Brewer and Unsworth (2012) reported that individuals with low episodic memory ability exhibit a larger testing effect, a finding with potentially important educational implications. We conducted two replication attempts of that study. Exp 1 (n=120) drew from a broad demographic sample and was conducted online, while Exp 2 (n=122) was conducted in the lab with undergraduate students. Both experiments demonstrated a large testing effect across the range of episodic ability in our sample, and with no trend suggesting a larger testing effect for lower ability subjects. We show that apparent differences in the distribution of episodic ability levels between our samples and that of Brewer and Unsworth provide a plausible account of the contrasting correlation results, and that, more generally, sampling from a restricted ability range can yield positive, negative, or no correlation even if there is no difference in the effectiveness of testing for low vs. high ability subjects in the broader population. We discuss methodological and theoretical issues that complicate interpretation of individual differences effects in this domain, individual difference predictions of testing effect models, and educational implications.

The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1α. We previously found that the RNase of IRE1α can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1α RNase (PAIRs), that partially antagonize the IRE1α RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix αC in the IRE1α kinase domain. In insulin-producing β-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory 'sweet spot', achieved by PAIR-bound IRE1α, captures a desirable conformation for drugging this master UPR sensor/effector.