Spectroscopic Characterization of Highly Excited Neutral Chromium Tricarbonyl.

Spectroscopic characterization of highly excited neutral transition-metal complexes is important for understanding the multifaceted reaction mechanisms between metals and ligands. In this work, the reactions of neutral chromium atoms with carbon monoxide were probed by size-specific infrared spectroscopy. Interestingly, Cr(CO)3 was found to have an unprecedented 7A2″ septet excited state rather than the singlet ground state. A combination of experiment and theory shows that the gas-phase formation of this highly excited Cr(CO)3 is facile both thermodynamically and kinetically. Electronic structure and bonding analyses indicate that the valence electrons of Cr atoms in the septet Cr(CO)3 are in a relatively stable configuration, which facilitate the highly excited structure and the planar geometric shape (D3h symmetry). The observed septet Cr(CO)3 affords a paradigm for exploring the structure, properties, and formation mechanism of a large variety of excited neutral compounds.

Restraining vocal fold vertical motion reduces source-filter interaction in a two-mass model.

Previous experimental studies suggested that restraining the vocal fold vertical motion may reduce the coupling strength between the voice source and vocal tract. In this study, the effects of vocal fold vertical motion on source-filter interaction were systematically examined in a two-dimensional two-mass model coupled to a compressible flow simulation. The results showed that when allowed to move vertically, the vocal folds exhibited subharmonic vibration due to entrainment to the first vocal tract acoustic resonance. Restraining the vertical motion suppressed this entrainment. This indicates that the vertical mobility of the vocal folds may play a role in regulating source-filter interaction.

Register transitions in an in vivo canine model as a function of intrinsic laryngeal muscle stimulation, fundamental frequency, and sound pressure level.

Phonatory instabilities and involuntary register transitions can occur during singing. However, little is known regarding the mechanisms which govern such transitions. To investigate this phenomenon, we systematically varied laryngeal muscle activation and airflow in an in vivo canine larynx model during phonation. We calculated voice range profiles showing average nerve activations for all combinations of fundamental frequency (F0) and sound pressure level (SPL). Further, we determined closed-quotient (CQ) and minimum-posterior-area (MPA) based on high-speed video recordings. While different combinations of muscle activation favored different combinations of F0 and SPL, in the investigated larynx there was a consistent region of instability at about 400 Hz which essentially precluded phonation. An explanation for this region may be a larynx specific coupling between sound source and subglottal tract or an effect based purely on larynx morphology. Register transitions crossed this region, with different combinations of cricothyroid and thyroarytenoid muscle (TA) activation stabilizing higher or lower neighboring frequencies. Observed patterns in CQ and MPA dependent on TA activation reproduced patterns found in singers in previous work. Lack of control of TA stimulation may result in phonation instabilities, and enhanced control of TA stimulation may help to avoid involuntary register transitions, especially in the singing voice.

Spectroscopic characterization of carbon monoxide activation by neutral chromium carbides.

Spectroscopic characterization of carbon monoxide activation by neutral metal carbides is of essential importance for understanding the structure-reactivity relationships of catalytic sites, but has been proven to be very challenging owing to the difficulty in size selection. Here, we report a size-specific infrared-vacuum ultraviolet spectroscopic study of the reactions between carbon monoxide with neutral chromium carbides. Quantum chemical calculations were carried out to identify the low-lying structures and to interpret the experimental features. The results reveal that the most stable structure of CrC3(CO)2 consists of a CCO ketenylidene unit and that of CrC4(CO)2 has a semi-bridging CO with a very low CO stretching vibrational frequency at 1821 cm-1. The electron structure analyses show that this semi-bridging CO is highly activated through the delocalized Cr-C-C three-center two-electron (3c-2e) interaction between the antibonding orbitals of CO and the metal carbide skeleton. The formation of these metal carbide carbonyls is found to be both thermodynamically exothermic and kinetically facile in the gas phase. The present findings have important implications for the mechanical understanding of the catalytic processes with isolated metal atoms/clusters dispersed on supports.

