Biology subjects

Fuchs, A.

Publications and source records attributed to Fuchs, A..

At least 19 recordsLinked to original sources

bioRxiv2026

A moonlighting serpin of Tannerella forsythia compromises the bactericidal activity of neutrophils

Serine protease inhibitors (serpins) are extremely rare in prokaryotes, and their role in immune evasion remains unclear. We identified a bifunctional TLR2-binding serpin (miropin) produced by Tannerella forsythia that broadly suppresses neutrophil antimicrobial capacity. Miropin binding to TLR2 primed neutrophils, enhancing phagocytic capacity yet, counterintuitively, promoting bacterial persistence. Mechanistically, like other serpins, miropin acted as an irreversible suicide inhibitor of neutrophil serine proteases (NSPs), blocking their activity upon granule mobilization and NETosis. Unexpectedly, miropin, independent of its protease-inhibitory activity, bound and inhibited myeloperoxidase (MPO), thereby blocking the oxidative burst. This simultaneous suppression of oxidative and non-oxidative bactericidal mechanisms promoted bacterial survival in vivo without significantly altering the tissue inflammatory response. Thus, we identified novel moonlighting roles (TLR2 signaling and MPO inhibition) for an unorthodox prokaryotic serpin and provided context for how T. forsythia and other oral pathogens survive within the subgingival niche, an environment highly enriched in activated neutrophils.

immunology↗

bioRxiv2026

Postnatal Autonomic Development Predicts Adolescent Psychosocial Outcome

BackgroundThe maturation of the autonomic nervous system (ANS) has been suggested to play a crucial role in the development of emotion regulation and later psychosocial functioning. However, longitudinal evidence linking early autonomic development to long-term outcomes remains limited. This longitudinal study investigated the interplay between birth-related factors, early autonomic activity, and psychosocial outcomes across development. MethodsThe sample comprised 101 participants followed from two weeks to 14 years of age, with heart rate (HR) and vagally ediated heart rate variability (vmHRV) assessed at 2 weeks, 6 weeks, 3 months, 14 months, and 14 years. Linear models were used to examine associations between birth-related factors and early HR and vmHRV, as well as whether HR and vmHRV trajectories during the first 14 months predicted psychosocial outcomes at 5 and 14 years. ResultsMultiple birth-related factors significantly predicted HR and vmHRV at two weeks after birth. Moreover, flatter age-related increases in vmHRV and weaker decreases in HR during infancy predicted higher maternally reported psychosocial difficulties at 14 years in males only, with no such effects at 5 years or in females. ConclusionsThese findings underscore the importance of early autonomic maturation in shaping later psychosocial functioning, with effects on adolescent outcomes observed in males only. Early ANS trajectories may represent meaningful predictors of neurodevelopmental outcomes, highlighting their potential relevance for early identification of later psychosocial risk in a sex-specific manner.

physiology↗

bioRxiv2025

Innocent until proven guilty: Tannerella forsythia may attenuate the virulence of Porphyromonas gingivalis

Periodontitis is caused by a dysbiotic microbiome beneath the gum line, primarily driven by the major pathobionts Porphyromonas gingivalis (Pg) and Tannerella forsythia (Tf). Their virulence depends on the excessive, uncontrolled activity of secreted proteases that sustain chronic inflammation, leading to the destruction of tissues supporting the tooth. Paradoxically, Tf also encodes multiple protease inhibitors, including miropin, a serpin with a broad range of targets. Here, we demonstrate that both native and recombinant miropin effectively inhibit lysine-specific gingipain (Kgp) and thiol protease (Tpr), impairing the growth of Pg in peptide-limited media and reducing its virulence in vivo. A rationally designed variant, RVK-miropin, also inhibited both lysine-specific and arginine-specific gingipains, fully suppressing Pg proliferation and virulence in a mouse infection model. Miropin is abundant on the surface of Tf and forms covalent inhibitory complexes with Pg proteases. In an oral gavage model of periodontitis, coinfection with wild-type Tf (but not a miropin-deficient mutant) and Pg significantly reduced alveolar bone loss caused by Pg alone. Miropin thus counteracts Pg virulence factors and host inflammatory responses, revealing an unexpected protective role for Tf. This challenges the traditional view of Tf as a primary periodontal pathogen, suggesting a context-dependent role as a microbial modulator within the dysbiotic biofilm. Beyond periodontal disease, the unique ability of miropin to inhibit structurally diverse proteases makes it a promising candidate for the development of new therapies that restore proteolytic balance in the periodontium.

