Biology subjects

Huff, A.

Publications and source records attributed to Huff, A..

3 recordsLinked to original sources

bioRxiv2025

Mecp2 deficiency induces dysphagia in a preclinical model of Rett Syndrome

Rett Syndrome is a rare, x-linked genetic neurological disorder caused by MECP2 gene mutations. This progressive neurodevelopmental disorder hinders patients ability to breathe and eat normally. It is unclear how Mecp2-deficiency results in a high percentage of dysphagia and aspiration pneumonia in patients with Rett syndrome. We aim to determine the effects of Mecp2-deficiency on swallow related neuromuscular mechanisms contributing to dysphagia in Rett syndrome. Swallow and breathing were detected using electrophysiology in the submental and laryngeal muscle complexes and the hypoglossal and vagus nerves. Several medullary motoneuron populations involved in swallowing were examined by immunohistochemistry in pre and post symptomatic Mecp2-deficient male and female mice. Swallow-related submental complex duration and amplitude were significantly decreased in both Mecp2-/y and Mecp2+/-compared to wild-type, due to decreased motor unit activation. In both Mecp2-deficient mice, cholinergic staining in hypoglossal, facial, and trigeminal nuclei were decreased. We noted a significant increase in the transition time from inspiration to swallow, swallow to the subsequent inspiration, and impaired respiratory rhythm regeneration in Mecp2-/y, but not Mecp2+/- mice. Mecp2-deficiency resulted in impaired brainstem cholinergic signaling, which contribute to weakened submental muscle complex activity, and impaired swallow related laryngeal vestibular closure. These results suggest Mecp2-deficient mice are a viable pre-clinical model to further study dysphagia in Rett syndrome.

neuroscience↗

bioRxiv2025

Differential cell signaling testing for cell-cell communication inference from single-cell data by dominoSignal

Algorithms for ligand-receptor network inference have emerged as commonly used tools to estimate cell-cell communication from reference single-cell data. Many studies employ these algorithms to compare signaling between conditions and lack methods to statistically identify signals that are significantly different. We previously developed the cell communication inference algorithm Domino, which considers ligand and receptor gene expression in association with downstream transcription factor activity scoring. We developed the dominoSignal software to innovate upon Domino and extend its functionality to test statistically differential cellular signaling. This new functionality includes compilation of active signals as linkages from multiple subjects in a single-cell data set and testing condition-dependent signaling linkage. The software is applicable for analysis of single-cell data sets with multiple subjects as biological replicates as well as with bootstrapped replicates from data sets with few or pooled subjects. We use simulation studies to benchmark the number of subjects in compared groups and cells within an annotated cell type sufficient to accurately identify differential linkages. We demonstrate the application of the Differential Cell Signaling Test (DCST) in the dominoSignal software to investigate consequences of cancer cell phenotypes and immunotherapy on cell-cell communication in tumor microenvironments. These applications in cancer studies demonstrate the ability of differential cell signaling analysis to infer changes to cell communication networks from therapeutic or experimental perturbations, which is broadly applicable across biological systems.

bioinformatics↗

bioRxiv2021

Laryngeal and swallow dysregulation following acute cervical spinal cord injury

Proper function of the larynx is vital to airway protection, including swallow. While the swallow reflex is controlled by the brainstem, patients with cervical spinal cord injuries (cSCI) are likely at increased risk of disordered swallow (dysphagia) and pneumonia, and the underlying mechanisms are unknown. We aimed to determine if acute spinal cord injury would disrupt swallow function in animal models. We hypothesized that 1) loss of descending efferent information to the diaphragm would affect swallow and breathing differently, and that 2) loss of ascending spinal afferent information would alter central swallow regulation to change motor drive to the upper airway. We recorded amplitudes of laryngeal and inspiratory muscle electromyograms (EMGs), submental and pharyngeal muscle EMGs, and cardiorespiratory measures in freely breathing pentobarbital-anesthetized cats and rats. First, we assessed the effect of a lateral hemisection at the second cervical level (C2) in cats during breathing. Posterior cricoarytenoid (laryngeal abductor) EMG activity during inspiration increased nearly two-fold, indicating that inspiratory laryngeal drive increased following cSCI. Ipsilateral to the injury, the crural diaphragm EMG was significantly reduced during breathing (62 {+/-} 25 percent change post-injury), but no animal had a complete termination of all activity; 75% of animals had an increase in contralateral diaphragm recruitment after cSCI, but this did not reach significance. Next, we assessed the effect of C2 lateral hemisection in cats during swallow. The thyroarytenoid (laryngeal adductor) and thyropharyngeus (pharyngeal constrictor) both increased EMG activity during swallow, indicating increased upper airway drive during swallow following cSCI. There was no change in the number of swallows stimulated per trial. We also found that diaphragm activity during swallow (schluckatmung) was bilaterally suppressed after lateral C2 hemisection, which was unexpected because this injury did not suppress contralateral diaphragm activity during breathing. Swallow-breathing coordination was also affected by cSCI, with more post-injury swallows occurring during early expiration. Finally, because we wanted to determine if the chest wall is a major source of feedback for laryngeal regulation, we performed T1 total transections in rats. As in the cat C2 lateral hemisection, a similar increase in inspiratory laryngeal activity (posterior cricoarytenoid) was the first feature noted after rat T1 complete spinal cord transection. In contrast to the cat C2 lateral hemisection, diaphragmatic respiratory drive increased after T1 transection in every rat (215 {+/-} 63 percent change), and this effect was significant. Overall, we found that spinal cord injury alters laryngeal drive during swallow and breathing, and alters swallow-related diaphragm activity. Our results show behavior-specific effects, suggesting that swallow may be more affected than breathing is by cSCI, and emphasizing the need for additional studies on laryngeal function during breathing and swallow after spinal cord injury.

neuroscience↗