Biology subjects

Cortina-Borja, M.

Publications and source records attributed to Cortina-Borja, M..

6 recordsLinked to original sources

bioRxiv2026

GPNMB and glycosphingolipid measurements in cerebrospinal fluid and plasma from Parkinson's disease patients in the BioFind cohort

BackgroundParkinsons disease (PD) is a prevalent neurodegenerative disorder characterized by progressive motor dysfunction and broad cellular impairment, including significant disruptions in lysosomal function, lipid metabolism, and intracellular trafficking. Glycosphingolipids (GSLs), critical for various cellular processes, depend on effective lysosomal degradation. Aberrant GSL metabolism has been linked to PD pathology, and glycoprotein non-metastatic melanoma protein B (GPNMB) has emerged as a biomarker associated with lysosomal dysfunction and lipid imbalance in PD ObjectivesTo assess the relationship between GPNMB and GSL levels in cerebrospinal fluid (CSF) and plasma from PD patients and controls within the BioFIND cohort. We also investigated potential sex differences and associations with PD-related biomarkers such as -synuclein MethodsGSL species and GPNMB protein levels were quantified using high-performance liquid chromatography (HPLC) and ELISA assays, respectively, in matched CSF and plasma samples from PD patients and controls ResultsLevels of the paraglobosides GSL species, alpha-2,3SpG and pGb were significantly elevated in the plasma of PD patients compared to healthy controls, while levels of the ganglioside GD1a and the lacto-series GSL, Leb combined (GD1a + Leb), were significantly reduced in PD. GPNMB levels positively correlated with several GSL species in both plasma and CSF. Plasma GSLs and GPNMB concentrations were significantly higher in females compared to males, independent of PD diagnosis. CSF GPNMB correlated positively with age and -synuclein concentrations InterpretationOur findings confirm that GSL metabolism is altered in PD. They also highlight significant sex-based biochemical variations in GSL and GPNMB levels, emphasizing the need for sex-specific analyses in PD biomarker research. The relationship between GSLs and GPNMB supports their potential as interconnected biomarkers of lipid pathology in PD.

neuroscience↗

bioRxiv2025

Spatial transcriptomic analysis of muscle biopsy from treatment-naive juvenile dermatomyositis patients reveals mitochondrial abnormalities despite disease-related interferon driven signature

ObjectivesThis study aimed to investigate the spatial transcriptomic landscape of muscle tissue from treatment-naive juvenile dermatomyositis (JDM) patients in comparison to healthy paediatric muscle tissue. MethodsMuscle biopsies from three JDM patients and three age-matched controls were analysed using the Nanostring GeoMx(R) Digital Spatial Profiler. Regions of interest were selected based on muscle fibres without immune cells, immune cell infiltration and CD68+ macrophage enrichment. Differential gene expression, pathway analysis and pathways clustering analysis were conducted. Key findings were validated in 19 cases of JDM using immunohistochemistry and chemical stains, and a bulk RNAseq dataset of four cases of JDM. ResultsJDM muscle tissues exhibited significant interferon pathway activation and mitochondrial dysfunction compared to controls. A 15-gene interferon signature was significantly elevated in JDM muscle and macrophage-enriched regions, correlating with clinical weakness. In contrast, mitochondrial dysregulation, characterized by downregulated respiratory chain pathways, was present regardless of interferon activity or muscle strength. The interferon-driven and mitochondrial signatures were replicated in an independent RNAseq dataset from JDM muscle; lack of association between interferon signature and mitochondrial dysregulation was validated in 19 cases by conventional staining methods. Clustering analysis revealed distinct transcriptomic profiles between JDM and control tissues, as well as between JDM patients with varying clinical phenotypes. ConclusionsThis study highlights mitochondrial dysfunction as a consistent pathological feature in JDM muscle, which may be independent of interferon-driven inflammation. These findings highlight the potential for mitochondrial-targeted therapies in JDM management and emphasise the need for further studies to explore their therapeutic value. KEY MESSAGESWhat is already known on this topic O_LIJuvenile dermatomyositis (JDM) involves interferon-driven inflammation and immune-mediated muscle damage. C_LIO_LIMitochondrial abnormalities in blood immune cells persist despite treatment and contribute to disease pathology. C_LI What this study adds O_LIMitochondrial dysfunction is present in both muscle fibres and tissue-infiltrating immune cells within JDM muscle. C_LIO_LIThese abnormalities are detectable even in clinically less severe muscle weakness. C_LIO_LIDegree of mitochondrial abnormality at transcript and protein level may be independent of strength of IFN-driven signal. C_LIO_LIMitochondrial dysregulation detected at transcriptional level correlates with abnormal transcription of muscle (sarcomere) and the subcellular peroxisome organelle. C_LI How this study might affect research, practice, or policy O_LITargeting mitochondrial dysfunction could enhance treatment outcomes for JDM, especially in patients whose disease is refractory to current therapies. C_LIO_LIInsights from this study support the development of stratification tools to detect aspects of pathology which are not tightly correlated with IFN-driven pathology. C_LI

