Functional expression of KCNQ (Kv7) channels in guinea-pig bladder smooth muscle and their contribution to spontaneous activity

Background and Purpose: The aim of the study was to determine whether KCNQ channels are functionally expressed in bladder smooth muscle cells (SMC) and to investigate their physiological significance in bladder contractility. 

Experimental Approach: KCNQ channels were examined at the genetic, protein, cellular and tissue level in guinea pig bladder smooth muscle using RT-PCR, immunofluorescence, patch-clamp electrophysiology, calcium imaging, detrusor strip myography, and a panel of KCNQ activators and inhibitors. 

Key Results: KCNQ subtypes 1-5 are expressed in bladder detrusor smooth muscle. Detrusor strips typically displayed TTX-insensitive myogenic spontaneous contractions that were increased in amplitude by the KCNQ channel inhibitors XE991, linopirdine or chromanol 293B. Contractility was inhibited by the KCNQ channel activators flupirtine or meclofenamic acid (MFA). The frequency of Ca2+-oscillations in SMC contained within bladder tissue sheets was increased by XE991. Outward currents in dispersed bladder SMC, recorded under conditions where BK and KATP currents were minimal, were significantly reduced by XE991, linopirdine, or chromanol, and enhanced by flupirtine or MFA. XE991 depolarized the cell membrane and could evoke transient depolarizations in quiescent cells. Flupirtine (20M) hyperpolarized the cell membrane with a simultaneous cessation of any spontaneous electrical activity. 

Conclusions and Implications: These novel findings reveal the role of KCNQ currents in the regulation of the resting membrane potential of detrusor SMC and their important physiological function in the control of spontaneous contractility in the guinea pig bladder.

Spontaneous and cued gaze-following in autism and Williams syndrome

Background: From a young age the typical development of social functioning relies upon the allocation of attention to socially relevant information, which in turn allows experience at processing such information and thus enhances social cognition. As such, research has attempted to identify the developmental processes that are derailed in some neuro-developmental disorders that impact upon social functioning. Williams syndrome (WS) and Autism are disorders of development that are characterized by atypical yet divergent social phenotypes and atypicalities of attention to people.

Methods: We used eye tracking to explore how individuals with WS and Autism attended to, and subsequently interpreted, an actor’s eye gaze cue within a social scene. Images were presented for three seconds, initially with an instruction simply to look at the picture. The images were then shown again, with the participant asked to identify the object being looked at. Allocation of eye-gaze in each condition was analyzed by ANOVA and accuracy of identification was compared with t-tests.

Results: Participants with WS allocated more gaze time to face and eyes than their matched controls both with and without being asked to identify the item being looked at; while participants with Autism spent less time on face and eyes in both conditions. When cued to follow gaze, participants with WS increased gaze to the correct targets, while those with Autism looked more at the face and eyes but did not increase gaze to the correct targets, while continuing to look much more than their controls at implausible targets. Both groups identified fewer objects than their controls.

Conclusions: The atypicalities found are likely to be entwined with the deficits shown in interpreting social cognitive cues from the images. WS and Autism are characterised by atypicalities of social attention that impact upon socio-cognitive expertise but importantly the type of atypicality is syndrome-specific.

A Corpus-Based Approach to Speech Enhancement from Nonstationary Noise

Temporal dynamics and speaker characteristics are two important features of speech that distinguish speech from noise. In this paper, we propose a method to maximally extract these two features of speech for speech enhancement. We demonstrate that this can reduce the requirement for prior information about the noise, which can be difficult to estimate for fast-varying noise. Given noisy speech, the new approach estimates clean speech by recognizing long segments of the clean speech as whole units. In the recognition, clean speech sentences, taken from a speech corpus, are used as examples. Matching segments are identified between the noisy sentence and the corpus sentences. The estimate is formed by using the longest matching segments found in the corpus sentences. Longer speech segments as whole units contain more distinct dynamics and richer speaker characteristics, and can be identified more accurately from noise than shorter speech segments. Therefore, estimation based on the longest recognized segments increases the noise immunity and hence the estimation accuracy. The new approach consists of a statistical model to represent up to sentence-long temporal dynamics in the corpus speech, and an algorithm to identify the longest matching segments between the noisy sentence and the corpus sentences. The algorithm is made more robust to noise uncertainty by introducing missing-feature based noise compensation into the corpus sentences. Experiments have been conducted on the TIMIT database for speech enhancement from various types of nonstationary noise including song, music, and crosstalk speech. The new approach has shown improved performance over conventional enhancement algorithms in both objective and subjective evaluations.

