Advances in the Study of Etiology and Molecular Mechanisms of Sensorineural Hearing Loss.

Sensorineural hearing loss (SNHL), a multifactorial progressive disorder, results from a complex interplay of genetic and environmental factors, with its underlying mechanisms remaining unclear. Several pathological factors are believed to contribute to SNHL, including genetic factors, ion homeostasis, cell apoptosis, immune inflammatory responses, oxidative stress, hormones, metabolic syndrome, human cytomegalovirus infection, mitochondrial damage, and impaired autophagy. These factors collectively interact and play significant roles in the onset and progression of SNHL. The present review offers a comprehensive overview of the various factors that contribute to SNHL, emphasizes recent developments in understanding its etiology, and explores relevant preventive and intervention measures.

mRNA-responsive two-in-one nanodrug for enhanced anti-tumor chemo-gene therapy.

The combination of chemotherapy and gene therapy holds great promise for the treatment and eradication of tumors. However, due to significant differences in physicochemical properties between chemotherapeutic agents and functional nucleic acid drugs, direct integration into a single nano-agent is hindered, impeding the design and construction of an effective co-delivery nano-platform for synergistic anti-tumor treatments. In this study, we have developed an mRNA-responsive two-in-one nano-drug for effective anti-tumor therapy by the direct self-assembly of 2'-fluoro-substituted antisense DNA against P-glycoprotein (2'F-DNA) and chemo drug paclitaxel (PTX). The 2'-fluoro modification of DNA could significantly increase the interaction between the therapeutic nucleic acid and the chemotherapeutic drug, promoting the successful formation of 2'F-DNA/PTX nanospheres (2'F-DNA/PTX NSs). Due to the one-step self-assembly process without additional carrier materials, the prepared 2'F-DNA/PTX NSs exhibited considerable loading efficiency and bioavailability of PTX. In the presence of endogenous P-glycoprotein mRNA, the 2'F-DNA/PTX NSs were disassembled. The released 2'F-DNA could down-regulate the expression of P-glycoprotein, which decreased the multidrug resistance of tumor cells and enhanced the chemotherapy effect caused by PTX. In this way, the 2'F-DNA/PTX NSs could synergistically induce the apoptosis of tumor cells and realize the combined anti-tumor therapy. This strategy might provide a new tool to explore functional intracellular co-delivery nano-systems with high bioavailability and exhibit potential promising in the applications of accurate diagnosis and treatment of tumors.

Changes in the global burden of foreign body aspiration among under-5 children from 1990 to 2019.

Background: To evaluate the changes in the global burden of foreign body aspiration (FBA) among children under 5 years old at regional, age, sex, and socio-demographic index (SDI) levels between 1990 and 2019. Methods: Data on FBA was derived from the Global Burden of Disease (GBD) Study 2019 database on pulmonary aspiration and foreign body in airway. The means and 95% uncertainty intervals (UIs) were calculated for incidence, and disability-adjusted life-years (DALYs). The temporal trends were represented by estimated annual percentage change (EAPC) using Joinpoint regression. Results: Globally, FBA caused 109.6 (95% UI: 69.5, 175.7) per 100,000 incidence and 317.9 (95% UI: 270.7, 372.4) per 100,000 DALYs under 5 years old in 2019. Many European countries (such as Italy, Netherlands, Iceland, etc.) showed a high incidence rate, but did not cause a large disease burden (DALYs all less than 200 per 100,000). Compared to 1990, although a decrease in both incidence and DALYs occurred in 2019, the Joinpoint regression showed an increasing trend in incidence rate from 2014 to 2019 [APC: both (2.10), female (2.25), male (1.98), P < 0.05)], especially China, Netherlands, and Malta. Despite the lower incidence rate in early neonatal group and middle SDI areas, they instead resulted in higher DALYs than other age groups and areas. Conclusion: Although declines occurred in incidence and DALYs of FBA among children under 5 years of age from 1990 to 2014, an upward trend began to emerge from 2014 to 2019. The incidence and DALY rates were correlated with age and SDI. Increased efforts are needed to improve the necessary monitoring and reporting systems, hazard assessment, and public education activities.

Bacillus thuringiensis EM-A1: A novel bacterium for high concentration of ammonium elimination with low nitrite accumulation.

