Modified nucleobases are found in functionally important regions of RNA and are often responsible for essential structural roles. Many of these nucleobase modifications are dynamically regulated in nature, with each modification having a different biological role in RNA. Despite the high abundance of modifications, many of their characteristics are still poorly understood. One important property of a nucleobase is its pK a value, which has been widely studied for unmodified nucleobases, but not for the modified versions. In this study, the pK a values of modified nucleobases were determined by performing ab initio quantum mechanical calculations using a B3LYP density functional with the 6-31+G­(d,p) basis set and a combination of implicit–explicit solvation systems. This method, which was previously employed to determine the pK a values of unmodified nucleobases, is applicable to a variety of modified nucleobases. Comparisons of the pK a values of modified nucleobases give insight into their structural and energetic impacts within nucleic acids.

SUMMARY A series of 20 patients with definite or clasrical rheumatoid arthritis who subsequently developed a lymphoproliferative malignancy are described. The mean time between the onset of the 2 diseases was 13 2 years. A wide range of types of non-Hodgkin's lymphoma and Hodgkin's disease were found; there were no unusual histological features in the lymphomas. Although many of the patients had had gold, penicillamine, and other second-line drugs, none of them had received cytotoxic drugs, and there was no evidence that therapy was a cause of their malignancies. The likely cause of the association is a predisposition to both diseases.

Purpose This paper aims to investigate the immunoinhibitory properties of a lymph nodes-targeting suppressive oligonucleotide (ODN) for the potential treatment of autoimmune diseases or chronic inflammation. Methods Synthetic suppressive ODN engineered with an albumin-binding diacyl lipid at the 5’-terminal (lipo-ODN) was synthesized. In vitro and in vivo experiments were designed to compare the immune suppressive properties of lipo-ODN and unmodified ODN. Cellular uptake and distribution, inhibition of Toll-like receptor (TLR) activation, lymph nodes (LN) draining, and the suppression of antigen-specific immune responses in an ovalbumin protein model was investigated. Results Compared to unmodified ODN, lipid functionalized suppressive ODN demonstrated enhanced cellular uptake and TLR-9 specific immune suppression in TLR reporter cells. Additionally, injection of a low dose of lipid-modified suppressive ODN, but not the unconjugated ODN, accumulated in the draining LNs and exhibited potent inhibition of antigen-specific CD8+ T cell and B cell responses in vivo. Conclusions Targeting suppressive ODN to antigen presenting cells (APCs) in the local LNs is an effective approach to amplify the immune modulation mediated by ODN containing repetitive TTAGGG motif. This approach might be broadly applicable to target molecular adjuvants to the keyimmune cells in the LNs draining from disease site, providing a simple strategy to improve the efficacy of many molecular immune modulators.

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