Biology subjects

Farkas, A.

Publications and source records attributed to Farkas, A..

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↗

bioRxiv2025

How big is enough? Movement-informed zoning for African swine fever mitigation

O_LIAfrican swine fever (ASF) poses a serious threat to domestic pigs and wild boar populations. Wild boar can disperse the virus, making effective containment crucial. One of the main control strategies involves establishing restricted zones around detected cases, i.e., areas with temporary restrictions on access and hunting; however, determining the appropriate size of these zones remains a major challenge. C_LIO_LITo inform the size of restricted zones, we analyzed GPS data from 527 wild boar across 46 European study sites using a two-step approach combining first-passage time analysis and survival modelling to quantify the risk of wild boar leaving areas of different radii (i.e., spatial scales). We investigated how the risk of leaving varied over time and across environmental gradients. To go further, we used our model findings to develop an online application that generates predictive maps of optimal buffer sizes for ASF management at the European scale, based on a given risk threshold (the maximum acceptable probability that a wild boar leaves the area). C_LIO_LIWe found that the relationship between radius and the risk of leaving is negative exponential, and the risk of leaving increased over time, with a more rapid increase for smaller radii. Landscape homogeneity, terrain ruggedness and human impact increased the risk of leaving, with stronger effects at small scales. Contrary to other predictors, agricultural cover exerted a strong effect on risk of leaving over large spatial scales, especially when it was abundant. C_LIO_LIAcross Europe, a buffer radius of [~]8 km is likely sufficient around high-risk infection zones in most areas (considering an infectious period of 14 days and a risk threshold of 5%); however, in certain areas, a radius of up to 20 km may be needed to effectively limit wild boar movement. C_LIO_LISynthesis and applications: Our results highlight the need for adaptive, context-specific restricted zones. Buffers of 8 km around ASF-affected areas can limit the risk of infected wild boar dispersal, but they may be reduced to 5 km in highly heterogeneous landscapes or high-human impacted areas. Larger buffers may be required in agricultural landscapes. We provide spatially explicit outputs (optimal buffer sizes) that can directly inform policy and wildlife disease response strategies. The approach can be adapted to any other infectious disease. C_LI

ecology↗

bioRxiv2025

Bayesian multilevel modeling of group and participant level effect sizes: Stronger inter-individual differences in pupil dilation compared to EEG alpha power during aversive conditioning

Aversive conditioning prompts reliable changes in the power of EEG alpha-band oscillations and pupil dilation. Both variables have been used to test hypotheses on the acquisition, generalization, and extinction of conditioned threat. Existing studies have largely relied on trial averages and group-level analyses. Thus, the variability of these physiological markers to aversive learning at the subject level is currently unknown. Comparisons of group-level analyses in prior studies suggest that pupil dilation and EEG-alpha activity capture complementary information. However, to date, no study has directly compared these two markers in terms of their effect sizes at the level of individual participants. The present study employed Bayesian multilevel modeling to quantify the variability of conditioning effect estimates for alpha-band power and pupillometry. Estimates were examined at the group level and at the participant level, across two conditioning paradigms, involving visual and auditory cues. Although the two metrics shared similar effect sizes at the group level, participant-level variability in these effect sizes was substantially higher for pupil-dilation compared to alpha-power, and this finding was replicated across both paradigms. These findings have important implications for clinical and inter-individual difference research which requires both the quantification of effects at the participant-level as well as meaningful variability between-participants that can be linked to relevant differences such as anxiety.

neuroscience↗

bioRxiv2025

Emotional Responses to Naturalistic and AI-generated Affective Pictures: A Systematic Comparison

Pictures depicting naturalistic scenes are widely used in studies of human emotion. However, the practical use of affective pictures is limited by several factors, including the difficulty of obtaining content-diverse, high-quality, openly accessible, and standardized stimuli that are necessary for specific research questions. The use of artificially generated (AI) pictures could address this limitation, but it is unclear if AI-generated pictures evoke reliable emotional responses. The present study sought to address these challenges by comparing emotional responses to AI-generated pictures with responses to original, standardized, pictures. In two study iterations, standardized pictures containing pleasant, neutral, and unpleasant content were selected from the International Affective Picture System (IAPS) and other sources. Then, a matched AI-counterpart was created for each original picture using generative deep neural networks. A total of 109 participants viewed the picture sets while pupil diameter and electroencephalogram (EEG) were recorded. Evaluative ratings of hedonic valence and emotional arousal were also collected. For both AI and original exemplars, pictures depicting emotional content elicited stronger responses than neutral content for ratings and EEG-derived variables, with weaker effect sizes for the AI-generated pictures. Furthermore, picture-level analyses found that ratings and EEG measures were strongly correlated between matched AI and original pictures. Pupil data also showed the expected content effects in study iteration 2, but not in iteration 1. Together, this initial study suggests that AI-generated picture sets can effectively elicit well-established self-reported affect and physiological responses, presenting a promising avenue for future studies of human emotion.

