Biology subjects

Nagy, Z.

Publications and source records attributed to Nagy, Z..

11 recordsLinked to original sources

bioRxiv2026

Platelet GARP-dependent activation of TGF-β1 limits inflammation and promotes cardiac repair after myocardial infarction

Platelets are increasingly recognized as active regulators of inflammation beyond their canonical hemostatic functions. Although platelets rapidly accumulate in the injured myocardium after myocardial infarction (MI), the mechanisms by which they coordinate the inflammatory response remain poorly understood. Glycoprotein A repetitions predominant (GARP) is a membrane receptor that presents latent transforming growth factor-{beta}1 (TGF-{beta}1) on activated platelets and supports its activation. Given the central role of TGF-{beta}1 in inflammation and tissue repair, we hypothesized that platelet GARP-dependent activation of TGF-{beta}1 regulates inflammatory resolution and repair after MI. Using mice with megakaryocyte-and platelet-specific Garp deletion, we demonstrate that loss of platelet GARP selectively impaired generation of bioactive TGF-{beta}1 without altering platelet reactivity. Following permanent coronary artery ligation, platelet-specific Garp deficiency markedly increased mortality from ventricular rupture and exacerbated adverse left ventricular remodeling, independent of initial infarct size. Transcriptomic and histological analyses revealed heightened endothelial cell activation, increased leukocyte recruitment, delayed inflammatory resolution, and defective extracellular matrix deposition in the absence of platelet GARP. Mechanistically, platelet GARP-dependent TGF-{beta}1 signaling restrained endothelial activation after MI. Together, these findings identify platelet GARP-mediated activation of TGF-{beta}1 as a critical platelet-intrinsic counter-regulatory checkpoint that limits endothelial-driven inflammation and promotes infarct stabilization. Our study reveals an unexpected protective immunoregulatory function of platelets in cardiac repair after ischemic injury.

pathology↗

bioRxiv2026

A computational neuroimaging account of impulsive premature decision-making

Impulsivity is a multidimensional construct with distinct implications for the pathophysiology and treatment of various neuropsychiatric conditions, including substance use disorders, behavioural addictions, attention deficit hyperactivity disorder, psychosis, and personality disorders. One proposed behavioural subtype, premature responding impulsivity (PRI), appears to be influenced by neuromodulatory pathways frequently implicated in these disorders, in particular dopamine neurotransmission, known for its role in contingency learning. Still, the neurobiological basis of PRI in humans remains insufficiently understood. Here, we theorize that PRI reflects the brains capacity to adapt to environmental uncertainty. To test this hypothesis, twenty-four healthy adults (mean age 22.6 years; 12 females) completed a novel decision-making task featuring alternating stable and volatile probabilistic cue contingencies while undergoing functional magnetic resonance imaging (fMRI). A hierarchical Bayesian model estimated PRI as an urgency-to-respond process, whose parameters were dynamically modulated by volatility. These model-derived indices correlated with established trait impulsivity measures, supporting their construct validity. Model-based fMRI analyses identified a distributed cortico-subcortical network including anterior insula, dorsal anterior cingulate cortex, striatum, and monoaminergic midbrain regions, whose activity tracked within-trial PRI estimates as they evolved over time. Connectivity analyses further showed that high volatility enhanced interactions between subnetworks typically associated with promoting or inhibiting impulsive action. Together, these results outline a neurocomputational account in which environmental uncertainty modulates PRI through interacting brain circuits, offering a principled framework for further probing the transdiagnostic role of impulsivity across neuropsychiatric and neuropsychopharmacological contexts.

neuroscience↗

bioRxiv2022

Analysis of the abomasal transcriptome of LDA affected cattle

Left displacement of the abomasum (LDA) is a common condition in Holstein population mainly occur around the time of parturition. The entrapped abomasum located between the rumen and the abdominal wall caused by the abomasal hypomotility. The heritability of LDA estimated higher than for other bovine diseases but a number of management and nutritional conditions are also affecting the disease appearance. Genome studies revealed many significant genomic regions associated with LDA, although an RNA sequencing analysis of abomasum is missing from the literature. Within the framework of this research, we tried to patch up this area missing from the literature and to reveal the genetic causes and a complex interaction between the endocrine and neuromuscular pathways behind the symptoms of the disease with the help of transcriptomic analysis.

