Editorial: NK Cell Subsets in Health and Disease: New Developments

Natural killer (NK) cells were discovered ca 1975, as the first group of lymphoid cells that were neither T cells nor B cells. Since then, the dissection of the biology of NK cells has been growing exponentially with many seminal discoveries from the identification of MHC class I-specific inhibitory receptors to the discovery of receptor\u2013ligand pairs involved in NK cell activation and to the manipulation of NK cells in cancer. In this research topic, we asked a group of thought leaders in NK cell biology to review recent advances in their origins and biology, and their roles in cancer, infection, and inflammation. Together, these 25 articles provide a timely survey of NK cells as critical immunologic components of health and disease. They will hopefully prompt further dialog and developments in basic and translational immunology

MAISTAS: a tool for automatic structural evaluation of alternative splicing products

Motivation: Analysis of the human genome revealed that the amount of transcribed sequence is an order of magnitude greater than the number of predicted and well-characterized genes. A sizeable fraction of these transcripts is related to alternatively spliced forms of known protein coding genes. Inspection of the alternatively spliced transcripts identified in the pilot phase of the ENCODE project has clearly shown that often their structure might substantially differ from that of other isoforms of the same gene, and therefore that they might perform unrelated functions, or that they might even not correspond to a functional protein. Identifying these cases is obviously relevant for the functional assignment of gene products and for the interpretation of the effect of variations in the corresponding proteins

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

Spin caloritronics in a CrBr3_3-based magnetic van der Waals heterostructure

The recently reported magnetic ordering in insulating two-dimensional (2D) materials, such as chromium triiodide (CrI$_3$) and chromium tribromide (CrBr$_3$), opens new possibilities for the fabrication of magneto-electronic devices based on 2D systems. Inevitably, the magnetization and spin dynamics in 2D magnets are strongly linked to Joule heating. Therefore, understanding the coupling between spin, charge and heat, i.e. spin caloritronic effects, is crucial. However, spin caloritronics in 2D ferromagnets remains mostly unexplored, due to their instability in air. Here we develop a fabrication method that integrates spin-active contacts with 2D magnets through hBN encapsulation, allowing us to explore the spin caloritronic effects in these materials. The angular dependence of the thermal spin signal of the CrBr$_3$/Pt system is studied, for different conditions of magnetic field and heating current. We highlight the presence of a significant magnetic proximity effect from CrBr$_3$ on Pt revealed by an anomalous Nernst effect in Pt, and suggest the contribution of the spin Seebeck effect from CrBr$_3$. These results pave the way for future magnonic devices using air-sensitive 2D magnetic insulators

Adenoviral gene transfer of PLD1-D4 enhances insulin sensitivity in mice by disrupting phospholipase D1 interaction with PED/PEA-15.

Over-expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15) causes insulin resistance by interacting with the D4 domain of phospholipase D1 (PLD1). Indeed, the disruption of this association restores insulin sensitivity in cultured cells over-expressing PED/PEA-15. Whether the displacement of PLD1 from PED/PEA-15 improves insulin sensitivity in vivo has not been explored yet. In this work we show that treatment with a recombinant adenoviral vector containing the human D4 cDNA (Ad-D4) restores normal glucose homeostasis in transgenic mice overexpressing PED/PEA-15 (Tg ped/pea-15) by improving both insulin sensitivity and secretion. In skeletal muscle of these mice, D4 over-expression inhibited PED/PEA-15-PLD1 interaction, decreased Protein Kinase C alpha activation and restored insulin induced Protein Kinase C zeta activation, leading to amelioration of insulin-dependent glucose uptake. Interestingly, Ad-D4 administration improved insulin sensitivity also in high-fat diet treated obese C57Bl/6 mice. We conclude that PED/PEA-15-PLD1 interaction may represent a novel target for interventions aiming at improving glucose tolerance

Present and Future CP Measurements

We review theoretical and experimental results on CP violation summarizing the discussions in the working group on CP violation at the UK phenomenology workshop 2000 in Durham.Comment: 104 pages, Latex, to appear in Journal of Physics

A Human Monoclonal Antibody with Neutralizing Activity against Highly Divergent Influenza Subtypes

The interest in broad-range anti-influenza A monoclonal antibodies (mAbs) has recently been strengthened by theidentification of anti-hemagglutinin (HA) mAbs endowed with heterosubtypic neutralizing activity to be used in the designof ‘‘universal’’ prophylactic or therapeutic tools. However, the majority of the single mAbs described to date do not bindand neutralize viral isolates belonging to highly divergent subtypes clustering into the two different HA-based influenzaphylogenetic groups: the group 1 including, among others, subtypes H1, H2, H5 and H9 and the group 2 including, amongothers, H3 subtype. Here, we describe a human mAb, named PN-SIA28, capable of binding and neutralizing all testedisolates belonging to phylogenetic group 1, including H1N1, H2N2, H5N1 and H9N2 subtypes and several isolates belongingto group 2, including H3N2 isolates from the first period of the 1968 pandemic. Therefore, PN-SIA28 is capable ofneutralizing isolates belonging to subtypes responsible of all the reported pandemics, as well as other subtypes withpandemic potential. The region recognized by PN-SIA28 has been identified on the stem region of HA and includes residueshighly conserved among the different influenza subtypes. A deep characterization of PN-SIA28 features may represent auseful help in the improvement of available anti-influenza therapeutic strategies and can provide new tools for thedevelopment of universal vaccinal strategies