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The effect of additive chemistry on the surface fatigue of gears was investigated using an FZG gear tester and fluids based on an API GL-5 grade gear oil. Surface fatigue lives were determined as a function of load and additive chemistry. At 1.52 GPa, the removal of the primary extreme pressure (EP) additive from the fully formulated gear oil decreased the fatigue life of gears slightly (4%). However, the removal of the primary antiwear (AW) additive decreased the fatigue life of gears significantly (83%). At 1.86 GPa, the removal of the EP additive from the fully formulated gear oil decreased the gear fatigue life by 27%. However, the removal of the primary AW additive decreased the fatigue life of gears significantly (75%). Micro-pitting was the dominant surface morphology in the dedendum of the gears tested with two oils at load stage eleven: one using the complete additive package, and a second where the EP additive had been removed. However, spalling was the primary failure mode of gears tested without an AW additive, independent of whether an EP agent was present. Surface analysis of the pinion gears showed the formation of a mixed phosphate/phosphite—oxide layer on the surface of gears tested with fluids containing an AW additive. Formation of this layer seems to be the key to a long fatigue life.

P-glycoprotein is phosphorylated in cells, and it has been suggested that phosphorylation may regulate the drug transport activity of P-glycoprotein. Domain mapping, utilizing a combination of cyanogen bromide digestion and immunoblot analysis, was used to reveal the major phosphorylation sites in murine mdr1b P-glycoprotein. After labeling of J7.V1-1 cells with [32P]Pi, or labeling membranes with [gamma-32P]ATP and either protein kinase A or protein kinase C, it was found that the majority of the label was contained within a single cyanogen bromide fragment (amino acid 627-682) that encompassed the majority of the linker region. The in vitro protein kinase C phosphorylation sites within this fragment were analyzed by a combination of fast atom bombardment mass spectrometry (FABMS) and two-dimensional phosphopeptide mapping. FABMS analysis of a protein kinase C-phosphorylated synthetic peptide, corresponding to a segment of the linker region of P-glycoprotein, identified serine 669 as the single site of phosphorylation. Comparison of two-dimensional tryptic phosphopeptide maps prepared from synthetic peptide and P-glycoprotein, both of which were phosphorylated in vitro with protein kinase C, revealed that serine 669 was also the major phosphorylation site in the intact glycoprotein. The in vitro protein kinase A phosphorylation site was identified as serine 681 by site-directed mutagenesis. Inspection of the gene organization and the deduced amino acid sequence of mdr1b P-glycoprotein revealed that the linker region, although shorter than the R domain (55 versus 241 amino acids), fits the operational definition of the R domain of cystic fibrosis conductance regulator. Like the R domain, the linker region is encoded by a single exon, is highly charged with alternating acidic and basic side chains, and contains several protein kinase A/protein kinase C consensus phosphorylation sites. Since the R domain is believed to be involved in the regulation of cystic fibrosis conductance regulator function by phosphorylation, it is possible that the linker region plays a similar regulatory role in P-glycoprotein function.

Heterocyclic para-aminobenzoate modifications of 2-desamino-2-methyl-5,8-dideazafolic acid and a series of its N10-substituted analogs have produced a number of interesting compounds that have enabled a deeper understanding of the biochemical events required for activity in this class of antimetabolite. There is a relationship that has become apparent between compound potency and both uptake via the reduced-folate carrier and FPGS substrate activity. Rapid cellular uptake and metabolism of polyglutamate forms that are approximately 100-fold more potent as inhibitors of TS can translate a modest TS inhibitor such as ICI D1694 into a very potent inhibitor of cell growth (approximately 500- and approximately 10-fold more potent than CB3717 or ICI 198583, respectively). Polyglutamation may therefore act as an almost essential activation step and ICI D1694 may be highly specific for tumors expressing both the reduced-folate carrier and FPGS. Polyglutamation of folate analogs also leads to drug retention which may play a major role in the pharmacodynamics of TS inhibition by ICI D1694 in vivo. Current studies with 3H-ICI D1694 are aimed at demonstrating metabolism to polyglutamates in tumor cells. The serious toxic limitations of CB3717, i.e., liver and kidney toxicities, are not seen with ICI D1694 reflecting the good water solubility of the drug compared with CB3717. The toxicities observed in mice are however to hematological tissues and are due to its TS inhibitory effects. Thus ICI D1694 may elicit toxicities in man more typical of an antimetabolite than of CB3717. The clinical evaluation of ICI D1694 may further our understanding of the role that metabolism to polyglutamates may have in therapeutic activity.

