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📰 "The nucleus forms a dynamic contact with the plasma membrane to maintain the glandular epithelial architecture"
doi.org/doi:10.1101/2025.06.13
pubmed.ncbi.nlm.nih.gov/406616
#Mechanical #Actin

bioRxiv · The nucleus forms a dynamic contact with the plasma membrane to maintain the glandular epithelial architectureThe maintenance of epithelial architecture relies on precise mechanical and biochemical cues. Recent studies reveal an unexpected role for the nucleus in maintaining epithelial architecture, but how the nucleus is physically and molecularly integrated into epithelia remains unclear. Here, we identify a dynamic basal actin spot that links the nucleus to plasma membrane β1-integrin through the linker of nucleoskeleton and cytoskeleton (LINC) in 3D breast acini. Depletion of LINC complex nesprin-2G, SUNs or FHOD1 disrupts nuclear positioning and inhibits lumen formation. Activation of a nesprin-2 degron causes acute loss of the basal actin spot and collapse of acini. Active Src and β1-integrin accumulate in the basal actin spot and Src activity is required to prevent collapse of acinar structure. These findings reveal an unexpected mode of nuclear-plasma membrane contact that we propose homeostatically regulates intracellular contractility through a Src signaling pathway to maintain global epithelial architecture. ### Competing Interest Statement The authors have declared no competing interest. National Institutes of Health, R35 GM136403, UO1 CA2255663

📰 "Formation of extracellular vesicles depends on mechanical feedback of the cortex and the glycocalyx"
doi.org/doi:10.1101/2025.06.14
pubmed.ncbi.nlm.nih.gov/406615
#Extracellular #Mechanical #Cell

bioRxiv · Formation of extracellular vesicles depends on mechanical feedback of the cortex and the glycocalyxCell-secreted extracellular vesicles (EVs) play a pivotal role in local and distant cell-to-cell communication by delivering specific cargoes to other cells or to the extracellular space. In many cells, the glycocalyx, a thick sugar-rich layer at the cell surface, and the membrane-cortex attachment are crucially linked to the formation of EVs, yet it is unclear what determines the successful formation of EVs when multiple physical factors are involved. In this work, we developed a model for glycocalyx-membrane-cortex composite to investigate the effects of gly-cocalyx and membrane-cortex adhesion on the formation of EVs by combining polymer physics-based theory and Helfrich membrane theory. By performing linear stability analysis, we show that modulating the mechanical feedback among the glycocalyx, membrane-cortex attachment, and membrane curvature can give rise to two types of instabilities: a conserved Turing-type instability and a Cahn-Hilliard-type instability. Furthermore, using an equilibrium model, we identified two critical conditions for EV formation: an initial detachment of the membrane from the underlying cortex and then a sufficient driving force to induce membrane deformation for successful EV formation. We further demonstrated that there exists an optimal glycocalyx coating area at which the formation of EVs is most favorable. Finally, we use our model to predict that a heterogeneous size distribution of EVs can be generated through the regulation of glycocalyx properties, shedding insight into how EVs of different radii may be generated. Significance Statement Extracellular vesicles (EVs) are important for cell biology because they facilitate active communication between cells. Understanding the governing factors that control the formation of EVs is crucial to many cellular processes ranging from tumor progression and metastasis evolution to the disposal of unwanted biomolecules. However, whether EV secretion is a consequence of the glycocalyx and the role of membrane-cortex adhesion in the formation of EVs are still elusive. To address these issues, here we develop a biophysical model for EV formation that couples the presence of glycocalyx and membrane-cortex adhesion. We find that the glycocalyx-membrane-cortex composite system exhibits two types of instabilities utilizing stability analysis – a Turing instability and a Cahn-Hilliard type instability. Based on our proposed equilibrium model, we identified that for the initiation of membrane detachment and the formation of EVs each need to meet a critical threshold. In addition, our model predicts that the formation of EVs is most favorable when an optimal glycocalyx coating area reaches and a heterogeneous distribution EV sizes can be produced by regulating glycocalyx properties. ### Competing Interest Statement The authors have declared no competing interest. NIH, R01GM132106 Office of Naval Research, N00014-20-1-2469
bioRxiv · The Desmoglein 2 interactome in primary neonatal cardiomyocytesMechanical coupling and chemical communication between cardiomyocytes are facilitated through a specialized adhesive structure known as the intercalated disc (ICD). The ICD is essential for heart organization and contraction. Yet, the network of adhesion, adaptor, and signaling proteins that form the ICD remains poorly defined. Here, we combined proximity labeling and quantitative mass spectrometry to identify proteins associated with the desmosomal cadherin, Desmoglein 2 (DSG2), in cultured neonatal cardiomyocytes. We identified over 300 proteins in the DSG2 interactome; half of which are shared with the N-cadherin (CDH2) interactome in cardiomyocytes. Proteins unique to DSG2 include the gap junction protein connexin 43 and the plakin family of cytolinker proteins. Comparison of the cardiomyocyte DSG2 interactome with the interactomes of desmosomal proteins from epithelia revealed only a small number of shared proteins. In cardiomyocytes, plakoglobin (JUP) and plakophilin 2 (PKP2) were the most abundant shared proteins between the DSG2 and CDH2 interactomes. PKP2 is a dynamic protein whose membrane recruitment in cardiomyocytes is tension-dependent. Our analysis of the DSG2 interactome provides a critical new dimension to the proteomic atlas of the essential molecular complexes required for cardiomyocyte adhesion. ### Competing Interest Statement The authors have declared no competing interest. National Heart Lung and Blood Institute, https://ror.org/012pb6c26, HL127711

