Biology subjects

Meyer, R.

Publications and source records attributed to Meyer, R..

11 recordsLinked to original sources

bioRxiv2026

Exploring Ventilator-Induced Lung Injury: A Comprehensive Ex-Vivo Study Using Phase-Contrast MicroCT and Atomic Force Microscopy

Mechanical ventilation (MV) can induce or exacerbate ventilator-induced lung injury (VILI), particularly in mechanically heterogeneous lungs with pre-existing injury. We investigated VILI in a rat model of bleomycin-induced lung injury and compared it with healthy controls using a combined in-vivo and ex-vivo imaging approach. Previously acquired in-vivo data from four-dimensional (4D) phase-contrast synchrotron micro-computed tomography (microCT) and forced oscillation measurements showed increased lung elastance and reduced local acinar strain in bleomycin-induced injured lungs at baseline and after injurious MV. To identify structural and mechanical correlates, we performed automated three-dimensional (3D) pore analysis and atomic force microscopy (AFM) on formalin-fixed, paraffin-embedded lung tissue, complemented by histology and spatial co-registration. Ex-vivo analysis revealed pronounced airspace enlargement after injurious MV of healthy lungs, whereas this effect was attenuated in fibrotic lungs. AFM demonstrated region-specific mechanical responses, and correlation analyses linked pore geometry and nanoscale stiffness to in-vivo lung mechanics. Spatial analysis further showed colocalization of VILI-associated airspace damage with injured regions. Overall, extracellular matrix remodelling modifies the lungs mechanical response to injurious MV. This multiscale correlative approach provides mechanistic insight into the interplay between lung injury and VILI and informs ventilation strategies in structurally altered lungs.

pathology↗

bioRxiv2026

Stretching drives Membrane Homogenization of Phase-Separated Supported Lipid Bilayers

Cell plasma membranes exhibit heterogeneous lateral organization whose dynamic compartmentalization is critical for processes such as viral infection and fertilization. While membrane tension is known to influence crucial cell remodeling processes, its role in regulating membrane heterogeneous organization remains unclear. To reveal the effect of tension on lateral membrane organization, we used supported lipid bilayers on flexible substrates. These were prepared by rupturing ternary-composition giant unilamellar vesicles exhibiting liquid order-disorder phase coexistence. The phase coexistence is observed using a fluorescent probe that preferentially partitions to the disordered phase. Using a motorized equibiaxial stretching device, we observed progressive homogenization of domain morphology with increasing strain up to a critical strain, beyond which the membrane remains uniform. We define an order parameter based on the relative concentration of the dye in the two phases, which is a proxy for the membrane lateral organization. Order parameter analysis revealed power-law scaling below the critical strain with an exponent {beta} = 1.0 {+/-} 0.3, consistent with an elastic theoretical model predicting {beta} = 1. The progressive broadening of the interfacial region width near the critical strain, and continuous transition to a homogeneous phase, is consistent with a second-order phase transition. These findings indicate that membrane tension may serve as a physical regulator of lateral lipid organization, with implications for how cells use mechanical forces to regulate their structure and function. Significance StatementCell membranes are fundamental structures serving as the interface between a cells interior and its external environment. Membrane tension regulates critical cellular processes, yet how it affects the essential heterogeneous organization of membrane domains remains controversial. We combine artificial supported membranes on flexible substrates with a motorized equibiaxial stretching device, to directly visualize domain morphology under controlled tension. We observed that stretching drives the membrane to become progressively more uniformly distributed until it appears homogeneous. This transformation is consistent with a second-order phase transition. These findings demonstrate that mechanical tension acts as a direct physical regulator of cell membrane structure and lateral lipid organization.

biophysics↗

bioRxiv2025

The keratin cortex stabilizes cells at high strains

The eukaryotic cytoskeleton consists of three filament types: actin filaments, microtubules and intermediate filaments (IFs). IF proteins are expressed in a cell-type specific manner, and keratins are found in epithelial cells. In certain cell types, keratin forms a layer close to the membrane which may be referred to as an "IF-cortex". It is hypothesized that this IF-cortex arranges with radial bundles in a "rim-and-spokes" structure in epithelia. Based on this hypothesis, IFs and actin filaments might add complementary mechanical properties to the cortex. It was previously shown that single IFs in vitro remain undamaged at high strains and display a non-linear stretching behavior. We now ask the question of whether this unique force-extension behavior of single IFs is also relevant in the context of a filament network within a cell. We show that keratin-deficient (KO) MDCK II cells readily form 2D cell layers and 3D cysts and withstand high equibiaxial strains. High-resolution imaging using STED microscopy reveals altered actin cortex structures in KO cells, presumably in response to the missing keratin. We investigate the influence of the equibiaxial strain on the viscoelastic properties of wild-type (WT) and KO cells using atomic force microscopy. We find that the KO cells exhibit a higher pre-stress than the WT cells, likely due to the change of the cortical structure. Interestingly, both the pre-stress and the fluidity of the KO cells are altered already at intermediate strains, whereas the WT cells show a response only at high strain. Similarly, the KO cysts are stretched more easily at low strains than the WT cysts during injection experiments. The compressibility modulus is analyzed in a spatially resolved manner and we find this modulus to be increased at the cell rim, compared to the inside region, due to the geometry of the cell layer. Our results indicate that KO cells compensate for the missing keratin, but are nevertheless very sensitive to external strain, whereas the intricate interplay between the actin and keratin cortices in WT cells preserves the mechanical state and cell stability.

