Monocytes Release Pro-Cathepsin D to Drive Blood-to-Brain Transcytosis in Diabetes.

BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.

Calmodulin triggers activity-dependent rRNA biogenesis via interaction with DDX21.

Protein synthesis in response to neuronal activity, known as activity-dependent translation, is critical for synaptic plasticity and memory formation. However, the signaling cascades that couple neuronal activity to the translational events remains elusive. In this study, we identified the role of calmodulin (CaM), a conserved Ca2+-binding protein, in rRNA biogenesis in neurons. We found the CaM-regulated rRNA synthesis is Ca2+-dependent and necessary for nascent protein synthesis and axon growth in hippocampal neurons. Mechanistically, CaM interacts with nucleolar DDX21 in a Ca2+-dependent manner to regulate nascent rRNA transcription within nucleoli. We further found CaM alters the conformation of DDX21 to liberate the DDX21-sequestered RPA194, the catalytic subunit of RNA polymerase I, to facilitate transcription of rDNA. Using high-throughput screening, we identified the small molecules Batefenterol and Indacaterol that attenuate the CaM-DDX21 interaction and suppress nascent rRNA synthesis and axon growth in hippocampal neurons. These results unveiled the previously unrecognized role of CaM as a messenger to link the activity-induced Ca2+ influx to the nucleolar events essential for protein synthesis. We thus identified the ability of CaM to transmit information to the nucleoli of neurons in response to stimulation.Significance statement Protein synthesis in response to neuronal activity, known as activity-dependent translation, is critical for synaptic plasticity and long-term memory formation. In this study, we identify the novel role of calmodulin (CaM), a highly conserved Ca2+-binding protein, which is well-known by regulating myriad vital biological processes, in activity-dependent translation by regulating rRNA synthesis in neurons. We find that CaM can shuttle into the nucleolus upon depolarization and modulate the activity-induced de novo rRNA biogenesis, which is associated with ribosome assembly and protein synthesis in neurons. Mechanistically, CaM interacts with DDX21, an RNA helicase directly associated with Pol I subunit, to regulate the transcription of rDNA. Our study demonstrates CaM as a messenger linking neuronal activity to ribosome-dependent protein biosynthesis.

Machine-learning and scRNA-Seq-based diagnostic and prognostic models illustrating survival and therapy response of lung adenocarcinoma.

Lung cancer is a major cause accounting for cancer-related mortalities, with lung adenocarcinoma (LUAD) being the most prevalent subtype. Given the high clinical and cellular heterogeneities of LUAD, accurate diagnosis and prognosis are crucial to avoid overdiagnosis and overtreatment. Taking full advantage of scRNA-Seq data to resolve the tumor heterogeneities, we explored the overall landscape of LUAD microenvironment. Utilizing the stage-specific tumor cell markers, we have developed highly accurate diagnostic and prognostic models with elevated sensitivity and specificity. The diagnostic model, developed through random forest algorithms with a thirteen-gene signature, achieved an accuracy of 96.4% and an AUC of 0.993. These metrics were further demonstrated by benchmarking with available models and scoring systems in independent cohorts. Concurrently, the prognostic model, formulated via Cox regression with a six-gene signature, effectively predicted overall survival, with elevated risk scores associated with increased fractions of cancer-associated fibroblasts, and higher likelihood of immune escape and T-cell exclusion. Subsequently, two nomograms were developed to predict survival and drug responses, facilitating their integration into clinical practice. Overall, this study underscores the potential of our models for efficient, rapid, and cost-effective diagnosis and prognosis of LUAD, adaptable to multiple expression profiling platforms and quantification methods.

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

BACKGROUND: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. METHODS: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). RESULTS: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. CONCLUSIONS: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. TRIAL REGISTRATION: NCT03534453. Registered at May 23, 2018.

Monocytes release cystatin F dimer to associate with Aß and aggravate amyloid pathology and cognitive deficits in Alzheimer's disease.

BACKGROUND: Understanding the molecular mechanisms of Alzheimer's disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aß) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aß clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aß by monocytes in AD remains unclear. METHODS: Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aß by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aß. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology. RESULTS: Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aß deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aß by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aß to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aß. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice. CONCLUSIONS: Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aß metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.

