Probing the underlying principles of dynamics in piano performances using a modelling approach.

Variations in dynamics are an essential component of musical performance in most instruments. To study the factors that contribute to dynamic variations, we used a model approaching, allowing for determination of the individual contribution of different musical features. Thirty monophonic melodies from 3 stylistic eras with all expressive markings removed were performed by 20 pianists on a Disklavier piano. The results indicated a relatively high agreement among the pianists (Cronbach's alpha = 0.88). The overall average dynamics (across pianists) could be predicted quite well using support vector regression (R2 = 66%) from a set of 48 score-related features. The highest contribution was from pitch-related features (37.3%), followed by phrasing (12.3%), timing (2.8%), and meter (0.7%). The highest single contribution was from the high-loud principle, whereby higher notes were played louder, as corroborated by the written feedback of many of the pianists. There were also differences between the styles. The highest contribution from phrasing, for example, was obtained from the Romantic examples, while the highest contribution from meter came from the Baroque examples. An analysis of each individual pianist revealed some fundamental differences in approach to the performance of dynamics. All participants were undergraduate-standard pianists or above; however, varied levels of consistency and predictability highlighted challenges in acquiring a reliable group in terms of expertise and preparation, as well as certain pianistic challenges posed by the task. Nevertheless, the method proved useful in disentangling some underlying principles of musical performance and their relation to structural features of the score, with the potential for productive adaptation to a wider range of expressive and instrumental contexts.

Discovery and characterization of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists.

PPAR gamma (PPARG) is a ligand activated transcription factor that regulates genes involved in inflammation, bone biology, lipid homeostasis, as well as a master regulator of adipogenesis and a potential lineage driver of luminal bladder cancer. While PPARG agonists lead to transcriptional activation of canonical target genes, inverse agonists have the opposite effect through inducing a transcriptionally repressive complex leading to repression of canonical target gene expression. While many agonists have been described and tested clinically, inverse agonists offer an underexplored avenue to modulate PPARG biology in vivo. Current inverse agonists lack favorable in vivo properties; herein we describe the discovery and characterization of a series of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists, BAY-5516, BAY-5094, and BAY-9683. Structural studies of this series revealed distinct pre- and post-covalent binding positions, which led to the hypothesis that interactions in the pre-covalent conformation are primarily responsible for driving affinity, while interactions in the post-covalent conformation are more responsible for cellular functional effects by enhancing PPARG interactions with its corepressors. The need to simultaneously optimize for two distinct states may partially explain the steep SAR observed. Exquisite selectivity was achieved over related nuclear receptors in the subfamily due in part to a covalent warhead with low reactivity through an SNAr mechanism in addition to the specificity gained through covalent binding to a reactive cysteine uniquely positioned within the PPARG LBD. BAY-5516, BAY-5094, and BAY-9683 lead to pharmacodynamic regulation of PPARG target gene expression in vivo comparable to known inverse agonist SR10221 and represent new tools for future in vivo studies to explore their potential utility for treatment of disorders of hyperactivated PPARG including luminal bladder cancer and other disorders.

Relations between perceived affect and liking for melodies and visual designs.

Sensory valuation is a fundamental aspect of cognition. It involves assigning hedonic value to a stimulus based on its sensory information considering personal and contextual factors. Hedonic values (e.g., liking) can be deemed affective states that motivate behavior, but the relations between hedonic and affective judgments have yet to be established. To fill this gap, we investigated the relations between stimulus features, perceived affect, and liking across domains and with potentially relevant individual traits. Fifty-eight participants untrained in music and visual art rated their liking and perceived valence and arousal for visual designs and short melodies varying in balance, contour, symmetry, or complexity and filled out several questionnaires. First, we examined group-level relations between perceived affect and liking across domains. Second, we inspected the relations between the individual use of musical and visual properties in judgments of liking and perceived affect-that is, between aesthetic and perceived-affect sensitivities. Third, we inquired into the influence of information-related (need for cognition, or NFC) and affect-related (need for emotion) traits on individual sensitivities. We found domain-specific effects of the stimulus features on liking, a linear association between valence and liking, the inverted-U model of arousal and liking, a binary profile of musical aesthetic sensitivities, and a modulatory effect of NFC on how people use stimulus properties in their hedonic and affective judgments. In summary, the results suggest that hedonic value is primarily computed from domain-specific sensory information partially moderated by NFC. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069.

