No abstract

Cancer cells’ ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells, and quantification of 18 cell lineage and apoptosis proteins. We identified an enrichment for BCL2 in immune, and BAK, SMAC, and XIAP in cancer cells. Ordinary differential equation-based modeling of apoptosis sensitivity at single-cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in apoptosis susceptibility generated. Systems modeling at single-cell resolution identified an enhanced sensitivity of cancer cells to mitochondrial permeabilization and executioner caspase activation compared to immune and stromal cells, but showed significant inter- and intra-tumor heterogeneity.

Down syndrome (DS) is a common birth defect characterized by the trisomy of chromosome 21. DS-affected umbilical cords (UCs) of fetuses show altered architecture of the extracellular matrix. Overexpression of the chromosome 21 genes encoding the collagen type VI (COLVI) chains a1 (VI) and a2(VI), COL6A1 and COL6A2, respectively, has also reported to occur in the nuchal skin of DS fetuses. The aim of this study was therefore to evaluate the COLVI content in euploid and DS-affected UCs and human skin fibroblasts, and to investigate the relationships between COL-VI and hyaluronan (HA) and HA synthase-2 (HAS2). We found that the UCs of DS fetuses showed denser staining of COLVI and increased COL6A2 expression at both early and term gestational ages. In vitro expression studies in DS-derived fibroblasts showed similarly increased amounts of a1(VI) and a2(VI) chains at the protein and transcriptional level, supporting the hypothesis of the gene dosage effect. Furthermore, increased levels of HA and HAS2 were also found in DS-derived skin fibroblast cultures. Notably, silencing of COL6A2 in DS-derived cells resulted in downregulation of HAS2, with a simultaneous decrease in secreted HA. Exogenous addition of COLVI to normal fibroblasts did not have any effect on HAS2 expression. In conclusion, UCs and skin fibroblasts in DS show significant increases in COLVI and HA; the overexpression of COL6A2 in DS tissue and cells is closely related to the increased expression of HAS2. These data may explain the DS phenotypes and their effects in organ tissue maturation.

This study, a tribute to Aristotle's 2400 years, used a juxtaposition of valid Aristotelian arguments to the paradoxes formulated by Zeno the Eleatic, in order to investigate the electrophysiological correlates of attentional and /or memory processing effects in the course of deductive reasoning. Participants undertook reasoning tasks based on visually presented arguments which were either (a) valid (Aristotelian) statements or (b) paradoxes. We compared brain activation patterns while participants maintained the premises / conclusions of either the valid statements or the paradoxes in working memory (WM). Event-related brain potentials (ERPs), specifically the P300 component of ERPs, were recorded during the WM phase, during which participants were required to draw a logical conclusion regarding the correctness of the valid syllogisms or the paradoxes. During the processing of paradoxes, results demonstrated a more positive event-related potential deflection (P300) across frontal regions, whereas processing of valid statements was associated with noticeable P300 amplitudes across parieto-occipital regions. These findings suggest that paradoxes mobilize frontal attention mechanisms, while valid deduction promotes parieto-occipital activity associated with attention and/or subsequent memory processing.