Vascular network-inspired fluidic system (VasFluidics) with spatially functionalizable membranous walls.

In vascular networks, the transport across different vessel walls regulates chemical compositions in blood over space and time. Replicating such trans-wall transport with spatial heterogeneity can empower synthetic fluidic systems to program fluid compositions spatiotemporally. However, it remains challenging as existing synthetic channel walls are typically impermeable or composed of homogeneous materials without functional heterogeneity. This work presents a vascular network-inspired fluidic system (VasFluidics), which is functionalizable for spatially different trans-wall transport. Facilitated by embedded three-dimensional (3D) printing, elastic, ultrathin, and semipermeable walls self-assemble electrostatically. Physicochemical reactions between fluids and walls are localized to vary the trans-wall molecules among separate regions, for instance, by confining solutions or locally immobilizing enzymes on the outside of channels. Therefore, fluid compositions can be regulated spatiotemporally, for example, to mimic blood changes during glucose absorption and metabolism. Our VasFluidics expands opportunities to replicate biofluid processing in nature, providing an alternative to traditional fluidics.

Stem Cell-Based Hair Cell Regeneration and Therapy in the Inner Ear.

Hearing loss has become increasingly prevalent and causes considerable disability, thus gravely burdening the global economy. Irreversible loss of hair cells is a main cause of sensorineural hearing loss, and currently, the only relatively effective clinical treatments are limited to digital hearing equipment like cochlear implants and hearing aids, but these are of limited benefit in patients. It is therefore urgent to understand the mechanisms of damage repair in order to develop new neuroprotective strategies. At present, how to promote the regeneration of functional hair cells is a key scientific question in the field of hearing research. Multiple signaling pathways and transcriptional factors trigger the activation of hair cell progenitors and ensure the maturation of newborn hair cells, and in this article, we first review the principal mechanisms underlying hair cell reproduction. We then further discuss therapeutic strategies involving the co-regulation of multiple signaling pathways in order to induce effective functional hair cell regeneration after degeneration, and we summarize current achievements in hair cell regeneration. Lastly, we discuss potential future approaches, such as small molecule drugs and gene therapy, which might be applied for regenerating functional hair cells in the clinic.

Harnessing astaxanthin-loaded diselenium cross-linked apotransferrin nanoparticles for the treatment of secretory otitis media.

Secretory otitis media (SOM) is a clinical condition characterized by the accumulation of fluids and oxidative stress in the middle ear, leading to hearing impairment and infection complications. One potential solution for mitigating oxidative stress associated with SOM is the use of antioxidants such as astaxanthin. However, its effectiveness is limited due to its poor bioavailability and rapid oxidation. Herein, we developed a novel diselenium-crosslinked apotransferrin enriched with astaxanthin (AST@dSe-AFT) nanoparticles to augment the transport of astaxanthin across biological membranes, resulting in increased bioavailability and reduced oxidative stress in SOM. Our research demonstrated that AST@dSe-AFT efficiently accumulated in the middle ear, allowing for controlled delivery of astaxanthin in response to reactive oxygen species and reducing oxidative stress. Additionally, AST@dSe-AFT stimulated macrophages to polarize towards M2 phenotype and neutrophils to polarize towards N2 phenotype, thereby facilitating an anti-inflammatory response and tissue restoration. Importantly, AST@dSe-AFT exhibited no toxicity or adverse effects, suggesting its potential for safety and future clinical translation. Our findings suggested that AST@dSe-AFT represents a promising approach for the treatment of secretory otitis media and other oxidative stress-related disorders.

Stem cells as potential therapeutics for hearing loss.

Hearing impairment is a global health problem. Stem cell therapy has become a cutting-edge approach to tissue regeneration. In this review, the recent advances in stem cell therapy for hearing loss have been discussed. Nanomaterials can modulate the stem cell microenvironment to augment the therapeutic effects further. The potential of combining nanomaterials with stem cells for repairing and regenerating damaged inner ear hair cells (HCs) and spiral ganglion neurons (SGNs) has also been discussed. Stem cell-derived exosomes can contribute to the repair and regeneration of damaged tissue, and the research progress on exosome-based hearing loss treatment has been summarized as well. Despite stem cell therapy's technical and practical limitations, the findings reported so far are promising and warrant further investigation for eventual clinical translation.

