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Die „European Foundation for Quality Management (E.F.Q.M.)“ wurde im September 1988 gegrundet, und von Anfang an stand die Schaffung eines Europaischen Qualitatspreises fur Wirtschaftsunternehmen ganz oben auf der Liste wichtiger Aktivitaten. Die Uberzeugung von der Richtigkeit dieses Vorhabens wurde zum einen gestutzt durch den Erfolg des amerikanischen Qualitatspreises, des „Malcolm Baldrige National Quality Award“, zum anderen durch die Aussicht, auf diese Weise Paradebeispiele fur Spitzenleistungen zu identifizieren, die fur Unternehmen in ganz Europa als wertvolle Vorbilder dienen konnten. Um die grostmogliche Akzeptanz des Awards zu gewahrleisten, wurde mit der Europaischen Kommission und der „European Organisation for Quality (EOQ)“ eine Partnerschaft eingegangen; gleichwohl liegen Management und die Mittelbeschaffung in der Verantwortung der E.F.Q.M.

We have observed that a murine IgG1 monoclonal antibody directed against human urokinase-type plasminogen activator (uPA) greatly potentiates pro-uPA-mediated plasminogen activation. This effect was dependent on the interaction between the immunoglobulin and the kringle domain of pro-uPA and could be competed efficiently by kringle-containing proteolytic fragments of uPA. In addition, the potentiation could also be competed by the lysine analog 6-aminohexanoic acid, an antagonist of plasminogen binding. This unexpected plasminogen binding dependence was found to be due to a carboxyl-terminal lysine residue on the immunoglobulin gamma chain, which by analogy with other proteins represents a potential binding site for plasminogen. Removal of this residue with carboxypeptidase B resulted in a complete abolition of the potentiation. It appears therefore that the potentiatory effect involves a novel mechanism with the antibody acting to provide a specific template for the assembly of a ternary complex involving pro-uPA/uPA and plasminogen, enabling them to interact in a catalytically favorable manner. This interpretation was confirmed by studying the kinetics of plasminogen activation by the complex between active, two-chain uPA and the antibody, which resulted in an overall 50-fold increase in reaction efficiency (kcat/Km), primarily due to a reduction in Km from 20 to 0.1 microM. Pro-uPA activation by plasmin was also accelerated, although to a lesser extent. The potentiation due to complex formation also provides a mechanism for the initiation of this system, dependent only on the low intrinsic proteolytic activity of the zymogen forms. The effects observed here, mediated by ternary complex formation, simulate the effects we have previously observed on assembly of the uPA receptor-mediated cellular plasminogen activation system and may therefore represent a mechanistic model for both its activity and initiation.

Publisher Summary This chapter discusses the methods that are developed for the study of urokinase-type plasminogen activator (uPa) and plasmin activity in relation to urokinase-type plasminogen activator (uPAR). These methods may also have a more general applicability in the study of other cell surface-associated protease systems, particularly, those that may have an intimate involvement with the plasminogen activation system, for example, the matrix metalloproteases. Numerous studies have delineated a system whereby the generation of cell surface proteolytic activity can be mediated by uPAR, the cellular receptor for the urokinase-type plasminogen activator (uPA). Because of the saturability of the inhibitory effect of isolated uPAR it is possible, under the experimental conditions to derive an approximation to the dissociation constant for the uPA-uPAR interaction in solution. The requirement for quantitative assays to investigate the functional effects of cell surface uPAR on the activity of the uPA-catalyzed plasminogen activation system presents a number of difficulties, particularly with respect to sensitivity and specific quantification.

We have compared the cell-specific expression and regulation of the receptor for urokinase-type plasminogen activator (u-PAR) by transforming growth factor beta type 1 (TGF-beta 1) in 10 human cell lines derived from both normal and neoplastic tissues. The basal expression of u-PAR mRNA as well as its response to TGF-beta 1 varied strongly between different cell lines; however, five out of the 10 cell lines responded to TGF-beta 1 by an increase in the u-PAR mRNA level. Among these, A549 cells were selected for a detailed elucidation of the molecular mechanism involved in TGF-beta 1 regulation of u-PAR mRNA expression. TGF-beta 1 caused an early increase in u-PAR mRNA level, with a maximal 15-fold enhancement after 24 h of treatment. This was paralleled by an increase in u-PAR protein as detected by crosslinking studies with radiolabeled ligand, and also resulted in an increase in cell surface plasmin generation. The protein synthesis inhibitor cycloheximide also increased the level of u-PAR mRNA in a time-dependent fashion and when both cycloheximide and TGF-beta 1 were used, an additive effect was seen. Nuclear run-on experiments demonstrated only a moderate (3-fold) increase in the u-PAR gene transcription rate after exposure of the cells to TGF-beta 1 for 3 h compared with a 12-fold increase in the mRNA level. TGF-beta 1 also caused an increase of both u-PA and PAI-1 antigens, while there was no detectable effect on t-PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of cell to cell contacts and of cell migration is thought to require the action of protease systems which are needed to sever the ties that link cells to other cells and to the extracellular matrix, and to overcome barriers like the basement membranes. Since cell migration phenomena occur from gametogenesis through embryonic development to adulthood, and since also many pathological disorders are associated with or require tissue destruction and cell migration, the requirement for extracellular proteolytic enzymes is a very widespread phenomenon, which however has not yet been clearly understood on a molecular biological and biochemical basis.1–3

