Biology subjects

Kuhn, S.

Publications and source records attributed to Kuhn, S..

At least 19 recordsLinked to original sources

bioRxiv2026

An integrative cardio-informatics approach identifies positionally conserved ancestors of human lncRNA genes transcribed across vertebrate hearts

The poor conservation of lncRNA genes limits their comprehensive functional studies, as genetic engineering of relevant animal models presupposes the presence of corresponding defined orthologs. This limitation is prominently evident in cardiovascular research, where heart-related lncRNAs are rarely conserved between humans and other vertebrates, despite the highly conserved nature of cardiac function. Because lncRNAs frequently regulate neighboring protein-coding genes essential for cardomyocyte function (herein termed cardiomyocyte indispensable, CMIs), we hypothesized that they are under evolutionary pressure to retain their genomic position and transcriptional activity, irrespective of sequence similarities to prototypical human lncRNA genes. By integrating mouse cardiac knockout phenotypes with human single-cell transcriptomics data, we systematically identified heart-expressed CMIs and their neighboring. lncRNA genes. Cross-species synteny analyses revealed regions flanking 109 CMIs with conserved relative positions and transcriptional orientations across vertebrate genomes. As most of these loci reside within poorly annotated non-coding regions, we developed VertLncRNAchecker, a neural network-based web interface, that predicts lncRNA-like genes within these regions, which we termed positional ancestors. Finally, we validated in situ that these positional ancestors express mature lncRNA transcripts in the hearts of mice, pigs, and frogs, mirroring the expression of their human lncRNA counterparts. We present an accurate and retrainable computational platform for cross-species lncRNA discovery that prioritizes conserved genomic position over sequence conservation or existing genome annotations. This pipeline revealed putative ancestors of human heart-related lncRNAs hidden within the vertebrate non-coding dark genome, providing novel insights into lncRNA biology and evolution.

evolutionary biology↗

bioRxiv2026

In situ vaccine effect of radiotherapy is associated with intratumoural ERV reactivation and RNA virus sensing

Radiotherapy (RT) transforms tumour tissues into in situ vaccines that trigger antitumor immunity. Immunogenicity depends on how RT is delivered, since heterogeneous RT (spatially fractionated RT, SFRT) elicits more prominent responses than the conventional homogenous one. However, this phenomenon cannot be clinically harnessed, unless the relevant pathways are identified. To gain insights, we developed a hybrid dry-lab/wet-lab approach that integrates systems-level immune phenotypes established by homogenous or heterogenous RT (SFRT) with the transcriptomic profiling of irradiated tumors. By further combining feature extraction with machine-learning, including multilayer perceptron modelling, we ranked predictors of immune infiltration and patient survivability for each RT type. We found that conventional RT induces coordinated upregulation of cytosolic sensors of RNA viruses (OASes and RIG I-like receptors) along with ERV RNAs predominately 400-800 base-pairs long, which might serve as their ligands. For schemes establishing abscopal effects, a coordinated upregulation of the OAS sensors and shared ERV transcripts was observed in both irradiated and distant tumours. Compared to homogenous RT, SFRT triggered earlier and stronger activation of OAS signaling along with NK cell responses. Overall, we show a co-involvement of tumour cell-intrinsic ERVs and their cytosolic RNA sensors in RT-induced antitumor immunity. This key finding could guide mechanistic studies and future precision oncology.

cancer biology↗

bioRxiv2026

A TCER-1-siRNA Regulatory Axis Suppresses Antibacterial Innate Immunity in C. elegans