immunology↗

bioRxiv2025

Donor-derived airway ALI model for high-throughput screening of antiviral combinations with concurrent analysis of antiviral efficacy and epithelial toxicity using ciliR

Respiratory RNA viral infections significantly impact quality of life and productivity, both in terms of pandemics (e.g., SARS-CoV-2, influenza A viruses) and seasonal infections such as respiratory syncytial virus (RSV). Globally, RSV causes an estimated 33.8 million cases annually in children under five, leading to 2.8-4.3 million hospital admissions and up to 199,000 deaths. Human-relevant drug screening models are key to addressing the urgent need for effective antiviral treatments for RSV, particularly in vulnerable patient groups. Here, we present a donor-derived differentiated primary human nasal epithelial cell, 96-HTS Transwell air-liquid interface (ALI) model designed to investigate the effects of combination antiviral therapies on RSV infection in primary human ciliated airway epithelium. Additionally, we describe novel analytical tools using R (ciliR) to screen drug combinations by concurrently measuring efficacy and ciliary beat frequency as a sensitive marker of cell toxicity. Our results demonstrate that the smaller 96-HTS ALI cultures retain comparable epithelial composition and ciliary function to conventional ALI culture formats. These cultures are permissible to infection with an RSV-GFP reporter virus, enabling quantitative comparison and combination treatment across multiple epithelial cultures from the same donor. We anticipate that our disease-relevant system will serve as a foundation for larger-scale experiments aimed at optimizing combination therapy for RSV and other respiratory viruses.

microbiology↗

bioRxiv2023

ciliR: a new R package for determining ciliary beat frequency using fast-Fourier transformation.

Cilia are motile hair-like structures that play a vital role in our body. Accurate assessment of ciliary beat frequency is pivotal for investigating ciliary dynamics and diagnosing ciliopathies. This study aims to develop software for accurately measuring the beat frequency of cilia captured using high-speed video microscopy. To achieve this, we developed the ciliR package in R, which was validated against manual counting and three other automated methods of counting cilia beat frequency. The results showed that ciliR produced results that were comparable to manual counting. The accuracy of ciliR was defined by its ability to reduce noise, including only counting data in a biologically significant range (0-60 Hz). Our software is a valuable tool for researchers in the field of ciliobiology as it offers a reliable method for detailed ciliary function analysis, thereby contributing to the broader understanding of mechanisms underlying ciliary-related disease. We encourage researchers to try this package and feed-back their findings to the authors. Instructions for use and processes for providing feedback are provided in supplementary material. SummaryciliR is a novel R package designed for analysing ciliary beat frequency (CBF) via ImageJ and RStudio. The advantage of the ciliR system, lies in its integration with the R environment, increasing processing speed and access to data visualization tools and analysis pipelines available in other R packages. The open-source platform invites community feedback to refine functionality, aiming to advance ciliopathy research with an accessible, comprehensive toolkit.

