The long-term efficacy and safety of balloon dilation eustachian tuboplasty combined with tympanostomy tube insertion for patients with otitis media with effusion: study protocol for a prospective randomized controlled trial.

BACKGROUND: Otitis media with effusion (OME) is a common disease in ear, nose, and throat clinics characterized by aural fullness and hearing loss and mainly caused by eustachian tube dysfunction (ETD). Tympanostomy tube insertion (TTI) is a conventional surgical treatment option that can alleviate symptoms but does not provide a definitive cure, and it is prone to recurrence. Balloon dilation eustachian tuboplasty (BDET) has become a novel procedure for the treatment of ETD, demonstrating significant potential in addressing the aforementioned limitations. However, it is not widely available in the clinic and few high-quality randomized clinical trials was conducted to investigate its long-term efficacy and security in OME. Therefore, the purpose of this study is to verify the efficacy of BDET combined with TTI for patients with OME and its prospects for providing a definitive cure. METHODS AND ANALYSIS: This is a prospective, parallel-group, single-blind, randomized controlled prospective trial. Totally 124 patients with OME will be randomized into either group A or B. Group A will receive conventional therapy (TTI) while group B will use BDET therapy in addition to TTI. Outcome assessments will take place at baseline and at the 3rd, 6th, 12th, and 24th months after surgery. The primary outcome is eustachian tube function, which will be measured by the eustachian tube dysfunction questionnaire (ETDQ-7) and eustachian tube score (ETS). The secondary outcomes include middle ear function, hearing situation, and quality of life, which will be measured by acoustic impedance measurement, pure-tone audiometry, and Chinese-version Chronic Ear Survey (CCES). The main analysis of change in the outcomes will use mixed-model with repeated measures (MMRM) analyses of variance (ANOVAs). DISCUSSION: This is the first prospective trial in Chinese populations that aims to validate the long-term efficacy and safety of BDET-combined TTI therapy in patients with OME. This parallel-group, single-blind, randomized controlled trial may provide an opportunity to decrease the recurrence rate of OME and explore a definitive cure for patients with OME. This trial's rigorous design enhances the reliability of the findings, ensuring a robust answer to the research question. In the future, the research team will further expand upon the clinical evidence and applications of the BDET combined therapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2400079632. Registered on 8 January 2024, https://www.chictr.org.cn/bin/project/edit?pid=214452 .

Integration of Functional Human Auditory Neural Circuits Based on a 3D Carbon Nanotube System.

The physiological interactions between the peripheral and central auditory systems are crucial for auditory information transmission and perception, while reliable models for auditory neural circuits are currently lacking. To address this issue, mouse and human neural pathways are generated by utilizing a carbon nanotube nanofiber system. The super-aligned pattern of the scaffold renders the axons of the bipolar and multipolar neurons extending in a parallel direction. In addition, the electrical conductivity of the scaffold maintains the electrophysiological activity of the primary mouse auditory neurons. The mouse and human primary neurons from peripheral and central auditory units in the system are then co-cultured and showed that the two kinds of neurons form synaptic connections. Moreover, neural progenitor cells of the cochlea and auditory cortex are derived from human embryos to generate region-specific organoids and these organoids are assembled in the nanofiber-combined 3D system. Using optogenetic stimulation, calcium imaging, and electrophysiological recording, it is revealed that functional synaptic connections are formed between peripheral neurons and central neurons, as evidenced by calcium spiking and postsynaptic currents. The auditory circuit model will enable the study of the auditory neural pathway and advance the search for treatment strategies for disorders of neuronal connectivity in sensorineural hearing loss.

Varying mechanical forces drive sensory epithelium formation.

The mechanical cues of the external microenvironment have been recognized as essential clues driving cell behavior. Although intracellular signals modulating cell fate during sensory epithelium development is well understood, the driving force of sensory epithelium formation remains elusive. Here, we manufactured a hybrid hydrogel with tunable mechanical properties for the cochlear organoids culture and revealed that the extracellular matrix (ECM) drives sensory epithelium formation through shifting stiffness in a stage-dependent pattern. As the driving force, moderate ECM stiffness activated the expansion of cochlear progenitor cell (CPC)-derived epithelial organoids by modulating the integrin α3 (ITGA3)/F-actin cytoskeleton/YAP signaling. Higher stiffness induced the transition of CPCs into sensory hair cells (HCs) through increasing the intracellular Ca2+ signaling mediated by PIEZO2 and then activating KLF2 to accomplish the cell specification . Our results identify the molecular mechanism of sensory epithelium formation guided by ECM mechanical force and contribute to developing therapeutic approaches for HC regeneration.