Small interfering RNA (siRNA) are important regulators of gene expression with well-established roles in pathogen defense. Yet, their specific roles in antibacterial immunity are not well understood. Here, we identify an siRNA pathway involved in repressing antibacterial innate immunity in Caenorhabditis elegans. We show that genes required for the biogenesis or function of WAGO Argonaute-associated siRNAs, called 22G-RNAs, function in a common genetic pathway with the immune-suppressive transcription elongation and splicing factor TCER-1 to inhibit immunity. Loss of tcer-1 reduced levels of 22G-RNAs from a subset of WAGO targets, while mutations in several WAGO 22G-RNA pathway genes phenocopied the enhanced immunoresistance of tcer-1 mutants, suggesting a shared regulatory module. Integrative 22G-RNA-mRNA analyses and molecular genetic studied show that this module does not induce widespread gene silencing, but instead targets a restricted set of immune-relevant effectors, including scrm-4, encoding a phospholipid translocase that promotes host resistance. Together, our findings establish endogenous WAGO 22G-RNAs as repressors of antibacterial immunity and identify TCER-1 as a physiological regulator that promotes 22G-RNA biogenesis to constrain host defense. The results uncover a previously unrecognized small RNA-dependent mechanism linking transcription, metabolism, and antibacterial innate immunity.

immunology↗

bioRxiv2025

Glucocorticoids regulate the human non-coding genome

Glucocorticoids (GCs) are widely used anti-inflammatory and immunosuppressive agents known to induce dramatic changes in gene expression, yet their effects on non-coding RNAs such as long non-coding RNAs (lncRNAs) or microRNAs (miRNAs) remain poorly characterized. We present the first comprehensive and systematic analysis of GC regulation of the non-coding genome across nine human primary cell types from both hematopoietic and non-hematopoietic lineages. In vitro GC treatment was applied to each cell type, with transcriptomic profiling (total RNA-seq and small RNA-seq) at 2 and 6 hours post-treatment. We identified over 2,000 GC-responsive non-coding transcripts, including 654 annotated lncRNAs, 1,376 novel lncRNAs, and 39 miRNAs. The non-coding RNA response to GCs was highly cell type-dependent: 80% of GC-responsive lncRNAs and 97% of miRNAs were unique to a single cell type. Hematopoietic cells exhibited a greater magnitude of lncRNA induction than non-hematopoietic cells. Notably, dozens of facultative lncRNAs (undetectable at baseline) were induced de novo by GC. GC-responsive transcripts spanned diverse lncRNA classes, with enrichment of host lncRNAs. By contrast, only a limited number of miRNAs were GC-responsive. GC regulation of transcript abundance for miRNAs and their host lncRNAs appears to be independent. Our results, which are accessible through an interactive web application, establish a framework for studying how non-coding transcription contributes to physiological and clinical heterogeneity in GC responses. The newly identified GC-responsive non-coding transcripts could represent biomarkers of GC exposure, determinants of GC sensitivity or resistance, or candidate regulators of tissue-specific GC effects.

genomics↗

bioRxiv2025

The germline-restricted chromosome orchestrates germ cell development in passerine birds

While the definition of germ cell fate has been extensively studied in model organisms, evolutionary innovations and mechanistic novelties may remain hidden in understudied systems. The phenomenon of programmed DNA elimination allows germ cells to acquire germline-restricted genes, offering a novel paradigm of germ cell specificity. In passerine birds, the germline-restricted chromosome (GRC) is eliminated from somatic cells in early embryogenesis, yet the role and consequences of its maintenance in the germ cells remain poorly understood. Here, using the zebra finch Taeniopygia guttata as a model, we combined RNA-seq and Spatial Transcriptomics to construct a high-resolution spatiotemporal expression map to understand the role of the GRC across germ cell development. We found a GRC-linked integrin-BMP signaling in maturing oocytes and tfebGRC upregulation at blastoderm embryos, suggesting the involvement of the GRC in oocyte maturation and germ cell determination. We also identified developmental specialization of GRC-linked gene expression relative to their paralogs on the autosomes and sex chromosomes, revealing a gene repertoire which promotes germline stemness and germline/soma distinction. Together, the passerine GRC constitutes a unique system that manifests germ cell complexity, whilst allowing pinpointing the effects on gene expression that may elucidate vertebrate germ cell fate.

developmental biology↗

bioRxiv2025

Expression of human CEACAMs promotes inflammation and organ damage during systemic Candida albicans infection in mice

