[Clinical analysis of transcranial facial nerve bridging with interpositional graft for the treatment of facial nerve injury].

Objective:To retrospectively analyze the effectiveness of transcranial facial nerve bridging in the treatment of facial nerve dysfunction. Methods:A retrospective analysis was conducted on 27 patients with facial nerve dysfunction who underwent transcranial facial nerve bridging at the Eye, Ear, Nose, and Throat Hospital affiliated with Fudan University from 2017 to 2022. The main collected data includes the patient's age, gender, primary lesion, damaged location, interval from facial paralysis to surgery, and preoperative and postoperative House-Brackmann（HB） scale for facial nerve function. Statistical comparisons were made between the average HB level of patients before and after surgery. Results:A total of 27 patients included 17 males and 10 females. The average age of patients during surgery is（42.50±3.38） years old. Primary lateral skull base diseases include trauma（n=3）, tumors（n=22）, and infections（n=2）. The duration of facial paralysis varies from 6 months to 5 years. Statistics analysis has found that the average postoperative HB score of patients who underwent transcranial facial nerve bridging was significantly lower at（3.750 ± 0.183） compared to preoperative（4.875±0.168）. The proportion of patients with good facial nerve function increased significantly from 7.4% before surgery to 42.9% after surgery. Conclusion:Transcranial facial nerve bridging surgery with interpositional graft has a significant effect on improving facial nerve function in patients with facial nerve injury. Further research is still needed to evaluate the long-term effectiveness of this surgery, to determine the optimal patient selection criteria and postoperative rehabilitation strategies.

Audiological Characteristics of Vestibular Schwannoma Patients With Normal Pure-Tone Audiometry.

OBJECTIVE: To investigate the audiological characteristics of vestibular schwannoma (VS) patients with normal pure-tone audiometry (PTA) results. STUDY DESIGN: A retrospective study. SETTING: Forty-two VS patients with normal PTA results from October 2016 to October 2022 were included. METHODS: Normal PTA was defined when the hearing threshold is ≤25 dB hearing loss (HL) in each test frequency and the PTA is ≤25 dB HL. Results of multiple audiological tests such as the auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), multiple auditory steady-state responses threshold (ASSR), and speech discrimination score were retrospectively reviewed. Demographic data of these patients were also been collected. RESULTS: According to our results, the ABR and average ASSR threshold of the affected side were statistically significantly higher in VS patients with normal PTA. ABR waveforms on the affected side also showed more abnormalities. The DPOAE pass rates of the affected side were lower than the unaffected side while the amplitude and signal-to-noise ratio rate was also lower. In addition, we used magnetic resonance imaging 3-dimensional reconstruction images to measure the volume of tumors in these patients. We also found that higher ABR threshold means lager tumor size in patients with normal PTA. CONCLUSION: VS patients with normal PTA result cannot be assumed to have no impairment of hearing function. ABR, DPOAE, and ASSR results showed the characteristic changes in the affect ear. ABR threshold has the highest sensitivity for hearing abnormalities and is strong relative with tumor size in patients with normal PTA.

Automatic detection of quartz glass subsurface defects by laser scattering method based on an ellipsoidal mirror.

With the improvement of quality requirements of optical components, the detection of subsurface defects of optical components has become a key technology. The existing detection methods still have some limitations in detection depth and detection efficiency. In this paper, a defect scattering light collection method based on ellipsoidal mirror model is used to analyze the scattering light collection efficiency under different experimental conditions theoretically, and the favorable conditions for improving the scattering light collection are proposed. After simulation verification, the use of ellipsoidal reflectors to collect scattered light can effectively avoid the impact of surface defects compared to lenses. At the same time, an experimental system based on this method is set up to filter the stray light by mean filtering method. The system detected three scratches (2 µm in width and 252 nm in depth) on the underside of a piece of quartz glass. The results show that the system can clearly detect the subsurface defects of optical components.

Microbial bile acid metabolite ameliorates mycophenolate mofetil-induced gastrointestinal toxicity through vitamin D3 receptor.

Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of lithocholic acid on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, a Food and Drug Administration-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.

A New Floating Piezoelectric Microphone for Fully Implantable Cochlear Implants in Middle Ear.

