Biology subjects

Mueller, C.

Publications and source records attributed to Mueller, C..

52 records · Page 3Linked to original sources

bioRxiv2021

Fighting over defence chemicals disrupts mating behaviour

Studies on intraspecific contest behaviour predominantly focus on contests between individuals of the same sex, however contest behaviour is also expected to occur between individuals of the opposite sex including possible mates. Here we investigate potential trade-offs between mating and fighting behaviour in the turnip sawfly (Athalia rosae). Adults of this species collect chemical defence compounds (clerodanoids) directly from plants but also indirectly by nibbling on conspecifics that have already obtained clerodanoids themselves, a highly aggressive behavioural interaction. An A. rosae individual without clerodanoids may therefore be the potential mate or attacker of an individual of the opposite sex that has gained clerodanoids. We paired males and females with or without clerodanoid access and manipulated body mass differences between the sexes via the early life starvation of females. We show that asymmetrical clerodanoid acquisition between male-female pairs causes an increase in agonistic nibbling behaviour, irrespective of sex. Moreover, fighting over clerodanoids disrupted mating behaviour, and the frequency of aggressive nibbling behaviour in these pairs was determined by the comparative body mass of the attacking individual. Our study highlights the vital importance of investigating agonistic intersex interactions not only over mating but also over resources.

zoology↗

bioRxiv2021

Consequences of pharmacophagous uptake from plants and conspecifics in a sawfly elucidated using chemical and molecular techniques

Pharmacophagy involves the sequestration of specialised plant metabolites for non-nutritive purposes and commonly occurs in insects. Here we investigate pharmacophagy in the turnip sawfly, Athalia rosae, where adults not only collect specialised metabolites (clerodanoids) from a plant (Ajuga reptans), but also from the exterior of conspecifics via fighting. Using behavioural assays, chemical analytics, and RNAseq we show that when individuals nibble on conspecifics that have already acquired clerodanoids from A. reptans leaves, this nibbling results in the transfer of compounds between individuals. Furthermore, unlike other pharmacophagous insects, the acquisition of clerodanoids by A. rosae from the leaves of A. reptans does not induce the upregulation of known detoxification or sequestration genes and pathways. In contrast, pharmacophagous nibbling on conspecifics results in the upregulation of metabolic pathways associated with elevated metabolic rates and increased energy consumption. It therefore seems that individuals attack conspecifics to acquire clerodanoids despite the apparent metabolic costs of this form of pharmacophagy compared to clerodanoid uptake from a plant. Changes in the metabolic phenotype of A.rosae individuals consequently has profound consequences for social interactions with possible ramifications for their social niche. Summary statementThe turnip sawfly (Athalia rosae) gains potentially beneficial compounds from the leaf surface of non-food plants (e.g. Ajuga reptans), but can also steal these compounds from conspecifics via aggressive nibbling.

zoology↗

bioRxiv2020

The rocaglate CR-31-B (-) inhibits SARS-CoV-2 replication at non-cytotoxic, low nanomolar concentrations in vitro and ex vivo

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a betacoronavirus in the subgenus Sarbecovirus causes a respiratory disease with varying symptoms referred to as coronavirus disease 2019 (COVID-19) and is responsible for a pandemic that started in early 2020. With no vaccines or effective antiviral treatments available, and infection and fatality numbers continuing to increase globally, the quest for novel therapeutic solutions remains an urgent priority. Rocaglates, a class of plant-derived cyclopenta[b]benzofurans, exhibit broad-spectrum antiviral activity against positive- and negative-sense RNA viruses. This compound class inhibits eukaryotic initiation factor 4A (eIF4A)-dependent mRNA translation initiation, resulting in strongly reduced viral RNA translation. The synthetic rocaglate CR-31-B (-) has previously been shown to inhibit the replication of human coronaviruses, such as HCoV-229E and MERS-CoV, as well as Zika-, Lassa-, Crimean Congo hemorrhagic fever virus in primary cells. Here, we assessed the antiviral activity of CR-31-B (-) against SARS-CoV-2 using both in vitro and ex vivo cell culture models. In African green monkey Vero E6 cells, CR-31-B (-) inhibited SARS-CoV-2 replication with an EC50 of ~1.8 nM. In line with this, viral protein accumulation and replication/transcription complex formation were found to be strongly reduced by this compound. In an ex vivo infection system using human airway epithelial cells, CR-31-B (-) was found to cause a massive reduction of SARS-CoV-2 titers by about 4 logs to nearly non-detectable levels. The data reveal a potent anti-SARS-CoV-2 activity by CR-31-B (-), corroborating previous results obtained for other coronaviruses and supporting the idea that rocaglates may be used in first-line antiviral intervention strategies against novel and emerging RNA virus outbreaks.