Contribution of oxygen vacancies to phase transition and ferroelectricity of Al:HfO2films.

We investigate the effects of oxygen vacancies on the ferroelectric behavior of Al:HfO2films annealed in O2and N2atmosphere. X-ray photoelectron spectroscopy results showed that the O/Hf atomic ratio was 1.88 for N2-annealed samples and 1.96 for O2-annealed samples, implying a neutralization of oxygen vacancies during O2atmosphere annealing. The O2-annealed films exhibited an increasing remanent polarization from 23µC cm-2to 28µC cm-2after 104cycles, with a negligible leakage current density of ∼2µA cm-2, while the remanent polarization decreased from 29µC cm-2to 20µC cm-2after cycling in the N2-annealed films, with its severe leakage current density decreasing from ∼1200µA cm-2to ∼300µA cm-2.A phase transition from the metastable tetragonal (t) phase to the low-temperature stable orthorhombic (o) phase and monoclinic (m) phase was observed during annealing. As a result of the fierce· competition between the t-to-o transition and the t-to-m transition, clear grain boundaries of several ruleless atomic layers were formed in the N2-annealed samples. On the other hand, the transition from the t-phase to the low-temperature stable phase was found to be hindered by the neutralization of oxygen vacancies, with almost continuous grain boundaries observed. The results elucidate the phase transformation caused by oxygen vacancies in the Al:HfO2films, which may be helpful for the preparation of HfO2-based films with excellent ferroelectricity.

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study.

BACKGROUND: Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. PRIMARY OBJECTIVE: To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. STUDY HYPOTHESIS: A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. TRIAL DESIGN: The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. PRIMARY ENDPOINT: Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. SAMPLE SIZE: 160 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment is estimated to be completed by 2024 and results may be published by 2027. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05044871.

Efficacy of early clinical interventions for children with global developmental delay.

OBJECTIVE: To evaluate the efficacy of early clinical interventions for children with global developmental delay. METHODS: A total of 127 initial subjects with GDD met the complete inclusion criteria. Seven cases were excluded due to withdrawal or refusal for follow-up. Eventually, the remaining 120 children were divided into two groups based on different treatment regimens: an experimental group and a control group. Ninety children received individualized treatment in the experimental group, while 30 children, due to various reasons, did not receive inpatient treatment and only underwent home-based intervention therapy in the control group. The developmental progress under different intervention methods was compared, and their clinical effectiveness was analyzed. RESULTS: Both groups of patients showed no significant differences in general characteristics such as gender and age (p > 0.05), demonstrating comparability. The initial comparison of developmental quotient scores in all patients before treatment revealed no significant differences. Post-treatment, there was improvement observed in both groups. However, children in the experimental group exhibited significantly higher scores in gross motor skills, fine motor skills, adaptability, language, and personal-social skills compared to those in the control group (p < 0.05). Additionally, the clinical effective rate in the experimental group was notably higher than that in the control group (p < 0.05). CONCLUSION: The combined use of acupuncture with home-based intervention therapy demonstrates favorable therapeutic outcomes in young children with comprehensive developmental delays. This approach has the potential to enhance gross motor skills, fine motor skills, cognition, language, and overall intellectual development in affected children.

Federated Learning-Oriented Edge Computing Framework for the IIoT.

With the maturity of artificial intelligence (AI) technology, applications of AI in edge computing will greatly promote the development of industrial technology. However, the existing studies on the edge computing framework for the Industrial Internet of Things (IIoT) still face several challenges, such as deep hardware and software coupling, diverse protocols, difficult deployment of AI models, insufficient computing capabilities of edge devices, and sensitivity to delay and energy consumption. To solve the above problems, this paper proposes a software-defined AI-oriented three-layer IIoT edge computing framework and presents the design and implementation of an AI-oriented edge computing system, aiming to support device access, enable the acceptance and deployment of AI models from the cloud, and allow the whole process from data acquisition to model training to be completed at the edge. In addition, this paper proposes a time series-based method for device selection and computation offloading in the federated learning process, which selectively offloads the tasks of inefficient nodes to the edge computing center to reduce the training delay and energy consumption. Finally, experiments carried out to verify the feasibility and effectiveness of the proposed method are reported. The model training time with the proposed method is generally 30% to 50% less than that with the random device selection method, and the training energy consumption under the proposed method is generally 35% to 55% less.

