Down-regulation of T cell activation following inhibition of dipeptidyl peptidase IV/CD26 by the N-terminal part of the thromboxane A2 receptor.

Using synthetic inhibitors, it has been shown that the ectopeptidase dipeptidyl peptidase IV (DP IV) (CD26) plays an important role in the activation and proliferation of T lymphocytes. The human immunodeficiency virus-1 Tat protein, as well as the N-terminal nonapeptide Tat(1-9) and other peptides containing the N-terminal sequence XXP, also inhibit DP IV and therefore T cell activation. Studying the effect of amino acid exchanges in the N-terminal three positions of the Tat(1-9) sequence, we found that tryptophan in position 2 strongly improves DP IV inhibition. NMR spectroscopy and molecular modeling show that the effect of Trp(2)-Tat(1-9) could not be explained by significant alterations in the backbone structure and suggest that tryptophan enters favorable interactions with DP IV. Data base searches revealed the thromboxane A2 receptor (TXA2-R) as a membrane protein extracellularly exposing N-terminal MWP. TXA2-R is expressed within the immune system on antigen-presenting cells, namely monocytes. The N-terminal nonapeptide of TXA2-R, TXA2-R(1-9), inhibits DP IV and DNA synthesis and IL-2 production of tetanus toxoid-stimulated peripheral blood mononuclear cells. Moreover, TXA2-R(1-9) induces the production of the immunosuppressive cytokine transforming growth factor-beta1. These data suggest that the N-terminal part of TXA2-R is an endogenous inhibitory ligand of DP IV and may modulate T cell activation via DP IV/CD26 inhibition.

N-terminal HIV-1 Tat nonapeptides as inhibitors of dipeptidyl peptidase IV. Conformational characterization.

Compared to the N-terminal nonapeptide of the HIV-1 Tat protein as inhibitor of activity of DP IV which is supposed to mediate the immunosuppressive effects of HIV-1 Tat, the Ile5 and Leu6 analogues showed strongly reduced inhibitory activity. Interestingly, replacement of Asp2 with Gly or Lys led to compounds with considerably enhanced inhibition. Therefore, we have applied 1H NMR spectroscopy and restrained molecular dynamics calculations to elucidate the molecular conformation of a series of Tat nonapeptides. Conformational backbone differences of these peptides as well as the nature and the arrangement of the side chains per se at significant positions preventing effective binding to DP IV might explain their different inhibitory activity on DP IV.

Effects of nonapeptides derived from the N-terminal structure of human immunodeficiency virus-1 (HIV-1) Tat on suppression of CD26-dependent T cell growth.

The human immunodeficiency virus-1 (HIV-1) transactivator Tat occurs extracellularly and exerts immunosuppressive effects. Interestingly, Tat inhibits dipeptidyl peptidase IV (DP IV) activity of the T cell activation marker CD26. The short N-terminal nonapeptide Tat(1-9), MDPVDPNIE, also inhibits DP IV activity and suppresses DNA synthesis of tetanus toxoid-stimulated peripheral blood mononuclear cells (PBMC). Here, we present the influence of amino acid exchanges in the first three positions of Tat(1-9). For instance, the replacement of D2 of Tat(1-9) by G or K generated peptides, which inhibit DP IV-catalyzed IL-2(1-12) cleavage nearly threefold stronger. Similar effects were observed on the suppression of DNA synthesis of Tetanus toxoid-stimulated PBMC. This correlation suggests that Tat(1-9)-deduced peptides mediate antiproliferative effects at least in part via specific DP IV interactions and supports the hypothesis that CD26 plays a key role in the regulation of lymphocyte growth.

Development and validation of homology models of human cathepsins K, S, H, and F.

Models of the tertiary structures of cathepsins K, S, H, and F were constructed by using homology protein modelling methods and refinements by interactive graphics and energy minimisation. The predicted structures yield information regarding their substrate binding sites and indicate the residues surrounding these sites. The ligand binding sites were characterised and compared with each other by means of calculated molecular electrostatic surface potentials. This will allow designing and development of new ligands specific for these cathepsins in future investigations.

1H NMR conformational study on N-terminal nonapeptide sequences of HIV-1 Tat protein: a contribution to structure-activity relationships.

