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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.
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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.
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Nanopartículas , Dióxido de Silicio , Nanopartículas/química , Polietilenglicoles/química , Dióxido de Silicio/químicaRESUMEN
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.
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Pérdida Auditiva Sensorineural , Pérdida Auditiva de Alta Frecuencia , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Humanos , Mutación , Cadenas Pesadas de Miosina/genética , Linaje , FenotipoRESUMEN
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.
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Implantes Cocleares , Percepción del Habla , Adulto , Niño , Femenino , Audición , Humanos , Masculino , Enmascaramiento Perceptual , HablaRESUMEN
This study aimed to investigate the role of miRNA-1225-5p (miR-1225) in laryngeal carcinoma (LC). We found that the expression of miR-1225 was suppressed in human LC samples, while CDC14B (cell division cycle 14B) expression was reinforced in comparison with surrounding normal tissues. We also demonstrated that enhanced expression of miR-1225 impaired the proliferation and survival of LC cells, and resulted in G1/S cell cycle arrest. In contrast, reduced expression of miR-1225 promoted cell survival. Moreover, miR-1225 resulted in G1/S cell cycle arrest and enhanced cell death. Further, miR-1225 targets CDC14B 3'-UTR and recovery of CDC14B expression counteracted the suppressive influence of miR-1225 on LC cells. Thus, these findings offer insight into the biological and molecular mechanisms behind the development of LC.
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Fosfatasas de Especificidad Dual/genética , Genes Supresores de Tumor , Neoplasias Laríngeas/genética , MicroARNs/genética , Puntos de Control del Ciclo Celular/genética , Muerte Celular/genética , Proliferación Celular/genética , Supervivencia Celular/genética , Células Hep G2 , Humanos , Neoplasias Laríngeas/patologíaRESUMEN
Sponges, Neofibularia nolitangere, can regenerate spontaneously after being broken down into small pieces, and the regenerated structure maintains the original appearance and function. Synthetic materials with such capabilities are highly desired but hardly achieved. Presented here is a sponge-inspired self-regenerative powder from a double-network (DN) tough hydrogel. Hydrogels are regenerated from their powder form, by addition of water, with preservation of the original appearance and mechanical properties. The powder-hydrogel-powder cycle can be repeated multiple times with little loss in mechanical properties, analogous to the regeneration of sponges. These DN hydrogels can be conveniently stored and easily shaped upon regeneration. This work may have implications in the development of regenerative materials for coatings and adhesives.
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Hidrogeles/síntesis química , Poríferos/química , Animales , Conformación de Carbohidratos , Hidrogeles/química , Ensayo de Materiales , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
Matrix-styled sentence tests offer a closed-set paradigm that may be useful when evaluating speech intelligibility. Ideally, sentence test materials should reflect the distribution of phonemes within the target language. We developed and validated the Closed-set Mandarin Sentence (CMS) test to assess Mandarin speech intelligibility in noise. CMS test materials were selected to be familiar words and to represent the natural distribution of vowels, consonants, and lexical tones found in Mandarin Chinese. Ten key words in each of five categories (Name, Verb, Number, Color, and Fruit) were produced by a native Mandarin talker, resulting in a total of 50 words that could be combined to produce 100,000 unique sentences. Normative data were collected in 10 normal-hearing, adult Mandarin-speaking Chinese listeners using a closed-set test paradigm. Two test runs were conducted for each subject, and 20 sentences per run were randomly generated while ensuring that each word was presented only twice in each run. First, the level of the words in each category were adjusted to produce equal intelligibility in noise. Test-retest reliability for word-in-sentence recognition was excellent according to Cronbach's alpha (0.952). After the category level adjustments, speech reception thresholds (SRTs) for sentences in noise, defined as the signal-to-noise ratio (SNR) that produced 50% correct whole sentence recognition, were adaptively measured by adjusting the SNR according to the correctness of response. The mean SRT was -7.9 (SE=0.41) and -8.1 (SE=0.34) dB for runs 1 and 2, respectively. The mean standard deviation across runs was 0.93 dB, and paired t-tests showed no significant difference between runs 1 and 2 (p=0.74) despite random sentences being generated for each run and each subject. The results suggest that the CMS provides large stimulus set with which to repeatedly and reliably measure Mandarin-speaking listeners' speech understanding in noise using a closed-set paradigm.
