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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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AU Microscopii (AU Mic) is the second closest pre-main-sequence star, at a distance of 9.79 parsecs and with an age of 22 million years1. AU Mic possesses a relatively rare2 and spatially resolved3 edge-on debris disk extending from about 35 to 210 astronomical units from the star4, and with clumps exhibiting non-Keplerian motion5-7. Detection of newly formed planets around such a star is challenged by the presence of spots, plage, flares and other manifestations of magnetic 'activity' on the star8,9. Here we report observations of a planet transiting AU Mic. The transiting planet, AU Mic b, has an orbital period of 8.46 days, an orbital distance of 0.07 astronomical units, a radius of 0.4 Jupiter radii, and a mass of less than 0.18 Jupiter masses at 3σ confidence. Our observations of a planet co-existing with a debris disk offer the opportunity to test the predictions of current models of planet formation and evolution.
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X-inactive specific transcript (XIST) is a 17-19 kb long non-coding ribonucleic acid (RNA) critical for X-chromosome inactivation. Tandem repeats within the RNA serve as functional domains involved in the cis-limited recruitment of heterochromatic changes and silencing. To explore the sufficiency of these domains while generating a functional mini-XIST for targeted silencing approaches, we tested inducible constructs integrated into 8p in a male cell line. Previous results suggested silencing could be accomplished with a transgene comprised of the repeat A, which is highly conserved and critical for silencing; the repeat F that overlaps regulatory elements and the repeat E that contributes to XIST localization by binding proteins such as CIZ1 (AFE). As polycomb-repressive complex 1 (PRC1) is recruited through HNRNPK binding of repeats B-C-D, we included a second 'mini-XIST' comprising AFE with the mouse Polycomb Interaction Domain (PID), a 660-nucleotide region known to recruit PRC1. Silencing of an adjacent gene was possible with and without PID; however, silencing more distally required the addition of PID. The recruitment of heterochromatic marks, evaluated by immunofluorescence combined with RNA fluorescence in situ hybridization, revealed that the AFE domains were sufficient only for CIZ1 recruitment. However, mini-XIST transgene recruited all marks, albeit not to full XIST levels. The ability of the PID domain to facilitate silencing and heterochromatic mark recruitment was unexpected, and inhibition of PRC1 suggested that many of these are PRC1 independent. These results suggest that the addition of this small region allowed the partial recruitment of all the features induced by a full XIST, demonstrating the feasibility of finding a minimal functional XIST.
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RNA Longo não Codificante , Humanos , Masculino , Animais , Camundongos , Hibridização in Situ Fluorescente , RNA Longo não Codificante/genética , Inativação do Cromossomo X , Proteínas do Grupo Polycomb/genética , Núcleo Celular/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Proteínas Nucleares/genéticaRESUMO
OBJECTIVES: To describe the effects of two types of auditory training on both behavioral and physiological measures of auditory function in cochlear implant (CI) users, and to examine whether a relationship exists between the behavioral and objective outcome measures. DESIGN: This study involved two experiments, both of which used a within-subject design. Outcome measures included behavioral and cortical electrophysiological measures of auditory processing. In Experiment I, 8 CI users participated in a music-based auditory training. The training program included both short training sessions completed in the laboratory as well as a set of 12 training sessions that participants completed at home over the course of a month. As part of the training program, study participants listened to a range of different musical stimuli and were asked to discriminate stimuli that differed in pitch or timbre and to identify melodic changes. Performance was assessed before training and at three intervals during and after training was completed. In Experiment II, 20 CI users participated in a more focused auditory training task: the detection of spectral ripple modulation depth. Training consisted of a single 40-minute session that took place in the laboratory under the supervision of the investigators. Behavioral and physiologic measures of spectral ripple modulation depth detection were obtained immediately pre- and post-training. Data from both experiments were analyzed using mixed linear regressions, paired t tests, correlations, and descriptive statistics. RESULTS: In Experiment I, there was a significant improvement in behavioral measures of pitch discrimination after the study participants completed the laboratory and home-based training sessions. There was no significant effect of training on electrophysiologic measures of the auditory N1-P2 onset response and acoustic change complex (ACC). There were no significant relationships between electrophysiologic measures and behavioral outcomes after the month-long training. In Experiment II, there was no significant effect of training on the ACC, although there was a small but significant improvement in behavioral spectral ripple modulation depth thresholds after the short-term training. CONCLUSIONS: This study demonstrates that auditory training improves spectral cue perception in CI users, with significant perceptual gains observed despite cortical electrophysiological responses like the ACC not reliably predicting training benefits across short- and long-term interventions. Future research should further explore individual factors that may lead to greater benefit from auditory training, in addition to optimization of training protocols and outcome measures, as well as demonstrate the generalizability of these findings.