Heterogeneous Self-Assembly of a Single Type of Nanoparticle Modulated by Skin Formation.

Self-assembly of colloidal nanoparticles has generated tremendous interest due to its widespread applications in structural colorations, sensors, and optoelectronics. Despite numerous strategies being developed to fabricate sophisticated structures, the heterogeneous self-assembly of a single type of nanoparticle in one step remains challenging. Here, facilitated by spatial confinement induced by a skin layer in a drying droplet, we achieve the heterogeneous self-assembly of a single type of nanoparticle by quickly evaporating a colloid-poly (ethylene glycol) (PEG) droplet. During the drying process, a skin layer forms at the droplet surface. The resultant spatial confinement assembles nanoparticles into face-centered-cubic (FCC) lattices with (111) and (100) plane orientations, generating binary bandgaps and two structural colors. The self-assembly of nanoparticles can be regulated by varying the PEG concentration so that FCC lattices with homo- or heterogeneous orientation planes can be prepared on demand. Besides, the approach is applicable for diverse droplet shapes, various substrates, and different nanoparticles. The one-pot general strategy breaks the requirements for multiple types of building blocks and predesigned substrates, extending the fundamental understanding underlying colloidal self-assembly.

Curcumin-loaded graphene oxide quantum dots enhance otoprotective effects via blocking cuproptosis.

Background: Cisplatin (CIS) is widely used to treat various cancers but can cause ototoxicity and sensory hair cell loss in the inner ear. Copper induces an excessive production of reactive oxygen species (ROS) in hair cells, leading to the development of various antioxidants. Methods and results: This study aimed to evaluate the potential antioxidant properties of curcumin (CUR) in the inner ear organ of corti-1 cells (OC1) and animal models (zebrafish and guinea pigs). Graphene oxide quantum dots (GOQDs) enabled CUR to penetrate the round window membrane (RWM) and maintain the concentration in the perilymph after inner ear administration. The results showed that CUR/GOQDs had favorable biocompatibility and strongly affected ROS generation induced by CIS in OC1 cells. DCFHDA Green staining demonstrated that CUR/GOQDs successfully reversed the decrease in mitochondrial membrane potential induced by CIS in vitro and rescued cells from early cuproptosis, which was confirmed by FDX1 staining. Additionally, the experiment found that CUR decreased the expression of cuproptosis proteins (FDX1, LIAS, and LIPT1) and increased the expression of the Bcl-2 protein. Conclusion: The results demonstrate that CUR/GOQDs is a promising therapeutic agent that can prevent CIS-induced ototoxicity by blocking the cuproptosis signal pathway.

Phase-separation facilitated one-step fabrication of multiscale heterogeneous two-aqueous-phase gel.

Engineering heterogeneous hydrogels with distinct phases at various lengths, which resemble biological tissues with high complexity, remains challenging by existing fabricating techniques that require complicated procedures and are often only applicable at bulk scales. Here, inspired by ubiquitous phase separation phenomena in biology, we present a one-step fabrication method based on aqueous phase separation to construct two-aqueous-phase gels that comprise multiple phases with distinct physicochemical properties. The gels fabricated by this approach exhibit enhanced interfacial mechanics compared with their counterparts obtained from conventional layer-by-layer methods. Moreover, two-aqueous-phase gels with programmable structures and tunable physicochemical properties can be conveniently constructed by adjusting the polymer constituents, gelation conditions, and combining different fabrication techniques, such as 3D-printing. The versatility of our approach is demonstrated by mimicking the key features of several biological architectures at different lengths: macroscale muscle-tendon connections; mesoscale cell patterning; microscale molecular compartmentalization. The present work advances the fabrication approach for designing heterogeneous multifunctional materials for various technological and biomedical applications.

[Correlation between video head impulse test parameters and DHI score in patients with vestibular neuritis].

