Novel inhibitors of the calcineurin/NFATc hub - alternatives to CsA and FK506?

The drugs cyclosporine A (CsA) and tacrolimus (FK506) revolutionized organ transplantation. Both compounds are still widely used in the clinic as well as for basic research, even though they have dramatic side effects and modulate other pathways than calcineurin-NFATc, too. To answer the major open question - whether the adverse side effects are secondary to the actions of the drugs on the calcineurin-NFATc pathway - alternative inhibitors were developed. Ideal inhibitors should discriminate between the inhibition of (i) calcineurin and peptidyl-prolyl cis-trans isomerases (PPIases; the matchmaker proteins of CsA and FK506), (ii) calcineurin and the other Ser/Thr protein phosphatases, and (iii) NFATc and other transcription factors. In this review we summarize the current knowledge about novel inhibitors, synthesized or identified in the last decades, and focus on their mode of action, specificity, and biological effects

Gravity modeling of the Muertos Trough and tectonic implications (north-eastern Caribbean)

The Muertos Trough in the northeast Caribbean has been interpreted as a subduction zone from seismicity, leading to infer a possible reversal subduction polarity. However, the distribution of the seismicity is very diffuse and makes definition of the plate geometry difficult. In addition, the compressive deformational features observed in the upper crust and sandbox kinematic modeling do not necessarily suggest a subduction process. We tested the hypothesized subduction of the Caribbean plate’s interior beneath the eastern Greater Antilles island arc using gravity modeling. Gravity models simulating a subduction process yield a regional mass deficit beneath the island arc independently of the geometry and depth of the subducted slab used in the models. This mass deficit results from sinking of the less dense Caribbean slab beneath the lithospheric mantle replacing denser mantle materials and suggests that there is not a subducted Caribbean plateau beneath the island arc. The geologically more realistic gravity model which would explain the N–S shortening observed in the upper crust requires an overthrusted Caribbean slab extending at least 60 km northward from the deformation front, a progressive increase in the thrusting angle from 8 to 30 reaching a maximum depth of 22 km beneath the insular slope. This new tectonic model for the Muertos Margin, defined as a retroarc thrusting, will help to assess the seismic and tsunami hazard in the region. The use of gravity modeling has provided targets for future wide-angle seismic surveys in the Muertos Margin

Influence of CD4 or CD8 deficiency on collagen-induced arthritis

The role of T cells in the mouse collagen-induced arthritis (CIA) model for rheumatoid arthritis is not clarified, and different results have been reported concerning the role of CD4 and CD8 T cells. To address this issue, we have investigated B10.Q mice deficient for CD4 or CD8. The mice lacking CD4 were found to be less susceptible to disease, but not completely resistant, whereas the CD8 deficiency had no significant impact on the disease. No difference in the development of late occurring relapses was noted. Interestingly, the CD4-deficient mice had a severely reduced response to the glycosylated form of the immunodominant type II collagen (CII) 256–270 peptide whereas the response to the non-glycosylated peptide was not significantly different. Furthermore, CD4-deficient mice had lower antibody responses to CII, explaining the lower disease susceptibility. In comparison with previously reported results, it is apparent that the lack of CD4 molecules has a different impact on CIA if present on different genetic backgrounds, findings that could possibly be related to the occurrence of different disease pathways of CIA in different mouse strains