Drug discovery and optimization based on the co-crystal structure of natural product with target.

Due to their structural diversities and prevalent biological activities, natural products (NPs) are momentous resources for drug discovery. Although NPs have a wide range of biological activities, many exhibit structural complexity that leads to synthetic difficulties, which combines with inefficient biological activity, toxicity, and unfavorable pharmacokinetic characteristics and ultimately imparts poor safety and efficacy outcomes. Progress in crystallization and computational techniques allow crystallography to have a seasonable influences on drug discovery. By co-crystallizing with proteins, therapeutic targets of NPs in specific diseases can be identified. By analyzing the co-crystal information, the structure-activity relationships (SARs) of NPs targeting specific proteins can be grasped. Under the guidance of co-crystal information, directional structural modification and simplification are powerful strategies for overcoming limitations of NPs, improving the success rate of NP-based drug discovery, and obtaining NP-based drugs with high selectivity, low toxicity and favorable pharmacokinetic characteristics. Here, we review the co-crystal information of a selection of NPs, focusing on the SARs of NPs reflected by co-crystal information and the modification and simplification strategies of NPs, and discuss how to apply co-crystal information in the optimization of NP-based lead compound.

Effects of Thyroarytenoid Activation Induced Vibratory Asymmetry on Voice Acoustics and Perception.

INTRODUCTION: Asymmetry of vocal fold (VF) vibration is common in patients with voice complaints and also observed in 10% of normophonic individuals. Although thyroarytenoid (TA) muscle activation plays a crucial role in regulating VF vibration, how TA activation asymmetry relates to voice acoustics and perception is unclear. We evaluated the relationship between TA activation asymmetry and the resulting acoustics and perception. METHODS: An in vivo canine model of phonation was used to create symmetric and increasingly asymmetric VF vibratory conditions via graded stimulation of bilateral TA muscles. Naïve listeners (n = 89) rated the perceptual quality of 100 unique voice samples using a visual sort-and-rate task. For each phonatory condition, cepstral peak prominence (CPP), harmonic amplitude (H1-H2), and root-mean-square (RMS) energy of the voice were measured. The relationships between these metrics, vibratory asymmetry, and perceptual ratings were evaluated. RESULTS: Increasing levels of TA asymmetry resulted in declining listener preference. Furthermore, only severely asymmetric audio samples were perceptually distinguishable from symmetric and mildly asymmetric conditions. CPP was negatively correlated with TA asymmetry: voices produced with larger degrees of asymmetry were associated with lower CPP values. Listeners preferred audio samples with higher values of CPP, high RMS energy, and lower H1-H2 (less breathy). CONCLUSION: Listeners are sensitive to changes in voice acoustics related to vibratory asymmetry. Although increasing vibratory asymmetry is correlated with decreased perceptual ratings, mild asymmetries are perceptually tolerated. This study contributes to our understanding of voice production and quality by identifying perceptually salient and clinically meaningful asymmetry. LEVEL OF EVIDENCE: N/A (Basic Science Study) Laryngoscope, 134:1327-1332, 2024.

Cell-Based Outer Vocal Fold Replacement Both Treats and Prevents Vocal Fold Scarring in Rabbits.

OBJECTIVE: Numerous pharmacological and cell-based treatments have shown promise in preventing vocal fold (VF) scarring when applied at the time of injury. A common clinical scenario, however, is the finding of mature scar impeding voicing. Many treatments are less effective in remodeling existing scar tissue. This objective of this study is to determine if a cell-based outer vocal fold replacement (COVR) effectively restores VF function when applied to existing scar. METHODS: Eighteen rabbits were allocated to three groups: unilateral COVR implant at the time of cordectomy (acute COVR); unilateral cordectomy followed by COVR implant 2 months later (chronic COVR); and unilateral cordectomy followed by sham implant surgery 2 months later (chronic scar). Larynges were harvested 2 months after implant or sham surgery. RESULTS: All larynges in the COVR groups demonstrated human leukocyte antigen labeling on immunohistochemistry (IHC). COVR groups had increased hyaluronic acid content compared with normal. VF stiffness as measured by elastic moduli in acute COVR and chronic COVR were similar to their contralateral unoperated VF. CONCLUSION: COVR implantation in both acutely injured and chronically scarred VF demonstrate persistence of implanted cells, restored tissue biomechanics, and increased hyaluronic acid content. LEVEL OF EVIDENCE: NA Laryngoscope, 134:764-772, 2024.