On the basis of our recent results, the N-terminal sequence of HIV-1 Tat protein as a natural competitive inhibitor of dipeptidyl peptidase IV (DP IV) is supposed to interact directly with the active site of DP IV hence mediating its immunosuppressive effects via specific DP IV interactions. Of special interest is the finding that amino acid substitutions of the Tat(1-9) peptide (MDPVDPNIE) in position 5 with S-isoleucine and in position 6 with S-leucine led to peptides with strongly reduced inhibitory activity suggesting differences in the solution conformation of the three analogues. Therefore, 1H NMR techniques in conjunction with molecular modelling have been used here to determine the solution structure of Tat(1-9), I5-Tat(1-9) and L6-Tat(1-9) and to examine the influence of amino acid exchanges on structural features of these peptides. The defined structures revealed differences in the conformations what might be the reason for different interactions of these Tat(1-9) analogues with certain amino acids of the active site of DP IV.

Three-dimensional structures of the cysteine proteases cathepsins K and S deduced by knowledge-based modelling and active site characteristics.

Human cathepsins K and S are recently identified proteins with high primary sequence homology to members of papain superfamily, including cathepsins B, L, H and papain. Models of the tertiary structures of cathepsins K and S and their complexes with a specific substrate and inhibitor were constructed and compared with the recently determined X-ray structure of cathepsin K. A major problem in the determination of the three-dimensional structure of proteins concerns the quality of the structural models obtained from the interpretation of experimental data. The framework of the tertiary structures of cathepsins K and S consisted of structurally conserved regions from the tertiary structure of the papain superfamily and the variable regions were constructed with fragments of other proteins from the protein data base. Based on docking studies the non-bonded interaction energies of ligands with the cathepsins were estimated. These energies correlate with experimentally determined substrate and inhibitory potency.

Homesharing: how social exchange helps elders live at home.

Social exchange theory is used to analyze the relationships in traditional and caregiving homesharing arrangements. Satisfaction with basic money and service exchanges is high among the majority in both arrangements. In traditional matches, client satisfaction is also related to life style fit, amount of social interaction desired and received, and amount of lodger access in the provider's home. In caregiving matches, satisfaction is also related to the intensive interpersonal relationship developed between sharers; stress is a particular problem for the caregiver.

Correlates of dimensions of happiness in urban and nonurban settings.

The NORC happiness scale, widely used in Administration on Aging (A.O.A.) needs assessment surveys, is a composite of both a negative and a positive dimension. A re-examination of this scale based on a survey of 1400 urban and nonurban elderly indicates that the independence of these two dimensions varies for different residences. Results indicate that a high proportion of urban elderly were bored, depressed, and lonely as well as pleased, proud, excited, and interested in things about them. This group of urban elders was extremely disadvantaged in a wide range of both objective and subjective indices; their apparent inconsistent feeling states may result from a general feeling of relative deprivation.

Perceived and objective conditions as predictors of the life satisfaction of urban and non urban elderly.

The effects of objective and subjective conditions on the life satisfaction of urban and non urban elderly are examined in a sample consisting of 1405 randomly selected elderly Vermonters in a four-county area of Northwestern Vermont. Results confirm that there are few significant objective differences between urban and non urban elderly. However, the non urban feel subjectively that they are better off on most conditions. Perceived evaluations of status are found to be better predictors of life satisfaction than objective measures. Furthermore, most disadvantaged conditions' are better predictors of life satisfaction for urban residents than for non urban residents.

[Infected tibial shaft pseudarthroses, treatment and results (author's transl)]. / Infizierte Tibiaschaftpseudarthrosen, Behandlung und Ergebnisse

In a follow up study of 47 patients with infected pseudarthrosis of tibia therapy and results are declared. The most important matter in therapy is the osteosyntesis with compression of the pseudarthrosis. In the majority of cases externe stabilisation is used; seldom compression plate or medullary nailing is indicated. Such cases require much experience in the therapy of bone infection, although if the stabilisation with the fibula is tryed. Flush drainage, suction drainage, antibiotic therapy and cancellous bone grafting are necessary for localisation and decreasing of infection and for induction and acceleration of bone union. In some cases amutation can't be prevented. With correct judgement and consequent treatment in the majority of cases bone union will be obtained.

Attitudinal orientations of wives toward their husbands' retirement.

Most research tends to focus on the husband's attitudes toward retirement while overlooking the wife's evaluation of this event. In this study interviews with wives whose husbands were retired or approaching retirement suggested that a variety of orientations toward their husbands' retirement was present. Some women expressed grave reservations; others looked forward to it; still others had no opinion. It is felt that an understanding of the wife's reaction to her husband's retirement can be useful in understanding the adjustments that both husband and wife may have to make in their relationship to each other.