Objective:To explore the correlation between the parameters of video head impulse test （vHIT）and dizziness handicap inventory （DHI） score in patients with vestibular neuritis. Methods:Clinical data of 46 patients with vestibular neuritis were retrospectively analyzed. All the patients underwent DHI evaluation and vHIT examination. They were divided into mild handicap group, moderate handicap group and severe handicap group according to DHI score. The correlations between the parameters of vHIT and DHI score were compared among the three groups. The important parameters of vHIT were compared including vestibulo-ocular reflex （VOR） gain, gain asymmetry ratio （GA）, abnormal saccade dispersion （PR%）. Results:Of the 46 patients, 10 were in the mild handicap group, 21 in the moderate handicap group, and 15 in the severe handicap group. ①In the comparison of the mean value of lateral semicircular canal VOR gain, the vHIT gain of patients with mild, moderate and severe handicap were 0.64±0.06, 0.53±0.11 and 0.37±0.10, respectively, the mean value of VOR gain was negatively correlated with DHI score among the three groups（r=-0.545, P<0.001）, and the pairwise comparisons among the three groups was statistically significant（P<0.05）. In comparison of the mean values of lateral semicircular canal GA, the GA values of mild, moderate and severe handicap groups were 46.40±21.81, 47.59±15.17 and 56.57±17.39, respectively, there was no significant linear correlation between GA values and DHI scores among the three groups（r=0.246, P>0.05）, there was no significant difference between the three groups（P>0.05）. In comparison of the mean PR% of the lateral semicircular canal, the mean PR% of patients with mild, moderate and severe handicap group were 32.00±10.62, 53.82±17.09 and 76.00±10.01, respectively, PR% was positively correlated with DHI score（r=0.726, P<0.001）, and the comparison among the three groups was statistically significant（P<0.05）. ②The vertical semicircular canal vHIT gain of patients with mild, moderate and severe handicap was 0.63±0.06, 0.52±0.15 and 0.38±0.16, respectively, the mean of VOR gain was negatively correlated with DHI score among the three groups（r=-0.487, P<0.01）, the comparison of mild-severe and moderate-severe group was statistically significant（P<0.05）, while there was no significant difference between the mild and moderate group（P>0.05）. In the comparison of the mean values of vertical semicircular canal GA, the GA values of mild, moderate and severe handicap groups were 40.40±15.31, 46.10±19.59 and 47.87±18.05, respectively, there was no significant linear correlation between GA values and DHI scores among the three groups（r=0.047, P>0.05）, there was no significant difference in GA among the three groups（P>0.05）. The PR% of patients with mild, moderate and severe handicap were 42.40±15.39, 54.14±17.60 and 64.93±10.95, respectively, there was a positive significant correlation between PR% and DHI score（r=0.454, P<0.05）, there was statistically significant in the comparison of mild-severe group（P<0.05）, while there was no statistical significance between the other groups（P>0.05）. Conclusion:The VOR gain and PR% value of vHIT in patients with vestibular neuritis are closely related to the DHI score, which can evaluate the vestibular function and the degree of vertigo.

G protein-coupled receptors in cochlea: Potential therapeutic targets for hearing loss.

The prevalence of hearing loss-related diseases caused by different factors is increasing worldwide year by year. Currently, however, the patient's hearing loss has not been effectively improved. Therefore, there is an urgent need to adopt new treatment measures and treatment techniques to help improve the therapeutic effect of hearing loss. G protein-coupled receptors (GPCRs), as crucial cell surface receptors, can widely participate in different physiological and pathological processes, particularly play an essential role in many disease occurrences and be served as promising therapeutic targets. However, no specific drugs on the market have been found to target the GPCRs of the cochlea. Interestingly, many recent studies have demonstrated that GPCRs can participate in various pathogenic process related to hearing loss in the cochlea including heredity, noise, ototoxic drugs, cochlear structure, and so on. In this review, we comprehensively summarize the functions of 53 GPCRs known in the cochlea and their relationships with hearing loss, and highlight the recent advances of new techniques used in cochlear study including cryo-EM, AI, GPCR drug screening, gene therapy vectors, and CRISPR editing technology, as well as discuss in depth the future direction of novel GPCR-based drug development and gene therapy for cochlear hearing loss. Collectively, this review is to facilitate basic and (pre-) clinical research in this area, and provide beneficial help for emerging GPCR-based cochlear therapies.

