Biology subjects

Fekete, A.

Publications and source records attributed to Fekete, A..

5 recordsLinked to original sources

bioRxiv2026

SSB1 links stress granule regulation to cellular stress responses and renal ischemia-reperfusion injury

Mammalian single-stranded DNA binding protein 1 (SSB1) has been established as an essential component of genome stability in both human cells and mice. Moreover, SSB1 was recently implicated in cytoplasmic stress response by its involvement in Ras GTPase-activating protein-binding protein 1 (G3BP1)-containing cytoplasmic stress granules (SGs) upon various forms of stress. Here, we generated and analyzed human cellular knockout and rodent ischemia-reperfusion (I/R) models to define SSB1s roles in cytoplasmic stress response. Analysis of wild-type as well as SSB1 and G3BP1 knockout human retinal pigment epithelial (RPE-1) cells shows stress-specific incorporation of SSB1 into SGs and a negative regulator role for SSB1 in SG dynamics under sublethal stress conditions. We find that SSB1 knockout measurably increases cellular sensitivity to oxidative stress but does not alter cell proliferation following mild acute stress. Moreover, we detect SSB1 efflux from the nucleus upon stress that is dependent upon the presence of G3BP1 in a stress-specific manner. In addition, using mouse and rat models we observe significant upregulation and robust cytoplasmic granulation of SSB1 upon renal ischemia-reperfusion stress, establishing SSB1s involvement in complex organismal stress response in vivo. Together, our data demonstrate active involvement of SSB1 in cytoplasmic response to cellular stress and acute kidney injury, with implications for targeting stress response functions in cancerous versus non-cancerous contexts. HIGHLIGHTSO_LISSB1 is incorporated into cytoplasmic stress granules and negatively regulates stress granule assembly under sublethal stress conditions C_LIO_LISSB1 shows stress- and G3BP1-dependent nuclear efflux C_LIO_LISSB1 is upregulated and undergoes apical granulation in renal epithelial cells during renal ischemia-reperfusion injury C_LI

cell biology↗

bioRxiv2023

A novel preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs

In vitro secondary pharmacology assays are an important tool for predicting clinical adverse drug reactions (ADRs) of investigational drugs. We created the Secondary Pharmacology Database (SPD) by testing 1958 drugs using 200 assays to validate target-ADR associations. Compared to public and subscription resources, 95% of all and 36% of active (AC50 < 1 {micro}M) results were unique to SPD, with bias towards higher activity in public resources. Annotating drugs with free maximal plasma concentrations, we found 684 physiologically relevant novel off-target activities. Furthermore, 64% of putative ADRs linked to target activity in key literature reviews were not statistically significant in SPD. Systematic analysis of all target-ADR pairs identified several novel associations confirmed by publications. Finally, candidate mechanisms for known ADRs are proposed based on SPD off-target activities. Taken together, we present a unique freely-available resource for benchmarking ADR predictions, explaining novel phenotypic activity and investigating clinical properties of marketed drugs.

pharmacology and toxicology↗

bioRxiv2023

The circadian clock is required for rhythmic lipid transport in the Drosophila hemolymph in interaction with diet, photic condition and feeding

Modern lifestyle often is at odds with endogenously driven rhythmicity, which can lead to circadian disruption and metabolic syndrome. One signature for circadian disruption is a diminished or altered cycling of metabolites in the circulating tissue reflecting the current metabolic status. Drosophila is a well-established model in chronobiology, but day-time dependent variations of transport metabolites in the fly circulation are poorly characterized. Here, we sampled fly hemolymph throughout the day and analysed diacylglycerols (DGs), phosphoethanolamines (PEs) and phosphocholines (PCs) using LC-MS. In wildtype flies kept on sugar-only medium under a light-dark cycle, all transport lipid species showed a synchronized bimodal oscillation pattern with maxima at the beginning and end of the light phase which were impaired in period01 clock mutants. In wildtype flies under constant dark conditions, the oscillation became monophasic with a maximum in the middle of the subjective day. In strong support of clock-driven oscillations, levels of DGs, PEs and PCs peaked once in the middle of the light phase under time-restricted feeding independent of the time of food intake. Rearing of wildtype flies on lipid-containing standard medium masked the rhythmic alterations of hemolymph lipid levels. Our data suggest that the circadian clock aligns daily oscillations of DGs, PEs and PCs in the hemolymph to the anabolic siesta phase, whith a strong influence of light on phase and modality. This finding opens the question whether and to what extent the circadian regulation of transport lipid levels in the hemolymph contributes to the health of the fly.

systems biology↗

bioRxiv2020

Neural excitability increases with axonal resistance between soma and axon initial segment

The position of the axon initial segment (AIS) is thought to play a critical role in neuronal excitability. In particular, empirical studies have found correlations between a distal shift in AIS position and a reduction of excitability. Yet, theoretical work has suggested that the neuron should become more excitable as the distance between soma and AIS is increased, because of increased electrical isolation. Specifically, resistive coupling theory predicts that the action potential (AP) threshold decreases with the logarithm of the axial resistance (Ra) between the middle of the AIS and the soma. However, no direct experimental evidence has been provided so far to support this theoretical prediction. We therefore examined how changes in Ra at the axon hillock impact the voltage threshold (Vth) of the somatic AP in L5 pyramidal neurons. Increasing Ra by mechanically pinching the axon between the soma and the AIS was found to lower the spike threshold by ~6 mV. Conversely, decreasing Ra by replacing a weakly mobile ion (gluconate) by a highly mobile ion (chloride) elevated the spike threshold. All Ra-dependent changes in spike threshold could be reproduced in a Hodgkin-Huxley compartmental model. We conclude that in L5 pyramidal neurons, excitability increases with axial resistance, and therefore with a distal shift of the AIS.

neuroscience↗

bioRxiv2020

Endocrine fine-tuning of daily locomotor activity patterns under non-starving conditions in Drosophila

1.Animals need to balance competitive behaviours to maintain internal homeostasis. The underlying mechanisms are complex, but typically involve neuroendocrine signalling. Using Drosophila, we systematically manipulated signalling between energy-mobilising endocrine cells producing adipokinetic hormone (AKH), octopaminergic neurons and the energy-storing fat body to assess whether this neuroendocrine axis involved in starvation-induced hyperactivity also balances activity levels under ad libitum access to food. Our results suggest that AKH signals via two divergent pathways that are mutually competitive in terms of activity and rest. AKH increases activity via the octopaminergic system during the day, while it prevents high activity levels during the night by signalling to the fat body. This regulation involves feedback signalling from octopaminergic neurons to AKH-producing cells (APCs). APCs are known to integrate a multitude of metabolic and endocrine signals. Our results add a new facet to the versatile regulatory functions of APCs by showing that their output contributes to shape the daily activity pattern under ad libitum access to food.

neuroscience↗