Biology subjects

Bluethgen, N.

Publications and source records attributed to Bluethgen, N..

13 recordsLinked to original sources

bioRxiv2025

Perturb-seq identifies TCF7 as a central nexus linking MAPK- and Wnt-driven gene expression

The MAPK pathway is a central signaling cascade whose dysregulation contributes to numerous diseases. While its upstream regulation is well studied, the mechanisms by which MAPK activation leads to diverse transcriptional outcomes remain incompletely understood. To address this shortcoming, we mapped the target gene sets controlled by 22 RAF-inducible transcription factors using targeted Perturb-seq and integrated these data with time-resolved transcriptional profiling. Network reconstruction revealed a topology dominated by two central hubs, EGR1 and FOS, which co-regulate partially overlapping target gene sets. In addition, we uncovered a positive feedback loop between EGR1, a canonical RAF-MAPK effector, and TCF7, a transcription factor typically linked to Wnt signaling. Through this interaction, TCF7 emerges as a nexus that integrates MAPK and Wnt pathway inputs. Together, these findings define the architecture of RAF-MAPK-driven transcriptional regulation and demonstrate how cross-talk between oncogenic signaling pathways can be encoded in transcriptional networks. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/694273v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@53d6d5org.highwire.dtl.DTLVardef@3d6b5borg.highwire.dtl.DTLVardef@5333e6org.highwire.dtl.DTLVardef@74519e_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2025

Acoustic indices predict recovery of tropical bird communities for taxonomic and functional composition

Quantifying the success of biodiversity restoration is a major challenge in the UN Decade on Ecosystem Restoration. We evaluated the potential of acoustic indices to predict the recovery success of bird communities within abandoned agricultural areas. Using audio recordings from a lowland tropical forest region, we identified 334 bird species and calculated established acoustic indices. Community composition was analyzed using Hill numbers, accounting for incomplete sampling. Acoustic indices effectively predicted independent species data (R2 = 0.59-0.76), capturing not only taxonomic but also functional and phylogenetic composition. Taxonomic composition was best predicted for common and dominant species, while functional and phylogenetic compositions were more accurately predicted for rare and common species. In addition, community composition was strongly influenced by the surrounding habitat. Our findings demonstrate that a small set of acoustic indices, once validated by stratified ground truth data, provides a powerful tool for assessing restoration success over large tropical areas, even for functional composition of rare tropical birds.

ecology↗

bioRxiv2025

Experimental reduction of land use increases invertebrate abundance but not diversity in grasslands

Grasslands are diverse ecosystems that are increasingly threatened by intensive land use. Restoring grasslands by reducing land-use intensity may support insect abundance and diversity, helping to halt insect declines. To test for the effect of reduced land use on invertebrates, we studied an experiment (established 2020) at 45 sites across three regions of Germany. We hypothesized that reduced land use increases invertebrate abundance and diversity, with larger effects in less intensively used grasslands. Using suction sampling, invertebrates were quantitatively sampled in May 2021 and May 2023, with 2021 samples identified by DNA meta-barcoding. Reducing land use to a single late mowing increased invertebrate abundance by 41% after one year and 99% after three years. However, species richness, Shannon diversity, and Simpson diversity did not differ between treatments and controls. Finding more individuals in grasslands with reduced land use suggests that species already present benefit, rather than additional species being recruited from the surrounding area. The effect of land-use reduction on abundance was consistently influenced by land use in the surrounding matrix, with larger positive effect sizes at grasslands with lower mowing frequency but higher fertilization. In spite of these local differences in the magnitude of restoration effects, the consistent increase in invertebrate abundance suggests that reducing land-use intensity can enhance invertebrate populations with potential benefits for ecosystem functions. It will be important to study how outcomes of land-use reduction develop over time, as land-use reduction is likely more successful when implemented permanently.

ecology↗

bioRxiv2025

Advancing the quantification of land-use intensity in forests: the ForMIX index combining tree species composition, tree removal, deadwood availability, and stand maturity