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BACKGROUND: To compare the impact of telbivudine (LDT) and entecavir (ETV) administration on nephritic function. METHOD: One hundred thirty patients diagnosed with hepatitis B virus (HBV)-related compensated cirrhosis were randomly divided into LDT (600 mg/d) or ETV (0.5 mg/d) groups. RESULTS: The drug resistance rate was higher following LDT treatment compared to ETV treatment (16.9% vs. 1.5%, P=0.0006). The mean creatinine level decreased compared to baseline in the LDT group (0.81 vs. 0.94 mg/dl, P=0.000). The change in median glomerular filtration rate (eGFR) compared to baseline in the LTD and ETV groups was 22.3 and -3.3, respectively, at 2 years (P=0.000). In patients with mild nephritic injury (eGFR< 90 ml/min/1.73m2), the median eGFR increased by 28.0 ml/min/1.73m2 in the LDT group and decreased by 4.3 ml/min/1.73m2 in the ETV group (p=0.000). The eGFR in 88.5% of patients (23/26) from the LDT group increased > 90 ml/min/1.73m2. The percentage of patients with an eGFR > 90 ml/min/1.73m2 increased from 60.0% to 92.3% in the LDT group and from 64.6% to 69.2% in the ETV group. CONCLUSION: In patients with HBV-related compensated cirrhosis, LDT treatment was more effective in protecting nephritic function and was associated with a higher drug resistance rate, but did not contribute to a better outcome compared with ETV treatment.
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Farmacorresistencia Viral , Guanina/análogos & derivados , Virus de la Hepatitis B/fisiología , Riñón/fisiopatología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/virología , Timidina/análogos & derivados , Creatinina/sangre , ADN Viral/genética , Farmacorresistencia Viral/efectos de los fármacos , Femenino , Tasa de Filtración Glomerular , Guanina/efectos adversos , Guanina/farmacología , Guanina/uso terapéutico , Humanos , Riñón/efectos de los fármacos , Pruebas de Función Renal , Cirrosis Hepática/sangre , Cirrosis Hepática/fisiopatología , Masculino , Persona de Mediana Edad , Telbivudina , Timidina/efectos adversos , Timidina/farmacología , Timidina/uso terapéuticoAsunto(s)
Pruebas Calóricas , Dexametasona/administración & dosificación , Glucocorticoides/administración & dosificación , Enfermedad de Meniere/tratamiento farmacológico , Potenciales Vestibulares Miogénicos Evocados , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inyección Intratimpánica , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
OBJECTIVE: To explore the distribution and expression of three T-type calcium channel receptors (α1G; α1H; α1I) and understand their protective effects in spiral neurons of C57BL/6J mice. METHODS: The distribution and expression of three T-type calcium channel receptors in spiral ganglion neurons were observed by in situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) in 6-8-week-old C57BL/6J mice. The mice of 24-26-week-old C57BL/6J were divided into 3 groups of zonisamide, benidipine and saline. And the expression changes of calcium-binding proteins calmodulin and calbindin were observed by immunohistochemistry. RESULTS: Three subunits were expressed in spiral ganglion neurons. The decremented quantities were α1H (24.21 ± 0.10), α1I (14.88 ± 0.04) and α1G (10.42 ± 0.02). The expression level of calmodulin in spiral ganglion neurons was lower in the zonisamide-treated group than that in the saline-treated group (0.336 ± 0.041 vs 0.504 ± 0.020, P < 0.05). The expression level of calbindin in spiral ganglion neurons was lower in the zonisamide (0.482 ± 0.045) and benidipine-treated groups (0.511 ± 0.032) than that in the saline-treated group (0.611 ± 0.035, P < 0.05). CONCLUSION: The expressions of calcium-binding proteins decrease after 4-week dosing of T-type calcium channel blockers in 24-26-week C57BL/6J mice. It implies a relief of calcium overload. T-type calcium channel blockers may protect the murine spiral ganglion neurons from degeneration.
