The giant sarcomeric protein titin contains a protein kinase domain (TK) ideally positioned to sense mechanical load. We identified a signaling complex where TK interacts with the zinc-finger protein nbr1 through a mechanically inducible conformation. Nbr1 targets the ubiquitin-associated p62/SQSTM1 to sarcomeres, and p62 in turn interacts with MuRF2, a muscle-specific RING-B-box E3 ligase and ligand of the transactivation domain of the serum response transcription factor (SRF). Nuclear translocation of MuRF2 was induced by mechanical inactivity and caused reduction of nuclear SRF and repression of transcription. A human mutation in the titin protein kinase domain causes hereditary muscle disease by disrupting this pathway.During muscle differentiation, a specific program of gene expression leads to the translation of myofibrillar proteins and their assembly into contractile units, the sarcomeres, which are constantly remodeled to adapt to changes in mechanical load. The giant protein titin (also known as connectin) acts as a molecular blueprint for sarcomere assembly by providing specific attachment sites for numerous sarcomeric proteins, as well as acting as a molecular spring (1, 2). Titin also contains a catalytic serine-threonine kinase domain (TK), which is inhibited by a specific dual mechanism (3). However, the upstream elements controlling TK activation, its range of cellular substrates, and particularly the role of TK in mature muscle are largely unknown. Spanning half sarcomeres from Z disk to M band, titin is in a unique position to sense mechanical strain along the sarcomere (1). The elastic properties of the titin molecule and the mechanical deformation of the M band during stretch and contraction (4) suggest that the signaling properties of TK might be modulated by mechanically induced conformational changes. Molecular dynamics simulations suggest that mechanical strain can induce a catalytically active conformation of TK (5).The catalytic kinase domain of titin interacts with nbr1. We searched for further elements of a putative signaling pathway that might recognize mechanically induced conformational intermediates of titin's catalytic domain. In a systematic two-hybrid screening approach with various structure-based open states of the catalytic site [kin1, kin2, and kin3 (6)], we identified the zinc-finger protein nbr1 (7) as a TK ligand, which interacted via its Nterminal PB1 domain with the semiopened construct kin3 (Fig. 1, A and B). This interaction was also seen in precipitation experiments with nbr1 and TK-kin3 ( fig. S1A). Kin1, where the complete regulatory domain closes the active site, and kin2, where the a helix R1 (3) is deleted, did not interact. Thus, aR1 was necessary but not sufficient for nbr1 binding, which also required a semiopened catalyt-

SUMMARYPorpoise echolocation has been studied previously, mainly in target detection experiments using stationed animals and steel sphere targets, but little is known about the acoustic behaviour of free-swimming porpoises echolocating for prey. Here, we used small onboard sound and orientation recording tags to study the echolocation behaviour of free-swimming trained porpoises as they caught dead, freely drifting fish. We analysed porpoise echolocation behaviour leading up to and following prey capture events, including variability in echolocation in response to vision restriction, prey species, and individual porpoise tested. The porpoises produced echolocation clicks as they searched for the fish, followed by fast-repetition-rate clicks (echolocation buzzes) when acquiring prey. During buzzes, which usually began when porpoises were about 1-2 body lengths from prey, tag-recorded click levels decreased by about 10 dB, click rates increased to over 300 clicks per second, and variability in body orientation (roll) increased. Buzzes generally continued beyond the first contact with the fish, and often extended until or after the end of prey handling. This unexplained continuation of buzzes after prey capture raises questions about the function of buzzes, suggesting that in addition to providing detailed information on target location during the capture, they may serve additional purposes such as the relocation of potentially escaping prey. We conclude that porpoises display the same overall acoustic prey capture behaviour seen in larger toothed whales in the wild, albeit at a faster pace, clicking slowly during search and approach phases and buzzing during prey capture.

RT can be used successfully as a therapeutic modality in several musculoskeletal conditions, especially those of a chronic variety. Although the exact application of training intensity and volume for maximal therapeutic effects is still unclear, it appears that RT guidelines, which have proven effective in a healthy population, can also be successfully applied in a rehabilitation context.