Stimulation of a glycosyl-phosphatidylinositol-specific phospholipase by insulin and the sulfonylurea, glimepiride, in rat adipocytes depends on increased glucose transport

Abstract. Lipoprotein lipase (LPL) and glycolipidanchored cAMP-binding ectoprotein (Gcel) are modified by glycosyl-phosphatidylinositol (GPI) in rat adipocytes, however, the linkage is potentially unstable. Incubation of the cells with either insulin (0.1-30 nM) or the sulfonylurea, glimepiride (0.5-20/zM), in the presence of glucose led to conversion of up to 35 and 20%, respectively, of the total amphiphilic LPL and Gcel to their hydrophilic versions. Inositol-phosphate was retained in the residual protein-linked anchor structure. This suggests cleavage of the GPI anchors by an endogenous GPI-specific insulin- and glimepiride-inducible phospholipase (GPI-PL). Despite cleavage, hydrophilic LPL and Creel remained membrane associated and were released only if a competitor, e.g., inositol-(cyclic)monophosphate, had been added. Other constituents of the GPI anchor (glucosamine and mannose) were less efficient. This suggests reat body of information exists regarding the structural diversity as well as the biosynthesis and posttranslational attachment of glycosyl-phosphatidylinositol (GPI) ~ structures (for recent reviews see Low, 1989; McConville et al., 1993). However, the functional significance of membrane anchorage via GPI structures versus transmembrane polypeptide domains is still a matter of debate. The accessibility of GPI molecules to cleavage by phospholipase [(G)PI-PL] opens the possibility of a regu-Address all correspondence to Dr. (;tinter Miiller, Hoechst AG Frankfurt

Peritumoral administration of GPI-anchored TIMP-1 inhibits colon carcinoma growth in Rag-2 gamma chain-deficient mice

Exogenous application of recombinant TIMP-1 protein modified by addition of a glycosylphosphatidylinositol (GPI) anchor allows efficient insertion of the fusion protein into cell membranes. This `cell surface engineering' leads to changes in the proteolytic environment. TIMP-1-GPI shows enhanced as well as novel in vitro biological activities including suppression of proliferation, reduced migration, and inhibition of invasion of the colon carcinoma cell line SW480. Treatment of SW480 tumors implanted in Rag (-/-) common gamma chain (-/-) C57BL/6 mice with peritumorally applied TIMP-1-GPI, control rhTIMP-1 protein, or vehicle shows that TIMP-1-GPI leads to a significant reduction in tumor growth

Algorithms for group isomorphism via group extensions and cohomology

The isomorphism problem for finite groups of order n (GpI) has long been known to be solvable in $n^{\log n+O(1)}$ time, but only recently were polynomial-time algorithms designed for several interesting group classes. Inspired by recent progress, we revisit the strategy for GpI via the extension theory of groups. The extension theory describes how a normal subgroup N is related to G/N via G, and this naturally leads to a divide-and-conquer strategy that splits GpI into two subproblems: one regarding group actions on other groups, and one regarding group cohomology. When the normal subgroup N is abelian, this strategy is well-known. Our first contribution is to extend this strategy to handle the case when N is not necessarily abelian. This allows us to provide a unified explanation of all recent polynomial-time algorithms for special group classes. Guided by this strategy, to make further progress on GpI, we consider central-radical groups, proposed in Babai et al. (SODA 2011): the class of groups such that G mod its center has no abelian normal subgroups. This class is a natural extension of the group class considered by Babai et al. (ICALP 2012), namely those groups with no abelian normal subgroups. Following the above strategy, we solve GpI in $n^{O(\log \log n)}$ time for central-radical groups, and in polynomial time for several prominent subclasses of central-radical groups. We also solve GpI in $n^{O(\log\log n)}$ time for groups whose solvable normal subgroups are elementary abelian but not necessarily central. As far as we are aware, this is the first time there have been worst-case guarantees on a $n^{o(\log n)}$-time algorithm that tackles both aspects of GpI---actions and cohomology---simultaneously.Comment: 54 pages + 14-page appendix. Significantly improved presentation, with some new result

Recombinant GPI-anchored TIMP-1 stimulates growth and migration of peritoneal mesothelial cells.

