Peripheral Auditory Nerve Impairment in a Mouse Model of Syndromic Autism.

Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity. Altered sound sensitivity is frequently observed in autism spectrum disorder (ASD), suggesting that AN deficits and changes in auditory information processing may contribute to ASD-associated symptoms, including social communication deficits and hyperacusis. The MEF2C transcription factor is associated with risk for several neurodevelopmental disorders, and mutations or deletions of MEF2C produce a haploinsufficiency syndrome characterized by ASD, language, and cognitive deficits. A mouse model of this syndromic ASD (Mef2c-Het) recapitulates many of the MEF2C haploinsufficiency syndrome-linked behaviors, including communication deficits. We show here that Mef2c-Het mice of both sexes exhibit functional impairment of the peripheral AN and a modest reduction in hearing sensitivity. We find that MEF2C is expressed during development in multiple AN and cochlear cell types; and in Mef2c-Het mice, we observe multiple cellular and molecular alterations associated with the AN, including abnormal myelination, neuronal degeneration, neuronal mitochondria dysfunction, and increased macrophage activation and cochlear inflammation. These results reveal the importance of MEF2C function in inner ear development and function and the engagement of immune cells and other non-neuronal cells, which suggests that microglia/macrophages and other non-neuronal cells might contribute, directly or indirectly, to AN dysfunction and ASD-related phenotypes. Finally, our study establishes a comprehensive approach for characterizing AN function at the physiological, cellular, and molecular levels in mice, which can be applied to animal models with a wide range of human auditory processing impairments.SIGNIFICANCE STATEMENT This is the first report of peripheral auditory nerve (AN) impairment in a mouse model of human MEF2C haploinsufficiency syndrome that has well-characterized ASD-related behaviors, including communication deficits, hyperactivity, repetitive behavior, and social deficits. We identify multiple underlying cellular, subcellular, and molecular abnormalities that may contribute to peripheral AN impairment. Our findings also highlight the important roles of immune cells (e.g., cochlear macrophages) and other non-neuronal elements (e.g., glial cells and cells in the stria vascularis) in auditory impairment in ASD. The methodological significance of the study is the establishment of a comprehensive approach for evaluating peripheral AN function and impact of peripheral AN deficits with minimal hearing loss.

Two distinct types of nodes of Ranvier support auditory nerve function in the mouse cochlea.

The auditory nerve (AN) of the inner ear is the primary conveyor of acoustic information from sensory hair cells to the brainstem. Approximately 95% of peripheral AN fibers are myelinated by glial cells. The integrity of myelin and the glial-associated paranodal structures at the node of Ranvier is critical for normal AN activity and axonal survival and function in the central auditory nervous system. However, little is known about the node of Ranvier's spatiotemporal development in the AN, how the aging process (or injury) affects the activity of myelinating glial cells, and how downstream alterations in myelin and paranodal structure contribute to AN degeneration and sensorineural hearing loss. Here, we characterized two types of Ranvier nodes-the axonal node and the ganglion node-in the mouse peripheral AN, and found that they are distinct in several features of postnatal myelination and age-related degeneration. Cellular, molecular, and structure-function correlations revealed that the two node types are each critical for different aspects of peripheral AN function. Neural processing speed and synchrony is associated with the length of the axonal node, while stimulus level-dependent amplitude growth and action potentials are associated with the ganglion node. Moreover, our data indicate that dysregulation of glial cells (e.g., satellite cells) and degeneration of the ganglion node structure are an important new mechanism of age-related hearing loss.

The dual effect of background music on creativity: perspectives of music preference and cognitive interference.