bioinformatics↗

bioRxiv2021

G6b-B regulates an essential step in megakaryocyte maturation

G6b-B is a megakaryocyte lineage-specific immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor, essential for platelet homeostasis. Mice with a genomic deletion of the entire Mpig6b locus develop severe macrothrombocytopenia and myelofibrosis, which is reflected in humans with null-mutations in MPIG6B. The current model proposes that megakaryocytes lacking G6b-B develop normally, while proplatelet release is hampered, but the underlying molecular mechanism remains unclear. Here, we report on a spontaneous recessive single nucleotide mutation in C57BL/6 mice, localized within the intronic region of the Mpig6b locus that abolishes G6b-B expression and reproduces macrothrombocytopenia, myelofibrosis and osteosclerosis. As the mutation is based on a single nucleotide exchange, Mpig6bmut mice represent an ideal model to study the role of G6b-B. Megakaryocytes from these mice were smaller in size, displayed a less developed demarcation membrane system and reduced expression of receptors. RNA sequencing revealed a striking global reduction in the level of megakaryocyte-specific transcripts, in conjunction with decreased protein levels of the transcription factor GATA-1, and impaired thrombopoietin signaling. The reduced number of mature MKs in the bone marrow was corroborated on a newly developed Mpig6b null mouse strain. Our findings highlight an unexpected essential role of G6b-B in the early differentiation within the megakaryocytic lineage.

cell biology↗

bioRxiv2021

Reduced platelet forces underlie impaired hemostasis in mouse models of MYH9-related disease

MYH9-related disease patients with mutations in the contractile protein non-muscle myosin heavy chain IIA display, among others, macrothrombocytopenia and a mild to moderate bleeding tendency. In this study, we used three mouse lines, each with one point mutation in the Myh9 gene at positions 702, 1424, or 1841, to investigate mechanisms underlying the increased bleeding risk. Agonist-induced activation of Myh9 mutant platelets was comparable to controls. However, myosin light chain phosphorylation after activation was reduced in mutant platelets, which displayed altered biophysical characteristics and generated lower adhesion, interaction, and traction forces. Treatment with tranexamic acid restored clot retraction and reduced bleeding. We verified our findings from the mutant mice with platelets from patients with the respective mutation. These data suggest that reduced platelet forces lead to an increased bleeding tendency in MYH9-related disease patients, and treatment with tranexamic acid can improve the hemostatic function. TeaserImpaired hemostasis in Myh9 mutant mice due to reduced platelet forces can be improved by tranexamic acid.

cell biology↗

bioRxiv2021

Microthrombocytopenia caused by impaired microtubule stability in RhoB-deficient mice

Megakaryocytes are large cells in the bone marrow, which give rise to blood platelets. Platelet biogenesis involves megakaryocyte maturation, the localization of mature cells in close proximity to bone marrow sinusoids and the formation of protrusions, which are shed into the circulation. Rho GTPases play important roles in platelet biogenesis and function. RhoA-deficient mice display macrothrombocytopenia and a striking mislocalization of megakaryocytes into bone marrow sinusoids and a specific defect in G-protein signaling in platelets. However, the role of the closely related protein RhoB in megakaryocytes or platelets remains unknown. In this study, we show that, in contrast to RhoA deficiency, genetic ablation of RhoB in mice results in microthrombocytopenia (decreased platelet count and size). RhoB-deficient platelets displayed mild functional defects predominantly upon induction of the collagen/glycoprotein VI pathway. Megakaryocyte maturation and localization within the bone marrow, as well as actin dynamics were not affected in the absence of RhoB. However, in vitro generated proplatelets revealed pronouncedly impaired microtubule organization. Furthermore, RhoB-deficient platelets and megakaryocytes displayed selective defects in microtubule dynamics/stability, correlating with pronouncedly reduced levels of acetylated -tubulin. Our findings imply that absence of this tubulin posttranslational modification results in decreased microtubule stability leading to microthrombocytopenia in RhoB-deficient mice. Our data thus points to specifically impaired microtubule - but not actin - dynamics as a general mechanism underlying the manifestation of microthrombocytopenia in vivo. We furthermore demonstrate that RhoA and RhoB have specific, non-redundant functions in the megakaryocyte lineage. KEY POINTSO_LIRhoB-deficient mice display microthrombocytopenia C_LIO_LIRhoB has different functions in the megakaryocyte lineage than RhoA and regulates microtubule dynamics C_LI

