Context-Aware Drift Detection

When monitoring machine learning systems, two-sample tests of homogeneity form the foundation upon which existing approaches to drift detection build. They are used to test for evidence that the distribution underlying recent deployment data differs from that underlying the historical reference data. Often, however, various factors such as time-induced correlation mean that batches of recent deployment data are not expected to form an i.i.d. sample from the historical data distribution. Instead we may wish to test for differences in the distributions conditional on \textit{context} that is permitted to change. To facilitate this we borrow machinery from the causal inference domain to develop a more general drift detection framework built upon a foundation of two-sample tests for conditional distributional treatment effects. We recommend a particular instantiation of the framework based on maximum conditional mean discrepancies. We then provide an empirical study demonstrating its effectiveness for various drift detection problems of practical interest, such as detecting drift in the distributions underlying subpopulations of data in a manner that is insensitive to their respective prevalences. The study additionally demonstrates applicability to ImageNet-scale vision problems.Comment: 25 pages, 26 figure

The nature of the GRE influences the screening for GR-activity enhancing modulators

Glucocorticoid resistance (GCR), i.e. unresponsiveness to the beneficial anti-inflammatory activities of the glucocorticoid receptor (GR), poses a serious problem in the treatment of inflammatory diseases. One possible solution to try and overcome GCR, is to identify molecules that prevent or revert GCR by hyper-stimulating the biological activity of the GR. To this purpose, we screened for compounds that potentiate the dexamethasone (Dex)induced transcriptional activity of GR. To monitor GR transcriptional activity, the screen was performed using the lung epithelial cell line A549 in which a glucocorticoid responsive element (GRE) coupled to a luciferase reporter gene construct was stably integrated. Histone deacetylase inhibitors (HDACi) such as Vorinostat and Belinostat are two broad-spectrum HDACi that strongly increased the Dex-induced luciferase expression in our screening system. In sharp contrast herewith, results from a genome-wide transcriptome analysis of Dexinduced transcripts using RNAseq, revealed that Belinostat impairs the ability of GR to transactivate target genes. The stimulatory effect of Belinostat in the luciferase screen further depends on the nature of the reporter construct. In conclusion, a profound discrepancy was observed between HDACi effects on two different synthetic promoter-luciferase reporter systems. The favorable effect of HDACi on gene expression should be evaluated with care, when considering them as potential therapeutic agents. GEO accession number GSE96649

Cognitive dysfunction in mice lacking proper glucocorticoid receptor dimerization

Stress is a major risk factor for depression and anxiety. One of the effects of stress is the (over-) activation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of stress hormones such as glucocorticoids (GCs). Chronically increased stress hormone levels have been shown to have detrimental effects on neuronal networks by inhibiting neurotrophic processes particularly in the hippocampus proper. Centrally, GCs modulate metabolic as well as behavioural processes by activating two classes of corticoid receptors, high-affinity mineralocorticoid receptors (MR) and low-affinity glucocorticoid receptors (GR). Upon activation, GR can modulate gene transcription either as a monomeric protein, or as a dimer interacting directly with DNA. GR can also modulate cellular processes via non-genomic mechanisms, for example via a GPCR-protein interaction. We evaluated the behavioral phenotype in mice with a targeted mutation in the GR in a FVB/NJ background. In GR(dim/dim) mice, GR proteins form poor homodimers, while the GR monomer remains intact. We evaluated the effect of poor GR dimerization on hippocampus-dependent cognition as well as on exploration and emotional behavior under baseline and chronically increased stress hormone levels. We found that GR(dim/dim) mice did not behave differently from GR(wt/wt) littermates under baseline conditions. However, after chronic elevation of stress hormone levels, GR(dim/dim) mice displayed a significant impairment in hippocampus-dependent memory compared to GR(wt/wt) mice, which correlated with differential expression of hippocampal Bdnf/TrkB and Fkbp5

Technical design

To convert Bergenmeersen from a flood control area (FCA) to a flood control area with controlled reduced tide (FCA-CRT), the existing dykes were modified and a new inlet and outlet construction was built. This chapter outlines the hydraulic and geotechnical design. This encompasses raising the existing ring dyke around the area, the new stability calculations and the modified dyke revetment along the water and land side. The inlet and outlet structure is also described. The hydraulic boundary conditions are extremely important to the design

A screening assay for Selective Dimerizing Glucocorticoid Receptor Agonists and Modulators (SEDIGRAM) that are effective against acute inflammation

It has been suggested that glucocorticoid receptor (GR) agonists that promote GR homodimerization more than standard glucocorticoids such as Dexamethasone could be more effective anti-inflammatory molecules against acute and life-threatening inflammatory conditions. To test this hypothesis, we set up a screening pipeline aimed at discovering such Selective Dimerizing GR Agonists and Modulators (SEDIGRAM). The pipeline consists of a reporter gene assay based on a palindromic glucocorticoid responsive element (GRE). This assay represents GR dimerization in human A549 lung epithelial cells. In the pipeline, this is followed by analysis of endogenous GRE-driven gene expression, a FRET assay confirming dimerization, and monitoring of in vitro and in vivo anti-inflammatory activity. In a proof of principle experiment, starting from seven candidate compounds, we identified two potentially interesting compounds (Cortivazol and AZD2906) that confer strong protection in a mouse model of aggressive TNF-induced lethal inflammation. A screening pipeline for SEDIGRAM may assist the search for compounds that promote GR dimerization and limit overwhelming acute inflammatory responses