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Herman, K.

Publications and source records attributed to Herman, K..

2 recordsLinked to original sources

Employment of self-organisation to achieve economy of scale in biology

Self-organisation is a striking phenomenon that fascinates many. Especially in homogeneous environments, the question why - and how - heterogeneous structure emerges is intriguing. We find a novel function of self-organisation in biology at the colony margin of the fungus Aspergillus niger. Here, the collection of interconnected hyphae splits into two subpopulations with differential expression of amylolytic enzymes. These enzymes are secreted and together break down starch in a multi-step process. We show with a mathematical model that concentrating production and secretion of all enzymes by part of the hyphae results in more efficient substrate degradation, as compared to equal distribution over all hyphae. This model result is corroborated by experimental observations of increased metabolic activity of the wild type that displays hyphal heterogeneity as compared to a mutant that lost this heterogeneity. The intermediate product (iso)maltose is known to induce upregulation of amylolytic enzymes. Incorporating this in the model enables the formation of hyphal heterogeneity through self-organisation. We generalize our results to a large class of multi- step processes and demonstrate wide applicability. Importantly, this shows that self-organisation may not be incidental, but favorable and thus selectable since it enhances efficiency. Due to its impact on system functioning, its study is not only of academic interest but also of practical value.

systems biology↗

Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation

Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.

immunology↗