📰 "The nucleus activates mechano-responsiveness via FHOD-associated LINC complexes"
doi.org/doi:10.1101/2025.06.13
pubmed.ncbi.nlm.nih.gov/406615
#Mechanical #Actin

bioRxiv · The nucleus activates mechano-responsiveness via FHOD-associated LINC complexesThe nucleus is the defining organelle of eukaryotic cells. It is usually considered a target organelle for cellular inputs. Here, we find that the nucleus is not simply a “passive” responder, but an active organelle directing the mechanical properties of the actin cytoskeleton it engages. Biochemically, interaction of FHOD formins with nesprin-2 of the nuclear LINC complex activates their actin bundling activity making them more potent than known bundlers like fascin or α-actinin. In cells, FHOD-associated LINC complexes enhance the mechanical resistance of nuclear-engaged actin cables in polarizing fibroblasts and sarcomeres in developing cardiomyocytes. Hypertrophic cardiomyopathy-associated variants of FHOD3 are defective in these processes. In mice, the FHOD3 R637P disease-causing allele results in embryonic lethality when homozygous and in stress-induced cardiac hypertrophy when heterozygous. These results show that the nucleus actively directs its mechanical environment and that disruption of this capability in heart leads to cardiac hypertrophy. ### Competing Interest Statement The authors have declared no competing interest. NIH, R35 GM136403 NIH, RO1 HL159389

📰 "A conserved Arf-GEF modulates axonal integrity through RAB-35 by altering neuron-epidermal attachment"
doi.org/doi:10.1101/2025.06.03
pubmed.ncbi.nlm.nih.gov/406613
#Cytoskeletal #Mechanical

bioRxiv · A conserved Arf-GEF modulates axonal integrity through RAB-35 by altering neuron-epidermal attachmentNeurites of sensory neurons densely innervate the skin and are embedded within it. These delicate structures are exposed to acute and chronic mechanical strain and yet their integrity is maintained throughout life. Although evidence suggests a neuroprotective role for the skin, the molecular pathways involved are still poorly understood. In C. elegans , the cytoskeletal molecule UNC-70/β-spectrin functions in synergy with the small GTPase RAB-35 within the skin to stabilize neuron-epidermal attachment structures against mechanical strain and prevent movement-induced damage to mechanosensitive axons. However, the full suite of molecules regulating these specialized attachments remains elusive. Here, through an unbiased forward genetic screen we have identified a guanine nucleotide exchange factor (GEF) previously associated with the endocytic-recycling machinery, AGEF-1a, that impacts axonal maintenance. We show that AGEF-1a functions selectively within the skin to regulate the integrity of the embedded axons. Mechanistically, we reveal that this effect is achieved through an interaction between AGEF-1a and epidermal RAB-35 to facilitate its activation, which in turn modulates the neuron-epidermal attachments. Finally, we demonstrate that the function of this GEF is highly conserved, with the expression of its human ortholog, BIG2 capable of replacing AGEF-1a. Together, we reveal the specific molecular machinery responsible for fine-tuning neuron-epidermal attachments and maintaining axonal integrity during life. ### Competing Interest Statement The authors have declared no competing interest. National Health and Medical Research Council, https://ror.org/011kf5r70, APP1108489, GNT2010532, APP1197860, APP1129546 Australian Research Council, LE130100078

