Molecular tension sensors have contributed to a growing understanding of mechanobiology. However, the limited dynamic range and inability to specify the mechanical sensitivity of these sensors has hindered their widespread use in diverse contexts. Here, we systematically examine the components of tension sensors that can be altered to improve their functionality. Guided by the development of a first principles model describing the mechanical behavior of these sensors, we create a collection of sensors that exhibit predictable sensitivities and significantly improved performance in cellulo. Utilized in the context of vinculin mechanobiology, a trio of these new biosensors with distinct force- and extension-sensitivities reveal that an extension-based control paradigm regulates vinculin loading in a variety of mechanical contexts. To enable the rational design of molecular tension sensors appropriate for diverse applications, we predict the mechanical behavior, in terms of force and extension, of additional 1020 distinct designs.

Abstract:6 Molecular tension sensors have contributed to a growing understanding of mechanobiology. However, 7 the limited dynamic range and inability to specify the mechanical sensitivity of these sensors has 8 hindered their widespread use in diverse contexts. Here, we systematically examine the components of 9 tension sensors that can be altered to improve their functionality. Guided by the development of a first 10 principles model describing the mechanical behavior of these sensors, we create a collection of sensors 11 that exhibit predictable sensitivities and significantly improved performance in cellulo. Utilized in the 12 context of vinculin mechanobiology, a trio of these new biosensors with distinct force-and extension-13 sensitivities reveal that an extension-based control paradigm regulates vinculin loading. To enable the 14 rational design of molecular tension sensors appropriate for diverse applications, we predict the 15 mechanical behavior, in terms of force and extension, of additional 1020 distinct designs.

No abstract

No abstract

The establishment and rise of the Council of Australian Governments (COAG) is, on balance, a story of the successful development of an executive-based institution for cooperative governance in the Australian federal system. By contrast, the Council of the Australian Federation (CAF), created in 2006 as a forum for interstate co-operation and policy development, has been far less effective. This article explores the reasons behind CAF's difficulties after a very short-lived initial impact. Integral to this account is the significance of Canadian experience of horizontal intergovernmental relations, which directly inspired the Australian Premiers to found CAF. The numerous indications of political congruence – some temporary, others systemic – between the Canadian and Australian settings obscured a deeper constitutional incongruence between the two jurisdictions and this is fundamental to appreciating CAF's failure as a transplant. CAF's ability to operate effectively as a significant institution was inevitably constrained by the parameters of the Australian federal system that its establishment was, in many ways, seeking to transcend.