molecular biology↗

bioRxiv2020

SF3B1 promotes tumor malignancy through splicing-independent co-activation of HIF1α

Mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies also demonstrate a positive correlation between expression levels of wildtype SF3B1 and tumor malignancy, but underlying mechanisms remain elusive. Here, we report that SF3B1 acts as an activator of HIF signaling through a splicing-independent mechanism. We demonstrate that SF3B1 forms a heterotrimer with HIF1 and HIF1{beta}, facilitating binding of the HIF1 complex to hypoxia response elements (HREs) to activate target gene expression. We further validate the relevance of this mechanism for tumor progression. Monoallelic deletion of Sf3b1 impedes formation and progression of hypoxic pancreatic cancer via impaired HIF signaling, but is well tolerated in normoxic chromophobe renal cell carcinoma. Our work uncovers an essential role of SF3B1 in HIF1 signaling, providing a causal link between high SF3B1 expression and aggressiveness of solid tumors.

cell biology↗

bioRxiv2020

CD8+ T cell priming in oral mucosa-draining lymph nodes supports systemic immunity

The gastrointestinal (GI) tract constitutes an essential barrier against ingested pathogens. While immune reactions are well-studied in the lower GI tract, it remains unclear how adaptive immune responses are initiated during microbial challenge of the oral mucosa, the primary site of pathogen encounter in the upper GI tract. Here, we identify mandibular lymph nodes (mandLN) as sentinel lymphoid organs that collect orally administered Listeria monocytogenes (Lm), leading to local CD8+ T cell activation. In contrast to CD8+ T effector cells (TEFF) generated in mesenteric lymph nodes, mandLN CD8+ TEFF lacked a gut-seeking phenotype but contributed to systemic host protection. Accordingly, mandLN stromal and dendritic cells expressed low levels of enzymes required for gut homing imprinting. Our findings extend the concept of regional specialization of immune responses along the length of the GI tract, with mandLN acting as oral lymph-draining counterparts of intestinal lymph-draining LN of the lower GI tract. SummaryListeria monocytogenes ingestion leads to priming of cytotoxic T cells in oral mucosa draining mandibular lymph nodes, which contribute to systemic host protection.

immunology↗

bioRxiv2020

Inhibiting coronavirus replication in cultured cells by chemical ER stress

Coronaviruses (CoVs) are important human pathogens for which no specific treatment is available. Here, we provide evidence that pharmacological reprogramming of ER stress pathways can be exploited to suppress CoV replication. We found that the ER stress inducer thapsigargin efficiently inhibits coronavirus (HCoV-229E, MERS-CoV, SARS-CoV-2) replication in different cell types, (partially) restores the virus-induced translational shut-down, and counteracts the CoV-mediated downregulation of IRE1 and the ER chaperone BiP. Proteome-wide data sets revealed specific pathways, protein networks and components that likely mediate the thapsigargin-induced antiviral state, including HERPUD1, an essential factor of ER quality control, and ER-associated protein degradation complexes. The data show that thapsigargin hits a central mechanism required for CoV replication, suggesting that thapsigargin (or derivatives thereof) may be developed into broad-spectrum anti-CoV drugs. One Sentence Summary / Running titleSuppression of coronavirus replication through thapsigargin-regulated ER stress, ERQC / ERAD and metabolic pathways

immunology↗

bioRxiv2020

Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish

Mammalian models have been instrumental to investigate adult heart function and human disease. However, electrophysiological differences with human hearts and high costs emphasize the need for additional models. The zebrafish is a well-established genetic model to study cardiac development and function; however, analysis of cardiac phenotypes in adult specimens is particularly challenging as they are opaque. Here, we optimized and combined multiple imaging techniques including echocardiography, magnetic resonance imaging and micro-computed tomography to identify and analyze cardiac phenotypes in adult zebrafish. Using alk5a/tgfbr1a mutants as a case study, we observed morphological and functional cardiac defects, which were undetected with conventional approaches. Correlation analysis of multiple parameters revealed an association between hemodynamic defects and structural alterations of the heart, as observed clinically. Thus, we report a comprehensive and sensitive platform to identify otherwise indiscernible cardiac phenotypes in adult zebrafish, a model with clear advantages to study cardiac function and disease.

