Mechanism of force generation by myosin heads in skeletal muscle

Muscles generate force and shortening in a cyclical interaction between the myosin head domains projecting from the myosin filaments and the adjacent actin filaments. Although many features of the dynamic performance of muscle are determined by the rates of attachment and detachment of myosin and actin, the primary event in force generation is thought to be a conformational change or 'working stroke' in the actin-bound myosin head. According to this hypothesis, the working stroke is much faster than attachment or detachment, but can be observed directly in the rapid force transients that follow step displacement of the filaments. Although many studies of the mechanism of muscle contraction have been based on this hypothesis, the alternative view-that the fast force transients are caused by fast components of attachment and detachment--has not been excluded definitively. Here we show that measurements of the axial motions of the myosin heads at ?ngstr?m resolution by a new X-ray interference technique rule out the rapid attachment/detachment hypothesis, and provide compelling support for the working stroke model of force generation.     

Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma-like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars. High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome-related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer.     

Enhanced inhibition of RNA synthesis by amanitins in in vitro cultured cells

Summary The inhibition of RNA synthesis by -amanitin on vitro cultured cells is very slow. The action of various analogues of the toxin was tested and some of them proved more effective. Moreover pretreatment of cell cultures with DEAE-dextran greatly enhanced the effect of -amanitin.Acknowledgments. We thank ProfessorTh. Wieland and Dr.H. Faulstich (Max-Planck-Institut, Heidelberg) for the generous gift of amanitins. This investigation was supported by grant No. 74.00637.65 from C.N.R. (Roma).     

Artero-venous differences in blood platelet clumping by ADP

Riassunto È stata studiata con aggregometro l'aggregazione delle piastrine di ratto in PRP ottenuto da sangue arterioso e da diversi vasi venosi. È risultato che l'effetto aggregante dell'ADP è molto più marcato sulle piastrine venose che su quelle arteriose.