Biology subjects

Fink, A.

Publications and source records attributed to Fink, A..

8 recordsLinked to original sources

bioRxiv2026

Optogenetic cross-linking of the actin cytoskeleton using DARPins

Precise tools to control actin filament organization and dynamics are essential for studying how the actin cytoskeleton regulates fundamental cell processes, such as morphological changes, migration and intracellular transport. Here, we present an optogenetic system for the reversible, spatiotemporal manipulation of actin cross-linking in living cells. Our approach employs actin-binding Designed Ankyrin Repeat Proteins (DARPins) fused to the improved Light-Induced Dimer (iLID) system, enabling actin cross-linking upon light-triggered dimerization. Following validation of cross-linking of bifunctional DARPins in reconstituted networks, the iLID system was integrated to create light-controlled associations inside cells. Optogenetic DARPin dimerization is rapid, reversible, and locally inducible. Activation of the DARPin-based actin cross-linkers revealed significant inhibition of cell traction forces when triggered throughout the cell. Our findings establish a versatile tool for investigating cytoskeletal dynamics with high spatial and temporal precision, paving the way for controlled manipulation of cellular architecture and mechanics. Graphical Abstract/Table of Contents Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/726659v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@c27701org.highwire.dtl.DTLVardef@112e82borg.highwire.dtl.DTLVardef@4892e4org.highwire.dtl.DTLVardef@a3d5a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

Herpes simplex virus infection promotes ALS pathology through ICP0-mediated PML body disruption

Transactive response DNA binding protein 43 kDa (TDP-43) pathology, is a central molecular hallmark of amyotrophic lateral sclerosis (ALS). However, the underlying triggers are incompletely understood. Here, we show that infection with herpes simplex virus (HSV) induces molecular hallmarks of ALS in various in vitro and in vivo models and is associated with an increased risk of ALS in human population data. German healthcare provider data (n = 238,440) and herpesvirus serology of an ALS patient and control cohort (n = 1,100) showed that HSV infection elevated the ALS risk by 210% and odds by [~]65%, respectively. On a molecular level, HSV infection promoted TDP-43 pathology in neuronal cell models, human iPSC-derived motoneurons and cerebral organoids, mice, and human tissue sections. This effect was triggered by HSV-1 or 2, but not by several other related herpesviruses. Mechanistically, the infected cell protein 0 (ICP0) of HSV-1/2 drives TDP-43 pathology by disturbance of promyelocytic leukemia nuclear bodies (PML-NBs), thereby abrogating TDP-43 SUMO2/3ylation. Taken together, we reveal a previously unrecognized association between HSV infection and ALS and clarify the underlying molecular mechanism that drives TDP-43 pathology. Our data may guide future studies into therapeutic and prophylactic interventions against ALS.

neuroscience↗

bioRxiv2024

A widespread electrical brain network encodes anxiety in health and depressive states

In rodents, anxiety is characterized by heightened vigilance during low-threat and uncertain situations. Though activity in the frontal cortex and limbic system is fundamental to supporting this internal state, the underlying network architecture that integrates activity across brain regions to encode anxiety across animals and paradigms remains unclear. Here, we utilize parallel electrical recordings in freely behaving mice, multiple translational paradigms known to induce anxiety, and machine learning to discover a multi-region network that encodes the anxious brain state. The network is composed of circuits widely implicated in anxiety behavior, it generalizes across many behavioral contexts that induce anxiety, and it fails to encode multiple behavioral contexts that do not. Strikingly, the activity of this network is also principally altered in two mouse models of depression. Thus, we establish a network-level process whereby the brain encodes anxiety in health and disease.

neuroscience↗

bioRxiv2023

Direct Antigen Presentation is the Canonical Pathway of Cytomegalovirus CD8 T-cell Priming Regulated by Balanced Immune Evasion Mounting a Strong Antiviral Response

CD8 T cells are the main antiviral effectors of the adaptive immune response to cytomegaloviruses (CMVs) in confining acute infection and in long-term surveillance of latent infection. An unresolved issue of debate, with diametrically opposite conclusions, is the mechanism by which CMV-specific naive CD8 T cells are primed. The idea of priming by antigen cross-presentation through uninfected professional antigen presenting cells taking up viral proteins derived from infected cells was based on the observation that the net response is not improved when direct presentation is enhanced by deletion of viral immune evasion genes affecting the classical MHC class-I pathway of antigen presentation. Redundance of priming mechanisms has been demonstrated by experimental models in which either pathway has been rendered inaccessible, so that both pathways are, in principle, capable of priming CD8 T cells. For studying CMV-specific priming in the normal host competent in both antigen presentation pathways, we took the novel approach to enhance instead of delete immune evasion protein expression. Surprisingly, the net magnitude of the CD8 T-cell response in the regional lymph node draining a local site of infection was identical for the contrasts of reduced or enhanced direct antigen presentation. At first glance, this may lead one to conclude that direct presentation plays no role in priming. This interpretation, however, is incompatible with the finding that an intermediate extent of direct antigen presentation, as it exists for wild-type virus, resulted in the best CD8 T-cell response. Our findings thus revealed an essential positive role of a balanced viral immune evasion in mounting a strong antiviral immune response. This novel insight sheds a completely new light on the acquisition of viral immune evasion genes during virus-host co-evolution.

