Visual biases in evaluation of speakers' and singers' voice type by cis and trans listeners.

Introduction: A singer's or speaker's Fach (voice type) should be appraised based on acoustic cues characterizing their voice. Instead, in practice, it is often influenced by the individual's physical appearance. This is especially distressful for transgender people who may be excluded from formal singing because of perceived mismatch between their voice and appearance. To eventually break down these visual biases, we need a better understanding of the conditions under which they occur. Specifically, we hypothesized that trans listeners (not actors) would be better able to resist such biases, relative to cis listeners, precisely because they would be more aware of appearance-voice dissociations. Methods: In an online study, 85 cisgender and 81 transgender participants were presented with 18 different actors singing or speaking short sentences. These actors covered six voice categories from high/bright (traditionally feminine) to low/dark (traditionally masculine) voices: namely soprano, mezzo-soprano (referred to henceforth as mezzo), contralto (referred to henceforth as alto), tenor, baritone, and bass. Every participant provided voice type ratings for (1) Audio-only (A) stimuli to get an unbiased estimate of a given actor's voice type, (2) Video-only (V) stimuli to get an estimate of the strength of the bias itself, and (3) combined Audio-Visual (AV) stimuli to see how much visual cues would affect the evaluation of the audio. Results: Results demonstrated that visual biases are not subtle and hold across the entire scale, shifting voice appraisal by about a third of the distance between adjacent voice types (for example, a third of the bass-to-baritone distance). This shift was 30% smaller for trans than for cis listeners, confirming our main hypothesis. This pattern was largely similar whether actors sung or spoke, though singing overall led to more feminine/high/bright ratings. Conclusion: This study is one of the first demonstrations that transgender listeners are in fact better judges of a singer's or speaker's voice type because they are better able to separate the actors' voice from their appearance, a finding that opens exciting avenues to fight more generally against implicit (or sometimes explicit) biases in voice appraisal.

Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing.

Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. SIGNIFICANCE: Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers. This article is highlighted in the In This Issue feature, p. 2945.

Basic science; metallothionein I and II attenuate the thalamic microglial response following traumatic axotomy in the immature brain.

The clinical manifestations of inflicted traumatic brain injury in infancy most commonly result from intracranial hemorrhage, axonal stretch and disruption, and cerebral edema. Often hypoxia ischemia is superimposed, leading to early forebrain and later thalamic neurodegeneration. Such acute and delayed cellular injury activates microglia in the CNS. Although activated microglia provide important benefits in response to injury, microglial release of reactive oxygen species can be harmful to axotomized neurons. We have previously shown that the antioxidants metallothionein I and II (MT I & II) promote geniculocortical neuronal survival after visual cortex lesioning. The purpose of this investigation was to determine the influence of MT I & II on the density and rate of thalamic microglial activation and accumulation following in vivo axotomy. We ablated the visual cortex of 10-day-old and adult MT I & II knock out (MT(-/-)) and wild-type mice and then determined the density of microglia in the dorsal lateral geniculate nucleus (dLGN) over time. Compared to the wild-type strain, microglial activation occurred earlier in both young and adult MT(-/-) mice. Similarly, microglial density was significantly greater in young MT(-/-) mice 30, 36, and 48 hours after injury, and 3, 4, and 5 days after injury in MT(-/-) adults. In both younger and older mice, time and MT I & II deficiency each contributed significantly to greater microglial density. Only in younger mice did MT I & II expression significantly slow the rate (density x time) of microglial accumulation. These results suggest that augmentation of MT I & II expression may provide therapeutic benefits to infants with inflicted brain injury.

Metallothionein I and II mitigate age-dependent secondary brain injury.

Both the immediate insult and delayed apoptosis contribute to functional deficits after brain injury. Secondary, delayed apoptotic death is more rapid in immature than in adult CNS neurons, suggesting the presence of age-dependent protective factors. To understand the molecular pathobiology of secondary injury in the context of brain development, we identified changes in expression of oxidative stress response genes during postnatal development and target deprivation-induced neurodegeneration. The antioxidants metallothionein I and II (MT I/II) were increased markedly in the thalamus of adult C57BL/6 mice compared to mice <15 days old. Target deprivation generates reactive oxygen species that mediate neuronal apoptosis in the central nervous system; thus the more rapid apoptosis observed in the immature brain might be due to lower levels of MT I/II. We tested this hypothesis by documenting neuronal loss after target-deprivation injury. MT I/II-deficient adult mice experienced greater thalamic neuron loss at 96 hr after cortical injury compared to that in controls (80 +/- 2% vs. 57 +/- 4%, P < 0.01), but not greater overall neuronal loss (84 +/- 4% vs. 79 +/- 3%, MT I/II-deficient vs. controls). Ten-day-old MT I/II-deficient mice, however, experienced both faster onset of secondary neuronal death (30 vs. 48 hr) and greater overall neuronal loss (88 +/- 2% vs. 69 +/- 4%, P = 0.02). MT I/II are thus inhibitors of age-dependent secondary brain injury, and the low levels of MT I/II in immature brains explains, in part, the enhanced susceptibility of the young brain to neuronal loss after injury. These findings have implications for the development of age-specific therapeutic strategies to enhance recovery after brain injury.