Boys Town National Research Hospital

Only a small proportion of the mouse genome is transcribed into mature messenger RNA transcripts. There is an international collaborative effort to identify all full-length mRNA transcripts from the mouse, and to ensure that each is represented in a physical collection of clones. Here we report the manual annotation of 60,770 full-length mouse complementary DNA sequences. These are clustered into 33,409 'transcriptional units', contributing 90.1% of a newly established mouse transcriptome database. Of these transcriptional units, 4,258 are new protein-coding and 11,665 are new non-coding messages, indicating that non-coding RNA is a major component of the transcriptome. 41% of all transcriptional units showed evidence of alternative splicing. In protein-coding transcripts, 79% of splice variations altered the protein product. Whole-transcriptome analyses resulted in the identification of 2,431 sense-antisense pairs. The present work, completely supported by physical clones, provides the most comprehensive survey of a mammalian transcriptome so far, and is a valuable resource for functional genomics.

OBJECTIVE: The primary purpose of this study was to examine the relationship between age of enrollment in intervention and language outcomes at 5 years of age in a group of deaf and hard-of-hearing children. METHOD: Vocabulary skills at 5 years of age were examined in a group of 112 children with hearing loss who were enrolled at various ages in a comprehensive intervention program. Verbal reasoning skills were explored in a subgroup of 80 of these children. Participants were evaluated using the Peabody Picture Vocabulary Test and a criterion-referenced measure, the Preschool Language Assessment Instrument, administered individually by professionals skilled in assessing children with hearing loss. A rating scale was developed to characterize the level of family involvement in the intervention program for children in the study. RESULTS: A statistically significant negative correlation was found between age of enrollment and language outcomes at 5 years of age. Children who were enrolled earliest (eg, by 11 months of age) demonstrated significantly better vocabulary and verbal reasoning skills at 5 years of age than did later-enrolled children. Regardless of degree of hearing loss, early-enrolled children achieved scores on these measures that approximated those of their hearing peers. In an attempt to understand the relationships among performance and factors, such as age of enrollment, family involvement, degree of hearing loss, and nonverbal intelligence, multiple regression models were applied to the data. The analyses revealed that only 2 of these factors explained a significant amount of the variance in language scores obtained at 5 years of age: family involvement and age of enrollment. Surprisingly, family involvement explained the most variance after controlling for the influence of the other factors (r =.615; F change = 58.70), underscoring the importance of this variable. Age of enrollment also contributed significantly to explained variance after accounting for the other variables in the regression (r = -.452; F change = 19.24). Importantly, there were interactions between the factors of family involvement and age of enrollment that influenced outcomes. Early enrollment was of benefit to children across all levels of family involvement. However, the most successful children in this study were those with high levels of family involvement who were enrolled early in intervention services. Late-identified children whose families were described as limited or average in involvement scored >2 standard deviations below their hearing peers at 5 years of age. Even in the best of circumstances (eg, early enrollment paired with high levels of family involvement), the children in this study scored within the low average range in abstract verbal reasoning compared with hearing peers, reflecting qualitative language differences in these groups of children. CONCLUSIONS: Consistent with the findings of Yoshinaga-Itano et al,(1) significantly better language scores were associated with early enrollment in intervention. High levels of family involvement correlated with positive language outcomes, and, conversely, limited family involvement was associated with significant child language delays at 5 years of age, especially when enrollment in intervention was late. The results suggest that success is achieved when early identification is paired with early interventions that actively involve families.

A second gene for autosomal dominant polycystic kidney disease was identified by positional cloning. Nonsense mutations in this gene (PKD2) segregated with the disease in three PKD2 families. The predicted 968-amino acid sequence of the PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini. The PKD2 protein has amino acid similarity with PKD1, the Caenorhabditis elegans homolog of PKD1, and the family of voltage-activated calcium (and sodium) channels, and it contains a potential calcium-binding domain.

