Biology subjects

Belz, G.

Publications and source records attributed to Belz, G..

6 recordsLinked to original sources

bioRxiv2026

bgnorm: A Generative Statistical Framework for Background Correction, Normalisation, and Quality Control in Multiplex Spatial Proteomics

Multiplex spatial proteomics enables highly multiplexed in situ profiling but remains limited by technical variation arising from autofluorescence, non-specific antibody binding, instrument noise, and staining variability, affecting downstream biological tasks like cell typing. We present bgnorm, a statistical framework that describes fluorescence measurements using a generative mixture model of background, non-specific binding, and biological signal components. As natural statistical consequences, the model yielded three new methods: a background-correction method through probabilistic deconvolution of protein intensities, quality control metrics, and a quantile normalisation approach to unify measurements across markers, samples, and sequential slices. Across multiple multiplex imaging technologies, bgnorm improves signal separation and downstream marker positivity classification compared with existing preprocessing approaches. In expert-annotated datasets comprising over 406,000 marker positivity annotations, bgnorm achieved the highest classification performance and enabled accurate use of a single global positivity threshold across markers and samples. The method is implemented in the bgnormR and bgnormpy packages.

bioinformatics↗

bioRxiv2025

SM3DD with Segmented PCA: A Comprehensive Method for Interpreting 3D Spatial Transcriptomics

We developed Standardised Minimum 3D Distance (SM3DD), an entirely cell segmentation/annotation-free approach to the analysis of spatial RNA datasets, using it to compare lung tissue from 16 clinically normal individuals to those of 18 SARS-CoV-2 patients who died from acute respiratory distress syndrome. RNA spatial coordinates were determined using the CosMx Spatial Molecular Imager (Bruker Spatial Biology, US). For each individual transcript location, we calculated the three-dimensional distances to the nearest transcript of each transcript type, standardising the distances to each transcript type. Mean SM3DDs were compared between normal and SARS-CoV-2 patients. Notably, hierarchical clustering of the directional log10(P) values organized genes by functionality, making it easier to interpret biological contexts and for FKBP11, where a decrease in distance to MZT2A was the most significant difference, suggesting a role in interferon signaling. Using a segmented principal components analysis of the entire SM3DD dataset, we identified multiple pathways, including SARS-CoV-2 infection, even though the assay did not include any SARS-CoV-2 transcripts.

bioinformatics↗

bioRxiv2023

Fecal microbial transfer and complex carbohydrates mediate protection against COPD

ObjectiveChronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear. DesignUsing an in vivo mouse model of cigarette smoke-induced COPD and fecal microbial transfer (FMT), we characterized the fecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology, and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in sixteen COPD patients using a randomized, double-blind, placebo-controlled pilot study of inulin supplementation. ResultsFMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in cigarette smoke-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes. ConclusionThe gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically. What is already known on this topicO_LIChanges in gut microbiota are associated with COPD but the underlying host and microbial mechanisms are unclear, limiting the therapeutic applications. C_LI What this study addsO_LIMicrobiome composition and metabolism is reproducibly correlated with lung and gastrointestinal pathology in experimental COPD. C_LIO_LIMicrobiome modifying interventions effectively alleviate disease, including protective effects supplementing smoking cessation. C_LIO_LINutritional interventions targeting the microbiome in COPD patients demonstrate efficacy in a small pilot study. C_LI How this study might affect research, practice or policyO_LIMicrobiome-targeting therapeutics and nutritional interventions may be developed for COPD, including as supplements to smoking cessation. C_LI

physiology↗

bioRxiv2023

A robust Platform for Integrative Spatial Multi-omics Analysis to Map Immune Responses to SARS-CoV-2 infection in Lung Tissues

