Biology subjects

Szabo, Z.

Publications and source records attributed to Szabo, Z..

6 recordsLinked to original sources

bioRxiv2025

A549 tumorigenic and BEAS-2B non-tumorigenic cell line derived small extracellular vesicles show distinct proteomic, N-glycoproteomic and chondroitin/dermatan sulfate profiles

Extracellular vesicles (EVs) are critical mediators of intercellular communication and hold promise as biomarkers and therapeutic targets in cancer, but their molecular alterations remain poorly understood. Protein glycosylation is a frequent post-translational modification; however, most EV studies focus only on proteomics, while mapping glycosylation changes of proteins are still underrepresented. To address this shortcoming, we analyzed the proteomic, N-glycoproteomic, and chondroitin/dermatan sulfate (CS/DS) glycosaminoglycan (GAG) profiles of small EVs (sEVs) derived from A549 lung adenocarcinoma and BEAS-2B non-tumorigenic epithelial cell lines. Principal component analysis and hierarchical clustering revealed that all three profiles are highly dependent on the origin of sEV, highlighting fundamental differences not only at the proteomic but also at the N-glycopeptide and CS/DS levels. Protein expression differences were primarily associated with the upregulation of cell cycle regulation, DNA repair, metabolism, and protein synthesis, while immune-related processes were predominantly downregulated. Proteomics revealed differential expressions of 5 CS proteoglycans, anticipating that their CS profile may also change. N-glycoproteomics highlighted a shift from complex to hybrid N-glycans in cancer sEVs, alongside a significant decrease in fucosylation. Prominent glycoproteins characterized with multiple glycosylation sites included versican, galectin-3-binding protein and laminins. The total amount of CS/DS increased 3.4-fold in cancer sEVs, while the ratio of the two monosulfated disaccharides changed 2-fold, suggesting altered sulfation mechanisms. These findings highlight the potential of N-glycoproteomics and GAG profiling to enhance biomarker discovery and EV-based cancer diagnostics. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/643059v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@c2dfdeorg.highwire.dtl.DTLVardef@1f79452org.highwire.dtl.DTLVardef@12a9dbborg.highwire.dtl.DTLVardef@d992da_HPS_FORMAT_FIGEXP M_FIG C_FIG Proteomic, N-glycoproteomic and chondroitin/dermatan sulfate disaccharide profiles differ between A549 lung adenocarcinoma and BEAS-2B non-tumorigenic epithelial cell derived small extracellular vesicles.

cancer biology↗

bioRxiv2024

GLE1 dysfunction compromises cellular homeostasis, spatial organization, and peripheral axon branching

The GLE1 protein is an enigmatic factor of RNA processing, associated with multiple developmental disorders including lethal congenital contracture syndrome 1 (LCCS1). Using in vivo genetic engineering to study disturbed GLE1 functions under physiological conditions we demonstrate that inactivation of Gle1 impedes cellular function and organization and causes pre-gastrulation lethality due to defects in adhesion and lineage specification. In contrast, the knock-in mice genocopying LCCS1-associated GLE1FinMajor variant (Gle1PFQ/PFQ) survive prenatal period but die suddenly at mid-adulthood. Gle1PFQ/PFQ mice present irregular count and distribution of spinal motor neurons and impaired development of neural crest-derived tissues as demonstrated by defects in their sympathetic innervation of heart ventricles, paravertebral sympathetic ganglia volume, and adrenal chromaffin cell counts. Unlike previously reported for yeast and HeLa cells, analysis of molecular consequences of GLE1FinMajor variant identified normal poly(A)+ RNA distribution in Gle1PFQ/PFQ cells, which however were impaired in RNA and protein synthesis and simultaneously showed typical signs of cellular senescence. Gle1PFQ/PFQ also induced disturbed stress responses with significant changes in G3BP1-positive stress granule count. Our results show necessity of GLE1 functions for life and indicate that LCCS1 etiology is resultant of pathogenic GLE1FinMajor variant impinging differentiation of neural crest derivatives and leading to complex multiorgan defects. HighlightsO_LITotal inactivation of GLE1 results in disorganization of blastocyst inner cell mass and early embryonic lethality. C_LIO_LIThe Gle1 knock-in (KI) mice, which genocopy the human GLE1FinMajor variant causative for lethal congenital contracture syndrome 1 (LCCS1), die suddenly in mid-adulthood. C_LIO_LINormal poly(A)+ RNA distribution was observed in Gle1 KI cells, but decreased number of G3BP1-positive stress granules were detected in response to stress. C_LIO_LIAbnormal sympathetic innervation of heart ventricles was detected in Gle1 KI mice. C_LIO_LINeural crest-derived tissues represent a new target of GLE1FinMajor and GLE1-related disorders. C_LI

developmental biology↗

bioRxiv2023

Shifts in attention drive context-dependent subspace encoding in anterior cingulate cortex during decision making

