Asymmetries in behavioral and neural responses to spectral cues demonstrate the generality of auditory looming bias.

Studies of auditory looming bias have shown that sources increasing in intensity are more salient than sources decreasing in intensity. Researchers have argued that listeners are more sensitive to approaching sounds compared with receding sounds, reflecting an evolutionary pressure. However, these studies only manipulated overall sound intensity; therefore, it is unclear whether looming bias is truly a perceptual bias for changes in source distance, or only in sound intensity. Here we demonstrate both behavioral and neural correlates of looming bias without manipulating overall sound intensity. In natural environments, the pinnae induce spectral cues that give rise to a sense of externalization; when spectral cues are unnatural, sounds are perceived as closer to the listener. We manipulated the contrast of individually tailored spectral cues to create sounds of similar intensity but different naturalness. We confirmed that sounds were perceived as approaching when spectral contrast decreased, and perceived as receding when spectral contrast increased. We measured behavior and electroencephalography while listeners judged motion direction. Behavioral responses showed a looming bias in that responses were more consistent for sounds perceived as approaching than for sounds perceived as receding. In a control experiment, looming bias disappeared when spectral contrast changes were discontinuous, suggesting that perceived motion in distance and not distance itself was driving the bias. Neurally, looming bias was reflected in an asymmetry of late event-related potentials associated with motion evaluation. Hence, both our behavioral and neural findings support a generalization of the auditory looming bias, representing a perceptual preference for approaching auditory objects.

Impoverished auditory cues limit engagement of brain networks controlling spatial selective attention.

Spatial selective attention enables listeners to process a signal of interest in natural settings. However, most past studies on auditory spatial attention used impoverished spatial cues: presenting competing sounds to different ears, using only interaural differences in time (ITDs) and/or intensity (IIDs), or using non-individualized head-related transfer functions (HRTFs). Here we tested the hypothesis that impoverished spatial cues impair spatial auditory attention by only weakly engaging relevant cortical networks. Eighteen normal-hearing listeners reported the content of one of two competing syllable streams simulated at roughly +30° and -30° azimuth. The competing streams consisted of syllables from two different-sex talkers. Spatialization was based on natural spatial cues (individualized HRTFs), individualized IIDs, or generic ITDs. We measured behavioral performance as well as electroencephalographic markers of selective attention. Behaviorally, subjects recalled target streams most accurately with natural cues. Neurally, spatial attention significantly modulated early evoked sensory response magnitudes only for natural cues, not in conditions using only ITDs or IIDs. Consistent with this, parietal oscillatory power in the alpha band (8-14 â€‹Hz; associated with filtering out distracting events from unattended directions) showed significantly less attentional modulation with isolated spatial cues than with natural cues. Our findings support the hypothesis that spatial selective attention networks are only partially engaged by impoverished spatial auditory cues. These results not only suggest that studies using unnatural spatial cues underestimate the neural effects of spatial auditory attention, they also illustrate the importance of preserving natural spatial cues in assistive listening devices to support robust attentional control.

Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload.

Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH2-terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study, we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF. We investigated mixed lineage kinase-3 (MLK3), a master regulator of upstream JNK-activating kinases, whose role in the remodeling process had not previously been studied. We observed increased MLK3 protein expression in myocardium from patients with nonischemic and hypertrophic cardiomyopathy and in hearts of mice subjected to transverse aortic constriction (TAC). Mice with genetic deletion of MLK3 (MLK3-/-) exhibited baseline cardiac hypertrophy with preserved cardiac function. MLK3-/- mice subjected to chronic left ventricular (LV) pressure overload (TAC, 4 wk) developed worsened cardiac dysfunction and increased LV chamber size compared with MLK3+/+ littermates ( n = 8). LV mass, pathological markers of hypertrophy ( Nppa, Nppb), and cardiomyocyte size were elevated in MLK3-/- TAC hearts. Phosphorylation of JNK, but not other MAPK pathways, was selectively impaired in MLK3-/- TAC hearts. In adult rat cardiomyocytes, pharmacological MLK3 kinase inhibition using URMC-099 blocked JNK phosphorylation induced by neurohormonal agents and oxidants. Sustained URMC-099 exposure induced cardiomyocyte hypertrophy. These data demonstrate that MLK3 prevents adverse cardiac remodeling in the setting of pressure overload. Mechanistically, MLK3 activates JNK, which in turn opposes cardiomyocyte hypertrophy. These results support modulation of MLK3 as a potential therapeutic approach in HF. NEW & NOTEWORTHY Here, we identified a role for mixed lineage kinase-3 (MLK3) as a novel antihypertrophic and antiremodeling molecule in response to cardiac pressure overload. MLK3 regulates phosphorylation of the stress-responsive JNK kinase in response to pressure overload and in cultured cardiomyocytes stimulated with hypertrophic agonists and oxidants. This study reveals MLK3-JNK signaling as a novel cardioprotective signaling axis in the setting of pressure overload.

