Innate immune activating ligand SUMOylation affects tumor cell recognition by NK cells

Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells.Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells

Influence of berry ripening stages over phenolics and volatile compounds in aged aglianicowine

The harvest time of grapes is a major determinant of berry composition and of the wine quality, and it is usually established through empirical testing of main biochemical parameters of the berry. In this work, we studied how the ripening stage of Aglianico grapes modulates key secondary metabolites of wines, phenolics and volatile compounds. Specifically, we analyzed and compared four berry ripening stages corresponding to total soluble solids of 18, 20, 22, and 25 Brix and related aged wines. Wine color intensity, anthocyanins level and total trans-resveratrol (free + glycosidic form) increased with grape maturity degree. Wines obtained from late-harvested grapes significantly differed from the others for a higher content of aliphatic alcohols, esters, acetates, a-terpineol and benzyl alcohol. The content of glycosidic terpene compounds, such as nerol, geraniol and a-terpineol, was higher in wines obtained with grapes harvested at 25 Brix compared to the earlier harvests. Our work indicated that the maturity of the grape is a determining factor in phenolic and volatile compounds of red Aglianico wines. Moreover, extending grape ripening to a sugar concentration higher than 22 Brix improves the biochemical profile of aged wine in terms of aroma compounds and of phytochemicals with known health-related benefits

Observation of the TeV gamma-ray source MGRO J1908+06 with ARGO-YBJ

The extended gamma ray source MGRO J1908+06, discovered by the Milagro air shower detector in 2007, has been observed for about 4 years by the ARGO-YBJ experiment at TeV energies, with a statistical significance of 6.2 standard deviations. The peak of the signal is found at a position consistent with the pulsar PSR J1907+0602. Parametrizing the source shape with a two-dimensional Gauss function we estimate an extension \sigma = 0.49 \pm 0.22 degrees, consistent with a previous measurement by the Cherenkov Array H.E.S.S.. The observed energy spectrum is dN/dE = 6.1 \pm 1.4 \times 10^-13 (E/4 TeV)^{-2.54 \pm 0.36} photons cm^-2 s^-1 TeV^-1, in the energy range 1-20 TeV. The measured gamma ray flux is consistent with the results of the Milagro detector, but is 2-3 times larger than the flux previously derived by H.E.S.S. at energies of a few TeV. The continuity of the Milagro and ARGO-YBJ observations and the stable excess rate observed by ARGO-YBJ along 4 years of data taking support the identification of MGRO J1908+06 as the steady powerful TeV pulsar wind nebula of PSR J1907+0602, with an integrated luminosity above 1 TeV about 1.8 times the Crab Nebula luminosity.Comment: 6 pages, accepted for pubblication by ApJ. Replaced to correct the author lis

PTPN11 mutations are not responsible for the Cardiofaciocutaneous (CFC) syndrome

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomalies/mental retardation syndrome characterized by congenital heart defects, characteristic facial appearance, short stature, ectodermal abnormalities and mental retardation. It was described in 1986, and to date is of unknown genetic etiology. All reported cases are sporadic, born to non-consanguineous parents and have apparently normal chromosomes. Noonan and Costello syndromes remain its main differential diagnosis. the recent finding of PTPN11 missense mutations in 45-50% of the Noonan patients studied with penetrance of almost 100% and the fact that in animals mutations of this gene cause defects of semilunar valvulogenesis, made PTPN11 mutation screening in CFC patients a matter of interest. We sequenced the entire coding region of the PTPN11 gene in ten well-characterised CFC patients and found no base changes. We also studied PTPN11 cDNA in our patients and demonstrated that there are no interstitial deletions either. the genetic cause of CFC syndrome remains unknown, and PTPN11 can be reasonably excluded as a candidate gene for the CFC syndrome, which we regard as molecular evidence that CFC and Noonan syndromes are distinct genetic entities.Univ Sacred Heart, Ist Genet Med, I-00168 Rome, ItalyUniversidade Federal de São Paulo, Escola Paulista Med, Ctr Med Genet, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Dermatol, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Ctr Med Genet, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Dermatol, São Paulo, BrazilWeb of Scienc

Soil-landscape and climatic relationships in the middle Miocene of the Madrid Basin

The Miocene alluvial-lacustrine sequences of the Madrid Basin, Spain, formed in highly varied landscapes. The presence of various types of palaeosols allows assessment of the effects of local and external factors onsedimentation, pedogenesis and geomorphological development. In the northern, more arid, tectonicallyactive arca, soils were weakly developed in aggrading alluvial fans, dominated by mass flows. reflecting high sedimentation rates. In more distal parts of the fans and in playa lakes calcretes and dolocretes developed: the former were associated with Mg-poor fan sediments whitc: the latter formed on Mg-rich lake clays exposed during minar lake lowstands. The nonh-east part of the basin had a less arid climate. Alluvial fans in this area were dominated by stream Aood deposits, sourced by carbonate terrains. Floodplain and freshwater lakc deposits formed in distal areas. The high local supply of calcium carbonate may have contributed to the preferential developmenl on calcretes on the fans. Both the fan and floodplain palaeosols exhibit pedofacies relationships and more mature soils developed in settings more distant from the sediment sources. Palaeosols also developed on pond and lake margin carbonates, and led to the formation of palustrine limestones. The spatial distributions and stratigraphies of palaeosols in the Madrid Basin alluvial fans suggest that soil formation was controlled by local factors. These palaeosols differ from those seen in Quatemary fans. Which are characterized by climatically induced periods of stability and instability

Citizenship Education and Liberalism: A State of the Debate Analysis 1990–2010

What kind of citizenship education, if any, should schools in liberal societies promote? And what ends is such education supposed to serve? Over the last decades a respectable body of literature has emerged to address these and related issues. In this state of the debate analysis we examine a sample of journal articles dealing with these very issues spanning a twenty-year period with the aim to analyse debate patterns and developments in the research field. We first carry out a qualitative analysis where we design a two-dimensional theoretical framework in order to systematise the various liberal debate positions, and make us able to study their justifications, internal tensions and engagements with other positions. In the ensuing quantitative leg of the study we carry out a quantitative bibliometric analysis where we weigh the importance of specific scholars. We finally discuss possible merits and flaws in the research field, as evidenced in and by the analysis

Long-term Monitoring on Mrk 501 for Its VHE gamma Emission and a Flare in October 2011

As one of the brightest active blazars in both X-ray and very high energy $\gamma$-ray bands, Mrk 501 is very useful for physics associated with jets from AGNs. The ARGO-YBJ experiment is monitoring it for $\gamma$-rays above 0.3 TeV since November 2007. Starting from October 2011 the largest flare since 2005 is observed, which lasts to about April 2012. In this paper, a detailed analysis is reported. During the brightest $\gamma$-rays flaring episodes from October 17 to November 22, 2011, an excess of the event rate over 6 $\sigma$ is detected by ARGO-YBJ in the direction of Mrk 501, corresponding to an increase of the $\gamma$-ray flux above 1 TeV by a factor of 6.6$\pm$2.2 from its steady emission. In particular, the $\gamma$-ray flux above 8 TeV is detected with a significance better than 4 $\sigma$. Based on time-dependent synchrotron self-Compton (SSC) processes, the broad-band energy spectrum is interpreted as the emission from an electron energy distribution parameterized with a single power-law function with an exponential cutoff at its high energy end. The average spectral energy distribution for the steady emission is well described by this simple one-zone SSC model. However, the detection of $\gamma$-rays above 8 TeV during the flare challenges this model due to the hardness of the spectra. Correlations between X-rays and $\gamma$-rays are also investigated.Comment: have been accepted for publication at Ap