The biological elimination of high concentration of ammonium from wastewater has attracted increasing attention in recent years. However, few studies on the efficient elimination of high concentration of ammonium by a single bacterium have been reported. Here, the efficient elimination of NH4+-N (>99%) and total nitrogen (TN) (>77%) were attained by Bacillus thuringiensis EM-A1 under 150 rpm at pH 7.2 with sodium succinate and a carbon/nitrogen ratio of 15 at 30 °C with an inoculum size (as measured by absorbance at 600 nm) of 0.2. Strain EM-A1 effectively eliminated 100 mg/L of inorganic nitrogen with maximal NH4+-N, NO3--N, and NO2--N elimination rates of 4.88, 2.57, and 3.06 mg/L/h, respectively. The elimination efficiencies of NH4+-N were 99.87% and 97.13% at initial concentrations of 500 and 1000 mg/L, respectively. Only 0.91 mg/L of NO2--N was accumulated with the elimination of 1000 mg/L NH4+-N. A concentration of 5 mg/L exogenous hydroxylamine was toxic and further inhibited heterotrophic nitrification and aerobic denitrification (HN-AD). The NH4+-N and NO2--N elimination capacities of strain EM-A1 were specifically inhibited by 2-Octyne (OCT) over 4 µmol/L and diethyldithiocarbamate (DDC) over 0.5 mmol/L, respectively. Above 25 mg/L procyanidin (PCY) inhibited the bioconversion of NO3--N and NO2--N. The results demonstrated that strain EM-A1 had HN-AD capacity under halophilic conditions, and has great potential for use in the treatment of nitrogen pollution wastewater; this study also provides new insights into this strain's nitrogen elimination mechanism, helping advance environmental biotechnology.

Morphological and phylogenetic characterisation of two new soil-borne fungal taxa belonging to Clavicipitaceae (Hypocreales, Ascomycota).

The fungal taxa belonging to the Clavicipitaceae (Hypocreales, Ascomycota) are widely distributed and include diverse saprophytic, symbiotic and pathogenic species that are associated with soils, insects, plants, fungi and invertebrates. In this study, we identified two new fungal taxa belonging to the family Clavicipitaceae that were isolated from soils collected in China. Morphological characterisation and phylogenetic analyses showed that the two species belong to Pochonia (Pochoniasinensissp. nov.) and a new genus for which we propose Paraneoaraneomycesgen. nov. in Clavicipitaceae.

ADAM17 Aggravates the Inflammatory Response by Modulating Microglia Polarization Through the TGF-ß1/Smad Pathway Following Experimental Traumatic Brain Injury.

Microglia-mediated neuroinflammatory responses play important roles in secondary neurological injury after traumatic brain injury (TBI). The TGF-ß pathway participates in the regulation of M1/M2 phenotype transformation of microglia. TGF-ß can activate the Smad pathway by binding to TGF-ßRs, which is regulated by the cleavage function of A disintegrin and metalloproteinase 17 (ADAM17). However, the role of ADAM17 and the associated signaling pathways in the pathological process after TBI remain unclear. Herein, we assessed the transformation of microglia M1/M2 phenotype polarization and the neuroinflammatory response after the inhibition of ADAM17. The formation of TGF-ßRs and TGF-ß1/TGF-ßRII complexes on microglia were detected to evaluate the effect of ADAM17 inhibition on the TGF-ß1/Smad pathway. ADAM17 was highly expressed after TBI and mainly located in the microglia. the inhibition of ADAM17 improved neurological function after TBI. The neuroprotective effect of ADAM17 inhibition was related to a shift from the M1 microglial phenotype to the M2 microglial phenotype, thus reducing TBI-induced neuroinflammation. ADAM17 inhibition increased expression of TGF-ßRs on the microglia membrane, promoted formation of TGF-ß1/TGF-ßRII complexes, and induced intranuclear translocation of Smads, which activated the TGF-ß/Smad pathway. In conclusion, our study suggested that ADAM17 inhibition regulated microglia M1/M2 phenotype polarization through the TGF-ß1/Smad pathway and influenced the neuroinflammatory response after TBI.

[Denitrifying phosphate accumulating organisms and its mechanism of nitrogen and phosphorus removal].