Erratum: Modeling sound-source localization in sagittal planes for human listeners [J. Acoust. Soc. Am. 136, 791-802 (2014)].

This erratum concerns Eq. (4) of the original article, which defines the distance metric of the comparison process of the sagittal-plane sound localization model. The distance metric was actually implemented as a mean absolute difference but was erroneously described as a L1-norm difference.

Modeling Localization of Amplitude-Panned Virtual Sources in Sagittal Planes.

Vector-base amplitude panning (VBAP) aims at creating virtual sound sources at arbitrary directions within multichannel sound reproduction systems. However, VBAP does not consistently produce listener-specific monaural spectral cues that are essential for localization of sound sources in sagittal planes, including the front-back and up-down dimensions. In order to better understand the limitations of VBAP, a functional model approximating human processing of spectro-spatial information was applied to assess accuracy in sagittal-plane localization of virtual sources created by means of VBAP. First, we evaluated VBAP applied on two loudspeakers in the median plane, and then we investigated the directional dependence of the localization accuracy in several three-dimensional loudspeaker arrangements designed in layers of constant elevation. The model predicted a strong dependence on listeners' individual head-related transfer functions, on virtual source directions, and on loudspeaker arrangements. In general, the simulations showed a systematic degradation with increasing polar-angle span between neighboring loudspeakers. For the design of VBAP systems, predictions suggest that spans up to 40° polar angle yield a good trade-off between system complexity and localization accuracy. Special attention should be paid to the frontal region where listeners are most sensitive to deviating spectral cues.

Modeling sound-source localization in sagittal planes for human listeners.

Monaural spectral features are important for human sound-source localization in sagittal planes, including front-back discrimination and elevation perception. These directional features result from the acoustic filtering of incoming sounds by the listener's morphology and are described by listener-specific head-related transfer functions (HRTFs). This article proposes a probabilistic, functional model of sagittal-plane localization that is based on human listeners' HRTFs. The model approximates spectral auditory processing, accounts for acoustic and non-acoustic listener specificity, allows for predictions beyond the median plane, and directly predicts psychoacoustic measures of localization performance. The predictive power of the listener-specific modeling approach was verified under various experimental conditions: The model predicted effects on localization performance of band limitation, spectral warping, non-individualized HRTFs, spectral resolution, spectral ripples, and high-frequency attenuation in speech. The functionalities of vital model components were evaluated and discussed in detail. Positive spectral gradient extraction, sensorimotor mapping, and binaural weighting of monaural spatial information were addressed in particular. Potential applications of the model include predictions of psychophysical effects, for instance, in the context of virtual acoustics or hearing assistive devices.

Cortical signatures of auditory looming bias show cue-specific adaptation between newborns and young adults.

Adaptive biases in favor of approaching, or "looming", sounds have been found across ages and species, thereby implicating the potential of their evolutionary origin and universal basis. The human auditory system is well-developed at birth, yet spatial hearing abilities further develop with age. To disentangle the speculated inborn, evolutionary component of the auditory looming bias from its learned counterpart, we collected high-density electroencephalographic data across human adults and newborns. As distance-motion cues we manipulated either the sound's intensity or spectral shape, which is pinna-induced and thus prenatally inaccessible. Through cortical source localisation we demonstrated the emergence of the bias in both age groups at the level of Heschl's gyrus. Adults exhibited the bias in both attentive and inattentive states; yet differences in amplitude and latency appeared based on attention and cue type. Contrary to the adults, in newborns the bias was elicited only through manipulations of intensity and not spectral cues. We conclude that the looming bias comprises innate components while flexibly incorporating the spatial cues acquired through lifelong exposure.

The effects of aging and hearing impairment on listening in noise.