According to the traditional views mites of the family Pterygosomatidae belong to the cohort Anystina (Krantz, 1978; Kethley, 1982). Kethley (1982), however, noted similarities between these mites and representatives of the cohort Eleutherengona. In the tree diagram suggesting relationships among higher taxa Prostigmata proposed by Kethley (in Norton et al., 1993) this family derives from the eleutherengone clade. However, the characters and ranges of taxa upon which Kethley's hypothesis was based were not stated. In this paper, the external morphology of pterygosomatid mites is analyzed. The data provide strong evidence supporting a close relationship between Pterygosomatidae and thehighereleutherengone mites (Raphignathae and Heterostigmata). The setation of Pterygosomatidae is similar that of Raphignathae by the absence of trichobothria, adanal setae, and by the strongly reduced leg setation. In these mites, as in thehighereleutherengones (Raphignathae) an aedeagus is present, in females, the genital and anal openings are situated close to each other and are covered by a pair of common folds, in males these openings are fused, the leg femora are not separated onto basi- and telofemur, the naso, sejugal furrow, genital papillae, and the larval Claparede's organs are absent. Some similarities in the structure of the gnathosoma and the chelicerae with Anystina (including Parasitengona) are, probably, symplesiomorphies or convergently developed. Moreover, in pterygosomatids, the gnathosomal setation is represented by a single pair of gnathobasal setae, and the cheliceral and adoral setae, present in anystoid mites and early derivative eleutherengones, are absent. We believe, therefore, that Pterygosomatidae is a separate branch within the cohort Eleutherengona. Its exact position is, however, still unclear. Among pterygosomatid genera, mites of the genus Pimeliaphilus, which possess the maximal setation, are closest to thefreelivingshabitus. These mites are known from different parts of the world parasitizing mostly secretively living arthropods. We suggest that ancestors of the family were initially associated with arthropods and parasitism of pterygosomatids on lizards is the result of host switching from arthropods to these hosts.

Gear micropitting has been a highly visible issue in selected applications in recent years, most notably in large wind turbine transmissions. Various industry groups have addressed the problem from their own area of expertise. This has included evaluation of the gear design characteristics, surface finishing, the use of special coatings, and lubrication. A common approach to improve the lubrication has been first to increase the viscosity and create thicker films, which, in turn, reduce the amount of surface asperity interaction. Another approach from the lubricant side has been to alter the additive chemistry to effect a change in the wear properties of the system. This paper discusses the potential effects observed for different antiwear and EP chemistry on the micropitting of cylindrical gears. Tests were conducted in an FZG test rig which has been used by the industry as a guide to general gear performance. Fluids were examined in a series of experimental designs which served as the iterative process leading toward an optimized additive system. The results show that the EP, or antiscuff agent, was the most effective component at reducing the level of micropitting.Copyright © 2003 by ASME

The ectoparasitic mite Knemidokoptes jamaicensis Turk burrows into the cornified epithelium of the legs and feet of Passeriform birds and has been reported from 12 species of North American birds. Here we establish new host and distribution records for K. jamaicensis from eight species of birds from three habitats in the Dominican Republic. These species include Hispaniolan pewee (Contopus hispaniolensis Bryant), northern mockingbird (Mimus polyglottos L.), Cape May warbler (Dendoica tigrina Gmelin), prairie warbler (Dendroica discolor Vieillot), palm warbler (Dendroica palmarum Gmelin), green-tailed warbler (Microligea palustris Cory), black-crowned palm tanager (Phaenicophilus palmarum L.), and Greater Antillean bullfinch (Loxigilla violacea L.). Rates of infestation were as great as 18.2% but varied between species and habitats. Mites were far more common in the dry desert thorn scrub than they were in higher elevation and more moist habitats, despite the fact that many of the affected species had distributions that spanned multiple habitat types. Results suggest that the abundance of scaley-leg mites is controlled by the abundance of suitable host species and by specific ecological conditions that promote transmission.