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XIST establishes inactivation across its chromosome of origin, even when expressed from autosomal transgenes. To identify the regions of human XIST essential for recruiting heterochromatic marks we generated a series of overlapping deletions in an autosomal inducible XIST transgene present in 8p of the HT1080 male fibrosarcoma cell line. We examined the ability of each construct to enrich its unified XIST territory with the histone marks established by PRC1 and PRC2 as well as the heterochromatin factors MacroH2A and SMCHD1. Chromatin enrichment of ubH2A by PRC1 required four distinct regions of XIST, and these were completely distinct from the two domains crucial for enrichment of H3K27me3 by PRC2. Both the domains required, as well as the impact of PRC1 and PRC2 inhibitors, suggest that PRC1 is required for SMCHD1 while PRC2 function is necessary for MacroH2A recruitment, although incomplete overlap of regions implicates roles for additional factors. This cooperativity between factors contributes to the requirement for multiple separate domains being required for each feature examined. The independence of the PRC1/PRC2 pathways was observed when XIST was expressed both autosomally or from the X chromosome suggesting that these observations are not purely a result of the context in which XIST operates. Although independent domains were required for the PRC1 and PRC2 pathways overall all regions tested were important for some aspect of XIST functionality, demonstrating both modularity and cooperativity across the XIST lncRNA.
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Proteínas de Ciclo Celular/metabolismo , Regulação da Expressão Gênica , RNA Longo não Codificante/genética , Proteínas de Ciclo Celular/química , Linhagem Celular , Cromossomos Humanos X , Heterocromatina/genética , Heterocromatina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Modelos Biológicos , Proteínas do Grupo Polycomb/genética , Ligação Proteica , RNA Longo não Codificante/metabolismo , Sequências Repetitivas de Ácido Nucleico , Deleção de SequênciaRESUMO
INTRODUCTION: Expanding cochlear implant (CI) candidacy criteria and advances in electrode arrays and soft surgical techniques have increased the number of CI recipients who have residual low-frequency hearing. Objective measures such as obligatory cortical auditory-evoked potentials (CAEPs) may help clinicians make more tailored recommendations to recipients regarding optimal listening mode. As a step toward this goal, this study investigated how CAEPs measured from hybrid CI users differ in two listening modes: acoustic alone (A-alone) versus acoustic plus electric (A + E). METHODS: Eight successful hybrid CI users participated in this study. Two CAEPs, the P1-N1-P2 and the acoustic change complex (ACC), were measured simultaneously in response to the onset and change of a series of different and spectrally complex acoustic signals, in each of the two listening modes (A-alone and A + E). We examined the effects of listening mode and stimulus type on the onset and ACC N1-P2 amplitudes and peak latencies. RESULTS: ACC amplitudes in hybrid CI users significantly differed as a function of listening mode and stimulus type. ACC responses in A + E were larger than those in the A-alone mode. This was most evident for stimuli involving a change from low to high frequency. CONCLUSIONS: Results of this study showed that the ACC varies as a function of listening mode and stimulus type. This finding suggests that the ACC can be used as a physiologic, objective measure of the benefit of hybrid CIs, potentially supporting clinicians in making clinical recommendations on individualized listening mode, or to document subjective preference for a given listening mode. Further research into this potential clinical application in a range of hybrid recipients and/or long electrode users who have residual low-frequency hearing is warranted.