Attention is a cognitive faculty that selects part of a larger set of percepts, driven by cues such as stimulus saliency, internal goals or priors. The enhancement of the attended representation and inhibition of distractors have been proposed as potential neural mechanisms driving this selection process. Yet, how attention operates when the cue has to be internally constructed from conflicting stimuli, decision rules, and reward contingencies, is less understood. Here we recorded from populations of neurons in the anterior cingulate cortex (ACC), an area implicated in ongoing error monitoring and correction during decision conflicts, in a challenging attention-shifting task. In this task, mice had to attend to the rewarded modality when presented identical auditory and visual stimuli in two contexts without direct external cues. In the ACC, the irrelevant stimulus continuously became less decodable than the relevant stimulus as the trial progressed to the decision point. This contrasted strongly with our previous findings in V1 where both relevant and irrelevant stimuli were equally decodable throughout the trial. Using analytical tools and a recurrent neural network (RNN) model, we found that the linearly independent representation of stimulus modalities in ACC was well suited to context-gated suppression of a stimulus modality. We demonstrated that the feedback structure of lateral connections in the RNN consisted of excitatory interactions between cell ensembles representing the same modality and mutual inhibition between cell ensembles representing distinct stimulus modalities. Using this RNN model showing signatures of context-gated suppression, we predicted that the level of contextual modulation of individual neurons should be correlated with their relative responsiveness to the two stimulus modalities used in the task. We verified this prediction in recordings from ACC neurons but not from recordings from V1 neurons. Therefore, ACC effectively operates on low-dimensional neuronal subspaces to combine stimulus related information with internal cues to drive actions under conflict.

neuroscience↗

bioRxiv2023

α-Melanocyte-Stimulating Hormone Regulates Pathological Cardiac Remodeling by Activating Melanocortin 5 Receptor in Cardiomyocytes

Background-Melanocyte-stimulating hormone (-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). -MSH is predominantly expressed in the pituitary gland, but it is also found in several peripheral tissues such as the skin and heart. However, the role of -MSH and its possible target receptors in the heart remain completely unknown. Therefore, we sought to investigate whether -MSH could be involved in the regulation of pathological cardiac remodeling. MethodsTissue -MSH concentrations and the effects of chronic -MSH administration were investigated in mice subjected to transverse aortic constriction (TAC). Rat H9c2 cells, neonatal mouse ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) were used to study the effects of -MSH and selective MC-R agonists. Inducible cardiomyocyte-specific melanocortin 5 receptor (MC5-R) knockout mouse model was engineered to investigate the role of MC5-R in cardiac hypertrophy. Results-MSH was highly expressed in the mouse heart, particularly in the ventricles, and its level was reduced in the left ventricles of TAC-operated mice. Administration of a stable -MSH analogue protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction. In vitro experiments revealed that cardiomyocytes serve as effector cells for the -MSH mediated antihypertrophic signaling and that selective activation of MC5-R mimics the actions of -MSH. In keeping with these findings, MC5-R was downregulated in the failing mouse heart and stressed hiPSC-CMs. Silencing of MC5-R in mouse cardiomyocytes induced hypertrophy and fibrosis markers in vitro and aggravated TAC-induced cardiac hypertrophy and fibrosis in vivo. Conversely, pharmacological activation of MC5-R improved systolic function and reduced cardiac fibrosis in TAC-operated mice. Conclusions-MSH is expressed in the heart and protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes. These results suggest that analogues of naturally occurring -MSH, that have been recently approved for clinical use and have agonistic activity at MC5-R, may be of benefit in treating heart failure.

physiology↗

bioRxiv2023

The Medicago truncatula nodule-specific cysteine-rich peptides, NCR343 and NCR-new35 are required for the maintenance of rhizobia in nitrogen-fixing nodules.

In the nodules of Inverted Repeat-Lacking Clade legumes, including M. truncatula, nitrogen-fixing rhizobia undergo terminal differentiation resulting in elongated and endoreduplicated bacteroids specialised for nitrogen fixation. This irreversible transition of rhizobia is mediated by host produced nodule-specific cysteine-rich (NCR) peptides, of which about 700 are encoded in the M. truncatula genome. Some of these NCR peptides, NCR169, NCR211 and NCR247, are essential for nitrogen-fixing symbiosis. The analysis of bacteroid and symbiotic host cell differentiation revealed that the symbiotic phenotype of M. truncatula mutants, Mtsym19, Mtsym20 and NF-FN9363, were defective likewise in the formerly studied ncr mutants, Mtdnf4-1 and Mtdnf7-2. The incomplete differentiation of bacteroids triggered premature senescence of rhizobia in the nitrogen fixation zones of mutant nodules. Mtsym19 and Mtsym20 mutants are defective in the same peptide NCR-new35 and the lack of NCR343 is responsible for the ineffective symbiosis of NF-FN9363. The activity of NCR-new35 is significantly lower and limited to the transition zone of the nodule compared with other crucial NCRs. The fluorescent protein-tagged version of NCR343 and NCR-new35 localize to the symbiotic compartment. Our discovery added two additional members to the group of NCR genes essential for nitrogen-fixing symbiosis in M. truncatula.

plant biology↗

bioRxiv2022

The effect of grey wolf (Canis lupus) and human disturbance on the activity of big game species in the Bükk Hills, Hungary

The recent return of wolves to the Hungarian forests escalates conflicts among stakeholders. Hunting management agencies communicate that the presence of wolves may change the behaviour of big game species leading to difficulties for hunting organization and logistics. Here, we take a data driven approach to explore the activity of wolves and big game species. For this purpose we analysed camera trap data, collected in the Bukk National Park, Hungary. To estimate avoidance among wolves, humans and games we calculated a non-parametric activity overlap coefficient ({Delta}4) and used a machine learning (XGBoost) model. Our results show that game species have higher overlap coefficient with wolf ({Delta}4 = 0.83-0.89) than with human activity ({Delta}4 = 0.26-0.52), because predators and games are active in the same periods of the day, mainly night and dawn, and human activity mainly takes place during daytime. We could detect the refugee effects in the case of all game species. Our XGBoost analyses only found a moderate negative effect of wolf on red deer occurrence, while human activity had higher importance value and lowered the occurrence of all three game species investigated. Our results may thus indicate that human disturbance might be more important in shaping game activity than the presence of the grey wolf in Hungary.

zoology↗