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Bloqueadores de los Canales de Calcio/farmacología , Ganglio Espiral de la Cóclea , Animales , Canales de Calcio Tipo T , Proteínas de Unión al Calcio , Hibridación in Situ , Ratones , Ratones Endogámicos C57BL , NeuronasRESUMEN
BACKGROUND: Dabrafenib, an inhibitor of the B-Raf proto-oncogene (BRAF) V600E mutant, has become the major drug for targeted therapy of papillary thyroid cancer (PTC) with the BRAF V600E mutant; however, acquired resistance is inevitable. OBJECTIVE: To identify key transcription factors (TFs) involved in dabrafenib resistance and identify targets to reverse dabrafenib resistance. METHODS: Dabrafenib-resistant PTC cell lines BCPAP/DabR and K1/DabR were established, and phenotypic assays were performed to validate the malignant phenotype. RNA sequencing and bioinformatics analyses were used to identify differentially expressed genes (DEGs) and screen TFs involved in resistant phenotype-related pathways. The role of the key TF POU5F1B in dabrafenib resistance was further validated using gene gain-and-loss assays. RESULTS: BCPAP/DabR and K1/DabR were resistant to dabrafenib, with a resistance index of 5-8. Resistant cells exhibited slower proliferation, strong migration, and spheroid-forming abilities. RNA sequencing screened 6233 DEGs in the resistant group, including 2687 protein-coding RNA (mRNA). Venn analysis indicated that three genes, E2F2, WNT4, and POU5F1B, were involved in resistant phenotype-related pathways and were included in the TF regulatory network. Four TFs of the three genes, POU5F1B, TBX4, FOXO4, and FOXP3, were validated, and POU5F1B showed the highest validated fold-change. Overexpression of POU5F1B in sensitive cells resulted in resistance to dabrafenib and induced a malignant phenotype, whereas silencing it sensitized the resistant cells and reversed the resistant phenotype. CONCLUSION: This study successfully established two dabrafenib-resistant PTC cell lines, and POU5F1B could be a potential target for reversing dabrafenib resistance.
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Objective:To explore the correlation between the parameters of suppression head impulse paradigmï¼SHIMPï¼ and changes in dizziness handicap inventoryï¼DHIï¼ scores. Additionally, to evaluate the degree of vertigo and prognosis of patients with acute vestibular neuritis through SHIMP parameters. Methods:Thirty-three patients with acute vestibular neuritis were enrolled for DHI evaluation, vHIT and SHIMP. A secondary DHI score were evaluated after after two weeks, once patients no longer exhibited spontaneous nystagmus. The decrease in the second DHI score was used as the efficacy indexï¼EIï¼. All patients were divided into significantly effective group, effective group and ineffective group based on EI. Differences of the VOR gain values of SHIMP and the anti-compensatory saccade were compared among the three groups. Results:There were 13 cases in the significant effective group, 11 cases in the effective group, and 9 cases in the ineffective group. â The mean gain of the horizontal semicircular canal in the significant effective group, the effective group, and the ineffective group wasï¼0.50±0.11ï¼, ï¼0.44±0.12ï¼, andï¼0.34±0.08ï¼, respectively. The difference between the significant effective group and the ineffective group was statistically significantï¼P<0.01ï¼. The gain of horizontal semicircular canal was positively correlated with EIï¼r=0.538 5, P<0.01ï¼ ãâ¡The occurrence rate of the anti-compensatory saccade in the significant effective group, the effective group, and the ineffective group wasï¼51.23±19.59ï¼, ï¼33.64±17.68ï¼, andï¼13.78±11.81ï¼, respectively. Pairwise comparisons between each group showed statistical significanceï¼P<0.05ï¼. The occurrence rate of anti-compensatory saccade was positively correlated with EIï¼r=0.658 2, P<0.01ï¼. Conclusion:The horizontal semicircular canal gain and the occurrence rate of the anti-compensatory saccade in SHIMP for patients with acute vestibular neuritis were closely correlated with decrease in DHI score.
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Prueba de Impulso Cefálico , Neuronitis Vestibular , Humanos , Neuronitis Vestibular/fisiopatología , Neuronitis Vestibular/diagnóstico , Prueba de Impulso Cefálico/métodos , Femenino , Masculino , Mareo , Enfermedad Aguda , Vértigo , Persona de Mediana Edad , Pronóstico , Adulto , Canales Semicirculares/fisiopatologíaRESUMEN
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.
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Apoproteínas , Nanopartículas , Otitis Media con Derrame , Transferrina , Humanos , Otitis Media con Derrame/tratamiento farmacológico , Antioxidantes/uso terapéutico , Estrés Oxidativo , XantófilasRESUMEN
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.