Invasive candidiasis is a fungal infection characterized by a high mortality rate. CEACAM family receptors play a crucial role in regulating innate responses of both leukocytes and epithelia. Human CEACAM3, CEACAM5 and CEACAM6 receptors recognize C. albicans and are expressed in transgenic CEABAC10 mice. In a murine C. albicans infection model, CEABAC10 mice exhibited a shortened survival period attributed to an early cytokine storm, an exacerbated acute phase response, and heightened systemic inflammation compared to their wild-type littermates. The livers and kidneys of CEABAC10 mice displayed intensified purulent necrotizing inflammation, accompanied by increased infiltration of neutrophils and macrophages. Our in vivo and in vitro data indicated that the expression of CEACAM6 on monocytes of CEABAC10 mice caused the elevated cytokine levels and the subsequent exacerbation of the acute phase response upon C. albicans infection, resulting in decreased survival.

immunology↗

bioRxiv2025

Vulnerability to memory decline in aging. A mega-analysis of structural brain change.

Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leveraged 13 longitudinal datasets, including 3,737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimers Disease. Both factors are associated with accelerated brain decline, yet it remains unclear whether memory loss is exacerbated beyond what atrophy alone would predict. Additionally, we assessed whether memory decline aligns with a global pattern of atrophy or stems from distinct regional contributions. Our mega-analysis revealed a nonlinear relationship between memory decline and brain atrophy, primarily affecting individuals with above-average brain structural decline. The associations were stronger in the hippocampus but also spread across diverse cortical and subcortical regions. The associations strengthened with age, reaching moderate associations in participants in their eighties. While APOE {varepsilon}4 carriers exhibited steeper brain and memory loss, genetic risk had no effect on the change-change associations. These findings support the presence of common biological macrostructural substrates underlying memory function in older age which are vulnerable to multiple age-related factors, even in the absence of overt pathological changes.

neuroscience↗

bioRxiv2025

The small molecule ML233 is a direct inhibitor of tyrosinase function

Melanogenesis is the biological process regulating the synthesis of melanin pigments in melanocytes. Defective melanogenesis is associated with numerous human skin diseases, including, but not limited to, albinism, vitiligo, melasma, and hypo- and hyperpigmentation disorders. Tyrosinase is the rate-limiting enzyme controlling melanogenesis, and hence tremendous efforts have been made to identify potent and safe inhibitors of tyrosinase function. However, despite decades of research, currently there is no effective treatment that inhibits melanogenesis or tyrosinase activity with no adverse side effects. In this study, we report characterization of the ML233 chemical as a potent inhibitor of tyrosinase activity in vivo and in vitro. We demonstrate that ML233 reduces melanin production in the zebrafish model with no observable significant toxic side effects, and in murine melanoma cells. We also predict that these effects are mediated through direct tyrosinase-ML233 interaction, i.e., binding of the ML233 molecule to the active site of the protein to inhibit its function. Together, our results reveal that ML233 plays roles in both healthy and pathological skin cells via inhibition of melanin production. ML233-mediated tyrosinase inhibition is a potentially safe and effective approach to alleviate the symptoms of melanocyte-associated diseases and thereby substantially improve human health.

pharmacology and toxicology↗

bioRxiv2025

Conspecific brood parasitism in the barn swallow (Hirundo rustica)

Conspecific brood parasitism (CBP) has been reported in many altricial avian species, yet its prevalence and underlying behavioural mechanisms remain poorly understood. We studied CBP in the barn swallow (Hirundo rustica), a species in which conspecific brood parasitism has been reported. We conducted parentage analysis on 1945 barn swallow broods involving 7816 offspring. Samples were collected over 12 breeding seasons at 5 colonies/populations. Contrary to expectations, we identified only six cases of CBP (0.3 % of broods). By identifying all individuals involved, i.e. the parasitic females, the female hosts and the males that fathered the parasitic eggs, we determined these cases of CBP resulted most likely from either a failed nest take-over (three times), the disappearance of a female partner or a disruption caused by researchers while only one case could be interpreted as a result of females mixed reproductive tactic. Based on a review of the literature on CBP in seven other Hirundinidae, we conclude that the only reliable evidence for CBP comes from cliff swallows (Petrochelidon pyrrhonata). Studies on other species either failed to identify the parasitic females or do not present sufficient evidence supporting the occurrence of CBP. Several studies relied on the appearance of two eggs in a nest within 24 hours to conclude that CBP occurred. However, based on the parentage analysis, we show that CBP only occurred in one out of 11 such cases in our barn swallow data. Our findings highlight that CBP is rare in our barn swallow populations, and have been likely overestimated in other studies. We emphasize the importance of frequent nest checks and rigorous genetic validation in CBP research. Overall, our results challenge existing assumptions about the prevalence of CBP and provide insights into the behavioural mechanisms that lead to CBP, with ecological and evolutionary implications.