Diagnosing the benign paroxysmal positional vertigo via 1D and deep-learning composite model.

BACKGROUND: Benign Paroxysmal Positional Vertigo (BPPV) is the leading cause of vertigo, and its characteristic nystagmus induced by positional maneuvers makes it a good model for Artificial Intelligence (AI) diagnosis. However, during the testing procedure, up to 10 min of indivisible long-range temporal correlation data are produced, making the AI-informed real-time diagnosing unlikely in clinical practice. METHODS: A combined 1D and Deep-Learning (DL) composite model was proposed. Two separate cohorts were recruited, with one for model generation and the other for evaluation of model's real-world generalizability. Eight features, including two head traces and three eye traces and their corresponding slow phase velocity (SPV) value, were served as the inputs. Three candidate models were tested, and a sensitivity study was conducted to determine the saliently important features. RESULTS: The study included 2671 patients in the training cohort and 703 in the test cohort. A hybrid DL model achieved a micro-area under the receiver operating curve (AUROC) of 0.982 (95% CI 0.965, 0.994) and macro-AUROC of 0.965 (95% CI 0.898, 0.999) for overall classification. The highest accuracy was observed for right posterior BPPV, with an AUROC of 0.991 (95% CI 0.972, 1.000), followed by left posterior BPPV, with an AUROC of 0.979 (95% CI 0.940, 0.998), the lowest AUROC was 0.928 (95% CI 0.878, 0.966) for lateral BPPV. The SPV was consistently identified as the most predictive feature in the models. If the model process is carried out 100 times for a 10-min data, one single running takes 0.79 ± 0.06 s. CONCLUSION: This study designed DL models which can accurately detect and categorize the subtype of BPPV, enabling a quick and straightforward diagnosis of BPPV in clinical setting. The critical feature identified in the model helps expand our understanding of this disorder.

A highly accumulated secretory protein from cotton bollworm interacts with basic helix-loop-helix transcription factors to dampen plant defense.

Caterpillar oral secretion (OS) contains active molecules that modulate plant defense signaling. We isolated an effector-like protein (Highly Accumulated Secretory Protein 1, HAS1) from cotton bollworm (Helicoverpa armigera) that is the most highly accumulated secretory protein of the nondigestive components in OS and belongs to venom R-like protein. Elimination of HAS1 by plant-mediated RNA interference reduced the suppression of OS on the defense response in plants. Plants expressing HAS1 are more susceptible to insect herbivory accompanied by the reduced expressions of multiple defense genes. HAS1 binds to the basic helix-loop-helix (bHLH) transcription factors, including GoPGF involved in pigmented gland formation and defense compounds biosynthesis in cotton and MYC3/MYC4 the main regulators in jasmonate (JA) signaling in Arabidopsis. The binding activity is required for HAS1 to inhibit the activation of bHLHs on plant defense gene expressions. Together with our previous study that another venom R-like protein HARP1 in cotton bollworm OS blocks JA signaling by interacting with JASMONATE-ZIM-domain repressors, we conclude that the venom R-like proteins in OS interfere with plant defense in a dual suppression manner. Considering the venom proteins in parasitic wasp assault the immune system of its host animal, our investigation reveals their conserved function in carnivorous and herbivorous insects.

Evaluation of acoustic changes in and the healing outcomes of rat eardrums with pars tensa and pars flaccida perforations.

