ATP allosterically stabilizes integrin-linked kinase for efficient force generation

Focal adhesions link the actomyosin cytoskeleton to the extracellular matrix regulating cell adhesion, shape, and migration. Adhesions are dynamically assembled and disassembled in response to extrinsic and intrinsic forces, but how the essential adhesion component integrin-linked kinase (ILK) dynamically responds to mechanical force and what role adenosine triphosphate (ATP) bound to this pseudokinase plays remain elusive. Here, we apply force-probe molecular-dynamics simulations of human ILK:alpha-parvin coupled to traction force microscopy to explore ILK mechanotransducing functions. We identify two key salt-bridge-forming arginines within the allosteric, ATP-dependent force-propagation network of ILK. Disrupting this network by mutation impedes parvin binding, focal adhesion stabilization, force generation, and thus migration. Under tension, ATP shifts the balance from rupture of the complex to protein unfolding, indicating that ATP increases the force threshold required for focal adhesion disassembly. Our study proposes a role of ATP as an obligatory binding partner for structural and mechanical integrity of the pseudokinase ILK, ensuring efficient cellular force generation and migration.Peer reviewe

Hydrostatic pressure prevents chondrocyte differentiation through heterochromatin remodeling

Articular cartilage protects and lubricates joints for smooth motion and transmission of loads. Owing to its high water content, chondrocytes within the cartilage are exposed to high levels of hydrostatic pressure, which has been shown to promote chondrocyte identity through unknown mechanisms. Here, we investigate the effects of hydrostatic pressure on chondrocyte state and behavior, and discover that application of hydrostatic pressure promotes chondrocyte quiescence and prevents maturation towards the hyperlrophic state. Mechanistically, hydrostatic pressure reduces the amount of trimethylated H3K9 (K3K9me3)-marked constitutive heterochromatin and concomitantly increases H3K27me3-marked facultative heterochromatin. Reduced levels of H3K9me3 attenuates expression of pre-hypertrophic genes, replication and transcription, thereby reducing replicative stress. Conversely, promoting replicative stress by inhibition of topoisomerase II decreases Sox9 expression, suggesting that it enhances chondrocyte maturation. Our results reveal how hydrostatic pressure triggers chromatin remodeling to impact cell fate and function. This article has an associated First Person interview with the first author of the paper.Peer reviewe

Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage

Summary Tissue homeostasis requires maintenance of functional integrity under stress. A central source of stress is mechanical force that acts on cells, their nuclei, and chromatin, but how the genome is protected against mechanical stress is unclear. We show that mechanical stretch deforms the nucleus, which cells initially counteract via a calcium-dependent nuclear softening driven by loss of H3K9me3-marked heterochromatin. The resulting changes in chromatin rheology and architecture are required to insulate genetic material from mechanical force. Failure to mount this nuclear mechanoresponse results in DNA damage. Persistent, high-amplitude stretch induces supracellular alignment of tissue to redistribute mechanical energy before it reaches the nucleus. This tissue-scale mechanoadaptation functions through a separate pathway mediated by cell-cell contacts and allows cells/tissues to switch off nuclear mechanotransduction to restore initial chromatin state. Our work identifies an unconventional role of chromatin in altering its own mechanical state to maintain genome integrity in response to deformation.Peer reviewe

Mechanochemical control of epidermal stem cell divisions by B-plexins

The precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. However, the molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we identify a critical requirement of B-plexin transmembrane receptors in the response to crowding-induced mechanical forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail to sense mechanical compression, resulting in disinhibition of the transcriptional coactivator YAP, hyperproliferation, and tissue overgrowth. Mechanistically, we show that B-plexins mediate mechanoresponses to crowding through stabilization of adhesive cell junctions and lowering of cortical stiffness. Finally, we provide evidence that the B-plexin-dependent mechanochemical feedback is also pathophysiologically relevant to limit tumor growth in basal cell carcinoma, the most common type of skin cancer. Our data define a central role of B-plexins in mechanosensation to couple cell density and cell division in development and disease.Peer reviewe

Cooling quasiparticles in A(3)C(60) fullerides by excitonic mid-infrared absorption

Long after its discovery, superconductivity in alkali fullerides A(3)C(60) still challenges conventional wisdom. The freshest inroad in such ever-surprising physics is the behaviour under intense infrared excitation. Signatures attributable to a transient superconducting state extending up to temperatures ten times higher than the equilibrium T-c similar to 20 K have been discovered in K3C60 after ultra-short pulsed infrared irradiation-an effect which still appears as remarkable as mysterious. Motivated by the observation that the phenomenon is observed in a broad pumping frequency range that coincides with the mid-infrared electronic absorption peak still of unclear origin, rather than to transverse optical phonons as has been proposed, we advance here a radically new mechanism. First, we argue that this broad absorption peak represents a 'super-exciton' involving the promotion of one electron from the t(1u) half-filled state to a higher-energy empty t(1g) state, dramatically lowered in energy by the large dipole-dipole interaction acting in conjunction with the Jahn-Teller effect within the enormously degenerate manifold of (t(1u))(2)(t(1g))(1) states. Both long-lived and entropy-rich because they are triplets, the infrared-induced excitons act as a sort of cooling mechanism that permits transient superconductive signals to persist up to much higher temperatures

Computational Modelling of Tissue-Engineered Cartilage Constructs

Cartilage is a fundamental tissue to ensure proper motion between bones and damping of mechanical loads. This tissue often suffers damage and has limited healing capacity due to its avascularity. In order to replace surgery and replacement of joints by metal implants, tissue engineered cartilage is seen as an attractive alternative. These tissues are obtained by seeding chondrocytes or mesenchymal stem cells in scaffolds and are given certain stimuli to improve establishment of mechanical properties similar to the native cartilage. However, tissues with ideal mechanical properties were not obtained yet. Computational models of tissue engineered cartilage growth and remodelling are invaluable to interpret and predict the effects of experimental designs. The current model contribution in the field will be presented in this chapter, with a focus on the response to mechanical stimulation, and the development of fully coupled modelling approaches incorporating simultaneously solute transport and uptake, cell growth, production of extracellular matrix and remodelling of mechanical properties.publishe

Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involvedSupplementary Information: Supplementary Data 1; Supplementary Data 2; Reporting Summary.NHMRC; Women’s and Children’s Hospital Research Foundation; Muir Maxwell Trust; Epilepsy Society; The European Fund for Regional Development; The province of Friesland, Dystonia Medical Research Foundation; Stichting Wetenschapsfonds Dystonie Vereniging; Fonds Psychische Gezondheid; Phelps Stichting; The Italian Ministry of Health; Istituto Superiore di Sanità, Italy; Undiagnosed Disease Network Italy; The Fondation maladies rares, University Hospital Essen and UK Department of Health’s NIHR.https://www.nature.com/ncommspm2020Neurolog

MAGIC and H.E.S.S. detect VHE gamma rays from the blazar OT081 for the first time: a deep multiwavelength study

https://pos.sissa.it/395/815/pdfPublished versio