Tissue metal concentrations and metal transfer functions of Glaucous Gulls (Larus hyperboreus) from Bjørnøya and Jan Mayen

Heavy metals (Cd, Cu, Fe, Mn and Zn) concentrations were determined in different tissues (muscle, kidney, liver, brain, gonads, heart and feathers) of Glaucous Gulls (Larus hyperboreus) from Bjornoya and Jan Mayen. The age and spatial dependent variations in heavy metals were quantified and interpreted in view of the three chemometric techniques, i.e. non-parametric Mann-Whitney U test, redundancy gradient analysis and detrended correspondence analysis. The Glaucous Gulls from Bjornoya contained significantly higher (p < 0.05) levels of Cd, Cu and Zn than those inhabited Jan Mayen. Adult birds were characterized by greater (p < 0.01) concentration of muscle, hepatic and renal heavy metals in comparison to chicks. Insignificantly higher slope constant Zn/Cd for the liver than for the kidney may reflect insignificant Cd exposure. Estimate of transfer factor (TF) allows us to assess variations in heavy metal concentrations during the individual development of Glaucous Gulls. It may be stated that there is a distinct increase of bioaccumulation of all the studied metals during subsequent stages of the bird life.

Functions of FKBP12 and Mitochondrial Cyclophilin Active Site Residues In Vitro and In Vivo in Saccharomyces cerevisiae

Cyclophilin and FK506 binding protein (FKBP) accelerate cis–trans peptidyl-prolyl isomerization and bind to and mediate the effects of the immunosuppressants cyclosporin A and FK506. The normal cellular functions of these proteins, however, are unknown. We altered the active sites of FKBP12 and mitochondrial cyclophilin from the yeast Saccharomyces cerevisiae by introducing mutations previously reported to inactivate these enzymes. Surprisingly, most of these mutant enzymes were biologically active in vivo. In accord with previous reports, all of the mutant enzymes had little or no detectable prolyl isomerase activity in the standard peptide substrate-chymotrypsin coupled in vitro assay. However, in a variation of this assay in which the protease is omitted, the mutant enzymes exhibited substantial levels of prolyl isomerase activity (5–20% of wild-type), revealing that these mutations confer sensitivity to protease digestion and that the classic in vitro assay for prolyl isomerase activity may be misleading. In addition, the mutant enzymes exhibited near wild-type activity with two protein substrates, dihydrofolate reductase and ribonuclease T1, whose folding is accelerated by prolyl isomerases. Thus, a number of cyclophilin and FKBP12 “active-site” mutants previously identified are largely active but protease sensitive, in accord with our findings that these mutants display wild-type functions in vivo. One mitochondrial cyclophilin mutant (R73A), and also the wild-type human FKBP12 enzyme, catalyze protein folding in vitro but lack biological activity in vivo in yeast. Our findings provide evidence that both prolyl isomerase activity and other structural features are linked to FKBP and cyclophilin in vivo functions and suggest caution in the use of these active-site mutations to study FKBP and cyclophilin functions.

Functional disorders of the sympathetic nervous system in mice lacking the α1B subunit (Cav 2.2) of N-type calcium channels

N-type voltage-dependent Ca2+ channels (VDCCs), predominantly localized in the nervous system, have been considered to play an essential role in a variety of neuronal functions, including neurotransmitter release at sympathetic nerve terminals. As a direct approach to elucidating the physiological significance of N-type VDCCs, we have generated mice genetically deficient in the α1B subunit (Cav 2.2). The α1B-deficient null mice, surprisingly, have a normal life span and are free from apparent behavioral defects. A complete and selective elimination of N-type currents, sensitive to ω-conotoxin GVIA, was observed without significant changes in the activity of other VDCC types in neuronal preparations of mutant mice. The baroreflex response, mediated by the sympathetic nervous system, was markedly reduced after bilateral carotid occlusion. In isolated left atria prepared from N-type-deficient mice, the positive inotropic responses to electrical sympathetic neuronal stimulation were dramatically decreased compared with those of normal mice. In contrast, parasympathetic nervous activity in the mutant mice was nearly identical to that of wild-type mice. Interestingly, the mutant mice showed sustained elevation of heart rate and blood pressure. These results provide direct evidence that N-type VDCCs are indispensable for the function of the sympathetic nervous system in circulatory regulation and indicate that N-type VDCC-deficient mice will be a useful model for studying disorders attributable to sympathetic nerve dysfunction.

Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice.

