Randolph Paulsen (stitchsushi5)

A similar RNAP II degradation is also evident in mutant ATXN3-expressing Drosophila larval brains and eyes. Importantly, SCA3 phenotype in Drosophila was completely amenable to PNKP complementation. Hence, salvaging PNKP's activity can be a promising therapeutic strategy for SCA3.The cell surface proteome, the surfaceome, is the interface for engaging the extracellular space in normal and cancer cells. Here we apply quantitative proteomics of N-linked glycoproteins to reveal how a collection of some 700 surface proteins is dramatically remodeled in an isogenic breast epithelial cell line stably expressing any of six of the most prominent proliferative oncogenes, including the receptor tyrosine kinases, EGFR and HER2, and downstream signaling partners such as KRAS, BRAF, MEK, and AKT. We find that each oncogene has somewhat different surfaceomes, but the functions of these proteins are harmonized by common biological themes including up-regulation of nutrient transporters, down-regulation of adhesion molecules and tumor suppressing phosphatases, and alteration in immune modulators. Addition of a potent MEK inhibitor that blocks MAPK signaling brings each oncogene-induced surfaceome back to a common state reflecting the strong dependence of the oncogene on the MAPK pathway to propagate signaling. Cell surface protein capture is mediated by covalent tagging of surface glycans, yet current methods do not afford sequencing of intact glycopeptides. selleck kinase inhibitor Thus, we complement the surfaceome data with whole cell glycoproteomics enabled by a recently developed technique called activated ion electron transfer dissociation (AI-ETD). We found massive oncogene-induced changes to the glycoproteome and differential increases in complex hybrid glycans, especially for KRAS and HER2 oncogenes. Overall, these studies provide a broad systems-level view of how specific driver oncogenes remodel the surfaceome and the glycoproteome in a cell autologous fashion, and suggest possible surface targets, and combinations thereof, for drug and biomarker discovery. Copyright © 2020 the Author(s). Published by PNAS.Climate change is likely to change the relationships between commonly used climate indices and underlying patterns of climate variability, but this complexity is rarely considered in studies using climate indices. Here, we show that the physical and ecological conditions mapping onto the Pacific Decadal Oscillation (PDO) index and North Pacific Gyre Oscillation (NPGO) index have changed over multidecadal timescales. These changes apparently began around a 1988/1989 North Pacific climate shift that was marked by abrupt northeast Pacific warming, declining temporal variance in the Aleutian Low (a leading atmospheric driver of the PDO), and increasing correlation between the PDO and NPGO patterns. Sea level pressure and surface temperature patterns associated with each climate index changed after 1988/1989, indicating that identical index values reflect different states of basin-scale climate over time. The PDO and NPGO also show time-dependent skill as indices of regional northeast Pacific ecosystem variability. Since the late 1980s, both indices have become less relevant to physical-ecological variability in regional ecosystems from the Bering Sea to the southern California Current. Users of these climate indices should be aware of nonstationary relationships with underlying climate variability within the historical record, and the potential for further nonstationarity with ongoing climate change.Uncertainty is inherent to our knowledge about the state of the world yet often not communicated alongside scientific facts and numbers. In the "posttruth" era where facts are increasingly contested, a common assumption is that communicating uncertainty will reduce public trust. However, a lack of systematic research makes it difficult to evaluate such claims. We conducted five experiments-including one preregistered replication with