BACKGROUND: Weak intermolecular interactions such as hydrogen bonding and hydrophobic interactions are key players in stabilizing energetically-favored ligands, in an open conformational environment of protein structures. However, it is still poorly understood how the binding parameters associated with these interactions facilitate a drug-lead to recognize a specific target and improve drugs efficacy. To understand this, comprehensive analysis of hydrophobic interactions, hydrogen bonding and binding affinity have been analyzed at the interface of c-Src and c-Abl kinases and 4-amino substituted 1H-pyrazolo [3, 4-d] pyrimidine compounds. METHODOLOGY: In-silico docking studies were performed, using Discovery Studio software modules LigandFit, CDOCKER and ZDOCK, to investigate the role of ligand binding affinity at the hydrophobic pocket of c-Src and c-Abl kinase. Hydrophobic and hydrogen bonding interactions of docked molecules were compared using LigPlot program. Furthermore, 3D-QSAR and MFA calculations were scrutinized to quantify the role of weak interactions in binding affinity and drug efficacy. CONCLUSIONS: The in-silico method has enabled us to reveal that a multi-targeted small molecule binds with low affinity to its respective targets. But its binding affinity can be altered by integrating the conformationally favored functional groups at the active site of the ligand-target interface. Docking studies of 4-amino-substituted molecules at the bioactive cascade of the c-Src and c-Abl have concluded that 3D structural folding at the protein-ligand groove is also a hallmark for molecular recognition of multi-targeted compounds and for predicting their biological activity. The results presented here demonstrate that hydrogen bonding and optimized hydrophobic interactions both stabilize the ligands at the target site, and help alter binding affinity and drug efficacy.

OBJECTIVES: This study examined the language outcomes of children with mild to severe hearing loss during the preschool years. The longitudinal design was leveraged to test whether language growth trajectories were associated with degree of hearing loss and whether aided hearing influenced language growth in a systematic manner. The study also explored the influence of the timing of hearing aid fitting and extent of use on children's language growth. Finally, the study tested the hypothesis that morphosyntax may be at particular risk due to the demands it places on the processing of fine details in the linguistic input. DESIGN: The full cohort of children in this study comprised 290 children who were hard of hearing (CHH) and 112 children with normal hearing who participated in the Outcomes of Children with Hearing Loss (OCHL) study between the ages of 2 and 6 years. CHH had a mean better-ear pure-tone average of 47.66 dB HL (SD = 13.35). All children received a comprehensive battery of language measures at annual intervals, including standardized tests, parent-report measures, and spontaneous and elicited language samples. Principal components analysis supported the use of a single composite language score for each of the age levels (2, 3, 4, 5, and 6 years). Measures of unaided (better-ear pure-tone average, speech intelligibility index) and aided (residualized speech intelligibility index) hearing were collected, along with parent-report measures of daily hearing aid use time. Mixed modeling procedures were applied to examine the rate of change (227 CHH; 94 children with normal hearing) in language ability over time in relation to (1) degree of hearing loss, (2) aided hearing, (3) age of hearing aid fit and duration of use, and (4) daily hearing aid use. Principal components analysis was also employed to examine factor loadings from spontaneous language samples and to test their correspondence with standardized measures. Multiple regression analysis was used to test for differential effects of hearing loss on morphosyntax and lexical development. RESULTS: Children with mild to severe hearing loss, on average, showed depressed language levels compared with peers with normal hearing who were matched on age and socioeconomic status. The degree to which CHH fell behind increased with greater severity of hearing loss. The amount of improved audibility with hearing aids was associated with differential rates of language growth; better audibility was associated with faster rates of language growth in the preschool years. Children fit early with hearing aids had better early language achievement than children fit later. However, children who were fit after 18 months of age improved in their language abilities as a function of the duration of hearing aid use. These results suggest that the language learning system remains open to experience provided by improved access to linguistic input. Performance in the domain of morphosyntax was found to be more delayed in CHH than their semantic abilities. CONCLUSION: The data obtained in this study largely support the predictions, suggesting that mild to severe hearing loss places children at risk for delays in language development. Risks are moderated by the provision of early and consistent access to well-fit hearing aids that provide optimized audibility.

International audience

Outer hair cells (OHCs) of the mammalian cochlea actively change their cell length in response to changes in membrane potential. This electromotility, thought to be the basis of cochlear amplification, is mediated by a voltage-sensitive motor molecule recently identified as the membrane protein prestin. Here, we show that voltage sensitivity is conferred to prestin by the intracellular anions chloride and bicarbonate. Removal of these anions abolished fast voltage-dependent motility, as well as the characteristic nonlinear charge movement ("gating currents") driving the underlying structural rearrangements of the protein. The results support a model in which anions act as extrinsic voltage sensors, which bind to the prestin molecule and thus trigger the conformational changes required for motility of OHCs.

