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Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, but the mechanistic basis of their contribution to disease remains unresolved. Here, we demonstrated that loss of a muscle-specific protein, kelch-like family member 40 (KLHL40), results in a nemaline-like myopathy in mice that closely phenocopies muscle abnormalities observed in KLHL40-deficient patients. We determined that KLHL40 localizes to the sarcomere I band and A band and binds to nebulin (NEB), a protein frequently implicated in NM, as well as a putative thin filament protein, leiomodin 3 (LMOD3). KLHL40 belongs to the BTB-BACK-kelch (BBK) family of proteins, some of which have been shown to promote degradation of their substrates. In contrast, we found that KLHL40 promotes stability of NEB and LMOD3 and blocks LMOD3 ubiquitination. Accordingly, NEB and LMOD3 were reduced in skeletal muscle of both Klh[l40.sup.-/-] mice and KLHL40-deficient patients. Loss of sarcomere thin filament proteins is a frequent cause of NM; therefore, our data that KLHL40 stabilizes NEB and LMOD3 provide a potential basis for the development of NM in KLHL40-deficient patients., Introduction Nemaline myopathies (NMs) encompass a set of genetically heterogeneous diseases that are defined pathologically by the presence of characteristic rod-like structures, called nemaline bodies, in myofibers (1). Clinically, presentation [...]

LADY Longford, who died late last year at the age of ninety-six, was a modest hero of social change and a celebrated biographer. From a comfortable background, with strong connections [...]

DYSLEXIA is a singular condition. Concerning as it does brain processes, it is 'invisible'. Many dyslexics function entirely well in social and professional situations, to the extent that many lay [...]

THE death last year of Roy Boulting saw the passing of one of the more singular and successful of British film making partnerships. Roy and his twin brother John wrote, [...]

AS an aspiring Ph.D. student in 1998, I asked myself which writers I had read extensively, which I had always enjoyed and in whose works I had always found something [...]

Editor's Note: In last month s issue Jonathan Doering assessed the career of the Labour hereditary peer, Lord Longford, who died in 2001. Now we look at his Tory contemporary, [...]

Editor's Note: It is somewhat ironic that the two British politicians whose deaths received the widest and most sympathetic coverage last year were hereditary peers. At a time when the [...]

Witney, a modest country town twelve miles to the west of Oxford, has stood in one form or another for centuries. Its small size, and the modern, blank-faced housing estates [...]

LEO Marks, who died in January, made a startling impact in different spheres: as an intelligence officer and script writer. In view of his characteristic discretion, it seems inevitable that [...]

THE death last November of the academic and author Malcolm Bradbury from a rare form of pneumonia has robbed British Literature of a generous and expansive voice which had much [...]

Background: The SH3 and cysteine-rich domain 3 (Stac3) gene is specifically expressed in the skeletal muscle. Stac3 knockout mice die perinatally. In this study, we determined the potential role of Stac3 in postnatal skeletal muscle growth, fiber composition, and contraction by generating conditional Stac3 knockout mice. Methods: We disrupted the Stac3 gene in 4-week-old male mice using the Flp-FRT and tamoxifen-inducible Cre-loxP systems. Results: RT-qPCR and western blotting analyses of the limb muscles of target mice indicated that nearly all Stac3 mRNA and more than 70 % of STAC3 protein were deleted 4 weeks after tamoxifen injection. Postnatal Stac3 deletion inhibited body and limb muscle mass gains. Histological staining and gene expression analyses revealed that postnatal Stac3 deletion decreased the size of myofibers and increased the percentage of myofibers containing centralized nuclei, with no effect on the total myofiber number. Grip strength and grip time tests indicated that postnatal Stac3 deletion decreased limb muscle strength in mice. Muscle contractile tests revealed that postnatal Stac3 deletion reduced electrostimulation-induced but not the ryanodine receptor agonist caffeine-induced maximal force output in the limb muscles. Calcium imaging analysis of single flexor digitorum brevis myofibers indicated that postnatal Stac3 deletion reduced electrostimulation- but not caffeine-induced calcium release from the sarcoplasmic reticulum. Conclusions: This study demonstrates that STAC3 is important to myofiber hypertrophy, myofiber-type composition, contraction, and excitation-induced calcium release from the sarcoplasmic reticulum in the postnatal skeletal muscle. [ABSTRACT FROM AUTHOR]

The Horses of St Mark's: A Story of Triumph in Byzantium, Paris and Venice. Charles Freeman. Little, Brown. £16.99. xv + 298 pages. ISBN 0-316-86118-9. The handsome horses of the [...]

Through Gates of Fire: A Journey into World Disorder. Martin Bell. Weidenfeld & Nicolson. £16.99. 360 pages. ISBN 0-297-84748-1. Reading this third instalment in a trilogy of memoir and comment, [...]

The Outcast's Outcast: Lord Longford. Peter Stanford. Sutton Publishing. £20.00. 512 pages. ISBN 0-7509-3248-1. Peter Stanford's 1994 authorized life was considered by at least one associate to be 'so well-balanced [...]

The First Freedom: A History of Free Speech. Robert Hargreaves. Sutton Publishing. £20.00. 320 pages. ISBN 0-7509-2923-5. Whilst reading this erudite and thought-provoking book, this reviewer visited Speaker's Corner, a [...]

Signor Marconi's Magic Box: How an Amateur Inventor Defied Scientists and Began the Radio Revolution. Gavin Weightman. HarperCollins. £15.99. 312 pages. ISBN 0-00-713005-8. Gavin Weightman's engaging book on Guglielmo Marconi's [...]

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White Rajah. Nigel Barley. Little, Brown. £16.99. 262 pages. ISBN 0-316-85920-6. This involving book deals with the enigmatic Sir James Brooke, self-styled Rajah of Sarawak, then an unprepossessing region in [...]