A calming cacophony: Social identity can shape the experience of loud noise

Environmental Psychology has typically considered noise as pollution and focused upon its negative impact. However, recent research in psychology and anthropology indicates the experience of noise as aversive depends upon the meanings with which it is attributed. Moreover, such meanings seem to be dependent on the social context. Here we extend this research through studying the aural experience of a religious festival in North India which is characterised by loud, continuous and cacophonous noise. Reporting an experiment and semi-structured interviews, we show that loud noise is experienced as pleasant or unpleasant according to the meanings attributed to it. Specifically, the experiment shows the same noise is experienced more positively (and listened to longer) when attributed to the festival rather than to a non-festival source. In turn, the qualitative data show that within the Mela, noises judged as having a religious quality are reported as more positive than noises that are not. Moreover, the qualitative data suggest a key factor in the evaluation of noise is our participants’ social identities as pilgrims. This identity provides a framework for interpreting the auditory environment and noises judged as intruding into their religious experience were judged negatively, whereas noises judged as contributing to their religious experience were judged more positively. Our findings therefore point to the ways in which our social identities are implicated in the process of attributing meaning to the auditory environment.

Th1 not Th17 cells drive spontaneous MS-like disease despite a functional regulatory T cell response

Multiple sclerosis is considered a disease of complex autoimmune etiology, yet there remains a lack of consensus as to specific immune effector mechanisms. Recent analyses of experimental autoimmune encephalomyelitis, the common mouse model of multiple sclerosis, have investigated the relative contribution of Th1 and Th17 CD4 T cell subsets to initial autoimmune central nervous system (CNS) damage. However, inherent in these studies are biases influenced by the adjuvant and toxin needed to break self-tolerance. We investigated spontaneous CNS disease in a clinically relevant, humanized, T cell receptor transgenic mouse model. Mice develop spontaneous, ascending paralysis, allowing unbiased characterization of T cell immunity in an HLA-DR15-restricted T cell repertoire. Analysis of naturally progressing disease shows that IFN?(+) cells dominate disease initiation with IL-17(+) cells apparent in affected tissue only once disease is established. Tregs accumulate in the CNS but are ultimately ineffective at halting disease progression. However, ablation of Tregs causes profound acceleration of disease, with uncontrolled infiltration of lymphocytes into the CNS. This synchronous, severe disease allows characterization of the responses that are deregulated in exacerbated disease: the correlation is with increased CNS CD4 and CD8 IFN? responses. Recovery of the ablated Treg population halts ongoing disease progression and Tregs extracted from the central nervous system at peak disease are functionally competent to regulate myelin specific T cell responses. Thus, in a clinically relevant mouse model of MS, initial disease is IFN? driven and the enhanced central nervous system responses unleashed through Treg ablation comprise IFN? cytokine production by CD4 and CD8 cells, but not IL-17 responses.

Rapid formation of robust auditory memories: Insights from noise

Before a natural sound can be recognized, an auditory signature of its source must be learned through experience. Here we used random waveforms to probe the formation of new memories for arbitrary complex sounds. A behavioral measure was designed, based on the detection of repetitions embedded in noises up to 4 s long. Unbeknownst to listeners, some noise samples reoccurred randomly throughout an experimental block. Results showed that repeated exposure induced learning for otherwise totally unpredictable and meaningless sounds. The learning was unsupervised and resilient to interference from other task-relevant noises. When memories were formed, they emerged rapidly, performance became abruptly near-perfect, and multiple noises were remembered for several weeks. The acoustic transformations to which recall was tolerant suggest that the learned features were local in time. We propose that rapid sensory plasticity could explain how the auditory brain creates useful memories from the ever-changing, but sometimes repeating, acoustical world. © 2010 Elsevier Inc.

Informational masking in young and elderly listeners for speech masked by simultaneous speech and noise

Three experiments measured the effects of age on informational masking of speech by competing speech. The experiments were designed to minimize the energetic contributions of the competing speech so that informational masking could be measured with no large corrections for energetic masking. Experiment 1 used a "speech-in-speech-in-noise" design, in which the competing speech was presented in noise at a signal-to-noise ratio (SNR) of -4 dB. This ensured that the noise primarily contributed the energetic masking but the competing speech contributed the informational masking. Equal amounts of informational masking (3 dB) were observed for young and elderly listeners, although less was found for hearing-impaired listeners. Experiment 2 tested a range of SNRs in this design and showed that informational masking increased with SNR up to about an SNR of -4 dB, but decreased thereafter. Experiment 3 further reduced the energetic contribution of the competing speech by filtering it into different frequency bands from the target speech. The elderly listeners again showed approximately the same amount of informational masking (4-5 dB), although some elderly listeners had particular difficulty understanding these stimuli in any condition. On the whole, these results suggest that young and elderly listeners were equally susceptible to informational masking. © 2009 Acoustical Society of America.

The detection of repetitions in noise before and after perceptual learning.

In noise repetition-detection tasks, listeners have to distinguish trials of continuously running noise from trials in which noise tokens are repeated in a cyclic manner. Recently, it has been shown that using the exact same noise token across several trials (“reference noise”) facilitates the detection of repetitions for this token [Agus et al. (2010). Neuron 66, 610–618]. This was attributed to perceptual learning. Here, the nature of the learning was investigated. In experiment 1, reference noise tokens were embedded in trials with or without cyclic presentation. Naïve listeners reported repetitions in both cases, thus responding to the reference noise even in the absence of an actual repetition. Experiment 2, with the same listeners, showed a similar pattern of results even after the design of the experiment was made explicit, ruling out a misunderstanding of the task. Finally, in experiment 3, listeners reported repetitions in trials containing the reference noise, even before ever hearing it presented cyclically. The results show that listeners were able to learn and recognize noise tokens in the absence of an immediate repetition. Moreover, the learning mandatorily interfered with listeners' ability to detect repetitions. It is concluded that salient perceptual changes accompany the learning of noise.