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Implante Coclear , Implantes Cocleares , Percepção da Fala , Potenciais Evocados Auditivos/fisiologia , Audição , Acústica , Estimulação Acústica , Percepção da Fala/fisiologiaRESUMO
OBJECTIVES: Less traumatic intracochlear electrode design and the introduction of the soft surgery technique allow for the preservation of low-frequency acoustic hearing in many cochlear implant (CI) users. Recently, new electrophysiologic methods have also been developed that allow acoustically evoked peripheral responses to be measured in vivo from an intracochlear electrode. These recordings provide clues to the status of peripheral auditory structures. Unfortunately, responses generated from the auditory nerve (auditory nerve neurophonic [ANN]) are somewhat difficult to record because they are smaller than the hair cell responses (cochlear microphonic). Additionally, it is difficult to completely segregate the ANN from the cochlear microphonic, complicating the interpretation and limiting clinical applications. The compound action potential (CAP) is a synchronous response of multiple auditory nerve fibers and may provide an alternative to ANN where the status of the auditory nerve is of primary interest. This study is a within-subject comparison of CAPs recorded using traditional stimuli (clicks and 500 Hz tone bursts) and a new stimulus (CAP chirp). We hypothesized that the chirp stimulus might result in a more robust CAP than that recorded using traditional stimuli, allowing for a more accurate assessment of the status of the auditory nerve. DESIGN: Nineteen adult Nucleus L24 Hybrid CI users with residual low-frequency hearing participated in this study. CAP responses were recorded from the most apical intracochlear electrode using a 100 µs click, 500 Hz tone bursts, and chirp stimuli presented via the insert phone to the implanted ear. The chirp stimulus used in this study was CAP chirp generated using parameters from human-derived band CAPs ( Chertoff et al. 2010 ). Additionally, nine custom chirps were created by systematically varying the frequency sweep rate of the power function used to construct the standard CAP chirp stimulus. CAPs were recorded using all acoustic stimuli, allowing for within-subject comparisons of the CAP amplitude, threshold, percentage of measurable CAP responses, and waveform morphology. RESULTS: Considerable variation in response morphology was apparent across stimuli and stimulation levels. Clicks and CAP chirp significantly evoked identifiable CAP response more compared to 500 Hz tone bursts. At relatively high stimulation levels, the chirp-evoked CAPs were significantly larger in amplitude and less ambiguous in morphology than the click-evoked CAPs. The status of residual acoustic hearing at high frequencies influenced the likelihood that a CAP could be reliably recorded. Subjects with better preserved hearing at high frequencies had significantly larger CAP amplitudes when CAP chirp was used. Customizing the chirp stimulus by varying the frequency sweep rates significantly affected the CAP amplitudes; however, pairwise comparisons did not show significant differences between chirps. CONCLUSIONS: CAPs can be measured more effectively using broadband acoustic stimuli than 500 Hz tone bursts in CI users with residual low-frequency acoustic hearing. The advantage of using CAP chirp stimulus relative to standard clicks is dependent on the extent of preserved acoustic hearing at high frequencies and the stimulus level. The chirp stimulus may present an attractive alternative to standard clicks or tone bursts for this CI population when the goal is to record robust CAP responses.
