Nogo-A Drives Alzheimer's Disease Progression by Inducing Tauopathy Vulnerability.

Tauopathies, a group of neurodegenerative disorders, are characterized by disrupted homeostasis of the microtubule binding protein tau. Nogo-A mainly hinders axonal growth and development in neurons, but the underlying mechanism of tau vulnerability has not been determined. Here, to gain more comprehensive insights into the impact of Nogo-A on tau protein expression, we showed that Nogo-A induces tau hyperphosphorylation, synapse loss and cognitive dysfunction. Consistent with the biological function of tau hyperphosphorylation, Nogo-A-induced tau hyperphosphorylation altered microtubule stability, which causes synaptic dysfunction. Mechanistically, Nogo-A-induced tau hyperphosphorylation was abolished by the Nogo-A antagonist NEP1-40 in primary neurons. Surprisingly, downregulation of Nogo-A in the hippocampus of AD mice (hTau. P301S) inhibited tau hyperphosphorylation at the AT8, Thr181, The231 and Ser404 sites and rescued synaptic loss and cognitive impairment in AD mice. Our findings exhibit a strong degree of consistency with Nogo-A-induced tauopathy vulnerability, reinforcing the coherence and reliability of our research. Furthermore, in mice, Nogo-A increases tauopathy vulnerability to exacerbate AD progression via ROCK/AKT/GSK3ß signaling. Together, our findings provide new insight into the function of Nogo-A in regulating tau hyperphosphorylation and reveal an effective treatment strategy for tauopathies.

Small-molecule Molephantin induces apoptosis and mitophagy flux blockage through ROS production in glioblastoma.

Glioblastoma (GBM), one of the most malignant brain tumors in the world, has limited treatment options and a dismal survival rate. Effective and safe disease-modifying drugs for glioblastoma are urgently needed. Here, we identified a small molecule, Molephantin (EM-5), effectively penetrated the blood-brain barrier (BBB) and demonstrated notable antitumor effects against GBM with good safety profiles both in vitro and in vivo. Mechanistically, EM-5 not only inhibits the proliferation and invasion of GBM cells but also induces cell apoptosis through the reactive oxygen species (ROS)-mediated PI3K/Akt/mTOR pathway. Furthermore, EM-5 causes mitochondrial dysfunction and blocks mitophagy flux by impeding the fusion of mitophagosomes with lysosomes. It is noteworthy that EM-5 does not interfere with the initiation of autophagosome formation or lysosomal function. Additionally, the mitophagy flux blockage caused by EM-5 was driven by the accumulation of intracellular ROS. In vivo, EM-5 exhibited significant efficacy in suppressing tumor growth in a xenograft model. Collectively, our findings not only identified EM-5 as a promising, effective, and safe lead compound for treating GBM but also uncovered its underlying mechanisms from the perspective of apoptosis and mitophagy.

METTL3-Mediated LINC00475 Alternative Splicing Promotes Glioma Progression by Inducing Mitochondrial Fission.

Mitochondrial fission promotes glioma progression. The function and regulation mechanisms of lncRNAs in glioma mitochondrial fission are unclear. The expression of LINC00475 and its correlation with clinical parameters in glioma were analyzed using bioinformatics. Then, in vitro and in vivo assays were performed to explore the function of spliced variant LINC00475 (LINC00475-S) in gliomas. To explore the mechanisms, RNA-seq, MeRIP, RIP, pulldown-IP, dCas9-ALKBH5 editing system, LC/MS, and Western blotting were utilized. LINC00475 was confirmed to be overexpressed and with higher frequencies of AS events in gliomas compared to normal brain tissue and was associated with worse prognosis. In vitro and animal tumor formation experiments demonstrated that the effect of LINC00475-S on proliferation, metastasis, autophagy, and mitochondrial fission of glioma cells was significantly stronger than that of LINC00475. Mechanistically, METTL3 induced the generation of LINC00475-S by splicing LINC00475 through m6A modification and subsequently promotes mitochondrial fission in glioma cells by inhibiting the expression of MIF. Pull-down combined LC/MS and RIP assays identified that the m6A recognition protein HNRNPH1 bound to LINC00475 within GYR and GY domains and promoted LINC00475 splicing. METTL3 facilitated HNRNPH1 binding to LINC00475 in an m6A-dependent manner, thereby inducing generation of LINC00475-S. METTL3 facilitated HNRNPH1-mediated AS of LINC00475, which promoted glioma progression by inducing mitochondrial fission. Targeting AS of LINC00475 and m6A editing could serve as a therapeutic strategy against gliomas.