Noise Quartet

Performance at the International Computer Music Conference, University of Huddersfield (with Eric Lyon, Franziska Schroder & Steve Davis).

Determination of Spontaneous Mutation Frequencies in Measles Virus under Nonselective Conditions

There is a paradox between the remarkable genetic stability of measles virus (MV) in the field and the high mutation rates implied by the frequency of the appearance of monoclonal antibody escape mutants generated when the virus is pressured to revert in vitro (S. J. Schrag, P. A. Rota, and W. J. Bellini, J. Virol. 73: 51-54, 1999). We established a highly sensitive assay to determine frequencies of various categories of mutations in large populations of wild-type and laboratory-adapted MVs using recombinant viruses containing an additional transcription unit (ATU) encoding enhanced green fluorescent protein (EGFP). Single and double mutations were made in the fluorophore of EGFP to ablate fluorescence. The frequencies of reversion mutants in the population were determined by measuring the appearance of fluorescence indicating a revertant virus. This allows mutation rates to be measured under nonselective conditions, as phenotypic reversion to fluorescence requires only either a single-or a double-nucleotide change and amino acid substitution, which does not affect the length of the nonessential reporter protein expressed from the ATU. Mutation rates in MV are the same for wild-type and laboratory-adapted viruses, and they are an order of magnitude lower than the previous measurement assessed under selective conditions. The actual mutation rate for MV is approximately 1.8 x 10(-6) per base per replication event. Copyright © 2013, American Society for Microbiology. All Rights Reserved.

Rethinking Local Government Support for Youth Arts:The Case of NOISE South Dublin

Within Ireland, interest in strategically supporting young people’s participation in the arts has increased. Additionally, awareness of the Internet’s potential for promot- ing engagement with the arts has grown. Addressing national directives and local needs assessments, South Dublin County Council’s Arts Office initiated NOISE South Dublin (http://www.noisesouthdublin.com), an interactive Web site based on Australia Council’s NOISE project (http://www.noise.net), to promote the creative development of young people in the county. This article presents the practical chal- lenges and potential of youth arts Web-based programs for harnessing the creative engagement of youth. It concludes that the Internet is only useful if it expands online engagement offline.

Impaired activities of antioxidant enzymes elicit endothelial dysfunction in spontaneous hypertensive rats despite enhanced vascular nitric oxide generation

Objective: Enhanced oxidative stress is involved in mediating the endothelial dysfunction associated with hypertension. The aim of this study was to investigate the relative contributions of pro-oxidant and anti-oxidant enzymes to the pathogenesis of endothelial dysfunction in genetic hypertension. Methods: Dilator responses to endothelium-dependent and endothelium-independent agents such as acetylcholine (ACh) and sodium nitroprusside were measured in the thoracic aortas of 28-week-old spontaneously hypertensive rats (SHR) and their matched normotensive counterparts, Wistar Kyoto rats (WKY). The activity and expression (mRNA and protein levels) of endothelial nitric oxide synthase (eNOS), p22-phox, a membrane-bound component of NAD(P)H oxidase, and antioxidant enzymes, namely, superoxide dismutases (CuZn- and Mn-SOD), catalase and glutathione peroxidase (GPx), were also investigated in aortic rings. Results: Relaxant responses to ACh were attenuated in phenylephrine-precontracted SHR aortic rings, despite a 2-fold increase in eNOS expression and activity. Although the activity and/or expression of SODs, NAD(P)H oxidase (p22-phox) and GPx were elevated in SHR aorta, catalase activity and expression remained unchanged compared to WKY. Pretreatment of SHR aortic rings with the inhibitor of xanthine oxidase, allopurinol, and the inhibitor of cyclooxygenase, indomethacin, significantly potentiated ACh-induced relaxation. Pretreatment of SHR rings with catalase and Tiron, a superoxide anion (O) scavenger, increased the relaxant responses to the levels observed in WKY rings whereas pyrogallol, a O -generator, abolished relaxant responses to ACh. Conclusion: These data demonstrate that dysregulation of several enzymes, resulting in oxidative stress, contributes to the pathogenesis of endothelial dysfunction in SHR and indicate that the antioxidant enzyme catalase is of particular importance in the reversal of this defect. © 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Understanding Astrophysical Noise from Stellar Surface Magneto-Convection

To obtain cm/s precision, stellar surface magneto-convection must be disentangled from observed radial velocities (RVs). In order to understand and remove the convective signature, we create Sun-as-a-star model observations based on a 3D magnetohydrodynamic solar simulation. From these Sun-as-a-star model observations, we find several line characteristics are correlated with the induced RV shifts. The aim of this campaign is to feed directly into future high precision RV studies, such as the search for habitable, rocky worlds, with forthcoming spectrographs such as ESPRESSO.