Many forests have a long history of human land use, which relates to species communities and ecosystem processes, making robust and quantitative measures of land-use intensity in forests desirable. We here introduce the ForMIX (Forest Management IndeX), a compound index combining altered tree species composition, tree removal, deadwood availability and stand maturity, which are each calculated as the deviation from expectations in a natural old-growth forest reference. By relating to resources and niches directly affected by forest land use, the compound index and its components allow for mechanistic inference on the consequences of land use in forests. Using basic forest inventory data from 150 sites distributed over three regions of Germany, we demonstrate the properties of ForMIX, which differentiates well among forest types and silvicultural systems and is robust to decisions regarding reference values and components. Reference values used in ForMIX are dynamic, may shift with ongoing climate change and may require refinement for different geographic regions. ForMIX advances the quantification of land-use intensity in forests by being biologically meaningful, being usable and comparable across forest types, being derivable from standard forest inventory data, and by being easy to apply, understand and interpret.

ecology↗

bioRxiv2024

Rewired type I IFN signaling is linked to age-dependent differences in COVID-19

Advanced age is the most important risk factor for severe disease or death from COVID-19, but a thorough mechanistic understanding of the molecular and cellular underpinnings is lacking. Multi-omics analysis of samples from SARS-CoV-2 infected persons aged 1 to 84 years, revealed a rewiring of type I interferon (IFN) signaling with a gradual shift from signal transducer and activator of transcription 1 (STAT1) to STAT3 activation in monocytes, CD4+ T cells and B cells with increasing age. Diversion of interferon IFN signaling was associated with increased expression of inflammatory markers, enhanced release of inflammatory cytokines, and delayed contraction of infection-induced CD4+ T cells. A shift from IFN-responsive germinal center B (GCB) cells towards CD69high GCB and atypical B cells corresponded to the formation of IgA in children while complement fixing IgG was dominant in adults. Our data provide a mechanistic basis for inflammation-prone responses to infections and associated pathology during aging. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/619479v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@723896org.highwire.dtl.DTLVardef@e12b2aorg.highwire.dtl.DTLVardef@d8de22org.highwire.dtl.DTLVardef@1df96ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

RUCova: Removal of Unwanted Covariance in mass cytometry data

High dimensional mass cytometry is confounded by unwanted covariance due to variations in cell size and staining efficiency, making analysis and interpretation challenging. We present RUCova, a novel method designed to address confounding factors in mass cytometry data. RUCova removes unwanted covariance using multivariate linear regression on Surrogates of Unwanted Covariance (SUCs), and Principal Component Analysis (PCA). We exemplify the use of RUCova and show that it effectively removes unwanted covariance while preserving genuine biological signals. Our results demonstrate the efficacy of RUCova in elucidating complex data patterns, facilitating the identification of activated signalling pathways, and improving the classification of important cell populations. By providing a robust framework for data normalization and interpretation, RUCova enhances the accuracy and reliability of mass cytometry analyses, contributing to advancements in our understanding of cellular biology and disease mechanisms. The R package is available on https://github.com/molsysbio/RUCova. Detailed documentation, data, and the code required to reproduce the results are available on https://doi.org/10.5281/zenodo.10913464. Supplementary material: Available at bioRxiv.

bioinformatics↗

bioRxiv2024

Subcellular mRNA kinetic modeling reveals nuclear retention as rate-limiting

Eukaryotic mRNAs are transcribed, processed, translated, and degraded in different subcellular compartments. Here, we measured mRNA flow rates between subcellular compartments in mouse embryonic stem cells. By combining metabolic RNA labeling, biochemical fractionation, mRNA sequencing, and mathematical modeling, we determined the half-lives of nuclear pre-, nuclear mature, cytosolic, and membrane-associated mRNAs from over 9000 genes. In addition, we estimated transcript elongation rates. Many matured mRNAs have long nuclear half-lives, indicating nuclear retention as the rate-limiting step in the flow of mRNAs. In contrast, mRNA transcripts coding for transcription factors show fast kinetic rates, and in particular short nuclear half-lives. Differentially localized mRNAs have distinct rate constant combinations, implying modular regulation. Membrane stability is high for membrane-localized mRNA and cytosolic stability is high for cytosol-localized mRNA. mRNAs encoding target signals for membranes have low cytosolic and high membrane half-lives with minor differences between signals. Transcripts of nuclear-encoded mitochondrial proteins have long nuclear retention and cytoplasmic kinetics that do not reflect co-translational targeting. Our data and analyses provide a useful resource to study spatiotemporal gene expression regulation.

