Biology subjects

Koch, S.

Publications and source records attributed to Koch, S..

21 records · Page 2Linked to original sources

bioRxiv2019

Wnt activator FOXB2 drives prostate cancer neuroendocrine differentiation

The Wnt signaling pathway is of paramount importance for development and disease. However, the tissue-specific regulation of Wnt pathway activity remains incompletely understood. Here we identify FOXB2, an uncharacterized forkhead box family transcription factor, as a potent activator of Wnt signaling in normal and cancer cells. Mechanistically, FOXB2 induces the non-classical Wnt ligand WNT7B, which increases TCF/LEF-dependent transcription without activating LRP6 or {beta}-catenin. Proximity ligation and RNA interference identified YAP1, JUN, and DDX5 as transcriptional co-regulators required for FOXB2-dependent Wnt activation. Although FOXB2 expression is limited in adults, it is induced in select cancers, particularly advanced prostate cancer. RNA-seq data analysis suggests that FOXB2/WNT7B expression in prostate cancer is associated with a transcriptional program that favors neuronal differentiation and decreases recurrence-free survival. Consistently, FOXB2 is induced during neuroendocrine transformation of LNCaP prostate carcinoma cells, and conversely, FOXB2 overexpression is sufficient to induce their differentiation. Our results suggest that FOXB2 is a tissue-specific Wnt enhancer that promotes prostate cancer malignant transformation.

cancer biology↗

bioRxiv2019

Human defensive freezing is associated with acute threat coping, long term hair cortisol levels and trait anxiety.

The detection and anticipation of threat facilitates innate defensive behaviours including freezing reactions. Freezing in humans is characterized by reductions in body sway and heart rate and limited evidence suggests that individual differences in freezing reactions are associated with hypothalamic-pituitary-adrenal (HPA) axis activity and anxiety. However, previous measurements of human freezing reactions were largely based on passive threat contexts where natural variations in adaptive threat coping could not be assessed. In a well powered sample (N=419), we studied individual differences in anticipatory freezing reactions, by measuring body sway and heart rate, during an active shooting task where shooting decisions had to be taken under threat of shock. We linked freezing measures to subsequent actions and predictors of anxiety-related psychopathology, including accumulated long-term (3 months) hair cortisol concentrations (HCC) and trait anxiety. The anticipation of threat of shock elicited significant body sway- and heart rate reductions consistent with freezing. Whereas both freezing-related reductions in body sway and heart rate were associated with faster correct shooting decisions, body sway reductions were additionally related to more impulsive shooting (false alarms). Individual differences in threat-related reductions in body sway but not heart rate were further associated to lower HCC and higher trait anxiety. The observed links between freezing and subsequent defensive actions as well as predictors of stress-related psychopathology suggest the potential value of defensive freezing reactions as somatic marker for stress-vulnerability and resilience.

physiology↗

bioRxiv2018

Online parallel accumulation - serial fragmentation (PASEF) with a novel trapped ion mobility mass spectrometer

In bottom-up proteomics, peptides are separated by liquid chromatography with elution peak widths in the range of seconds, while mass spectra are acquired in about 100 microseconds with time-of-fight (TOF) instruments. This allows adding ion mobility as a third dimension of separation. Among several formats, trapped ion mobility spectrometry (TIMS) is attractive due to its small size, low voltage requirements and high efficiency of ion utilization. We have recently demonstrated a scan mode termed parallel accumulation - serial fragmentation (PASEF), which multiplies the sequencing speed without any loss in sensitivity (Meier et al., PMID: 26538118). Here we introduce the timsTOF Pro instrument, which optimally implements online PASEF. It features an orthogonal ion path into the ion mobility device, limiting the amount of debris entering the instrument and making it very robust in daily operation. We investigate different precursor selection schemes for shotgun proteomics to optimally allocate in excess of 100 fragmentation events per second. More than 800,000 fragmentation spectra in standard 120 min LC runs are easily achievable, which can be used for near exhaustive precursor selection in complex mixtures or re-sequencing weak precursors. MaxQuant identified more than 6,400 proteins in single run HeLa analyses without matching to a library, and with high quantitative reproducibility (R > 0.97). Online PASEF achieves a remarkable sensitivity with more than 2,900 proteins identified in 30 min runs of only 10 ng HeLa digest. We also show that highly reproducible collisional cross sections can be acquired on a large scale (R > 0.99). PASEF on the timsTOF Pro is a valuable addition to the technological toolbox in proteomics, with a number of unique operating modes that are only beginning to be explored.

systems biology↗