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Impresión Tridimensional , HecesRESUMEN
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.
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Oído Interno , Células Ciliadas Auditivas Internas , Recién Nacido , Humanos , Células Ciliadas Auditivas Internas/fisiología , Oído Interno/fisiología , Células Ciliadas Auditivas/fisiología , Regeneración/genética , Células MadreRESUMEN
Fibrosis is a complex pathological process that can lead to the permanent loss of biological function, with P2ry2 playing a crucial role in this process. Long non-coding RNAs (lncRNAs) have been reported to play an critically important role in the fibrotic process. However, it remains unclear whether lncRNAs can regulate fibrosis through P2ry2. In this study, we detected the expression of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lnc-MALAT1). We investigated the expression patterns of lnc-MALAT1 and P2ry2 in denervated skeletal muscle, a classical model of fibrosis. Additionally, we utilized a TGF-ß-mediated fibrosis model in NIH/3T3 cells to examine the effects of lnc-MALAT1 and P2ry2 on fibroblast activation and the underlying regulatory mechanisms in vitro. Our results demonstrated that the expression levels of lnc-MALAT1 and P2ry2 were consistently elevated in denervated skeletal muscle, correlating with the degree of fibrosis. In vitro experiments confirmed the regulatory effect of lnc-MALAT1 on P2ry2. Furthermore, we identified miR-335-3p as a potential key molecule in the regulatory relationship of lnc-MALAT1/P2ry2. Dual luciferase reporter assays and AGO2-RIP verified the molecular sponging effect of lnc-MALAT1 on miR-335-3p. Additionally, we validated the regulation of the lnc-MALAT1/miR-335-3p/P2ry2 axis through experimental approaches. In conclusion, our study identified a crucial role of lnc-MALAT1/miR-335-3p/P2ry2 axis in fibroblast activation, providing a promising treatment option against the fibrosis.
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Fibroblastos , Fibrosis , MicroARNs , ARN Largo no Codificante , Animales , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Ratones , Fibroblastos/metabolismo , Células 3T3 NIH , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Masculino , Ratones Endogámicos C57BL , Factor de Crecimiento Transformador beta/metabolismo , Regulación de la Expresión Génica , ARN Endógeno CompetitivoRESUMEN
BACKGROUND: Obstructive sleep apnoea (OSA) is commonly associated with insulin resistance (IR) and dyslipidaemia. Apolipoprotein E (APOE) plays important roles in lipid metabolism. The study aimed to disentangle the multifactorial relationships between IR and APOE based on a large-scale population with OSA. METHODS: A total of 5,591 participants who underwent polysomnography for OSA diagnosis were finally enrolled. We collected anthropometric, fasting biochemical and polysomnographic data for each participant. Linear regression analysis was performed to evaluate the relationships between APOE, IR, and sleep breathing-related parameters. Logistic regression, restricted cubic spline (RCS) and mediation analyses were used to explore relationships between APOE and IR in patients with OSA. RESULTS: Increasing OSA severity was associated with greater obesity, more obvious dyslipidaemia, and higher levels of APOE and IR. APOE was positively correlated with the apnoea-hypopnoea index (AHI), oxygen desaturation index (ODI) and microarousal index (MAI) even after adjusting for age, sex, body mass index, and smoking and drinking levels (ß = 0.107, ß = 0.102, ß = 0.075, respectively, all P < 0.001). The risks of IR increased from the first to fourth quartiles of APOE (odds ratio (OR) = 1.695, 95% CI: 1.425-2.017; OR = 2.371, 95% confidence interval (CI): 2.009-2.816; OR = 3.392, 95% CI: 2.853-4.032, all P < 0.001) after adjustments. RCS analysis indicated non-linear and dose response relationships between APOE, AHI, ODI, MAI and insulin resistance. Mediation analyses showed that HOMA-IR explained 9.1% and 10% of the association between AHI, ODI and APOE. The same trends were observed in men, but not in women. CONCLUSIONS: This study showed that APOE is a risk factor for IR; moreover, IR acts as a mediator between OSA and APOE in men. APOE, IR, and OSA showed non-linear and multistage relationships. Taken together, these observations revealed the complex relationships of metabolic disorders in patients with OSA, which could lead to the development of new treatment modalities and a deeper understanding of the systemic impact of OSA.
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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.
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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.