Biology subjects

Torok, Z.

Publications and source records attributed to Torok, Z..

6 recordsLinked to original sources

bioRxiv2026

A preclinical resistance framework discovers the virulence risks of antibiotics in development

Several new antibiotics target multidrug-resistant pathogens, yet resistance is still evaluated mainly by drug-susceptibility, leaving consequences for bacterial pathogenicity poorly understood. Here, we develop a framework integrating resistance evolution, genomic surveillance and host-pathogen phenotyping to classify antibiotics by resistance potential and pathogenic consequences. Applying this framework to Klebsiella pneumoniae identified functionally distinct antibiotic candidates associated with elevated virulence risk. Resistance evolution rapidly increased virulence through clinically-relevant mutations, without direct selection for pathogenicity. Despite distinct genetic routes, resistance converged on cell-envelope rewiring. A single resistance mutation increased epithelial adhesion, intracellular colonization, macrophage immune-evasion, and tissue persistence in murine infection models, transforming K. pneumoniae into a more invasive and cytotoxic pathogen. Risk-profile analysis revealed partial decoupling of resistance and pathogenicity, with some low-resistance antibiotics yielding highly-virulent populations. These findings establish resistance-driven virulence as an underappreciated translational hazard and call for incorporating host-pathogen interactions into resistance surveillance and preclinical antibiotic development.

microbiology↗

bioRxiv2024

Mild hyperthermia-induced thermogenesis in the endoplasmic reticulum defines stress response mechanisms

Previous studies reported that a mild, non-protein denaturing, fever-like temperature increase induced the unfolded protein response (UPR) in mammalian cells. Our dSTORM super-resolution microscopy experiments revealed that the master regulator of the UPR, the IRE1 (inositol-requiring enzyme 1) protein is clustered as a result of UPR activation in a human osteosarcoma cell line (U2OS) upon mild heat stress. Using ER thermo yellow, a temperature-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we detected significant intracellular thermogenesis in mouse embryonic fibroblast (MEF) cells. Temperatures reached at least 8{degrees}C higher than the external environment (40{degrees}C), resulting in exceptionally high ER temperatures similar to those previously described for mitochondria. Mild heat-induced thermogenesis in the ER of MEF cells was likely due to the uncoupling of the Ca2+/ATPase (SERCA) pump. The high ER temperatures initiated a pronounced cytosolic heat shock response in MEF cells, which was significantly lower in U2OS cells in which both the ER thermogenesis and SERCA pump uncoupling were absent. Our results suggest that, depending on intrinsic cellular properties, mild hyperthemia-induced intracellular thermogenesis defines the cellular response mechanism, and determines the outcome of hyperthermic stress.

cell biology↗

bioRxiv2023

Recovery of a learned behavior despite partial restoration of neuronal dynamics after chronic inactivation of inhibitory neurons

Maintaining motor behaviors throughout life is crucial for an individuals survival and reproductive success. The neuronal mechanisms that preserve behavior are poorly understood. To address this question, we focused on the zebra finch, a bird that produces a highly stereotypical song after learning it as a juvenile. Using cell-specific viral vectors, we chronically silenced inhibitory neurons in the pre-motor song nucleus called the high vocal center (HVC), which caused drastic song degradation. However, after producing severely degraded vocalizations for around 2 months, the song rapidly improved, and animals could sing songs that highly resembled the original. In adult birds, single-cell RNA sequencing of HVC revealed that silencing interneurons elevated markers for microglia and increased expression of the Major Histocompatibility Complex I (MHC I), mirroring changes observed in juveniles during song learning. Interestingly, adults could restore their songs despite lesioning the lateral magnocellular nucleus of the anterior neostriatum (LMAN), a brain nucleus crucial for juvenile song learning. This suggests that while molecular mechanisms may overlap, adults utilize different neuronal mechanisms for song recovery. Chronic and acute electrophysiological recordings within HVC and its downstream target, the robust nucleus of the archistriatum (RA), revealed that neuronal activity in the circuit permanently altered with higher spontaneous firing in RA and lower in HVC compared to control even after the song had fully recovered. Together, our findings show that a complex learned behavior can recover despite extended periods of perturbed behavior and permanently altered neuronal dynamics. These results show that loss of inhibitory tone can be compensated for by recovery mechanisms partly local to the perturbed nucleus and do not require circuits necessary for learning.

neuroscience↗

bioRxiv2023

The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by which LA1011 may Improve the Prognosis of Alzheimer's Disease.

Chaperone systems play a major role in the decline of cognition and contribute to neurological pathologies such as Alzheimers disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained elusive. The current models suggest that amyloid-{beta} (A{beta}) plaque formation leads to the hyperphosphorylation of tau by a Hsp90 dependent process that triggers tau neurofibrillary tangle formation and neurotoxicity. Several co-chaperones of Hsp90 can influence the phosphorylation of tau, including FKBP51, FKBP52 and PP5. In particular elevated levels of FKBP51 occur with age and stress and are further elevated in AD. Recently, the dihydropyridine, LA1011 was shown to reduce tau pathology and amyloid plaque formation in transgenic AD mice, probably through its interaction with Hsp90 although the precise mode of action is currently unknown. Here, we present a co-crystal structure of LA1011 in complex with a fragment of Hsp90. We show that LA1011 can disrupt binding of FKBP51, which might help to rebalance the Hsp90-FKBP51 chaperone machinery and provide a favourable prognosis towards AD. Clinically, this is highly significant, as AD is generally a disease affecting older patients, where slowing of disease progression could result in AD no longer being life limiting.

molecular biology↗

bioRxiv2022

Unsupervised Restoration of a Complex Learned Behavior After Large-Scale Neuronal Perturbation

Reliable execution of behaviors requires that brain circuits correct for variations in neuronal dynamics. Genetic perturbation of the majority of excitatory neurons in a brain region involved in song production in adult songbirds with stereotypical songs triggered severe degradation of their songs. The song fully recovered within two weeks, and substantial improvement occurred even when animals were prevented from singing during the recovery period, indicating that offline mechanisms enable recovery in an unsupervised manner. Song restoration was accompanied by increased excitatory synaptic inputs to unmanipulated neurons in the same region. A model inspired by the behavioral and electrophysiological findings suggests that a combination of unsupervised single-cell and population-level homeostatic plasticity rules can support the observed functional restoration after large-scale disruption of networks implementing sequential dynamics. In the model the sequence is restored through a parallel homeostatic process, rather than regrown serially, and predicts that sequences should recover in a saltatory fashion. Correspondingly, we observed such recovery in the songs of manipulated animals, with syllables that rapidly alternate between abnormal and normal durations from rendition to rendition until eventually they permanently settled into their original length. These observations indicate the existence of cellular and systems-level restorative mechanisms that ensure behavioral resilience.

neuroscience↗

bioRxiv2018

Looking at the map -- or navigating in a virtual city. Interaction of visuospatial display and spatial strategies in VR

To study geo-visualization processes a Cognitive Cartography Lab was established at Eotvos University, and the \"Virtual Tourist\" experiment was designed for the better understanding of actual map use during navigation. In this paper we present some preliminary results of the experiment. We explored the use of a static, north-oriented city map during navigation in an interactive, 3D town. Participants explored the virtual environment or followed verbal instructions before they completed spatial tasks. Their spatial behavior, verbal reactions were recorded, and also eye tracking data from 64 participants was collected. The experiment was designed by a multidisciplinary research group, including students of Eotvos Lorand University.

neuroscience↗