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Implante Coclear , Implantes Cocleares , Adulto , Humanos , Potenciais de Ação/fisiologia , Audição , Estimulação Acústica/métodos , Acústica , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Limiar Auditivo/fisiologiaRESUMO
OBJECTIVE: Minimally traumatic surgical techniques and advances in cochlear implant (CI) electrode array designs have allowed acoustic hearing present in a CI candidate prior to surgery to be preserved postoperatively. As a result, these patients benefit from combined electric-acoustic stimulation (EAS) postoperatively. However, 30% to 40% of EAS CI users experience a partial loss of hearing up to 30 dB after surgery. This additional hearing loss is generally not severe enough to preclude use of acoustic amplification; however, it can still impact EAS benefits. The use of electrocochleography (ECoG) measures of peripheral hair cell and neural auditory function have shed insight into the pathophysiology of postimplant loss of residual acoustic hearing. The present study aims to assess the long-term stability of ECoG measures and to establish ECoG as an objective method of monitoring residual hearing over the course of EAS CI use. We hypothesize that repeated measures of ECoG should remain stable over time for EAS CI users with stable postoperative hearing preservation. We also hypothesize that changes in behavioral audiometry for EAS CI users with loss of residual hearing should also be reflected in changes in ECoG measures. DESIGN: A pool of 40 subjects implanted under hearing preservation protocol was included in the study. Subjects were seen at postoperative visits for behavioral audiometry and ECoG recordings. Test sessions occurred 0.5, 1, 3, 6, 12 months, and annually after 12 months postoperatively. Changes in pure-tone behavioral audiometric thresholds relative to baseline were used to classify subjects into two groups: one group with stable acoustic hearing and another group with loss of acoustic hearing. At each test session, ECoG amplitude growth functions for several low-frequency stimuli were obtained. The threshold, slope, and suprathreshold amplitude at a fixed stimulation level was obtained from each growth function at each time point. Longitudinal linear mixed effects models were used to study trends in ECoG thresholds, slopes, and amplitudes for subjects with stable hearing and subjects with hearing loss. RESULTS: Preoperative, behavioral audiometry indicated that subjects had an average low-frequency pure-tone average (125 to 500 Hz) of 40.88 ± 13.12 dB HL. Postoperatively, results showed that ECoG thresholds and amplitudes were stable in EAS CI users with preserved residual hearing. ECoG thresholds increased (worsened) while ECoG amplitudes decreased (worsened) for those with delayed hearing loss. The slope did not distinguish between EAS CI users with stable hearing and subjects with delayed loss of hearing. CONCLUSIONS: These results provide a new application of postoperative ECoG as an objective tool to monitor residual hearing and understand the pathophysiology of delayed hearing loss. While our measures were conducted with custom-designed in-house equipment, CI companies are also designing and implementing hardware and software adaptations to conduct ECoG recordings. Thus, postoperative ECoG recordings can potentially be integrated into clinical practice.
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Implante Coclear , Implantes Cocleares , Surdez , Perda Auditiva , Humanos , Estimulação Acústica , Audiometria de Resposta Evocada/métodos , Implante Coclear/métodos , Perda Auditiva/reabilitação , Surdez/reabilitação , Audiometria de Tons Puros , Limiar Auditivo , Estimulação ElétricaRESUMO
In most countries, major development projects must satisfy an Environmental Impact Assessment (EIA) process that considers positive and negative aspects to determine if it meets environmental standards and appropriately mitigates or offsets negative impacts on the values being considered. The benefits of before-after-control-impact monitoring designs have been widely known for more than 30 years, but most development assessments fail to effectively link pre- and post-development monitoring in a meaningful way. Fish are a common component of EIA evaluation for both socioeconomic and scientific reasons. The Ecosystem Services (ES) concept was developed to describe the ecosystem attributes that benefit humans, and it offers the opportunity to develop a framework for EIA that is centred around the needs of and benefits from fish. Focusing an environmental monitoring framework on the critical needs of fish could serve to better align risk, development, and monitoring assessment processes. We define the ES that fish provide in the context of two common ES frameworks. To allow for linkages between environmental assessment and the ES concept, we describe critical ecosystem functions from a fish perspective to highlight potential monitoring targets that relate to fish abundance, diversity, health, and habitat. Finally, we suggest how this framing of a monitoring process can be used to better align aquatic monitoring programs across pre-development, development, and post-operational monitoring programs.