biophysics↗

bioRxiv2024

M2 Macrophages are Major Mediators of Germline Risk of Endometriosis and Explain Pleiotropy with Comorbid Traits

Endometriosis is a common gynecologic condition that causes chronic life-altering symptoms including pain, infertility, and elevated cancer risk. There is an urgent need for new non-hormonal targeted therapeutics to treat endometriosis, but until very recently, the cellular and molecular signatures of endometriotic lesions were undefined, severely hindering the development of clinical advances. Integrating inherited risk data from analyses of >450,000 individuals with [~]350,000 single cell transcriptomes from 21 patients, we uncover M2-macrophages as candidate drivers of disease susceptibility, and nominate IL1 signaling as a central hub impacted by germline genetic variation associated with endometriosis. Extensive functional follow-up confirmed these associations and revealed a pleiotropic role for this pathway in endometriosis. Population-scale expression quantitative trail locus analysis demonstrated that genetic variation controlling IL1A expression is also associated with endometriosis risk variants. Manipulation of IL1 signaling in state-of-the-art in vitro decidualized assembloids impacted epithelial differentiation, and in an in vivo endometriosis model, treatment with anakinra (an interleukin-1 receptor antagonist) resulted in a significant, dose-dependent reduction in both spontaneous pain and evoked pain. Together these studies highlight non-diagnostic cell types as central to endometriosis susceptibility and support IL1 signaling as an important actionable pathway for this disease.

immunology↗

bioRxiv2023

Microbial pathway thermodynamics: structural models unveil anabolic and catabolic processes

The biotechnological exploitation of microorganisms enables the use of metabolism for the production of economically valuable substances, such as drugs or food. It is, thus, unsurprising that the investigation of microbial metabolism and its regulation has been an active research field for many decades. As a result, several theories and techniques were developed that allow the prediction of metabolic fluxes and yields as biotechnologically relevant output parameters. One important approach is to derive macrochemical equations that describe the overall metabolic conversion of an organism and basically treat microbial metabolism as a black box. The opposite approach is to include all known metabolic reactions of an organism to assemble a genomescale metabolic model. Interestingly, both approaches are rather successful to characterise and predict the expected product yield. Over the years, especially macrochemical equations have been extensively characterised in terms of their thermodynamic properties. However, a common challenge when characterising microbial metabolism by a single equation is to split this equation into two, describing the two modes of metabolism, anabolism and catabolism. Here, we present strategies to systematically identify separate equations for anabolism and catabolism. Based on metabolic models, we systematically identify all theoretically possible catabolic routes and determine their thermodynamic efficiency. We then show how anabolic routes can be derived, and use these to approximate biomass yield. Finally, we challenge the view of metabolism as a linear energy converter, in which the free energy gradient of catabolism drives the anabolic reactions.

systems biology↗

bioRxiv2022

AMPK activation restores salivary function following radiation treatment

Head and neck cancers represent a significant portion of cancer diagnoses, with head and neck cancer incidence increasing in some parts of the world. Typical treatment of early-stage head and neck cancers includes either surgery or radiotherapy; however, advanced cases often require surgery followed by radiation and chemotherapy. Salivary gland damage following radiotherapy leads to severe and chronic hypofunction with decreased salivary output, xerostomia, impaired ability to chew and swallow, increased risk of developing oral mucositis, and malnutrition. There is currently no standard of care for radiation-induced salivary gland dysfunction and treatment is often limited to palliative treatment that provides only temporary relief. AMP-activated protein kinase (AMPK) is an enzyme that activates catabolic processes and has been shown to influence the cell cycle, proliferation, and autophagy. In the present study, we found that radiation (IR) treatment decreases tissue levels of phosphorylated AMPK following radiation and decreases intracellular NAD+ and AMP while increasing intracellular ATP. Further, expression of Sirtuin-1 (SIRT1) and nicotinamide phosphoribosyl transferase (NAMPT) were lower five days following IR. Treatment with AMPK activators, AICAR and metformin, attenuated compensatory proliferation (days 6, 7 and 30) following IR, and reversed chronic (day 30) salivary gland dysfunction post-IR. Additionally, treatment with metformin or AICAR increased markers of apical/basolateral polarity (phosphorylated aPKC{zeta}T560 positive area) and differentiation (amylase positive area) within irradiated parotid glands to levels similar to untreated controls. Taken together, these data suggest that AMPK may be a novel therapeutic target for treatment of radiation-induced salivary damage.

molecular biology↗

bioRxiv2021

FAIR enough? A perspective on the status of nucleotide sequence data and metadata on public archives