developmental biology↗

bioRxiv2020

Chemical patterns of colony membership and mother-offspring similarity in Antarctic fur seals are reproducible over time

Replication studies are essential for assessing the validity of previous research findings and for probing their generality. However, it has proven challenging to reproduce the results of ecological and evolutionary studies, partly because of the complexity and lability of many of the phenomena being investigated, but also due to small sample sizes, low statistical power and publication bias. Additionally, replication is often considered too difficult in field settings where many factors are beyond the investigators control and where spatial and temporal dependencies may be strong. We investigated the feasibility of reproducing original research findings in the field of chemical ecology by attempting to replicate a previous study by our team on Antarctic fur seals (Arctocephalus gazella). In the original study, skin swabs from 41 mother-offspring pairs from two adjacent breeding colonies on Bird Island, South Georgia, were analysed using gas chromatography-mass spectrometry. Seals from the two colonies differed significantly in their chemical fingerprints, suggesting that colony membership may be chemically encoded, and mothers were also chemically similar to their pups, implying that phenotype matching may be involved in mother-offspring recognition. Here, we generated and analysed comparable chemical data from a non-overlapping sample of 50 mother-offspring pairs from the same two colonies five years later. The original results were corroborated in both hypothesis testing and estimation contexts, with p-values remaining highly significant and effect sizes, standardized between studies by bootstrapping the chemical data over individuals, being of comparable magnitude. We furthermore expanded the geographic coverage of our study to include pups from a total of six colonies around Bird Island. Significant chemical differences were observed in the majority of pairwise comparisons, indicating not only that patterns of colony membership persist over time, but also that chemical signatures are colony-specific in general. Our study systematically confirms and extends our previous findings, while also implying that temporal and spatial heterogeneity need not necessarily negate the reproduction and generalization of ecological research findings.

ecology↗

bioRxiv2020

Tissue-specific multiOMICs analysis of atrial fibrillation

Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, novel multiOMICs approaches are needed for deciphering the underlying molecular networks. Here, we integrated genomics, transcriptomics, and proteomics of human atrial tissue which allowed for identifying widespread effects of genetic variants on both transcript (cis eQTL) and protein (cis pQTL) abundance. We further established a novel targeted trans QTL approach based on polygenic risk scores to identify candidates for AF core genes. Using this approach, we identified two trans eQTLs and four trans pQTLs for AF GWAS hits, and elucidated the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and AF. Altogether, we present an integrative multiOMICs method to uncover trans-acting networks in small datasets and provide a rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization.

genetics↗

bioRxiv2020

In cell architecture of the nuclear pore complex and snapshots of its turnover

Nuclear pore complexes (NPCs) mediate exchange across the nuclear envelope. They consist of hundreds of proteins called nucleoporins (Nups) that assemble in multiple copies to fuse the inner and outer nuclear membranes. Elucidating the molecular function and architecture of NPCs imposes a formidable challenge and requires the convergence of in vitro and in situ approaches. How exactly NPC architecture accommodates processes such as mRNA export or NPC assembly and turnover inside of cells remains poorly understood. Here we combine integrated in situ structural biology, correlative light and electron microscopy with yeast genetics to structurally analyze NPCs within the native context of Saccharomyces cerevisiae cells under conditions of starvation and exponential growth. We find an unanticipated in situ layout of nucleoporins with respect to overall dimensions and conformation of the NPC scaffold that could not have been predicted from previous in vitro analysis. Particularly striking is the configuration of the Nup159 complex, which appears critical to spatially accommodate not only mRNA export but also NPC turnover by selective autophagy. We capture structural snapshots of NPC turnover, revealing that it occurs through nuclear envelope herniae and NPC-containing nuclear vesicles. Our study provides the basis for understanding the various membrane remodeling events that happen at the interface of the nuclear envelope with the autophagy apparatus and emphasizes the need of investigating macromolecular complexes in their cellular context.

