Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration.

Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L. Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits. Immune cells are mainly in the vicinity of apoptotic tumor cells, revealing tumor immune attack. Moreover, contrary to un-selected ovarian carcinomas, 65% of our Yo-PCD tumors presented at least one somatic mutation in Yo-Ags, with a predominance of missense mutations. Recurrent gains of the CDR2L gene with tumor protein overexpression were also present in 59% of Yo-PCD patients. Overall, each Yo-PCD ovarian carcinomas carried at least one genetic alteration of Yo-Ags. These data demonstrate an association between massive infiltration of Yo-PCD tumors by activated immune effector cells and recurrent gains and/or mutations in autoantigen-encoding genes, suggesting that genetic alterations in tumor cells trigger immune tolerance breakdown and initiation of the auto-immune disease.

Circling Around the Uncanny Valley: Design Principles for Research Into the Relation Between Human Likeness and Eeriness.

The uncanny valley effect (UVE) is a negative emotional response experienced when encountering entities that appear almost human. Research on the UVE typically investigates individual, or collections of, near human entities but may be prone to methodological circularity unless the properties that give rise to the emotional response are appropriately defined and quantified. In addition, many studies do not sufficiently control the variation in human likeness portrayed in stimulus images, meaning that the nature of stimuli that elicit the UVE is also not well defined or quantified. This article describes design criteria for UVE research to overcome the above problems by measuring three variables (human likeness, eeriness, and emotional response) and by using stimuli spanning the artificial to human continuum. These criteria allow results to be plotted and compared with the hypothesized uncanny valley curve and any effect observed can be quantified. The above criteria were applied to the methods used in a subset of existing UVE studies. Although many studies made use of some of the necessary measurements and controls, few used them all. The UVE is discussed in relation to this result and research methodology more broadly.

Glycoprotein of nonpathogenic rabies viruses is a major inducer of apoptosis in human jurkat T cells.

This study sought to identify the RV protein that causes apoptosis. For this purpose, we first compared the ability of G and N proteins of a pathogenic and a nonpathogenic strain to trigger apoptosis of Jurkat rtTA by using an inducible Tet-on expression system. Then we analyzed apoptosis induced by a reverse genetic-engineered recombinant rabies virus in which the G gene from a nonpathogenic strain was replaced by its pathogenic strain counterpart. No other virus proteins than G of nonpathogenic RV strains induce apoptosis, and the G polypeptide of RV is a critical determinant for apoptosis in human cells.

Glycoprotein of nonpathogenic rabies viruses is a key determinant of human cell apoptosis.

We showed that, unlike pathogenic rabies virus (RV) strain CVS, attenuated RV strain ERA triggers the caspase-dependent apoptosis of human cells. Furthermore, we observed that the induction of apoptosis is correlated with a particular virus antigen distribution: the overexpression of the viral G protein on the cell surface, with continuous localization on the cytoplasmic membrane, and large cytoplasmic inclusions of the N protein. To determine whether one of these two major RV proteins (G and N proteins) triggers apoptosis, we constructed transgenic Jurkat T-cell lines that drive tetracycline-inducible gene expression to produce the G and N proteins of ERA and CVS individually. The induction of ERA G protein (G-ERA) expression but not of ERA N protein expression resulted in apoptosis, and G-ERA was more efficient at triggering apoptosis than was CVS G protein. To test whether other viral proteins participated in the induction of apoptosis, human cells were infected with recombinant RV in which the G protein gene from the attenuated strain had been replaced by its virulent strain counterpart (CVS). Only RV containing the G protein from the nonpathogenic RV strain was able to trigger the apoptosis of human cells. Thus, the ability of RV strains to induce apoptosis is largely determined by the viral G protein.