Mitochondrial dysfunction can cause cochlear dysfunction and accelerate noise-induced hearing loss (NIHL). NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and has a role in the assembly and stabilization of complex I. However, the involvement of Ndufs4 in the pathogenesis of NIHL has not been reported. The aim of this study was to evaluate whether Ndufs4 deletion causes vulnerability to noise exposures. The wild-type (WT) and Ndufs4 knockout (KO) mice with C57BL/6J genetic background were used. Cochlear histology and hearing thresholds were assessed after noise exposure at 100 or 86 dB sound pressure level (SPL). Immunostaining showed the widespread expression of Ndufs4 in the cochlea. After noise exposure at 100 dB SPL, auditory brainstem response (ABR) threshold shifts at 4 kHz in Ndufs4 KO mice were significantly higher than that in WT mice. After noise exposure at 86 dB SPL, ABR threshold shifts, wave 1 amplitudes, and the number of synapses in the inner hair cells were not significantly different. RNA sequencing revealed the decreased expression of energy generation-related genes inNdufs4 KO mice. Ndufs4 deficiency accelerates permanent low-frequency threshold shifts after moderate noise exposure.

Oral squamous cell carcinoma (OSCC) remains the most prevalent malignance in the head and neck with highly aggressive attributes. This study investigates the functions of nuclear receptor interacting protein 1 (NRIP1) and its target transcripts in the progression of OSCC. By analyzing four OSCC-related Gene Expression Omnibus (GEO) datasets (GSE9844, GSE23558, GSE25104 and GSE74530) and querying bioinformatics systems, we obtained NRIP1 as an aberrantly highly expressed transcription factor in OSCC. Increased NRIP1 was detected in OSCC cell lines. Artificial downregulation of NRIP1 significantly suppressed proliferation, migration and invasion, resistance to apoptosis, tumorigenicity, and in vivo metastatic potential of OSCC cells. Moreover, the bioinformatics analyses suggested nuclear receptor binding SET domain protein 2 (NSD2) as a target of NRIP1 and DGCR8 microprocessor complex subunit (DGCR8) as a target of NSD2. Indeed, we validated by chromatin immunoprecipitation and luciferase assays that NRIP1 activated the transcription of NSD2, and NSD2 increased DGCR8 transcription by modulating histone methylation near the DGCR8 promoter. Either NSD2 or DGCR8 upregulation in OSCC cells rescued their malignant properties. Collectively, this study demonstrates that NRIP1 augments malignant properties of OSCC cells by activating NSD2-mediated histone methylation of DGCR8.

Glioblastoma (GBM) is a highly aggressive primary brain tumor that shows intratumoral heterogeneity at the cellular and molecular level. Activation of programmed death receptor 1 (PD-1) interaction with its ligand PD-L1 is a well-known mechanism requisite for immune evasion deployed by malignant tumors including GBM. Herein, we set out to dissect the mechanism explaining the regulation of PD-L1 gene expression in GBM. The clinical samples consisted of 37 GBM tissues and 18 normal brain tissues. GBM cell model was treated by microRNA (miRNA) inhibitor, DNA constructs, and siRNAs. Assays of CCK-8 and Transwell insert were employed to assess the survival, migratory and invasive ability of GBM cell model. The immunosuppressive factor production, T cell apoptosis, and T cell cytotoxicity to GBM cells were evaluated in the co-culture system. GBM exhibited more miR-10b-5p abundance than normal at both tissue and cellular level. Suppression of miR-10b-5p weakened the ability of GBM cell model to survive, migrate, and invade, decreased the release of immunosuppressive factors, reduced T cell apoptosis, and strengthened the T cell cytotoxicity to GBM cell model. MiR-10b-5p conferred a negative control of Ten-eleven translocation 2 (TET2) that was downregulated in GBM. The functions of miR-10b-5p on GBM cell aggressiveness and immune evasion were mediated by TET2. TET2 recruited histone deacetylases HDAC1 and HDAC2 into the PD-L1 promoter region thus inhibiting its transcription. The study demonstrated the importance of miR-10b-5p-mediated repression of TET2 in PD-L1-driven immune evasion and their potential for immunotherapeutic targeting in GBM.