OBJECTIVE: Our team designed a long-lasting, well-sealed microphone, which uses laser welding and vacuum packaging technology. This study examined the sensitivity and effectiveness of this new floating piezoelectric microphone (NFPM) designed for totally implantable cochlear implants (TICIs) in animal experiments and intraoperative testing. METHODS: Different NFPM frequency responses from 0.25 to 10 kHz at 90 dB SPL were analyzed using in vivo testing of cats and human patients. The NFPM was tested in different positions that were clamped to the ossicular chains or placed in the tympanic cavity of cats and human patients. Two volunteers' long incus foot and four cats' malleus neck of the ossicular chain were clamped with the NSFM. The output electrical signals from different locations were recorded, analyzed, and compared. The NFPM was removed after the test without causing any damage to the middle-ear structure of the cats. Intraoperative tests of the NFPM were performed during the cochlear implant surgery and the cochlear implant surgery was completed after all tests. RESULTS: Compared with the results in the tympanic cavity, the NFPM could detect the vibration from the ossicular chain more sensitively in cat experiments and intraoperative testing. We also found that the signal output level of the NFPM decreased as the acoustic stimulation strength decreased in the intraoperative testing. CONCLUSION: The NFPM is effective in the intraoperative testing, making it feasible as an implantable middle-ear microphone for TICIs. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:937-944, 2024.

Comprehensive analysis of necroptosis-related genes in renal ischemia-reperfusion injury.

Background: Oxidative stress is the primary cause of ischemia-reperfusion injury (IRI) in kidney transplantation, leading to delayed graft function (DGF) and implications on patient health. Necroptosis is believed to play a role in renal IRI. This research presents a comprehensive analysis of necroptosis-related genes and their functional implications in the context of IRI in renal transplantation. Methods: The necroptosis-related differentially expressed genes (NR-DEGs) were identified using gene expression data from pre- and post-reperfusion renal biopsies, and consensus clustering analysis was performed to distinguish necroptosis-related clusters. A predictive model for DGF was developed based on the NR-DEGs and patients were divided into high- and low-risk groups. We investigated the differences in functional enrichment and immune infiltration between different clusters and risk groups and further validated them in single-cell RNA-sequencing (scRNA-seq) data. Finally, we verified the expression changes of NR-DEGs in an IRI mouse model. Results: Five NR-DEGs were identified and were involved in various biological processes. The renal samples were further stratified into two necroptosis-related clusters (C1 and C2) showing different occurrences of DGF. The predictive model had a reliable performance in identifying patients at higher risk of DGF with the area under the curve as 0.798. Additionally, immune infiltration analysis indicated more abundant proinflammatory cells in the high-risk group, which was also found in C2 cluster with more DGF patients. Validation of NR-DEG in scRNA-seq data further supported their involvement in immune cells. Lastly, the mouse model validated the up-regulation of NR-DEGs after IR and indicated the correlations with kidney function markers. Conclusions: Our research provides valuable insights into the identification and functional characterization of NR-DEGs in the context of renal transplantation and sheds light on their involvement in immune responses and the progression of IRI and DGF.

Ferroptosis related gene signature in T cell-mediated rejection after kidney transplantation.

BACKGROUND: T cell-mediated rejection is an important factor affecting early transplant kidney survival. Ferroptosis has been shown to play a pathogenic role in a variety of diseases, which was not reported in TCMR. Here we developed a model for assessing activation of ferroptosis-related genes in TCMR to find a better screening method and explore the contribution of ferroptosis in TCMR. METHODS: We performed unsupervised consensus clustering according to expression of ferroptosis-related genes based on RNA-seq data from kidney transplant biopsies, and developed an assessment model characterized by ferroptosis gene expression through PCA, which was evaluated in multiple external datasets as well as blood and urine samples. Pathway enrichment and immune cell infiltration analysis were used to explore the possible targets and pathways involved in ferroptosis and TCMR. RESULTS: A ferroptosis gene expression scoring model was established. The diagnostic specificity and sensitivity of TCMR in renal biopsy samples were both over 80%, AUC = 0.843, and AUC was around 0.8 in multi-dataset validation, and was also close to 0.7 in blood and urine samples, while in predicting of graft survival at 3 years, scoring model had a good prognostic effect as well. Pathway enrichment and PPI network speculated that TLR4, CD44, IFNG, etc. may be the key genes of ferroptosis in TCMR. CONCLUSIONS: Ferroptosis scoring model could better diagnose TCMR and predict graft loss, and could be used as a potential screening method in blood and urine samples. We speculate that ferroptosis plays an important role in TCMR.