The ligand-activated nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARG or PPARγ) represents a potential target for a new generation of cancer therapeutics, especially in muscle-invasive luminal bladder cancer where PPARγ is a critical lineage driver. Here we disclose the discovery of a series of chloro-nitro-arene covalent inverse-agonists of PPARγ that exploit a benzoxazole core to improve interactions with corepressors NCOR1 and NCOR2. In vitro treatment of sensitive cell lines with these compounds results in the robust regulation of PPARγ target genes and antiproliferative effects. Despite their imperfect physicochemical properties, the compounds showed modest pharmacodynamic target regulation in vivo. Improvements to the in vitro potency and efficacy of BAY-4931 and BAY-0069 compared to those of previously described PPARγ inverse-agonists show that these compounds are novel tools for probing the in vitro biology of PPARγ inverse-agonism.

Structural Evidence for Isoform-Selective Allosteric Inhibition of Lactate Dehydrogenase A.

Lactate dehydrogenase A (LDHA) is frequently overexpressed in tumors, thereby sustaining high glycolysis rates, tumor growth, and chemoresistance. High-throughput screening resulted in the identification of phthalimide and dibenzofuran derivatives as novel lactate dehydrogenase inhibitors, selectively inhibiting the activity of the LDHA isoenzyme. Cocrystallization experiments confirmed target engagement in addition to demonstrating binding to a novel allosteric binding site present in all four LDHA subunits of the LDH5 homotetramer.

Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C.

Due to its frequent mutations in multiple lethal cancers, KRAS is one of the most-studied anticancer targets nowadays. Since the discovery of the druggable allosteric binding site containing a G12C mutation, KRASG12C has been the focus of attention in oncology research. We report here a computationally driven approach aimed at identifying novel and selective KRASG12C covalent inhibitors. The workflow involved initial enumeration of virtual molecules tailored for the KRAS allosteric binding site. Tools such as pharmacophore modeling, docking, and free-energy perturbations were deployed to prioritize the compounds with the best profiles. The synthesized naphthyridinone scaffold showed the ability to react with G12C and inhibit KRASG12C . Analogues were prepared to establish structure-activity relationships, while molecular dynamics simulations and crystallization of the inhibitor-KRASG12C complex highlighted an unprecedented binding mode.

Probing the Underlying Principles of Perceived Immanent Accents Using a Modeling Approach.

This article deals with the question of how the perception of the "immanent accents" can be predicted and modeled. By immanent accent we mean any musical event in the score that is related to important points in the musical structure (e.g., tactus positions, melodic peaks) and is therefore able to capture the attention of a listener. Our aim was to investigate the underlying principles of these accented notes by combining quantitative modeling, music analysis and experimental methods. A listening experiment was conducted where 30 participants indicated perceived accented notes for 60 melodies, vocal and instrumental, selected from Baroque, Romantic and Post-tonal styles. This produced a large and unique collection of perceptual data about the perceived immanent accents, organized by styles consisting of vocal and instrumental melodies within Western art music. The music analysis of the indicated accents provided a preliminary list of musical features that could be identified as possible reasons for the raters' perception of the immanent accents. These features related to the score in different ways, e.g., repeated fragments, single notes, or overall structure. A modeling approach was used to quantify the influence of feature groups related to pitch contour, tempo, timing, simple phrasing, and meter. A set of 43 computational features was defined from the music analysis and previous studies and extracted from the score representation. The mean ratings of the participants were predicted using multiple linear regression and support vector regression. The latter method (using cross-validation) obtained the best result of about 66% explained variance (r = 0.81) across all melodies and for a selected group of raters. The independent contribution of each feature group was relatively high for pitch contour and timing (9.6 and 7.0%). There were also significant contributions from tempo (4.5%), simple phrasing (4.4%), and meter (3.9%). Interestingly, the independent contribution varied greatly across participants, implying different listener strategies, and also some variability across different styles. The large differences among listeners emphasize the importance of considering the individual listener's perception in future research in music perception.

The novel dihydroorotate dehydrogenase (DHODH) inhibitor BAY 2402234 triggers differentiation and is effective in the treatment of myeloid malignancies.