cell biology↗

bioRxiv2020

DIffusion-Prepared Phase Imaging (DIPPI): quantifying myelin in crossing fibres

PurposeMyelin has long been the target of neuroimaging research due to its importance in brain development, plasticity, and disease. However, most available techniques can only provide a voxel-averaged estimate of myelin content. In the human brain, white matter fibre pathways connecting different brain areas and carrying different functions often cross each other in the same voxel. A measure that can differentiate the degree of myelination of crossing fibres would provide a more specific marker of myelination. Theory & MethodsOne MRI signal property sensitive to myelin is the phase accumulation, which to date has also been limited to voxel-averaged myelin estimates. We use this sensitivity by measuring the phase accumulation of the signal remaining after diffusion weighting, which we call DIffusion-Prepared Phase Imaging (DIPPI). Including diffusion weighting before estimating the phase accumulation has two distinct advantages for estimating the degree of myelination: (1) it increases the relative contribution of intra-axonal water, whose phase is related linearly to the amount of myelin surrounding the axon (in particular the log g-ratio) and (2) it gives directional information, which can be used to distinguish between crossing fibres. ResultsUsing simulations and phantom data we argue that other sources of phase accumulation (i.e., movement-induced phase shift during the diffusion gradients, eddy currents, and other sources of susceptibility) can be either corrected for or are sufficiently small to still allow the g-ratio to be reliably estimated. ConclusionsThis new sequence is capable of providing a g-ratio estimate per fibre population crossing within a voxel.

neuroscience↗

bioRxiv2019

Neural Arbitration between Social and Individual Learning Systems

Decision making often requires integrating self-gathered information with information acquired from observing others. Depending on the situation, it may be beneficial to rely more on one than the other source, taking into account that either information may be imprecise or deceiving. The process by which one source is selected over the other based on perceived reliability, here defined as arbitration, has not been fully elucidated. In this study, we formalised arbitration as the relative reliability (precision) of predictions afforded by each learning system using hierarchical Bayesian models. In a probabilistic learning task, participants predicted the outcome of a lottery using recommendations from a more informed advisor and self-sampled outcomes. The number of points participants wagered on their predictions reflected arbitration: The higher the relative precision of one learning system over the other and the lower the intention volatility, the more points participants wagered on a given trial. Functional neuroimaging demonstrated that the arbitration signal was independent of decision confidence and involved modalityspecific brain regions. Arbitrating in favour of self-gathered information activated the dorsolateral prefrontal cortex and the midbrain whereas arbitrating in favour of social information engaged ventromedial prefrontal cortex and the temporoparietal junction. These findings are in line with domain specificity and indicate that relative precision captures arbitration between social and individual learning systems at both the behavioural and neural level.

