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Pandey, P. R.

Publications and source records attributed to Pandey, P. R..

3 recordsLinked to original sources

The Listening Effort Profile of Eye Movements: Easy, Difficult, and Impossible Speech Comprehension

Speech comprehension in noisy environments often requires cognitive effort, but listeners may disengage when comprehension becomes impossible. Eye movements have recently emerged as a promising new measure of listening effort, but it remains unclear whether eye movements are sensitive to the full effort profile across easy, difficult, and impossible speech comprehension. Across four experiments, participants listened to sentences at easy, difficult, and impossible levels of multi-talker background babble while pupil size and eye movements were recorded. Pupil size generally followed the expected inverted u-shaped effort profile: low for easy speech, maximal for difficult but still intelligible speech and lower again for impossible speech, although this pattern partly reflected sustained, condition-specific differences and not only sentence-evoked responses. Gaze dispersion - measuring the spread of eye movements - decreased with high temporal selectivity during difficult relative to easy and impossible speech, indicating reduced eye movements during active, effortful listening. However, gaze dispersion was also lower, but less temporally selective, during impossible compared to easy listening, especially in non-baseline-corrected analyses, suggesting that reduced eye movements do not index listening effort uniquely. Instead, eye movements appear to reflect both attentional engagement during difficult listening and disengagement or inward attention when meaningful listening is no longer possible. These findings indicate that pupil size and eye movements provide complementary indices of listening-related cognition, and highlight the integration of listening, cognition, and motor systems.

neuroscience↗

Role of Myc family proteins in transcriptional regulation of growth and oncogenic transformation in fusion-positive rhabdomyosarcoma

Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by a PAX3::FOXO1 (P3F) or PAX7::FOXO1 fusion gene. After finding that MYCN is required for P3F-induced oncogenic transformation in a human myoblast model of FP-RMS, we further investigated the role of Myc family proteins in FP-RMS. Expression studies revealed that myoblast models and a subset of FP-RMS lines have predominant MYCN or MYC expression whereas other FP-RMS lines have both high MYCN and MYC expression. In myoblast models, MYCN was required for optimal P3F binding to and high-level activation of FGF8, a P3F target that is necessary and sufficient for oncogenic transformation. MYCN or MYC knockdown suppressed transformation in myoblast and FP-RMS lines with dominant MYCN or MYC expression, respectively. In FP-RMS lines with high MYCN and MYC expression, there was partial loss of transformation when one gene was targeted and complete loss when both genes were targeted. Despite the loss of oncogenic activity in lines with knockdown of a dominant Myc family member, FGF8 expression was not decreased. Transcriptomic analyses revealed that P3F target genes were not affected by MYCN or MYC knockdown, and instead a group of Myc-specific targets was down-regulated. Collectively, these results indicate that MYCN or MYC is functionally dominant in myoblast models and FP-RMS lines with dominant expression of one Myc family protein whereas MYCN and MYC are functionally redundant in FP-RMS cell lines with high expression of both. These Myc family proteins contribute to oncogenic properties by facilitating P3F activation of FGF8 and increasing expression of Myc-specific targets.

cancer biology↗

Structural variability and concerted motions of the T cell receptor - CD3 complex

We investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) - CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15{degrees} to 55{degrees}. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR - CD3 complex, in particular in the EC interactions of the C{beta} FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR - CD3 complex revealed in our simulations provide atomistic insights for force-based models of TCR activation, which involve such structural changes in response to tilt-inducing forces on antigen-bound TCRs.

immunology↗