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Biology subjects

Smits, C.

Publications and source records attributed to Smits, C..

2 recordsLinked to original sources

The Nucleosome Remodeling and Deacetylase complex has an asymmetric, dynamic, and modular architecture

The Nucleosome Remodeling and Deacetylase (NuRD) complex is essential for development in complex animals but has been refractory to biochemical analysis. We present the first integrated analysis of the architecture of the native mammalian NuRD complex, combining quantitative mass spectrometry, covalent cross-linking, protein biochemistry and electron microscopy. NuRD is built around a 2:2:4 pseudo-symmetric deacetylase module comprising MTA, HDAC and RBBP subunits. This module interacts asymmetrically with a remodeling module comprising one copy each of MBD, GATAD2 and CHD subunits. The previously enigmatic GATAD2 controls the asymmetry of the complex and directly recruits the ATP-dependent CHD remodeler. Unexpectedly, the MTA-MBD interaction acts as a point of functional switching. The transcriptional regulator PWWP2A modulates NuRD assembly by competing directly with MBD for binding to the MTA-HDAC-RBBP subcomplex, forming a moonlighting PWWP2A-MTA-HDAC-RBBP complex that likely directs deacetylase activity to PWWP2A target sites. Taken together, our data describe the overall architecture of the intact NuRD complex and reveal aspects of its structural dynamics and functional plasticity.

biochemistry↗

Improving Sensitivity of the Digits-in-Noise Test using Antiphasic Stimuli

ObjectiveThe digits-in-noise test (DIN) has become increasingly popular as a consumer-based method to screen for hearing loss. Current versions of all DINs either test ears monaurally or present identical stimuli binaurally (i.e., diotic noise and speech, NoSo). Unfortunately, presentation of identical stimuli to each ear inhibits detection of unilateral sensorineural hearing loss (SNHL), and neither diotic nor monaural presentation sensitively detects conductive hearing loss (CHL). Following an earlier finding of enhanced sensitivity in normally hearing listeners, this study tested the hypothesis that interaural antiphasic digit presentation (NoS{pi}) would improve sensitivity to hearing loss caused by unilateral or asymmetric SNHL, symmetric SNHL, or CHL.\n\nDesignThis cross-sectional study, recruited adults (18-84 years) with various levels of hearing, based on a four-frequency pure tone average (PTA) at 0.5, 1, 2 and 4kHz. The study sample was comprised of listeners with normal hearing (n=41; PTA [≤] 25 dB HL in both ears), symmetric SNHL (n=57; PTA > 25 dB HL), unilateral or asymmetric SNHL (n=24; PTA > 25 dB HL in the poorer ear) and CHL (n=23; PTA > 25 dB HL and PTA air-bone gap [≥] 20 dB HL in the poorer ear). Antiphasic and diotic speech reception thresholds (SRTs) were compared using a repeated-measures design.\n\nResultsAntiphasic DIN was significantly more sensitive to all three forms of hearing loss than the diotic DIN. SRT test-retest reliability was high for all tests (ICC r > 0.89). Area under the receiver operating characteristics (ROC) curve for detection of hearing loss (> 25 dB HL) was higher for antiphasic DIN (0.94) than for diotic DIN (0.77) presentation. After correcting for age, PTA of listeners with normal hearing or symmetric SNHL was more strongly correlated with antiphasic (rpartial[96]=0.69) than diotic (rpartial=0.54) SRTs. Slope of fitted regression lines predicting SRT from PTA was significantly steeper for antiphasic than diotic DIN. For listeners with normal hearing or CHL, antiphasic SRTs were more strongly correlated with PTA (rpartial[62]=0.92) than diotic SRTs (rpartial[62]=0.64). Slope of regression line with PTA was also significantly steeper for antiphasic than diotic DIN. Severity of asymmetric hearing loss (poorer ear PTA) was unrelated to SRT. No effect of self-reported English competence on either antiphasic or diotic DIN among the mixed first-language participants was observed\n\nConclusionsAntiphasic digit presentation markedly improved the sensitivity of the DIN test to detect SNHL, either symmetric or asymmetric, while keeping test duration to a minimum by testing binaurally. In addition, the antiphasic DIN was able to detect CHL, a shortcoming of previous monaural or binaurally diotic DIN versions. The antiphasic DIN is thus a powerful tool for population-based screening. This enhanced functionality combined with smartphone delivery could make the antiphasic DIN suitable as a primary screen that is accessible to a large global audience.

pathology↗