Biology subjects

Farkas, B.

Publications and source records attributed to Farkas, B..

5 recordsLinked to original sources

bioRxiv2026

Regional history outweighs phylogeny in shaping recent demographic trajectories of Indo-West Pacific sea snakes

Aim Understanding how biodiversity is formed and distributed is fundamental to anticipating how populations will respond to ongoing climate change and conserving future diversity. Sea snakes are a recent marine radiation comprising replicate lineages separated by vicariance and long-term isolation among major Indo-Pacific ocean basins. This system provides a powerful opportunity for testing whether demographic trajectories are shaped by regional history, phylogeny, or geographic range size. We therefore compare the demographic and phylogeographic histories of fully marine sea snakes to evaluate the role of Pleistocene climate change in structuring biodiversity across major biogeographic regions, including the global marine hotspot of the Indo-Australian Archipelago. Location Indo-Pacific tropical and sub-tropical marine. Methods We quantified demographic trajectories using whole-genome sequencing and integrated these with a broad-scale phylogeographic analysis of genome-wide single nucleotide polymorphisms (SNP). SNP sequencing used 652 individuals to investigate the phylogeographic structure of 20 species across the Indian Ocean, Southeast Asian and Australian West-Pacific biogeographic regions. Whole genome data from 36 individuals provided coalescent estimates of effective population size (Ne) through time. These Ne trajectories were then analysed using phylogenetic comparative methods to test the effects of regional history, phylogeny, and geographic range size. Results Distinct within-species phylogeographic structure was uncovered between the regions supporting vicariance across biogeographic barriers. Ne trajectories in the last 200 thousand years (kyr) were more strongly influenced by regional history than by phylogeny or contemporary range size. Southeast Asian lineages maintained the largest historical populations and experienced the shallowest population declines compared to lineages in the Indian Ocean and Australian West-Pacific. These results are consistent with the role of the marine biodiversity hotspot centred on the Indo-Australian Archipelago (IAA) as a region of long-term population persistence and stability during Pleistocene climatic fluctuations. Main Conclusions Demographic responses to Pleistocene climate change are strongly region-specific across the Indo-West Pacific, reflecting variation in habitat persistence and connectivity among ocean basins. Over the last 200kyr, regional biogeographic history is a stronger determinant of demographic history than shared ancestry and species range size. Based on these patterns, we recommend a hierarchical conservation framework in which ocean basins represent primary management units, and within-basin genetic structure informs finer-scale spatial planning. Of particular concern are Indian Ocean lineages, which exhibit lower effective population sizes and face intense fishing pressure and habitat loss. In contrast, Australian populations maintain relatively high genetic diversity and may represent an important regional refuge under future change. The demographic stability of Southeast Asian lineages supports the IAA as a long-term centre of population persistence, but this historical resilience offers little protection against current pressures: shallow marine habitats in the region are heavily degraded and sea snakes are directly harvested for trade.

genomics↗

bioRxiv2025

Temporal control of feeding attenuates allergic dermatitis via reduced leptin production in mice

Irregular and unhealthy eating behavior contributes to the development of both metabolic and inflammatory disorders. Time-restricted eating modulates metabolism and immune function without reducing caloric intake, yet its role in inflammatory skin diseases remains unclear. Here, we examined how feeding time and diet influence contact hypersensitivity, a murine model of allergic dermatitis--a disease that affects 20% of the population. Mice were fed with normal (NC) or high-fat (HF) chow under ad libitum (AL) or 10/14 time-restricted feeding (TRF) conditions. Under AL conditions, HF diet induced metabolic dysfunction and exacerbated inflammation, characterized by increased ear swelling, leukocyte infiltration, neutrophil and cytokine accumulation, and intraepidermal pustule formation. TRF attenuated these effects and accelerated resolution, even when initiated after disease onset. HF feeding altered both the level and diurnal dynamics of serum leptin, while TRF partially restored these changes. Elevated leptin levels were associated with increased inflammatory responses including intense neutrophil accumulation and pustule formation, and both genetic and pharmacological inhibition of leptin signaling reduced disease severity. Analysis of patients transcriptomic data also suggested a link between leptin signaling and inflammatory skin conditions in humans. We propose that time-restricted eating beneficially influences disease progression in contact dermatitis and that leptin-associated pathways may contribute to this effect.