Therapeutic potential of dihydroartemisinin in mitigating radiation-induced lung injury: Inhibition of ferroptosis through Nrf2/HO-1 pathways in mice.

BACKGROUND: Radiation-induced lung injury (RILI) is a common consequence of thoracic radiation therapy that lacks effective preventative and treatment strategies. Dihydroartemisinin (DHA), a derivative of artemisinin, affects oxidative stress, immunomodulation, and inflammation. It is uncertain whether DHA reduces RILI. In this work, we investigated the specific mechanisms of action of DHA in RILI. METHODS: Twenty-four C57BL/6J mice were randomly divided into four groups of six mice each: Control group, irradiation (IR) group, IR + DHA group, and IR + DHA + Brusatol group. The IR group received no interventions along with radiation treatment. Mice were killed 30 days after the irradiation. Morphologic and pathologic changes in lung tissue were observed with hematoxylin and eosin staining. Detection of hydroxyproline levels for assessing the extent of pulmonary fibrosis. Tumor necrosis factor α (TNF-α), transforming growth factor-ß (TGF-ß), glutathione peroxidase (GPX4), Nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) expression in lung tissues were detected. In addition, mitochondrial ultrastructural changes in lung tissues were also observed, and the glutathione (GSH) content in lung tissues was assessed. RESULTS: DHA attenuated radiation-induced pathological lung injury and hydroxyproline levels. Additionally, it decreased TNF-α and TGF-ß after irradiation. DHA may additionally stimulate the Nrf2/HO-1 pathway. DHA upregulated GPX4 and GSH levels and inhibited cellular ferroptosis. Brusatol reversed the inhibitory effect of DHA on ferroptosis and its protective effect on RILI. CONCLUSION: DHA modulated the Nrf2/HO-1 pathway to prevent cellular ferroptosis, which reduced RILI. Therefore, DHA could be a potential drug for the treatment of RILI.

A novel PLS-DYW type PPR protein OsASL is essential for chloroplast development in rice.

Oryza longistaminata (OL), an AA-genome African wild rice which can propagate clonally via rhizome, is an important germplasm for improvement of Asian cultivated rice, however recessive lethal alleles can hitchhike clonal propagation in heterozygous state. Selfing of OL is difficult due to its self-incompatibility, but simple selfing of hybrid progeny between OL and O. sativa is effective to disclose and eliminate recessive lethal alleles. Here, we identified an exhibited albino-lethal phenotype mutant, from an F2 population between OL and O. sativa, named it albino seedling-lethal (asl). The leaves of asl mutant showed abnormal chloroplast development. The albino characteristics of asl were determined to be governed by a set of recessive nuclear genes through genetic analysis. Map-based cloning experiments found that a single nucleotide variation (G to A) was detected in the exon of OsASL in OL, which causes a premature stop codon. OsASL encodes a PLS-type PPR protein with 12 pentratricopeptide repeat domains, and is translocalized to chloroplasts. Complementation and knockout transgenic experiments further confirmed that OsASL is responsible for the albino-lethal phenotype. Loss-of-function OsASL (i.e. osasl) resulted in devoid of intron splicing of chloroplast RNA atpF, ndhA, rpl2 and rps12, and also RNA editing of ndhB, but facilitates the RNA editing of rpl2 in the plastid. Transcriptome sequencing showed that OsASL was mainly involved in chlorophyll synthesis pathway. The expression of Chlorophyll-associated genes were significantly decreased in asl plants, especially PEP (plastid-encoded RNA polymerase)-mediated genes. Our results suggest that OsASL is crucial for RNA editing, RNA splicing of chloroplast RNA group II genes, and plays an essential role in chloroplast development during early leaf development in rice.

Direct investigations of interactions between nucleolins and aptamers on pancreatic cancer and normal cells by atomic force microscopy.