Objectives: To systematically explore the differences in acoustic changes and healing outcomes of tympanic membranes (TMs) with pars flaccida perforation (PFP) and pars tensa perforation (PTP). Methods: We created PFPs and PTPs of various sizes in Sprague-Dawley rats, and evaluated TM umbo velocity and hearing function using laser Doppler vibrometry and auditory brainstem response (ABR) measurement before and immediately after perforation. Two weeks later, hearing was reevaluated and TMs were investigated by immunohistochemical staining. Results: Small PFPs and PTPs did not significantly affect umbo velocity and hearing function. Large PFPs increased umbo velocity loss at low frequency (1.5 kHz) and elevated ABR thresholds within 1-2 kHz. Large PTP caused significant velocity loss at low frequencies from 1.5 to 3.5 kHz and threshold elevations at full frequencies (1-2 kHz). Two weeks after the perforation, the hearing function of rats with healed PFPs recovered completely. However, high-frequency hearing loss (16-32 kHz) persisted in rats with healed PTPs. Morphological staining revealed that no increase in the thickness and obvious increase in collagen I level of regenerated par flaccida; regenerated pars tensa exhibited obvious increase in thickness and increased collagen I, while the collagen II regeneration was limited with discontinuous and disordered structure in regenerated pars tensa. Conclusion: The hearing loss caused by large PFP limits at low frequencies while large PTP can lead to hearing loss at wide range frequencies. PFP and PTP have different functional outcomes after spontaneous healing, which is determined by the discrepant structure reconstruction and collagen regeneration.

Generation of an integration-free induced pluripotent stem cell line (JTUi004-A) from an otosclerosis patient.

Otosclerosis is caused by abnormal bone remodeling in the middle ear, resulting in progressive hearing loss, dizziness, balance problems, and tinnitus. Previous infection, stress fractures of the bony tissue surrounding the inner ear, immune disorders, and genetic factors are believed to contribute to this disease. Currently, no effective drug treatment for otosclerosis is known. Herein, we generated an induced pluripotent stem cell line from the peripheral blood mononuclear cells of an otosclerosis patient. The cell line exhibited normal morphology, karyotype, and pluripotency marker expression. A teratoma assay revealed successful differentiation into all three germ layers.

Establishment of an induced pluripotent stem cell line (JTUi003-A) from a patient with otosclerosis.

Otosclerosis is characterized by abnormal bone remodeling in the osseous labyrinth and progressive hearing loss. Although the etiology of otosclerosis is not fully understood, both environmental and genetic factors play important roles in its pathogenesis. Here, we generated an induced pluripotent stem cell line using episomal plasmid vectors from the peripheral blood mononuclear cells of a 48-year-old male with otosclerosis. The morphology and karyotype of the cells were normal. The expression of pluripotency markers was verified by mRNA and protein levels; the pluripotency state of the cell line was verified by successful differentiation into all three germ layers.

Volume quantification of endolymphatic hydrops in patients with vestibular schwannoma.

OBJECTIVE: The origin of vestibular symptoms in patients with vestibular schwannoma (VS) is uncertain. We used intratympanic gadolinium-enhanced magnetic resonance imaging (MRI) to confirm the labyrinthine lesions in patients with VS and to explore the features of endolymphatic hydrops (EH) in these patients. METHODS: In total, 66 patients diagnosed with unilateral VS were enrolled in this study and underwent intratympanic gadolinium-enhanced MRI. The borders of the vestibule and endolymph were mapped on the axial MRI images, and the area and volume of vestibule and endolymph were automatically calculated using Osirix software, and the area and volume percentage of vestibular endolymph were obtained. RESULTS: The area and volume percentages of vestibular endolymph on the affected side were significantly larger than those on the healthy side (both p < 0.001). Using Kendall's W test, we found that the area and volume percentages of vestibular endolymph on the affected side were consistent (p < 0.001), but the consistency was moderate (k = 0.574). The healthy side was also consistent (p < 0.001), and the degree of consistency was moderate (k = 0.444). We used 19.1% as the cut-off point to distinguish the presence or absence of vestibular EH; that is, the volume percentage of vestibular endolymph that was more than 19.1% were defined as the subgroup with hydrops, while the subgroup without hydrops included patients with a baseline level below 19.1%. No volume classification for vestibular EH was proposed. Based on this standard, 11/66 (16.7%) of the patients with VS in this study had vestibular EH. CONCLUSIONS: The volume percentage of the vestibular endolymph was more accurate than the area percentage for assessing vestibular EH. Using 19.1% as the cut-off point to distinguish the presence or absence of vestibular EH, we found that 16.7% of patients with VS had varying degrees of vestibular EH. We believe that the vestibular symptoms in patients with VS may originate from the peripheral lesions.

An effector from cotton bollworm oral secretion impairs host plant defense signaling.