immunology↗

bioRxiv2023

Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA Damage Response inhibitors

Combination therapy is well established as a key intervention strategy for cancer treatment, with the potential to overcome monotherapy resistance and deliver a more durable efficacy. However, given the scale of unexplored potential target space and the resulting combinatorial explosion, identifying efficacious drug combinations is a critical unmet need that is still evolving. In this paper, we demonstrate a network biology-driven, simulation-based solution, the Simulated Cell. Integration of omics data with a curated signaling network enables the accurate and interpretable prediction of 66,348 combination-cell line pairs obtained from a large-scale combinatorial drug sensitivity screen of 684 combinations across 97 cancer cell lines (BAC= 0.62, AUC=0.7). We highlight drug combination pairs that interact with DNA Damage Response pathways and are predicted to be synergistic, and deep network insight to identify biomarkers driving combination synergy. We demonstrate that the cancer cell avatars capture the biological complexity of their in vitro counterparts, enabling the identification of pathway-level mechanisms of combination benefit to guide clinical translatability.

cancer biology↗

bioRxiv2021

AlphaFold2 transmembrane protein structure prediction shines

Transmembrane (TM) proteins are major drug targets, indicated by the high percentage of prescription drugs acting on them. For a rational drug design and an understanding of mutational effects on protein function, structural data at atomic resolution are required. However, hydrophobic TM proteins often resist experimental structure determination and in spite of the increasing number of cryo-EM structures, the available TM folds are still limited in the Protein Data Bank. Recently, the DeepMinds AlphaFold2 machine learning method greatly expanded the structural coverage of sequences, with high accuracy. Since the employed algorithm did not take specific properties of TM proteins into account, the validity of the generated TM structures should be assessed. Therefore, we investigated the quality of structures at genome scales, at the level of ABC protein superfamily folds, and also in specific individual cases. We tested template-free structure prediction also with a new TM fold, dimer modeling, and stability in molecular dynamics simulations. Our results strongly suggest that AlphaFold2 performs astoundingly well in the case of TM proteins and that its neural network is not overfitted. We conclude that a careful application of its structural models will advance TM protein associated studies at an unexpected level.

bioinformatics↗

bioRxiv2021

Nanomechanics combined with HDX reveal allosteric drug binding sites of CFTR NBD1

Cystic fibrosis is most frequently caused by the deletion of F508 ({Delta}F508) in CFTRs nucleotide binding domain 1 (NBD1), compromising CFTR folding, stability and domain assembly. The limitation of developing a successful therapy is due to the lack of molecules that synergistically facilitate folding by targeting distinct structural defects of {Delta}F508-CFTR. To improve drug efficacy by targeting the {Delta}F508-NBD1 folding and stability, and to study potential {Delta}F508-NBD1 allosteric corrector binding sites at the atomic level, we combined molecular dynamics (MD) simulations, atomic force spectroscopy (AFM) and hydrogen-deuterium exchange (HDX) experiments. These methods allowed us to describe unfolding intermediates and forces acting during NBD1 mechanical unfolding and to elucidate the stabilization mechanism of {Delta}F508-NBD1 by 5-bromoindole-3-acetic acid (BIA). An NBD1 region, including the -subdomain, was identified as a potentially important participant of the first folding steps, characterized by non-native interactions of F508, thus destabilized in the deletion mutant. The instability was counteracted by the low-potency corrector BIA, increasing the mechanical resistance of the {Delta}F508-NBD1 -subdomain, which was confirmed as a binding site by computational modeling and HDX experiments. Our results underline the complementarity of computational and experimental methods and provide a possible strategy to improve folding correctors.

biophysics↗