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Ecossistema , Peixes , Animais , Meio Ambiente , Monitoramento AmbientalRESUMO
OBJECTIVES: The objective of this study was to evaluate the sensitivity and reliability of one subjective (rating scale) and three objective (dual-task paradigm, pupillometry, and skin conductance response amplitude) measures of listening effort across multiple signal to noise ratios (SNRs). DESIGN: Twenty adults with normal hearing attended two sessions and listened to sentences presented in quiet and in stationary noise at three different SNRs: 0, -3, and -5 dB. Listening effort was assessed by examining change in reaction time (dual-task paradigm), change in peak to peak pupil diameter (pupillometry), and change in mean skin conductance response amplitude; self-reported listening effort on a scale from 0 to 100 was also evaluated. Responses were averaged within each SNR and based on three word recognition ability categories (≤50%, 51% to 71%, and >71%) across all SNRs. Measures were considered reliable if there were no significant changes between sessions, and intraclass correlation coefficients were a minimum of 0.40. Effect sizes were calculated to compare the sensitivity of the measures. RESULTS: Intraclass correlation coefficient values indicated fair-to-moderate reliability for all measures while individual measurement sensitivity was variable. Self-reports were sensitive to listening effort but were less reliable, given that subjective effort was greater during the dual task than either of the physiologic measures. The dual task was sensitive to a narrow range of word recognition abilities but was less reliable as it exhibited a global decrease in reaction time across sessions. Pupillometry was consistently sensitive and reliable to changes in listening effort. Skin conductance response amplitude was not sensitive or reliable while the participants listened to the sentences. Skin conductance response amplitude during the verbal response was sensitive to poor (≤50%) speech recognition abilities; however, it was less reliable as there was a significant change in amplitude across sessions. CONCLUSIONS: In this study, pupillometry was the most sensitive and reliable objective measure of listening effort. Intersession variability significantly influenced the other objective measures of listening effort, which suggests challenges for cross-study comparability. Therefore, intraclass correlation coefficients combined with other statistical tests more fully describe the reliability of measures of listening effort across multiple difficulties. Minimizing intersession variability will increase measurement sensitivity. Further work toward standardized methods and analysis will strengthen our understanding of the reliability and sensitivity of measures of listening effort and better facilitate cross-modal and cross-study comparisons.
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Percepção da Fala , Percepção Auditiva , Testes Auditivos , Humanos , Ruído , Reprodutibilidade dos TestesRESUMO
One of the two X chromosomes in females is epigenetically inactivated, thereby compensating for the dosage difference in X-linked genes between XX females and XY males. Not all X-linked genes are completely inactivated, however, with 12% of genes escaping X chromosome inactivation and another 15% of genes varying in their X chromosome inactivation status across individuals, tissues or cells. Expression of these genes from the second and otherwise inactive X chromosome may underlie sex differences between males and females, and feature in many of the symptoms of XXY Klinefelter males, who have both an inactive X and a Y chromosome. We review the approaches used to identify genes that escape from X-chromosome inactivation and discuss the nature of their sex-biased expression. These genes are enriched on the short arm of the X chromosome, and, in addition to genes in the pseudoautosomal regions, include genes with and without Y-chromosomal counterparts. We highlight candidate escape genes for some of the features of Klinefelter syndrome and discuss our current understanding of the mechanisms underlying silencing and escape on the X chromosome as well as additional differences between the X in males and females that may contribute to Klinefelter syndrome.
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Cromossomos Humanos X/genética , Genes Ligados ao Cromossomo X/genética , Síndrome de Klinefelter/genética , Inativação do Cromossomo X/genética , Animais , Cromossomos Humanos Y/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Síndrome de Klinefelter/patologia , MasculinoRESUMO
The X chromosome is unique in the genome. In this review we discuss recent advances in our understanding of the genetics and epigenetics of the X chromosome. The X chromosome shares limited conservation with its ancestral homologue the Y chromosome and the resulting difference in X-chromosome dosage between males and females is largely compensated for by X-chromosome inactivation. The process of inactivation is initiated by the long non-coding RNA X-inactive specific transcript (XIST) and achieved through interaction with multiple synergistic silencing pathways. Identification of Xist-interacting proteins has given insight into these processes yet the cascade of events from initiation to maintenance have still to be resolved. In particular, the initiation of inactivation in humans has been challenging to study as: it occurs very early in development; most human embryonic stem cell lines already have an inactive X; and the process seems to differ from mouse. Another difference between human and mouse X inactivation is the larger number of human genes that escape silencing. In humans over 20% of X-linked genes continue to be expressed from the otherwise inactive X chromosome. We are only beginning to understand how such escape occurs but there is growing recognition that escapees contribute to sexually dimorphic traits. The unique biology and epigenetics of the X chromosome have often led to its exclusion from disease studies, yet the X constitutes 5% of the genome and is an important contributor to disease, often in a sex-specific manner.