Pitavastatin protects against neomycin-induced ototoxicity through inhibition of endoplasmic reticulum stress.

Irreversible injury to inner ear hair cells induced by aminoglycoside antibiotics contributes to the formation of sensorineural hearing loss. Pitavastatin (PTV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been reported to exert neuroprotective effects. However, its role in aminoglycoside-induced hearing loss remains unknown. The objectives of this study were to investigate the beneficial effects, as well as the mechanism of action of PTV against neomycin-induced ototoxicity. We found that PTV remarkably reduced hair cell loss in mouse cochlear explants and promoted auditory HEI-OC1 cells survival after neomycin stimulation. We also observed that the auditory brainstem response threshold that was increased by neomycin was significantly reduced by pretreatment with PTV in mice. Furthermore, neomycin-induced endoplasmic reticulum stress in hair cells was attenuated by PTV treatment through inhibition of PERK/eIF2α/ATF4 signaling. Additionally, we found that PTV suppressed the RhoA/ROCK/JNK signal pathway, which was activated by neomycin stimulation in HEI-OC1 cells. Collectively, our results showed that PTV might serve as a promising therapeutic agent against aminoglycoside-induced ototoxicity.

Aquabots.

Soft robots, made from elastomers, easily bend and flex, but deformability constraints severely limit navigation through and within narrow, confined spaces. Using aqueous two-phase systems we print water-in-water constructs that, by aqueous phase-separation-induced self-assembly, produce ultrasoft liquid robots, termed aquabots, comprised of hierarchical structures that span in length scale from the nanoscopic to microsciopic, that are beyond the resolution limits of printing and overcome the deformability barrier. The exterior of the compartmentalized membranes is easily functionalized, for example, by binding enzymes, catalytic nanoparticles, and magnetic nanoparticles that impart sensitive magnetic responsiveness. These ultrasoft aquabots can adapt their shape for gripping and transporting objects and can be used for targeted photocatalysis, delivery, and release in confined and tortuous spaces. These biocompatible, multicompartmental, and multifunctional aquabots can be readily applied to medical micromanipulation, targeted cargo delivery, tissue engineering, and biomimetics.

Oriented Growth of Neural Stem Cell-Derived Neurons Regulated by Magnetic Nanochains.

Neural stem cell therapy has become a promising cure in the treatment of neurodegenerative disorders. Owing to the anisotropy of the nervous system, the newly derived neurons need not only the functional integrity but also the oriented growth to contact with the partner cells to establish functional connections. So the oriented growth of the newly derived neurons is a key factor in neural stem cell-based nerve regeneration. Nowadays, various biomaterials have been applied to assist in the oriented growth of neural stem cell-derived neurons. However, among these biomaterials, the magnetic materials applied in guiding the neuronal growth are still fewer than the other materials, such as the fibers. So in this work, we developed the magnetic nanochains to guide the oriented growth of neural stem cell-derived neurons. With the guidance of the magnetic nanochains, the seeded neural stem cells exhibited a good arrangement, and the neural stem cell-derived neurons showed well-oriented growth with the orientation of the nanochains. We anticipated that the magnetic nanochains would have huge potential in stem cell-based nerve regeneration.

One-Pot Self-Assembly of Dual-Color Domes Using Mono-Sized Silica Nanoparticles.

Spots with dual structural colors on the skin of some organisms in nature are of tremendous interest due to the unique function of their dye-free colors. However, imitation of them requires complicated manufacturing processes, expensive equipment, and multiple predesigned building blocks. In this work, a one-pot strategy based on the phase-separation-assisted nonuniform self-assembly of monosized silica nanoparticles is developed to construct domes with dual structural colors. In drying poly(ethylene glycol)-dextran-based (PEG-DEX) droplets, monosized nanoparticles distribute nonuniformly in two compartments due to the droplet inner flow and different nanoparticle compatibility with the two phases. The dome colors are derived from the self-assembled nanoparticles and are programmable by regulating the assembly conditions. The one-pot strategy enables the preparation of multicolor using only one type of building block. With the dual-color domes, encrypted patterns with a high volume of contents are designed, showing promising applications in information delivery.

