The development of ultrasensitive force probes (AFM, optical tweezers, biomembrane force probe etc.) continues to fuel discovery in nano-to-microscale biophysics. Examples like our recent work on the mechano-regulation of leukocyte adhesion demonstrate how it often takes a multiscale, molecular-to-cellular approach to validate the biological relevance of insight gained from single-molecule techniques.  This is partly due to the "weakness" (or susceptibility to thermal activation) of biomolecular interactions.  Consequently, their interaction strength is a dynamic quantity that depends on the stress history experienced by the participating molecules.  This history, in turn, is affected by the mechanical properties of the supporting subcellular structures like membranes or the cytoskeleton.

Two examples of biomolecular interactions will be discussed in this context:  one intermolecular, the other intramolecular.  First, the P-selectin: PSGL-1 catch bond is at the molecular root of an intricate biosystem of switches, fuses, and shock absorbers that mechano-regulate the leukocyte response to inflammation.  Second, the first direct observation of the folding of individual spectrin repeats under force is changing our view of the molecular basis for the red-blood-cell membrane's hyperelasticity, enabling red cells to their amazing feat of 3 - 4 months circulatory survival.