Bioinformatic analysis of the SPs and NFTs proteomes unravel putative biomarker candidates for Alzheimer's disease

Aging is the main risk factor for the appearance of age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common form of dementia, characterized by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the main histopathological hallmarks in AD brains. The core of these deposits are predominantly amyloid fibrils in SPs and hyperphosphorylated Tau protein in NFTs, but other molecular components can be found associated with these pathological lesions. Herein, an extensive literature review was carried out to obtain the SPs and NFTs proteomes, followed by a bioinformatic analysis and further putative biomarker validation. For SPs, 857 proteins were recovered, and, for NFTs, 627 proteins of which 375 occur in both groups and represent the common proteome. Gene Ontology (GO) enrichment analysis permitted the identification of biological processes and the molecular functions most associated with these lesions. Analysis of the SPs and NFTs common proteins unraveled pathways and molecular targets linking both histopathological events. Further, validation of a putative phosphotarget arising from the in silico analysis was performed in serum-derived extracellular vesicles from AD patients. This bioinformatic approach contributed to the identification of putative molecular targets, valuable for AD diagnostic or therapeutic intervention.     

Childhood cancer and residential radon exposure – results of a population-based case-control study in Lower Saxony (Germany)

A population-based case-control study on risk factors for childhood malignancies was used to investigate a previously reported association between elevated indoor radon concentrations and childhood cancer, with special regard to leukaemia. The patients were all children suffering from leukaemia and common solid tumours (nephroblastoma, neuroblastoma, rhabdomyosarcoma, central nervous system (CNS) tumours) diagnosed between July 1988 and June 1993 in Lower Saxony (Germany) and aged less than 15 years. Two population-based control groups were matched by age and gender to the leukaemia patients. Long-term (1 year) radon measurements were performed in those homes where the children had been living for at least 1 year, with particular attention being paid to those rooms where they had stayed most of the time. Due to the sequential study design, radon measurements in these rooms could only be done for 36% (82 leukaemias, 82 solid tumours and 209 controls) of the 1038 families initially contacted. Overall mean indoor radon concentrations (27 Bq m^–3) were low compared with the measured levels in other studies. Using a prespecified cutpoint of 70 Bq m^–3, no association with indoor radon concentrations was seen for the leukaemias (odds ratio (OR): 1.30; 95% confidence interval (95% CI): 0.32–5.33); however, the risk estimates were elevated for the solid tumours (OR: 2.61; 95% CI: 0.96–7.13), mainly based on 6 CNS tumours. We did not find any evidence for an association between indoor radon and childhood leukaemia, which is in line with a recently published American case-control study. There is little support for an association with CNS tumours in the literature. Received: 14 December 1998 / Accepted in revised form: 10 June 1999     

Chemistry and conformation of vitamin D molecules

1,25-Dihydroxyvitamin D₃ (1,25) is a structurally unique steroid hormone because it not only possesses the complete 25-hydroxycholesterol side chain, but most notably, it possesses a seco-B triene structure (it lacks a B-ring and is usually depicted in a non-steroidal, extended conformation). In contrast, the classical steroid hormones possess a truncated side chain (progesterone, cortisol, and aldosterone) or no side chain (estradiol and testosterone) and they all possess the fully intact ABCD steroid rings. These structural differences render the seco-B-steroid 1,25 considerably more conformationally flexible. Since 1,25 is now known to target a myriad of tissues where specific interactions occur to produce an array of biological responses, it is of interest to determine whether different topologies of 1,25 (resulting from different conformational orientations of 1,25) are necessary to interact effectively at the different target sites. The array of biological responses include both non-genomic and genomic effects and there is considerable promise for the efficacy of 1,25 analogs as chemotherapeutic agents in a variety of human disease states. For the non-genomic calcium transport response of transcaltachia, the finding that two 6-s-cis locked analogs, 1,25-dihydroxyprevitamin D₃ (pre-1,25) and 1,25-dihydroxylumisterol₃ (1,25-Lumi), are equipotent to 1,25, points strongly to the involvement of the 6-s-cis conformer of 1,25 as the biologically active conformer. Since there is a continuum of easily interconvertible 6,7-single bond conformers of the seco-B ring available to 1,25, conformational minima (either local or global) may have little to do with the manner in which 1,25 is bound to receptor. For the genomic calcium transport response, and for other genomic (or non-genomic) effects, there is no clear evidence whether the steroidal (s-cis) or non-steroidal (s-trans) conformer of 1,25 is involved. In order to address this matter further, efforts are underway to evaluate other conformationally locked analogs of 1,25 which might mimic either the planar 6-s-trans-1,25 or some intermediate conformer between it and the planar-6-s-cis form.