Histologic Examination of Vocal Fold Mucosal Wave and Vibration.

OBJECTIVES: Despite gross anatomic and histologic differences between human and canine vocal folds, similar wave patterns have been described yet not fully characterized. We reconstructed vocal fold (VF) vibration in a canine hemilarynx and performed histologic examination of the same vocal fold. We demonstrate comparable wave patterns while exploring the importance of certain anatomic architectures. METHODS: An in vivo canine hemilarynx was phonated against a glass prism at low and high muscle activation conditions. Vibration was captured using high-speed video, and trajectories of VF medial surface tattooed landmarks were 3D-reconstructed. The method of empirical eigenfunctions was used to capture the essential dynamics of vibratory movement. Histologic examination of the hemilarynx was performed. RESULTS: Oscillation patterns were highly similar between the in vivo canine and previous reports of ex vivo human models. The two most dominant eigenfunctions comprised over 90% of total variance of movement, representing opening/closing and convergent/divergent movement patterns, respectively. We demonstrate a vertical phase difference during the glottal cycle. The time delay between the inferior and superior VF was greater during opening than closing for both activation conditions. Histological examination of canine VF showed not only a thicker lamina propria layer superiorly but also a distinct pattern of thyroarytenoid muscle fibers and fascicles as described in human studies. CONCLUSIONS: Histologic and vibratory examination of the canine vocal fold demonstrated human vocal fold vibratory patterns despite certain microstructural differences. This study suggests that the multilayered lamina propria may not be fundamental to vibratory patterns necessary for human-like voice production. LEVEL OF EVIDENCE: NA (Basic science study) Laryngoscope, 134:264-271, 2024.

Neural Adaptive H∞ Sliding-Mode Control for Uncertain Nonlinear Systems with Disturbances Using Adaptive Dynamic Programming.

This paper focuses on a neural adaptive H∞ sliding-mode control scheme for a class of uncertain nonlinear systems subject to external disturbances by the aid of adaptive dynamic programming (ADP). First, by combining the neural network (NN) approximation method with a nonlinear disturbance observer, an enhanced observer framework is developed for estimating the system uncertainties and observing the external disturbances simultaneously. Then, based on the reliable estimations provided by the enhanced observer, an adaptive sliding-mode controller is meticulously designed, which can effectively counteract the effects of the system uncertainties and the separated matched disturbances, even in the absence of prior knowledge regarding their upper bounds. While the remaining unmatched disturbances are attenuated by means of H∞ control performance on the sliding surface. Moreover, a single critic network-based ADP algorithm is employed to learn the cost function related to the Hamilton-Jacobi-Isaacs equation, and thus, the H∞ optimal control is obtained. An updated law for the critic NN is proposed not only to make the Nash equilibrium achieved, but also to stabilize the sliding-mode dynamics without the need for an initial stabilizing control. In addition, we analyze the uniform ultimate boundedness stability of the resultant closed-loop system via Lyapunov's method. Finally, the effectiveness of the proposed scheme is verified through simulations of a single-link robot arm and a power system.

The impact of esterified nanofibrillated cellulose content on the properties of thermoplastic starch/PBAT biocomposite films through ball-milling.