Knowledge derived from nucleotide sequence data is increasing in importance in the life sciences, as well as decision making (mainly in biodiversity policy). Metadata standards have been established to facilitate sustainable sequence data management according to the FAIR principles (Findability, Accessibility, Interoperability, Reusability). Here, we review the status of metadata available for raw read Illumina amplicon and whole genome shotgun sequencing data derived from ecological metagenomic material that are accessible at the European Nucleotide Archive (ENA), as well as the compliance of the primary sequence data (fastq files) with data submission requirements. While overall basic metadata, such as geographic coordinates, were retrievable in 98% of the cases for this type of sequence data, interoperability was not always ensured and other (mainly conditionally) mandatory parameters were often not provided at all. Metadata standards, such as the Minimum Information about any(x) Sequence (MIxS), were only infrequently used despite a demonstrated positive impact on metadata quality. Furthermore, the sequence data itself did not meet the prescribed requirements in 31 out of 39 studies that were manually inspected. To tackle the most immediate needs to improve FAIR sequence data management, we provide a list of minimal suggestions to researchers, research institutions, funding agencies, reviewers, publishers, and databases, that we believe might have a potentially large positive impact on sequence data and metadata FAIRness, which is crucial for further research and its derived applications.

molecular biology↗

bioRxiv2020

Traceback of Core Transcription Factors for Soybean Root Growth Maintenance under Water Deficit

Some crops inhibit shoot growth but maintain root growth under water-deficit conditions. Unraveling the molecular mechanisms of root plasticity under water deficit conditions in plants remains a major challenge. We developed an efficient platform for identifying core transcription factors (TFs) that collectively regulate each other and/or themselves in response to water stress, and exploring their interconnected regulatory circuitry involved in root growth maintenance under water deficit in soybean. We performed multi-species phylogenetic footprinting combined with spatial-temporal transcriptome analysis of soybean (Glycine max) roots under water deficit to identify conserved motifs that function in the water-stress response. Using these functional conserved cis-motifs, we applied a new approach to trace back motifs-associated core TFs ingroup as signal mediators, which mediate signaling between abiotic and endogenous stimuli. We integrated a co-functional TF-TF network and conserved motif-centered TF-DNA networks to construct a core TF network defined by mutual cross-regulation among core TFs. We found that core TF ARG (Abscisic acid response element binding factor-like Root Growth regulator) represses BRG (Brassinosteroid enhanced expression-like Root Growth regulator) expression through binding to its promoter at a conserved binding site. ARG and BRG antagonistically regulate Phytochrome-interacting factor-like Root Growth regulator (PRG) and combinatorially regulate some other core TFs. These core TFs form complex regulatory circuits to integrate light and multiple hormone signaling pathways and maintain root growth in response to varying degrees of water stress. Our study provides valuable information to unravel the complicated mechanisms of molecular networks involved in the regulation of root growth under water deficit.

plant biology↗

bioRxiv2020

Biomarker-guided treatment strategies for ovarian cancer identified from a heterogeneous panel of patient-derived tumor xenografts

Advanced ovarian cancers are a leading cause of cancer-related death in women. Such cancers are currently treated with surgery and chemotherapy which is often temporarily successful but exhibits a high rate of relapse after which treatment options are few. Here we assess the responses of a panel of patient-derived ovarian cancer xenografts (PDXs) to 19 mono and combination therapies, including small molecules and antibody-drug conjugates. The PDX panel aimed to mimic the heterogeneity of disease observed in patients, and exhibited a distribution of responsiveness to standard of care chemotherapy similar to human clinical data. Three monotherapies and one drug combination were found to be active in different subsets of PDXs. By analyzing gene expression data we identified gene expression biomarkers predictive of responsiveness to each of three novel targeted therapy regimens. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. Biomarker frequency was similar in human patients, suggesting the possibility of a new therapeutic approach to ovarian cancer and demonstrating the potential power of PDX-based trials in broadening the reach of precision cancer medicine.

cancer biology↗

bioRxiv2019

The California Environmental DNA \"CALeDNA\" Program

Global change is leading to habitat shifts that threaten species persistence throughout Californias unique ecosystems. Baseline biodiversity data provide opportunities for ecosystems to be managed for community complexity and connectivity. In 2017, the University of California Conservation Genomics Consortium launched the California Environmental DNA (CALeDNA) program, a community science initiative monitoring Californias biodiversity through environmental DNA (eDNA)--DNA shed from organisms through fur, mucus, spores, pollen, etc. Community scientists collect soil and sediment samples, then researchers analyze the eDNA in the samples and share results with the public. The results are catalogues of thousands of organisms per sample, ranging from microbes to mammals. The CALeDNA website presents biodiversity inventories in a platform designed for the public and researchers alike, as well as user-friendly analysis tools and educational modules. Here, we present CALeDNA as a scalable community science framework that can harmonize with future biodiversity research and education initiatives.

scientific communication and education↗

bioRxiv2018

VarSome: The Human Genomic Variant SearchEngine

SummaryVarSome.com is a search engine, aggregator and impact analysis tool for human genetic variation and a community-driven project aiming at sharing global expertise on human variants.\n\nAvailabilityVarSome is freely available at http://varsome.com.

bioinformatics↗