Role of Stoichiometry in the Dimer-Stabilizing Effect of AMPA Receptor Allosteric Modulators

Protein dimerization provides a mechanism for the modulation of cellular signaling events. In α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, the rapidly desensitizing, activated state has been correlated with a weakly dimeric, glutamate-binding domain conformation. Allosteric modulators can form bridging interactions that stabilize the dimer interface. While most modulators can only bind to one position with a one modulator per dimer ratio, some thiazide-based modulators can bind to the interface in two symmetrical positions with a two modulator per dimer ratio. Based on small-angle X-ray scattering (SAXS) experiments, dimerization curves for the isolated glutamate-binding domain show that a second modulator binding site produces both an increase in positive cooperativity and a decrease in the EC₅₀ for dimerization. Four body binding equilibrium models that incorporate a second dimer-stabilizing ligand were developed to fit the experimental data. The work illustrates why stoichiometry should be an important consideration during the rational design of dimerizing modulators

Descriptive statistics of the characteristics of children with developmental disabilities and their caregivers (N = 215).

<p>Descriptive statistics of the characteristics of children with developmental disabilities and their caregivers (N = 215).</p

Item-saving assessment of self-care performance in children with developmental disabilities: A prospective caregiver-report computerized adaptive test

<div><p>Objective</p><p>The purpose of this study was to construct a computerized adaptive test (CAT) for measuring self-care performance (the CAT-SC) in children with developmental disabilities (DD) aged from 6 months to 12 years in a content-inclusive, precise, and efficient fashion.</p><p>Methods</p><p>The study was divided into 3 phases: (1) item bank development, (2) item testing, and (3) a simulation study to determine the stopping rules for the administration of the CAT-SC. A total of 215 caregivers of children with DD were interviewed with the 73-item CAT-SC item bank. An item response theory model was adopted for examining the construct validity to estimate item parameters after investigation of the unidimensionality, equality of slope parameters, item fitness, and differential item functioning (DIF). In the last phase, the reliability and concurrent validity of the CAT-SC were evaluated.</p><p>Results</p><p>The final CAT-SC item bank contained 56 items. The stopping rules suggested were (a) reliability coefficient greater than 0.9 or (b) 14 items administered. The results of simulation also showed that 85% of the estimated self-care performance scores would reach a reliability higher than 0.9 with a mean test length of 8.5 items, and the mean reliability for the rest was 0.86. Administering the CAT-SC could reduce the number of items administered by 75% to 84%. In addition, self-care performances estimated by the CAT-SC and the full item bank were very similar to each other (Pearson <i>r</i> = 0.98).</p><p>Conclusion</p><p>The newly developed CAT-SC can efficiently measure self-care performance in children with DD whose performances are comparable to those of TD children aged from 6 months to 12 years as precisely as the whole item bank. The item bank of the CAT-SC has good reliability and a unidimensional self-care construct, and the CAT can estimate self-care performance with less than 25% of the items in the item bank. Therefore, the CAT-SC could be useful for measuring self-care performance in children with DD in clinical and research settings.</p></div

Illustration of the steps of computer adaptive testing (CAT).

<p>Illustration of the steps of computer adaptive testing (CAT).</p

Reliability of CAT-SC under different test lengths.

<p>Note: CI = confidence interval.</p

Item-person map of the final item bank.

<p>Note: On the left is the histogram of the estimated self-care performances from 215 children. On the right is the item difficulty aligned vertically. The number, for two-point items, indicates the item number, whereas the number also indicates the response category for three-point items. For example, 4.1 indicates the first step difficulty of item 4.</p

The cumulative reliability (SEM% calculated on the basis of ICC) over trials.

<p>The SEM% of each dot is the cumulative reliability (calculated from the first trial to that trial).</p

Concurrent validity and convergent validity of the 5 segments of the C-DVT (Pearson’s r, n = 90).

Concurrent validity and convergent validity of the 5 segments of the C-DVT (Pearson’s r, n = 90).</p

Standard error of measurement (SEM) and minimal detectable change (MDC) of the 5 segments and the C-DVT (n = 44).

<p>Standard error of measurement (SEM) and minimal detectable change (MDC) of the 5 segments and the C-DVT (n = 44).</p

Demographic characteristics and stroke-related information of the patients.

<p>Demographic characteristics and stroke-related information of the patients.</p