Mutations in actin-bundling protein plastin 3 (PLS3) emerged as a cause of congenital osteoporosis, but neither the role of PLS3 in bone development nor the mechanisms underlying PLS3-dependent osteoporosis are understood. Of the over 20 identified osteoporosis-linked PLS3 mutations, we investigated all five that are expected to produce full-length protein. One of the mutations distorted an actin-binding loop in the second actin-binding domain of PLS3 and abolished F-actin bundling as revealed by cryo-EM reconstruction and protein interaction assays. Surprisingly, the remaining four mutants fully retained F-actin bundling ability. However, they displayed defects in Ca2+ sensitivity: two of the mutants lost the ability to be inhibited by Ca2+, while the other two became hypersensitive to Ca2+. Each group of the mutants with similar biochemical properties showed highly characteristic cellular behavior. Wild-type PLS3 was distributed between lamellipodia and focal adhesions. In striking contrast, the Ca2+-hyposensitive mutants were not found at the leading edge but localized exclusively at focal adhesions/stress fibers, which displayed reinforced morphology. Consistently, the Ca2+-hypersensitive PLS3 mutants were restricted to lamellipodia, while chelation of Ca2+ caused their redistribution to focal adhesions. Finally, the bundling-deficient mutant failed to co-localize with any F-actin structures in cells despite a preserved F-actin binding through a non-mutation-bearing actin-binding domain. Our findings revealed that severe osteoporosis can be caused by a mutational disruption of the Ca2+-controlled PLS3’s cycling between adhesion complexes and the leading edge. Integration of the structural, biochemical, and cell biology insights enabled us to propose a molecular mechanism of plastin activity regulation by Ca2+.

The compound helicopter has much to offer as a means of expanding the¯ight envelope of rotorcraft. There have been signi®cant amounts of research performed, albeit disjointed, and manȳ ight demonstrator compound helicopters produced and trialled since the end of the Second World WarÐmainly with the aim of increasing the helicopter's maximum forward speed. This paper aims to pool this knowledge, along with relevant developments in other ®elds, not only to state the current level of understanding of the compound helicopter con®guration but also to use it to predict likely con®gurations and technologies that would be best suited to future compound helicopter designs. From this basis it is suggested that the most likely con®guration will be a low wing of minimized area to alleviate retreating blade stall at a minimum hover blockage, with plain¯aps for blockage reduction and control of the rotor±wing load share. In terms of propulsion a ducted fan or propeller are deemed most suitable, driven by either an advanced mechanical drive or variable cycle engine. The areas of rotor±wing interaction and advanced rotor design are also noted as subjects of signi®cant interest in the optimal design of a compound helicopter.

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Compounding offers a way of advancing the performance of the standard helicopter significantly for a moderate increase in complexity through the addition of wings and/or auxiliary propulsion. The compound helicopter configuration has the potential advantages of increased speed, range, agility, productivity and reduced vibration levels over conventional helicopters. Despite several significant efforts, however, no compound helicopter has ever been put into production. This paper looks at three aircraft that came close to being accepted by operators and examines the reasons why they were not ultimately put into production. The cancellation of these projects appeared to be of a political nature rather than technical. Also addressed are the issues that still face prospective designers of compound helicopters and the lessons that can be extracted and applied to modern day efforts to build and sell an aircraft of this configuration.