SUMMARYNumerous motile cell functions depend on signaling from the cytoskeleton to the nucleus. Myocardin-related transcription factors (MRTFs) translocate to the nucleus in response to actin polymerization and cooperate with serum response factor (Srf) to regulate the expression of genes encoding actin and other components of the cytoskeleton. Here, we show that MRTF-A (Mkl1) and MRTF-B (Mkl2) redundantly control neuronal migration and neurite outgrowth during mouse brain development. Conditional deletion of the genes encoding these Srf coactivators disrupts the formation of multiple brain structures, reflecting a failure in neuronal actin polymerization and cytoskeletal assembly. These abnormalities were accompanied by dysregulation of the actin-severing protein gelsolin and Pctaire1 (Cdk16) kinase, which cooperates with Cdk5 to initiate a kinase cascade that governs cytoskeletal rearrangements essential for neuron migration and neurite outgrowth. Thus, the MRTF/Srf partnership interlinks two key signaling pathways that control actin treadmilling and neuronal maturation, thereby fulfilling a regulatory loop that couples cytoskeletal dynamics to nuclear gene transcription during brain development.
Histone deacetylase inhibitors (HDACi) represent a new group of drugs currently being tested in a wide variety of clinical applications. They are especially effective in preclinical models of cancer where they show antiproliferative action in many different types of cancer cells. Recently, the first HDACi was approved for the treatment of cutaneous T cell lymphomas. Most HDACi currently in clinical development act by unspecifically interfering with the enzymatic activity of all class I HDACs (HDAC1, 2, 3, and 8), and it is widely believed that the development of isoform-specific HDACi could lead to better therapeutic efficacy. The contribution of the individual class I HDACs to different disease states, however, has so far not been fully elucidated. Here, we use a genetic approach to dissect the involvement of the different class I HDACs in tumor cells. We show that deletion of a single HDAC is not sufficient to induce cell death, but that HDAC1 and 2 play redundant and essential roles in tumor cell survival. Their deletion leads to nuclear bridging, nuclear fragmentation, and mitotic catastrophe, mirroring the effects of HDACi on cancer cells. These findings suggest that pharmacological inhibition of HDAC1 and 2 may be sufficient for anticancer activity, providing an experimental framework for the development of isoform-specific HDAC inhibitors.cancer ͉ mitotic catastrophe ͉ HDAC inhibitor ͉ acetylation ͉ tumorigenesis
In response to skeletal muscle injury, satellite cells, which function as a myogenic stem cell population, become activated, expand through proliferation, and ultimately fuse with each other and with damaged myofibers to promote muscle regeneration. Here, we show that members of the Myocardin family of transcriptional coactivators, MASTR and MRTF-A, are up-regulated in satellite cells in response to skeletal muscle injury and muscular dystrophy. Global and satellite cell-specific deletion of MASTR in mice impairs skeletal muscle regeneration. This impairment is substantially greater when MRTF-A is also deleted and is due to aberrant differentiation and excessive proliferation of satellite cells. These abnormalities mimic those associated with genetic deletion of MyoD, a master regulator of myogenesis, which is down-regulated in the absence of MASTR and MRTF-A. Consistent with an essential role of MASTR in transcriptional regulation of MyoD expression, MASTR activates a muscle-specific postnatal MyoD enhancer through associations with MEF2 and members of the Myocardin family. Our results provide new insights into the genetic circuitry of muscle regeneration and identify MASTR as a central regulator of this process.
Summary The gene networks regulating heart morphology and cardiac integrity are largely unknown. We previously reported a role for the heterotrimeric G protein γ subunit 1 (Gγ1) in mediating cardial-pericardial cell adhesion in Drosophila. Here we show G-oα47A and Gβ13F cooperate with Gγ1 to maintain cardiac integrity. Cardial-pericardial cell adhesion also relies on the septate junction (SJ) proteins Neurexin-IV (Nrx-IV), Sinuous, Coracle, and Nervana2, and which together function in a common pathway with Gγ1. Furthermore, Gγ1 signaling is required for proper SJ protein localization, and loss of at least one SJ protein, Nrx-IV, induces cardiac lumen collapse. These results are surprising because the embryonic heart lacks SJs and suggest that SJ proteins perform non-canonical functions to maintain cardiac integrity in Drosophila. Our findings unveil the components of a previously unrecognized network of genes that couple G-protein signaling with novel structural constituents of the heart.