microbiology↗

bioRxiv2025

The cortical scene processing network emerges in infancy, prior to independent navigation experience

Sighted people rely on vision to recognize and navigate the local environment. By adulthood, human cortex contains at least three regions that respond selectively to visual scene information, but it remains unknown when or how these regions develop. One hypothesis is that scene selectivity emerges gradually in regions that initially prefer certain low-level visual features (e.g., peripheral visual input, high spatial frequencies, rectilinearity), and then exposure to the visual statistics of natural scenes drives the emergence of scene selective responses. However, both aspects of this hypothesis remain to be tested: how early scene selectivity first arises in human development, and whether it is driven by passive exposure to visual statistics. We therefore collected functional magnetic resonance imaging data from awake 2-9-month-old infants while they watched videos of real-world scenes with ego-motion, as well as faces, objects, and scrambled videos. We found stronger responses to scenes than control conditions in the location of all three scene regions. Scene-selective responses could not be explained by low-level visual properties of the stimuli, and were found in infants as young as 2-5 months old, with no evidence of age-related change. We also measured infants experience independently navigating (e.g., crawling), which was not necessary for the development of scene-selectivity. In sum, cortical regions are scene-selective in human infants prior to independent navigation, and after only limited exposure to visual scene statistics. Significance statementDespite extensive work on the functional organization of scene processing in the human adult visual cortex, little is known about the developmental origins of category selectivity for visual scenes. Here we used fMRI in awake human infants to discover that all three regions of the known visual scene processing system are present within the first few months of life - the youngest age yet detected. Scene-selective cortex therefore develops after only a few months of limited visual exposure, and prior to active experience using visual scene information to plan and guide independent navigation (e.g., by crawling). These findings provide a fundamental constraint on theories of how scene selectivity develops in high-level visual cortex.

neuroscience↗

bioRxiv2024

At-RS31 orchestrates hierarchical cross-regulation of splicing factors and integrates alternative splicing with TOR-ABA pathways

O_LIAlternative splicing is essential for plants, enabling a single gene to produce multiple transcript variants to boost functional diversity and fine-tune responses to environmental and developmental cues. At-RS31, a plant-specific splicing factor in the Serine/Arginine (SR)-rich protein family, responds to light and the Target of Rapamycin (TOR) signaling pathway, yet its downstream targets and regulatory impact remain unknown. C_LIO_LITo identify At-RS31 targets, we applied individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) and RNAcompete assays. Transcriptomic analyses of At-RS31 mutant and overexpressing plants further revealed its effects on alternative splicing. C_LIO_LIiCLIP identified 4,034 At-RS31 binding sites across 1,421 genes, enriched in CU-rich and CAGA RNA motifs. Comparative iCLIP and RNAcompete data indicate that the RS domain of At-RS31 may influence its binding specificity in planta, underscoring the value of combining in vivo and in vitro approaches. Transcriptomic analysis showed that At-RS31 modulates diverse splicing events, particularly intron retention and exitron splicing, and influences other splicing modulators, acting as a hierarchical regulator. C_LIO_LIBy regulating stress-response genes and genes in both TOR and abscisic acid (ABA) signaling pathways, At-RS31 may help integrate these signals, balancing plant growth with environmental adaptability through alternative splicing. C_LI

plant biology↗

bioRxiv2024

Mesenchymal-epithelial transition reduces proliferation but increases immune evasion in tumor spheroids

Mesenchymal-epithelial transition (MET) has been associated with secondary tumor outgrowth during metastasis but the underlying mechanism remains elusive. Using MET-inducible mesenchymal breast cancer cells, we investigated whether MET benefits tumor outgrowth by enhancing proliferation. We found that crowding inhibition of proliferation is present before and after MET, but mesenchymal cells gain a proliferative advantage through more effective escape from crowded cell islands. In 3D culture, proliferation is reduced upon MET with differential effects of focal-adhesion-signalling and actomyosin activity. In particular, inhibition of Src-signalling leads to increased growth after MET. Finally, in co-culture experiments, MET-induced tumor spheroids evade immune cell attack to a larger extent, likely due to more confined epithelial spheroid shape and changes in immunomodulatory molecules. Our data suggest that, contrary to previous assumptions in the field, MET might promote secondary tumor outgrowth not through a proliferation boost but through increased survival rate in the presence of immune cells.

cell biology↗

bioRxiv2024

E cadherin appears to be an essential on/off switch for initiating bile canaliculi formation