Interleukin 1 receptor antagonist (IL-1ra) is a cytokine whose only known action is competitive inhibition of the binding of interleukin 1 (IL-1) to its receptor. To investigate the physiological roles of endogenously produced IL-1ra, we generated mice that either lack IL-1ra or overproduce it under control of the endogenous promoter. Mice lacking IL-1ra have decreased body mass compared with wild-type controls. They are more susceptible than controls to lethal endotoxemia but are less susceptible to infection with Listeria monocytogenes. Conversely, IL-1ra overproducers are protected from the lethal effects of endotoxin but are more susceptible to listeriosis. Serum levels of IL-1 following an endotoxin challenge are decreased in IL-1ra nulls and increased in IL-1ra overproducers in comparison to controls. These data demonstrate critical roles for endogenously produced IL-1ra in growth, responses to infection and inflammation, and regulation of cytokine expression.

Differential functions of the two Src homology 2 domains in protein tyrosine phosphatase SH-PTP1.

SH-PTP1 (also known as PTP1C, HCP, and SHP) is a non-transmembrane protein tyrosine phosphatase (PTPase) containing two tandem Src homology 2 (SH2) domains. We show here that the two SH2 (N-SH2 and C-SH2) domains in SH-PTP1 have different functions in regulation of the PTPase domain and thereby signal transduction. While the N-terminal SH2 domain is both necessary and sufficient for autoinhibition through an intramolecular association with the PTPase domain, truncation of the C-SH2 domain [SH-PTP1 (delta CSH2) construct] has little effect on SH-PTP1 activity. A synthetic phosphotyrosine residue (pY) peptide derived from the erythropoietin receptor (EpoR pY429) binds to the N-SH2 domain and activates both wild-type SH-PTP1 and SH-PTP1 (delta CSH2) 60- to 80-fold. Another pY peptide corresponding to a phosphorylation site on the IgG Fc receptor (Fc gamma RIIB1 pY309) associates with both the C-SH2 domain (Kd = 2.8 microM and the N-SH2 domain (Kd = 15.0 microM) and also activates SH-PTP1 12-fold. By analysis of the effect of the Fc gamma RIIB1 pY309 peptide on SH-PTP1 (delta CSH2), SH-PTP1 (R30K/R33E), SH-PTP1 (R30K/R136K), and SH-PTP1 (R136K) mutants in which the function of either the N- or C-SH2 domain has been impaired, we have determined that both synthetic pY peptides stimulate SH-PTP1 by binding to its N-SH2 domain; binding of pY ligand to the C-SH2 domain has no effect on SH-PTP1 activity. We propose that the N-terminal SH2 domain serves both as a regulatory domain and as a recruiting unit, whereas the C-terminal SH2 domain acts merely as a recruiting unit.

Regulation of blood pressure by the type 1A angiotensin II receptor gene.

The renin-angiotensin system plays a critical role in sodium and fluid homeostasis. Genetic or acquired alterations in the expression of components of this system are strongly implicated in the pathogenesis of hypertension. To specifically examine the physiological and genetic functions of the type 1A receptor for angiotensin II, we have disrupted the mouse gene encoding this receptor in embryonic stem cells by gene targeting. Agtr1A(-/-) mice were born in expected numbers, and the histomorphology of their kidneys, heart, and vasculature was normal. AT1 receptor-specific angiotensin II binding was not detected in the kidneys of homozygous Agtr1A(-/-) mutant animals, and Agtr1A(+/-) heterozygotes exhibited a reduction in renal AT1 receptor-specific binding to approximately 50% of wild-type [Agtr1A(+/+)] levels. Pressor responses to infused angiotensin II were virtually absent in Agtr1A(-/-) mice and were qualitatively altered in Agtr1A(+/-) heterozygotes. Compared with wild-type controls, systolic blood pressure measured by tail cuff sphygmomanometer was reduced by 12 mmHg (1 mmHg = 133 Pa) in Agtr1A(+/-) mice and by 24 mmHg in Agtr1A(-/-) mice. Similar differences in blood pressure between the groups were seen when intraarterial pressures were measured by carotid cannulation. These studies demonstrate that type 1A angiotensin II receptor function is required for vascular and hemodynamic responses to angiotensin II and that altered expression of the Agtr1A gene has marked effects on blood pressures.

Prediction of the growth of wear-type rail corrugation

The growth behaviour of the vibrational wear phenomenon known as rail corrugation is investigated analytically and numerically using mathematical models. A simplified feedback model for wear-type rail corrugation that includes a wheel pass time delay is developed with an aim to analytically distil the most critical interaction occurring between the wheel/rail structural dynamics, rolling contact mechanics and rail wear. To this end, a stability analysis on the complete system is performed to determine the growth of wear-type rail corrugations over multiple wheelset passages. This analysis indicates that although the dynamical behaviour of the system is stable for each wheel passage, over multiple wheelset passages, the growth of wear-type corrugations is shown to be the result of instability due to feedback interaction between the three primary components of the model. The corrugations are shown analytically to grow for all realistic railway parameters. From this analysis an analytical expression for the exponential growth rate of corrugations in terms of known parameters is developed. This convenient expression is used to perform a sensitivity analysis to identify critical parameters that most affect corrugation growth. The analytical predictions are shown to compare well with results from a benchmarked time-domain finite element model. (C) 2004 Elsevier B.V. All rights reserved.