ecology↗

bioRxiv2024

Reliability of structural brain change in cognitively healthy adult samples.

In neuroimaging research, tracking individuals over time is key to understanding the interplay between brain changes and genetic, environmental, or cognitive factors across the lifespan. Yet, the extent to which we can estimate the individual trajectories of brain change over time with precision remains uncertain. In this study, we estimated the reliability of structural brain change in cognitively healthy adults from multiple samples and assessed the influence of follow-up time and number of observations. Estimates of cross-sectional measurement error and brain change variance were obtained using the longitudinal FreeSurfer processing stream. Our findings showed, on average, modest longitudinal reliability with two years of follow-up. Increasing the follow-up time was associated with a substantial increase in longitudinal reliability while the impact of increasing the number of observations was comparatively minor. On average, 2-year follow-up studies require {approx}2.7 and {approx}4.0 times more individuals than designs with follow-ups of 4 and 6 years to achieve comparable statistical power. Subcortical volume exhibited higher longitudinal reliability compared to cortical area, thickness, and volume. The reliability estimates were comparable to those estimated from empirical data. The reliability estimates were affected by both the cohorts age where younger adults had lower reliability of change, and the preprocessing pipeline where the FreeSurfers longitudinal stream was notably superior than the cross-sectional. Suboptimal reliability inflated sample size requirements and compromised the ability to distinguish individual trajectories of brain aging. This study underscores the importance of long-term follow-ups and the need to consider reliability in longitudinal neuroimaging research.

neuroscience↗

bioRxiv2024

MATRIN3 deficiency triggers autoinflammation via cGAS-STING activation

Interferon-stimulated genes (ISGs) comprise a program of immune effectors important for host immune defense. When uncontrolled, ISGs play a central role in interferonopathies and other inflammatory diseases. The mechanisms responsible for turning on ISGs are not completely known. By investigating MATRIN3 (MATR3), a nuclear RNA-binding protein mutated in familial ALS, we found that perturbing MATR3 results in elevated expression of ISGs. Using an integrative approach, we elucidate a pathway that leads to activation of cGAS-STING. This outlines a plausible mechanism for pathogenesis in a subset of ALS, and suggests new diagnostic and therapeutic approaches for this fatal disease. One-Sentence SummaryMis-splicing of Tudor Domain Containing 3 (TDRD3) in the absence of MATR3 unleashes R-loops and interferon-stimulated genes.

molecular biology↗

bioRxiv2023

No evidence for a link between childhood (6-10y) cellular aging and brain morphology (12y) in a preregistered longitudinal study.