A mouse model for the autosomal form of Alport syndrome was produced. These mice develop a progressive glomerulonephritis with microhematuria and proteinuria, consistent with the human disease. End-stage renal disease develops at approximately 14 weeks of age. TEM analysis of the glomerular basement membranes (GBM) during development of renal pathology revealed focal multilaminated thickening and thinning beginning in the external capillary loops at 4 weeks and spreading throughout the GBM by 8 weeks. By 14 weeks, half of the glomeruli were fibrotic with collapsed capillaries. Immunofluorescence analysis of the GBM showed the absence of type IV collagen alpha-3, alpha-4, and alpha-5 chains and a persistence of alpha-1 and alpha-2 chains (these chains normally localize to the mesangial matrix). Northern blot analysis using probes specific for the collagen chains illustrate the absence of COL4A3 in the knockout, whereas mRNAs for the remaining chains are unchanged. An accumulation of fibronectin, heparan sulfate proteoglycan, laminin-1, and entactin was observed in the GBM of the affected animals. The temporal and spatial pattern of accumulation was consistent with that for thickening of the GBM as observed by TEM. Thus, expression of these basement membrane-associated proteins may be involved in the progression of Alport renal disease pathogenesis. The levels of mRNAs encoding the basement membrane-associated proteins at 7 weeks were unchanged.

The gene responsible for DNFB1 and DFNA3, connexin 26 ( GJB2 ), was recently identified and more than 20 disease causing mutations have been reported so far. This paper presents mutation analysis for GJB2 in Japanese non-syndromic hearing loss patients compatible with recessive inheritance. It was confirmed that GJB2 mutations are an important cause of hearing loss in this population, with three mutations, 235delC, Y136X, and R143W, especially frequent. Of these three mutations, 235delC was most prevalent at 73%. Surprisingly, the 35delG mutation, which is the most common GJB2 mutation in white subjects, was not found in the present study. Our data indicated that specific combinations of GJB2 mutation exist in different populations.

In Brief The purpose of this paper is to provide a review of past and current research regarding language and literacy development in children with mild to severe hearing impairment. A related goal is to identify gaps in the empirical literature and suggest future research directions. Included in the language development review are studies of semantics (vocabulary, novel word learning, and conceptual categories), morphology, and syntax. The literacy section begins by considering dimensions of literacy and the ways in which hearing impairment may influence them. It is followed by a discussion of existing evidence on reading and writing, and highlights key constructs that need to be addressed for a comprehensive understanding of literacy in these children. This review surveys the evidence regarding language and literacy development in children with mild to severe sensorineural hearing impairment. The language development section synthesizes studies of semantics (vocabulary, novel word learning and conceptual categories), morphology, and syntax. The literacy section synthesizes studies of reading and writing, along with considering key constructs for understanding literacy and the potential effects of hearing impairment on literacy. Evidence regarding the timing of intervention is examined. Gaps in our empirical knowledge are highlighted to identify further research needs.

A linear, mathematical model of cochlear biomechanics is presented in this paper. In this model, active elements are essential for simulating the high sensitivity and sharp tuning characteristic of the mammalian cochlea. The active elements are intended to represent the motile action of outer hair cells; they are postulated to be mechanical force generators that are powered by electrochemical energy of the cochlear endolymph, controlled by the bending of outer hair cell stereocilia, and bidirectionally coupled to cochlear partition mechanics. The active elements are spatially distributed and function collectively as a cochlear amplifier. Excessive gain in the cochlear amplifier causes spontaneous oscillations and thereby generates spontaneous otoacoustic emissions.

OBJECTIVES: 1) To describe distortion product otoacoustic emission (DPOAE) measurements in large groups of subjects with normal hearing and with hearing loss, and to use these data to provide comprehensive descriptions of DPOAE test performance. 2) To describe the effects of primary frequency and audiometric threshold on the extent to which DPOAE measurements accurately identify auditory status. 3) To develop an approach that describes the probability that any measured response is coming from either a normal or an impaired ear. 4) To develop an approach for representing DPOAE data clinically. 5) To explore the relation between magnitude of hearing loss and DPOAE measurements. DESIGN: DPOAE measurements were made in 1267 ears of 806 subjects, using stimulus conditions that previously had been demonstrated to result in the greatest separation between normal and impaired ears (i.e., primary levels of 65/55 dB SPL for f1/f2; Stover et al., 1996). Subjects were recruited from local clinical populations and through local advertisements. All data were analyzed using clinical decision theory, including relative operating characteristic (ROC) curves and estimates of areas under these curves (Az). In addition, cumulative distributions were constructed of response properties from both normal and hearing-impaired ears. These cumulative distributions were used to select specific probabilities that measured responses were coming from either the normal or impaired distributions, and to develop an approach for describing clinical DPOAE data. RESULTS: For no conditions were the distributions of DPOAE responses from normal and impaired ears completely separated, meaning that optimal criterion values would still result in errors in identification of auditory status. Test performance, defined by Az, was best for mid and high frequencies and poorest for lower frequencies and for the highest frequency tested (8000 Hz). Performance was best when normal hearing was defined as audiometric thresholds between 20 and 30 dB HL, with poorer performance for more stringent or lax audiometric criteria. CONCLUSIONS: Within the limits related to the effects of primary frequency and audiometric criterion, it appears that DPOAE measurements can be used to accurately identify auditory status. An approach is described, using the present data set, that allows one to assign to any measured DPOAE value (DPOAE amplitudes, DPOAE/noise) the probability that the response is coming either from the distribution of normal or impaired responses. In addition, DPOAE/noise systematically decreases as hearing loss increases over the range of hearing losses from 0 to about 40 to 60 dB HL (depending on frequency), thus potentially enabling one to differentiate hearing losses over this range. For hearing losses greater than 50 to 60 dB HL, ears do not produce measurable DPOAEs and thus, no predictive relationship exists.

