Biology subjects

Gabriel, G.

Publications and source records attributed to Gabriel, G..

8 recordsLinked to original sources

bioRxiv2026

Temporal Profiling of Upper-Layer Neurons Reveals Changes in the Molecular Landscape Upon Maternal Immune Activation

Neuronal differentiation is a dynamic, multi-layered process that transforms progenitor cells into functionally integrated neurons, yet the coordinated molecular programs underlying this transition remain incompletely understood. Here, we define the developmental trajectory of murine upper-layer cortical neurons using an integrated multi-omics approach combining transcriptomics and proteomics across key stages of neurogenesis. We find that neuronal identity emerges gradually through coordinated transitions from RNA processing and splicing programs toward synaptic and metabolic maturation. Integration of matched transcriptomic and proteomic datasets reveals a compact set of concordant molecular modules that define this trajectory, highlighting post-transcriptional regulation as a central driver of neuronal maturation. We further show that maternal immune activation (MIA), a model of prenatal inflammation, deranges this developmental program. MIA induces sustained upregulation of Wnt signalling pathways alongside a downregulation of synaptic regulators, without detectable global alterations in DNA methylation. These molecular changes are accompanied by defects in neuronal positioning during cortical development, linking altered molecular trajectories to functional outcomes. Together, our findings establish a temporal molecular framework of neuronal differentiation and demonstrate that prenatal environmental perturbations reshape cortical development primarily through post-transcriptional and signalling-based mechanisms.

neuroscience↗

bioRxiv2025

Low-temperature integration of printed electrochemical sensors into OSTE+ micrfluidics for oxygen monitoring and sensing

Real-time monitoring of biological events is essential for advancing in drug testing, disease modeling, and precision medicine. However, conventional analytical methods often lack the spatiotemporal resolution to capture dynamic cellular responses, particularly in Organ-on-a-Chip (OoC) platforms and microphysiological systems (MPS). While progress has been made in sensor development, integrating sensors into microfluidic devices remains technically challenging. Materials commonly used in microfluidics, such as polydimethylsiloxane (PDMS), are poorly suited for stable sensor integration due to low metal adhesion. Off-stoichiometry thiol-ene-epoxy (OSTE+) polymers present a promising alternative due to the presence of unreacted thiol groups. These groups enable dual functionalities: strong metal affinity for direct for robust sensor integration, and oxygen scavenging essential for microscale oxygen level control. However, their compatibility with conventional sensor fabrication methods, particularly those requiring elevated temperatures, is limited. This work introduces a low-temperature fabrication method based on inkjet printing and photonic curing, suitable for thermally sensitive substrates. Gold and silver nanoparticle inks were directly sintered onto OSTE+ using photonic curing, producing functional electrochemical sensors for spatially resolved and real-time oxygen detection. Unlike conventional thermal sintering, which is incompatible with many microfluidic materials, photonic curing preserves the chemical reactivity and mechanical properties of the polymer without requiring surface treatment or adhesive layers. To demonstrate functionality, sensors were integrated into microfluidic devices for continuous monitoring of dissolved oxygen. Real-time oxygen depletion driven by the materials intrinsic scavenging capability was successfully quantified. These findings support the compatibility of sensor integration into OSTE+ polymers enhancing the real-time monitoring capabilities in OoC and MPS systems. HighlightsO_LIInkjet-printed sensors are integrated into OSTE+ using a low-temperature protocol. C_LIO_LIPhotonic curing enables sintering of gold and silver nanoparticle inks without damaging the polymer substrate. C_LIO_LIOxygen scavenging is monitored in real time using integrated electrochemical sensors. C_LIO_LITunable oxygen gradients are achieved in OSTE+ microfluidics for organ-on-chip models. C_LI

bioengineering↗

bioRxiv2025

Snapshot of in-cell protein contact sites reveals new host factors and hijacking of paraspeckles during influenza A virus infection

Influenza A virus (IAV) hijacks host cellular machinery, but many virus-IAV interactions and contacting protein sites remain uncharacterised, particularly those dependent on intact cellular architecture, such as membrane-associated or phase-separated compartments. Here, we applied in-cell cross-linking mass spectrometry (XL-MS), integrated with AlphaFold-based structural modelling and functional assays, to map protein-protein contact sites in IAV-infected human cells. This approach revealed previously unrecognised virus-host interactions linked to spatially organised processes, including the maturation pathway of HA through the membrane-bound ER- Golgi system, the novel interaction of M2 with the membrane-embedded LAT1 amino acid transporter, and the progressive disassembly of paraspeckles-phase-separated compartments in the nucleus. We validate M2-LAT1 interaction and paraspeckle disassembly in human primary lung epithelial cells and show that the paraspeckle disassembly constitutes a new and unique infection mechanism through which IAV releases RNA-binding proteins that support viral RNA replication. These findings advance the understanding of IAV manipulation of host cellular processes and illustrate how the integrative in-cell structural system biology approach captures native host-pathogen interactomes, infection pathways, and host cell perturbations.

microbiology↗

bioRxiv2023

Spatial transcriptome profiling uncovers metabolic regulation of left-right patterning

Left-right patterning disturbance can cause severe birth defects, but it remains least understood of the three body axes. We uncovered an unexpected role for metabolic regulation in left-right patterning. Analysis of the first spatial transcriptome profile of left-right patterning revealed global activation of glycolysis, accompanied by right-sided expression of Bmp7 and genes regulating insulin growth factor signaling. Cardiomyocyte differentiation was left-biased, which may underlie the specification of heart looping orientation. This is consistent with known Bmp7 stimulation of glycolysis and glycolysis suppression of cardiomyocyte differentiation. Liver/lung laterality may be specified via similar metabolic regulation of endoderm differentiation. Myo1d, found to be left-sided, was shown to regulate gut looping in mice, zebrafish, and human. Together these findings indicate metabolic regulation of left-right patterning. This could underlie high incidence of heterotaxy-related birth defects in maternal diabetes, and the association of PFKP, allosteric enzyme regulating glycolysis, with heterotaxy. This transcriptome dataset will be invaluable for interrogating birth defects involving laterality disturbance.