systems biology↗

bioRxiv2023

Single-cell-resolved interspecies comparison identifies a shared inflammatory axis and a dominant neutrophil-endothelial program in severe COVID-19

Key issues for research of COVID-19 pathogenesis are the lack of biopsies from patients and of samples at the onset of infection. To overcome these hurdles, hamsters were shown to be useful models for studying this disease. Here, we further leveraged the model to molecularly survey the disease progression from time-resolved single-cell RNA-sequencing data collected from healthy and SARS-CoV-2-infected Syrian and Roborovski hamster lungs. We compared our data to human COVID-19 studies, including BALF, nasal swab, and post-mortem lung tissue, and identified a shared axis of inflammation dominated by macrophages, neutrophils, and endothelial cells, which we show to be transient in Syrian and terminal in Roborovski hamsters. Our data suggest that, following SARS-CoV-2 infection, commitment to a type 1 or type 3-biased immunity determines moderate versus severe COVID-19 outcomes, respectively. One-Sentence SummaryActivation of different immunological programs upon SARS-CoV-2 infection determines COVID-19 severity.

immunology↗

bioRxiv2023

On minimising tumoural growth under treatment resistance

AO_SCPLOWBSTRACTC_SCPLOWDrug resistance is a major challenge for curative cancer treatment, representing the main reason of death in patients. Evolutionary biology suggests pauses between treatment rounds as a way to delay or even avoid resistance emergence. Indeed, this approach has already shown promising preclinical and early clinical results, and stimulated the development of mathematical models for finding optimal treatment protocols. Due to their complexity, however, these models do not lend themself to a rigorous mathematical analysis, hence so far clinical recommendations generally relied on numerical simulations and ad-hoc heuristics. Here, we derive two mathematical models describing tumour growth under genetic and epigenetic treatment resistance, respectively, which are simple enough for a complete analytical investigation. First, we find key differences in response to treatment protocols between the two modes of resistance. Second, we identify the optimal treatment protocol which leads to the largest possible tumour shrinkage rate. Third, we fit the "epigenetic model" to previously published xenograft experiment data, finding excellent agreement, underscoring the biological validity of our approach. Finally, we use the fitted model to calculate the optimal treatment protocol for this specific experiment, which we demonstrate to cause curative treatment, making it superior to previous approaches which generally aimed at stabilising tumour burden. Overall, our approach underscores the usefulness of simple mathematical models and their analytical examination, and we anticipate our findings to guide future preclinical and, ultimately, clinical research in optimising treatment regimes.

cancer biology↗

bioRxiv2022

Shifts from non-obligate generalists to obligate specialists in simulations of mutualistic network assembly

Understanding ecosystem recovery after perturbation is crucial for ecosystem conservation. Mutualisms contribute key functions for plants such as pollination and seed dispersal. We modelled the assembly of mutualistic networks based on trait matching between plants and their animal partners that have different degrees of specialization on plant traits. Additionally, we addressed the role of non-obligate animal mutualists, including facultative mutualists or non-resident species that have their main resources outside the target site. Our computer simulations show that non-obligate animals facilitate network assembly during the early stages, furthering colonization by an increase in niche space and reduced competition. While non-obligate and generalist animals provide most of the fitness benefits to plants in the early stages of the assembly, obligate and specialist animals dominate at the end of the assembly. Our results thus demonstrate the combined occurrence of shifts from diet, trait, and habitat generalists to more specialised animals.

ecology↗

bioRxiv2021

Maintaining and escaping feedback control in hierarchically organised tissue: a case study of the intestinal epithelium