📰 "A Platform for Mitochondrial Profiling in Enriched Kidney Segments Under Thermodynamic Control"
doi.org/doi:10.1101/2025.05.05
pubmed.ncbi.nlm.nih.gov/406549
#Mechanical #Cell

bioRxiv · A Platform for Mitochondrial Profiling in Enriched Kidney Segments Under Thermodynamic ControlMitochondrial function varies widely across kidney nephron segments, yet conventional approaches lack the resolution and control needed to assess cell-type-specific bioenergetics in situ. We present a methodological platform that enables segment-resolved profiling of mitochondrial respiration, conductance, and membrane potential in freshly isolated mouse nephron segments. Combining mechanical sieving and adhesion-based enrichment with permeabilized high-resolution respirometry, we adapted the creatine kinase clamp to quantify oxygen flux and mitochondrial membrane potential across defined free energies. Using this approach, we found that proximal tubules exhibit high respiratory conductance and dynamic mitochondrial polarization, while distal tubules and glomeruli maintain static membrane potential and low conductance. In a model of adenine-induced nephropathy, only proximal tubule mitochondria showed marked reductions in respiration and ATP production. This segment-specific dysfunction was not detectable in bulk mitochondrial isolates. Our approach provides thermodynamically anchored, segment-resolved insight into mitochondrial adaptation under physiological and pathological conditions. It is broadly applicable to other tissues with metabolic heterogeneity and compatible with disease models, genetic tools, and pharmacological interventions. This platform bridges a critical gap between conventional respirometry and functional mitochondrial phenotyping in native tissue structures. ### Competing Interest Statement The authors have declared no competing interest. National Institute of Diabetes and Digestive and Kidney Diseases, https://ror.org/00adh9b73, DK107397, DK127979, DK133271, DK132487, DK091317 National Cancer Institute, https://ror.org/040gcmg81, CA278826 National Kidney Foundation of Utah and Idaho National Institute of General Medical Sciences, https://ror.org/04q48ey07, GM144613 National Institute on Aging, https://ror.org/049v75w11, AG074535

📰 "Actin Branching Regulates Cell Spreading and Force on Talin, but not Activation of YAP"
doi.org/doi:10.1101/2025.05.09
pubmed.ncbi.nlm.nih.gov/406549
#Mechanical #Actin #Force #Cell

bioRxiv · Actin Branching Regulates Cell Spreading and Force on Talin, but not Activation of YAPCells sense the mechanical properties of their environment through physical engagement and spreading, with high stiffness driving nuclear translocation of the mechanosensitive transcription factor YAP. Restriction of cell spread area or environmental stiffness both inhibit YAP activation and nuclear translocation. The Arp2/3 complex plays a critical role in polymerization of branched actin networks that drive cell spreading, protrusion, and migration. While YAP activation has been closely linked to cellular spreading, the specific role of actin branching in force buildup and YAP activation is unclear. To assess the role of actin branching in this process, we measured cell spreading, YAP nuclear translocation, force on the adhesion adaptor protein Talin (FRET tension sensor), and extracellular forces (traction force microscopy, TFM) in 3T3 cells with and without inhibition of actin branching. The results indicate that YAP activation still occurs when actin branching and cell spreading is reduced. Interestingly, while actin de-branching resulted in decreased force on talin, relatively little change in average traction stress was observed, highlighting the distinct difference between molecular level and cellular level force regulation of YAP. While cell spreading is a driver of YAP nuclear translocation, this is likely through indirect effects. Changes in cell spreading induced by actin branching inhibition do not significantly perturb YAP activation. Additionally, this work provides evidence that focal adhesion molecular forces are not a direct regulator of YAP activation. ### Competing Interest Statement The authors have declared no competing interest. National Institute of General Medical Sciences, 1R35GM155264

📰 "A Cryogenic Uniaxial Strain Cell for Elastoresistance Measurements"
arxiv.org/abs/2507.08428 #Cond-Mat.Supr-Con #Physics.Ins-Det #Mechanical #Cell

arXiv logo
arXiv.orgA Cryogenic Uniaxial Strain Cell for Elastoresistance MeasurementsWe present the design, implementation, and validation of a cryo-compatible strain cell for elastoresistance measurements in quantum materials. The cell is actuated by three large-format piezoelectric stacks and enables both compressive and tensile strain up to approximately $\pm5\%$. The relative displacement of the sample holders is measured in situ using a high-resolution capacitive displacement sensor, ensuring precise strain control throughout measurement. To operate the strain cell over a broad temperature range from 4.2\,K to 300\,K, a modular measurement probe was developed, allowing efficient thermal coupling and integration into cryogenic environments. The functionality and precision of the setup were demonstrated by elastoresistance measurements on the iron-based superconductor BaFe$_2$As$_2$ along the [110] direction. The results were validated against conventional techniques based on glued samples and strain gauges, showing excellent agreement in amplitude and temperature dependence of the elastoresistance coefficient. Additional tests revealed that the system remains robust under mechanical vibrations introduced by vacuum pumps, enabling stable operation even with liquid nitrogen cooling. This highlights the high mechanical and thermal reliability of the developed platform for low-temperature transport measurements under controlled uniaxial strain.