immunology↗

bioRxiv2021

Fluid Menisci and In Vitro Particle Dosimetry of Submerged Cells

Understanding the mechanisms of interaction between cells and particulate nanomaterials lies in the heart of assessing the hazard associated with nanoparticles. The paradigm of toxicology requires quantifying and interpreting dose-response relationships, and cells cultured in vitro and exposed to particle dispersions rely on mathematical models that estimate the received nanoparticle dose. Yet, none of these models acknowledges the fact that aqueous cell-culture media wet the inner surface of hydrophilic open wells, which results in curved fluid-air interface called meniscus. We show that omitting this phenomenon leads to a nontrivial but systematic error and twists the fundamental concept of nanotoxicology. Given that reproducibility and harmonization between meta analyses, in vitro, in silico, and in vivo studies must be improved, we present an adequate mathematical model that greatly advances such efforts.

pharmacology and toxicology↗

bioRxiv2020

Antagonism Between Brain Regions Relevant for Cognitive Control and Emotional Memory Facilitates the Generation of Humorous Ideas

The ability to generate humor gives rise to positive emotions and thus facilitate the successful resolution of adversity. Although there is consensus that inhibitory processes might be related to broaden the way of thinking, the neural underpinnings of these mechanisms are largely unknown. Here, we use functional Magnetic Resonance Imaging, a humorous alternative uses task and a stroop task, to investigate the brain mechanisms underlying the emergence of humorous ideas in 24 subjects. Neuroimaging results indicate that greater cognitive control abilities are associated with increased activation in the amygdala, the hippocampus and the superior and medial frontal gyrus during the generation of humorous ideas. Examining the neural mechanisms more closely shows that the downregulation of frontal brain regions is associated with an upregulation in the amygdala, which is concurrently linked with an increased number of humorous ideas and enhanced amygdala responses during the task. Our data therefore suggests that a neural antagonism previously related to the emergence and regulation of negative affective responses, is linked with the generation of emotionally positive ideas and may represent an important neural pathway supporting mental health.

neuroscience↗

bioRxiv2019

Area and Geometry Dependence of Cell Migration in Asymmetric Two-State Micropatterns

Micro-structured surfaces provide a unique framework to probe cell migration and cytoskeletal dynamics in a standardized manner. Here, we report on the steady-state occupancy probability of cells in asymmetric two-state microstructures that consist of two fibronectin-coated adhesion sites connected by a thin guidance cue. In these dumbbell-like structures, cells transition between the two sites in a repeated and stochastic manner and average dwell times in the respective microenvironments are determined from the cell trajectories. We study the dynamics of human breast carcinoma cells (MDA-MB-231) in these microstructures as a function of area, shape and orientation of the adhesion sites. On square adhesive sites with different areas, we find that the occupancy probability ratio is directly proportional to the ratio of corresponding adhesion site areas. Sites of equal area but different shape lead to equal occupancy, if shapes are isotropic, e.g. squared or circular. In contrast, an asymmetry in the occupancy is induced by anisotropic shapes like rhombi, triangles or rectangles that enable motion in the direction perpendicular to the transition axis. Analysis of the 2D motion of cells between two rectangles with orthogonal orientation suggests that cellular transition rates depend on the cell polarisation induced by anisotropic micropatterns. Taken together, our results illustrate how two-state-micropatterns provide a dynamic migration assay with distinct dwell times and relative cell occupancy as readouts, which may potentially be useful to probe cell-microenvironment interactions.

biophysics↗

bioRxiv2019

Disentangling the Behavioural Variability of Confined Cell Migration

Cell-to-cell variability is inherent to numerous biological processes, including cell migration. Quantifying and characterizing the variability of migrating cells is challenging, as it requires monitoring many cells for long time windows under identical conditions. Here, we observe the migration of single human breast cancer cells (MDA-MB-231) in confining two-state micropatterns. To describe the stochastic dynamics of this confined migration, we employ a dynamical systems approach. We identify statistics to measure the behavioural variance of the migration, which significantly exceed those predicted by a population-averaged stochastic model. This additional variance can be explained by the combination of an aging process and population heterogeneity. To quantify population heterogeneity, we decompose the cells into subpopulations of slow and fast cells, revealing the presence of distinct classes of dynamical systems describing the migration, ranging from bistable to limit cycle behaviour. Our findings highlight the breadth of migration behaviours present in cell populations.

biophysics↗