The study investigates age-related decline in listening abilities, particularly in noisy environments, where the challenge lies in extracting meaningful information from variable sensory input (figure-ground segregation). The research focuses on peripheral and central factors contributing to this decline using a tone-cloud-based figure detection task. Results based on behavioral measures and event-related brain potentials (ERPs) indicate that, despite delayed perceptual processes and some deterioration in attention and executive functions with aging, the ability to detect sound sources in noise remains relatively intact. However, even mild hearing impairment significantly hampers the segregation of individual sound sources within a complex auditory scene. The severity of the hearing deficit correlates with an increased susceptibility to masking noise. The study underscores the impact of hearing impairment on auditory scene analysis and highlights the need for personalized interventions based on individual abilities.

Is renal thrombotic angiopathy an emerging problem in the treatment of ovarian cancer recurrences?

BACKGROUND AND OBJECTIVE: Ovarian cancer is usually diagnosed at an advanced stage, with most patients undergoing surgery followed by platinum- and taxane-based chemotherapy. After initial clinical remission, the majority recur, leading to additional treatments, including not only platinums and taxanes but also pegylated liposomal doxorubicin (PLD), gemcitabine, topotecan, and, more recently, bevacizumab, which may extend survival times. PLD, in particular, has been extensively studied by our group, with encouraging therapeutic results. We, however, observed instances of chronic kidney disease (CKD) developing among patients who received long-term treatment for recurrent ovarian cancer. To document the frequency and contributing factors to the emergence of CKD, we initiated a retrospective review at two institutions. PATIENTS AND METHODS: Fifty-six consecutive patients with recurrent ovarian cancer receiving treatment at New York University Cancer Institute were reviewed for the presence of renal disease in 1997-2010. At Shaare Zedek Medical Center, 73 consecutive patients with ovarian cancer were reviewed in 2002-2010. Patients were diagnosed with CKD if they had an estimated GFR <60 mL/minute per 1.73 m2 for >3 months and were staged according to the National Kidney Foundation guidelines. RESULTS: Thirteen patients (23%) developed stage ≥3 CKD. Three patients had renal biopsies performed that showed thrombotic microangiopathy. CONCLUSIONS: CKD is emerging as a potential long-term consequence of current chemotherapy for recurrent ovarian cancer.

Effects of individualized brain anatomies and EEG electrode positions on inferred activity of the primary auditory cortex.

Due to its high temporal resolution and non-invasive nature, electroencephalography (EEG) is considered a method of great value for the field of auditory cognitive neuroscience. In performing source space analyses, localization accuracy poses a bottleneck, which precise forward models based on individualized attributes such as subject anatomy or electrode locations aim to overcome. Yet acquiring anatomical images or localizing EEG electrodes requires significant additional funds and processing time, making it an oftentimes inaccessible asset. Neuroscientific software offers template solutions, on which analyses can be based. For localizing the source of auditory evoked responses, we here compared the results of employing such template anatomies and electrode positions versus the subject-specific ones, as well as combinations of the two. All considered cases represented approaches commonly used in electrophysiological studies. We considered differences between two commonly used inverse solutions (dSPM, sLORETA) and targeted the primary auditory cortex; a notoriously small cortical region that is located within the lateral sulcus, thus particularly prone to errors in localization. Through systematical comparison of early evoked component metrics and spatial leakage, we assessed how the individualization steps impacted the analyses outcomes. Both electrode locations as well as subject anatomies were found to have an effect, which though varied based on the configuration considered. When comparing the inverse solutions, we moreover found that dSPM more consistently benefited from individualization of subject morphologies compared to sLORETA, suggesting it to be the better choice for auditory cortex localization.

Neural Mechanisms Underlying the Auditory Looming Bias.

Our auditory system constantly keeps track of our environment, informing us about our surroundings and warning us of potential threats. The auditory looming bias is an early perceptual phenomenon, reflecting higher alertness of listeners to approaching auditory objects, rather than to receding ones. Experimentally, this sensation has been elicited by using both intensity-varying stimuli, as well as spectrally varying stimuli with constant intensity. Following the intensity-based approach, recent research delving into the cortical mechanisms underlying the looming bias argues for top-down signaling from the prefrontal cortex to the auditory cortex in order to prioritize approaching over receding sonic motion. We here test the generalizability of that finding to spectrally induced looms by re-analyzing previously published data. Our results indicate the promoted top-down projection but at time points slightly preceding the motion onset and thus considered to reflect a bias driven by anticipation. At time points following the motion onset, our findings show a bottom-up bias along the dorsal auditory pathway directed toward the prefrontal cortex.