biophysics↗

bioRxiv2019

Rapid and independent evolution of ancestral and novel defenses in a genus of toxic plants (Erysimum, Brassicaceae)

Phytochemical diversity is thought to result from coevolutionary cycles as specialization in herbivores imposes diversifying selection on plant chemical defenses. Plants in the speciose genus Erysimum (Brassicaceae) produce both ancestral glucosinolates and evolutionarily novel cardenolides as defenses. Here we test macroevolutionary hypotheses on co-expression, co-regulation, and diversification of these potentially redundant defenses across this genus. We sequenced and assembled the genome of E. cheiranthoides and foliar transcriptomes of 47 additional Erysimum species to construct a highly resolved phylogeny, revealing that cardenolide diversity increased rapidly rather than gradually over evolutionary time. Concentrations, inducibility, and diversity of the two defenses varied independently among species, with no evidence for trade-offs. Closely related species shared similar cardenolide traits, but not glucosinolate traits, likely as a result of specific selective pressures acting on distinct molecular diversification mechanisms. Ancestral and novel chemical defenses in Erysimum thus appear to provide complementary rather than redundant functions.

plant biology↗

bioRxiv2019

mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations

BackgroundMitochondria produce cellular energy in the form of ATP and are involved in various metabolic and signaling processes. However, the cellular requirements for mitochondria are different depending on cell type, cell state or organism. Information on the expression dynamics of genes with mitochondrial functions (mito-genes) is embedded in publicly available transcriptomic or proteomic studies and the variety of available datasets enables us to study the expression dynamics of mito-genes in many different cell types, conditions and organisms. Yet, we lack an easy way of extracting these data for gene groups such as mito-genes.\n\nResultsHere, we introduce the web-based visual data mining platform mitoXplorer, which systematically integrates expression and mutation data of mito-genes. The central part of mitoXplorer is a manually curated mitochondrial interactome containing [~]1200 genes, which we have annotated in 35 different mitochondrial processes. This mitochondrial interactome can be integrated with publicly available transcriptomic, proteomic or mutation data in a user-centric manner. A set of analysis and visualization tools allows the mining and exploration of mitochondrial expression dynamics and mutations across various datasets from different organisms and to quantify the adaptation of mitochondrial dynamics to different conditions. We apply mitoXplorer to quantify expression changes of mito-genes of a set of aneuploid cell lines that carry an extra copy of chromosome 21. mitoXplorer uncovers remarkable differences in the regulation of the mitochondrial transcriptome and proteome due to the dysregulation of the mitochondrial ribosome in retinal pigment epithelial trisomy 21 cells which results in severe defects in oxidative phosphorylation.\n\nConclusionsWe demonstrate the power of the visual data mining platform mitoXplorer to explore expression data in a focused and detailed way to uncover underlying potential mechanisms for further experimental studies. We validate the hypothesis-creating power of mitoXplorer by testing predicted phenotypes in trisomy 21 model systems. MitoXplorer is freely available at http://mitoxplorer.ibdm.univ-mrs.fr. MitoXplorer does not require installation nor programming knowledge and is web-based. Therefore, mitoXplorer is accessible to a wide audience of experimental experts studying mitochondrial dynamics.

bioinformatics↗

bioRxiv2018

Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology

Intraneuronal accumulation of -synuclein (Syn) is key in the pathogenesis of Parkinsons disease (PD). Published studies suggest that this process begins in the enteric nervous system (ENS) and propagates into the brain decades before clinical diagnosis of PD. The triggers and mechanisms underlying the accumulation of Syn remain unknown but evidence is growing, that immune pathways and in particular colitis may play a critical role. Here we demonstrate that patients with inflammatory bowel disease (IBD) exhibit Syn accumulation in their colon. We then confirmed in an experimental model of IBD that intestinal inflammation can trigger Syn accumulation in the ENS of wildtype and Syn transgenic mice. We discovered that the type and degree of inflammation modulates the extent of Syn accumulation in the colon and that macrophage-related signaling limits this process. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 Syn in the midbrain, including the substantia nigra, in 21-month but not 9-month-old Syn transgenic mice. This was accompanied by loss of nigral tyrosine hydroxylase-immunoreactive neurons, another neuropathological hallmark of PD. Together, our data suggest a critical role for intestinal inflammation in the initiation and progression of PD.