To enhance the mechanical properties and interfacial compatibility of thermoplastic starch (TPS) highly filled poly(butylene adipate co-terephthalate) (PBAT) composite films, esterified NFC was innovatively fabricated and introduced into the composite system. The influences of NFC content and ball-milling treatment were thoroughly investigated. Interestingly, the amphiphilic esterified NFC provided a "bridge-like" effect between TPS and PBAT interfaces, which significantly improved the interfacial compatibility and mechanical properties. Notably, the tensile properties of the composite films reached their maximums at a 7 wt% NFC content, displaying a tensile strength of 6.2 MPa and an elastic modulus of 263 MPa. These values corresponded to a 59 % and 180 % increase, respectively, compared to the composition without NFC. More importantly, ball-milling contributed to uniform dispersion and surface activation of NFC, preventing starch retrogradation, and enhancing the tensile strength and elastic modulus by 30.3 % and 56.6 %, respectively. Additionally, the film exhibited excellent UV-blocking, foldable, writable, and transparent performance. These findings provide valuable data supporting the expanded applications of starch-based composite films.

The influence of source-filter interaction on the voice source in a three-dimensional computational model of voice production.

The goal of this computational study is to quantify global effects of vocal tract constriction at various locations (false vocal folds, aryepiglottic folds, pharynx, oral cavity, and lips) on the voice source across a large range of vocal fold conditions. The results showed that while inclusion of a uniform vocal tract had notable effects on the voice source, further constricting the vocal tract only had small effects except for conditions of extreme constriction, at which constrictions at any location along the vocal tract decreased the mean and peak-to-peak amplitude of the glottal flow waveform. Although narrowing in the epilarynx increased the normalized maximum flow declination rate, vocal tract constriction in general slightly reduced the source strength and high-frequency harmonic production at the glottis, except for a limited set of vocal fold conditions (e.g., soft, long vocal folds subject to relatively high pressure). This suggests that simultaneous laryngeal and vocal tract adjustments are required to maximize source-filter interaction. While vocal tract adjustments are often assumed to improve voice production, our results indicate that such improvements are mainly due to changes in vocal tract acoustic response rather than improved voice production at the glottis.

Validation and enhancement of a vocal fold medial surface 3D reconstruction approach for in-vivo application.

In laryngeal research, studying the vertical vocal fold oscillation component is often disregarded. However, vocal fold oscillation by its nature is a three-dimensional process. In the past, we have developed an in-vivo experimental protocol to reconstruct the full, three-dimensional vocal fold vibration. The goal of this study is to validate this 3D reconstruction method. We present an in-vivo canine hemilarynx setup using high-speed video recording and a right-angle prism for 3D reconstruction of vocal fold medial surface vibrations. The 3D surface is reconstructed from the split image provided by the prism. For validation, reconstruction error was calculated for objects located at a distance of up to 15 mm away from the prism. The influence of camera angle, changing calibrated volume, and calibration errors were determined. Overall average 3D reconstruction error is low and does not exceed 0.12 mm at 5 mm distance from the prism. Influence of a moderate (5°) and large (10°) deviation in camera angle led to a slight increase in error to 0.16 mm and 0.17 mm, respectively. This procedure is robust towards changes in calibration volume and small calibration errors. This makes this 3D reconstruction approach a useful tool for the reconstruction of accessible and moving tissue surfaces.

Autoxidation Mechanism and Kinetics of Methacrolein in the Atmosphere.

Elucidating the autoxidation of volatile organic compounds (VOCs) is crucial to understanding the formation mechanism of secondary organic aerosols, but it has been proven to be challenging due to the complexity of reactions under atmospheric conditions. Here, we report a comprehensive theoretical study of atmospheric autoxidation in VOCs exemplified by the atmospherically important methacrolein (MACR), a major oxidation product of isoprene. The results indicate that the Cl-adducts and H-abstraction products of MACR readily react with O2 and undergo subsequent isomerizations via H-shift and cyclization, forming a large variety of lowly and highly oxygenated organic molecules. In particular, the first- and third-generation oxidation products derived from the Cl-adducts and the methyl-H-abstraction complexes are dominated in the atmospheric autoxidation, for which the fractional yields are remarkably affected by the NO concentration. The present findings have important implications for a systematical understanding of the oxidation processes of isoprene-derived compounds in the atmospheric environments.

