Biology subjects

Mueller, D. J.

Publications and source records attributed to Mueller, D. J..

9 recordsLinked to original sources

bioRxiv2026

Coupled nucleoplasmic flows and envelope expansion govern the mechanical resistance of the nucleus

In recent year, it became clear that the cell nucleus can undergo large deformations, during immune cell migration and tumor growth. These deformations generate signals that allow cells to sense their environment and adapt to it. How cells cope with and respond to large deformations thus strongly depends on the nuclear mechanics, but our understanding of the physical properties of the nucleus remains incomplete. In particular, it is not clear how the nuclear volume responds to deformation. Here we combine controlled confinement assays, high-resolution imaging and atomic force microscopy with theoretical modelling to propose a physical model of the cell nucleus that accounts for its surface and bulk properties and addresses both steady-state and transient regimes. Our results establish the nucleus as a poroelastic body in which mechanics are dominated by the envelope and dynamics by the chromatin, and suggest that regulating water permeability may be as important as softening the envelope for cells migrating rapidly through dense tissues.

biophysics↗

bioRxiv2025

Load-dependent RGD-context sensing via αV-class integrins reprograms cellular adhesion and mechanics within seconds

The cellular ability to biophysically and biochemically recognize extracellular matrix proteins is fundamental to adhesion, mechanics, migration, and morphogenesis, and influences homeostasis and disease. However, the mechanisms underlying integrin-mediated mechanosensing of the arginine-glycine-aspartic acid (RGD)-motif of vitronectin and fibronectin remain elusive. Here, we discover that within seconds of sensing vitronectin, V-class integrins initiate and strengthen adhesion biphasically through complementary mechanotransduction pathways, which rely on the catch bond behavior of single V{beta}3 integrins. The first adhesion phase requires V{beta}3 and V{beta}5 integrin-associated actomyosin and FAK activity, while V{beta}5 integrin additionally requires clathrin-mediated endocytosis. With elevating mechanical load, the second phase requires V{beta}3 integrin-directed Arp2/3, cSrc, and PI3K signaling that dominates V{beta}5 integrin in organizing the consensus adhesome on vitronectin. Simultaneously, V{beta}5 integrin regulates the mechanical stiffening of fibroblasts. Thus, V-class integrins exhibit rapid RGD-motif- and {beta}-subunit-specific programs to synergistically guide mammalian cell adhesion and mechanics upon encountering diverse extracellular environments.

biophysics↗

bioRxiv2025

The fecal microbiota transplantation from drug-naive schizophrenia patients distinctively changes gut microbiome and metabolic profiles in male and female mice

BackgroundEmerging evidence suggests a role for the gut microbiome in schizophrenia (SCZ) and antipsychotic-induced metabolic perturbations. Using human fecal microbiota transplantation (FMT) in mice, this study investigated the role of gut microbiome in metabolic changes related to SCZ and antipsychotic (olanzapine) treatment. Methods5-6 weeks old germ-free NIH Swiss mice of both sexes received microbiota from either SCZ patients (SCZ-FMT) or healthy controls (HC-FMT) followed by a diet with or without olanzapine for six-weeks. Food intake and body weight were monitored weekly, and an intraperitoneal glucose tolerance test and open field test were performed. Serum glucose, and insulin were measured. Gut microbiome characterization and short-chain fatty acids (SCFAs) quantification were performed in the cecal samples using 16S rRNA gene sequencing and gas chromatography-mass spectrometry, respectively. ResultsOlanzapine treatment decreased the locomotor activity in the open field test, irrespective of sex or microbiota. Female SCZ-FMT recipient mice exhibited insulin resistance compared to HC-FMT, irrespective of olanzapine treatment. Female SCZ-FMT mice showed significantly lower alpha-diversity compared to HC-FMT, whereas olanzapine treatment increased alpha-diversity. SCZ-FMT and olanzapine treatment differentially altered the microbial abundances, and metabolic pathways in male and female mice. Interestingly, cecal SCFAs, mainly acetate levels, were significantly decreased in female SCZ-FMT mice compared to HC-FMT, while olanzapine treatment increased acetate levels in male mice. Both male and female SCZ-FMT mice showed elevated levels of isovaleric acid compared to HC-FMT. ConclusionThese preliminary findings suggest that gut microbiome could be a predisposing factor contributing to the intrinsic risk of developing type 2 diabetes associated with SCZ in females. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/675957v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@8cfd10org.highwire.dtl.DTLVardef@3a6031org.highwire.dtl.DTLVardef@813428org.highwire.dtl.DTLVardef@87609e_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