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Cromossomos Humanos X/genética , Cromossomos Humanos X/metabolismo , Inativação do Cromossomo X/fisiologia , Animais , Cromossomos Humanos X/fisiologia , Feminino , Inativação Gênica/fisiologia , Genes Reguladores/genética , Genes Ligados ao Cromossomo X/genética , Genes Ligados ao Cromossomo X/fisiologia , Humanos , Masculino , Camundongos , RNA Longo não Codificante/genética , Cromossomo X/genética , Cromossomo X/metabolismo , Cromossomo X/fisiologia , Inativação do Cromossomo X/genéticaRESUMO
A long-standing question concerning X-chromosome inactivation (XCI) has been how some genes avoid the otherwise stable chromosome-wide heterochromatinization of the inactive X chromosome. As 20% or more of human X-linked genes escape from inactivation, such genes are an important contributor to sex differences in gene expression. Although both human and mouse have genes that escape from XCI, more genes escape in humans than mice, with human escape genes often clustering in larger domains than the single escape genes of mouse. Mouse models offer a well-characterized and readily manipulated system in which to study XCI, but given the differences in genes that escape it is unclear whether the mechanism of escape gene regulation is conserved. To address conservation of the process and the potential to identify elements by modelling human escape gene regulation using mouse, we integrated a human and a mouse BAC each containing an escape gene and flanking subject genes at the mouse X-linked Hprt gene. Escape-level expression and corresponding low promoter DNA methylation of human genes RPS4X and CITED1 demonstrated that the mouse system is capable of recognizing human elements and therefore can be used as a model for further refinement of critical elements necessary for escape from XCI in humans.
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Proteínas Nucleares , Caracteres Sexuais , Fatores de Transcrição , Inativação do Cromossomo X , Cromossomo X , Animais , Proteínas Reguladoras de Apoptose , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Transativadores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Cromossomo X/genética , Cromossomo X/metabolismoRESUMO
When compared with cochlear implant (CI) users utilizing electric-only (E-Only) stimulation, CI users utilizing electric-acoustic stimulation (EAS) in the implanted ear show improved speech recognition in modulated noise relative to steady-state noise (i.e., speech masking release). It has been hypothesized, but not shown, that masking release is attributed to spectral resolution and temporal fine structure (TFS) provided by acoustic hearing. To address this question, speech masking release, spectral ripple density discrimination thresholds, and fundamental frequency difference limens (f0DLs) were evaluated in the acoustic-only (A-Only), E-Only, and EAS listening modes in EAS CI users. The spectral ripple and f0DL tasks are thought to reflect access to spectral and TFS cues, which could impact speech masking release. Performance in all three measures was poorest when EAS CI users were tested using the E-Only listening mode, with significant improvements in A-Only and EAS listening modes. f0DLs, but not spectral ripple density discrimination thresholds, significantly correlated with speech masking release when assessed in the EAS listening mode. Additionally, speech masking release correlated with AzBio sentence recognition in noise. The correlation between speech masking release and f0DLs likely indicates that TFS cues provided by residual hearing were used to obtain speech masking release, which aided sentence recognition in noise.