In 1996, an application was submitted to the US Food and Drug Administration for the use of mifepristone (RU-486) plus the prostaglandin misoprostol in medical abortion. Over 100,000 women in more than 20 countries have received this regimen, which results in pregnancy termination in 92.7-99.0% of treated women. This article presents state-of-the-art information on medical abortion. Reviewed are its pharmacokinetics and metabolism, mechanism of action, and history of use. The article outlines a standard protocol that includes RU-486 administration at the first visit (day 1), misoprostol administration at the second visit (day 3), and post-treatment examination at the third visit (days 14-20) and suggests counseling guidelines. It discusses the contraindications and potential complications of abortifacient agents. Finally, the article compares the experience in the US and Europe of medical versus surgical abortion in terms of effectiveness, complications, and acceptability.

The relationship between neutrophil activation and complement activation during open heart surgery was evaluated by measuring plasma lactoferrin and C3a des Arg (C3a) in 30 adult patients undergoing coronary artery surgery. Measurements were made before induction of anesthesia, before cardiopulmonary bypass, at the end of bypass, and 10 min after protamine infusion. Changes in the measured parameters thus reflected activation during the three distinct phases of cardiac surgery: pre cardiopulmonary bypass, the bypass phase, and the heparin neutralization phase. A major rise in lactoferrin occurred in the pre bypass period, from 99 +/- 13 (mean +/- SEM) to 647 +/- 48 ng/ml (p0.001). During this time, C3a levels did not rise significantly (384 +/- 22 to 439 +/- 36 ng/ml). The bypass procedure resulted in a rise of both lactoferrin and C3a levels, with lactoferrin reaching 1,092 +/- 69 ng/ml and C3a increasing to 1,884 +/- 179 ng/ml after bypass (p0.001 for both). In individual patients, however, the changes in lactoferrin during bypass did not correlate with changes in C3a levels (r = -0.06). After protamine infusion, C3a levels reached 3,301 +/- 324 ng/ml, while the plasma lactoferrin levels declined to 522 +/- 57 ng/ml. Thus, during open heart surgery, neutrophil activation, as measured by plasma lactoferrin concentration, does not correlate with complement activation resulting from the bypass procedure or the protamine neutralization of heparin. The potential clinical relevance of the neutrophil granular release of lactoferrin is discussed.

P-glycoprotein is phosphorylated in cells, and it has been suggested that phosphorylation may regulate the drug transport activity of P-glycoprotein. Domain mapping, utilizing a combination of cyanogen bromide digestion and immunoblot analysis, was used to reveal the major phosphorylation sites in murine mdr1b P-glycoprotein. After labeling of J7.V1-1 cells with [32P]Pi, or labeling membranes with [gamma-32P]ATP and either protein kinase A or protein kinase C, it was found that the majority of the label was contained within a single cyanogen bromide fragment (amino acid 627-682) that encompassed the majority of the linker region. The in vitro protein kinase C phosphorylation sites within this fragment were analyzed by a combination of fast atom bombardment mass spectrometry (FABMS) and two-dimensional phosphopeptide mapping. FABMS analysis of a protein kinase C-phosphorylated synthetic peptide, corresponding to a segment of the linker region of P-glycoprotein, identified serine 669 as the single site of phosphorylation. Comparison of two-dimensional tryptic phosphopeptide maps prepared from synthetic peptide and P-glycoprotein, both of which were phosphorylated in vitro with protein kinase C, revealed that serine 669 was also the major phosphorylation site in the intact glycoprotein. The in vitro protein kinase A phosphorylation site was identified as serine 681 by site-directed mutagenesis. Inspection of the gene organization and the deduced amino acid sequence of mdr1b P-glycoprotein revealed that the linker region, although shorter than the R domain (55 versus 241 amino acids), fits the operational definition of the R domain of cystic fibrosis conductance regulator. Like the R domain, the linker region is encoded by a single exon, is highly charged with alternating acidic and basic side chains, and contains several protein kinase A/protein kinase C consensus phosphorylation sites. Since the R domain is believed to be involved in the regulation of cystic fibrosis conductance regulator function by phosphorylation, it is possible that the linker region plays a similar regulatory role in P-glycoprotein function.