neuroscience↗

bioRxiv2023

Morphometry and mechanical instability at the onset of epithelial bladder cancer

Malignancies of epithelial tissues, called carcinomas, account for the majority of cancer cases. Much cancer research has focused on genetic alterations and their relation to different carcinoma phenotypes. Besides a rewiring in the signalling networks, carcinoma progression is accompanied by mechanical changes in the epithelial cells and the extracellular matrix. Here, we reveal intricate morphologies in the basement membrane at the onset of bladder cancer, and propose that they emerge from a mechanical buckling instability upon epithelial overgrowth. Using a combination of microscopy imaging of the mouse and human bladder tissue, elasticity theory, and numerical simulations of differential growth in the bladder mucosa, we find that aberrant tissue morphologies can emerge through stiffness changes in the different mucosa layers. The resulting thickening, wrinkles and folds exhibit qualitative and quantitative similarity with imaged early papillary tumors and carcinomas in situ. Atomic force microscopy indeed reveals local stiffness changes in the pathological basement membrane. Our findings suggest a mechanical origin of the different carcinoma subtypes in the bladder, which have vastly different clinical prognosis. They might provide the basis for a new line of attack in medical carcinoma treatment and prophylaxis.

cancer biology↗

bioRxiv2022

The CRL4B E3 ligase regulates mitosis by recruiting phospho-specific DCAFs

The cullin-4 paralogs CUL4A and CUL4B assemble E3 ubiquitin ligase complexes regulating multiple chromatin-associated cellular functions. Although they are structurally similar, we found that the unique N-terminal extension of CUL4B is heavily phosphorylated during mitosis, and the phosphorylation pattern is perturbed in the CUL4B-P50L mutation causing X-linked intellectual disability (XLID). Phenotypic characterization and mutational analysis revealed that CUL4B phosphorylation is required for efficient progression through mitosis, controlling spindle positioning and cortical tension. Interestingly, while CUL4B phosphorylation triggers chromatin exclusion, it critically promotes binding to actin regulators and two previously unrecognized, CUL4B-specific DCAFs, LIS1 and WDR1. Indeed, co-immunoprecipitation experiments and biochemical analysis revealed that LIS1 and WDR1 interact with DDB1, but their binding requires the phosphorylated N-terminal domain of CUL4B. Together, our study uncovers previously unrecognized DCAFs relevant for mitosis and brain development that specifically bind CUL4B, but not the CUL4B-P50L patient mutant, by a phosphorylation-dependent mechanism.

cell biology↗

bioRxiv2022

Advected percolation in the actomyosin cortex drives amoeboid cell motility

Spontaneous locomotion is a common feature of most metazoan cells, generally attributed to the fundamental properties of the actomyosin network. This force-producing machinery has been studied down to the most minute molecular details, especially in lamellipodium-driven migration. Nevertheless, how actomyosin networks work inside contraction-driven amoeboid cells still lacks unifying principles. Here, using stable motile blebs as a model amoeboid motile system, we image the dynamics of the actin cortex at the single filament level and reveal the co-existence of three phases of the actin network with distinct rheological properties. Physical modelling shows that these three phases organize spontaneously due to a rigidity percolation transition combined with an active advection of the percolated network. This spontaneous spatial organization of the mechanical properties of the actin network, which we propose to call advected percolation, constitutes a minimal and generic locomotion mechanism. It explains, down to the single actin filament level and up to the scale of the entire cell, how amoeboid cells can propel efficiently through complex 3D environments, a feature shared by immune and cancer cells.

