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Objective The topic of tinnitus has received considerable scholarly interest. Contributing factors to the development of tinnitus encompass aging, exposure to loud noise, smoking, and hearing impairment. Nevertheless, the precise risk factors, particularly those that can be modified, remain uncertain. This study aimed to explore the potential genetic factors that may be associated with an increased susceptibility to tinnitus. Methods Mendelian randomization analyses were performed using data from the United Kingdom Biobank and the FinnGen Biobank data infrastructure. The present study examined the correlation between 13 prevalent life factors, which were identified as potential risk factors for tinnitus through a comprehensive review of the literature. The inverse-variance weighted model was employed to analyze the associations. To mitigate database source bias and strengthen the reliability of our findings, data from the United Kingdom Biobank were used for the discovery cohort, whereas data from FinnGen were used for the validation cohort. Subsequently, a meta-analysis was conducted to combine the findings, thereby bolstering the robustness of the results. Results In the United Kingdom Biobank discovery cohort, waist circumference (odds ratio = 1.37, 95% confidence interval 1.09–1.71, p = 0.006), waist-to-hip ratio (odds ratio = 1.71, 95% confidence interval 1.17–2.50, p = 0.005), fasting glucose (odds ratio = 0.70, 95% confidence interval 0.54–0.90, p = 0.007), and fasting insulin (odds ratio = 2.07, 95% confidence interval 1.07–4.01, p = 0.03) showed significant associations with tinnitus. In the FinnGen validation cohort, smoking was associated with tinnitus (odds ratio = 1.20, 95% confidence interval 1.03–1.40, p = 0.018). However, in the meta-analysis combining both cohorts, only waist circumference remained significantly associated with tinnitus (odds ratio = 1.27, 95% confidence interval 1.08–1.49, p = 0.003). Conclusions Our findings indicate a causal relationship between waist circumference, an indicator of central obesity, and tinnitus. This implies that abdominal obesity could serve as a modifiable target for the prevention of tinnitus. Other factors that initially appeared to be associated did not demonstrate consistent results across different cohorts, underscoring the critical role of meta-analysis in Mendelian randomization studies.

Parkinson’s disease (PD) is the second most common neurodegenerative disease characterized by bradykinesia, rigidity, and tremor. However, familial PD caused by single-gene mutations remain relatively rare. Herein, we described a Chinese family affected by PD, which associated with a missense heterozygous glucocerebrosidase 1 (GBA1) mutation (c.231C > G). Clinical data on the proband and her family members were collected. Brain MRI showed no difference between affected and unaffected family members. Whole-exome sequencing (WES) was performed to identify the pathogenic mutation. WES revealed that the proband carried a missense mutation (c.231C > G) in GBA1 gene, which was considered to be associated with PD in this family. Sanger sequencing and co-segregation analyses were used to validate the mutation. Bioinformatics analysis indicated that the mutation was predicted to be damaging. In vitro functional analyses were performed to investigated the mutant gene. A decrease in mRNA and protein expression was observed in HEK293T cells transfected with mutant plasmids. The GBA1 c.231C > G mutation caused a decreased GBA1 concentration and enzyme activity. In conclusion, a loss of function mutation (c.231C > G) in GBA1 was identified in a Chinese PD family and was confirmed to be pathogenic through functional studies. This study help the family members understand the disease progression and provide a new example for studying the pathogenesis of GBA1-associated Parkinson disease.

Inflammation has been reported to be related to anemia. As a novel inflammatory marker, Systemic immune-inflammation index (SII) has not been studied with Anemia. The aim of this study was to investigate the possible relationship between SII and anemia. This retrospective cross-sectional survey was conducted using data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES) population. In total, 19851 American adults aged ≥18 years were included. SII was calculated as the platelet count×neutrophil count/lymphocyte count. Anemia was defined as hemoglobin (Hgb) levels of < 13 g/dL in males and < 12 g/dL in females. Logistic regression analyses, subgroup analyses and sensitivity analyses were performed to investigate the relationship between SII and anemia. Our study included a total of 19851 patients, of which 1501 (7.6%) had anemia. After adjusting for all covariates, the multivariate logistic regression analysis showed that a higher SII (In-transform) level was associated with increased likelihood of anemia (OR=1.51, 95% CI: 1.36-1.68, P<0.001). The association between SII and anemia exhibited a nonlinear manner. The positive correlation between SII and anemia was related to the severity of anemia. Subgroup analysis showed that there was no significant dependence on age, family income, body mass index, hypertension, kidney disease and cancer except gender on this positive association. Furthermore, sensitivity analyses confirmed the robustness of our results. Our study demonstrated that SII was positively associated with anemia especially among female participants. And this positive correlation was related to the severity of anemia. Further large-scale prospective studies are still needed to analyze the role of SII in anemia.

