DNA Sequence Analysis of SLC26A5, Encoding Prestin, in a Patient-Control Cohort: Identification of Fourteen Novel DNA Sequence Variations

Prestin, encoded by the gene SLC26A5, is a transmembrane protein of the cochlear outer hair cell (OHC). Prestin is required for the somatic electromotile activity of OHCs, which is absent in OHCs and causes severe hearing impairment in mice lacking prestin. In humans, the role of sequence variations in SLC26A5 in hearing loss is less clear. Although prestin is expected to be required for functional human OHCs, the clinical significance of reported putative mutant alleles in humans is uncertain.To explore the hypothesis that SLC26A5 may act as a modifier gene, affecting the severity of hearing loss caused by an independent etiology, a patient-control cohort was screened for DNA sequence variations in SLC26A5 using sequencing and allele specific methods. Patients in this study carried known pathogenic or controversial sequence variations in GJB2, encoding Connexin 26, or confirmed or suspected sequence variations in SLC26A5; controls included four ethnic populations. Twenty-three different DNA sequence variations in SLC26A5, 14 of which are novel, were observed: 4 novel sequence variations were found exclusively among patients; 7 novel sequence variations were found exclusively among controls; and, 12 sequence variations, 3 of which are novel, were found in both patients and controls. Twenty-one of the 23 DNA sequence variations were located in non-coding regions of SLC26A5. Two coding sequence variations, both novel, were observed only in patients and predict a silent change, p.S434S, and an amino acid substitution, p.I663V. In silico analysis of the p.I663V amino acid variation suggested this variant might be benign. Using Fisher's exact test, no statistically significant difference was observed between patients and controls in the frequency of the identified DNA sequence variations. Haplotype analysis using HaploView 4.0 software revealed the same predominant haplotype in patients and controls and derived haplotype blocks in the patient-control cohort similar to those generated from the International HapMap Project.Although these data fail to support a hypothesis that SLC26A5 acts as a modifier gene of GJB2-related hearing loss, the sample size is small and investigation of a larger population might be more informative. The 14 novel DNA sequence variations in SLC26A5 reported here will serve as useful research tools for future studies of prestin

Ansiedad dimensional: Un análisis desde la teoría clásica del formulario autodiligenciado de Zung

RESUMEN Introducción: A pesar del uso extendido del formulario de Zung para ansiedad no se encontraron artículos sobre la invarianza de la prueba. Objetivo: Establecer la invarianza por género del formulario para ansiedad autodiligenciado de Zung desde la Teoría Clásica. Métodos: Muestra no aleaotoria de 336 mujeres y 205 hombres estudiantes de varias universidades colombianas que diligenciaron el formulario. El análisis se realizo con análisis confimatorio de factores. Se investigó la invarianza dimensional, de configuración y métrica. Resultados: Se encontró que las invarianzas dimensional y de configuración se cumplen al demostrarse que el constructo es unidimensional en los 2 géneros, seleccionando los modelos con el Criterio de información Bayesiano y que la carga de los ítems es en general alta. No así la invarianza métrica para la cual debieron eliminarse 9 ítems para lograr invarianza en las cargas. Conclusión: El formulario de Zung presenta invarianzas dimensional, de configuración y métrica con 11 ítems. Salud UIS 2011; 43 (2): 159-166 Palabras clave: Formulario autodiligenciado de Zung, invarianza, análisis de factores   ABSTRACT Introduction: There is not a published report of the invariance of anxiety Zung test, although is widely used. Objective: To stablish gender invariance of the Zung self-rating anxiety scale using Classical Test Theory. Methods: A non random sample of 336 women and 205 men students from several colombian universities that answered the scale. Confirmatory factor analysis was performed. Dimensional, configurational and metric invariance were investigated. Results: Dimensional and configurational invariance are met because for both genders theres is one dimension, using Bayesian Information Crietria as the model selection strategy, and the loadings are generally high. The metric invariance was obtained after deleting 9 items. Conclusion: Eleven items of The Zung self-rating anxiety scale show dimensional, configurational and metric invariance. Salud UIS 2011; 43 (2): 159-166 Keywords: The Zung self-rating scale, invariance, factor analysi

Ansiedad dimensional: Un análisis desde la teoría clásica del formulario autodiligenciado de Zung