biophysics↗

bioRxiv2020

Visual QC Protocol for FreeSurfer Cortical Parcellations from Anatomical MRI

Quality control of morphometric neuroimaging data is essential to improve reproducibility. Owing to the complexity of neuroimaging data and subsequently the interpretation of their results, visual inspection by trained raters is the most reliable way to perform quality control. Here, we present a protocol for visual quality control of the anatomical accuracy of FreeSurfer parcellations, based on an easy-to-use open source tool called VisualQC. We comprehensively evaluate its utility in terms of error detection rate and inter-rater reliability on two large multi-site datasets, and discuss site differences in error patterns. This evaluation shows that VisualQC is a practically viable protocol for community adoption.

neuroscience↗

bioRxiv2019

Nonlinear mechanics of lamin filaments and the meshwork topology build an emergent nuclear lamina

The nuclear lamina - a meshwork of intermediate filaments termed lamins - functions as a mechanotransduction interface between the extracellular matrix and the nucleus via the cytoskeleton. Although lamins are primarily responsible for the mechanical stability of the nucleus in multicellular organisms, in situ characterization of lamin filaments under tension has remained elusive. Here, we apply an integrative approach combining atomic force microscopy, cryo-electron tomography, network analysis, and molecular dynamics simulations to directly measure the mechanical response of single lamin filaments in its three-dimensional meshwork. Endogenous lamin filaments portray non-Hookean behavior - they deform reversibly under a force of a few hundred picoNewtons and stiffen at nanoNewton forces. The filaments are extensible, strong and tough, similar to natural silk and superior to the synthetic polymer Kevlar(R). Graph theory analysis shows that the lamin meshwork is not a random arrangement of filaments but the meshwork topology follows small world properties. Our results suggest that the lamin filaments arrange to form a robust, emergent meshwork that dictates the mechanical properties of individual lamin filaments. The combined approach provides quantitative insights into the structure-function organization of lamins in situ, and implies a role of meshwork topology in laminopathies.

biophysics↗

bioRxiv2018

Affectively-biased Competition Favoring Rewarding Expressions is Not Modulated by Common Variation in Norepinephrine Receptor Function

It is well established that emotionally salient stimuli evoke greater visual cortex activation than neutral ones, and can distract attention from competing tasks. Yet less is known about underlying neurobiological processes. As a proxy of population level biased competition, EEG steady-state visual evoked potentials are sensitive to competition effects from salient stimuli. Here we wished to examine whether individual differences in norepinephrine activity play a role in emotionally-biased competition.\n\nOur previous research has found robust effects of a common variation in the ADRA2B gene, coding for alpha2B norepinephrine (NE) receptors, on emotional modulation of attention and memory. In the present study, EEG was collected while 87 carriers of the ADRA2B deletion variant and 95 non-carriers (final sample) performed a change detection task in which target gratings (gabor patches) were superimposed directly over angry, happy, and neutral faces. Participants indicated the number of phase changes (0-3) in the target. Overlapping targets and distractors were flickered at a distinct driving frequencies. Relative EEG power for faces vs. targets at the driving frequency served as an index of cortical resources allocated to each of the competing stimuli. Deletion carriers and non-carriers were randomly assigned to Discovery and Replication samples and reliability of results across samples was assessed before the groups were combined for greater power.\n\nOverall happy faces evoked higher competition than angry or neutral faces; however, we observed no hypothesized effects of ADRA2B. Increased competition from happy faces was not due to the effect of low-level visual features or individuals low in social anxiety. Our results indicate that emotionally biased competition during sustained attention, while reliably observed in young adults, is not influenced by commonly observed individual differences linked to NE receptor function. They further indicate an overall pattern of affectively-biased competition for happy faces, which we interpret in relation to previously observed boundary conditions.

neuroscience↗