Background The molecular mechanisms and signaling pathways involved in tooth morphogenesis have been the research focus in the fields of tooth and bone development. However, the cell population in molars at the late bell stage and the mechanisms of hard tissue formation and mineralization remain limited knowledge. Results Here, we used the rat mandibular first and second molars as models to perform single-cell RNA sequencing (scRNA-seq) analysis to investigate cell identity and driver genes related to dental mesenchymal cell differentiation during the late bell hard tissue formation stage. We identified seven main cell types and investigated the heterogeneity of mesenchymal cells. Subsequently, we identified novel cell marker genes, including Pclo in dental follicle cells, Wnt10a in pre-odontoblasts, Fst and Igfbp2 in periodontal ligament cells, and validated the expression of Igfbp3 in the apical pulp. The dynamic model revealed three differentiation trajectories within mesenchymal cells, originating from two types of dental follicle cells and apical pulp cells. Apical pulp cell differentiation is associated with the genes Ptn and Satb2 , while dental follicle cell differentiation is associated with the genes Tnc , Vim , Slc26a7 , and Fgfr1 . Cluster-specific regulons were analyzed by pySCENIC. In addition, the odontogenic function of driver gene TNC was verified in the odontoblastic differentiation of human dental pulp stem cells. The expression of osteoclast differentiation factors was found to be increased in macrophages of the mandibular first molar. Conclusions Our results revealed the cell heterogeneity of molars in the late bell stage and identified driver genes associated with dental mesenchymal cell differentiation. These findings provide potential targets for diagnosing dental hard tissue diseases and tooth regeneration.

Background X-linked hypophosphatemic rickets (XLH, OMIM: 307800) is the most prevalent hereditary ricket characterized by hypophosphatemia, rickets, and osteomalacia. XLH resulted from pathogenic variants in PHEX gene. Patients with XLH may experience symptoms that begin in childhood and persist into adulthood or even throughout life, significantly impacting their quality of life. Therefore, studying the genetic etiology and pathogenic mechanisms of XLH is fundamental for the prevention, diagnosis, and treatment of the disease. Results We identified a novel pathogenic variant in PHEX within XLH families: c.1814delC p.Thr605MetfsTer14. This variant has not been previously reported in patients with XLH. In in vitro functional studies, the variant (c.1814delC p.Thr605MetfsTer14) reduced the protein expression and stability of PHEX and altered its localization. Furthermore, the overexpression of wild-type PHEX inhibited mineralization in contrast to the control group. The PHEX variant (p.Thr605MetfsTer14) exhibited a greater capacity to promote mineralization than the wild-type group. Conclusions We propose a potential correlation between reduced protein degradation rate and XLH phenotypes. The PHEX variant protein (p.Thr605MetfsTer14) changed the protein structure, induced mislocalization, accelerated protein degradation, and finally caused a decrease in protein expression, which affected mineralization. Our findings provide valuable data on XLH pathogenesis and genotype-phenotype correlations. The expression and mineralization studies of the PHEX variant offer important insights into the pathogenesis of XLH disease.