Water eutrophication poses great threats to protection of water environment. Microbial remediation of water eutrophication has shown high efficiency, low consumption and no secondary pollution, thus becoming an important approach for ecological remediation. In recent years, researches on denitrifying phosphate accumulating organisms and their application in wastewater treatment processes have received increasing attention. Different from the traditional nitrogen and phosphorus removal process conducted by denitrifying bacteria and phosphate accumulating organisms, the denitrifying phosphate accumulating organisms can simultaneously remove nitrogen and phosphorus under alternated anaerobic and anoxic/aerobic conditions. It is worth noting that microorganisms capable of simultaneously removing nitrogen and phosphorus absolutely under aerobic conditions have been reported in recent years, but the mechanisms remain unclear. This review summarizes the species and characteristics of denitrifying phosphate accumulating organisms and the microorganisms capable of performing simultaneous nitrification-denitrification and phosphorous removal. Moreover, this review analyzes the relationship between nitrogen removal and phosphorus removal and the underlying mechanisms, discusses the challenges of denitrifying phosphorus removal, and prospects future research directions, with the aim to facilitate process improvement of denitrifying phosphate accumulating organisms.

Global, regional, and national burden and attributable risk factors of neurological disorders: The Global Burden of Disease study 1990-2019.

Background: Neurological disorders are a major and increasing global health challenge, which accounts for a substantial portion of the disease burden worldwide. The aim of this systematic analysis is to present the most comprehensive and up-to-date estimates of disease burden, epidemiological trends, and attributable risk factors of neurological disorders at global, regional, and national levels. Methods: We extracted data of 18 neurological disorders from the Global Burden of Disease 2019 study database. The burden of neurological disorders was measured using the incidence, prevalence, mortality, and disability-adjusted life years (DALYs), and further described according to age, sex, year, geographical location and socio-demographic Index (SDI). All estimates were presented with corresponding 95% uncertainty intervals (UIs). Findings: Globally, in 2019, there were nearly 10 million deaths and 349 million DALYs due to neurological disorders. Among the 18 neurological disorders, stroke was the biggest contributor to DALYs (143232.18 [95%UI 133095.81-153241.82] in thousands) and deaths (6552.72 [95%UI 5995.20-7015.14] in thousands), followed by neonatal encephalopathy due to birth asphyxia and trauma. From 1990 to 2019, the DALYs of neurological diseases belonging to the communicable, maternal, neonatal and nutritional categories showed a sharp decrease, while Alzheimer's disease and other dementias and Parkinson's disease showed a large increase. Neurological disorders exhibited different profiles in different regions and age groups. A significant correlation between the SDI and the age-standardized DALY rates was also found except for Alzheimer's disease and other dementias. In addition, risk factors such as high systolic blood pressure, low birth weight and short gestation period, and metabolic risk contribute significantly to neurological disorders. Interpretation: The overall burden of neurological disorders has increased from 1990 to 2019, especially for non-communicable neurological disorders. The substantial variations of burden across regions emphasize the need for region-specific interventional strategies and allocation of resources based on priorities.

Biomineralized hybrid nanodots for tumor therapy via NIR-II fluorescence and photothermal imaging.

Chemodynamic therapy (CDT) is an emerging and promising therapeutic strategy that suppresses tumor growth by catalytically converting intracellular hydrogen peroxide (H2O2) into highly-reactive hydroxyl radicals (•OH). However, the inherent substrate of H2O2 is relatively insufficient to achieve desirable CDT efficacy. Therefore, searching for integrated therapeutic methods with synergistic therapeutic modality is especially vital to augment therapeutic outcomes. Herein, we reported nanodot- CuxMnySz @BSA@ICG (denoted as CMS@B@I) and bovine serum albumin (BSA)-based biomineralization CuxMnySz (CMS) loaded with photodynamic agent-indocyanine green (ICG). CMS@B@I converts endogenous hydrogen peroxide (H2O2) into highly active hydroxyl radical (•OH) via Fenton reaction, and effectively produces reactive oxygen species (ROS) after being exposed to 808 nm laser irradiation, attributable to the excellent photodynamic agent-ICG. This results in eliciting a ROS storm. Additionally, CMS@B@I exhibits a superior photothermal effect under NIR-II 1064 nm laser irradiation to enhance tumor CDT efficacy. The NIR-II fluorescence imaging agent of ICG and the excellent photothermal effect of CMS@B@I are highly beneficial to NIR-II fluorescence and infrared thermal imaging, respectively, resulting in tracing the fate of CMS@B@I. This study attempts to design a bimodal imaging-guided and photothermal-enhanced CDT nanoagent for augmenting tumor catalytic therapy.

Integrative and comparative single-cell analysis reveals transcriptomic difference between human tumefactive demyelinating lesion and glioma.

