Podoconiosis in the Ethiopian Rift Valley - Role of beryllium and zirconium

A geogenic origin has been proposed in the aetiology of non-filarial elephantiasis of the feet and legs, recently renamed podoconiosis. Soil collected in an area of the Ethiopian Rift Valley, the borough of Ocholo, known for its high prevalence of podoconiosis (5.06%), has been submitted to mineral analysis. High values of sulphur (S), cerium (Ce), lanthanum (La) and neodymium (Nd), typical for basaltic bedrocks, were found. Of special interest were the values for zirconium (Zr) and beryllium (Be), 618 +/- 87 ppm and 4.6 +/- 0.5 ppm respectively, twice as high as those recorded for soils sampled in neighbouring areas where the prevalence of podoconiosis is low. To be noted also, a high content in vanadium, above 250 ppm, in half of the soil samples collected in this region. Year-long exposure of unprotected feet to Zr and Be, known for their ability to induce granuloma formation in the lymphoid tissue of man, and present in a clay rich in colloidal silica particle, highly abrasive to skin, is doubtlessly a factor involved in the development of lymph node sclerosis leading to elephantiasis.

Stable isotope composition of smectite in suevites at the Ries crater, Germany: Implications for hydrous alteration of impactites

The 24-km diameter Ries crater, Germany, exhibits well-preserved crater filling and surficial melt-rich breccia deposits that are believed to have been altered by post-impact hydrothermal fluids. The alteration mineralogy of the crater filling breccias is characterized by clay (smectite, chlorite) and a zeolite assemblage, and secondary clay phases (smectite, minor halloysite) in surficial melt-bearing breccia deposits. Using stable isotope analysis of secondary smectitic clay fractions, evidence of significant hydrous alteration of impactites at large water/rock ratios was found. The estimated fluid temperatures, using data derived by delta(18)O and delta D fractionation, suggest smectite precipitation in surficial breccias in equilibrium with meteoric fluids at temperatures 16 +/- 5 degrees C in agreement with the long-term variation of modern precipitation in the area. The stable isotope composition of smectite in crater-fill breccia, however, suggests a trend of monotonously increasing temperatures from 43 to 112 degrees C. with increasing depth through the breccia sequence. This demonstrates a different origin of alteration and temperature distribution for the surficial and crater filling melt-bearing impact breccias in the Ries crater. Our results suggest that the inverted structure of hydrothermal systems observed in some terrestrial impact craters, including the Ries crater, could indicate the initial configuration of a thermal anomaly in the crater filling sequence, but which is replaced with a normal hydrothermal convection in crater proper, during the course of post-impact cooling. (C) 2010 Elsevier B.V. All rights reserved.

Cysteine-rich Domain 1 of CD40 Mediates Receptor Self-assembly.

The activation of CD40 on B cells, macrophages, and dendritic cells by its ligand CD154 (CD40L) is essential for the development of humoral and cellular immune responses. CD40L and other TNF superfamily ligands are noncovalent homotrimers, but the form under which CD40 exists in the absence of ligand remains to be elucidated. Here, we show that both cell surface-expressed and soluble CD40 self-assemble, most probably as noncovalent dimers. The cysteine-rich domain 1 (CRD1) of CD40 participated to dimerization and was also required for efficient receptor expression. Modelization of a CD40 dimer allowed the identification of lysine 29 in CRD1, whose mutation decreased CD40 self-interaction without affecting expression or response to ligand. When expressed alone, recombinant CD40-CRD1 bound CD40 with a KD of 0.6 μm. This molecule triggered expression of maturation markers on human dendritic cells and potentiated CD40L activity. These results suggest that CD40 self-assembly modulates signaling, possibly by maintaining the receptor in a quiescent state.

Basal and antigen-induced exposure of the proline-rich sequence in CD3ε.

The CD3ε cytoplasmic tail contains a conserved proline-rich sequence (PRS) that influences TCR-CD3 expression and signaling. Although the PRS can bind the SH3.1 domain of the cytosolic adapter Nck, whether the PRS is constitutively available for Nck binding or instead represents a cryptic motif that is exposed via conformational change upon TCR-CD3 engagement (CD3Δc) is currently unresolved. Furthermore, the extent to which a cis-acting CD3ε basic amino acid-rich stretch (BRS), with its unique phosphoinositide-binding capability, might impact PRS accessibility is not clear. In this study, we found that freshly harvested primary thymocytes expressed low to moderate basal levels of Nck-accessible PRS ("open-CD3"), although most TCR-CD3 complexes were inaccessible to Nck ("closed-CD3"). Ag presentation in vivo induced open-CD3, accounting for half of the basal level found in thymocytes from MHC(+) mice. Additional stimulation with either anti-CD3 Abs or peptide-MHC ligands further elevated open-CD3 above basal levels, consistent with a model wherein antigenic engagement induces maximum PRS exposure. We also found that the open-CD3 conformation induced by APCs outlasted the time of ligand occupancy, marking receptors that had been engaged. Finally, CD3ε BRS-phosphoinositide interactions played no role in either adoption of the initial closed-CD3 conformation or induction of open-CD3 by Ab stimulation. Thus, a basal level of open-CD3 is succeeded by a higher, induced level upon TCR-CD3 engagement, involving CD3Δc and prolonged accessibility of the CD3ε PRS to Nck.