Cervical cancer (CC) remains a significant global health issue, accounting for approximately 7% of all cancer cases in women. This study investigated the anti-cancer potential of pectolinarigenin (PEC), a bioactive compound derived from plants, aiming to explore its therapeutic effects and underlying mechanisms against CC. By integrating network pharmacology analysis with cellular assays, we identified 13 key targets of PEC related to CC, with molecular docking highlighting AKT as a primary target. Experimentally, PEC demonstrated strong anti-cancer effects on cervical cancer both in vivo and in vitro . Western blotting analysis revealed that PEC treatment led to a dose-dependent decrease in Bcl-2 protein levels, coupled with increased activation of pro-apoptotic markers Bax and cleaved caspase-3 in both cell lines. PEC also elevated the levels of LC3B II protein, indicating the induction of autophagy. Notably, this autophagic response was inhibited by 3-MA, an autophagy inhibitor, suggesting that PEC played a regulatory role in activating autophagy. Mechanistic studies confirmed that PEC effectively suppressed the AKT/mTOR signaling pathway, a critical regulator of both autophagy and apoptosis in cancer cells. Overall, this is the first study to demonstrate that PEC exerted potent anti-cancer effects against CC by concurrently inducing autophagy and apoptosis through targeted inhibition of the AKT/mTOR pathway. These findings highlighted the potential of PEC as a promising natural therapeutic agent for CC, paving the way for new treatment strategies. Further comprehensive research is warranted to fully explore PEC’s therapeutic capabilities and to develop innovative anti-cancer therapies.

Background Zika virus (ZIKV) infection is a global health problem, and its complications, including congenital Zika syndrome and Guillain-Barré syndrome, constitute a continued threat to humans. Unfortunately, effective therapeutics against ZIKV infection are not available thus far. Methods We screened the compounds collection consisting of 1789 FDA-approved drugs by a computational docking method to obtain anti-ZIKV candidate compounds targeting ZIKV RNA-dependent RNA polymerase (RdRp). SPR (BIAcore) assay was employed to demonstrate the candidate compounds’ direct binding to ZIKV RdRp, and polymerase activity assay was used to determine the inhibitory effect on ZIKV RdRp-catalyzed RNA synthesis. The antiviral effects on ZIKV in vitro and in vivo were detected in infected cultured cells and in Ifnar1 −/− mice infected by ZIKV virus using plaque assay, western blotting, tissue immunofluorescence, and immunohistochemistry. Results Here, we report that a first-in-class macrocyclic antibiotic, which has been clinically used to treat Clostridium difficile infection, fidaxomicin, potently inhibits ZIKV replication in vitro and in vivo. Our data showed that fidaxomicin was effective against African and Asian lineage ZIKV in a wide variety of cell lines of various tissue origins, and prominently suppressed ZIKV infection and significantly improved survival of infected mice. In addition, fidaxomicin treatment reduced the virus load in the brains and testes, and alleviated ZIKV-associated pathological damages, such as paralysis, hunching, and neuronal necrosis in the cerebra. Furthermore, our mechanistic study showed that fidaxomicin directly bound ZIKV NS5 protein and inhibited the RNA synthesis-catalyzing activity of ZIKV RdRp. Conclusions Our data suggest that fidaxomicin may represent an effective anti-ZIKV agent. In the light that fidaxomicin is already a clinically used drug, there might be a promising prospect in the development of fidaxomicin to be an antiviral therapeutic.

Objectives The SOX5 gene has been identified as the pathogenic gene responsible for Lamb-Shaffer syndrome. In this study, we examined the SOX5 variant (c.221C > T, p.Thr74Met) within a Chinese family presenting with intellectual disability and evaluated the functional implications of SOX5 by in vitro experiment. Materials and methods The family underwent a clinical assessment of intellectual development, which included precise clinical exome sequencing to identify causative genetic variants. The potential deleterious effects and pathogenicity of the variant were predicted using bioinformatics tools such as Mutation Taster, PROVEAN, and SIFT. Additionally, protein stability was evaluated using I-Mutant, and 3D protein structures were modeled with I-TASSER. Western blots and QPCR were employed to assess gene expression and protein stability. Flow cytometry was utilized to compare the cell cycle dynamics between wild-type and mutant cells. Results A previously identified missense variant (c.221C > T) in the SOX5 gene was determined to be the underlying cause of intellectual disability in a Chinese family. Functional assays demonstrated that mutant cells exhibited increased levels of SOX5 mRNA and protein relative to wild-type cells, accompanied by enhanced protein stability. Additionally, the mutant SOX5 protein was found to alter the cell cycle and downregulate the mRNA expression levels of the ACAN , AXIN2 , SOX9 , and PDGFRA genes. Conclusions We confirmed that the SOX5 p.Thr74Met variant is associated with intellectual disability in a second-generation Chinese family. This mutant protein potentially exhibits increased stability, influences the cell cycle, and downregulates genes related to bone and neural functions.