Nucleolin is overexpressed on the surface of pancreatic cancer cells and are regarded as the remarkable therapeutic target. Aptamers are capable of binding the external domain of nucleolin on the cell surface with high affinity and specificity. But nucleolin has not been localized on pancreatic cancer cells at very high spatial resolution, and the interactions between nucleolin and aptamers have not been investigated at very high force resolution level. In this work, nucleolin was localized on pancreatic cancer and normal cells by aptamers (9FU-AS1411-NH2, AS1411-NH2 and CRONH2) in Single Molecule Recognition Imaging mode of Atomic Force Microscopy. There are plenty of nucleolin on the surfaces of pancreatic cancer cells (area percentage about 5 %), while there are little nucleolin on the surfaces of normal cells. The interactions between three types of aptamers and nucleolins on the surfaces of pancreatic cancer cells were investigated by Single Molecule Force Spectroscopy. The unbinding forces of nucleolins-(9FU-AS1411-NH2) are larger than nucleolins-(AS1411-NH2). The dissociation activation energy on nucleolin-(9FU-AS1411-NH2) is higher than nucleolin-(AS1411-NH2), which indicates that the former complex is more stable and harder to dissociate than the later complex. There are no unbinding forces between nucleolin and CRONH2. All these demonstrate that nucleolin was localized on pancreatic cancer and normal cells at single molecule level quantitatively, and the interactions (unbinding forces and kinetics) between nucleolin and aptamers were studied at picoNewton level. The approaches and results of this work will pave new ways in the investigations of nucleolin and aptamers, and will also be useful in the studies on other proteins and their corresponding aptamers.

Retrospective analysis of the clinical utility of multi-cytokine profiles in smear-negative pulmonary tuberculosis.

OBJECTIVES: To evaluate cytokine profiles and interferon-gamma release assay (IGRA) for their diagnostic capabilities in the differentiation of tuberculosis (TB) from non-TB conditions, as well as smear-negative pulmonary tuberculosis (SNPT) from smear-positive pulmonary tuberculosis (SPPT). METHODS: A total of 125 participants were included, 77 of whom had TB and 48 who didn't, and demographic, clinical, and laboratory data were collected, including cytokine levels and IGRA results. The TB patients were further divided into 2 subgroups: SNPT (n=42) and SPPT (n=35). RESULTS: Compared to non-TB, the TB group had lower BMI, higher WBC, neutrophils, monocytes, ESR and CRP (p<0.05). TB patients showed higher IL-2, IL-6, IFN-γ, IL-8 (p<0.001) and higher IGRA positivity (88.3% versus [vs.] 29.2%, p<0.001). Between SNPT and SPPT, moderate effect sizes were observed for IFN-α, IL-2, IL-10, IL-8 (Cohen's d 0.59-0.76), with lower IGRA positivity in SNPT (81.0% vs. 97.1%, p=0.015). ROC analysis indicated IFN-α, IL-2, IL-10, IL-8 had moderate accuracy for SNPT diagnosis (AUCs 0.668-0.734), and combining these improved accuracy (AUC 0.759, 80% sensitivity, 64.2% specificity). CONCLUSION: A multi-biomarker approach combining these cytokines demonstrates enhanced diagnostic accuracy for tuberculosis.

Enhancing insight into ferroptosis mechanisms in sepsis: A genomic and pharmacological approach integrating single-cell sequencing and Mendelian randomization.

This research investigated the intricate relationship between ferroptosis and sepsis by utilizing advanced genomic and pharmacological methodologies. Specifically, we obtained expression quantitative trait loci (eQTLs) for 435 genes associated with ferroptosis from the eQTLGen Consortium and detected notable cis-eQTLs for 281 of these genes. Next, we conducted a detailed analysis to assess the impact of these eQTLs on susceptibility to sepsis using Mendelian randomization (MR) with data from a cohort of 10,154 sepsis patients and 452,764 controls sourced from the UK Biobank. MR analysis revealed 16 ferroptosis-related genes that exhibited significant associations with sepsis outcomes. To bolster the robustness of these findings, sensitivity analyses were performed to assess pleiotropy and heterogeneity, thus confirming the reliability of the causal inferences. Furthermore, single-cell RNA sequencing data from sepsis patients offered a detailed examination of gene expression profiles, demonstrating varying levels of ferroptosis marker expression across different cell types. Pathway enrichment analysis utilizing gene set enrichment analysis (GSEA) further revealed the key biological pathways involved in the progression of sepsis. Additionally, the use of computational molecular docking facilitated the prediction of interactions between identified genes and potential therapeutic compounds, highlighting novel drug targets. In conclusion, our integrated approach combining genomics and pharmacology offers valuable insights into the involvement of ferroptosis in sepsis, laying the groundwork for potential therapeutic strategies targeting this cell death pathway to enhance sepsis management.