We describe the characterization of human lymphoblastoid cell lines with acquired resistance (greater than 20,000-fold) to a novel folate-based thymidylate synthase (TS) (EC 2.1.1.45) inhibitor, C2-desamino-C2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI198583). This acquired resistance was associated with a 64-fold amplification of the TS gene, a similar elevation in the corresponding mRNA, and an approximately 200-fold increase in both TS activity and TS protein. This amplification was maintained when the cells were grown in the absence of the selective agent, ICI198583, for 340 generations. TS isolated from one of the resistant cell lines, W1-L2:C1, displayed inhibition kinetic parameters similar to those of TS isolated from the parent W1-L2 cell line. It thus appears unlikely that resistance is due to an altered TS enzyme having a lower affinity for ICI198583. The resistant cell line, W1-L2:C1, was cross-resistant to other folate-based TS inhibitors but was as sensitive as the parent cell line, W1-L2, to 5-fluorodeoxyuridine. The W1-L2:C1 cell line was collaterally sensitive to the classical dihydrofolate reductase (EC 1.5.1.3) inhibitor methotrexate as well as to the lipophilic dihydrofolate reductase inhibitors metoprine and 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazolin e glucuronic acid salt (also called trimetrexate). When the W1-L2 and W1-L2:C1 cell lines were exposed to 1 microM ICI198583 for 24 h they accumulated the same concentration of total cellular ICI198583 polyglutamates despite the fact that the latter cell line accumulated a 300-fold greater concentration of ICI198583 monoglutamate. As polyglutamates, the tetra- and pentaglutamate forms predominated in the W1-L2 cell line, whereas the diglutamate form predominated in the W1-L2:C1 cell line, with few higher polyglutamates being detected. The lack of tri- and higher polyglutamates of ICI198583 (i.e., the more active species) in the W1-L2:C1 cell line may also contribute to the observed resistance. These findings may have important implications in light of the rapid onset of resistance to antifolates in the clinic.

gamma-Glutamyl hydrolase (also known as conjugase) is a ubiquitous enzyme that has the capacity to cleave folyl- and antifolylpolyglutamates. This study has revealed that the enzyme is secreted by primary cultures of rat hepatocytes and by H35 hepatoma cells. H35 cells have lower cellular levels of gamma-glutamyl hydrolase than do hepatocytes but secrete a greater proportion of gamma-glutamyl hydrolase. More than 99% of the total enzyme from H35 cells accumulated in the medium after 48 h. The cells were shown to remain intact during the secretion period since lactate dehydrogenase, dihydrofolate reductase, and lysosomal hydrolases other than gamma-glutamyl hydrolase were retained within the cell. Using the substrate 4-amino-10-methyl-pteroyldiglutamate (4-NH2-10-CH3-Pte-Glu2), the intracellular and secreted enzyme form(s) from H35 cells were found to have the following properties (a) Km values of 24.3 +/- 3.7 microM and 34.8 +/- 8.6 microM, respectively, and (b) maximal activity at pH 5 to 7 and apparent molecular weights of 120,000 by gel filtration. Both the cellular and secreted enzymes convert 4-NH2-10-CH3-PteGlu4 and pteroylpentaglutamate acid, to the corresponding monoglutamates with little or no appearance of intermediate chain length polyglutamates. This suggests that both act primarily as endopeptidases. Thus far, the cellular and secreted enzymes cannot be differentiated although the current studies do not establish this point unequivocally. Alterations in the cellular and secreted H35 cell gamma-glutamyl hydrolase levels in response to changes in culture conditions revealed that glutamine enhances activity while insulin diminishes it. Other transformed cells found to secrete this protein are Hep-G2 human hepatoma, JAR human choriocarcinoma, HeLa, and rat glioma. gamma-Glutamyl hydrolase could not be detected in medium conditioned by human MCF-7 breast cancer cells, and relatively low activities were found in the medium from CCRF-CEM or K562 leukemia cells. These studies directly establish for the first time the secretion of gamma-glutamyl hydrolase in vitro.