cell biology↗

bioRxiv2021

Spatial and temporal analysis of neutrophil trans-epithelial migration in response to RSV infection

The recruitment of neutrophils to the infected airway occurs early following respiratory syncytial virus (RSV) infection and high numbers of activated neutrophils in airway and blood is associated with the development of severe disease. Here, we investigated whether trans-epithelial migration across primary human airway epithelial cells (AECs) is sufficient and necessary for neutrophil activation during RSV infection. Using flow cytometry, we identified three populations of neutrophils in our in vitro model; those in suspension in basolateral and apical compartments and those that migrated and adhered to AECs. After 1h incubation, the number of adherent neutrophils was significantly greater following RSV infection compared to mock infected. We found that, when migration occurred, neutrophil expression of CD11b, CD62L, CD64, NE and MPO increased in all compartments. However, this did not occur when neutrophils were prevented from migrating. This suggests that the heightened neutrophil activation we detected in the basolateral compartment may be due to reverse migrating neutrophils, as has been suggested by clinical observations. Using live-cell fluorescent microscopy, we then profiled the early temporal and spatial movement and adherence of human neutrophils during migration. Our findings suggest three main phases of early neutrophil recruitment and behaviour in the airways during RSV infection, with neutrophil recruitment, activation and adherence to RSV infected AECs, with clustering, occurring within the first 20 minutes. This work and the model we developed could provide new insight into how neutrophil activation and a dysregulated neutrophil response to RSV mediates disease severity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/463016v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@16639c5org.highwire.dtl.DTLVardef@5aeeacorg.highwire.dtl.DTLVardef@1eb96ceorg.highwire.dtl.DTLVardef@1f9b899_HPS_FORMAT_FIGEXP M_FIG Building on previous work of neutrophil function we propose 3 main phases of early neutrophil recruitment and behaviour in the airways during RSV infection. Phase 1. Initial chemotaxis and adherence: Here unstimulated circulating neutrophils expressing baseline levels of CD11b migrate across infected AECs in response to chemotactic signals in the apical supernatant. Some neutrophils remain adherent to the infected AECs. Phase 2: Activation and reverse migration: once on the apical side of the epithelium, neutrophils increase expression of CD11b and other activation associated markers, and some activated neutrophils undergo reverse migration. Neutrophils with greater expression of CD11b are detected on the basolateral side Phase 3: Amplified chemotaxis and clustering: after 20 minutes, adherent neutrophils begin to rapidly cluster on RSV infected primary airway epithelial cells cultures, mediated by signalling from a dying neutrophil. Drawing created using BioRender.com. C_FIG

immunology↗

bioRxiv2020

Acetyl-Leucine slows disease progression in lysosomal storage disorders

Acetyl-DL-leucine (ADLL) is a derivative of the branched chain amino acid leucine. In observational clinical studies ADLL improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder (LSD), Niemann-Pick disease type C 1 (NPC1). Here, we investigated ADLL and its enantiomers acetyl-L-leucine (ALL) and acetyl-D-leucine (ADL) in symptomatic Npc1-/- mice and observed an improvement in ataxia with both enantiomers and ADLL. When ADLL and ALL were administered pre-symptomatically to Npc1-/- mice, both treatments delayed disease progression and extended life span, whereas ADL did not. These data are consistent with ALL being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were found to be implicated as one of the potential mechanisms of action of the L enantiomer in Npc1-/- mice. When miglustat and ADLL were used in combination significant synergy resulted. In agreement with these pre-clinical data, when NPC1 patients were evaluated after 12 months of ADLL treatment, rates of disease progression were slowed, with stabilisation or improvement in multiple neurological domains. A beneficial effect of ADLL on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-L-leucine and underlying mechanisms of action in LSDs, supporting its further evaluation in clinical trials in lysosomal disorders.

neuroscience↗