[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.

Lignin-based Carbon Nanomaterials for Biochemical Sensing Applications.

Lignin-based carbon nanomaterials offer several advantages, including biodegradability, biocompatibility, high specific surface area, ease of functionalization, low toxicity, and cost-effectiveness. These materials show promise in biochemical sensing applications, particularly in the detection of metal ions, organic compounds, and human biosignals. Various methods can be employed to synthesize carbon nanomaterials with different dimensions ranging from 0D to 3D, resulting in diverse structures and physicochemical properties. This study provides an overview of the preparation techniques and characteristics of multidimensional (0-3D) lignin-based carbon nanomaterials, such as carbon dots (CDs), carbon nanotubes (CNTs), graphene, and carbon aerogels (CAs). Additionally, the sensing capabilities of these materials are compared and summarized, followed by a discussion on the potential challenges and future prospects in sensor development.

Fabrication and Temporal Dependency Osteogenic Regulation of Dual-Scale Hierarchical Microstructures on Medical Metal Surface.

The structural characteristics at the interface of bone implants can guide biological regulation. In this study, a dual-scale hierarchical microstructure is proposed and customized using hybrid machining to achieve temporal dependency osteogenic regulation. It is observed that osteoblasts induced by dual-scale hierarchical structure exhibit adequate protrusion development and rapid cell attachment through the modulation of mechanical forces in the cell growth environment, and further promot the upregulation of the cell membrane receptor PDGFR-α, which is related to cell proliferation. Afterward, transcriptomic analysis reveals that during the differentiation stage, the DSH structure regulates cellular signaling cascades primarily through integrin adhesion mechanisms and then accelerates osteogenic differentiation by activating the TGF-ß pathway and cAMP signaling pathway. Furthermore, the calcium nodules are preferentially deposited within the lower honeycomb-like channels, thereby endowing the proposed dual-scale hierarchical structure with the potential to induce oriented deposition and improve the long-term stability of the implant.

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.

Pyroptotic T cell-derived active IL-16 has a driving function in ovarian endometriosis development.

Endometriosis, affecting 6%-10% of women, often leads to pain and infertility and its underlying inflammatory mechanisms are poorly understood. We established endometriosis models in wild-type and IL16KO mice, revealing the driver function of IL-16 in initiating endometriosis-related inflammation. Using an in vitro system, we confirmed iron overload-induced GSDME-mediated pyroptosis as a key trigger for IL-16 activation and release. In addition, our research led to the development of Z30702029, a compound inhibiting GSDME-NTD-mediated pyroptosis, which shows promise as a therapeutic intervention for endometriosis. Importantly, our findings extend beyond endometriosis, highlighting GSDME-mediated pyroptosis as a broader pathway for IL-16 release and offering insights into potential treatments for various inflammatory conditions.

Two cases of driver death caused by airbag rupture.

OBJECTIVE: This article reports two accidents caused by defective Takata airbags ruptured, which led to the deaths of the drivers. This is the first public report on the deaths caused by Takata airbags in China. METHODS: Determine the relationship between the driver death and airbag rupture through autopsy indings and vehicle inspection. RESULTS: Due to defects in the design of Takata's inflator, moist air was permitted to slowly enter the inflator, resulting the PSAN slowly degraded physically. The damaged propellant burned more rapidly than intended and overpressurized the inflator's steel housing, causing fragmentation and flying debris at high speed, killing or injuring vehicle occupants. CONCLUSIONS: To date, there are still tens of millions of defective Takata airbags that have not been recalled for repair, posing safety risks. This article suggests taking preventive measures to avoid the occurrence of similar accidents.