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While the mechanisms by which chemical signals control cell fate have been well studied, the impact of mechanical inputs on cell fate decisions is not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through linker of nucleoskeleton and cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate.

A shortcut review of the literature was conducted to determine whether manual pressure augmentation improves the outcome from cardiac arrest. A total of nine publications were screened by title and abstract and one study (a case report and literature review) underwent full-text review. A further review of bibliographies of relevant papers found one further relevant study protocol. Details about the author, date of publication, country of publication, patient group studied, study type, relevant outcomes (survival and return of spontaneous circulation rate), results and study limitations were tabulated. The clinical bottom line is that, in adult patients in ventricular fibrillation or ventricular tachycardia, manual pressure augmentation during defibrillation may reduce impedance. This might improve defibrillation success, but there is insufficient evidence to recommend this without further research.

The exploration of cell-type and environmentally-responsive nuclear pore complex (NPC) plasticity requires new, accessible tools. Using pan-Expansion Microscopy (pan-ExM), NPCs were identified by machine learning-facilitated segmentation with resolved cytoplasmic rings (CR), inner rings (IR) and nuclear rings (NR). They exhibited a large range of diameters with a bias for dilated NPCs at the basal nuclear surface in clusters suggestive of local islands of nuclear envelope (NE) tension. Whereas hyperosmotic shock constricted NPCs analogously to those found in annulate lamellae (AL), depletion of LINC complexes specifically eliminated the modest nuclear surface diameter biases. Therefore, LINC complexes may contribute locally to nuclear envelope tension to toggle NPC diameter between dilated, but not constricted, states. Lastly, POM121 shifts from the NR to the IR specifically in induced pluripotent stem cell derived neurons (iPSNs) from a patient with amyotrophic lateral sclerosis (ALS). Thus, pan-ExM is a powerful tool to visualize NPC plasticity in physiological and pathological contexts at single NPC resolution.

Abstract While the mechanisms by which chemical signals control cell fate have been well studied, how mechanical inputs impact cell fate decisions are not well understood. Here, using the well-defined system of keratinocyte differentiation in the skin, we examine whether and how direct force transmission to the nucleus regulates epidermal cell fate. Using a molecular biosensor, we find that tension on the nucleus through Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes requires integrin engagement in undifferentiated epidermal stem cells, and is released during differentiation concomitant with decreased tension on A-type lamins. LINC complex ablation in mice reveals that LINC complexes are required to repress epidermal differentiation in vivo and in vitro and influence accessibility of epidermal differentiation genes, suggesting that force transduction from engaged integrins to the nucleus plays a role in maintaining keratinocyte progenitors. This work reveals a direct mechanotransduction pathway capable of relaying adhesion-specific signals to regulate cell fate. Competing Interest Statement The authors have declared no competing interest. Footnotes * This revised manuscript includes three major additions: 1) further characterization of the N2G-JM-TSMod LINC complex tension sensor (Fig. 1); 2) ATAC-seq analysis demonstrating precocious accessibility of epidermal differentiation genes in the absence of LINC complexes (Fig. 5) and 3) use of mouse keratinocytes lacking beta-1 integrin to probe the requirement for cell-ECM engagement to both drive high tension on the LINC complex (Fig. 1) and to repress epidermal differentiation (Fig. 4). Supplementary files for bioinformatic analysis and the links to the raw sequencing data are also provided. * https://www.ncbi.nlm.nih.gov/bioproject/PRJNA636991

COLLINGWOOD midfielder Tarkyn Lockyer believes Adelaide will meet a more intense and faster-starting opponent should they meet again next weekend in the first week of the finals.

ESSENDON champion James Hird says he will retire at the end of this season regardless of his current good form and whether or not the Bombers make the finals.

ESSENDON champion James Hird says he will retire at the end of this season regardless of his current good form and whether or not the Bombers make the finals.

AT QUARTER-TIME on Friday night, David Hille was just like his team: getting run past, run over, and running out of time. At the half-time break the contest was more even, but the gap not bridged.

AT QUARTER-TIME on Friday night, David Hille was just like his team: getting run past, run over, and running out of time. At the half-time break the contest was more even, but the gap not bridged.

COLLINGWOOD is hopeful its 10-day break before fronting up against a revitalised Melbourne next round will give Heath Shaw and Simon Prestigiacomo ample time to recover from leg injuries.