The mechanisms underlying cell polarization are fundamental in biology, yet they are not fully understood. This is particularly true for hepatocytes, which exhibit a complex polarization, enabling the formation of the bile canaliculi (BCs) network that is essential for liver excretion functions. To identify key proteins involved in hepatocyte polarization and BC formation, we performed a proteomic approach to compare the human hepatocyte cell line HepG2 to its sub clone HepG2/C3A which shows much greater efficiency in forming mature BCs. We localized LimA1 and Espin to the BC for the first time, suggesting their important role there, and confirmed the presence of NHE-RF1. Using a protein repression strategy directed against selected proteins, we highlighted the essential role of E cadherin in the initiation of BC formation. Our data showed, for the first time, that in absence of E cadherin, hepatocytes lose their ability to form BCs.

cell biology↗

bioRxiv2024

APCalign: an R package workflow and app for aligning and updating flora names to the Australian Plant Census

Here we present "APCalign", an R package and accompanying browser-sourced application to align and update scientific names for Australian vascular plants to the most likely currently accepted name using the Australian Plant Census (APC) or a name in the Australian Plant Names Index (APNI). Scientific names are the label assigned to unique taxon concepts by the scientific community, but this common terminology is most useful if a taxon concept is consistently referred to by the same name. These links can be broken due to either spelling mistakes or taxonomic changes. Automated tools are required to resolve taxon lists, aligning and updating long lists of possibly erroneous scientific names to the most likely currently accepted names. It is essential that tools specific to the APC/APNI be developed, as these lists specify an endorsed national-level nomenclature used in government legislation and include the uniquely Australian concept of phrase names, absent in global taxonomic datasets. To align input names to names within the APC or APNI, "APCalign" works progressively through a sequence of checks that combine different permutations of the input name, exact versus fuzzy matches, matches that consider the entire name input versus a subset of words, and character strings that indicate a name can only be resolved to a genus or family. The aligned names are then, when possible, updated to a currently accepted taxon concept within the APC. This package should facilitate all research outputs that require diverse scientific name lists to be merged or outdated lists to be updated.

plant biology↗

bioRxiv2023

Self-organization of Long-lasting Human Endothelial Capillary Networks guided by DLP Bioprinting

Tissue engineering holds great promise for regenerative medicine, drug discovery and as an alternative to animal models. However, as soon as the dimensions of engineered tissue exceed the diffusion limit of oxygen and nutriments, a necrotic core forms leading to irreversible damage. To overcome this constraint, the establishment of a functional perfusion network is essential and is a major challenge to be met. In this work, we explore a promising Digital Light Processing (DLP) bioprinting approach to encapsulate endothelial progenitor cells (EPCs) in 3D photopolymerized hydrogel scaffolds to guide them towards vascular network formation. We observed that EPCs encapsulated in the appropriate photopolymerized hydrogel can proliferate and self-organize within a few days into branched tubular structures with predefined geometry, forming capillary-like vascular tubes or trees of various diameters (in the range of 10 to 100 m). Presenting a monolayer wall of endothelial cells strongly connected by tight junctions around a central lumen, these structures can be microinjected with fluorescent dye and are stable for several weeks in vitro. Interestingly, our technology has proven to be versatile in promoting the formation of vascular structures using a variety of vascular cell lines, including EPCs, human vascular endothelial cells (HUVECs) and human dermal lymphatic endothelial cells (HDLECs). We have also demonstrated that these vascular structures can be recovered and manipulated in an alginate patch without altering their shape or viability. This opens new opportunities for future applications, such as stacking these endothelial vascular structures with other cell sheets or multicellular constructs to yield bioengineered tissue with higher complexity and functionality.

bioengineering↗

bioRxiv2022

Never let me down: Optimizing performance of serum free culture medium for bovine satellite cells

Cultivated meat may be a more ethical, environmentally friendly, antibiotic-free meat alternative of the future. As of now, one of the main limiting factors for bringing cultivated meat to the market is the high cost of the cell culture media and their great dependency on serum albumins, production of which is predicted to become a major bottleneck of this industry. Here, using bovine muscle stem cells (BSC) we optimized B8/B9 medium - one of the well-established serum free, fully defined medium compositions available for purchase or for preparation in-house. We show several combinations of the growth factors/myokines/hormones, which were able to substantially increase BSCs proliferation rate, as well as treatment schemes allowing for five to ten times lower concentrations of signaling molecules for the same effect. Additionally, we identified several food grade, low-price medium stabilizers, exhibiting comparable or even superior stabilization of the B8 medium in short-term cultivations, as compared to recombinant human serum albumin (HSA). DoE aided in identifying the best cultivation conditions. Other satellite cells (porcine, chicken and fish) were grown in several final cell culture medium compositions, showing significant cell-line specific differences in performance. Also, the proliferation and yield of CHO cell line, which is relevant e.g. for the production of growth factors, was also successfully increased using our stabilization approach. We conclude that stabilizers tested here can act as versatile low-cost medium additives, partly by prolonging the half-life of growth factors. Thus, we provide an alternative to HSA, enabling up to an overall 73% reduction of medium price.

