Biology subjects

Pajkrt, D.

Publications and source records attributed to Pajkrt, D..

4 recordsLinked to original sources

bioRxiv2024

Parechovirus-3 infection disrupts immunometabolism and leads to glutamate excitotoxicity in neural organoids

Parechovirus ahumpari 3 (HPeV-3), is among the main agents causing severe neonatal neurological infections such as encephalitis and meningitis. However, the underlying molecular mechanisms and changes to the host cellular landscape leading to neurological disease has been understudied. Through quantitative proteomic analysis of HPeV-3 infected neural organoids, we identified unique metabolic changes following HPeV-3 infection that indicate immunometabolic dysregulation. Protein and pathway analyses showed significant alterations in neurotransmission and potentially, neuronal excitotoxicity. Elevated levels of extracellular glutamate, lactate dehydrogenase (LDH), and neurofilament light (NfL) confirmed glutamate excitotoxicity to be a key mechanism contributing to neuronal toxicity in HPeV-3 infection and can lead to apoptosis induced by caspase signaling. These insights are pivotal in delineating the metabolic landscape following severe HPeV-3 CNS infection and may identify potential host targets for therapeutic interventions.

neuroscience↗

bioRxiv2024

A Human Biomimetic Intestinal Mucosa Model to Study Gastrointestinal Development and Disease

The intestinal mucosa plays a vital role in nutrient absorption, drug metabolism, and pathogen defence. Advances in single-cell technologies have highlighted the specialised roles of various cell types that execute these diverse functions. Aside from intestinal epithelial cells, fibroblasts play an essential role in regulating the extracellular matrix and controlling pro- inflammatory signalling, and antigen-presenting cells (macrophages and dendritic cells) maintain intestinal homeostasis and immune responses. The incorporation of such cellular complexity within the existing in vitro models of the human intestine is currently challenging. To address this, we developed a human intestinal model that accurately mimics the mucosal cellular environment comprising intestinal epithelial cells, intestinal fibroblasts, and antigen presenting cells. This model includes co-cultures of adult and foetal cells, facilitating studies on barrier function, inflammation, and viral infections. It replicates extracellular matrix deposition, Paneth cell differentiation, immune interactions, and can be used to model host- pathogen interactions. Our advanced co-culture model improves the physiological relevance of in vitro studies, enabling the exploration of epithelial-mesenchymal-immune crosstalk and its role in intestinal health and disease.

cell biology↗

bioRxiv2023

Assessment of The Broad-Spectrum Host Targeting Antiviral Efficacy of Halofuginone Hydrobromide in Human Airway, Intestinal and Brain Organoid Models.

Halofuginone hydrobromide has shown potent antiviral efficacy against a variety of viruses such as SARS-CoV-2, dengue, or chikungunya virus, and has, therefore, been hypothesized to have broad-spectrum antiviral activity. In this paper, we tested this broad-spectrum antiviral activity of Halofuginone hydrobomide against viruses from different families (Picornaviridae, Herpesviridae, Orthomyxoviridae, Coronaviridae, and Flaviviridae). To this end, we used relevant human models of the airway and intestinal epithelium and regionalised neural organoids. Halofuginone hydrobomide showed antiviral activity against SARS-CoV-2 in the airway epithelium with no toxicity at equivalent concentrations used in human clinical trials but not against any of the other tested viruses. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/565121v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@10d562eorg.highwire.dtl.DTLVardef@94f903org.highwire.dtl.DTLVardef@683b6forg.highwire.dtl.DTLVardef@11620ba_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIHalofuginone hydrobromide was identified as a possible broad-spectrum host targeting antiviral drug. C_LIO_LIHuman organoid models offer a physiologically relevant and clinically translatable model for antiviral research. C_LIO_LIHalofuginone hydrobromide shows antiviral efficacy against SARS-CoV-2, but not against EV-A71, PeV-A1, IAV, RV-A16, HCMV or ZIKV in relevant organoid models. C_LIO_LIThe efficacy of Halofuginone hydrobromide is concentration dependent as well as on proline content of the host receptor(s) or host factors for the specific virus in question. C_LI

microbiology↗

bioRxiv2019

ExploreASL: an image processing pipeline for multi-center ASL perfusion MRI studies

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. The toolbox adheres to previously defined international standards for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts to increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

neuroscience↗