developmental biology↗

bioRxiv2022

Hamsters are a model for COVID-19 alveolar regeneration mechanisms: an opportunity to understand post-acute sequelae of SARS-CoV-2

A relevant number of coronavirus disease 2019 (COVID-19) survivors suffers from post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (PASC). Current evidence suggests a dysregulated alveolar regeneration in COVID-19 as a possible explanation for respiratory PASC symptoms, a phenomenon which deserves further investigation in a suitable animal model. This study investigates morphological, phenotypical and transcriptomic features of alveolar regeneration in SARS-CoV-2 infected Syrian golden hamsters. We demonstrate that CK8+ alveolar differentiation intermediate (ADI) cells occur following SARS-CoV-2-induced diffuse alveolar damage. A subset of ADI cells shows nuclear accumulation of TP53 at 6- and 14-days post infection (dpi), indicating a prolonged arrest in the ADI state. Transcriptome data show the expression of gene signatures driving ADI cell senescence, epithelial-mesenchymal transition, and angiogenesis. Moreover, we show that multipotent CK14+ airway basal cell progenitors migrate out of terminal bronchioles, aiding alveolar regeneration. At 14 dpi, presence of ADI cells, peribronchiolar proliferates, M2-type macrophages, and sub-pleural fibrosis is observed, indicating incomplete alveolar restoration. The results demonstrate that the hamster model reliably phenocopies indicators of a dysregulated alveolar regeneration of COVID-19 patients. The results provide important information on a translational COVID-19 model, which is crucial for its application in future research addressing pathomechanisms of PASC and in testing of prophylactic and therapeutic approaches for this syndrome.

pathology↗

bioRxiv2018

Alternative interaction sites in the influenza A virus nucleoprotein mediate viral escape from the importin-α7 mediated nuclear import pathway

Influenza A viruses are able to adapt to restrictive conditions due to their high mutation rates. Here, we addressed the question by which mechanisms influenza A viruses may escape restriction by the cellular importin-7 protein, a component of the nuclear import machinery required for avian-mammalian adaptation and replicative fitness in human cells. Therefore, we assessed viral evolution in mice lacking the importin-7 gene. Here, we show that particularly three mutations occur with high frequency in the viral NP protein (G102R, M105K and D375N) in a specific structural area upon in vivo adaptation. Moreover, our findings suggest that the adaptive NP mutations mediate viral escape from importin-7 requirement likely due to the utilization of alternative interaction sites in NP beyond the classical nuclear localization signal and importin- isoforms. However, viral escape from importin-7 is, at least in part, associated with reduced replicative fitness in human cells.

molecular biology↗

bioRxiv2018

Structures and functions linked to genome-wide adaptation of human influenza A viruses

Human influenza A viruses elicit short-term respiratory infections with considerable mortality and morbidity. While H3N2 viruses circulate since almost 50 years, the recent introduction of pH1N1 viruses presents an excellent opportunity for a comparative analysis of the genome-wide evolutionary forces acting on both subtypes. Here, we inferred patches of sites relevant for adaptation, i.e. being under positive selection, on eleven viral protein structures, from all available data since 1968 and correlated these with known functional properties. Overall, pH1N1 had more patches than H3N2 viruses, especially in the viral polymerase complex, while antigenic evolution is more apparent for H3N2 viruses. In both subtypes, NS1 had the highest patch and patch site frequency, indicating that NS1-mediated viral attenuation of host inflammatory responses is a continuously intensifying process, elevated even in the longtime-circulating subtype H3N2. We confirmed the resistance-causing effects of two pH1N1 changes against oseltamivir in NA activity assays, demonstrating the value of the resource for discovering functionally relevant changes. Our results represent an atlas of protein regions and sites with links to host adaptation, antiviral drug resistances and immune evasion for both subtypes for further study.

bioinformatics↗

bioRxiv2017

Sweep Dynamics (SD) plots: Computational identification of selective sweeps to monitor the adaptation of influenza A viruses

Monitoring changes in influenza A virus genomes is crucial to understand its rapid evolution and adaptation to changing conditions e.g. establishment within novel host species. Selective sweeps represent a rapid mode of adaptation and are typically observed in human influenza A viruses. We describe Sweep Dynamics (SD) plots, a computational method combining phylogenetic algorithms with statistical techniques to characterize the molecular adaptation of rapidly evolving viruses from longitudinal sequence data. To our knowledge, it is the first method that identifies selective sweeps, the time periods in which these occurred and associated changes providing a selective advantage to the virus. We studied the past genome-wide adaptation of the 2009 pandemic H1N1 influenza A (pH1N1) and seasonal H3N2 influenza A (sH3N2) viruses. The pH1N1 influenza virus showed simultaneous amino acid changes in various proteins, particularly in seasons of high pH1N1 activity. Partially, these changes resulted in functional alterations facilitating sustained human-to-human transmission. In the evolution of sH3N2 influenza viruses, we detected changes characterizing vaccine strains, which were occasionally revealed in selective sweeps one season prior to the WHO recommendation. Taken together, SD plots allow monitoring and characterizing the adaptive evolution of influenza A viruses by identifying selective sweeps and their associated signatures.

bioinformatics↗