Anti-aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and Sjögren syndrome (SS) are likely comorbidities. However, the exact effects of age and disease duration on the positivity rates of serum anti-Ro/SSA and anti-La/SSB (anti-SSA/SSB) antibodies and the presence of sicca symptoms in patients with AQP4-IgG remain unknown. In the present study, we evaluated the data from patients with suspected NMOSD who had neurological episodes and tested for serum AQP4-IgG. Associations between the presence of serum AQP4-IgG and SS-related findings were evaluated. The presence of anti-SSA/SSB antibodies [odds ratio (OR), 7.34; 95% confidence interval (CI), 5.71-9.43; p < 0.0001] and that of sicca symptoms (OR, 2.08; 95% CI, 1.67-2.58; p < 0.0001) were both higher in patients with AQP4-IgG (n = 1,651) than in those without AQP4-IgG (n = 2,796). Meanwhile, neither age nor the elapsed time from neurological onset was linked to the prevalence of anti-SSA/SSB antibodies or sicca symptoms, and the prevalence rates of the SS-related factors were elevated since the onset of neurological episodes in those with AQP4-IgG. The frequency of sicca symptoms among those with anti-SSA/SSB antibodies was irrespective of AQP4-IgG (OR, 1.11; 95% CI, 0.67-1.85; p = 0.6892). The measured AQP4-IgG titers did not differ significantly according to the presence of anti-SSA/SSB antibodies (p = 0.2386; Mann-Whitney U test). In summary, age and duration of NMOSD were not the factors producing an elevated prevalence of anti-SSA/SSB antibodies and sicca symptoms in patients with AQP4-IgG, implying that the occurrence of comorbid SS is likely to temporarily precede or synchronize with the onset of AQP4-IgG-positive NMOSD.

Long-term voice abuse or sudden vocal fold microvascular disruption may lead to injury and subsequent repair/remodeling in the vocal fold mucosa. Periostin is known to be involved in airway remodeling and also in various otolaryngological diseases. D-β-aspartic acid is the major isomer of D-aspartic acid found in elderly tissue. In this study we investigated the expression and the role of D-β-aspartic acid and periostin in the formation of vocal fold polyps. The expression patterns of D-β-aspartic acid and periostin in 36 surgical specimens of vocal fold polyps from 36 patients were investigated immunohistochemically. In the epithelium of vocal polyps, D-β-aspartic acid was expressed in all cases. Expression of D-β-aspartic acid was detected in 25 samples obtained from patients with vocal fold polyps stroma. Expression of periostin was detected in 28 samples obtained from patients with vocal fold polyps. Two patterns of D-β-aspartic acid expression were observed in vocal fold polyps stroma: positive type and negative type. The following four patterns of periostin expression were observed in vocal fold polyps: negative type, superficial type, infiltrative type, and diffuse type. An association was observed between D-β-aspartic acid expression patterns and periostin expression patterns. From these findings we speculate that periostin and D-β-aspartic acid participate in certain pathological changes in vocal fold polyps, such as extracellular matrix accumulation, local fibrosis, and the formation and development of vocal fold polyps.

The coronavirus disease 2019 (COVID-19) pandemic remains a global public health concern. The clinical course and risk of developing severe illness among patients with COVID-19 who are at low-risk of severe COVID-19 remain uncertain. This retrospective cohort study from an isolation facility for low-risk COVID-19 patients in Japan evaluated the potential risks for severe disease with hypoxia (SpO₂ ≤ 93%) or experiencing prolonged isolation period longer than 14 days with persistent acute symptoms. The study was performed before the spread of the alpha variant in the country and before the start of a nationwide mass vaccination campaign against COVID-19. Among the 929 participants with reliable outcome data regarding the development of hypoxia, 63 (6.8%) developed severe disease with hypoxia during their stays at the facility. Higher age [adjusted odds ratio (aOR), 1.08; 95% confidence interval (CI), 1.06-1.10] and male sex (aOR, 4.70; 95% CI, 2.39-9.22) were associated with this outcome. As for the experience of prolonged isolation period, higher age (aOR, 1.02; 95% CI, 1.01-1.04), atopic diseases (aOR, 1.69, 95% CI, 1.09-2.64), presence of cough at onset (aOR, 1.64; 95% CI, 1.09-2.48), and prescription of oral antibiotics before positive test results for COVID-19 (aOR, 2.37; 95% CI, 1.33-4.22) were associated with this outcome. In summary, 5-10% of low-risk COVID-19 patients later develop hypoxia. Older age and male sex were associated with both the development of hypoxia and prolonged acute symptoms. The unnecessary prescription of antibiotics before COVID-19 diagnosis may prolong COVID-19 symptoms.