The intestinal epithelium is one of the fastest renewing tissues in mammals. It shows a hierarchical organisation, where intestinal stem cells at the base of crypts give rise to rapidly dividing transit amplifying cells that in turn renew the pool of short-lived differentiated cells. Upon injury and stem-cell loss, cells can also dedifferentiate. Tissue homeostasis require a tightly regulated balance of differentiation and stem cell proliferation, and failure can lead to tissue extinction or to unbounded growth and cancerous lesions. Here, we present a two-compartment mathematical model of intestinal epithelium population dynamics that includes a known feedback inhibition of stem cell differentiation by differentiated cells. The model shows that feedback regulation stabilises the number of differentiated cells as these become invariant to changes in their apoptosis rate. Stability of the system is largely independent of feedback strength and shape, but specific thresholds exist after unbounded growth occurs. When dedifferentiation is added to the model, we find that the system can recover more gracefully after certain external perturbations. However, dedifferentiation makes the system more prone to loosing homoeostasis. Taken together, our mathematical model shows how a feedback-controlled hierarchical tissue can maintain homeostasis and can be robust to many external perturbations.

cancer biology↗

bioRxiv2020

An Integrative Genetic, Epigenetic and Proteomic Characterization of Pancreatic Neuroendocrine Neoplasms (PanNENs) defines Distinct Molecular Features of α- and β-cell like Subgroups

Pancreatic Neuroendocrine Carcinomas (PanNECs) are high-grade, poorly-differentiated tumors grouped together with Pancreatic Neuroendocrine Tumors (PanNETs) and placed within the Pancreatic Neuroendocrine Neoplasms (PanNENs) WHO tumor classification. Despite recent studies suggesting the endocrine origin of low-grade PanNETs, high-grade PanNEC origin remains unknown. DNA methylation analysis using the Illumina 850K beadchip array was conducted on 57 PanNEN samples, including 14 PanNECs. Distinct methylation profiles separated PanNEN samples into two major groups, clearly distinguishing high-grade PanNECs from other PanNETs including high-grade NETG3. DNA mutations, copy number changes and Immunohistochemistry of pancreatic cell-type markers PDX1, ARX and SOX9 were utilized to further characterize PanNECs and their hierarchical cell of origin in the pancreas. Phylo-epigenetic and cell-type signature features using methylation data from normal alpha, beta, acinar and ductal adult cells indicate an exocrine cell of origin for PanNECs, thus separating them in cell lineage from other PanNENs of endocrine origin. Our study provides a robust and clinically relevant method relying on methylation profiles to clearly distinguish PanNECs from PanNETG3s to improve patient stratification and treatment.

cancer biology↗

bioRxiv2018

Cell type-dependent differential activation of ERK by oncogenic KRAS or BRAF in the mouse intestinal epithelium

Mutations activating the KRAS GTPase or the BRAF kinase are frequent in colorectal cancer and are thought to constitutively activate the terminal mitogen-activated protein kinase, ERK. Using mass cytometry, we found graded phosphorylation of ERK anti-correlated with cell differentiation in patient-derived colorectal cancer organoids, independent of KRAS mutational status. Reporter, single cell transcriptome and mass cytometry analyses showed that transgenic KRASG12V activated ERK in a cell type-specific pattern in mouse intestinal organoids. In contrast, transgenic BRAFV600E triggered high ERK activity and downstream gene expression in all intestinal cell types, followed by epithelial disorganisation. Quantitative network modelling from perturbation data revealed that activation of ERK is shaped by cell type-specific MEK to ERK feed forward and negative feedback signalling. We identified dual-specificity phosphatases as candidate modulators of ERK activity between intestinal cell types. Furthermore, we found that oncogenic KRAS, together with {beta}-Catenin, favoured expansion of crypt cells with high ERK activity. Our experiments highlight key differences between ERK activity elicited by the BRAF or KRAS oncogenes in colorectal cancer and find unexpected heterogeneity in a signalling pathway with fundamental relevance for cancer therapy.

cell biology↗