📰 "Paralemmin-3 sustains the integrity of the lateral plasma membrane and subsurface cisternae of auditory hair cells"
biorxiv.org/content/10.1101/20 #Mechanical #Actin

bioRxiv · Paralemmin-3 sustains the integrity of the lateral plasma membrane and subsurface cisternae of auditory hair cellsIn the mammalian inner ear, cochlear inner hair cells (IHCs) enable accurate and faithful synaptic sound encoding, while outer hair cells (OHCs) perform frequency-specific sound amplification and fine-tuning through their intrinsic voltage-dependent somatic electromotility. This latter process is facilitated by the unique trilaminate structure of the OHC lateral wall, which consists of the plasma membrane that is densely occupied by the transmembrane motor protein Prestin, the submembrane actin- and spectrin-based cytoskeleton, and the endomembranous subsurface cisternae. This complex system provides mechanical resilience while allowing for cell expansion and contraction during electromotility. Whereas the ultrastructure of the lateral wall is well described, its molecular architecture remains largely elusive. Here, we identified Paralemmin-3 (Palm3) as a novel protein specifically localized to the lateral walls of auditory HCs to play a crucial role in connecting the plasma membrane to the underlying cytoskeleton and subsurface cisternae. Palm3 -KO mice display early-onset and progressive hearing impairment that results from diminished cochlear amplification. Subsequent multiscale morphological analyses revealed structural collapse of OHCs that led to progressive and extensive OHC loss along the tonotopic axis. Palm3 -KO OHCs exhibited disrupted expression and distribution of several membrane-associated proteins − including spectrin isoforms and Prestin − suggesting an essential role of Palm3 in plasma membrane scaffolding. Electron tomography of OHC lateral walls revealed significantly fewer and structurally perturbed subsurface cisternae. Finally, adeno-associated virus (AAV)-mediated rescue of Palm3 during early postnatal development partly restored hearing function, enhanced OHC survival, and restored OHC cell shape as well as membrane protein expression levels. In summary, Palm3 is a key component of the submembrane cytoskeleton in cochlear hair cells, playing a fundamental role in hair cell biology and hearing, and emerges as an attractive candidate for the long-elusive ″pillar″ component of the hair cell lateral wall ultrastructure. ### Competing Interest Statement The authors have declared no competing interest. Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, VO 2466/1-1, 257917528, 130725592 Europäische Fonds für regionale Entwicklung (EFRE), ETomoH&H: Elektronentomografie an Herz und Hirn Elisabeth and Helmuth Uhl Foundation, Otto Creutzfeldt Fellowship Collaborative Research Centre, 889 Innsbruck Medical University, https://ror.org/03pt86f80 University Medical Center Göttingen

📰 "Ploidy alters root anatomy and shapes the evolution of wheat polyploids"
biorxiv.org/content/10.1101/20 #Mechanical #Cell

bioRxiv · Ploidy alters root anatomy and shapes the evolution of wheat polyploidsPolyploidization played a crucial role in crop domestication and modern agriculture. While increased cell size in polyploids is known to enhance plant biomass and vigor, its impact on soil exploration remains poorly understood. Using wheat as a model, we identify a ploidy-induced belowground domestication syndrome, characterized by (a) increased root cortical cell size reducing root respiration, nitrogen content, and phosphorus content; (b) enlarged metaxylem vessels, increasing axial hydraulic conductance; and (c) blunter root tips, limiting penetration ability in compacted soils. Our empirical and in silico experiments show that reduced root respiration and reduced cellular nutrient content in wheat polyploids improved nutrient use and acquisition efficiency under suboptimal nitrogen and phosphorus availability. These adaptations would have been advantageous in nutrient-depleted agroecosystems of the Pre-Pottery Neolithic B (PPNB) Fertile Crescent, where continuous cultivation depleted soil fertility over time. Functional-structural modeling indicates that larger cortical cells in wheat polyploids increase vacuolar occupancy, reducing root metabolic costs. Enhanced axial hydraulic conducta nce may have improved water transport, an advantage in irrigated PPNB agroecosystems. However, polyploids have blunter root tips, which reduces their penetration ability in compacted soils, making them less suited for native soils with greater mechanical impedance. We propose that root anatomical changes driven by ploidy played an important role in adaptations of wheat domesticates to PPNB agriculture. ### Competing Interest Statement The authors have declared no competing interest. US Department of Energy ARPA-E, DE-AR0000821 Howard G. Buffett Foundation, https://ror.org/05v76zz53 US Department of Agriculture National Institute of Food and Agriculture, Hatch Appropriations Projects PEN04732, PENW-2020-03632 and Accession #:7009406