Biology subjects

Wanner, N.

Publications and source records attributed to Wanner, N..

2 recordsLinked to original sources

bioRxiv2020

beta-blocker reverses inhibition of beta-2 adrenergic receptor resensitization by hypoxia

Ischemia/hypoxia is major underlying cause for heart failure and stroke. Although beta-adrenergic receptor ({beta}AR) is phosphorylated in response to hypoxia, less is known about the underlying mechanisms. Hypoxia results in robust GRK2-mediated {beta}2AR phosphorylation but does not cause receptor internalization. However, hypoxia leads to significant endosomal-{beta}2AR phosphorylation accompanied by inhibition of {beta}2AR-associated protein phosphatase 2A (PP2A) activity impairing resensitization. Phosphoinositide 3-kinase {gamma} (PI3K{gamma}) impedes resensitization by phosphorylating endogenous inhibitor of protein phosphatase 2A, I2PP2A that inhibits PP2A activity. Hypoxia increased PI3K{gamma} activity leading to significant phosphorylation of I2PP2A resulting in inhibition of PP2A and consequently resensitization. Surprisingly, {beta}-blocker abrogated hypoxia-mediated {beta}2AR phosphorylation instead of phosphorylation in normoxia. Subjecting mice to hypoxia leads to significant cardiac dysfunction and {beta}2AR phosphorylation showing conservation of non-canonical hypoxia-mediated pathway in vivo. These findings provide mechanistic insights on hypoxia-mediated {beta}AR dysfunction which is rescued by {beta}-blocker and will have significant implications in heart failure and stroke.

biochemistry↗

bioRxiv2020

Deep learning-based molecular morphometrics for kidney biopsies

Morphologic examination of tissue biopsies is essential for histopathological diagnosis. However, accurate and scalable cellular quantification in human samples remains challenging. Here, we present a deep learning-based approach for antigen-specific cellular morphometrics in human kidney biopsies, which combines indirect immunofluorescence imaging with U-Net-based architectures for image-to-image translation and dual segmentation tasks, achieving human-level accuracy. In the kidney, podocyte loss represents a hallmark of glomerular injury and can be estimated in diagnostic biopsies. Thus, we profiled over 27,000 podocytes from 110 human samples, including patients with anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN), an immune-mediated disease with aggressive glomerular damage and irreversible loss of kidney function. Previously unknown morphometric signatures of podocyte depletion were identified in patients with ANCA-GN, which allowed patient classification and showed potential for risk stratification in combination with routine clinical tools. Together, our approach enables robust and scalable molecular morphometric analysis of human tissues, yielding deeper biological insights into the human kidney pathophysiology. SummaryDeep learning enables robust and scalable molecular morphometric analysis of human tissues, yielding deeper biological insights into the human kidney pathophysiology.

pathology↗