Urokinase-type plasminogen activator (u-PA) is a key enzyme involved in migration and invasiveness of cells, both in cancer and in several normal physiological processes (Reich, 1978; Dana et al., 1985; Saksela and Rifkin, 1988; Blasi and Verde, 1990). The application of modem biochemical and molecular biological techniques has identified some of the steps at which u-PA activity is regulated. A large number of studies have dealt with the biological roles of u-PA catalyzed plasminogen activation. These can be summarized as follows: (1) u-PA-dependent proteolysis can take place on cells with surface-bound reactants; physiologically, this may well be the most relevant form of plasminogen activation; (2) the plasminogen activating system and its regulation are complex and several molecules are known to be involved (activators, substrate, inhibitors, receptors), although other, as yet unidentified, components are also implicated and (3) on a biochemical basis the u-PA system exploited by cancer cells appears to be qualitatively identical to that used in normal

The rate of inactivation of human coagulation factor Xa by the plasma proteinase inhibitors antithrombin III and alpha 1-antitrypsin has been studied in the presence of the accessory components which constitute the prothrombinase complex. The rate of inactivation of factor Xa by antithrombin III was found to be decreased in the presence of phospholipid vesicles with high affinity for factor Xa. The second-order rate constant for the reaction fell from 6.21 X 10(4) to 3.40 X 10(4) M-1 min-1 in the presence of 20 microM phospholipid. Purified factor Va had no effect on the rate of inactivation of factor Xa in the absence of phospholipid. In the presence of phospholipid, factor Va increased the protective effect displayed by phospholipid, further reducing the rate constant to 2.20 X 10(4) M-1 min-1. The rate of inactivation of factor Xa by alpha 1-antitrypsin was unaffected under these conditions. Platelet-bound prothrombinase complex was formed by incubation of factor Xa with washed human platelets activated by a mixture of collagen and thrombin. The prothrombinase activity was inhibited by antithrombin III was a second-order rate constant of 0.85 X 10(4) M-1 min-1. This rate was obtained in both the presence and absence of exogenous factor Va. Platelet factor 3 vesicles, isolated from platelet aggregation supernatants, also formed prothrombinase complex in the presence of factor Va, and this was inhibited by antithrombin III at the same rate as the platelet-bound complex. There was no protection of the platelet-bound prothrombinase complex from inhibition by alpha 1-antitrypsin.

Many marine sedimentary black shale and phosphorite formations contain 0.01 to 0.02 percent uranium, and one, the alum shale of Sweden, contains as much as 0.5 percent. The published fact that uranium is already being recovered on a laboratory scale from Swedish deposits forcefully suggests that similar deposits in the United States and possibly many other countries may prove to be an important future source of uranium.The marine uranium-bearing black shales are rich in organic matter and sulfides and contain little or no carbonate. The best are found in relatively thin formations of pre-Mesozoic age. The nature of the uranium-bearing mineral or compound is not known. In contrast, nonmarine black shales, as a group, are not uraniferous.All marine phosphorites tested thus far are uraniferous and so too are the phosphatic nodules found in many marine black shales. With some exceptions, the uranium increases in a general way with increase in phosphate content and is believed to be in the phosphate mineral. Like the black shales, the phosphorite formations are characteristically thin; many are associated with unconformities or, in other words, periods during which little else in the way of sediment accumulated.Significant concentrations of uranium in marine sediments other than black shales and phosphorites are thus far known only in beach placer deposits and the gold-bearing conglomerates of the Witwatersrand district, South Africa.Uranium may be found in other types of marine sediments on further prospecting, but especially promising are the sediments rich in organic matter, phosphate, or both, found in relatively thin formations believed to be the entire depositional products of long periods of geologic time. Such formations are most characteristic of those areas where, at the time of deposition, the adjacent land masses were so stable and low that the influx of clastic materials was small; the basin of deposition was large or of such configuration that fine-grained sediments could accumulate; and chemical conditions in the seawater prevented deposition of large amounts of carbonate.