neuroscience↗

bioRxiv2018

Structural analysis of the interaction between the bacterial cell division proteins FtsQ and FtsB

Most bacteria and archaea use similar proteins within their cell division machinery, which uses the tubulin homologue FtsZ as its central organiser. In Gram-negative Escherichia coli bacteria, FtsZ recruits cytosolic, transmembrane, periplasmic and outer membrane proteins, assembling the divisome that facilitates bacterial cell division. One such divisome component, FtsQ, a bitopic membrane protein with a globular domain in the periplasm, has been shown to interact with many other divisome proteins. Despite its otherwise unknown function, it has been shown to be a major divisome interaction hub. Here, we investigated the interactions of FtsQ with FtsB and FtsL, two small bitopic membrane proteins that act immediately downstream of FtsQ. In biochemical assays we show that the periplasmic domains of E. coli FtsB and FtsL interact with FtsQ, but not with each other. Our crystal structure of FtsB bound to the {beta} domain of FtsQ shows that only residues 64-87 of FtsB interact with FtsQ. A synthetic peptide comprising those 24 FtsB residues recapitulates the FtsQ:FtsB interactions. Protein deletions and structure-guided mutant analyses validate the structure. Furthermore, the same structure-guided mutants show cell division defects in vivo that are consistent with our structure of the FtsQ:FtsB complex that shows their interactions as they occur during cell division. Our work provides intricate details of the interactions within the divisome and also provides a tantalising view of a highly conserved protein interaction in the periplasm of bacteria that is an excellent target for cell division inhibitor searches.\n\nImportanceCells in most bacteria and archaea divide through a cell division process that is characterised through its filamentous organiser, FtsZ protein. FtsZ forms a ring structure at the division site and starts the recruitment of 10-20 downstream proteins that together form an elusive multi-protein complex termed divisome. The divisome is thought to facilitate many of the steps required to make two cells out of one. FtsQ and FtsB are part of the divisome, with FtsQ being a central hub, interacting with most of the other divisome components. Here we show for the first time how FtsQ interacts with its downstream partner FtsB and show that mutations that disturb the interface between the two proteins effectively inhibit cell division.

microbiology↗

bioRxiv2017

Long-lived rodents reveal signatures of positive selection in genes associated with lifespan and eusociality

The genetic mechanisms that determine lifespan are poorly understood. Most research has been done on short lived animals and it is unclear if these insights can be transferred to long-lived mammals like humans. Some African mole-rats (Bathyergidae) have life expectancies that are multiple times higher than similar sized and phylogenetically closely related rodents. We obtained genomic and transcriptomic data from 17 rodent species and systematically scanned eleven lineages associated with the evolution of longevity and eusociality for positively selected genes (PSGs). The set of 319 PSGs contains regulators of mTOR and is enriched in functional terms associated with (i) processes that are regulated by the mTOR pathway, e.g. translation, autophagy and mitochondrial biogenesis, (ii) the immune system and (iii) antioxidant defense. Analyzing gene expression of PSGs during aging in the long-lived naked mole-rat and up-regulation in the short-lived rat, we found a pattern fitting the antagonistic pleiotropy theory of aging.

evolutionary biology↗

bioRxiv2016

Extrachromosal DNA elements can drive disease evolution in glioblastoma

To understand how genomic heterogeneity of glioblastoma (GBM) contributes to the poor response to therapy, which is characteristic of this disease, we performed DNA and RNA sequencing on GBM tumor samples and the neurospheres and orthotopic xenograft models derived from them. We used the resulting data set to show that somatic driver alterations including single nucleotide variants, focal DNA alterations, and oncogene amplification in extrachromosomal DNA (ecDNA) elements were in majority propagated from tumor to model systems. In several instances, ecDNAs and chromosomal alterations demonstrated divergent inheritance patterns and clonal selection dynamics during cell culture and xenografting. Longitudinal patient tumor profiling showed that oncogenic ecDNAs are frequently retained after disease recurrence. Our analysis shows that extrachromosomal elements increase the genomic heterogeneity during tumor evolution of glioblastoma, independent of chromosomal DNA alterations.

cancer biology↗