Genetic hearing impairment is highly heterogeneous. In this study, targeted next-generation sequencing (NGS) in two Chinese Han families identified a novel p.G141R homozygous mutation in ILDR1 as the genetic cause of the deafness. Consistent with the recessive inheritance, cosegregation of the p.G141R variant with the hearing loss was confirmed in members of both families by PCR amplification and Sanger sequencing. SNP genotyping analysis suggested that those two families were not closely related. Our study showed that targeted NGS is an effective tool for diagnosis of genetic deafness and that p.G141R in ILDR1 may be a relatively frequent mutation for DFNB42 in Chinese Hans.

The AlkB homolog 7 (ALKBH7) is a nonheme iron (II) α-ketoglutarate-dependent dioxygenase superfamily member, which may affect the progression of several types of human cancer. However, the biological effect, especially the immune-related effect, of ALKBH7 in HNSC remains unclear. Herein, several databases were employed at first to assess the different expression of ALKBH7 as well as their relationship to the prognosis, RNA modification, DNA methylation modulation, immune microenvironment and chemotherapeutic responses of various types of cancers. We found that ALKBH7 was expressed differentially in pan-cancer, and correlated with a satisfied prognosis especially in HNSC. The expression of ALKBH7 was also associated with the level of immune cell infiltration, TMB, MSI, HRD, MMR deficiency, and DNA methyltransferases in a wide variety of cancers, which might be potentially related to the responses against chemotherapeutic agents. Next, the role of ALKBH7 in HNSC was further investigated. Western blot and immunohistochemical analysis in HNSC patients from the NMU cohort showed the reduced ALKBH7 expression level in tumor tissues. In vitro experiments of cell migration, invasion, and proliferation showed a potential protective effect of ALKBH7 in HNSC. Collectively, ALKBH7 might play a protective role in the development and progression of multiple cancers by affecting the metabolism and immune cell infiltration, especially HNSC, which could be a potential biomarker to predict prognosis and chemotherapeutic response.

Ribbon synapses of inner hair cells are uniquely designed for ultrafast and indefatigable neurotransmission of the sound. The molecular machinery ensuring the efficient, compensatory recycling of the synaptic vesicles, however, remains elusive. This study showed that hair cell knockout of murineDmxl2, whose human homolog is responsible for non-syndromic sensorineural hearing loss DFNA71, resulted in auditory synaptopathy by impairing synaptic endocytosis and recycling. The mutant mice in the C57BL/6J background of either sex had mild hearing loss with severely diminished wave-I amplitude of the auditory brainstem response. Membrane capacitance measurements of the inner hair cells revealed deficiency in sustained synaptic exocytosis and endocytic membrane retrieval. Consistent with the electrophysiological findings, 3D electron microscopy reconstruction showed reduced reserve pool of synaptic vesicles and endocytic compartments, while the membrane-proximal and ribbon-associated vesicles remain intact. Our results propose an important role of DMXL2 in hair cell endocytosis and recycling of the synaptic vesicles.Significance StatementThe molecular basis underlying efficient recycling of the ribbon synaptic vesicles in cochlear hair cells remains elusive. In this study, investigation of a hair cell-specific knockout mouse for Dmxl2 identifies its import roles in endocytosis and recycling of the auditory synaptic vesicles. The mutant mice display auditory synaptopathy, a common feature for noise-induced hearing loss and age-related hearing loss. The inner hair cells show deficiency in sustained synaptic exocytosis and endocytic membrane retrieval with reduced reserve pool of synaptic vesicles and endocytic compartments. Our results provide new insights into the molecular machinery ensuring ultrafast and indefatigable neurotransmission of the sound.

Long noncoding RNAs (lncRNAs) perform indispensable functions in cancer pathologies and are involved in the onset and progression of multiple cancers. Multiple platforms were performed to comprehensively analyze the head and neck squamous cell carcinoma (HNSCC) for determining molecular subtypes. Molecular subtypes were clustered and analyzed by the “ConsensusClusterPlus” R package. The Limma software was utilized to screen for differentially expressed genes (DEGs). Functional enrichment analyses, including Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO), were performed on the three database resources. Seventeen lncRNAs were determined as HNSCC-specific immune lncRNAs that were dysregulated. Our research identified and redefined two distinct molecular subtypes, C1 (230 samples) and C2 (269 samples). Moreover, the C1 subtype had a higher survival rate than the C2 subtype in HNSCC samples, as well as a prolonged median survival duration with activated immune response. 1531 DEGs, including 529 upmodulated genes and 1002 downmodulated genes, were identified in the above two subtypes. Functional enrichment analysis revealed that upmodulated genes in C2 were associated with tumorigenesis and development, while downregulated genes in C2 were associated with immune response. By comparing with the existing immunophenotyping group, it found that C1 had more overlaps with the existing Atypical and Basal, and C2 and Classical and Mesenchymal had a high degree of coincidence. On the basis of lncRNA, there were significant differences in the aspect of prognostic and immunological characteristics in the two identified molecular subtypes of HNSCC.