MLK3 mediates impact of PKG1α on cardiac function and controls blood pressure through separate mechanisms.

cGMP-dependent protein kinase 1α (PKG1α) promotes left ventricle (LV) compensation after pressure overload. PKG1-activating drugs improve heart failure (HF) outcomes but are limited by vasodilation-induced hypotension. Signaling molecules that mediate PKG1α cardiac therapeutic effects but do not promote PKG1α-induced hypotension could therefore represent improved therapeutic targets. We investigated roles of mixed lineage kinase 3 (MLK3) in mediating PKG1α effects on LV function after pressure overload and in regulating BP. In a transaortic constriction HF model, PKG activation with sildenafil preserved LV function in MLK3+/+ but not MLK3-/- littermates. MLK3 coimmunoprecipitated with PKG1α. MLK3-PKG1α cointeraction decreased in failing LVs. PKG1α phosphorylated MLK3 on Thr277/Ser281 sites required for kinase activation. MLK3-/- mice displayed hypertension and increased arterial stiffness, though PKG stimulation with sildenafil or the soluble guanylate cyclase (sGC) stimulator BAY41-2272 still reduced BP in MLK3-/- mice. MLK3 kinase inhibition with URMC-099 did not affect BP but induced LV dysfunction in mice. These data reveal MLK3 as a PKG1α substrate mediating PKG1α preservation of LV function but not acute PKG1α BP effects. Mechanistically, MLK3 kinase-dependent effects preserved LV function, whereas MLK3 kinase-independent signaling regulated BP. These findings suggest augmenting MLK3 kinase activity could preserve LV function in HF but avoid hypotension from PKG1α activation.

Sound Externalization: A Review of Recent Research.

Sound externalization, or the perception that a sound source is outside of the head, is an intriguing phenomenon that has long interested psychoacousticians. While previous reviews are available, the past few decades have produced a substantial amount of new data.In this review, we aim to synthesize those data and to summarize advances in our understanding of the phenomenon. We also discuss issues related to the definition and measurement of sound externalization and describe quantitative approaches that have been taken to predict the outcomes of externalization experiments. Last, sound externalization is of practical importance for many kinds of hearing technologies. Here, we touch on two examples, discussing the role of sound externalization in augmented/virtual reality systems and bringing attention to the somewhat overlooked issue of sound externalization in wearers of hearing aids.

Modeling the Effects of Sensorineural Hearing Loss on Sound Localization in the Median Plane.

Listeners use monaural spectral cues to localize sound sources in sagittal planes (along the up-down and front-back directions). How sensorineural hearing loss affects the salience of monaural spectral cues is unclear. To simulate the effects of outer-hair-cell (OHC) dysfunction and the contribution of different auditory-nerve fiber types on localization performance, we incorporated a nonlinear model of the auditory periphery into a model of sagittal-plane sound localization for normal-hearing listeners. The localization model was first evaluated in its ability to predict the effects of spectral cue modifications for normal-hearing listeners. Then, we used it to simulate various degrees of OHC dysfunction applied to different types of auditory-nerve fibers. Predicted localization performance was hardly affected by mild OHC dysfunction but was strongly degraded in conditions involving severe and complete OHC dysfunction. These predictions resemble the usually observed degradation in localization performance induced by sensorineural hearing loss. Predicted localization performance was best when preserving fibers with medium spontaneous rates, which is particularly important in view of noise-induced hearing loss associated with degeneration of this fiber type. On average across listeners, predicted localization performance was strongly related to level discrimination sensitivity of auditory-nerve fibers, indicating an essential role of this coding property for localization accuracy in sagittal planes.

Efficient Approximation of Head-Related Transfer Functions in Subbands for Accurate Sound Localization.

Head-related transfer functions (HRTFs) describe the acoustic filtering of incoming sounds by the human morphology and are essential for listeners to localize sound sources in virtual auditory displays. Since rendering complex virtual scenes is computationally demanding, we propose four algorithms for efficiently representing HRTFs in subbands, i.e., as an analysis filterbank (FB) followed by a transfer matrix and a synthesis FB. All four algorithms use sparse approximation procedures to minimize the computational complexity while maintaining perceptually relevant HRTF properties. The first two algorithms separately optimize the complexity of the transfer matrix associated to each HRTF for fixed FBs. The other two algorithms jointly optimize the FBs and transfer matrices for complete HRTF sets by two variants. The first variant aims at minimizing the complexity of the transfer matrices, while the second one does it for the FBs. Numerical experiments investigate the latency-complexity trade-off and show that the proposed methods offer significant computational savings when compared with other available approaches. Psychoacoustic localization experiments were modeled and conducted to find a reasonable approximation tolerance so that no significant localization performance degradation was introduced by the subband representation.

