Biology subjects

Kamp, F.

Publications and source records attributed to Kamp, F..

5 recordsLinked to original sources

bioRxiv2025

Esophageal adenocarcinoma relapse after chemoradiation is dominated by a basal-like subtype

Neoadjuvant chemoradiation therapy (RCT) is a frequently used treatment regimen for esophageal adenocarcinoma (EAC); however, the response varies dramatically, and resistance is a clinical challenge. We aimed to identify the molecular mechanisms underlying RCT resistance. We established a mouse xenograft RCT model with human EAC cell lines representing different response groups, and tested enhanced genomic instability as a potential evolutionary modulator by reducing BRCA2 function. Xenografts that relapsed after RCT displayed upregulation of stress response keratins, including KRT6 and KRT16 connected with a basal-like transcriptomic/ proteomic phenotype. We screened our cohort of 728 patients with EAC and found significantly shorter overall survival for patients with KRT6-high tumors, driven by patients receiving neoadjuvant treatment. Overall, we identified a basal-like cell state in EAC that reflects RCT relapse. The basal-like subtype is a marker of treatment failure, providing a new avenue for translational research to overcome RCT resistance.

cancer biology↗

bioRxiv2023

AAontology: An ontology of amino acid scales for interpretable machine learning

Amino acid scales are crucial for protein prediction tasks, many of them being curated in the AAindex database. Despite various clustering attempts to organize them and to better understand their relationships, these approaches lack the fine-grained classification necessary for satisfactory interpretability in many protein prediction problems. To address this issue, we developed AAontology--a two-level classification for 586 amino acid scales (mainly from AAindex) together with an in-depth analysis of their relations--using bag-of-word-based classification, clustering, and manual refinement over multiple iterations. AAontology organizes physicochemical scales into 8 categories and 67 subcategories, enhancing the interpretability of scale-based machine learning methods in protein bioinformatics. Thereby it enables researchers to gain a deeper biological insight. We anticipate that AAontology will be a building block to link amino acid properties with protein function and dysfunctions as well as aid informed decision-making in mutation analysis or protein drug design.

bioinformatics↗

bioRxiv2023

Single-neuron spiking variability in hippocampus dynamically tracks sensory content during memory formation in humans

During memory formation, the hippocampus is presumed to represent the "content" of stimuli, but how it does so is unknown. Using computational modelling and human single-neuron recordings, we show that the more precisely hippocampal spiking variability tracks the composite features of each individual stimulus, the better those stimuli are later remembered. We propose that moment-to-moment spiking variability may provide a new window into how the hippocampus constructs memories from the building blocks of our sensory world.

neuroscience↗

bioRxiv2020

Microbiota-derived short chain fatty acids promote Aβ plaque deposition

Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimers disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD, including the microbial mediators and their cellular targets in the brain, were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as key metabolites along the gut-brain axis in AD. Germ-free (GF) AD mice exhibit a substantially reduced A{beta} plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice was sufficient to increase the A{beta} plaque load to levels of conventionally colonized animals. While A{beta} generation was only mildly affected, we observed strong microglial activation and upregulation of ApoE upon the SCFA supplementation. Taken together, our results demonstrate that microbiota-derived SCFA are the key mediators along the gut-brain axis resulting in increased microglial activation, ApoE upregulation and A{beta} deposition.

neuroscience↗

bioRxiv2018

Stabilization / destabilization of the APP transmembrane domain by mutations in the di-glycine hinge alter helical structure and dynamics, and impair cleavage by γ-secretase

Intramembrane cleavage of the {beta}-amyloid precursor protein C99 substrate by {gamma}-secretase is implicated in Alzheimers disease pathogenesis. Since conformational flexibility of a di-glycine hinge in the C99 transmembrane domain (TMD) might be critical for {gamma}-secretase cleavage, we mutated one of the glycine residues, G38, to a helix-stabilizing leucine and to a helix-distorting proline. CD, NMR and hydrogen/deuterium exchange measurements as well as MD simulations showed that the mutations distinctly altered the intrinsic structural and dynamical properties of the TMD. However, although helix destabilization/unfolding was not observed at the initial {varepsilon}-cleavage sites of C99, both mutants impaired {gamma}-secretase cleavage and altered its cleavage specificity. Moreover, helix flexibility enabled by the di-glycine hinge translated to motions of other helix parts. Our data suggest that both local helix stabilization and destabilization in the di-glycine hinge may decrease the occurrence of enzyme-substrate complex conformations required for normal catalysis and that hinge mobility can be conducive for productive substrate-enzyme interactions.

biophysics↗