RESUMEN Introducción: A pesar del uso extendido del formulario de Zung para ansiedad no se encontraron artículos sobre la invarianza de la prueba. Objetivo: Establecer la invarianza por género del formulario para ansiedad autodiligenciado de Zung desde la Teoría Clásica. Métodos: Muestra no aleaotoria de 336 mujeres y 205 hombres estudiantes de varias universidades colombianas que diligenciaron el formulario. El análisis se realizo con análisis confimatorio de factores. Se investigó la invarianza dimensional, de configuración y métrica. Resultados: Se encontró que las invarianzas dimensional y de configuración se cumplen al demostrarse que el constructo es unidimensional en los 2 géneros, seleccionando los modelos con el Criterio de información Bayesiano y que la carga de los ítems es en general alta. No así la invarianza métrica para la cual debieron eliminarse 9 ítems para lograr invarianza en las cargas. Conclusión: El formulario de Zung presenta invarianzas dimensional, de configuración y métrica con 11 ítems. Salud UIS 2011; 43 (2): 159-166 Palabras clave: Formulario autodiligenciado de Zung, invarianza, análisis de factores   ABSTRACT Introduction: There is not a published report of the invariance of anxiety Zung test, although is widely used. Objective: To stablish gender invariance of the Zung self-rating anxiety scale using Classical Test Theory. Methods: A non random sample of 336 women and 205 men students from several colombian universities that answered the scale. Confirmatory factor analysis was performed. Dimensional, configurational and metric invariance were investigated. Results: Dimensional and configurational invariance are met because for both genders theres is one dimension, using Bayesian Information Crietria as the model selection strategy, and the loadings are generally high. The metric invariance was obtained after deleting 9 items. Conclusion: Eleven items of The Zung self-rating anxiety scale show dimensional, configurational and metric invariance. Salud UIS 2011; 43 (2): 159-166 Keywords: The Zung self-rating scale, invariance, factor analysi

A model and experimental approach to the middle ear transfer function related to hearing in the humpback whale (Megaptera novaeangliae)

At present, there are no direct measures of hearing for any baleen whale (Mysticeti). The most viable alternative to in vivo approaches to simulate the audiogram is through modeling outer, middle, and inner ear functions based on the anatomy and material properties of each component. This paper describes a finite element model of the middle ear for the humpback whale (Megaptera novaeangliae) to calculate the middle ear transfer function (METF) to determine acoustic energy transmission to the cochlea. The model was developed based on high resolution computed tomography imaging and direct anatomical measurements of the middle ear components for this mysticete species. Mechanical properties for the middle ear tissues were determined from experimental measurements and published values. The METF for the humpback whale predicted a better frequency range between approximately 15 Hz and 3 kHz or between 200 Hz and 9 kHz based on two potential stimulation locations. Experimental measures of the ossicular chain, tympanic membrane, and tympanic bone velocities showed frequency response characteristics consistent with the model. The predicted best sensitivity hearing ranges match well with known vocalizations of this species

Fine Tuning of Ca(V)1.3 Ca2+ Channel Properties in Adult Inner Hair Cells Positioned in the Most Sensitive Region of the Gerbil Cochlea

Hearing relies on faithful signal transmission by cochlear inner hair cells (IHCs) onto auditory fibres over a wide frequency and intensity range. Exocytosis at IHC ribbon synapses is triggered by Ca2+ inflow through CaV1.3 (L-type) Ca2+ channels. We investigated the macroscopic (whole-cell) and elementary (cell-attached) properties of Ca2+ currents in IHCs positioned at the middle turn (frequency ,2 kHz) of the adult gerbil cochlea, which is their most sensitive hearing region. Using near physiological recordings conditions (body temperature and a Na+ based extracellular solution), we found that the macroscopic Ca2+ current activates and deactivates very rapidly (time constant below 1 ms) and inactivates slowly and only partially. Single-channel recordings showed an elementary conductance of 15 pS, a sub-ms latency to first opening, and a very low steady-state open probability (Po: 0.024 in response to 500-ms depolarizing steps at ,218 mV). The value of Po was significantly larger (0.06) in the first 40 ms of membrane depolarization, which corresponds to the time when most Ca2+ channel openings occurred clustered in bursts (mean burst duration: 19 ms). Both the Po and the mean burst duration were smaller than those previously reported in high-frequency basal IHCs. Finally, we found that middle turn IHCs are likely to express about 4 times more Ca2+ channels per ribbon than basal cells. We propose that middle-turn IHCs finely-tune CaV1.3 Ca2+ channel gating in order to provide reliable information upon timing and intensity of lower-frequency sounds

β-Actin and γ-Actin Are Each Dispensable for Auditory Hair Cell Development But Required for Stereocilia Maintenance