Melatonin Alleviates the Oxygen-Glucose Deprivation/Reperfusion-Induced Pyroptosis of HEI-OC1 Cells and Cochlear Hair Cells via MT-1,2/Nrf2 (NFE2L2)/ROS/NLRP3 Pathway.

Substantial evidence suggests that pyroptosis is involved in renal, cerebral, and myocardial ischemia-reperfusion injury. However, whether pyroptosis is involved in ischemia-reperfusion injury of cochlear hair cells has not been explored. In this study, we examined the effects of melatonin on the oxygen-glucose deprivation/reperfusion (OGD/R) of hair cell-like House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear hair cells in vitro to mimic cochlear ischemia-reperfusion injury in vivo. We found that melatonin treatment protected the HEI-OC1 and cochlear hair cells against OGD/R-induced cell pyroptosis and reduced the expression level of ROS in these cells. However, these effects were completely abolished by the application of luzindole (a non-selective melatonin receptor blocker) and largely offset by the use of ML385 (an nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor). These findings suggest that melatonin alleviates OGD/R-induced pyroptosis of the hair cell-like HEI-OC1 cells and cochlear hair cells via the melatonin receptor 1A (MT-1) and melatonin receptor 1B (MT-2)/Nrf2 (NFE2L2)/ROS/NLRP3 pathway, which may provide credible evidence for melatonin being used as a potential drug for the treatment of idiopathic sudden sensorineural hearing loss in the future.

Gene methylation status in focus of advanced prostate cancer diagnostics and improved individual outcomes.

Background: Prostate cancer (PCa) is the most prevalent type of male genitourinary tumor, remains the second leading cause of deaths due to cancer in the United States in men. The aim of this study was to perform an integrative epigenetic analysis to explore the epigenetic abnormalities involved in the development and progression of PCa, and present advanced diagnostics and improved individual outcomes. Methods: Genome-wide DNA methylation profiles obtained from The Cancer Genome Atlas (TCGA) were analyzed and a diagnostic model was constructed. For validation, we employed profiles from the Gene Expression Omnibus (GEO) and methylation data derived from clinical samples. Gene set enrichment analysis (GSEA) and the Tumor Immune Estimation Resource (TIMER) were employed for GSEA and to assess immune cell infiltration, respectively. Results: An accurate diagnostic method for PCa was established based on the methylation level of Cyclin-D2 (CCND2) and glutathione S-transferase pi-1 (GSTP1), with an impressive area under the curve (AUC) value of 0.937. The model's reliability was further confirmed through validation using four GEO datasets GSE76938 (AUC =0.930), GSE26126 (AUC =0.906), GSE112047 (AUC =1.000), GSE84749 (AUC =0.938) and clinical samples (AUC =0.980). Notably, the TIMER analysis indicated that hypermethylation of CCND2 and GSTP1 was associated with reduced immune cell infiltration, higher tumor purity, and an increased risk of tumor progression. Conclusions: In conclusion, our study provides a robust and reliable methylation-based diagnostic model for PCa. This model holds promise as an improved approach for screening and diagnosing PCa, potentially enhancing early detection and patient outcomes, as well as for an advanced clinical management for PCa in the framework of predictive, preventive and personalised medicine.

Identification of a novel CNV at the EYA4 gene in a Chinese family with autosomal dominant nonsyndromic hearing loss.

BACKGROUND: Hereditary hearing loss is a heterogeneous class of disorders that exhibits various patterns of inheritance and involves many genes. Variants in the EYA4 gene in DFNA10 are known to lead to postlingual, progressive, autosomal dominant nonsyndromic hereditary hearing loss. PATIENTS AND METHODS: We collected a four-generation Chinese family with autosomal-dominant nonsyndromic hearing loss (ADNSHL). We applied targeted next-generation sequencing (TNGS) in three patients of this pedigree and whole-genome sequencing (WGS) in the proband. The intrafamilial cosegregation of the variant and the deafness phenotype were confirmed by PCR, gap-PCR and Sanger sequencing. RESULTS: A novel CNV deletion at 6q23 in exons 8-11 of the EYA4 gene with a 10 bp insertion was identified by TNGS and WGS and segregated with the ADNSHL phenotypes. CONCLUSIONS: Our results expanded the variant spectrum and genotype‒phenotype correlation of the EYA4 gene and autosomal dominant nonsyndromic hereditary hearing loss in Chinese Han individuals. WGS is an accurate and effective method for verifying the genomic features of CNVs.