Insects have evolved effectors to conquer plant defense. Most known insect effectors are isolated from sucking insects, and examples from chewing insects are limited. Moreover, the targets of insect effectors in host plants remain unknown. Here, we address a chewing insect effector and its working mechanism. Cotton bollworm (Helicoverpa armigera) is a lepidopteran insect widely existing in nature and severely affecting crop productivity. We isolated an effector named HARP1 from H. armigera oral secretion (OS). HARP1 was released from larvae to plant leaves during feeding and entered into the plant cells through wounding sites. Expression of HARP1 in Arabidopsis mitigated the global expression of wounding and jasmonate (JA) responsive genes and rendered the plants more susceptible to insect feeding. HARP1 directly interacted with JASMONATE-ZIM-domain (JAZ) repressors to prevent the COI1-mediated JAZ degradation, thus blocking JA signaling transduction. HARP1-like proteins have conserved function as effectors in noctuidae, and these types of effectors might contribute to insect adaptation to host plants during coevolution.

Adjusting the rheological properties of corn-straw slurry to reduce the agitation power consumption in anaerobic digestion.

Agitation power consumption (P) in the anaerobic digestion of biogas plants is a major consumer of electric energy. To reduce P by adjusting the rheological properties, in this work, the rheological properties of the corn-straw slurry were studied systematically considering the effects of TS, temperature and particle-size, and P was calculated based on the rheological behavior of the corn-straw slurry. The investigation shows that the corn-straw slurry is a non-Newtonian fluid and exhibit shear-thinning behavior, and the rheological properties can be well described with the power law model. The size-reduction is more effective compared to the option of temperature-increase to improve the agitation power efficiency, and the value of P can be reduced by up to 48.11%. Since the size-reduction can also increase the methane yield, the reduction of the particle-size is a promising option to save P, especially at relatively high TSs and for the thermophilic AD process.

Arabidopsis Transcription Factors SPL1 and SPL12 Confer Plant Thermotolerance at Reproductive Stage.

Plant reproductive organs are vulnerable to heat, but regulation of heat-shock responses in inflorescence is largely uncharacterized. Here, we report that two of the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) transcriptional factors in Arabidopsis, SPL1 and SPL12, act redundantly in thermotolerance at the reproductive stage. The spl1-1 spl12-1 inflorescences displayed hypersensitivity to heat stress, whereas overexpression of SPL1 or SPL12 enhanced the thermotolerance in both Arabidopsis and tobacco. RNA sequencing revealed 1939 upregulated and 1479 downregulated genes in wild-type inflorescence upon heat stress, among which one-quarter (1,040) was misregulated in spl1-1 spl12-1, indicating that SPL1 and SPL12 contribute greatly to the heat-triggered transcriptional reprogramming in inflorescence. Notably, heat stress induced a large number of abscisic acid (ABA) responsive genes, of which ∼39% were disturbed in heat induction in spl1-1 spl12-1 inflorescence. Preapplication of ABA and overexpression of SPL1 restored the inflorescence thermotolerance in spl1-1 spl12-1 and in the ABA biosynthesis mutant aba2-1, but not in the pyl sextuple mutant defective in ABA receptors PYR1/PYL1/PYL2/PYL4/PYL5/PYL8. Thus, inflorescence thermotolerance conferred by SPL1 and SPL2 involves PYL-mediated ABA signaling. The molecular network consisting of SPL1 and SPL12 illustrated here shed new light on the mechanisms of plant thermotolerance at the reproductive stage.

Jasmonate response decay and defense metabolite accumulation contributes to age-regulated dynamics of plant insect resistance.

Immunity deteriorates with age in animals but comparatively little is known about the temporal regulation of plant resistance to herbivores. The phytohormone jasmonate (JA) is a key regulator of plant insect defense. Here, we show that the JA response decays progressively in Arabidopsis. We show that this decay is regulated by the miR156-targeted SQUAMOSA PROMOTER BINDING PROTEIN-LIKE9 (SPL9) group of proteins, which can interact with JA ZIM-domain (JAZ) proteins, including JAZ3. As SPL9 levels gradually increase, JAZ3 accumulates and the JA response is attenuated. We provide evidence that this pathway contributes to insect resistance in young plants. Interestingly however, despite the decay in JA response, older plants are still comparatively more resistant to both the lepidopteran generalist Helicoverpa armigera and the specialist Plutella xylostella, along with increased accumulation of glucosinolates. We propose a model whereby constitutive accumulation of defense compounds plays a role in compensating for age-related JA-response attenuation during plant maturation.