Music, an influential environmental factor, significantly shapes cognitive processing and everyday experiences, thus rendering its effects on creativity a dynamic topic within the field of cognitive science. However, debates continue about whether music bolsters, obstructs, or exerts a dual influence on individual creativity. Among the points of contention is the impact of contrasting musical emotions-both positive and negative-on creative tasks. In this study, we focused on traditional Chinese music, drawn from a culture known for its 'preference for sadness,' as our selected emotional stimulus and background music. This choice, underrepresented in previous research, was based on its uniqueness. We examined the effects of differing music genres (including vocal and instrumental), each characterized by a distinct emotional valence (positive or negative), on performance in the Alternative Uses Task (AUT). To conduct this study, we utilized an affective arousal paradigm, with a quiet background serving as a neutral control setting. A total of 114 participants were randomly assigned to three distinct groups after completing a music preference questionnaire: instrumental, vocal, and silent. Our findings showed that when compared to a quiet environment, both instrumental and vocal music as background stimuli significantly affected AUT performance. Notably, music with a negative emotional charge bolstered individual originality in creative performance. These results lend support to the dual role of background music in creativity, with instrumental music appearing to enhance creativity through factors such as emotional arousal, cognitive interference, music preference, and psychological restoration. This study challenges conventional understanding that only positive background music boosts creativity and provides empirical validation for the two-path model (positive and negative) of emotional influence on creativity.

Alginate oligosaccharide alleviates aging-related intestinal mucosal barrier dysfunction by blocking FGF1-mediated TLR4/NF-κB p65 pathway.

BACKGROUND: Alginate oligosaccharide (AOS) has been reported to exert a crucial role in maintaining the intestinal mucosal barrier (IMB) function. The current study aimed at ascertaining the protective effects of AOS on aging-induced IMB dysfunction and to elucidate the underlying molecular mechanisms. METHODS: An aging mouse model and a senescent NCM460 cell model were established using d-galactose. AOS was administered to aging mice and senescent cells, and IMB permeability, inflammatory response and tight junction proteins were assessed. In silico analysis was conducted to identify factors regulated by AOS. Using gain- and loss-of-function approaches, we evaluated the roles of FGF1, TLR4 and NF-κB p65 in the aging-induced IMB dysfunction and NCM460 cell senescence. RESULTS: AOS protected the IMB function of aging mice and NCM460 cells by reducing permeability and increasing tight junction proteins. In addition, AOS up-regulated FGF1, which blocked the TLR4/NF-κB p65 pathway, and identified as the mechanism responsible for the protective effect of AOS. CONCLUSION: AOS blocks the TLR4/NF-κB p65 pathway via inducing FGF1, ultimately reducing the risk of IMB dysfunction in aging mice. This study highlights the potential of AOS as a protective agent against aging-induced IMB disorder and provides insight into the underlying molecular mechanisms.

The role of socioeconomic status in different trajectories of depressive symptoms in Chinese college freshmen.

The associations between socioeconomic status (SES) and depressive symptoms have been found in previous studies. However, the role of SES in different trajectories of depressive symptoms in Chinese college freshmen has not been discovered. The present study aims to identify how depressive symptom trajectories are related to SES during the first semester of freshman. Six hundred fifty-two Chinese college freshmen (64.9% female) were followed 4 times across 4 months. The Latent Growth Mixture Model (LGMM) was used to identify trajectories of depressive symptoms. Multinomial Logical Regression was used to identify the influence of family socioeconomic status (FSES), subjective socioeconomic status (SSS), and demographic variables on trajectories of depressive symptoms for freshmen. Results found that college freshmen's depressive symptoms gradually decreased during the four tests, F(2.758, 1795.383) = 52.642, p < 0.001, and there are three trajectories of depressive symptoms: normal group (Class 1, 73.1%), depression risk group (Class 2, 20.7%), and depression deterioration group (Class 3, 6.1%). The decline of SSS predicted increasing depressive symptoms. Age and left-behind experience have significant effects on trajectories of depressive symptoms. FSES, birthplace, and gender had no significant impact on trajectories of depressive symptoms. These results demonstrated that low SSS, age, and left-behind might be risk factors for the development of depressive symptoms.

Long Non-coding RNAs as Communicators and Mediators Between the Tumor Microenvironment and Cancer Cells.