Hair cell stereocilia structure depends on actin filaments composed of cytoplasmic β-actin and γ-actin isoforms. Mutations in either gene can lead to progressive hearing loss in humans. Since β-actin and γ-actin isoforms are 99% identical at the protein level, it is unclear whether each isoform has distinct cellular roles. Here, we compared the functions of β-actin and γ-actin in stereocilia formation and maintenance by generating mice conditionally knocked out for Actb or Actg1 in hair cells. We found that, although cytoplasmic actin is necessary, neither β-actin nor γ-actin is required for normal stereocilia development or auditory function in young animals. However, aging mice with β-actin– or γ-actin–deficient hair cells develop different patterns of progressive hearing loss and distinct pathogenic changes in stereocilia morphology, despite colocalization of the actin isoforms. These results demonstrate overlapping developmental roles but unique post-developmental functions for β-actin and γ-actin in maintaining hair cell stereocilia

Merkel Cells as Putative Regulatory Cells in Skin Disorders: An In Vitro Study

Merkel cells (MCs) are involved in mechanoreception, but several lines of evidence suggest that they may also participate in skin disorders through the release of neuropeptides and hormones. In addition, MC hyperplasias have been reported in inflammatory skin diseases. However, neither proliferation nor reactions to the epidermal environment have been demonstrated. We established a culture model enriched in swine MCs to analyze their proliferative capability and to discover MC survival factors and modulators of MC neuroendocrine properties. In culture, MCs reacted to bFGF by extending outgrowths. Conversely, neurotrophins failed to induce cell spreading, suggesting that they do not act as a growth factor for MCs. For the first time, we provide evidence of proliferation in culture through Ki-67 immunoreactivity. We also found that MCs reacted to histamine or activation of the proton gated/osmoreceptor TRPV4 by releasing vasoactive intestinal peptide (VIP). Since VIP is involved in many pathophysiological processes, its release suggests a putative regulatory role for MCs in skin disorders. Moreover, in contrast to mechanotransduction, neuropeptide exocytosis was Ca2+-independent, as inhibition of Ca2+ channels or culture in the absence of Ca2+ failed to decrease the amount of VIP released. We conclude that neuropeptide release and neurotransmitter exocytosis may be two distinct pathways that are differentially regulated

Making Friends in the Rainforest: Negrito Adaptation to Risk and Uncertainty

The so-called negritos adapt not just to a tropical forest environment but also to an environment characterized by perturbations and fluctuations. As with other hunter-gatherers in the region and, indeed, throughout the world, they use both social and ecological methods to enhance their chances of survival in this changing environment: socially, they have developed networks of trading and marriage partners; ecologically, they maintain patches of key resources that are available for future harvesting. As evidenced in the case of the Batek (Orang Asli), patterns of forest structure and composition are sometimes direct outcomes of intentional resource concentration and enrichment strategies. While little of the above is controversial anthropologically, what has drawn some debate is the nature of the relationship with partner societies. Conventional wisdom posits relations of inequality between foragers and others : foragers and farmers are often construed as hierarchical dyads where foragers supply products or labor to farmers in exchange for agricultural harvests and other trade goods. This kind of adaptation appears to be one of divergent specialization. However, there are cases, such as in the relationship between Batek and Semaq Beri, where both societies follow a roughly similar mode of adaptation, and specialization has not materialized. In sum, while not denying that hierarchy and inequality exist, I suggest that they have to be contextualized within a larger strand of relationships that includes both hierarchy and egality. Further, such relationships are part of the general portfolio of risk reduction strategies, following which access to widely scattered environmental resources, and passage from one location to another, is enhanced not by competing with and displacing neighbors but by maintaining a flexible regime of friendly exchange partners

Excited-State Electronic Structure with Configuration Interaction Singles and Tamm–Dancoff Time-Dependent Density Functional Theory on Graphical Processing Units

Excited-state calculations are implemented in a development version of the GPU-based TeraChem software package using the configuration interaction singles (CIS) and adiabatic linear response Tamm–Dancoff time-dependent density functional theory (TDA-TDDFT) methods. The speedup of the CIS and TDDFT methods using GPU-based electron repulsion integrals and density functional quadrature integration allows full ab initio excited-state calculations on molecules of unprecedented size. CIS/6-31G and TD-BLYP/6-31G benchmark timings are presented for a range of systems, including four generations of oligothiophene dendrimers, photoactive yellow protein (PYP), and the PYP chromophore solvated with 900 quantum mechanical water molecules. The effects of double and single precision integration are discussed, and mixed precision GPU integration is shown to give extremely good numerical accuracy for both CIS and TDDFT excitation energies (excitation energies within 0.0005 eV of extended double precision CPU results)