Biology subjects

Rabe, K.

Publications and source records attributed to Rabe, K..

3 recordsLinked to original sources

bioRxiv2026

Preconception e-nicotine impairs airway development and progenitor proliferation across generations in Drosophila Melanogaster

Electronic nicotine delivery devices are increasingly used worldwide, raising concern about the potential effects of nicotine exposure during fetal and early postnatal development. However, evidence regarding the effects of vaping during pregnancy remains limited, and the consequences of exposure before conception are largely unknown. Here, we investigated whether maternal nicotine vaping prior to conception alters airway development using the fruit fly Drosophila melanogaster. Offspring of nicotine-exposed mothers exhibited abnormal airway architecture, epithelial remodelling, and impaired terminal branching. These defects were accompanied by reduced proliferation of airway progenitor cells without increased apoptosis, resulting in decreased hypoxia tolerance, altered activity patterns, and reduced lifespan. Transcriptomic and functional analyses revealed suppression of innate immune signalling mediated by nuclear factor kappa-B (NF-{kappa}B). Notably, knockdown of its regulator Relish reproduced key phenotypes. Developmental abnormalities persisted across generations, with their severity progressively declining. Together, these findings identify maternal preconception nicotine exposure as a previously unrecognized determinant of airway development and provide insight into early origins of chronic airway disease. TeaserPreconception e-nicotine exposure shapes airway development, structural and physiological abnormalities across generations in Drosophila.

Developmental Biology↗

bioRxiv2026

Electrostatic Engineering of Phosphoketolase Enhances Activity on Small Non-phosphorylated Sugars and Improves Cell-Free ATP Regeneration from Inexpensive C2-Substrates

Phosphoketolases can be used to convert non-phosphorylated sugars to the high energy compound acetyl phosphate and the versatile metabolic precursor acetyl-CoA. The performance of these pathways is limited by low catalytic activity of natural phosphoketolases towards these sugars. Here, we report the rational engineering of the phosphoketolase from Bifidobacterium adolescentis (Bad.F6Pkt) to enhance its activity and affinity towards glycoaldehyde (GA) and D-erythrulose (ERU) through re-organisation of the protein electric field to reproduce the role of terminal phosphate groups in cognate substrates. Guided by predicted induced side-chain pKa shifts, visualisation of electrostatic potential difference maps alongside molecular modelling and sequence variation analyses, we identified mutations that could promote in situ ring opening of the pre-dominant cyclic GA dimer form in solution. This approach to the electrostatic inverse design problem yielded the GA-specific double mutant H142N:E153D, exhibiting a ten-fold improved affinity and slightly enhanced catalytic efficiency (KM = 4.4 mM, kcat/ KM = 26.3 s-1 M-1) compared to the previously reported H142N variant (KM = 42.3 mM, kcat/ KM = 20.6 s-1 M-1). We additionally constructed a H256Y:H260Y:H548Y variant comprising long-range electrostatic mutations with a 3.8-fold increased catalytic efficiency (kcat/ KM = 49.6 s-1 M-1) on the acylic four-carbon ERU ketose compared to the wild-type enzyme. The engineered enzymes were evaluated in cell-free enzyme cascades for ATP regeneration via acetyl phosphate formation. The H142N variant enabled efficient ATP regeneration from GA and ethylene glycol, whereas the H142N:E153D mutant exhibited reduced stability under synthesis conditions. Furthermore, coupling of a highly GA-specific D-threose aldolase and a D-threose isomerase with the PKT triple mutant enabled rapid conversion of GA into C4 sugar intermediates and significantly improved ATP regeneration from GA.

synthetic biology↗

bioRxiv2020

Bayesian copy number detection and association in large-scale studies

Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging. We developed an approach called CNPBayes to identify latent batch effects, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. We demonstrate this approach in a Pancreatic Cancer Case Control study of 7,598 participants where the major sources of technical variation were not captured by study site and varied across the genome. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Supressor Candidate 3 (TUSC3). This study provides a robust Bayesian inferential framework for estimating copy number and evaluating the role of copy number in heritable diseases.

genetics↗