The Usher syndromes are genetically distinct disorders which share specific phenotypic characteristics. This paper describes a set of clinical criteria recommended for the diagnosis of Usher syndrome type I and Usher syndrome type II. These criteria have been adopted by the Usher Syndrome Consortium and are used in studies reported by members of this Consortium.

This chapter focuses on one of the first steps in comprehending spoken language: How do listeners extract the most fundamental linguistic elements-consonants and vowels, or the distinctive features which compose them-from the acoustic signal? We begin by describing three major theoretical perspectives on the perception of speech. Then we review several lines of research that are relevant to distinguishing these perspectives. The research topics surveyed include categorical perception, phonetic context effects, learning of speech and related nonspeech categories, and the relation between speech perception and production. Finally, we describe challenges facing each of the major theoretical perspectives on speech perception.

OBJECTIVE: Ménière's disease (MD) is a clinical condition defined by spontaneous vertigo attacks (each lasting 20 minutes to 12 hours) with documented low- to midfrequency sensorineural hearing loss in the affected ear before, during, or after one of the episodes of vertigo. It also presents with fluctuating aural symptoms (hearing loss, tinnitus, or ear fullness) in the affected ear. The underlying etiology of MD is not completely clear, yet it has been associated with inner ear fluid (endolymph) volume increases, culminating in episodic ear symptoms (vertigo, fluctuating hearing loss, tinnitus, and aural fullness). Physical examination findings are often unremarkable, and audiometric testing may or may not show low- to midfrequency sensorineural hearing loss. Conventional imaging, if performed, is also typically normal. The goals of MD treatment are to prevent or reduce vertigo severity and frequency; relieve or prevent hearing loss, tinnitus, and aural fullness; and improve quality of life. Treatment approaches to MD are many and typically include modifications of lifestyle factors (eg, diet) and medical, surgical, or a combination of therapies. PURPOSE: The primary purpose of this clinical practice guideline is to improve the quality of the diagnostic workup and treatment outcomes of MD. To achieve this purpose, the goals of this guideline are to use the best available published scientific and/or clinical evidence to enhance diagnostic accuracy and appropriate therapeutic interventions (medical and surgical) while reducing unindicated diagnostic testing and/or imaging.

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes.

Purpose For over two decades, we have known that children with developmental language disorder (DLD) are underserved. We have also known that DLD does not attract the research attention that it merits given its prevalence and impact. The purposes of this clinical focus article are to present evidence that these failures continue, explore the reasons behind these failures, and propose solutions. Method I reviewed the literature and applied bibliometric analysis procedures from Bishop (2010) to quantify research efforts aimed at DLD compared to other neurodevelopmental disorders. Results The percentage of children who are deemed eligible for clinical services because of DLD continues to fall well short of estimates based on the prevalence of DLD in community samples. The amount of research conducted on DLD relative to other neurodevelopmental disorders remains low. Contributing factors include a lack of awareness of DLD, the hidden nature of DLD, entrenched policies, and the dissonance created when speech-language pathologists must diagnose DLD in school settings. Conclusions Expanded approaches to supporting children with DLD are required. These might include engagement in advocacy and awareness campaigns; clearer communication with the families we serve and enhanced collaborations with classroom teachers; the implementation of school-based language screenings; participation in policymaking; and the development of service delivery models that operate alongside those that exist in our schools and complement their function. Supplemental Material https://doi.org/10.23641/asha.12743273.