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Implante Coclear , Implantes Cocleares , Percepção da Fala , Estimulação Acústica , Acústica , Sinais (Psicologia) , Audição , Mascaramento Perceptivo , FalaRESUMO
X-chromosome inactivation generally results in dosage equivalence for expression of X-linked genes between 46,XY males and 46,XX females. The 20-30% of genes that escape silencing are thus candidates for having a role in the phenotype of Turner syndrome. Understanding which genes escape from silencing, and how they avoid this chromosome-wide inactivation is therefore an important step toward understanding Turner Syndrome. We have examined the mechanism of escape using a previously reported knock-in of a BAC containing the human escape gene RPS4X in mouse. We now demonstrate that escape from inactivation for RPS4X is already established by embryonic Day 9.5, and that both silencing and escape are faithfully maintained across the lifespan. No overt abnormalities were observed for transgenic mice up to 1 year of age despite robust transcription of the human RPS4X gene with no detectable downregulation of the mouse homolog. However, there was no significant increase in protein levels, suggesting translational compensation in the mouse. Finally, while many of the protein-coding genes have been assessed for their inactivation status, less is known about the X-linked RNA genes, and we propose that for many microRNA genes their inactivation status can be predicted as they are intronic to genes for which the inactivation status is known.
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Proteínas Ribossômicas/genética , Síndrome de Turner/genética , Inativação do Cromossomo X , Animais , Feminino , Genes Ligados ao Cromossomo X , Genes de RNAr , Humanos , CamundongosRESUMO
Inactivation of one X chromosome in mammalian females achieves dosage compensation between XX females and XY males; however, over 15% of human X-linked genes continue to be expressed from the inactive X chromosome. New genomic methodologies have improved our identification and characterization of these escape genes, revealing the importance of DNA sequence, chromatin structure, and chromosome ultrastructure in regulating expression from an otherwise inactive chromosome. Study of these exceptions to the rule of silencing highlights the interconnectedness of chromatin and chromosome structure in X-chromosome inactivation (XCI). Recent advances also demonstrate the importance of these genes in sexually dimorphic disease risk, particularly cancer.
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Cromossomos Humanos X/genética , Mecanismo Genético de Compensação de Dose , Inativação do Cromossomo X/genética , Animais , Cromatina/genética , Metilação de DNA/genética , Feminino , Humanos , Masculino , MamíferosRESUMO
Down's syndrome is a common disorder with enormous medical and social costs, caused by trisomy for chromosome 21. We tested the concept that gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST (the X-inactivation gene). Using genome editing with zinc finger nucleases, we inserted a large, inducible XIST transgene into the DYRK1A locus on chromosome 21, in Down's syndrome pluripotent stem cells. The XIST non-coding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation to form a 'chromosome 21 Barr body'. This provides a model to study human chromosome inactivation and creates a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing one chromosome 21. Successful trisomy silencing in vitro also surmounts the major first step towards potential development of 'chromosome therapy'.
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Cromossomos Humanos Par 21/genética , Mecanismo Genético de Compensação de Dose , Síndrome de Down/genética , RNA Longo não Codificante/metabolismo , Animais , Linhagem Celular , Proliferação de Células , Metilação de DNA , Síndrome de Down/terapia , Inativação Gênica , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Camundongos , Mutagênese Insercional , Neurogênese , RNA Longo não Codificante/genética , Cromatina Sexual/genética , Inativação do Cromossomo X/genéticaRESUMO
OBJECTIVES: The mechanisms underlying age-related changes in speech perception are still unclear, most likely multifactorial and often can be difficult to parse out from the effects of hearing loss. Age-related changes in temporal resolution (i.e., the ability to track rapid changes in sounds) have long been associated with speech perception declines exhibited by many older individuals. The goals of this study were as follows: (1) to assess age-related changes in temporal resolution in cochlear implant (CI) users, and (2) to examine the impact of changes in temporal resolution and cognition on the perception of speech in noise. In this population, it is possible to bypass the cochlea and stimulate the auditory nerve directly in a noninvasive way. Additionally, CI technology allows for manipulation of the temporal properties of a signal without changing its spectrum. DESIGN: Twenty postlingually deafened Nucleus CI users took part in this study. They were divided into groups of younger (18 to 40 years) and older (68 to 82 years) participants. A cross-sectional study design was used. The speech processor was bypassed and a mid-array electrode was used for stimulation. We compared