Black-sand beach concentrates are more widely distributed along the beaches of North Carolina, South Carolina, and Georgia than has been recorded heretofore, as shown by a map prepared by airplane reconnaissance. The map shows also that the black sands diminish in abundance northward, that their distribution is in part related to the configuration of the shoreline, and that they are found only on beaches along the open sea.

Fluids and sedimentary rocks accounted for 48 and 36 percent, respectively, of the total value of the 1946 domestic mineral production. The epigenetic (vein and replacement) and metamorphic deposits each contributed 6 percent of the total, and residual and igneous deposits accounted for 3 and 1 percent, respectively. Fuels were the most valuable of all the minerals produced--77 percent of the total. Petroleum, natural gas, and similar fluid fuels accounted for 47 percent of the total production and 98 percent of that from fluids; bituminous coal made up 24 percent of the total production and 67 percent of that from sedimentary rocks; anthracite coal was valued at 6 percent of the total production and 92 percent of that from metamorphic rocks. Exclusive of fuels, the bulk of the production of nonmetallics, and of the total mineral production too, was from sedimentary rocks (74 and 50 percent, respectively) and from veins and replacements (8 and 28 percent, respectively). Most of the production of metals, however, was from veins, etc. (62 percent) and residuum (29 percent).

Recent publication of maps at scale 1:1,000,000 of the northeastern equatorial Pacific region showing publicly available information on the nickel plus copper content of manganese nodules has made it possible to outline the prime area between the Clarion and Clipperton fracture zones which has been the focus of several recent scientific and commercial studies. The area, defined as that in which the nodules contain more than 1.8 percent nickel plus copper, is about 2o5 million km2. The available evidence suggests that about half of it contains nodules in concentration (reported in wet weight units) greater than 5 kg/m2 and averaging 11.9 kg/m2. If we assume that 20 percent of the nodules in this area of 1.25 million km2 are recoverable, its potential recoverable resources are about 2.1 billion dry metric tons of nodules averaging about 25 percent Mn, 1.3 percent Ni, 1.0 percent Cu, 0.22 percent Co, and 0.05 percent Mo—enough to support about 27 mining operations each producing an average of 75 million metric tons of nodules over their lifetimes. Estimates based on other plausible assumptions would be higher or lower, but of the same order of magnitude. Thus it seems probable that the magnitude of the potentially recoverable nodule resources of the Clarion-Clipperton prime area—the most promising now known—is at most in the range of several tens of the average-size operations postulated.

This report contains statements made by U.S. representatives before the Economic and Technical Subcomittee of the United Nations Committee on the Peaceful Uses of the Seabed and Ocean Floor Beyond the Limits of National Jurisdiction during its March 1969 meeting. The titles of the statements are: Subsea physiographic provinces and their mineral potential; Progress in the exploration and exploitation of subsea petroleum resources and its implications for development beyond the limits of national jurisdiction; Progress in the exploration and exploitation of hard minerals from the seabed; Potential ill effects of subsea mineral exploitation and measures to prevent them; Topographic and geologic mapping of the sea bottom; The origin, incidence, effects, and means of prevention and control of oil-well blowouts; and Implications of geologic and economic factors to seabed resource allocation, development, and management. (MPG)

The beach deposits in a bay of Trout Lake in northern Wisconsin, are divided into eight textural zones which parallel the shore. The sediments of these zones are described and compared with each other, using data derived from 103 mechanical analyses. Samples collected at the same points on the beach, and others collected at points of equal distance from the water's edge, are compared to show textural changes taking place on the beach. The accuracy of sampling is tested by eight sets, of four samples each, taken at the same time and place.

The sediments covering the bottom of Devils Lake below the depth of about six meters are fine muds. Above six meters they increase in coarseness with decrease in depth to become sands or courser materials on the shores. The immediate bottom of the lake at short distances from the shores is covered with a black soupy liquid that is termed sludge. This has a maximum thickness estimated as about one meter. The sediments beneath the sludge are black and have an average water content of 82.5 per cent. Silicon dioxide is the chief constituent of the inorganic part of the sediments and ranges in percentage between 50 to more than 60 per cent. There is little or no calcium or magnesium carbonate, The organic content of the sediments is estimated to be between 15 and 20 per cent. Bacteria are ot particularly abundant in the muds beneath the sludge, but aerobic and facultative bacteria average over a million per gram of dry sludge.