cell biology↗

bioRxiv2021

Construction of functional biliary epithelial branched networks with predefined geometry using digital light stereolithography

Cholangiocytes, biliary epithelial cells, are known to spontaneously self-organize into spherical cysts with a central lumen. In this work, we explore a promising biocompatible stereolithographic approach to encapsulate cholangiocytes into geometrically-controlled 3D hydrogel structures to guide them towards the formation of branched tubular networks. We demonstrate that within the appropriate mix of hydrogels, normal rat cholangiocytes can proliferate, migrate and organize into branched tubular structures, form walls consisting of a cell monolayer, transport fluorescent dyes into the luminal space and show markers of epithelial maturation such as primary cilia. The resulting structures have dimensions typically found in the intralobular and intrahepatic bile ducts and are stable for weeks, without any requirement of bulk supporting material, thereby offering total access to the basal side of these biliary epithelial constructs.

bioengineering↗

bioRxiv2021

Assessing genome-wide dynamic changes in enhancer activity during early mESC differentiation by FAIRE-STARR-seq

Embryonic stem cells (ESCs) can differentiate into any given cell type and therefore represent a versatile model to study the link between gene regulation and differentiation. To quantitatively assess the dynamics of enhancer activity during the early stages of murine ESC differentiation, we analyzed accessible genomic regions using STARR-seq, a massively parallel reporter assay. This resulted in a genome-wide quantitative map of active mESC enhancers, in pluripotency and during the early stages of differentiation. We find that only a minority of accessible regions is active and that such regions are enriched near promoters, characterized by specific chromatin marks, enriched for distinct sequence motifs, and modeling shows that active regions can be predicted from sequence alone. Regions that change their activity upon retinoic acid-induced differentiation are more prevalent at distal intergenic regions when compared to constitutively active enhancers. Further, analysis of differentially active enhancers verified the contribution of individual TF motifs toward activity and inducibility as well as their role in regulating endogenous genes. Notably, the activity of retinoic acid receptor alpha (RAR) occupied regions can either increase or decrease upon the addition of its ligand, retinoic acid, with the direction of the change correlating with spacing and orientation of the RAR consensus motif and the co-occurrence of additional sequence motifs. Together, our genome-wide enhancer activity map elucidates features associated with enhancer activity levels, identifies regulatory regions disregarded by computational prediction tools, and provides a resource for future studies into regulatory elements in mESCs.

genomics↗

bioRxiv2021

AusTraits: a curated plant trait database for the Australian flora

We introduce the AusTraits database - a compilation of measurements of plant traits for taxa in the Australian flora (hereafter AusTraits). AusTraits synthesises data on 375 traits across 29230 taxa from field campaigns, published literature, taxonomic monographs, and individual taxa descriptions. Traits vary in scope from physiological measures of performance (e.g. photosynthetic gas exchange, water-use efficiency) to morphological parameters (e.g. leaf area, seed mass, plant height) which link to aspects of ecological variation. AusTraits contains curated and harmonised individual-, species- and genus-level observations coupled to, where available, contextual information on site properties. This data descriptor provides information on version 2.1.0 of AusTraits which contains data for 937243 trait-by-taxa combinations. We envision AusTraits as an ongoing collaborative initiative for easily archiving and sharing trait data to increase our collective understanding of the Australian flora.

ecology↗

bioRxiv2020

Androgen and glucocorticoid receptor direct distinct transcriptional programs by receptor-specific and shared DNA binding sites

The glucocorticoid (GR) and androgen (AR) receptors execute unique functions in vivo, yet have nearly identical DNA binding specificities. To identify mechanisms that facilitate functional diversification among these transcription factor paralogs, we studied AR and GR in an equivalent cellular context. Analysis of chromatin and sequence features suggest that divergent binding, and corresponding gene regulation, are driven by different abilities of AR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the results of subtle differences in DNA binding preference between AR and GR. Furthermore, the sequence composition of large regions (>10 kb) surrounding selectively occupied binding sites differs significantly, indicating a role for the sequence environment in selectively guiding AR and GR to distinct binding sites. The comparison of binding sites that are shared between AR and GR shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, we find that shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications. Genomic deletion of shared binding sites demonstrates their contribution to directing receptor-specific gene regulation. Together, these data suggest that differences in genomic occupancy as well as divergence in the events that occur downstream of receptor binding direct functional diversification among transcription factor paralogs.