Acoustic and non-acoustic factors in modeling listener-specific performance of sagittal-plane sound localization.

The ability of sound-source localization in sagittal planes (along the top-down and front-back dimension) varies considerably across listeners. The directional acoustic spectral features, described by head-related transfer functions (HRTFs), also vary considerably across listeners, a consequence of the listener-specific shape of the ears. It is not clear whether the differences in localization ability result from differences in the encoding of directional information provided by the HRTFs, i.e., an acoustic factor, or from differences in auditory processing of those cues (e.g., spectral-shape sensitivity), i.e., non-acoustic factors. We addressed this issue by analyzing the listener-specific localization ability in terms of localization performance. Directional responses to spatially distributed broadband stimuli from 18 listeners were used. A model of sagittal-plane localization was fit individually for each listener by considering the actual localization performance, the listener-specific HRTFs representing the acoustic factor, and an uncertainty parameter representing the non-acoustic factors. The model was configured to simulate the condition of complete calibration of the listener to the tested HRTFs. Listener-specifically calibrated model predictions yielded correlations of, on average, 0.93 with the actual localization performance. Then, the model parameters representing the acoustic and non-acoustic factors were systematically permuted across the listener group. While the permutation of HRTFs affected the localization performance, the permutation of listener-specific uncertainty had a substantially larger impact. Our findings suggest that across-listener variability in sagittal-plane localization ability is only marginally determined by the acoustic factor, i.e., the quality of directional cues found in typical human HRTFs. Rather, the non-acoustic factors, supposed to represent the listeners' efficiency in processing directional cues, appear to be important.

Intervention and management of congenital left heart obstructive lesions.

OPINION STATEMENT: While congenital heart defects are typically diagnosed in early childhood, depending on the severity of the lesion, they may not be recognized until later childhood or in adulthood. Left heart pressure loading lesions, including mitral valve stenosis, subaortic stenosis, valvular aortic stenosis, supravalvular aortic stenosis, and coarctation of the aorta, may be found as an isolated lesion or as a constellation together known as Shone syndrome. This review will highlight the literature published regarding the diagnosis, intervention, and long-term management of left heart pressure loading lesions.

Ovarian granulosa cell survival and proliferation requires the gonad-selective TFIID subunit TAF4b.

Oocyte development in the mammalian ovary requires productive interactions with somatic granulosa cells of the ovarian follicle. Proliferating granulosa cells support the progression of follicular growth and maturation, multiplying dramatically as it unfolds. The cell cycle recruitment of granulosa cells is regulated at least in part by hormones such as follicle-stimulating hormone (FSH) and estrogen. Follicles recruited into the growth phase following formation of multiple layers of granulosa cells have two major fates: either to continue proliferation followed by differentiation, or to die by programmed cell death, or atresia. While many of the signaling pathways orchestrating ovarian follicle development are known, the downstream transcriptional regulators that integrate such signals in the mammalian ovary remain to be defined. Recent experiments in diverse organisms have revealed multiple instances of gonad-selective components of the basal transcriptional machinery. One such protein, TAF4b, is a gonadal-enriched coactivator subunit of the TFIID complex required for normal female fertility in the mouse. To determine the etiology of female infertility of the TAF4b-deficient mice, we have determined multiple functions of TAF4b during postnatal ovarian follicle development. Here we demonstrate that the TAF4b protein is expressed in the granulosa cell compartment of the mammalian ovarian follicle. Furthermore, TAF4b-deficient mouse ovaries contain reduced numbers of primordial as well as growing follicles and a concomitant increased proportion of apoptotic follicles in comparison to wild type counterparts. Importantly, TAF4b-null follicles are largely resistant to induction of proliferation in response to multiple hormonal stimuli including estrogen and FSH and demonstrate compromised granulosa cell survival. Together, these data suggest that TAF4b integrates a program of granulosa cell gene expression required for normal ovarian follicle survival and proliferation in response to diverse ovarian signaling events.