Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans.

Rationale: Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation (MV). Paradoxically, MV itself results in a rapid loss of diaphragmatic strength in animals. However, very little is known about the time course or mechanistic basis for such a phenomenon in humans.

N-acetylcysteine protects against bupivacaine-induced myotoxicity caused by oxidative and sarcoplasmic reticulum stress in human skeletal myotubes.

Background: Local anesthetics offer the benefits of extended analgesia with greater patient satisfaction and faster rehabilitation compared with intravenous morphine. These benefits, however, can be offset by adverse iatrogenic muscle pain. Here, the authors investigate the mechanisms of local anesthetic-induced myotoxicity and assess the protective effect of N-acetylcysteine.

Resveratrol protects against protease inhibitor-induced reactive oxygen species production, reticulum stress and lipid raft perturbation.

Objective: HIV protease inhibitors have been successfully used in highly active antiretroviral therapy of HIV-1 infection, but their benefits are compromised by a number of clinically important adverse side-effects. Several studies showed that protease inhibitors induce sarco/endoplasmic reticulum stress and overproduction of reactive oxygen species (ROS), but the hierarchy of these events was never established in protease inhibitor-treated cells. Our objective was to determine whether ROS production and sarco/endoplasmic reticulum stress were co-induced by protease inhibitors in human primary skeletal myotubes and whether antioxidant treatment with resveratrol could protect against protease inhibitor-induced cellular damages.

TC10 controls human myofibril organization and is activated by the sarcomeric RhoGEF obscurin.

The contractile activity of striated muscle depends on myofibrils that are highly ordered macromolecular complexes. The protein components of myofibrils are well characterized, but it remains largely unclear how signaling at the molecular level within the sarcomere and the control of assembly are coordinated. We show that the Rho GTPase TC10 appears during differentiation of human primary skeletal myoblasts and it is active in differentiated myotubes.

Identification of Rho GTPases implicated in terminal differentiation of muscle cells in ascidia.

Background Information: Members of the Rho GTPase family mediate changes in the actin cytoskeleton and are also implicated in developmental processes, including myogenesis. Nevertheless, a comprehensive analysis of these proteins during myofibrillogenesis has never been performed in any organism.

Results: Using the ascidian model to identify the role of Rho GTPases on myofibrillogenesis, we show that transcripts for all Rho GTPases are detected in muscle cells of the embryo.

The caspase family in urochordates: distinct evolutionary fates in ascidians and larvaceans.

Background Information: Caspases are cysteine proteases that mediate apoptosis (programmed cell death) initiation and execution. Apoptosis is a conserved mechanism shared by all metazoans, although its physiological function and complexity show considerable taxon-dependent variations. To gain insight into the caspase repertoire of putative ancestors to vertebrates, we performed exhaustive genomic searches in urochordates, a sister taxon to vertebrates in which ascidians and appendicularians display chordate characters at early stages of their development.

Cyclin A repression in quiescent cells is associated with chromatin remodeling of its promoter and requires Brahma/SNF2alpha.

Cell cycle-dependent expression of cyclin A is controlled by transcriptional repression in early phase of the cell cycle. In this study, we directly examine the chromatin structure of the mouse cyclin A promoter through in vivo micrococcal nuclease footprinting. We describe here that cyclin A repression is associated with two positioned nucleosomes and that histones progressively lose DNA contact synchronously with gene activation.

Ascidians as a vertebrate-like model organism for physiological studies of Rho GTPase signaling.

GTPases of the Rho family are evolutionarily conserved proteins that control cell shape dynamics during physiological processes as diverse as cell migration and polarity, axon outgrowth and guidance, apoptosis and phagocytosis. In mammals, 18 Rho proteins are distributed in 7 subfamilies. Rho, Rac and Cdc42 are the best-characterized ones, benefiting from the use of worm and drosophila, which only express these 3 subfamilies.

Activation of cyclin D1 expression by the ERK5 cascade.

Transcriptional activation of the cyclin D1 gene is a key step in cell proliferation. Accordingly, cyclin D1 overexpression is frequently an early step in neoplastic transformation, particularly in mammary epithelium. Numerous studies have linked elevated cyclin D1 promoter activity to a sustained activation of the ERK1/2 cascade.

Oct-1 potentiates CREB-driven cyclin D1 promoter activation via a phospho-CREB- and CREB binding protein-independent mechanism.

Cyclin D1, the regulatory subunit for mid-G(1) cyclin-dependent kinases, controls the expression of numerous cell cycle genes. A cyclic AMP-responsive element (CRE), located upstream of the cyclin D1 mRNA start site, integrates mitogenic signals that target the CRE-binding factor CREB, which can recruit the transcriptional coactivator CREB-binding protein (CBP). We describe an alternative mechanism for CREB-driven cyclin D1 induction that involves the ubiquitous POU domain protein Oct-1.