Loss of RAD9B impairs early neural development and contributes to the risk for human spina bifida.

DNA damage response (DDR) genes orchestrating the network of DNA repair, cell cycle control, are essential for the rapid proliferation of neural progenitor cells. To date, the potential association between specific DDR genes and the risk of human neural tube defects (NTDs) has not been investigated. Using whole-genome sequencing and targeted sequencing, we identified significant enrichment of rare deleterious RAD9B variants in spina bifida cases compared to controls (8/409 vs. 0/298; p = .0241). Among the eight identified variants, the two frameshift mutants and p.Gln146Glu affected RAD9B nuclear localization. The two frameshift mutants also decreased the protein level of RAD9B. p.Ser354Gly, as well as the two frameshifts, affected the cell proliferation rate. Finally, p.Ser354Gly, p.Ser10Gly, p.Ile112Met, p.Gln146Glu, and the two frameshift variants showed a decreased ability for activating JNK phosphorylation. RAD9B knockdowns in human embryonic stem cells profoundly affected early differentiation through impairing PAX6 and OCT4 expression. RAD9B deficiency impeded in vitro formation of neural organoids, a 3D cell culture model for human neural development. Furthermore, the RNA-seq data revealed that loss of RAD9B dysregulates cell adhesion genes during organoid formation. These results represent the first demonstration of a DDR gene as an NTD risk factor in humans.

Alternative metrics for real-ear-to-coupler difference average values in children.

BACKGROUND: Ideally, individual real-ear-to-coupler difference (RECD) measurements are obtained for pediatric hearing instrument-fitting purposes. When RECD measurements cannot be obtained, age-related average RECDs based on typically developing North American children are used. Evidence suggests that these values may not be appropriate for populations of children with retarded growth patterns. PURPOSE: The purpose of this study was to determine if another metric, such as head circumference, height, or weight, can be used for prediction of RECDs in children. RESEARCH DESIGN: Design was a correlational study. For all participants, RECD values in both ears, head circumference, height, and weight were measured. STUDY SAMPLE: The sample consisted of 68 North American children (ages 3-11 yr). DATA COLLECTION AND ANALYSIS: Height, weight, head circumference, and RECDs were measured and were analyzed for both ears at 500, 750, 1000, 1500, 2000, 3000, 4000, and 6000 Hz. A backward elimination multiple-regression analysis was used to determine if age, height, weight, and/or head circumference are significant predictors of RECDs. RESULTS: For the left ear, head circumference was retained as the only statistically significant variable in the final model. For the right ear, head circumference was retained as the only statistically significant independent variable at all frequencies except at 2000 and 4000 Hz. At these latter frequencies, weight was retained as the only statistically significant independent variable after all other variables were eliminated. CONCLUSIONS: Head circumference can be considered as a metric for RECD prediction in children when individual measurements cannot be obtained. In developing countries where equipment is often unavailable and stunted growth can reduce the value of using age as a metric, head circumference can be considered as an alternative metric in the prediction of RECDs.

Performance at different stimulus intensities with the within- and across-channel adaptive tests of temporal resolution.

OBJECTIVE: The Adaptive Tests of Temporal Resolution (ATTR©) software provides within-channel (WC) and across-channel (AC) adaptive measures of temporal resolution that are feasible for clinical applications. The purpose of the present study was to obtain normative values for young adults on two of the ATTR tests: the narrow-band noise within-channel (NBN-WC) test and the narrow-band noise across-channel (NBN-AC) test, at different stimulus intensities. DESIGN: Gap detection thresholds were measured at five sensation levels. A Latin square design was used to control for practice effects. STUDY SAMPLE: The NBN-WC group and the NBN-AC group each consisted of 25 young adults with normal hearing. RESULTS: Gap detection thresholds for both conditions decreased with increasing stimulus intensity, and stimulus intensities above 20 dB SL were not associated with large improvements in performance. Variability was larger in the NBN-AC condition. Values obtained for the NBC-WC condition were very similar to previously reported ATTR results despite equipment and design differences. CONCLUSION: Results provide normative values for NBN-WC and NBN-AC performance on the ATTR and suggest that the ATTR is a robust test for clinical use.

Comparison of speechreading training regimens.

The regimen selected for use in speechreading training is an important consideration for audiological rehabilitation purposes and may play a role in its success. Short-term improvement on a commercially available speechreading training program was compared for two training regimens (daily and weekly). Two groups of university student volunteers (ages 20 to 31 years) (12 students per group) were trained daily or weekly on a vowel speechreading task. Percent correct was recorded for each training session. Both groups showed improved performance across training sessions, but there was no significant difference in improvement by type of training regimen.

Inducible nitric oxide synthase contributes to gender differences in ischemic brain injury.

Estrogens have antiinflammatory actions and protect the brain from ischemic injury. Cerebral ischemia is accompanied by an inflammatory reaction that contributes to the tissue damage, an effect mediated in part by toxic amounts of nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS). Therefore, estrogens may protect the female brain by modulating postischemic iNOS expression. To test this hypothesis, we studied whether iNOS plays a role in the mechanisms of the reduced susceptibility to ischemic injury observed in female mice. The middle cerebral artery was occluded for 20 mins using an intraluminal filament in C57Bl/6 mice, and infarct volume was assessed 3 days later in cresyl violet-stained sections. Infarcts were 53% smaller in female mice than in males (P < 0.05), a reduction abolished by ovariectomy (OVX) and reinstated by estrogen replacement. In normal female mice, postischemic iNOS mRNA was lower than in males (P < 0.05). Ovariectomy increased iNOS mRNA after ischemia and estrogen replacement blocked this effect. Furthermore, the iNOS inhibitor aminoguanidine reduced infarct volume in male, but not in female, mice. Similarly, male iNOS-null mice had smaller infarcts than wild-type mice, but female iNOS nulls were not protected. Ovariectomy and OVX with estrogen replacement did not affect infarct volume in iNOS-null female mice. The findings suggest that the neuroprotection conferred by estrogens is, in part, related to attenuation of iNOS expression. Such attenuation could result from the potent antiinflammatory effects of estrogens that downregulate iNOS expression via transcriptional or posttranscriptional mechanisms.