Vocal Fold Vertical Thickness in Human Voice Production and Control: A Review.

While current voice research often focuses on laryngeal adjustments in a two-dimensional plane from a superior endoscopic view, recent computational simulations showed that vocal control is three-dimensional and the medial surface vertical thickness plays an important role in regulating the glottal closure pattern and the spectral shape of the produced voice. In contrast, while a small glottal gap is required to initiate and sustain phonation, further changes in the glottal gap within this small range have only small effects on glottal closure and spectral shape. Vocal fold stiffness, particularly along the anterior-posterior direction, plays an important role in pitch control but has only a small effect on glottal closure and spectral shape. These results suggest that voice research should pay more attention to medial surface shape in the vertical dimension. Future studies in a large population of both normal speakers and patients are needed to better characterize the three-dimensional medial surface shape, its variability between speakers, changes throughout the life span, and how it is impacted by voice disorders and clinical interventions. The implications for voice pedagogy and clinical intervention are discussed.

A novel CDK8 inhibitor with poly-substituted pyridine core: Discovery and anti-inflammatory activity evaluation in vivo.

As an ideal anti-inflammatory target, cyclin-dependent kinase 8 (CDK8) has gradually attracted the attention of researchers. CDK8 inhibition up-regulates Interleukin-10 (IL-10) expression by enhancing the transcriptional activity of activator protein-1 (AP-1), and augmenting IL-10 abundance is a viable strategy for the treatment of inflammatory bowel disease (IBD). In this research, through structure-based drug design and dominant fragment hybridization, a series of poly-substituted pyridine derivatives were designed and synthesized as CDK8 inhibitors. Ultimately, compound CR16 was identified as the best one, which exhibited good inhibitory activity against CDK8 (IC50 = 74.4 nM). In vitro and in vivo studies indicated that CR16 could enhance the transcriptional activity of AP-1, augment the abundance of IL-10, and affect CDK8-related signaling pathways including TLR7/NF-κB/MAPK and IL-10-JAK1-STAT3 pathways. In addition, CR16 showed potent therapeutic effect in an animal model of IBD.

Effects of implant and vocal fold stiffness on voice production after medialization laryngoplasty in an MRI-based vocal fold model.

Medialization laryngoplasty is one of the primary surgical interventions in the treatment of glottal insufficiency due to vocal fold paralysis, paresis, or atrophy. During the surgery, an implant is laterally inserted into the larynx to medialize the affected vocal fold toward glottal midline, with the goal of improving glottal closure during phonation and voice production efficiency. While implants of different materials and geometry designs have been used, the effect of implant design on the voice outcome remains unclear. In this simulation study, the effect of implant stiffness was investigated in an MRI-based model of the vocal folds after medialization laryngoplasty. The results showed that implant stiffness had a significant impact on the phonation threshold pressure, glottal area waveform, and fundamental frequency, but only small effect on the closed quotient and other acoustic measures of the produced voice. The effect of implant stiffness also exhibited variability, depending on the stiffness conditions of the vocal fold and paraglottic tissues, indicating that individual differences need to be considered during the planning of medialization laryngoplasty.

Impact of the Paraglottic Space on Voice Production in an MRI-Based Vocal Fold Model.