Novel heterozygous mutations in the otogelin-like (OTOGL) gene in a child with bilateral mild nonsyndromic sensorineural hearing loss.

Hearing loss is a common disease, of which genetic factors are the main cause. The incidence of mild or moderate postlingual deafness in children is not high, and the impact on life and learning is not as severe as that of prelingual deafness. This leads to insufficient attention to the disorder in the clinic. To date, only a few disease-causing genes have been reported. This report describe a case of novel heterozygous mutations in OTOGL that causes nonsyndromic mild sensorineural hearing loss. Basic information, imaging examinations, audiological examination, and vestibular function tests of the proband were collected. Blood samples of the proband's family were collected and analyzed by whole exome sequencing and Sanger sequencing. A pedigree diagram was drawn and the genetic patterns were analyzed. The proband is a 16-year-old female student with mild sensorineural hearing loss. High-resolution CT of the inner ear and vestibular function tests showed no abnormalities. The age of onset was approximately 4 years old. Except for hearing loss, no lesions were seen in other organs. The parents of the proband were not close relatives and had normal hearing. Two novel heterozygous mutations were found in the OTOGL gene. The c.5038del (p.D1680Ifs*6) variant was inherited from the father, and the c.2770C > T (p.R924X) variant from the mother. They enriched the mutation spectrum of OTOGL, which provides the basis for gene function research and genetic consultation.

A novel MYH9 mutation related to non-syndromic delayed post-lingual sensorineural hearing loss.

OBJECTIVE: Hearing loss (HL) is the most common sensory organ dysfunction disease. The cause is often complex, though genetics are the main factor. METHODS: In this study, we investigated a Chinese family with non-syndromic delayed post-lingual deafness. Comprehensive data collection was performed on this family's members, including basic information, audiological examinations, blood system examinations and imaging examinations. A pedigree diagram was drawn and the genetic patterns were analyzed. RESULTS: A new gene mutation, c.314A>T:p.Y105F in the MYH9 exon, was confirmed by next generation sequencing and Sanger sequencing. This mutation co-segregated with the phenotype in the pedigree. Patients in this family present bilateral symmetry and gradual and delayed high-frequency sensorineural hearing loss. The age of onset was approximately 30 years old. Except for hearing loss, no lesions were seen in other organs, especially the blood system. CONCLUSION: The identification and detection of a novel MYH9 mutation may be of great significance to provide the basis for gene function research and genetic consultation.

Effect of Programmed Death-Ligand 1 in Cancer-Associated Fibroblasts on Advanced Laryngeal Squamous Cell Carcinoma.

This study aimed to explore the effect of programmed death-ligand 1 (PD-L1) in cancer-associated fibroblasts (CAFs) on advanced laryngeal squamous cell carcinoma (LSCC). The expression of PD-L1 in advanced LSCC tumor tissues was observed in 83 patients with LSCC by immunofluorescence microscopy and compared with that in normal laryngeal mucosa. The CAFs of LSCC and normal fibroblasts (NFs) were isolated, cultured, purified, and examined by fluorescence. The expression of PD-L1 in purified CAFs and NFs was measured by flow cytometry. The expression of PD-L1 in CAFs was downregulated through small interferring RNA (siRNA) transfection. The proliferation and migration capacities of CAFs were observed using proliferation and scratch tests, respectively. The proliferation of HEP-2 cells and T cells was measured after cocultured with CAFs. The secretion of interleukins IL-2 and IL-10 was detected using enzyme-linked immuno sorbent assay (ELISA). PD-L1 was expressed in 62 of 83 cases of the advanced LSCC tumor tissues. Also, CAFs expressed more PD-L1 compared with NFs. The proliferation and migration capacities of CAFs were significantly lower after transfection with PD-L1-siRNA. The proliferation rate of HEP-2 cells cocultured with CAFs decreased in PD-L1-siRNA-transfected cells. However, the proliferation rate of T cells increased in transfected cells. The ELISA results showed that the secretion of IL-2 increased and that of IL-10 decreased in PD-L1-siRNA-transfected cells. The expression of PD-L1 in CAFs of advanced LSCC was higher than that in NFs. The downregulation of PD-L1 reduced the proliferation and migration of CAFs and HEP-2 cells but enhanced the proliferation and pro-inflammatory function of T cells in the coculture experiment.