Acute myeloid leukemia (AML) is a devastating disease, with the majority of patients dying within a year of diagnosis. For patients with relapsed/refractory AML, the prognosis is particularly poor with currently available treatments. Although genetically heterogeneous, AML subtypes share a common differentiation arrest at hematopoietic progenitor stages. Overcoming this differentiation arrest has the potential to improve the long-term survival of patients, as is the case in acute promyelocytic leukemia (APL), which is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene. Treatment of APL with all-trans retinoic acid (ATRA) induces terminal differentiation and apoptosis of leukemic promyelocytes, resulting in cure rates of over 80%. Unfortunately, similarly efficacious differentiation therapies have, to date, been lacking outside of APL. Inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, was recently reported to induce differentiation of diverse AML subtypes. In this report we describe the discovery and characterization of BAY 2402234 - a novel, potent, selective and orally bioavailable DHODH inhibitor that shows monotherapy efficacy and differentiation induction across multiple AML subtypes. Herein, we present the preclinical data that led to initiation of a phase I evaluation of this inhibitor in myeloid malignancies.

A Computational Model of Immanent Accent Salience in Tonal Music.

Accents are local musical events that attract the attention of the listener, and can be either immanent (evident from the score) or performed (added by the performer). Immanent accents involve temporal grouping (phrasing), meter, melody, and harmony; performed accents involve changes in timing, dynamics, articulation, and timbre. In the past, grouping, metrical and melodic accents were investigated in the context of expressive music performance. We present a novel computational model of immanent accent salience in tonal music that automatically predicts the positions and saliences of metrical, melodic and harmonic accents. The model extends previous research by improving on preliminary formulations of metrical and melodic accents and introducing a new model for harmonic accents that combines harmonic dissonance and harmonic surprise. In an analysis-by-synthesis approach, model predictions were compared with data from two experiments, respectively involving 239 sonorities and 638 sonorities, and 16 musicians and 5 experts in music theory. Average pair-wise correlations between raters were lower for metrical (0.27) and melodic accents (0.37) than for harmonic accents (0.49). In both experiments, when combining all the raters into a single measure expressing their consensus, correlations between ratings and model predictions ranged from 0.43 to 0.62. When different accent categories of accents were combined together, correlations were higher than for separate categories (r = 0.66). This suggests that raters might use strategies different from individual metrical, melodic or harmonic accent models to mark the musical events.

Intermittent theta burst stimulation over right somatosensory larynx cortex enhances vocal pitch-regulation in nonsingers.

While the significance of auditory cortical regions for the development and maintenance of speech motor coordination is well established, the contribution of somatosensory brain areas to learned vocalizations such as singing is less well understood. To address these mechanisms, we applied intermittent theta burst stimulation (iTBS), a facilitatory repetitive transcranial magnetic stimulation (rTMS) protocol, over right somatosensory larynx cortex (S1) and a nonvocal dorsal S1 control area in participants without singing experience. A pitch-matching singing task was performed before and after iTBS to assess corresponding effects on vocal pitch regulation. When participants could monitor auditory feedback from their own voice during singing (Experiment I), no difference in pitch-matching performance was found between iTBS sessions. However, when auditory feedback was masked with noise (Experiment II), only larynx-S1 iTBS enhanced pitch accuracy (50-250 ms after sound onset) and pitch stability (>250 ms after sound onset until the end). Results indicate that somatosensory feedback plays a dominant role in vocal pitch regulation when acoustic feedback is masked. The acoustic changes moreover suggest that right larynx-S1 stimulation affected the preparation and involuntary regulation of vocal pitch accuracy, and that kinesthetic-proprioceptive processes play a role in the voluntary control of pitch stability in nonsingers. Together, these data provide evidence for a causal involvement of right larynx-S1 in vocal pitch regulation during singing.

Prediction of three articulatory categories in vocal sound imitations using models for auditory receptive fields.

Vocal sound imitations provide a new challenge for understanding the coupling between articulatory mechanisms and the resulting audio. In this study, the classification of three articulatory categories, phonation, supraglottal myoelastic vibrations, and turbulence, have been modeled from audio recordings. Two data sets were assembled, consisting of different vocal imitations by four professional imitators and four non-professional speakers in two different experiments. The audio data were manually annotated by two experienced phoneticians using a detailed articulatory description scheme. A separate set of audio features was developed specifically for each category using both time-domain and spectral methods. For all time-frequency transformations, and for some secondary processing, the recently developed Auditory Receptive Fields Toolbox was used. Three different machine learning methods were applied for predicting the final articulatory categories. The result with the best generalization was found using an ensemble of multilayer perceptrons. The cross-validated classification accuracy was 96.8% for phonation, 90.8% for supraglottal myoelastic vibrations, and 89.0% for turbulence using all the 84 developed features. A final feature reduction to 22 features yielded similar results.

