Receptor and secreted targets of Wnt-1/beta-catenin signalling in mouse mammary epithelial cells.

BackgroundDeregulation of the Wnt/ beta-catenin signal transduction pathway has been implicated in the pathogenesis of tumours in the mammary gland, colon and other tissues. Mutations in components of this pathway result in beta-catenin stabilization and accumulation, and the aberrant modulation of beta-catenin/TCF target genes. Such alterations in the cellular transcriptional profile are believed to underlie the pathogenesis of these cancers. We have sought to identify novel target genes of this pathway in mouse mammary epithelial cells.MethodsGene expression microarray analysis of mouse mammary epithelial cells inducibly expressing a constitutively active mutant of beta-catenin was used to identify target genes of this pathway.ResultsThe differential expression in response to DeltaNbeta-catenin for five putative target genes, Autotaxin, Extracellular Matrix Protein 1 (Ecm1), CD14, Hypoxia-inducible gene 2 (Hig2) and Receptor Activity Modifying Protein 3 (RAMP3), was independently validated by northern blotting. Each of these genes encodes either a receptor or a secreted protein, modulation of which may underlie the interactions between Wnt/beta-catenin tumour cells and between the tumour and its microenvironment. One of these genes, Hig2, previously shown to be induced by both hypoxia and glucose deprivation in human cervical carcinoma cells, was strongly repressed upon DeltaNbeta-catenin induction. The predicted N-terminus of Hig2 contains a putative signal peptide suggesting it might be secreted. Consistent with this, a Hig2-EGFP fusion protein was able to enter the secretory pathway and was detected in conditioned medium. Mutation of critical residues in the putative signal sequence abolished its secretion. The expression of human HIG2 was examined in a panel of human tumours and was found to be significantly downregulated in kidney tumours compared to normal adjacent tissue.ConclusionsHIG2 represents a novel non-cell autonomous target of the Wnt pathway which is potentially involved in human cancer

Helmet weight simulator

A device for providing acceleration cues to the helmet of a simulator pilot is described. Pulleys are attached to both shoulders of the pilot. A cable is attached to both sides of the helmet and extends through the pulleys to a takeup reel that is controlled by a torque motor. Control signals are applied to a servo system including the torque motor, the takeup reel and a force transducer which supplies the feedback signal. In one embodiment of the invention the force transducer is in the cable and in another it is in the takeup reel

A requirement for STAG2 in replication fork progression creates a targetable synthetic lethality in cohesin-mutant cancers.

Cohesin is a multiprotein ring that is responsible for cohesion of sister chromatids and formation of DNA loops to regulate gene expression. Genomic analyses have identified that the cohesin subunit STAG2 is frequently inactivated by mutations in cancer. However, the reason STAG2 mutations are selected during tumorigenesis and strategies for therapeutically targeting mutant cancer cells are largely unknown. Here we show that STAG2 is essential for DNA replication fork progression, whereby STAG2 inactivation in non-transformed cells leads to replication fork stalling and collapse with disruption of interaction between the cohesin ring and the replication machinery as well as failure to establish SMC3 acetylation. As a consequence, STAG2 mutation confers synthetic lethality with DNA double-strand break repair genes and increased sensitivity to select cytotoxic chemotherapeutic agents and PARP or ATR inhibitors. These studies identify a critical role for STAG2 in replication fork procession and elucidate a potential therapeutic strategy for cohesin-mutant cancers

Application of a helicopter mathematical model to the Langley differential maneuvering simulator for use in a helicopter/fighter evasive maneuver study

A real time simulation study was conducted using a differential maneuvering simulator to determine and evaluate helicopter evasive maneuvers when attacked by fighter aircraft. A general helicopter mathematical model was modified to represent an H-53 helicopter. The helicopter model was compared to H-53 flight test data to determine any differences between the simulated and actual vehicles. The simulated helicopter was also subjectively validated by participating pilots. Two fighter mathematical models validated in previous studies were utilized for the attacking aircraft. The results of this simulation study have been verified in a flight test program conducted by the U. S. Air Force and were found to closely match the flight results

Probing the electron EDM with cold molecules

We present progress towards a new measurement of the electron electric dipole moment using a cold supersonic beam of YbF molecules. Data are currently being taken with a sensitivity of $10^{-27}\textrm{e.cm}/\sqrt{\textrm{day}}$. We therefore expect to make an improvement over the Tl experiment of Commins' group, which currently gives the most precise result. We discuss the systematic and statistical errors and comment on the future prospect of making a measurement at the level of $10^{-29}\textrm{e.cm}/\sqrt{\textrm{day}}$.Comment: 8 pages, 6 figures, proceedings of ICAP 200

Noether Currents of Charged Spherical Black Holes

We calculate the Noether currents and charges for Einstein-Maxwell theory using a version of the Wald approach. In spherical symmetry, the choice of time can be taken as the Kodama vector. For the static case, the resulting combined Einstein-Maxwell charge is just the mass of the black hole. Using either a classically defined entropy or the Iyer-Wald selection rules, the entropy is found to be just a quarter of the area of the trapping horizon. We propose identifying the combined Noether charge as an energy associated with the Kodama time. For the extremal black hole case, we discuss the problem of Wald's rescaling of the surface gravity to define the entropy.Comment: 4 page