Long non-coding RNAs (lncRNAs) are a class of more than 200 nucleotides RNA transcripts which have limited protein coding capacity. They regulate numerous biological processes in cancers through diverse molecular mechanisms. Aberrant expression of lncRNAs has been frequently associated with human cancer. Furthermore, the tumor microenvironment (TME) is composed of different cells such as cancer-associated fibroblasts (CAFs), endothelial cells and infiltrated immune cells, and all of which participate in communication with tumor cells affecting the progression of tumor. LncRNAs are directly and indirectly involved in the crosstalk between stromal cells and tumor cells and dysregulated lncRNAs expression in these cells could drive tumorigenesis. In this review, we explore the influence of aberrantly expressed lncRNAs in tumor progression, clarify the critical roles of lncRNAs in the TME, summarize findings on crosstalk between infiltrated immune cells, CAFs, endothelial cells, and tumor cells via lncRNAs, and discuss the promise of lncRNAs as tumor diagnostic markers and therapeutic targets.

Identification of a transcription factor-microRNA network in esophageal adenocarcinoma through bioinformatics analysis and validation through qRT-PCR.

Purpose: The rapidly rising incidence of esophageal adenocarcinoma (EAC), which is usually diagnosed late with a poor prognosis, has become a growing problem. This study investigated the potential transcription factor (TF)-related molecular mechanisms of EAC by using bioinformatics analysis and qRT-PCR validation. Methods: Expression profile datasets for mRNAs (GSE92396, GSE13898, GSE26886 and GSE1420) and miRNAs (GSE16456) were downloaded from the GEO database. Overlapping differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified through integrative analysis. Then, a TF-miRNA-mRNA network was constructed based on bioinformatics data from the TRRUST, TRED and miRTarBase database. Furthermore, overall survival analysis for the mRNAs and miRNAs in the TF-miRNA-mRNA network was performed with data from TCGA, and qRT-PCR was used to validate the results. Results: A total of 294 overlapping DEGs were identified in EAC tissues compared to normal tissues, including 181 downregulated and 113 upregulated genes. Then, 16 TFs that could target the DEGs and were related to cancer were predicted based on public databases, and 41 DEGs that could be targeted were identified as key genes. Additionally, 12 DEMs were predicted through miRTarBase to be associated with the key genes, and TP53-(miR-125b)-ID2 and JUN-(miR-30a)-IL1A from the TF-miRNA-mRNA network were identified to potentially play significant roles in EAC. Furthermore, CCL20, IL1A, ABCC3, hsa-miR-23b, and hsa-miR-191, which are involved in the TF-miRNA-mRNA network, were found to be significantly associated with patient survival in EAC. Finally, the expression of a miRNA-mRNA pair (hsa-miR-30a-5p and IL1A) was revealed to be correlated with prognosis. Conclusion: In this study, a TF-miRNA-mRNA network was constructed to analyze the potential molecular mechanisms of EAC. Key genes and miRNAs associated with patient survival were identified, which may reveal promising approaches for EAC diagnosis and therapy.

[The value of lidocaine through different routes of administration in the treatment of tinnitus: a Meta-analysis].

OBJECTIVE: To evaluate the clinical value of lidocain in the treatment of tinnitus through three routes of administration (intravenous, intratympanic and acupoint injection) by analyzing literatures. METHOD: Articles were collected through Hownet, Wanfang, VIP, Pubmed, SciVerse ScienceDirect, Springer and OVID, etc. The articles were strictly evaluated based on their quality. The Meta-analysis was performed to evaluate the outcomes by RevMan 5. 2 software. RESULT: A total of 16 articles with 1203 patients were enrolled in the analysis. Their tinnitus history ranged from 7 hours to 20 years. Assessment methods include tinnitus loudness levels, severity scales and subjective feelings. None of articles refer to maintaining time, instead of "short-term", "short" and so on. A total of 133 cases received intravenous injection and the effective rate was 73.4% (98 cases). 50 cases and 332 cases received intratympanic and acupoint injection respectively and their effective rates were 74.0% and 87.7%, respectively. The effective rate ranged from 42.4% to 58.3% in control group. Meta-analysis results indicate that all three routes of lidocaine administrations are more effective than conventional methods (P < 0.05). CONCLUSION: Different routes of lidocaine administration have a good but short time effects on the tinnitus control. It can effectively reduce the time of tinnitus habituation as a complementary treatment. But its value still needs further evaluation.