Inducible arginase 1 deficiency in mice leads to hyperargininemia and altered amino acid metabolism

Arginase deficiency is a rare autosomal recessive disorder resulting from a loss of the liver arginase isoform, arginase 1 (ARG1), which is the final step in the urea cycle for detoxifying ammonia. ARG1 deficiency leads to hyperargininemia, characterized by progressive neurological impairment, persistent growth retardation and infrequent episodes of hyperammonemia. Using the Cre/loxP-directed conditional gene knockout system, we generated an inducible Arg1-deficient mouse model by crossing "floxed" Arg1 mice with CreER(T2) mice. The resulting mice (Arg-Cre) die about two weeks after tamoxifen administration regardless of the starting age of inducing the knockout. These treated mice were nearly devoid of Arg1 mRNA, protein and liver arginase activity, and exhibited symptoms of hyperammonemia. Plasma amino acid analysis revealed pronounced hyperargininemia and significant alterations in amino acid and guanidino compound metabolism, including increased citrulline and guanidinoacetic acid. Despite no alteration in ornithine levels, concentrations of other amino acids such as proline and the branched-chain amino acids were reduced. In summary, we have generated and characterized an inducible Arg1-deficient mouse model exhibiting several pathologic manifestations of hyperargininemia. This model should prove useful for exploring potential treatment options of ARG1 deficiency

Identification and characterization of insulin-like growth factor receptors on adult rat cardiac myocytes: linkage to inositol 1,4,5-trisphosphate formation.

Cultured cardiac myocytes from adult Sprague-Dawley rats express both insulin-like growth factor-I (IGF-I) receptors and insulin-like growth factor-II/mannose 6-phosphate (IGF-II/Man6P) receptors and respond to IGF-I with a dose-dependent accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and inositol 1,4-bisphosphate [Ins(1,4)P2]. Specific binding of [125I]IGF-I to isolated membranes from cultured cardiac myocytes amounted to 1-1.2%. Binding of [125I]IGF-I was inhibited by unlabeled IGF-I at nanomolar concentrations and insulin at much higher concentrations. These data suggest that IGF-I binds to its own receptor on rat cardiac myocytes. Competitive binding studies using isolated membranes from cardiac myocytes and [125I]IGF-II showed 2-4% specific binding. Binding of [125I]IGF-II was inhibited by IGF-II and much less potently by IGF-I and insulin. Immunoglobulin G (IgG) 3637 (an IgG directed against the IGF-II/Man6P receptor) partially inhibited binding of [125I]IGF-II whereas nonimmune IgG did not. Affinity cross-linking studies with [125I]IGF-II and cardiac myocyte membranes and subsequent analysis of the ligand-receptor complex using SDS-PAGE and autoradiography showed a radiolabeled band of approximately 250 kilodalton (kDa). The formation of the [125I]IGF-II-receptor complex was inhibited by incubation with IGF-II and IgG 3637 but not by insulin or nonimmune IgG. Western blotting of protein extracts from cultured cardiac myocytes was performed using IgG 3637 and an immunoperoxidase technique for the visualization of the IGF-II/Man6P receptor protein. A specific band at 220 kDa under nonreducing conditions was detected on the blots, providing further evidence for the expression of the IGF-II/Man6P receptor by cardiac myocytes. The effect of IGFs on the accumulation of inositol phosphates was measured by HPLC analysis of perchloric acid extracts from myo-[3H]inositol-labeled cultured cardiac myocytes. IGF-I (50 ng/ml) stimulated the accumulation both of Ins(1,4,5)P3 and Ins(1,4)P2 after 30 sec by 43% and 63%. IGF-II (up to 500 ng/ml) had no significant effect on inositol phosphate accumulation under the same conditions. However, in the presence of millimolar concentrations of Man6P, IGF-II (500 ng/ml) also increased Ins(1,4,5)P3 accumulation by 59%. We conclude that cardiac myocytes from adult rats express IGF receptors and respond to IGFs with the accumulation of Ins(1,4,5)P3 and Ins(1,4)P2. This effect seems to be mediated by an IGF-I receptor-specific pathway

Ventilation and transformation of Labrador Sea Water and its rapid export in the deep Labrador Current

A model of the subpolar North Atlantic Ocean is used to study different aspects of ventilation and water mass transformation during a year with moderate convection intensity in the Labrador Sea. The model realistically describes the salient features of the observed hydrographic structure and current system, including boundary currents and recirculations. Ventilation and transformation rates are defined and compared. The transformation rate of Labrador Sea Water (LSW), defined in analogy to several observational studies, is 6.3 Sv (Sv ≡ 106 m3 s−1) in the model. Using an idealized ventilation tracer, mimicking analyses based on chlorofluorocarbon inventories, an LSW ventilation rate of 10 Sv is found. Differences between both rates are particularly significant for those water masses that are partially transformed into denser water masses during winter. The main export route of the ventilated LSW is the deep Labrador Current (LC). Backward calculation of particle trajectories demonstrates that about one-half of the LSW leaving the Labrador Sea within the deep LC originates in the mixed layer during that same year. Near the offshore flank of the deep LC at about 55°W, the transformation of LSW begins in January and is at a maximum in February/March. While the export of transformed LSW out of the central Labrador Sea continues for several months, LSW generated near the boundary current is exported more rapidly, with maximum transport rates during March/April within the deep LC

Organization of personnel management in oil and gas corporation "Petrovietnam"

The petroleum industry is one of the most vital industries in the development strategy of Vietnam. Prevailing in this industry is Vietnam National Oil and Gas Group,“Petrovietnam”, operating under the directions of Ministry of Industry and Trade and controlling the oil and gas industry. A significant part in the steady growth path and the operational efficiency increment of the Group is contributed by the human resource policies. As oil prices were sharply declining, which began in 2014, a certain workforce reduction was planned by “Petrovietnam”, not only to deal with the situation but also to improve the quality of its workforce. Thus, managing human resources is one of the strategic tools of “Petrovietnam” corporate group

Estimating the ice thickness of mountain glaciers with a shape optimization algorithm using surface topography and mass-balance

We present a shape optimization algorithm to estimate the ice thickness distribution within a two-dimensional, non-sliding mountain glacier, given a transient surface geometry and a mass-balance distribution. The approach is based on the minimization of the surface topography misfit at the end of the glacier's evolution in the shallow ice approximation of ice flow. Neither filtering of the surface topography where its gradient vanishes nor interpolation of the basal shear stress is involved. Novelty of the presented shape optimization algorithm is the use of surface topography and mass-balance only within a time-dependent Lagrangian approach for moving-boundary glaciers. On real-world inspired geometries, it is shown to produce estimations of even better quality in smaller time than the recently proposed steady and transient inverse methods. A sensitivity analysis completes the study and evinces the method's higher susceptibility to perturbations in the surface topography than in surface mass-balance or rate facto

Physical and Biogeochemical Studies in the Subtropical and Tropical Atlantic

Maria S. Merian Cruise Report MSM18/L2 Cruise No. 18, Leg 2 May 11 – June 19, 2011 Mindelo (Cape Verde Islands) – Mindelo (Cape Verde Islands