From abstract: A comprehensive investigation of the western phosphate deposits, in progress since 1947, involves a study of the Phosphoria and Park City formations over an area of about 135,000 square miles in the states of Montana, Idaho, Wyoming, and Utah0 It was undertaken to acquire more data on the thickness, composition and quality, structure, and distribution of the deposits--data that would help industry select deposits suitable for mining and permit estimation of reserves, evaluation of potential byproduct elements, and establishment of the origin of the deposits.

The sediments of Little Long (Hiawatha) Lake are described. The lake is surrounded by forest and approximately one-half of the sediments is of organic origin. Water composes approximately between 80 and 90 per cent of the deposits which have a maximum thickness of about 10 feet. Lithification would produce a black carbonaceous or bituminous mudstone which would hardly exceed 2 feet in thickness. The sediments yield from 9 to nearly 12 pounds of oil per ton of dry weight. No stratification was seen in any of the organic-rich, fine-grained sediments.

Report containing abstracts of some stratigraphic sections of the Permian Phosphoria formation in western Wyoming.

Report discussing Sweden Upper Cambrian black shales, which contain uranium. The report contains sections on the distribution and geologic setting of the alum shales, stratigraphy and lithology of shales, mineralogy and composition, areal variations in facies, origin, and suggestions for prospecting.

Report describing the phosphorite deposits of the western United States with the objective of outlining features that are common to both the Kara Tau phosphorite deposits of Russia and the western United States deposits in an effort to define their origin.

Report discussing the intensive search for uranium in the United States. This report contains information regarding common uranium minerals, types of uranium deposits, methods of prospecting for uranium, distribution of uranium deposits in the United States, and a conclusion.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal defect in bone marrow-derived cells and is clinically associated with intravascular hemolysis, hemoglobinuria, and an increased frequency of venous thrombosis. The common denominator of PNH-affected blood cells appears to be a defect in the membrane attachment of proteins normally anchored by glycosyl-phosphatidylinositol (GPI). We report here that the cellular receptor for urokinase-type plasminogen activator (u-PAR) is deficient on affected peripheral blood monocytes and granulocytes from four individuals with PNH as evidenced by chemical cross-linking analysis as well as by immunofluorescence flow cytometry using a monoclonal anti-u-PAR antibody. In contrast, on normal blood monocytes and granulocytes we find significant amounts of u-PAR, which is attached to the plasma membrane by a GPI-anchor as defined by its sensitivity towards a specific phospholipase treatment. By two-color flow cytometry it was shown that deficiency of u-PAR expression paralleled that of another GPI-anchored protein. As u-PAR is involved in the initiation of pericellular proteolysis, the reduced expression of u-PAR on PNH-affected leukocytes led to an overall reduction in the capacity for plasminogen activation by cell-surface-bound urokinase. Whereas the abnormal susceptibility of PNH-affected erythrocytes to lysis by autologous complement has been related to the low expression of three GPI-anchored complement regulatory proteins on the cell surface, we now propose that lack of u-PAR expression on the surface of peripheral blood leukocytes may be causally related to the high incidence of venous thrombosis observed in PNH patients.

The specific cellular receptor for urokinase-type plasminogen activator (uPA) is found on a variety of cell types and has been postulated to play a central role in the mediation of pericellular proteolytic activity. We have studied the kinetics of plasminogen (Plg) activation catalyzed by uPA specifically bound to its receptor on the human monocytoid cell-line U937 and demonstrate this process to have properties differing widely from those observed for uPA in solution. The solution-phase reaction was characterized by a Km of 25 microM and for the cell-associated reaction this fell 40-fold to 0.67 microM, below the physiological Plg concentration of 2 microM. A concomitant 6-fold reduction in kcat resulted in an increase in the overall catalytic efficiency, kcat/Km, of 5.7-fold. This high affinity Plg activation was abolished in the presence of a Plg-binding antagonist. In contrast to intact cells, purified uPA receptor (isolated from phorbol 12-myristate 13-acetate-stimulated U937 cells) was observed to partially inhibit uPA-catalyzed Plg activation, although activity against low molecular weight substrates was retained. Therefore, the cellular binding of Plg appears to be of critical importance for the efficient activation of Plg by receptor-bound uPA. Plasmin generated in the cell-surface Plg activation system described here was also observed to be protected from its principal physiological inhibitor alpha-2-antiplasmin. Together, these data demonstrate that the cell surface constitutes the preferential site for Plg activation when uPA is bound to its specific cellular receptor, which therefore has the necessary characteristics to play an efficient role in the generation of pericellular proteolytic activity.