We examined the in vitro activity of 2-desamino-5,8-dideazafolate and 2-desamino-N10-propargyl-5,8-dideazafolate (desamino-CB3717), the more water-soluble 2-desamino analogues of 5,8-dideazafolate and N10-propargyl-5,8-dideazafolic acid (CB3717). We report Ki values for the inhibition of L1210 thymidylate synthase (TS) of 2 and 0.027 microM for 2-desamino-5,8-dideazafolate and desamino-CB3717, respectively, indicating a 30- and 10-fold loss in TS-inhibitory activity compared with the corresponding 2-NH2 compounds. The synthetic tri- and tetrapolyglutamate derivatives of desamino-CB3717 were 66- and 101-fold more potent than the monoglutamate form as inhibitors of TS. Both desamino compounds were more potent as inhibitors of L1210 and W1L2 cell growth than were their 2-amino counterparts. 2-Desamino-5,8-dideazafolate retains quite good activity against both the TS-overproducing W1L2:C1 line and the L1210 cell line grown in the presence of thymidine, suggesting that a secondary locus of action may be involved. This other target is a folate-dependent enzyme as evidenced by the protection of the inhibition of cell growth by the addition of hypoxanthine or folinic acid together with thymidine. The methotrexate-resistant, dihydrofolate reductase-overproducing L1210:R7A cell line is cross-resistant to 2-desamino-5,8-dideazafolate, which suggests that dihydrofolate reductase is the other target. An L1210 subline (1565) unable to transport reduced folates is 10-fold resistant to desamino-CB3717 and 2-desamino-5,8-dideazafolate but is not cross-resistant to CB3717 or 5,8-dideazafolate. The removal of the 2-amino function of CB3717 did not affect folylpolyglutamate synthetase substrate activity (CB3717 Km = 48 microM, desamino-CB3717 Km = 40 microM). However, both 5,8-dideazafolate and its desamino analogue were about 10-fold better substrates for folylpolyglutamate synthase than were the N10-propargyl compounds, and this may contribute to their good growth-inhibitory properties. In vivo, desamino-CB3717 cured approximately 75% of mice bearing the L1210:ICR tumor at doses of 50 mg/kg daily for 5 days and above (maximum tolerated dose greater than 1000 mg/kg daily for 5 days).(ABSTRACT TRUNCATED AT 400 WORDS)

Within the Department of Manufacturing and Engineering Systems at Brunel University work is being carried out which is directed towards the development of control systems for a flexible manufacturing robot cell. The programming system is dependent on the constraint modelling techniques developed within the department to handle implicit problems. In addition, substantial use is made of sensors in the system. For position determination of the robot end-effector an optical system employing the position sensitive detector has been developed, which depends for its precision on computer based accuracy enhancement techniques, and involving multiple readings. This paper reports on this part of the work, which refers to measurements carried out on a PUMA 560 robot. Of particular importance were measurements aimed at determining the long term stability of relative positioning of the robot, which showed wide discrepancies from day-to-day. These discrepancies were correlated with temperature variation, though very approximately. The case for sensor-derived error correction is presented, which is supported by the results obtained. The system is in the process of being incorporated in a robot control system to fulfil a sensor-derived auto-zeroing function.

