A Property of Integers Related to Quadratic Fields

departmental bulletin pape

Observation of B̅0→D(*)0pp̅

journal articl

Clinical samples.

Clinical samples.</p

Hierarchical clustering of 15 gene signature used by model to classify disease status.

A clear separation is observed between IPF and normal patient samples. Note that this is just for visualization purposes, and uses logistic regression to classify samples, not clustering. Row-scaled log intensity units are plotted. We use the complete linkage method for hierarchical clustering with a Euclidean distance measure.</p

Model performance is assessed on the test data and evaluated with Receiver Operating Characteristic (ROC) curves.

We compute the area under the curve (AUC) for each model and each cohort, where a perfect classifier has an AUC = 1 and a random classifier has an AUC = 0.5 (the diagonal line). The ROC curves and AUCs were calculated by passing the true positive fraction (the probability of a test positive among the diseased population) and false positive fraction (the probability of a test positive among the normal population) to the plotROC package (S5 Table) [38]. We performed 1000 bootstraps of the data for each cohort to establish a null distribution yielding a mean AUC of approximately 0.5, as expected. Based on the empirical p-values from these bootstrap AUCs, we find that all our reported AUCs are statistically significant, confirming the performance of our models across all test cohorts (S4 Table).</p

15-gene signature for IPF.

15-gene signature for IPF.</p

t-SNE models each high-dimensional observation into just two dimensions such that similar observations are modeled by nearby points and dissimilar objects are modeled by distant points.

Applying t-SNE to our clinical samples from the LTRC and NJH, We observe distinct grouping of IPF and normal samples with a few outliers. There does not appear to be any grouping of patients by cohort.</p

Bleomycin preclinical rat model samples.

Bleomycin preclinical rat model samples.</p

Cross-resistance profiles provide a strategy to predict resistance mechanisms.

<p>(A) Strains evolved in azole and FK506 were tested for cross-resistance to azole and the calcineurin inhibitor cyclosporin A as well as azole and the Hsp90 inhibitor geldanamycin. (B) Candidate resistance mechanisms based on specific cross-resistance profiles of strains evolved with azole and FK506. (C) Strains evolved in azole and geldanamycin were tested for cross-resistance to azole and the Hsp90 inhibitor radicicol as well as azole and the calcineurin inhibitor FK506. (D) Candidate resistance mechanisms based on specific cross-resistance profiles of strains evolved with azole and geldanamycin. GdA = geldanamycin; RAD = radicicol; and CsA = cyclosporin A.</p

Mutations in <i>HSP90</i> confer resistance to azole and geldanamycin in two <i>S. cerevisiae</i> lineages and in one <i>C. albicans</i> lineage.

<p> (A) Sc-G-12 (right panel) and Sc-G-14 (left panel) are both resistant to azole and geldanamycin and slightly cross-resistant to azole and radicicol, relative to their parental strains (above). (B) Resistance to azole and geldanamycin in Sc-G-14 is attributable to <i>HSC82^I117N</i>. Replacing the ancestral allele with the <i>HSC82^I117N</i> allele expressed on a plasmid increases resistance of the ancestral strain to the level observed in Sc-G-14, while replacing the <i>HSC82^I117N</i> allele with the ancestral allele on a plasmid abrogates resistance of Sc-G-14. (C) Deletion of <i>HSC82</i> in Sc-G-12 or its parental strain phenocopies resistance of Sc-G-12, suggesting that <i>HSC82^K385*</i> confers resistance by loss of function of <i>HSC82</i>. (D) Ca-G-10 has increased resistance to azole and geldanamycin but no cross-resistance to azole and FK506 or azole and radicicol. (E) Resistance to azole and geldanamycin in Ca-G-10 is attributable to <i>HSP90^D91Y</i>. Replacing the native <i>HSP90</i> allele in parental strain with <i>HSP90^D91Y</i> phenocopied resistance of Ca-G-10. Conversely, resistance of Ca-G-10 was abrogated when <i>HSP90^D91Y</i> was replaced with the ancestral <i>HSP90</i> allele. Resistance assays were performed and analyzed is in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003390#pgen-1003390-g002" target="_blank">Figure 2</a>, after incubation at 30°C for 2 days (D) or 3 days (A–C, E). Assays were performed in YPD (A, C–E) or SD with amino acid supplements (B). GdA = geldanamycin; RAD = radicicol; and FL = fluconazole.</p