Mesothelial cells are critical in the pathogenesis of post-surgical intraabdominal adhesions as well as in the deterioration of the peritoneal membrane associated with long-term peritoneal dialysis. Mesothelial denudation is a pathophysiolocigally important finding in these processes. Matrix metalloproteinase (MMP) biology underlies aspects of mesothelial homeostasis as well as wound repair. The endogenous tissue inhibitors of metalloproteinases (TIMPs) moderate MMP activity. METHODS AND FINDING: By modifying human TIMP-1 through the addition of a glycosylphosphatidylinositol (GPI) anchor, a recombinant protein was generated that efficiently focuses TIMP-1 on the cell surface. Treatment of primary mesothelial cells with TIMP-1-GPI facilitates their mobilization and migration leading to a dramatic increase in the rate of wound experimental closure. Mesothelial cells treated with TIMP-1-GPI showed a dose dependent increase in cell proliferation, reduced secretion of MMP-2, MMP-9, TNF-α and urokinase-type plasminogen activator (uPA), but increased tissue plasminogen activator (t-PA). Treatment resulted in reduced expression and processing of latent TGF-β1. TIMP-1-GPI stimulated rapid and efficient in vitro wound closure. The agent enhanced mesothelial cell proliferation and migration and was bioactive in the nanogram range. The application of TIMP-1-GPI may represent a new approach for limiting or repairing damaged mesothelium

A GPI-Based Critique of The Economic Profile of the Lower Mississippi River: an Update

The Genuine Progress Indicator, or GPI, is an alternative economic indicator that seeks to measure net economic welfare—the economic welfare that is gained by economic activity after the costs of producing that welfare (such as the costs of air pollution, water pollution, resource depletion, climate change, and the like) are deducted. From a GPI perspective, the economy of the Lower Mississippi River Corridor is not nearly as robust as traditional modes of economic analysis would suggest. There are clear paths to increasing GPI (and human economic wellbeing) that have implications for environmental, economic and river-management policy

Gemini Planet Imager Observational Calibrations VI: Photometric and Spectroscopic Calibration for the Integral Field Spectrograph

The Gemini Planet Imager (GPI) is a new facility instrument for the Gemini Observatory designed to provide direct detection and characterization of planets and debris disks around stars in the solar neighborhood. In addition to its extreme adaptive optics and corona graphic systems which give access to high angular resolution and high-contrast imaging capabilities, GPI contains an integral field spectrograph providing low resolution spectroscopy across five bands between 0.95 and 2.5 $\mu$m. This paper describes the sequence of processing steps required for the spectro-photometric calibration of GPI science data, and the necessary calibration files. Based on calibration observations of the white dwarf HD 8049B we estimate that the systematic error in spectra extracted from GPI observations is less than 5%. The flux ratio of the occulted star and fiducial satellite spots within coronagraphic GPI observations, required to estimate the magnitude difference between a target and any resolved companions, was measured in the $H$-band to be $\Delta m = 9.23\pm0.06$ in laboratory measurements and $\Delta m = 9.39\pm 0.11$ using on-sky observations. Laboratory measurements for the $Y$, $J$, $K1$ and $K2$ filters are also presented. The total throughput of GPI, Gemini South and the atmosphere of the Earth was also measured in each photometric passband, with a typical throughput in $H$-band of 18% in the non-coronagraphic mode, with some variation observed over the six-month period for which observations were available. We also report ongoing development and improvement of the data cube extraction algorithm.Comment: 15 pages, 6 figures. Proceedings of the SPIE, 9147-30

Endoplasmic Reticulum Export of GPI-Anchored Proteins

Protein export from the endoplasmic reticulum (ER) is an essential process in all eukaryotes driven by the cytosolic coat complex COPII, which forms vesicles at ER exit sites for transport of correctly assembled secretory cargo to the Golgi apparatus. The COPII machinery must adapt to the existing wide variety of different types of cargo proteins and to different cellular needs for cargo secretion. The study of the ER export of glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs), a special glycolipid-linked class of cell surface proteins, is contributing to address these key issues. Due to their special biophysical properties, GPI-APs use a specialized COPII machinery to be exported from the ER and their processing and maturation has been recently shown to actively regulate COPII function. In this review, we discuss the regulatory mechanisms by which GPI-APs are assembled and selectively exported from the ER.Ministerio de Economía y Competitividad de España (MINECO)-BFU2017-89700-