Tumefactive demyelinating lesion (TDL) is an immune-mediated disease which can be misdiagnosed as glioma. At present, there is no study comparing difference between the two disorders at the cellular level. Here, we perform integrative and comparative single-cell RNA sequencing (ScRNA-seq) transcriptomic analysis on TDL and glioma lesions. At single-cell resolution, TDL is comprised primarily of immune cells, which is completely different from glioma. The integrated analysis reveals a TDL-specific microglial subset involving in B cell activation and proliferation. Comparative analysis highlights remyelination function of glial cells and demyelination function of T cells in TDL. Subclustering and pseudotime trajectory analysis of T cells in TDL reveal their heterogeneity and diverse functions involving in TDL pathogenesis and recovery process. Our study identifies substantial differences between TDL and glioma at single-cell resolution. The observed heterogeneity and potentially diverse functions of cells in TDL may be critical in disease progression.

Single-cell RNA sequencing reveals intra-tumoral heterogeneity of glioblastoma and a pro-tumor subset of tumor-associated macrophages characterized by EZH2 overexpression.

BACKGROUND: Glioblastoma (GBM) is a highly heterogeneous disease with poor clinical outcome. AIM: To comprehensively dissect molecular landscape of GBM and heterogeneous distribution and potential role of Enhancer of zeste homolog 2 (EZH2) in tumor microenvironment (TME). METHODS: Single-cell RNA sequencing (scRNA-seq) analysis was performed in GBM samples from 8 patients. Deconvolution analysis, immunofluorescence (IF) microscopy, reverse-transcription quantitative polymerase chain reaction (RT-qPCR), colony formation experiments, and Cell Counting Kit-8 (CCK-8) assays were performed to confirmed the potential role of EZH2 in TME cells. RESULTS: Malignant cells exhibited remarkable heterogeneity in abnormal metabolic patterns. A mesenchymal-2-like (MES2-like) GBM subcluster with glial-immune dual feature was firstly discovered, which were associated with highly activated hallmark pathways, immune evasion associated transcription factor (IRF8), and poor survival. The oncogene, EZH2, was heterogeneously expressed in malignant cells and immune cells consistent with proliferative genes, cell-cycle transcription factors, and similar activated hallmark pathways. In a tumor-associated macrophages (TAMs) subset (macrophage.3), EZH2 was highly expressed with similar changes of transcriptomic dynamics with cell-cycle genes and macrophages M2-phetotype genes. In addition, the subset tightly interacted with malignant cells. Deconvolution analysis showed increased abundance of the subset in GBM compared to low-grade glioma (LGG) and significant association with worse prognosis. Functional verification experiments confirmed the pro-tumor role of TAMs with EZH2 overexpression in GBM. CONCLUSIONS: Our study illustrated a MES2-like GBM subcluster characterized by glial-immune dual feature and highlighted the pro-tumor role of a TAMs subset characterized by EZH2 overexpression.

New insight into the nitrogen removal capacity and mechanism of Streptomyces mediolani EM-B2.

The utilization of actinomycetes as the bioresources for heterotrophic nitrification and aerobic denitrification is rarely reported due to the lack of work to explore their nitrogen biodegradation capabilities. Streptomyces mediolani EM-B2 belonging to actinomycetes could effectively remove high concentration of multiple nitrogen forms, and the maximum removal rates of ammonium, nitrate and nitrite reached 3.46 mg/(L·h), 1.71 mg/(L·h) and 1.73 mg/(L·h), respectively. Nitrite was preferentially consumed from the simultaneous nitrification and denitrification reaction system. Nitrogen balance analysis uncovered that more than 37% of the initial total nitrogen was converted to nitrogenous gas by aerobic denitrification. Experiments with specific inhibitors of nitrification and denitrification revealed that strain EM-B2 contained ammonia monooxygenase, hydroxylamine oxidoreductase, nitrate reductase and nitrite oxidoreductase, which were successfully expressed and detected as 0.43, 0.59, 0.12 and 0.005 U/mg proteins, respectively. These findings may provide new insights into the actinomycetes for bioremediation of nitrogen pollution wastewater.

Efficient hydroxylamine removal through heterotrophic nitrification by novel bacterium Glutamicibacter arilaitensis EM-H8.