peripheral and central physiologic measures of temporal resolution with perceptual measures obtained using similar stimuli. Peripherally, temporal resolution was assessed with measures of the rate of recovery of the electrically evoked compound action potential (ECAP), evoked using a single pulse and a pulse train as maskers. The acoustic change complex (ACC) to gaps in pulse trains was used to assess temporal resolution more centrally. Psychophysical gap detection thresholds were also obtained. Cognitive assessment included two tests of processing speed (Symbol Search and Coding) and one test of working memory (Digit Span Test). Speech perception was tested in the presence of background noise (QuickSIN test). A correlational design was used to explore the relationship between temporal resolution, cognition, and speech perception. RESULTS: The only metric that showed significant age effects in temporal processing was the ECAP recovery function recorded using pulse train maskers. Younger participants were found to have faster rates of neural recovery following presentation of pulse trains than older participants. Age was not found to have a significant effect on speech perception. When results from both groups were combined, digit span was the only measure significantly correlated with speech perception performance. CONCLUSIONS: In this sample of CI users, few effects of advancing age on temporal resolution were evident. While this finding would be consistent with a general lack of aging effects on temporal resolution, it is also possible that aging effects are influenced by processing peripheral to the auditory nerve, which is bypassed by the CI. However, it is known that cross-fiber neural synchrony is improved with electrical (as opposed to acoustic) stimulation. This change in neural synchrony may, in turn, make temporal cues more robust/perceptible to all CI users. Future studies involving larger sample sizes should be conducted to confirm these findings. Results of this study also add to the growing body of literature that suggests that working memory is important for the perception of degraded speech.
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Implantes Cocleares , Cognição , Surdez/reabilitação , Potenciais Evocados Auditivos/fisiologia , Percepção da Fala , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Implante Coclear , Surdez/fisiopatologia , Feminino , Humanos , Masculino , Período Refratário Eletrofisiológico , Adulto JovemRESUMO
The process of X-chromosome inactivation (XCI) randomly silences one of two X chromosomes in normal female cells. The ability to predict if there is a preference for one of the two Xs to be chosen (and survive) more often as the active X has important repercussions in human health and X-linked disease. Mice have a genetic component that modulates non-random skewing called the X-controlling element (Xce). Although the nature of the locus and its mechanisms of action are still under investigation, it is clear that different mouse strains carry unique Xce alleles on their X chromosomes, resulting in distinct skewing phenotypes in the F1 progeny of hybrid crosses. Whether a similar mechanism exists in humans is unclear, and challenges to identifying such a locus include the complexity and diversity of the human genome, the restricted time points and tissue(s) of examination in human subjects, and the lack of a model system recapitulating XCI in early development. In this review we consider the evidence for such a controlling locus in humans, in addition to discussing if we have the power to recognize it given the contribution of selective growth in causing skewed patterns of XCI.
Assuntos
Cromossomo X/genética , Animais , Loci Gênicos , Humanos , Modelos Biológicos , Inativação do Cromossomo X/genéticaRESUMO
X-chromosome inactivation (XCI) achieves dosage compensation between males and females through the silencing of the majority of genes on one of the female X chromosomes. Thus, the female X chromosomes provide a unique opportunity to study euchromatin and heterochromatin of allelic regions within the same nuclear environment. We examined the interplay of DNA methylation (DNAm) with CpG density, transcriptional activity and chromatin state at genes on the X chromosome using over 1800 female samples analysed with the Illumina Infinium Human Methylation450 BeadChip. DNAm was used to predict an inactivation status for 63 novel transcription start sites (TSSs) across 27 tissues. There was high concordance of inactivation status across tissues, with 62% of TSSs subject to XCI in all 27 tissues examined, whereas 9% escaped from XCI in all tissues, and the remainder showed variable escape from XCI between females in subsets of tissues. Inter-female and twin data supported a model of predominately cis-acting influences on inactivation status. The level of expression from the inactive X relative to the active X correlated with the amount of female promoter DNAm to a threshold of â¼30%, beyond which genes were consistently subject to inactivation. The inactive X showed lower DNAm than the active X at intragenic and intergenic regions for genes subject to XCI, but not at genes that escape from inactivation. Our categorization of genes that escape from X inactivation provides candidates for sex-specific differences in disease.