The Notch pathway is a conserved cell-to-cell signaling mechanism, in which extracellular signals are transduced into transcriptional outputs through the nuclear effector CSL. CSL is converted from a repressor to an activator through the formation of the CSL-NotchIC-Mastermind ternary complex. The RAM (RBP-J associated molecule) domain of NotchIC avidly interacts with CSL; however, its role in assembly of the CSLNotchIC-Mastermind ternary complex is not understood. Here we provide a comprehensive thermodynamic, structural, and biochemical analysis of the RAM-CSL interaction for components from both mouse and worm. Our binding data show that RAM and CSL form a high affinity complex in the presence or absence of DNA. Our structural studies reveal a striking distal conformational change in CSL upon RAM binding, which creates a docking site for Mastermind to bind to the complex. Finally, we show that the addition of a RAM peptide in trans facilitates formation of the CSL-NotchIC-Mastermind ternary complex in vitro.

ObjectiveThe aim of this case series was to assess the impact of auditory rehabilitation with cochlear implantation on the cognitive function of elderly patients over time.DesignThis is a longitudinal case series of prospective data assessing neurocognitive function and speech perception in an elderly cohort pre- and post-implantation.SettingUniversity cochlear implant center.ParticipantsThe patients were post-lingually deafened elderly female (mean, 73.6 years; SD, 5.82; range, 67–81 years) cochlear implant recipients (n=7).MeasurementsA neurocognitive battery of 20 tests assessing intellectual function, learning, short- and long-term memory, verbal fluency, attention, mental flexibility, and processing speed was performed prior to and 2–4.1 years (mean, 3.7) after cochlear implant (CI). Speech perception testing using Consonant–Nucleus–Consonant words was performed prior to implantation and at regular intervals postoperatively. Individual and aggregate differences in cognitive function pre- and post-CI were estimated. Logistic regression with cluster adjustment was used to estimate the association (%improvement or %decline) between speech understanding and years from implantation at 1 year, 2 years, and 3 years post-CI.ResultsImprovements after CI were observed in 14 (70%) of all subtests administered. Declines occurred in five (25%) subtests. In 55 individual tests (43%), post-CI performance improved compared to a patient’s own performance before implantation. Of these, nine (45%) showed moderate or pronounced improvement. Overall, improvements were largest in the verbal and memory domains. Logistic regression demonstrated a significant relationship between speech perception and cognitive function over time. Five neurocognitive tests were predictive of improved speech perception following implantation.ConclusionComprehensive neurocognitive testing of elderly women demonstrated areas of improvement in cognitive function and auditory perception following cochlear implantation. Multiple neurocognitive tests were strongly associated with current speech perception measures. While these data shed light on the complex relationship between hearing and cognition by showing that CI may slow the expected age-related cognitive decline, further research is needed to examine the impact of hearing rehabilitation on cognitive decline.

Protein acetylation is an important posttranslational modification with the recent identification of new substrates and enzymes, new links to disease, and modulators of protein acetylation for therapy. α-tubulin acetyltransferase (αTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes. Here, we present the X-ray crystal structure of the human αTAT1/acetyl-CoA complex. Together with structure-based mutagenesis, enzymatic analysis, and functional studies in cells, we elucidate the catalytic mechanism and mode of tubulin-specific acetylation. We find that αTAT1 has an overall fold similar to the Gcn5 histone acetyltransferase but contains a relatively wide substrate binding groove and unique structural elements that play important roles in α-tubulin-specific acetylation. Conserved aspartic acid and cysteine residues play important catalytic roles through a ternary complex mechanism. αTAT1 mutations have analogous effects on tubulin acetylation in vitro and in cells, demonstrating that it is the central determining factor of α-tubulin K40 acetylation levels in vivo. Together, these studies provide general insights into distinguishing features between histone and tubulin acetyltransferases, and they have specific implications for understanding the molecular basis of tubulin acetylation and for developing small molecule modulators of microtubule acetylation for therapy.crystallography | enzymology

Objective To describe our experience with children undergoing unilateral cochlear implantation (CI) for treatment of single‐sided deafness (SSD). Study Design Retrospective case series. Methods A retrospective case review from a tertiary referral center involving 14 pediatric patients (<18 years) with SSD who underwent unilateral CI. Speech perception testing in quiet and noise in the CI‐only and bimodal conditions with at least 1 year of device use and device usage from data logs represent the main outcome measures. Results The mean age at CI was 5.0 years (median 4.4, range 1.0–11.8 years). The mean duration of deafness was 3.0 years (median 2.4, range 0.6–7.0 years). Mean follow‐up was 3.4 years. Speech perception testing with a minimum of 1 year post‐CI was available in eight patients. The mean word recognition scores (WRS) in the CI‐only condition was 56%; a significant improvement from baseline. Testing in background noise with spatially separated speech and noise revealed that patients scored as well or better with the CI‐on versus CI‐off in all conditions and in no cases was interference from the CI noted. Data logs were reviewed for device usage which revealed an average use of 6.5 hr/d. Conclusion Cochlear implantation is a viable treatment option for pediatric SSD in this self‐selected cohort. Open‐set speech and improvement in background noise can be achieved. Careful patient selection and thorough counseling on expectations is paramount to achieving successful outcomes. Level of Evidence IV Laryngoscope, 131:E271–E277, 2021

The JB is a dynamic structure that forms after 2 years, and its size stabilizes in adulthood. The determinants in its exact position and size are multifactorial and may be related to blood flow. Improved understanding of this structure's development may help to better understand the cause of the high-riding JB and JB diverticulum, both of which may cause clinical symptoms.