Predicting the perception of performed dynamics in music audio with ensemble learning.

By varying the dynamics in a musical performance, the musician can convey structure and different expressions. Spectral properties of most musical instruments change in a complex way with the performed dynamics, but dedicated audio features for modeling the parameter are lacking. In this study, feature extraction methods were developed to capture relevant attributes related to spectral characteristics and spectral fluctuations, the latter through a sectional spectral flux. Previously, ground truths ratings of performed dynamics had been collected by asking listeners to rate how soft/loud the musicians played in a set of audio files. The ratings, averaged over subjects, were used to train three different machine learning models, using the audio features developed for the study as input. The highest result was produced from an ensemble of multilayer perceptrons with an R2 of 0.84. This result seems to be close to the upper bound, given the estimated uncertainty of the ground truth data. The result is well above that of individual human listeners of the previous listening experiment, and on par with the performance achieved from the average rating of six listeners. Features were analyzed with a factorial design, which highlighted the importance of source separation in the feature extraction.

Corrigendum: Child-Computer Interaction at the Beginner Stage of Music Learning: Effects of Reflexive Interaction on Children's Musical Improvisation.

[This corrects the article on p. 65 in vol. 8, PMID: 28184205.].

Child-Computer Interaction at the Beginner Stage of Music Learning: Effects of Reflexive Interaction on Children's Musical Improvisation.

In this article children's musical improvisation is investigated through the "reflexive interaction" paradigm. We used a particular system, the MIROR-Impro, implemented in the framework of the MIROR project (EC-FP7), which is able to reply to the child playing a keyboard by a "reflexive" output, mirroring (with repetitions and variations) her/his inputs. The study was conducted in a public primary school, with 47 children, aged 6-7. The experimental design used the convergence procedure, based on three sample groups allowing us to verify if the reflexive interaction using the MIROR-Impro is necessary and/or sufficient to improve the children's abilities to improvise. The following conditions were used as independent variables: to play only the keyboard, the keyboard with the MIROR-Impro but with not-reflexive reply, the keyboard with the MIROR-Impro with reflexive reply. As dependent variables we estimated the children's ability to improvise in solos, and in duets. Each child carried out a training program consisting of 5 weekly individual 12 min sessions. The control group played the complete package of independent variables; Experimental Group 1 played the keyboard and the keyboard with the MIROR-Impro with not-reflexive reply; Experimental Group 2 played only the keyboard with the reflexive system. One week after, the children were asked to improvise a musical piece on the keyboard alone (Solo task), and in pairs with a friend (Duet task). Three independent judges assessed the Solo and the Duet tasks by means of a grid based on the TAI-Test for Ability to Improvise rating scale. The EG2, which trained only with the reflexive system, reached the highest average results and the difference with EG1, which did not used the reflexive system, is statistically significant when the children improvise in a duet. The results indicate that in the sample of participants the reflexive interaction alone could be sufficient to increase the improvisational skills, and necessary when they improvise in duets. However, these results are in general not statistically significant. The correlation between Reflexive Interaction and the ability to improvise is statistically significant. The results are discussed on the light of the recent literature in neuroscience and music education.

Experience-dependent modulation of right anterior insula and sensorimotor regions as a function of noise-masked auditory feedback in singers and nonsingers.

Previous studies on vocal motor production in singing suggest that the right anterior insula (AI) plays a role in experience-dependent modulation of feedback integration. Specifically, when somatosensory input was reduced via anesthesia of the vocal fold mucosa, right AI activity was down regulated in trained singers. In the current fMRI study, we examined how masking of auditory feedback affects pitch-matching accuracy and corresponding brain activity in the same participants. We found that pitch-matching accuracy was unaffected by masking in trained singers yet declined in nonsingers. The corresponding brain region with the most differential and interesting activation pattern was the right AI, which was up regulated during masking in singers but down regulated in nonsingers. Likewise, its functional connectivity with inferior parietal, frontal, and voice-relevant sensorimotor areas was increased in singers yet decreased in nonsingers. These results indicate that singers relied more on somatosensory feedback, whereas nonsingers depended more critically on auditory feedback. When comparing auditory vs somatosensory feedback involvement, the right anterior insula emerged as the only region for correcting intended vocal output by modulating what is heard or felt as a function of singing experience. We propose the right anterior insula as a key node in the brain's singing network for the integration of signals of salience across multiple sensory and cognitive domains to guide vocal behavior.

Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.

Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.

Colour Association with Music Is Mediated by Emotion: Evidence from an Experiment Using a CIE Lab Interface and Interviews.

Crossmodal associations may arise at neurological, perceptual, cognitive, or emotional levels of brain processing. Higher-level modal correspondences between musical timbre and visual colour have been previously investigated, though with limited sets of colour. We developed a novel response method that employs a tablet interface to navigate the CIE Lab colour space. The method was used in an experiment where 27 film music excerpts were presented to participants (n = 22) who continuously manipulated the colour and size of an on-screen patch to match the music. Analysis of the data replicated and extended earlier research, for example, that happy music was associated with yellow, music expressing anger with large red colour patches, and sad music with smaller patches towards dark blue. Correlation analysis suggested patterns of relationships between audio features and colour patch parameters. Using partial least squares regression, we tested models for predicting colour patch responses from audio features and ratings of perceived emotion in the music. Parsimonious models that included emotion robustly explained between 60% and 75% of the variation in each of the colour patch parameters, as measured by cross-validated R2. To illuminate the quantitative findings, we performed a content analysis of structured spoken interviews with the participants. This provided further evidence of a significant emotion mediation mechanism, whereby people tended to match colour association with the perceived emotion in the music. The mixed method approach of our study gives strong evidence that emotion can mediate crossmodal association between music and visual colour. The CIE Lab interface promises to be a useful tool in perceptual ratings of music and other sounds.

Modeling the perception of tempo.

A system is proposed in which rhythmic representations are used to model the perception of tempo in music. The system can be understood as a five-layered model, where representations are transformed into higher-level abstractions in each layer. First, source separation is applied (Audio Level), onsets are detected (Onset Level), and interonset relationships are analyzed (Interonset Level). Then, several high-level representations of rhythm are computed (Rhythm Level). The periodicity of the music is modeled by the cepstroid vector-the periodicity of an interonset interval (IOI)-histogram. The pulse strength for plausible beat length candidates is defined by computing the magnitudes in different IOI histograms. The speed of the music is modeled as a continuous function on the basis of the idea that such a function corresponds to the underlying perceptual phenomena, and it seems to effectively reduce octave errors. By combining the rhythmic representations in a logistic regression framework, the tempo of the music is finally computed (Tempo Level). The results are the highest reported in a formal benchmarking test (2006-2013), with a P-Score of 0.857. Furthermore, the highest results so far are reported for two widely adopted test sets, with an Acc1 of 77.3% and 93.0% for the Songs and Ballroom datasets.

The EBNA-2 N-Terminal Transactivation Domain Folds into a Dimeric Structure Required for Target Gene Activation.

Epstein-Barr virus (EBV) is a γ-herpesvirus that may cause infectious mononucleosis in young adults. In addition, epidemiological and molecular evidence links EBV to the pathogenesis of lymphoid and epithelial malignancies. EBV has the unique ability to transform resting B cells into permanently proliferating, latently infected lymphoblastoid cell lines. Epstein-Barr virus nuclear antigen 2 (EBNA-2) is a key regulator of viral and cellular gene expression for this transformation process. The N-terminal region of EBNA-2 comprising residues 1-58 appears to mediate multiple molecular functions including self-association and transactivation. However, it remains to be determined if the N-terminus of EBNA-2 directly provides these functions or if these activities merely depend on the dimerization involving the N-terminal domain. To address this issue, we determined the three-dimensional structure of the EBNA-2 N-terminal dimerization (END) domain by heteronuclear NMR-spectroscopy. The END domain monomer comprises a small fold of four ß-strands and an α-helix which form a parallel dimer by interaction of two ß-strands from each protomer. A structure-guided mutational analysis showed that hydrophobic residues in the dimer interface are required for self-association in vitro. Importantly, these interface mutants also displayed severely impaired self-association and transactivation in vivo. Moreover, mutations of solvent-exposed residues or deletion of the α-helix do not impair dimerization but strongly affect the functional activity, suggesting that the EBNA-2 dimer presents a surface that mediates functionally important intra- and/or intermolecular interactions. Our study shows that the END domain is a novel dimerization fold that is essential for functional activity. Since this specific fold is a unique feature of EBNA-2 it might provide a novel target for anti-viral therapeutics.