Whole genome methylation array analysis reveals new aspects in Balkan endemic nephropathy etiology

Background Balkan endemic nephropathy (BEN) represents a chronic progressive interstitial nephritis in striking correlation with uroepithelial tumours of the upper urinary tract. The disease has endemic distribution in the Danube river regions in several Balkan countries. DNA methylation is a primary epigenetic modification that is involved in major processes such as cancer, genomic imprinting, gene silencing, etc. The significance of CpG island methylation status in normal development, cell differentiation and gene expression is widely recognized, although still stays poorly understood. Methods We performed whole genome DNA methylation array analysis on DNA pool samples from peripheral blood from 159 affected individuals and 170 healthy individuals. This technique allowed us to determine the methylation status of 27 627 CpG islands throughout the whole genome in healthy controls and BEN patients. Thus we obtained the methylation profile of BEN patients from Bulgarian and Serbian endemic regions. Results Using specifically developed software we compared the methylation profiles of BEN patients and corresponding controls and revealed the differently methylated regions. We then compared the DMRs between all patient-control pairs to determine common changes in the epigenetic profiles. SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs. The CpG islands of all 3 genes were hypomethylated compared to controls. This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions and in both genders. Conclusion Our data propose a new hypothesis that immunologic dysregulation has a place in BEN etiopathogenesis. Keywords: Epigenetics; Whole genome array analysis; Balkan endemic nephropathy

From Similes to Allegory: The Deconstruction of Chariot Imagery in Early Buddhist Texts, Analyzed with Cognitive Metaphor Theory

The presentation will start by unfolding the various layers of chariot imagery in early Indian sources, namely, chariots as vehicles of gods such as the sun (sūrya), i.e. as symbol of cosmic stability; chariots as symbols of royal power and social prestige e.g. of Brahmins; and, finally, chariots as metaphors for the “person”, the “mind” and the “way to liberation” (e.g., Kaṭ.-Up. III.3; Maitr.-Up. II. 6). In Buddhist and non-Buddhist sources, chariots are in certain aspects used as a metaphor for the (old) human body (e.g., Caraka-S., Vi.3.37-38; D II.100; D II.107); apart from that, there is, of course, mention of the “real” use of chariots in sports, cults, journey, and combat. The most prominent example of the Buddhist use of chariot imagery is its application as a model for the person (S I.134 f.; Milindapañha, ed. Trenckner, 26), i.e., for highlighting the “non-substantial self”. There are, however, other significant examples of the usage of chariot imagery in early Buddhist texts. Of special interest are those cases in which chariot metaphors were applied in order to explain how the ‘self’ may proceed on the way to salvation – with ‘mindfulness’ or the ‘self’ as charioteer, with ‘wisdom’ and ‘confidence’ as horses etc. (e.g. S I. 33; S V.7; Dhp 94; or the Nārada-Jātaka, No. 545, verses 181-190). One might be tempted to say that these instances reaffirm the traditional soteriology of a substantial “progressing soul”. Taking conceptual metaphor analysis as a tool, I will, in contrast, argue that there is a special Buddhist use of this metaphor. Indeed, at first sight, it seems to presuppose a non-Buddhist understanding (the “self” as charioteer; the chariot as vehicle to liberation, etc.). Yet, it will be argued that in these cases the chariot imagery is no longer fully “functional”. The Buddhist usage may, therefore, best be described as a final allegorical phase of the chariot-imagery, which results in a thorough deconstruction of the “chariot” itself.