OBJECTIVE: While the vocal fold is in direct contact anteriorly with the thyroid cartilage, posteriorly the vocal fold connects to the thyroid cartilage through a soft tissue layer in the paraglottic space. Currently the paraglottic space is often neglected in computational models of phonation, in which a fixed boundary condition is often imposed on the lateral surface of the vocal fold. The goal of this study was to investigate the effect of the paraglottic space on voice production in an MRI-based vocal fold model, and how this effect may be counteracted by vocal fold stiffening due to laryngeal muscle activation. METHODS: Parametric simulation study using an MRI-based computational vocal fold model. RESULTS: The results showed that the presence of the paraglottic space increased the mean and amplitude of the glottal area waveform, decreased the phonation frequency and closed quotient. For the particular vocal fold geometry used in this study, the presence of the paraglottic space also reduced the occurrence of irregular vocal fold vibration. These effects of the paraglottic space became smaller with increasing paraglottic space stiffness and to a lesser degree with vocal fold stiffening. CONCLUSIONS: The results suggest that the paraglottic space may be neglected in qualitative evaluations of normal phonation, but needs to be included in simulations of pathological phonation or vocal fold posturing.

Voice Feature Selection to Improve Performance of Machine Learning Models for Voice Production Inversion.

OBJECTIVE: Estimation of physiological control parameters of the vocal system from the produced voice outcome has important applications in clinical management of voice disorders . Previously we developed a simulation-based neural network for estimation of vocal fold geometry, mechanical properties, and subglottal pressure from voice outcome features that characterize the acoustics of the produced voice. The goals of this study are to (1) explore the possibility of improving the estimation accuracy of physiological control parameters by including voice outcome features characterizing vocal fold vibration; and (2) identify voice feature sets that optimize both estimation accuracy and robustness to measurement noise. METHODS: Feedforward neural networks are trained to solve the inversion problem of estimating the physiological control parameters of a three-dimensional body-cover vocal fold model from different sets of voice outcome features that characterize the simulated voice acoustics, glottal flow, and vocal fold vibration. A sensitivity analysis is then performed to evaluate the contribution of individual voice features to the overall performance of the neural networks in estimating the physiologic control parameters. RESULTS AND CONCLUSIONS: While including voice outcome features characterizing vocal fold vibration increases estimation accuracy, it also reduces the network's robustness to measurement noise, due to high sensitivity of network performance to voice outcome features measuring the absolute amplitudes of the glottal flow and area waveforms, which are also difficult to measure accurately in practical applications. By excluding such glottal flow-based features and replacing glottal area-based features by their normalized counterparts, we are able to significantly improve both estimation accuracy and robustness to noise. We further show that similar estimation accuracy and robustness can be achieved with an even smaller set of voice outcome features by excluding features of small sensitivity.

Control of Pre-phonatory Glottal Shape by Intrinsic Laryngeal Muscles.

OBJECTIVES: Surgical manipulations to treat glottic insufficiency aim to restore the physiologic pre-phonatory glottal shape. However, the physiologic pre-phonatory glottal shape as a function of interactions between all intrinsic laryngeal muscles (ILMs) has not been described. Vocal fold posture and medial surface shape were investigated across concurrent activation and interactions of thyroarytenoid (TA), cricothyroid (CT), and lateral cricoarytenoid/interarytenoid (LCA/IA) muscles. STUDY DESIGN: In vivo canine hemilarynx model. METHODS: The ILMs were stimulated across combinations of four graded levels each from low-to-high activation. A total of 64 distinct medial surface postures (4 TA × 4 CT × 4 LCA/IA levels) were captured using high-speed video. Using a custom 3D interpolation algorithm, the medial surface shape was reconstructed. RESULTS: Combined activation of ILMs yielded a range of unique pre-phonatory postures. Both LCA/IA and TA activation adducted the vocal fold but with greater contribution from TA. The transition from a convergent to a rectangular glottal shape was primarily mediated by TA muscle activation but LCA/IA and TA together resulted in a smooth rectangular glottis compared to TA alone, which caused rectangular glottis with inferomedial bulging. CT activation resulted in a lengthened but slightly abducted glottis. CONCLUSIONS: TA was primarily responsible for the rectangular shape of the adducted glottis with synergistic contribution from the LCA/IA. CT contributed minimally to vocal fold medial shape but elongated the glottis. These findings further refine laryngeal posture goals in surgical correction of glottic insufficiency. LEVEL OF EVIDENCE: NA, Basic science Laryngoscope, 133:1690-1697, 2023.