neuroscience↗

bioRxiv2024

HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer

BackgroundBacillus Calmette-Guerin (BCG) is the standard of care treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), yet many patients develop recurrent disease despite evidence of ongoing immune activation. We investigated mechanisms of immune escape in BCG-unresponsive tumors and evaluated the therapeutic potential of targeting the HLA-E/NKG2A axis. MethodsSingle-cell RNA sequencing, spatial immunophenotyping, proteomic profiling, and functional ex vivo assays were performed using tumors and urine samples from patients with BCG-naive and BCG-unresponsive NMIBC. ResultsBCG-unresponsive tumors were enriched for HLA-E-expressing malignant cells compared with BCG-naive tumors. Increased HLA-E expression was associated with enhanced IFN-{gamma} signaling and was induced by IFN-{gamma} stimulation in primary tumor cells and bladder cancer tumor lines. Spatial analyses demonstrated accumulation of NKG2A+ NK and CD8 T cells in proximity to HLA-Ehigh tumor cells, with increased NKG2A:HLA-E interactions in BCG-unresponsive tumors. Despite high expression of cytotoxic mediators, NKG2A+ effector cells displayed impaired degranulation. Blockade of NKG2A with monalizumab restored degranulation of and cytotoxicity by tumor-infiltrating lymphocytes in autologous tumor co-cultures. ConclusionsBCG-unresponsive NMIBC tumors are enriched for HLA-E-expressing tumor cells and NKG2A+ effector lymphocytes, with increased engagement of the HLA-E/NKG2A axis within the tumor microenvironment. These findings identify the HLA-E/NKG2A axis as a therapeutic vulnerability and provide a rationale for clinical evaluation of NKG2A blockade as a bladder-sparing strategy for patients with BCG-unresponsive disease.

cancer biology↗

bioRxiv2024

The Neosartorya (Aspergillus) fischeri antifungal protein NFAP2 has low potential to trigger resistance development in Candida albicans in vitro

Due to the increase in the number of drug-resistant Candida albicans strains, new antifungal compounds with limited potential for development of resistance are urgently needed. NFAP2, an antifungal protein (AFP) secreted by Neosartorya (Aspergillus) fischeri, is a promising candidate. We investigated the ability of C. albicans to develop resistance to NFAP2 in a microevolution experiment compared with generic fluconazole (FLC). C. albicans adapted to only 1 x minimum inhibitory concentration (MIC) of NFAP2 compared with 32 x MIC of FLC. Genome analysis revealed non-silent mutations in only two genes in NFAP2-resistant strains and in several genes in FLC-resistant strains. Resistance development to NFAP2 did not influence cell morphology. The susceptibility of NFAP2-resistant strains did not change to FLC, amphotericin B, micafungin, terbinafine. These strains did not show altered susceptibility to AFPs from Penicillium chrysogenum, except one which had less susceptibility to P. chrysogenum antifungal protein B. FLC-resistant strains had decreased susceptibility to terbinafine and NFAP2, but not to other drugs and AFPs from P. chrysogenum. NFAP2- and FLC-resistant strains showed decreased and increased NFAP2 binding and uptake, respectively. The development of resistance to NFAP2 decreased tolerance to cell wall, heat, and UV stresses. The development of FLC resistance increased tolerance to cell wall stress and decreased tolerance to heat and UV stresses. Resistance to NFAP2 did not have significant metabolic fitness cost and could not increase virulence, compared with resistance to FLC. ImportanceDue to the increasing number of (multi)drug-resistant strains, only a few effective antifungal drugs are available to treat infections caused by opportunistic Candida species. Therefore, the incidence of hard-to-treat candidiasis has increased dramatically in the past decade, and the demand to identify antifungal compounds with minimal potential to trigger resistance is substantial. The features of NFAP2 make it a promising candidate for the topical treatment of Candida infection. Data on the development of resistance to AFPs in C. albicans are lacking. In this study, we provide evidence that NFAP2 has low potential to trigger resistance in C. albicans in vitro and the developed resistance mechanisms to NFAP2 are not associated with severe phenotypic changes compared with development of resistance to generic FLC. These results suggest the slow emergence of NFAP2-resistant Candida strains and that NFAP2 can reliably be used long-term in the clinic.

microbiology↗