OBJECTIVES: To review recent research studies concerning the importance of high-frequency amplification for speech perception in adults and children with hearing loss and to provide preliminary data on the phonological development of normal-hearing and hearing-impaired infants. DESIGN AND SETTING: With the exception of preliminary data from a longitudinal study of phonological development, all of the reviewed studies were taken from the archival literature. To determine the course of phonological development in the first 4 years of life, the following 3 groups of children were recruited: 20 normal-hearing children, 12 hearing-impaired children identified and aided up to 12 months of age (early-ID group), and 4 hearing-impaired children identified after 12 months of age (late-ID group). Children were videotaped in 30-minute sessions at 6- to 8-week intervals from 4 to 36 months of age (or shortly after identification of hearing loss) and at 2- and 6-month intervals thereafter. Broad transcription of child vocalizations, babble, and words was conducted using the International Phonetic Alphabet. A phoneme was judged acquired if it was produced 3 times in a 30-minute session. SUBJECTS: Preliminary data are presented from the 20 normal-hearing children, 3 children from the early-ID group, and 2 children from the late-ID group. RESULTS: Compared with the normal-hearing group, the 3 children from the early-ID group showed marked delays in the acquisition of all phonemes. The delay was shortest for vowels and longest for fricatives. Delays for the 2 children from the late-ID group were substantially longer. CONCLUSIONS: The reviewed studies and preliminary results from our longitudinal study suggest that (1) hearing-aid studies with adult subjects should not be used to predict speech and language performance in infants and young children; (2) the bandwidth of current behind-the-ear hearing aids is inadequate to accurately represent the high-frequency sounds of speech, particularly for female speakers; and (3) preliminary data on phonological development in infants with hearing loss suggest that the greatest delays occur for fricatives, consistent with predictions based on hearing-aid bandwidth.

Transforming growth factor-beta (TGF-beta) induces epithelial-mesenchymal transition (EMT) of epithelial cells in both normal embryonic development and certain pathological contexts. Here, we show that TGF-beta induced-EMT in human lung cancer cells (A549; adenocarcinoma cells) mediates tumor cell migration and invasion phenotypes. To gain insights into molecular events during EMT, we employed a global stable isotope labeled profiling strategy using iTRAQ reagents, followed by 2DLC-MS/MS, which identified a total of 51 differentially expressed proteins during EMT; 29 proteins were up-regulated and 22 proteins were down-regulated. Down-regulated proteins were predominantly enzymes involved in regulating nutrient or drug metabolism. The majority of the TGF-beta-induced proteins (such as tropomyosins, filamin A, B, & C, integrin-beta1, heat shock protein27, transglutaminase2, cofilin, 14-3-3 zeta, ezrin-radixin-moesin) are involved in the regulation of cell migration, adhesion and invasion, suggesting the acquisition of a invasive phenotype.

IMPORTANCE Hearing loss (HL) in children can be deleterious to their speech and language development. The standard of practice has been early provision of hearing aids (HAs) to moderate these effects; however, there have been few empirical studies evaluating the effectiveness of this practice on speech and language development among children with mild-to-severe HL. OBJECTIVE To investigate the contributions of aided hearing and duration of HA use to speech and language outcomes in children with mild-to-severe HL. DESIGN, SETTING, AND PARTICIPANTS An observational cross-sectional design was used to examine the association of aided hearing levels and length of HA use with levels of speech and language outcomes. One hundred eighty 3- and 5-year-old children with HL were recruited through records of Universal Newborn Hearing Screening and referrals from clinical service providers in the general community in 6 US states. INTERVENTIONS All but 4 children had been fitted with HAs, and measures of aided hearing and the duration of HA use were obtained. MAIN OUTCOMES AND MEASURES Standardized measures of speech and language ability were obtained. RESULTS Measures of the gain in hearing ability for speech provided by the HA were significantly correlated with levels of speech (ρ179 = 0.20; P = .008) and language: ρ155 = 0.21; P = .01) ability. These correlations were indicative of modest levels of association between aided hearing and speech and language outcomes. These benefits were found for children with mild and moderate-to-severe HL. In addition, the amount of benefit from aided hearing interacted with the duration of HA experience (Speech: F4,161 = 4.98; P < .001; Language: F4,138 = 2.91; P < .02). Longer duration of HA experience was most beneficial for children who had the best aided hearing. CONCLUSIONS AND RELEVANCE The degree of improved hearing provided by HAs was associated with better speech and language development in children. In addition, the duration of HA experience interacted with the aided hearing to influence outcomes. These results provide support for the provision of well-fitted HAs to children with HL. In particular, the findings support early HA fitting and HA provision to children with mild HL.