Animal studies show that early life environmental factors, such as stress and trauma, can have a significant impact on a variety of bodily processes, including cellular aging and brain development. However, whether cellular wear-and-tear effects are also associated with individual differences in brain structures in humans, remains unknown. In this pre-registered study in a community sample of children (N=94, Mean age=12.71 years), we prospectively investigated the predictive value of two markers of cellular aging in childhood (at age 6 and 10) for brain morphology in early adolescence (age 12). More specifically, we associated buccal cell telomere length and epigenetic age in childhood to individual differences in adolescent whole-brain grey matter volume (GMV) including volumes of three regions of interest that have been found to be sensitive to effects of early life stress (i.e. amygdala, hippocampus, (pre)frontal cortex -PFC). Multiple regression analyses revealed no significant associations between childhood cellular aging (at 6 and 10 years) and early adolescent brain morphology. Exploratory Bayesian analyses indicated moderate to strong evidence for the null-findings. These results suggest that although our sample is modest, the associations between middle childhood cellular aging and early adolescent brain morphology are, if they do exist, likely not particularly large in community children. Future work should investigate whether these effects are similarly absent in large samples, in samples with a higher risk profile and in samples characterized by different age ranges. Highlights (3-5)- Investigation of cellular aging in relation to brain morphology in a community sample (N=95) - Epigenetic aging and telomere shortening were not associated with brain structure - Exploratory Bayesian Analyses reveal moderate to strong evidence for null findings - No association was found between cellular aging and white matter volume

neuroscience↗

bioRxiv2023

Cell-free Chromatin Immunoprecipitation to detect molecular pathways in Physiological and Disease States

Patient monitoring is a cornerstone in clinical practice to define disease phenotypes and guide clinical management. Unfortunately, this is often reliant on invasive and/or less sensitive methods that do not provide deep phenotype assessments of disease state to guide treatment. This paper examined plasma cell-free DNA chromatin immunoprecipitation sequencing (cfChIP-seq) to define molecular gene sets in physiological and heart transplant patients taking immunosuppression medications. We show cfChIP-seq reliably detect gene signals that correlate with gene expression. In healthy controls and in heart transplant patients, cfChIP-seq reliably detected housekeeping genes. cfChIP-seq identified differential gene signals of the relevant immune and non-immune molecular pathways that were predominantly downregulated in immunosuppressed heart transplant patients compared to healthy controls. cfChIP-seq also identified tissue sources of cfDNA, detecting greater cell-free DNA from cardiac, hematopoietic, and other non-hematopoietic tissues such as the pulmonary, digestive, and neurological tissues in transplant patients than healthy controls. cfChIP-seq gene signals were reproducible between patient populations and blood collection methods. cfChIP-seq may therefore be a reliable approach to provide dynamic assessments of molecular pathways and tissue injury associated to disease.

genomics↗

bioRxiv2022

3'UTR-dependent dynamic changes in TP53 mRNA localization regulate p53 tumor suppressor activity

The tumor suppressor p53 triggers senescence in response to oncogenic stress in primary cells. However, the mechanisms by which tumor cells retaining p53 bypass senescence are not fully understood. Here we report that p53 cytostatic activity is inhibited in tumor cells by the 3 untranslated region (3UTR) of its mRNA, without altering p53 levels. 3UTR inhibition requires a long U-rich element (URE) and its binding protein, HuR. The 3UTR excluded TP53 mRNAs from a perinuclear compartment containing the CK2 kinase, suppressing p53 phosphorylation on an activating CK2 site, Ser392. In primary cells undergoing oncogene-induced senescence and tumor cells treated with genotoxic agents, TP53 mRNAs became concentrated in the perinuclear cytoplasm, coinciding with p53 phosphorylation and activation by CK2. In both cases, perinuclear re-localization of TP53 transcripts required AMPK2-dependent HuR nuclear translocation. ATM kinase activity was essential for DNA damage-induced spatial reprogramming of TP53 mRNAs, likely through phosphorylation and inactivation of MDM2. MDM2 was required for peripheral localization of TP53 transcripts and negatively regulated levels of the AMPK2 activating kinase, CaMKK{beta}. Our findings reveal a critical role for 3UTR sequences in suppressing p53 protein activity and provide a new mechanistic framework for p53 activation by DNA damaging agents.