Hydroxylamine, an intermediate product in the nitrification process, is widely found in nature. However, hydroxylamine accumulation can decrease the biological nitrogen removal efficiency by reducing the activities, inhibiting the reproductions, and even causing the death of microorganisms. In this study, a novel heterotrophic nitrification bacterium was separated from biogas digester and identified as Glutamicibacter arilaitensis EM-H8. Strain EM-H8 exhibited efficient hydroxylamine removal (93.75%). The optimal conditions for hydroxylamine removal were as follows: Carbon source, glucose; C/N ratio, 25; temperature, 20 °C; inoculum size, 0.53 × 108 CFU; and shaking speed, 150 rpm. The nitrogen balance results using strain EM-H8 showed that about 26.86% of the initial nitrogen was removed as nitrogenous gas, while 4.6% was converted into biomass under aerobic conditions, confirming that strain EM-H8 possessed the capacity for heterotrophic nitrification. Furthermore, the successful expression of hydroxylamine oxidase (0.065 U/mg protein) showed that strain EM-H8 had the ability to transform hydroxylamine from wastewater.

Machine-Learning Prediction of Postoperative Pituitary Hormonal Outcomes in Nonfunctioning Pituitary Adenomas: A Multicenter Study.

Objective: No accurate predictive models were identified for hormonal prognosis in non-functioning pituitary adenoma (NFPA). This study aimed to develop machine learning (ML) models to facilitate the prognostic assessment of pituitary hormonal outcomes after surgery. Methods: A total of 215 male patients with NFPA, who underwent surgery in four medical centers from 2015 to 2021, were retrospectively reviewed. The data were pooled after heterogeneity assessment, and they were randomly divided into training and testing sets (172:43). Six ML models and logistic regression models were developed using six anterior pituitary hormones. Results: Only thyroid-stimulating hormone (p < 0.001), follicle-stimulating hormone (p < 0.001), and prolactin (PRL; p < 0.001) decreased significantly following surgery, whereas growth hormone (GH) (p < 0.001) increased significantly. The postoperative GH (p = 0.07) levels were slightly higher in patients with gross total resection, but the PRL (p = 0.03) level was significantly lower than that in patients with subtotal resection. The optimal model achieved area-under-the-receiver-operating-characteristic-curve values of 0.82, 0.74, and 0.85 in predicting hormonal hypofunction, new deficiency, and hormonal recovery following surgery, respectively. According to feature importance analyses, the preoperative levels of the same type and other hormones were all important in predicting postoperative individual hormonal hypofunction. Conclusion: Fluctuation in anterior pituitary hormones varies with increases and decreases because of transsphenoidal surgery. The ML models could accurately predict postoperative pituitary outcomes based on preoperative anterior pituitary hormones in NFPA.

Establishment and Validation of an Integrated Model to Predict Postoperative Recurrence in Patients With Atypical Meningioma.

BACKGROUND: This study aims to establish an integrated model based on clinical, laboratory, radiological, and pathological factors to predict the postoperative recurrence of atypical meningioma (AM). MATERIALS AND METHODS: A retrospective study of 183 patients with AM was conducted. Patients were randomly divided into a training cohort (n = 128) and an external validation cohort (n = 55). Univariable and multivariable Cox regression analyses, the least absolute shrinkage and selection operator (LASSO) regression analysis, time-dependent receiver operating characteristic (ROC) curve analysis, and evaluation of clinical usage were used to select variables for the final nomogram model. RESULTS: After multivariable Cox analysis, serum fibrinogen >2.95 g/L (hazard ratio (HR), 2.43; 95% confidence interval (CI), 1.05-5.63; p = 0.039), tumor located in skull base (HR, 6.59; 95% CI, 2.46-17.68; p < 0.001), Simpson grades III-IV (HR, 2.73; 95% CI, 1.01-7.34; p = 0.047), tumor diameter >4.91 cm (HR, 7.10; 95% CI, 2.52-19.95; p < 0.001), and mitotic level ≥4/high power field (HR, 2.80; 95% CI, 1.16-6.74; p = 0.021) were independently associated with AM recurrence. Mitotic level was excluded after LASSO analysis, and it did not improve the predictive performance and clinical usage of the model. Therefore, the other four factors were integrated into the nomogram model, which showed good discrimination abilities in training cohort (C-index, 0.822; 95% CI, 0.759-0.885) and validation cohort (C-index, 0.817; 95% CI, 0.716-0.918) and good match between the predicted and observed probability of recurrence-free survival. CONCLUSION: Our study established an integrated model to predict the postoperative recurrence of AM.