the overall folding of type 2 RIPs. The key amino acids of the active site, described for ricin and other RIPs, are also conserved in the kirkiin A chain. Sugar affinity studies and docking experiments revealed that both the 1α and 2γ sites of the kirkiin B chain exhibit binding activity toward lactose and D-galactose, being lower than ricin. The replacement of His246 in the kirkiin 2γ site instead of Tyr248 in ricin causes a different structure arrangement that could explain the lower sugar affinity of kirkiin with respect to ricin

Supersymmetric Field-Theoretic Models on a Supermanifold

We propose the extension of some structural aspects that have successfully been applied in the development of the theory of quantum fields propagating on a general spacetime manifold so as to include superfield models on a supermanifold. We only deal with the limited class of supermanifolds which admit the existence of a smooth body manifold structure. Our considerations are based on the Catenacci-Reina-Teofillatto-Bryant approach to supermanifolds. In particular, we show that the class of supermanifolds constructed by Bonora-Pasti-Tonin satisfies the criterions which guarantee that a supermanifold admits a Hausdorff body manifold. This construction is the closest to the physicist's intuitive view of superspace as a manifold with some anticommuting coordinates, where the odd sector is topologically trivial. The paper also contains a new construction of superdistributions and useful results on the wavefront set of such objects. Moreover, a generalization of the spectral condition is formulated using the notion of the wavefront set of superdistributions, which is equivalent to the requirement that all of the component fields satisfy, on the body manifold, a microlocal spectral condition proposed by Brunetti-Fredenhagen-K\"ohler.Comment: Final version to appear in J.Math.Phy