neuroscience↗

bioRxiv2019

Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B

The immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B is critical for platelet production and activation, loss of which results in severe macrothrombocytopenia and aberrant platelet function in mice and humans. Using a combination of immunohistochemistry, affinity chromatography and proteomics, we identified the extracellular matrix heparan sulfate (HS) proteoglycan perlecan as a G6b-B binding partner. Subsequent in vitro biochemical studies and a cell-based genetic screen demonstrated that the interaction is specifically mediated by the HS chains of perlecan. Biophysical analysis revealed that heparin forms a high-affinity complex with G6b-B and mediates dimerization. Using platelets from humans and genetically-modified mice, we demonstrate that binding of G6b-B to HS and multivalent heparin inhibits platelet and megakaryocyte function by inducing downstream signaling via the tyrosine phosphatases Shp1 and Shp2. Our findings provide novel insights into how G6b-B is regulated and contribute to our understanding of the interaction of megakaryocytes and platelets with glycans.

biochemistry↗

bioRxiv2018

Targeting neuronal and glial cell types with synthetic promoter AAVs in mice, non-human primates, and humans

Targeting genes to specific neuronal or glial cell types is valuable both for understanding and for repairing brain circuits. Adeno-associated viral vectors (AAVs) are frequently used for gene delivery, but targeting expression to specific cell types is a challenge. We created a library of 230 AAVs, each with a different synthetic promoter designed using four independent strategies. We show that ~11% of these AAVs specifically target expression to neuronal and glial cell types in the mouse retina, mouse brain, non-human primate retina in vivo, and in the human retina in vitro. We demonstrate applications for recording, stimulation, and molecular characterization, as well as the intersectional and combinatorial labeling of cell types. These resources and approaches allow economic, fast, and efficient cell-type targeting in a variety of species, both for fundamental science and for gene therapy.

neuroscience↗

bioRxiv2018

Competing endogenous RNA network: Potential entrants to gene editing in Hepatocellular Carcinoma

BackgroundHepatocellular Carcinoma (HCC) is the leading cause of cancer deaths worldwide as well as in Egypt. We aimed to use Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR) gene editing technique to induce forced down-regulation of the circRNA which consequently modified miRNA expression in HepG2 cell line to prove the regulatory relationship between the RNA parts of an in silico-detected competing endogenous RNA network in HCC\n\nMethodWe first retrieved hsa_circ_0000064-miR-1285-TRIM2 mRNA from public microarray databases followed by in silico modelling to mimic the regulation kinetics of cirRNA associated ceRNA network. Secondly, we performed polymerase chain reaction (PCR)-based amplification of synthetic fragments, Gibson assembly of both CRISPR and non CRISPR based circuits, E-coli transformation, plasmid purification, HePG2 cell line transfection. Finally Expression levels of the chosen RNAs in hepatocellular carcinoma (HCC) cell line, HepG2, were examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and the cytotoxic effect was validated by viability assay.TRIM2 protein expression was proved by immunohistochemistry and flowcytometry.\n\nResultsInduction of hsa_circ_0000064 into HepG2 cell line via CRISPR-and non-CRISPR mediated synthetic circuit resulted in statistically significant decrease in cell number and, then, cellular viability with marked increase in hsa_circ_0000064 and TRIM2 mRNA levels and concomitant decrease in miR-1285 expression in HepG2 cell line compared with control (p<0.0). Moreover exogenous expression of hsa_circ_0000064 in HepG2 cell line showed increased expression of the tumor suppressor protein, TRIM2.\n\nConclusionsOur integrative approach, including in silico data analysis and experimental validation proved that CRISPR-mediated synthetic circuit-based overexpression of hsa_circ_0000064 was more efficient than conventional transient transfection, representing a promising therapeutic strategy for HCC.\n\nData AvailabilityOur Data was made available online on the IGEM wiki of team AFCM-EGYPT: http://2017.igem.org/Team:AFCM-Egypt. Synthetic parts have been submitted to IGEM Parts Registry.\n\nFinancial DisclosureThe project was funded by Armed Forces College of Medicine AFCM, Zewail City of Science and Technology, National Research Center NRC, VitaBiotics, PHARCO Pharmaceuticals, Sim Era and DANUB Paintings. IDT provided 20 kb of DNA synthesis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

bioengineering↗