Control over ionic composition and volume of the inner ear luminal fluid endolymph is essential for normal hearing and balance. Mice deficient in either the EphB2 receptor tyrosine kinase or the cognate transmembrane ligand ephrin-B2 (Efnb2) exhibit background strain-specific vestibular behavioral dysfunction and signs of abnormal endolymph homeostasis. Using various loss-of-function mouse models, we found that Efnb2 is required for growth and morphogenesis of the embryonic endolymphatic epithelium, a precursor of the endolymphatic sac (ES) and duct (ED), which mediate endolymph homeostasis. Conditional inactivation of Efnb2 in early-stage embryonic ear tissues disrupted cell proliferation, cell survival, and epithelial folding at the origin of the endolymphatic epithelium. This correlated with apparent absence of an ED, mis-localization of ES ion transport cells relative to inner ear sensory organs, dysplasia of the endolymph fluid space, and abnormally formed otoconia (extracellular calcite protein composites) at later stages of embryonic development. A comparison of Efnb2 and Notch signaling deficient mutant phenotypes indicated that these two signaling systems have distinct and non overlapping roles in ES/ED development. Homozygous deletion of the Efnb2 C terminus caused abnormalities similar to those found in the conditional Efnb2 null homozygote. Analyses of fetal Efnb2 C-terminus deletion heterozygotes found mis-localized ES ion transport cells only in the genetic background exhibiting vestibular dysfunction. We propose that developmental dysplasias described here are a gene dose sensitive cause of the vestibular dysfunction observed in EphB-Efnb2 signaling-deficient mice.

Background Steroid-dependent asthma (SDA) is characterized by oral corticosteroid (OCS) resistance and dependence. Wumeiwan (WMW) showed potentials in reducing the dose of OCS of SDA patients based on our previous studies. Methods Network pharmacology was conducted to explore the molecular mechanism of WMW against SDA with the databases of TCMSP, STRING, etcetera. GO annotation and KEGG functional enrichment analysis were conducted by metascape database. Pymol performed the molecular docking. In the experiment, the OVA-induced plus descending dexamethasone intervention chronic asthmatic rat model was conducted. Lung pathological changes were analyzed by H&E, Masson, and IHC staining. Relative expressions of the gene were performed by real-time PCR. Results A total of 102 bioactive ingredients in WMW were identified, as well as 191 common targets were found from 241 predicted targets in WMW and 3539 SDA-related targets. The top five bioactive ingredients were identified as pivotal ingredients, which included quercetin, candletoxin A, palmidin A, kaempferol, and beta-sitosterol. Besides, 35 HUB genes were obtained from the PPI network, namely, TP53, AKT1, MAPK1, JUN, HSP90AA1, TNF, RELA, IL6, CXCL8, EGFR , etcetera. GO biological process analysis indicated that HUB genes were related to bacteria, transferase, cell differentiation, and steroid. KEGG pathway enrichment analysis indicated that the potential mechanism might be associated with IL-17 and MAPK signaling pathways. Molecular docking results supported these findings. H&E and Masson staining proved that WMW could reduce airway inflammation and remodeling of model rats, which might be related to the downward expression of IL-8 proved by IHC staining and real-time PCR. Conclusion WMW could be a complementary and alternative therapy for SDA by reducing airway inflammation.

Subjects: 129/CD1 mice with the ephrin-B2 gene disrupted by the ␤-galactosidase (lacZ) gene were humanely killed at embryonic day 18 (E18) and evaluated for the presence and characterization of a laryngeal cleft. Homozygous and heterozygous lacZ knockout mice as well as wild-type littermates were evaluated. Main Outcome Measures: Microsurgical dissection of the oral cavity and pharynx allowed for a pseudoen-doscopic view of the larynx to determine the presence or absence of a cleft. The specimens were also histologically sectioned and examined for characterization and classification of the cleft. Results: A laryngeal cleft was identified in 12 of 27 ephrin-B2 homozygous lacZ knockout mice (44%). Laryngeal clefts were not identified in heterozygous ephrin-B2 knockout mice or in wild-type littermates. Conclusions: Disruption of ephrin-B2 reverse signaling results in laryngeal clefts in lacZ knockout mice. This presents a novel mouse model in which future investigations into etiology of laryngeal clefts may be examined.

This study investigates the use of shape memory polymers (SMPs) as a substrate for a self-coiling cochlear implant electrode array and investigates the self-coiling ability of a sham probe micromachined atop such a substrate. Through the use of a self-coiling cochlear implant, the capability to avoid contact with the tissue of the cochlear duct is investigated via the insertion of a dummy device into a model cochlea heated to an ambient 34 °C. Finally, a prototype straightening and insertion tool is developed for automated retraction and locking of the coiled shape into a bar geometry. Preliminary demonstration of the deployment of self-coiling cochlear implants is shown and paves the way for future studies focused on using histological analysis of the cochlear wall tissue to compare the degree of trauma resulting from linear cochlear implant arrays versus the self-coiling, non-contact probes demonstrated herein.

Background Tuo-Min-Ding-Chuan Decoction (TMDCD) is an effective traditional Chinese medicine (TCM) formula granule for allergic asthma (AA). Previous studies proved its effects on controlling airway inflammations, while the specific mechanism was not clear. Methods We conducted a network pharmacology study to explore the molecular mechanism of TMDCD against AA with the public databases of TCMSP. Then, HUB genes were screened with the STRING database. DAVID database performed GO annotation and KEGG functional enrichment analysis of HUB genes, and it was verified with molecular docking by Autodock. Then, we built a classic ovalbumin-induced allergic asthma mice model to explore the mechanism of anti-inflammation effects of TMDCD. Results In the network pharmacology study, we found out that the potential mechanism of TMDCD against AA might be related to NOD-like receptor (NLR) signaling pathway and Toll-like receptor (TLR) signaling pathway. In the experiment, TMDCD showed remarkable effects on alleviating airway inflammations, airway hyperresponsiveness (AHR), and airway remodeling in the asthmatic mice model. Further molecular biology and immunohistochemistry experiments suggested TMDCD could repress TLR4-NLRP3 pathway-mediated pyroptosis-related gene transcriptions to inhibit expressions of target proteins. Conclusion TMDCD could alleviate asthmatic mice model airway inflammations by regulating TLR4-NLRP3 pathway-mediated pyroptosis.