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Focal adhesion kinase (FAK) is a key signaling molecule regulating cell adhesion, migration, and survival. FAK localizes into focal adhesion complexes formed at the cytoplasmic side of cell attachment to the ECM and is activated after force generation via actomyosin fibers attached to this complex. The mechanism of translating mechanical force into a biochemical signal is not understood, and it is not clear whether FAK is activated directly by force or downstream to the force signal. We use experimental and computational single-molecule force spectroscopy to probe the mechanical properties of FAK and examine whether force can trigger activation by inducing conformational changes in FAK. By comparison with an open and active mutant of FAK, we are able to assign mechanoactivation to an initial rupture event in the lowforce range. This activation event occurs before FAK unfolding at forces within the native range in focal adhesions. We are also able to assign all subsequent peaks in the force landscape to partial unfolding of FAK modules. We show that binding of ATP stabilizes the kinase domain, thereby altering the unfolding hierarchy. Using all-atom molecular dynamics simulations, we identify intermediates along the unfolding pathway, which provide buffering to allow extension of FAK in focal adhesions without compromising functionality. Our findings strongly support that forces in focal adhesions applied to FAK via known interactions can induce conformational changes, which in turn, trigger focal adhesion signaling.

The effectiveness of skills laboratory training is widely recognized. Yet, the transfer of procedural skills acquired in skills laboratories into clinical practice has rarely been investigated. We conducted a prospective, randomised, double-blind, controlled trial to evaluate, if students having trained intravenous (IV) cannulation in a skills laboratory are rated as more professional regarding technical and communication skills compared to students who underwent bedside teaching when assessed objectively by independent video assessors and subjectively by patients. 84 volunteer first-year medical students were randomly assigned to one of two groups. Three drop-outs occurred. The intervention group (IG; n = 41) trained IV cannulation in a skills laboratory receiving instruction after Peyton's 'Four-Step Approach'. The control group (CG; n = 40) received a bedside teaching session with volunteer students acting as patients. Afterwards, performance of IV cannulation of both groups in a clinical setting with students acting as patients was video-recorded. Two independent, blinded video assessors scored students' performance using binary checklists (BC) and the Integrated Procedural Protocol Instrument (IPPI). Patients assessed students' performance with the Communication Assessment Tool (CAT) and a modified IPPI. IG required significantly shorter time needed for the performance on a patient (IG: 595.4 SD(188.1)s; CG: 692.7 SD(247.8)s; 95%CI 23.5 s to 45.1 s; p = 0.049) and completed significantly more single steps of the procedure correctly (IG: 64% SD(14) for BC items; CG: 53% SD(18); 95%CI 10.25% to 11.75%; p = 0.004). IG also scored significantly better on IPPI ratings (median: IG: 3.1; CG: 3.6; p = 0.015;). Rated by patients, students' performance and patient-physician communication did not significantly differ between groups. Transfer of IV cannulation-related skills acquired in a skills laboratory is superior to bedside teaching when rated by independent video raters by means of IPPI and BC. It enables students to perform IV cannulation more professionally on volunteer students acting as patients.

This white paper outlines a long-term scientific vision for the development of digital-democracy technology. We contend that if digital democracy is to meet the ambition of enabling a participatory renewal in our societies, then a comprehensive multi-methods research effort is required that could, over the years, support its development in a democratically principled, empirically and computationally informed way. The paper is co-authored by an international and interdisciplinary team of researchers and arose from the Lorentz Center Workshop on ``Algorithmic Technology for Democracy'' (Leiden, October 2022).