SUMMARYStriated muscle development requires the coordinated expression of genes involved in sarcomere formation and contractility, as well as genes that determine muscle morphology. However, relatively little is known about the molecular mechanisms that control the early stages of muscle morphogenesis. To explore this facet of myogenesis, we performed a genetic screen for regulators of somatic muscle morphology in Drosophila, and identified the putative RNA-binding protein (RBP) Hoi Polloi (Hoip). Hoip is expressed in striated muscle precursors within the muscle lineage and controls two genetically separable events: myotube elongation and sarcomeric protein expression. Myotubes fail to elongate in hoip mutant embryos, even though the known regulators of somatic muscle elongation, target recognition and muscle attachment are expressed normally. In addition, a majority of sarcomeric proteins, including Myosin Heavy Chain (MHC) and Tropomyosin, require Hoip for their expression. A transgenic MHC construct that contains the endogenous MHC promoter and a spliced open reading frame rescues MHC protein expression in hoip embryos, demonstrating the involvement of Hoip in pre-mRNA splicing, but not in transcription, of muscle structural genes. In addition, the human Hoip ortholog NHP2L1 rescues muscle defects in hoip embryos, and knockdown of endogenous nhp2l1 in zebrafish disrupts skeletal muscle development. We conclude that Hoip is a conserved, post-transcriptional regulator of muscle morphogenesis and structural gene expression.
A new pressure, volume, temperature, and, time (PVTt) primary gas flow standard at the National Institute of Standards and Technology has an expanded uncertainty (k = 2) of between 0.02 % and 0.05 %. The standard spans the flow range of 1 L/min to 2000 L/min using two collection tanks and two diverter valve systems. The standard measures flow by collecting gas in a tank of known volume during a measured time interval. We describe the significant and novel features of the standard and analyze its uncertainty. The gas collection tanks have a small diameter and are immersed in a uniform, stable, thermostatted water bath. The collected gas achieves thermal equilibrium rapidly and the uncertainty of the average gas temperature is only 7 mK (22 × 10−6 T). A novel operating method leads to essentially zero mass change in and very low uncertainty contributions from the inventory volume. Gravimetric and volume expansion techniques were used to determine the tank and the inventory volumes. Gravimetric determinations of collection tank volume made with nitrogen and argon agree with a standard deviation of 16 × 10−6 VT. The largest source of uncertainty in the flow measurement is drift of the pressure sensor over time, which contributes relative standard uncertainty of 60 × 10−6 to the determinations of the volumes of the collection tanks and to the flow measurements. Throughout the range 3 L/min to 110 L/min, flows were measured independently using the 34 L and the 677 L collection systems, and the two systems agreed within a relative difference of 150 × 10−6. Double diversions were used to evaluate the 677 L system over a range of 300 L/min to 1600 L/min, and the relative differences between single and double diversions were less than 75 × 10−6.
Waldenström macroglobulinemia (WM) is a low-grade B-cell clonal disorder characterized by lymphoplasmacytic bone marrow involvement associated with monoclonal immunoglobulin M (IgM). Although WM remains to be an incurable disease with a heterogeneous clinical course, the recent discovery of mutations in the MYD88 and CXCR4 genes further enhanced our understanding of its pathogenesis. Development of new therapies including monoclonal antibodies, proteasome inhibitors, and Bruton’s tyrosine kinase inhibitors have made the management of WM increasingly complex. Treatment should be tailored to the individual patient while considering many clinical factors. The clinical outcomes are expected to continue to improve given the emergence of novel therapeutics and better understanding of the underlying pathogenesis.
This study compared the effectiveness and side-effects of intra-operative fentanyl with fentanyl and morphine for elective adenotonsillectomy in a double-blind study, in 60 children randomly allocated to receive either intravenous fentanyl 1 microg x kg(-1) intra-operatively or intramuscular morphine 100 microg x kg(-1) at induction. All children received a standard anaesthetic induction with intravenous fentanyl 1 microg x kg(-1) and propofol 4-5 mg x kg(-1) and maintenance with oxygen, nitrous oxide and isoflurane. Pain scores, emetic episodes and supplemental morphine requirements were recorded for 24 h postoperatively. The overall incidence of postoperative vomiting was high in both groups: 70% in the fentanyl group and 78% in the morphine group. The incidence of postoperative vomiting was lower in the fentanyl group (p < 0.03) in the first 4 h, but similar by 24 h. Children who received morphine at any time in the first 24 h had more median (range) episodes of vomiting [2 (0-7)] than children receiving fentanyl only [l (0-3); p < 0.03]. Administration of rescue anti-emetics, pain scores in recovery and pain scores over the next 24 h were similar between the two groups.
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