The effects of assessment type on verbal ratings of conditional stimulus valence and contingency judgments: Implications for the extinction of evaluative learning

Recent research on causal learning found (a) that causal judgments reflect either the current predictive value of a conditional stimulus (CS) or an integration across the experimental contingencies used in the entire experiment and (b) that postexperimental judgments, rather than the CS's current predictive value, are likely to reflect this integration. In the current study, the authors examined whether verbal valence ratings were subject to similar integration. Assessments of stimulus valence and contingencies responded similarly to variations of reporting requirements, contingency reversal, and extinction, reflecting either current or integrated values. However, affective learning required more trials to reflect a contingency change than did contingency judgments. The integration of valence assessments across training and the fact that affective learning is slow to reflect contingency changes can provide an alternative interpretation for researchers' previous failures to find an effect of extinction training on verbal reports of CS valence.

Mechanical vibration characteristics of bell-type pump maintings

This thesis describes an analytical and experimental study to determine the mechanical characteristics of the pump mounting, bell housing type. For numerical purposes, the mount was modelled as a thin circular cylindrical shell with cutouts, stiffened with rings and stringers; the boundary conditions were considered to be either clamped-free or clamped-supporting rigid heavy mass. The theoretical study was concerned with both the static response and the free vibration characteristics of the mount. The approach was based on the Rayleigh-Ritz approximation technique using beam characteristic (axial) and trigonometric (Circumferential) functions in the displacement series, in association with the Love - Timoshenko thin shell theory. Studies were carried out to determine the effect of the supported heavy mass on the static response, frequencies and mode shapes; in addition, the effects of stringers, rings and cutouts on vibration characteristics were investigated. The static and dynamic formulations were both implemented on the Hewlett Packard 9845 computer. The experimental study was conducted to evaluate the results of the natural frequencies and mode shapes, predicted numerically. In the experimental part, a digital computer was used as an experiment controller, which allowed accurate and quick results. The following observations were made: 1. Good agreements were obtained with the results of other investigators. 2. Satisfactory agreement was achieved between the theoretical and experimental results. 3. Rings coupled the axial modal functions of the plain cylinder and tended to increase frequencies, except for the torsion modes where frequencies were reduced. Stringers coupled the circumferential modal functions and tended to decrease frequencies. The effect of rings was stronger than that of stringers. 4. Cutouts tended to reduce frequencies; in general, but this depends on the location of the cutouts; if they are near the free edge then an increase in frequencies is obtained. Cutouts coupled both axial and circumferential modal functions. 5. The supported heavy mass had similar effects to those of the rings, but in an exaggerated manner, particularly in the reduction of torsion frequencies. 6. The method of analysis was found to be a convenient analytical tool for estimating the overall behaviour of the shell with cutouts.

Generalized Problem of Sratlikeness for Products of P-Valent Starlike Functions

∗ Partially supported by grant No. 433/94 NSF of the Ministry of Education and Science of the Republic of Bulgaria 1991 Mathematics Subject Classification:30C45

Generalizing of Neural Nets: Functional Nets of Special Type

Special generalizing for the artificial neural nets: so called RFT – FN – is under discussion in the report. Such refinement touch upon the constituent elements for the conception of artificial neural network, namely, the choice of main primary functional elements in the net, the way to connect them(topology) and the structure of the net as a whole. As to the last, the structure of the functional net proposed is determined dynamically just in the constructing the net by itself by the special recurrent procedure. The number of newly joining primary functional elements, the topology of its connecting and tuning of the primary elements is the content of the each recurrent step. The procedure is terminated under fulfilling “natural” criteria relating residuals for example. The functional proposed can be used in solving the approximation problem for the functions, represented by its observations, for classifying and clustering, pattern recognition, etc. Recurrent procedure provide for the versatile optimizing possibilities: as on the each step of the procedure and wholly: by the choice of the newly joining elements, topology, by the affine transformations if input and intermediate coordinate as well as by its nonlinear coordinate wise transformations. All considerations are essentially based, constructively and evidently represented by the means of the Generalized Inverse.

Krätzel Function as a Function of Hypergeometric Type

2000 Mathematics Subject Classification: 33C60, 33C20, 44A15

On a Class of Elliptic Equations for the N-Laplacian in R^n with One-Sided Exponential Growth

2000 Mathematics Subject Classification: 35J40, 49J52, 49J40, 46E30

Complex Hyperbolic Surfaces of Abelian Type

2000 Mathematics Subject Classification: 11G15, 11G18, 14H52, 14J25, 32L07.