The SARS-CoV-2 (COVID-19) virus has caused a devastating global pandemic of respiratory illness. To understand viral pathogenesis, methods are available for studying dissociated cells in blood, nasal samples, bronchoalveolar lavage fluid, and similar, but a robust platform for deep tissue characterisation of molecular and cellular responses to virus infection in the lungs is still lacking. We developed an innovative spatial multi-omics platform to investigate COVID-19-infected lung tissues. Five tissue-profiling technologies were combined by a novel computational mapping methodology to comprehensively characterise and compare the transcriptome and targeted proteome of virus infected and uninfected tissues. By integrating spatial transcriptomics data (Visium, GeoMx and RNAScope) and proteomics data (CODEX and PhenoImager HT) at different cellular resolutions across lung tissues, we found strong evidence for macrophage infiltration and defined the broader microenvironment surrounding these cells. By comparing infected and uninfected samples, we found an increase in cytokine signalling and interferon responses at different sites in the lung and showed spatial heterogeneity in the expression level of these pathways. These data demonstrate that integrative spatial multi-omics platforms can be broadly applied to gain a deeper understanding of viral effects on cellular environments at the site of infection and to increase our understanding of the impact of SARS-CoV-2 on the lungs.

bioinformatics↗

bioRxiv2023

Whole transcriptome profiling of placental pathobiology in SARS-CoV-2 pregnancies identifies a preeclampsia-like gene signature

ObjectivesSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus infection in pregnancy is associated with higher incidence of placental dysfunction, referred to by a few studies as a "preeclampsia-like syndrome". However, the mechanisms underpinning SARS-CoV-2-induced placental malfunction are still unclear. Here, we investigated whether the transcriptional architecture of the placenta is altered in response to SARS-CoV-2 infection. MethodsWe utilized whole-transcriptome, digital spatial profiling, to examine gene expression patterns in placental tissues from participants who contracted SARS-CoV-2 in the third trimester of their pregnancy (n=7) and those collected prior to the start of the coronavirus disease 2019 (COVID-19) pandemic (n=9). ResultsThrough comprehensive spatial transcriptomic analyses of the trophoblast and villous core stromal cell subpopulations in the placenta, we identified signatures associated with hypoxia and placental dysfunction during SARS-CoV-2 infection in pregnancy. Notably, genes associated with vasodilation (NOS3), oxidative stress (GDF15, CRH), and preeclampsia (FLT1, EGFR, KISS1, PAPPA2), were enriched with SARS-CoV-2. Pathways related to increased nutrient uptake, vascular tension, hypertension, and inflammation, were also enriched in SARS-CoV-2 samples compared to uninfected controls. ConclusionsOur findings demonstrate the utility of spatially resolved transcriptomic analysis in defining the underlying pathogenic mechanisms of SARS-CoV-2 in pregnancy, particularly its role in placental dysfunction. Furthermore, this study highlights the significance of digital spatial profiling in mapping the intricate crosstalk between trophoblasts and villous core stromal cells, thus shedding light on pathways associated with placental dysfunction in pregnancies with SARS-CoV-2 infection. Graphical abstractIn this study, using spatial digital profiling transcriptomic approaches, we demonstrate that SARS-CoV-2 infection in pregnancy disrupts optimal placental function by altering the genomic architecture of trophoblasts and villous core stromal cells.

developmental biology↗

bioRxiv2019

Vasoactive intestinal peptide confers anticipatory mucosal immunity by regulating ILC3 activity

ILC3-mediated IL-22 cytokine production is critical for the maintenance of immune homeostasis in the gastrointestinal tract. Here, we show that group 3 ILC (ILC3) constitutive function is not constant across the day but instead oscilliates between active and resting phases. Coordinate responsiveness of ILC3 in the intestine depended on food-induced expression of the neuronal hormone vasoactive intestinal peptide (VIP). Intestinal ILC3 expressed high levels of the G protein-coupled receptor, VIPR2, and activation via enteric neuronal VIP markedly enhanced IL-22 production and conferred gut protection. Conversely, deficiency of VIPR2 signalling led to impaired production of IL-22 by ILC3 and increased susceptibility to inflammatory gut disease. As such, intrinsic cellular rhythms synergise with the cyclic patterns of food intake to drive IL-22 thereby syncronizing intestinal epithelial protection via the ILC3 VIP-VIPR2 pathway.

immunology↗