Results are presented of the third experiment in a series designed to test a discontinuity theory of psychological development. Use is made of the phenomenon of loss of skill under conditions of increasing rate of change of perceptual field. The scores provided by a population mixture of university undergraduates and graduates separate clearly into two groups which are identified with levels 4 and 5 of the theory. The series provides a compound indirect test of the theory and also substantiates earlier problem-solving experiments. A secondary analysis of the results provides indications of the proportions of schoolchildren (and university undergraduates) corresponding to the different levels of psychological development. Much wider differences in development are revealed than are suggested from conventional psychological and educational research.

This paper describes studies of transmission lubricants in an axle efficiency test rig. The test lubricants were evaluated over various temperature ranges, for each of five road load speed conditions. This was done for both truck and passenger car. Three synthetic gear oils were evaluated, based on various combinations of synthetic hydrocarbons, esters, and viscosity improvers, and were compared to conventional SAE 80W-90 lubricants. All three oils demonstrated improvements in axle eficiency. Also reported are evaluations of seven test lubricants in a high-temperature, high-torque test, and results of seal compatibility tests.

SUMMARYThis paper summarises the results of work carried out in planning the application of a robot in a working cell including a small number of metal cutting machines. The viewpoint assumed is that of a first-time user of robots, and includes the procedure for selecting a robot. Because the analysis calls for robot information not readily available to the user, or which is application specific, a significant conclusion is the necessity to establish a structured programme of collaboration between robot user and robot manufacturer, which becomes an essential part of the analytical and design process.

A discontinuity theory of psychological development is designed such that the associated experimental work relies on quantitative variates of behavior to discriminate stages. Using a dynamic element, expressed abstractly in terms of "poles" and "relations, " a series of structures relating to developmental stages is constructed. The element operates in either of two ways: in a discriminating mode or confusing mode. Operating in the discriminating mode, poles and relations become more defined; operating in the confusing mode leads to loss of discrimination of poles and relation. The element is applied to an imaginary situation of baby with mother. In the course of applying the element, a resolution of the situation into two components is introduced, which leads finally to a unity which comprises a self-structure and two classes of objects, things and persons. The essential structure of this unity, expressed in terms of a self-pole related to an object-pole serves as the level 1 structure of the series. In moving from one level to the next, a transformation of self and objects of the preceding level takes place, elements of the preceding level becoming integrated and serving aspolesfor the succeeding level. Finally, five levels of psychological development are constructed, comprising 15 fundamentally different modes of functioning. The quantitative statements arising from the theory opened possibilities for rigorous experimental testing. Problem-solving experiments and experiments involving loss of skill under increasing stress have been designed to test the theory, the results of which support the theory.

The principle employed by Martin and Stockmeyer in their determination of the fluorescent yield for gases is extended in the present paper to a determination of the fluorescent yield for metals. Preliminary measurements, using Burhop's probability values for the possible Auger transitions, give 0.164 ± 8% as the K Auger yield for tin or 0.836 ± 1.5% for the fluorescent yield. Though not forming part of the present paper the method allows the relative probability of the possible Auger transitions to be determined.

This paper discusses the importance and versatility of axle efficiency testing apparatus to predict lubricant performance in real world operations. The ability to predict field service fuel economy performance is in direct proportion to the ability of the test axle to kinematically simulate the field equipment and operating conditions. Having established the desired conditions the axle efficiency rig permits rapid and broad coverage of the lubricant's efficiency characteristics relative to a given application at a fraction of the vehicle test cost. Strengths and weaknesses of the lubricant can be isolated and performance then optimized through appropriate additive and/or viscosity changes. 6 refs.

The use of selected gear lubricants has been shown to give significant improvements in fuel economy in both commercial vehicles and passenger cars under a variety of test and operational conditions in the U. S. Similar evaluations have been conducted in a variety of European commercial and passenger vehicles to confirm the fuel saving potential observed with the aforementioned selected gear lubricants. In this paper, the investigation of each vehicle type has been presented separately. European commercial vehicles are examined in the first part; fuel consumption data were obtained in extensive over-the-road fleet tests. The second section details the results of investigations with European passenger cars. This includes controlled over-the-road tests and a modified version of the ECE 15 urban cycle operation.