Signal-3L 3.0: Improving Signal Peptide Prediction through Combining Attention Deep Learning with Window-Based Scoring.

Signal peptides play an important role in guiding and transferring transmembrane proteins and secreted proteins. In recent years, with the explosive growth of protein sequences, computationally predicting signal peptides and their cleavage sites from protein sequences is highly desired. In this work, we present an improved approach, Signal-3L 3.0, for signal peptide recognition and cleavage-site prediction using a 3-layer hybrid method of integrating deep learning algorithms and window-based scoring. There are three main components in the Signal-3L 3.0 prediction engine: (1) a deep bidirectional long short-term memory (Bi-LSTM) network with a soft self-attention learns abstract features from sequences to determine whether a query protein contains a signal peptide; (2) the statistics propensity window-based cleavage site screening method is applied to generate the set of candidate cleavage sites; (3) the prediction of a conditional random field with a hybrid convolutional neural network (CNN) and Bi-LSTM is fused with the window-based score for identifying the final unique cleavage site. Experimental results on the benchmark datasets show that the new deep learning-driven Signal-3L 3.0 yields promising performance. The online server of Signal-3L 3.0 is available at http://www.csbio.sjtu.edu.cn/bioinf/Signal-3L/.

Butyric acid normalizes hyperglycemia caused by the tacrolimus-induced gut microbiota.

Approximately 33.6% of nondiabetic solid organ transplant recipients who received tacrolimus developed hyperglycemia. Whether the tacrolimus-induced gut microbiota is involved in the regulation of hyperglycemia has not been reported. Hyperglycemia was observed in a tacrolimus-treated mouse model, with reduction in taxonomic abundance of butyrate-producing bacteria and decreased butyric acid concentration in the cecum. This tacrolimus-induced glucose metabolic disorder was caused by the gut microbiota, as confirmed by a broad-spectrum antibiotic model. Furthermore, oral supplementation with butyrate, whether for remedy or prevention, significantly increased the butyric acid content in the cecum and arrested hyperglycemia through the regulation of glucose-regulating hormones, including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and insulin, in serum. The butyrate-G-protein-coupled receptor 43-GLP-1 pathway in the intestinal crypts may be involved in the pathogenesis of normalization of hyperglycemia caused by the tacrolimus. Therefore, tacrolimus affects glucose metabolism through the butyrate-associated GLP-1 pathway in the gut, and oral supplementation with butyrate provides new insights for the prevention and treatment of tacrolimus-induced hyperglycemia in transplant recipients.

Topology Prediction Improvement of α-helical Transmembrane Proteins Through Helix-tail Modeling and Multiscale Deep Learning Fusion.

Transmembrane proteins (TMPs) play important roles in many biological processes, such as cell recognition and communication. Their structures are crucial for revealing complex functions but are hard to obtain. A variety of computational algorithms have been proposed to fill the gap by predicting structures from primary sequences. In this study, we mainly focus on α-helical TMP and develop a multiscale deep learning pipeline, MemBrain 3.0, to improve topology prediction. This new protocol includes two submodules. The first module is transmembrane helix (TMH) prediction, which features the capability of accurately predicting TMH with the tail part through the incorporation of tail modeling. The prediction engine contains a multiscale deep learning model and a dynamic threshold strategy. The deep learning model is comprised of a small-scale residue-based residual neural network and a large-scale entire-sequence-based residual neural network. Dynamic threshold strategy is designed to binarize the raw prediction scores and solve the under-split problem. The second module is orientation prediction, which consists of a support vector machine (SVM) classifier and a new Max-Min assignment (MMA) strategy. One typical merit of MemBrain 3.0 is the decision mode composed of the dynamic threshold strategy and the MMA strategy, which makes it more effective for hard TMHs, such as half-TMH, back-to-back TMH, and long-TMH. Systematic experiments have demonstrated the efficacy of the new model, which is available at: www.csbio.sjtu.edu.cn/bioinf/MemBrain/.

Knockdown of DSPP inhibits the migration and invasion of glioma cells.

