A Data-Driven Latent Variable Approach to Validating the Research Domain Criteria Framework.

Despite the widespread use of the Research Domain Criteria (RDoC) framework in psychiatry and neuroscience, recent studies suggest that the RDoC is insufficiently specific or excessively broad relative to the underlying brain circuitry it seeks to elucidate. To address these concerns of the RDoC framework, our study employed a latent variable approach, specifically utilizing bifactor analysis. We examined a total of 84 whole-brain task-based fMRI (tfMRI) activation maps from 19 studies with a total of 6,192 participants. Within this set of 84 maps, a curated subset of 37 maps with a balanced representation of RDoC domains constituted the training set of our analysis, and the remaining held-out maps formed the internal validation set. External validation was performed with 36 peak coordinate activation maps from Neurosynth, using terms of RDoC constructs as seeds for topic meta-analysis. Our results indicate that a bifactor model with a task-general domain and splitting the cognitive systems domain into sub-domains better fits the current corpus of tfMRI data than the current RDoC framework. Our data-driven validation supports revising the RDoC framework to accurately reflect underlying brain circuitry.

Antiproliferative activity of purine nucleoside dialdehydes against leukemia L1210 in vitro.

Sixteen purine nucleoside dialdehydes were assayed for antiproliferative activity against murine leukemia L1210 grown in vitro. These compounds either lacked the terminal hydroxymethyl group that is necessary in most cases for phosphorylation, and/or had stereochemically different configurations at one or two positions, or had some alteration in the purine ring structure. Among the latter were two lipophilic N6-benzyladenine containing dialdehydes, and two nucleoside dialdehydes with a bromine atom at C-8 of the purine. These nucleoside dialdehydes, unlike most clinically useful anticancer nucleosides, did not require enzymatic phosphorylation to become activated. The most interesting agent in this group of compounds was the lipophilic nucleoside dialdehyde obtained from N6-benzyladenosine after periodate oxidation. It had an IC50 of 1.0 +/- 0.2 microM, and appears to function by limiting the formation of deoxyguanosine diphosphate (dGDP) by inhibition of ribonucleoside diphosphate reductase, the rate limiting step in the biosynthesis of deoxyribonucleotides.