In clinical settings, bone grafting is frequently used to treat bone defects. Therefore, the development of bone graft substitutes with superior bone formation ability is expected, instead of autogenous bone grafting. Octacalcium phosphate (OCP) has been developed as a bone graft substitute, and preclinical studies using OCP have reported superior bone formation ability compared with β-tricalcium phosphate. Furthermore, OCP has been used in composite forms with natural polymers such as collagen and gelatin to improve the usability of OCP, and OCP/collagen composite forms have been clinically applied in the dental field because of their excellent usability and osteogenic potential. This review describes the development and preclinical results of OCP and OCP/gelatin (OCP/Gel) composites and prospects for future applications in orthopedics. The development of bone graft substitutes that achieve a high degree of biodegradability and strength will be needed for the clinical application of OCP composites in orthopedics in the future.

In forensic medicine, fatal hypothermia diagnosis is not always easy because findings are not specific, especially if traumatized. Post-mortem computed tomography (PMCT) is a useful adjunct to the cause-of-death diagnosis and some qualitative image character analysis, such as diffuse hyperaeration with decreased vascularity or pulmonary emphysema, have also been utilized for fatal hypothermia. However, it is challenging for inexperienced forensic pathologists to recognize the subtle differences of fatal hypothermia in PMCT images. In this study, we developed a deep learning-based diagnosis system for fatal hypothermia and explored the possibility of being an alternative diagnostic for forensic pathologists. An in-house dataset of forensic autopsy proven samples was used for the development and performance evaluation of the deep learning system. We used the area under the receiver operating characteristic curve (AUC) of the system for evaluation, and a human-expert comparable AUC value of 0.905, sensitivity of 0.948, and specificity of 0.741 were achieved. The experimental results clearly demonstrated the usefulness and feasibility of the deep learning system for fatal hypothermia diagnosis.

Tumor necrosis factor-α (TNF-α) blocking therapy is recommended to treat ankylosing spondylitis for patients who fail to respond to nonsteroidal anti-inflammatory drugs (NSAIDs). Herein, we attempt to dissect whether blood type I and II interferon (IFN) production can be predictive of ankylosing spondylitis progression and treatment response to the tumor necrosis factor inhibitor (TNFi). A total of 50 ankylosing spondylitis patients receiving originator TNFi with a 6-month period were retrospectively analyzed. The patients who reached the Assessment of SpondyloArthritis international Society 40 (ASAS40) response at the 6-month interval were classified as responders (n = 29) to TNFi treatment, otherwise as non-responders (n = 21). The serum type I IFN activity, and the serum levels of IFN-α and IFN-γ in the patients at baseline were notably greater than the healthy controls. Pearson correlation analysis showed positive correlations in the patients between the serum type I IFN activity or the serum levels of IFN-α and IFN-γ, and BASDAI scores, ASDAS_CRP or pro-inflammatory factor production. The responders were demonstrated with reduced serum type I IFN activity concomitant with lower serum levels of IFN-α and IFN-γ compared to the non-responders after anti-TNF treatment. The serum type I IFN activity, and the serum levels of IFN-α and IFN-γ used as a test to predict responders and non-responders to anti-TNF treatment produced an area under the curve (AUC) of 0.837, 0.814, and 0.787, respectively. In conclusion, the study demonstrates that blood type I and II IFN production may be correlated with disease activity, inflammatory cytokine production, and indicative of unsatisfying response to TNFi treatment in ankylosing spondylitis patients.