Biology subjects

Heinze, K.

Publications and source records attributed to Heinze, K..

4 recordsLinked to original sources

bioRxiv2022

Taxanes act as vascular disrupting agents and increase rate of metastasis when combined with anti-angiogenic therapy

Taxanes are known to have a profound effect on endothelial cells and the vasculature even at low doses. Here, we show that taxanes, rather than being anti-angiogenic, function more as vascular disrupting agents (VDAs), although they exert a different mechanism of vascular permeabilization when compared to traditional VDAs such as combretastatins. In the tumor context, this VDA-effect leads to a rapid vascular collapse and acute hypoxia. Concomitant treatment with anti-VEGF drugs aggravates hypoxia by blocking vasculogenic rescue mechanisms. While this results in a strong growth-suppressing effect on the tumor, it also increases its invasiveness and metastatic potential. We demonstrate that combination of anti-angiogenic drugs with taxanes blocks tumor reperfusion, intensifies intravasation of circulating tumor cells (CTCs) and strongly increases metastasis. Anti-VEGF drugs are commonly applied in combination with cytotoxic drugs including taxanes. Our findings have significant implications for the clinical use of this drug combination.

cancer biology↗

bioRxiv2022

Deciphering the conformational dynamics of gephyrin-mediated collybistin activation

Efficient neuronal signaling depends on the proper assembly of the postsynaptic neurotransmitter machinery and at inhibitory GABAergic synapses is controlled by the scaffolding protein gephyrin and collybistin, a Dbl-family guanine nucleotide exchange factor and neuronal adaptor protein. Collybistin usually contains an N-terminal SH3 domain and exists in closed/inactive or open/active states. Here, we elucidate the molecular basis of the gephyrin-collybistin interaction with newly designed collybistin FRET sensors. Using fluorescence lifetime-based FRET measurements, we deduce the affinity of the gephyrin-collybistin complex, thereby confirming that the C-terminal dimer-forming E domain binds collybistin, an interaction, which does not require E domain dimerization. Simulations based on fluorescence lifetime and sensor distance distributions reveal a dynamic behavior of the SH3 domain already in the closed state of collybistin. Finally, our data provide strong evidence for a collybistin-gephyrin communication network, where, unexpectedly, switching of collybistin from closed/inactive to open/active states is efficiently triggered by gephyrin.

biophysics↗

bioRxiv2021

How biological cells including platelets and megakaryocytes decide complex problems fast but risky

Short AbstractMathematical decision processes are accurate but sometimes take very long time or simply do not happen. Decisions in biology happen fast and driven by evolution, optimizing survival chances. This results in stochastic decisions with on average good adaptation to the environment but an inherent risk of individual errors e.g. developing cancer during cell regeneration. We calculate and show in platelets and megakaryocytes how cellular decision processes increases risk for errors and inflammation. Short cut solutions adapted from nature improve computer strategies for protein folding and network decision processes. Complex problems are not always solved in foreseeable time, instead the fast solutions in biology speed up errors everywhere including biochemical aging of blood vessels, misfolded proteins, mis-programmed cells, cancer and heart failure. One sentence abstractWe investigate in biological networks how complex decision problems are mastered not by an accurate but unforeseeable long mathematical search but rather pragmatic and fast, with an inherent risk of error, a basis for inflammation and cancer.

bioinformatics↗

bioRxiv2021

Sylites: Multipurpose markers for the visualization of inhibitory synapses

We introduce Sylites - small and versatile fluorogenic affinity probes for high-contrast visualization of inhibitory synapses. Having stoichiometric labeling and exceptional selectivity for neuronal gephyrin, a hallmark protein of the inhibitory post-synapse, Sylites enable superior synapse staining compared with antibodies. Combined with super-resolution microscopy, Sylites allow precise nanoscopic measurements of the synapse. In brain tissue, Sylites reveal the three-dimensional distribution of inhibitory synapses within just an hour.

neuroscience↗