cancer biology↗

bioRxiv2022

Brain aging differs with cognitive ability regardless of education

Higher general cognitive ability (GCA) is associated with lower risk of neurodegenerative disorders, but neural mechanisms are unknown. GCA could be associated with more cortical tissue, from young age, i.e. brain reserve, or less cortical atrophy in adulthood, i.e. brain maintenance. Controlling for education, we investigated the relative association of GCA with reserve and maintenance of cortical volume, -area and -thickness through the adult lifespan, using multiple longitudinal brain imaging cohorts (n = 3327, 7002 MRI scans, baseline age 20-88 years, followed-up up to 11 years). There were widespread positive relationships between GCA and cortical characteristics (level-level associations). In select regions, higher baseline GCA was associated with less atrophy over time (level-change associations). Relationships remained when controlling for polygenic scores for both GCA and education. Our findings suggest that higher GCA is associated with cortical volumes by both brain reserve and -maintenance mechanisms through the adult lifespan.

neuroscience↗

bioRxiv2022

Error quantification in multi-parameter mapping facilitates robust estimation and enhanced group level sensitivity

Multi-Parameter Mapping (MPM) is a comprehensive quantitative neuroimaging protocol that enables estimation of four physical parameters (longitudinal and effective transverse relaxation rates R1 and [Formula], proton density PD, and magnetization transfer saturation MTsat) that are sensitive to microstructural tissue properties such as iron and myelin content. Their capability to reveal microstructural brain differences, however, is tightly bound to controlling random noise and artefacts (e.g. caused by head motion) in the signal. Here, we introduced a method to estimate the local error of PD, R1 and MTsat maps that captures both noise and artefacts on a routine basis without requiring additional data. To investigate the methods sensitivity to random noise, we calculated the model-based signal-to-noise ratio (mSNR) and showed in measurements and simulations that it correlated linearly with an experimental raw-image-based SNR map. We found that the mSNR varied with MPM protocols, magnetic field strength (3T vs. 7T) and MPM parameters: it halved from PD to R1 and decreased from PD to MTsat by a factor of 3-4. Exploring the artefact-sensitivity of the error maps, we generated robust MPM parameters using two successive acquisitions of each contrast and the acquisition-specific errors to down-weight erroneous regions. The resulting robust MPM parameters showed reduced variability at the group level as compared to their single-repeat or averaged counterparts. The error and mSNR maps may better inform power-calculations by accounting for local data quality variations across measurements. Code to compute the mSNR maps and robustly combined MPM maps is available in the open-source hMRI toolbox.

neuroscience↗

bioRxiv2021

Age Differences in Diffusivity in the Locus Coeruleus and its Ascending Noradrenergic Tract

The noradrenergic locus coeruleus (LC) is a small brainstem nucleus that promotes arousal and attention. Recent studies have examined the microstructural properties of the LC using diffusion-weighted magnetic resonance imaging and found unexpected age-related differences in fractional anisotropy - a measure of white matter integrity. Here, we used three datasets (Berlin Aging Study-II, N = 301, the Leipzig Study for Mind-Body-Emotion Interactions, N = 220, and Stockholm Sleepy Brain, N = 49), to replicate published findings and expand them by investigating diffusivity in the LCs ascending noradrenergic bundle. In younger adults, LC fractional anisotropy was significantly lower, compared to older adults. However, in the LCs ascending noradrenergic bundle, we observed significantly higher fractional anisotropy in younger adults, relative to older adults. These findings indicate that diffusivity in the LC versus the ascending noradrenergic bundle are both susceptible to microstructural changes in aging that have opposing effects on fractional anisotropy. HighlightsO_LIFractional anisotropy in the locus coeruleus was lower in younger adults C_LIO_LIFractional anisotropy in the noradrenergic bundle was higher in younger adults C_LIO_LISleep deprivation may affect diffusivity in younger adults more than older adults C_LI

neuroscience↗

bioRxiv2021

Brain age relates to early life factors but not to accelerated brain aging

Brain age is a widely used index for quantifying individuals brain health as deviation from a normative brain aging trajectory. Higher than expected brain age is thought partially to reflect above-average rate of brain aging. We explicitly tested this assumption in two large datasets and found no association between cross-sectional brain age and steeper brain decline measured longitudinally. Rather, brain age in adulthood was associated with early-life influences indexed by birth weight and polygenic scores. The results call for nuanced interpretations of cross-sectional indices of the aging brain and question their validity as markers of ongoing within-person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging.

neuroscience↗