genomics↗

bioRxiv2020

Sponges as bioindicators for microparticulate pollutants

Amongst other threats, the worlds oceans are faced with man-made pollution, including an increasing number of microparticulate pollutants. Sponges, aquatic filter-feeding animals, are able to incorporate fine foreign particles, and thus may be a potential bioindicator for microparticulate pollutants. To address this question, 15 coral reef demosponges sampled around Bangka Island (North Sulawesi, Indonesia) were analyzed for the nature of their foreign particle content using traditional histological methods, advanced light microscopy, and Raman spectroscopy. Sampled sponges accumulated and embedded the very fine sediment fraction (< 200 {micro}m), absent in the surrounding sand, in the ectosome (outer epithelia) and spongin fibers (skeletal elements), which was confirmed by two-photon microscopy. A total of 34 different particle types were identified, of which degraded man-made products, i.e., polystyrene, cotton, titanium dioxide and blue-pigmented particles, were incorporated by eight specimens at concentrations between 91 to 612 particle/g dry sponge tissue. As sponges can weigh several hundreds of grams, we conservatively extrapolate that sponges can incorporate on average 10,000 microparticulate pollutants in their tissue. The uptake of particles, however, appears independent of the material, which suggests that the fluctuation in material ratios is due to the spatial variation of surrounding microparticles. Therefore, sponges have a strong potential to biomonitor microparticulate pollutants, such as microplastics and other degraded industrial products.

ecology↗

bioRxiv2019

Visualization of silver nanoparticle intracellular trafficking revealed nuclear translocation of silver ions leading to nuclear receptor impairment

The impact on human health of the increasing use of silver nanoparticles (AgNPs) in medical devices remains understudied, even though AgNP-containing dressings are known to release silver in the bloodstream leading to accumulation and slow clearance in the liver. Cellular studies have shown the intracellular dissolution of AgNPs within endo-lysosomes followed by Ag(I) binding to biomolecular thiolate-containing molecules. However, the precise subcellular distribution of Ag(I) and the nature of the disrupted physiological pathways remained unknown. Novel imaging approaches enabled us to visualize the trafficking of AgNP-containing lysosomes towards a perinuclear location and a direct nuclear transfer of Ag(I) species with accumulation in the nucleoli. These Ag(I) species impaired nuclear receptor activity, disrupting critical mechanisms of liver physiology in very low dose exposure scenarios, thus justifying further research into defining a framework for the safe use of AgNPs.

pharmacology and toxicology↗

bioRxiv2019

Nimodipine prevents the development of spasticity after spinal cord injury

Spasticity, one of the most frequent comorbidities of spinal cord injury (SCI), disrupts motor recovery and quality of life. Despite major progress in neurorehabilitative and pharmacological approaches, no curative treatment for spasticity exists. Here, we show in a mouse model of chronic SCI that treatment with nimodipine -- an FDA-approved L-type calcium channel blocker -- starting in the acute phase of SCI completely prevents the development of spasticity measured as increased muscle tone and spontaneous spasms. The aberrant muscle activities are permanently blocked even after termination of the treatment. Constitutive and conditional silencing in neuronal subtypes of CaV 1.3 channels shows that preventive effect of nimodipine on spasticity after SCI is mediated by the neuronal CaV 1.3 channels. This study identifies a potentially curative treatment protocol with a specific target for the prevention of spasticity after SCI.

pathology↗

bioRxiv2018

CRUP: A comprehensive framework to predict condition-specific regulatory units

We present the software CRUP (Condition-specific Regulatory Units Prediction) to infer from epigenetic marks a list of regulatory units consisting of dynamically changing enhancers with their target genes. The workflow consists of a novel pre-trained enhancer predictor that can be reliably applied across cell lines and species, solely based on histone modification ChIP-seq data. Enhancers are subsequently assigned to different conditions and correlated with gene expression to derive regulatory units. We thoroughly test and then apply CRUP to a rheumatoid arthritis model, identifying enhancer-gene pairs comprising known disease genes as well as new candidate genes.\n\nAvailabilityhttps://github.com/VerenaHeinrich/CRUP

bioinformatics↗