Dentin sialophosphoprotein (DSPP) is a member of the SIBLING (Small integrin-binding ligand N-linked glycoproteins) family of phosphoglycoproteins and has been proved to contribute to the migration of a variety of solid tumor cells. However, whether DSPP participates in the pathogenic process of glioma remains unknown. In this study, we aimed to investigate the expression and biological function of DSPP in human glioma cells. We demonstrated through Western blot that DSPP is overexpressed in glioma tissues comparing to normal brain tissues. To investigate the role of DSPP in glioma carcinogenesis, we reduced the DSPP expression by small interfering RNA (siRNA) and found that DSPP silencing significantly inhibited the migration and invasion of glioma cells, the critical characteristics of glioma. Furthermore, we showed that DSPP down-regulation significantly decreased the activation of the AKT/mTOR/p70S6K pathway in glioma cells. Taken together, these findings indicate that knockdown of DSPP inhibits glioma cells migration and invasion, suggesting that targeting DSPP might be a potentially effective therapeutic strategy for treating glioma.

Numerical Study of Double-Layered Microchannel Heat Sinks with Different Cross-Sectional Shapes.

This work numerically studies the thermal and hydraulic performance of double-layered microchannel heat sinks (DL-MCHS) for their application in the cooling of high heat flux microelectronic devices. The superiority of double-layered microchannel heat sinks was assessed by a comparison with a single-layered microchannel heat sink (SL-MCHS) with the same triangular microchannels. Five DL-MCHSs with different cross-sectional shapes-triangular, rectangular, trapezoidal, circular and reentrant Ω-shaped-were explored and compared. The results showed that DL-MCHS decreased wall temperatures and thermal resistance considerably, induced much more uniform wall temperature distribution, and reduced the pressure drop and pumping power in comparison with SL-MCHS. The DL-MCHS with trapezoidal microchannels performed the worst with regard to thermal resistance, pressure drop, and pumping power. The DL-MCHS with rectangular microchannels produced the best overall thermal performance and seemed to be the optimum when thermal performance was the prime concern. Nevertheless, the DL-MCHS with reentrant Ω-shaped microchannels should be selected when pumping power consumption was the most important consideration.

Mitochondrial phosphatase PGAM5 regulates Keap1-mediated Bcl-xL degradation and controls cardiomyocyte apoptosis driven by myocardial ischemia/reperfusion injury.

Phosphoglycerate mutase 5 (PGAM5) is a mitochondrial membrane protein that plays crucial roles in necroptosis and apoptosis. Though PGAM5 is known to be required for inducing intrinsic apoptosis through interacting with BCL2 associated X protein (Bax) and dynamin-related protein 1 (Drp1), the expression and role of PGAM5 in cardiomyocyte apoptosis driven by myocardial ischemia/reperfusion injury(MIRI) has not been studied. The present study shows that PGAM5 expression decreased after MIRI in vivo, positively correlated with Bcl-xL expression, negatively correlated with Kelch-ECH associating protein 1 (Keap1) expression. Furthermore, PGAM5 expression also decreased in cardiomyocytes after hypoxia/reoxygenation (H/R) treatment in vitro. PGAM5 silence promoted cardiomyocyte apoptosis and inhibited Bcl-xL expression, but with no effect on Keap1 expression. Accordingly, Keap1 overexpression further inhibited Bcl-xL and PGAM5 expression. Additionally, PGAM5-Bcl-xL-Keap1 interaction was identified, suggesting that PGAM5 might participate in the degradation of Bcl-xL mediated by Keap1. In summary, PGAM5 controls cardiomyocyte apoptosis induced by MIRI through regulating Keap1-mediated Bcl-xL degradation, which may supply a novel molecular target for acute myocardial infarction (AMI) therapy. Graphical abstract ᅟ.

iT2DM Project: A Framework for Secondary Use of EHR Data for High-Throughput Phenotyping in Diabetes.

Diabetes is one of the major burdens in health care, but could be controlled if the relevant data are well-managed. Referring to current successful cases, we designed a framework for the interoperability and integration of medical data in compliance with both archetype and reference information model specification. The clinical data model (CDM) was designed on the basis of OpenEHR archetypes and self-made patient generated health data (PGHD). Integrating healthcare enterprise (IHE) protocol was taken into integrating different modality data. After terminology mapping, the personal health record could be transferred and shared in different clinical information vendors complying with HL7 standards. Many fragment data such as blood glucose and gene data were also integrated to system. Those patients suspected of higher risk of diabetic retinopathy (DR) were grouped as case and other patients could be filtered as control cohort. Furthermore, the framework could be further developed for precision medicine.