Segregation of competing speech in adults and children with normal hearing and in children with cochlear implants.

Children with normal hearing (CNH) have greater difficulty segregating competing speech than do adults with normal hearing (ANH). Children with cochlear implants (CCI) have greater difficulty segregating competing speech than do CNH. In the present study, speech reception thresholds (SRTs) in competing speech were measured in Chinese Mandarin-speaking ANH, CNH, and CCIs. Target sentences were produced by a male Mandarin-speaking talker. Maskers were time-forward or -reversed sentences produced by a native Mandarin-speaking male (different from the target) or female or a non-native English-speaking male. The SRTs were lowest (best) for the ANH group, followed by the CNH and CCI groups. The masking release (MR) was comparable between the ANH and CNH group, but much poorer in the CCI group. The temporal properties differed between the native and non-native maskers and between forward and reversed speech. The temporal properties of the maskers were significantly associated with the SRTs for the CCI and CNH groups but not for the ANH group. Whereas the temporal properties of the maskers were significantly associated with the MR for all three groups, the association was stronger for the CCI and CNH groups than for the ANH group.

Deep sequencing of 1320 genes reveals the landscape of protein-truncating variants and their contribution to psoriasis in 19,973 Chinese individuals.

Protein-truncating variants (PTVs) have important impacts on phenotype diversity and disease. However, their population genetics characteristics in more globally diverse populations are not well defined. Here, we describe patterns of PTVs in 1320 genes sequenced in 10,539 healthy controls and 9434 patients with psoriasis, all of Han Chinese ancestry. We identify 8720 PTVs, of which 77% are novel, and estimate 88% of all PTVs are deleterious and subject to purifying selection. Furthermore, we show that individuals with psoriasis have a significantly higher burden of PTVs compared to controls (P = 0.02). Finally, we identified 18 PTVs in 14 genes with unusually high levels of population differentiation, consistent with the action of local adaptation. Our study provides insights into patterns and consequences of PTVs.

Suppression of delayed rectifier K+ channels by gentamicin induces membrane hyperexcitability through JNK and PKA signaling pathways in vestibular ganglion neurons.

Aminoglycoside antibiotics, such as gentamicin, are known to have vestibulotoxic effects, including ataxia and disequilibrium. To date, however, the underlying cellular and molecular mechanisms are still unclear. In this study, we determined the role of gentamicin in regulating the sustained delayed rectifier K+ current (IDR) and membrane excitability in vestibular ganglion (VG) neurons in mice. Our results showed that the application of gentamicin to VG neurons decreased the IDR in a concentration-dependent manner, while the transient outward A-type K+ current (IA) remained unaffected. The decrease in IDR induced by gentamicin was independent of G-protein activity and led to a hyperpolarizing shift of the inactivation Vhalf. The analysis of phospho-c-Jun N-terminal kinase (p-JNK) revealed that gentamicin significantly stimulated JNK, while p-ERK and p-p38 remained unaffected. Blocking Kv1 channels with α-dendrotoxin or pretreating VG neurons with the JNK inhibitor II abrogated the gentamicin-induced decrease in IDR. Antagonism of JNK signaling attenuated the gentamicin-induced stimulation of PKA activity, whereas PKA inhibition prevented the IDR response induced by gentamicin. Moreover, gentamicin significantly increased the number of action potentials fired in both phasic and tonic firing type neurons; pretreating VG neurons with the JNK inhibitor II and the blockade of the IDR abolished this effect. Taken together, our results demonstrate that gentamicin decreases the IDR through a G-protein-independent but JNK and PKA-mediated signaling pathways. This gentamicin-induced IDR response mediates VG neuronal hyperexcitability and might contribute to its pharmacological vestibular effects.