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-

In clinical practice, looking at the use of walking aids, investigating proprioception and spasticity, rating Expanded Disability Status Score and using Berg Balance Scale or Timed Up and Go cognitive all contribute when identifying fallers.

A locus on chromosome 9p21.3-p13.3 is linked to ALS-FTD.

It is sufficient to use only one attempt and to choose only one of the tests when evaluating people with moderate MS. In the case of the 30TW greater attention must be paid to the degree of disability when determining the smallest percentage difference needed to establish a genuine change, than

Thirteen patients with healthy hearts and lungs, and with a mean age of 68 years, who were scheduled for lower abdominal surgery during isoflurane anaesthesia with muscular paralysis, were investigated with arterial blood gases, spirometry, pulmonary x-ray and computed tomography (CT) of the chest before and during anaesthesia, as well as during the first 4 postoperative days. Before anaesthesia, lung function and gas exchange were normal in all patients. Pulmonary x-ray and CT scans of the lungs were also normal. During anaesthesia, 6 of 13 patients developed atelectasis (mean 1.0% of intrathoracic transverse area in all patients). Two hours postoperatively, 11 of 13 patients had atelectasis and the mean atelectatic area was 1.8%. Pao2 was significantly reduced by 2.1 kPa to 9.8 kPa. On the first postoperative day, the mean atelectasis was unaltered (1.8%). None of the atelectasis found on CT scanning could be detected on standard pulmonary x-ray. Forced vital capacity (FVC) and forced expired volume in 1 s (FEV1) were significantly decreased to 2/3 of preoperative level. Pao2 was significantly reduced to less than 80% of the preoperative level (mean 9.4 kPa). There were significant correlations between the atelectatic area and the impairment in FVC, FEV1, and Pao2. Spirometry and blood gases improved during the succeeding postoperative days, and atelectasis decreased. No patient suffered from pulmonary complications, as judged from clinical criteria and pulmonary x-ray, in contrast to the findings of atelectasis in 85% of the patients by computed tomography.

Motor neurone disease (MND) was studied in relation to various determinants in a case-control study covering nine counties in southern Sweden. A questionnaire about occupational exposures, medical history, lifestyle factors etc was given to all cases in the age range 45-79 and to a random sample of 500 population controls in the same age range. The questionnaires were answered by 92 cases and 372 controls, a response rate of 85% and 75% respectively. Among men high Mantel-Haenszel odds ratios (MHORs) were obtained for electricity work (MHOR = 6 7, 95% confidence interval (95% CI) 1-0-321), welding (MHOR = 37, 95% CI 1-1-13-0), and impregnating agents (MHOR = 3-5, 95% CI 0-9-13 1). Heritability with regard to a neurodegenerative disease or thyroid disease seemed to predispose to a risk of developing MND (OR = 2-1, 95% CI 1-0-4-3). The

Investigating accidental falls using the perspective of the patient gave important information about variables not earlier targeted in MS research.

All cases of ALS in Sweden during the period 1970-1983, i.e., 1961 cases, were compared with an age-stratified random sample of 2245 individuals from the Swedish population. On the basis of census information, the male cases were found to be heterogeneously distributed over occupational groups. Significantly more male cases than expected were found among office workers (OR = 1.8; 34 cases) as well as among farm workers (OR = 1.7; 56 cases). There was a cluster of male cases in agricultural work in one south-western county (OR = 3.4; 25 cases). Significantly more female cases than expected were medical service workers (OR = 1.7; 33 cases).