Laser swept-frequency interferometry with non-uniform fast Fourier transform and a linear regression frequency measurement method.

The laser swept-frequency interferometric ranging method is commonly used in the field of large-scale, high-precision, and non-cooperative measurements. However, this method requires the laser chirp curve to be a stable straight line. Nonlinearities in the chirp can cause broadening of the target spectrum, which affects the accuracy of the frequency extraction of the beat signal, resulting in increased ranging error. Herein, a linear regression laser swept-frequency interferometry method based on the non-uniform fast Fourier transform is proposed, which effectively suppresses the influence of frequency modulation nonlinearity on ranging accuracy.

Temperature influence on optical fiber and temperature compensation method for a frequency modulation continuous wave absolute distance measurement system.

A temperature compensation method is proposed to solve the ranging precision decrease problem of the frequency-modulated continuous wave distance measurement system. The set of phases spread frequency sampling method is used to correct the beat frequency signal non-linearity. The influence model of temperature on the optical fiber auxiliary interferometer is studied. The experimental results show that distance measurement error decreases from 0.3432 mm to 0.02260 mm, and the mean measurement standard deviation decreases from 0.1088 mm to 0.01733 mm on a maximum measurement range of 1.6 m after compensation.

Risk factors of intraoperative blood loss and transfusion for pediatric patients undergoing brain tumor removal: a retrospective cohort study.

OBJECTIVE: Intraoperative blood loss is a major challenge in pediatric brain tumor removal. Several clinical and surgical factors may influence the occurrence of intraoperative blood loss and blood transfusion. This study aimed to identify the risk factors of intraoperative blood loss and intraoperative red blood cell (RBC) transfusion for pediatric patients undergoing brain tumor removal. METHODS: A total of 297 pediatric patients undergoing brain tumor removal were selected in this retrospective, singlecenter study. Demographic data, laboratory data, imaging data, and surgical records were collected, and then independent risk factors for intraoperative blood loss and transfusion were identified using multivariate stepwise regression analysis. RESULTS: The median intraoperative blood loss in our cohort was 23.1 ml/kg (IQR 10.0-60.0 ml/kg). In total, 284 (95.6%) patients received intraoperative RBC transfusion, with a median amount of 0.2 U/kg (IQR 0.0-2.6 U/kg). Age (ß = -0.189; 95% CI [-1.359, -0.473]; p < 0.001); preoperative hemoglobin level (ß = -0.141; 95% CI [-1.528, -0.332]; p = 0.003); anesthesia time (ß = 0.189; 95% CI [0.098, 0.302]; p < 0.001); unclear tumor boundary (ß = 0.100; 95% CI [2.067, 41.053]; p = 0.031); tumor size (ß = 0.390; 95% CI [14.706, 24.342]; p < 0.001); and intraoperative continuous infusion of vasopressor (ß = 0.155; 95% CI [13.364, 52.400]; p = 0.001) were independent predictors of intraoperative blood loss. Independent predictors of the need for RBC transfusion included age (ß = -0.268; 95% CI [-0.007, -0.004]; p < 0.001); preoperative hemoglobin level (ß = -0.117; 95% CI [-0.005, -0.001]; p = 0.003); anesthesia time (ß = 0.221; 95% CI [0.001, 0.001]; p < 0.001); unclear tumor boundary (ß = 0.110; 95% CI [0.024, 0.167]; p = 0.010); tumor size (ß = 0.370; 95% CI [0.056, 0.092]; p < 0.001); intraoperative continuous infusion of vasopressor (ß = 0.157; 95% CI [0.062, 0.205]; p < 0.001); and tumor grade (ß = 0.107; 95% CI [0.007, 0.062]; p = 0.014). CONCLUSIONS: Overall, age, preoperative hemoglobin, tumor size, anesthesia time, continuous infusion of vasopressors, and unclear tumor boundary were the main determinants for intraoperative blood loss and RBC transfusion in pediatric patients undergoing brain tumor removal. Clinical trial registration no.: ChiCTR1900024803 (ChiCTR.org).

The identification of miRNA and mRNA expression profiles associated with pediatric atypical teratoid/rhabdoid tumor.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant pediatric tumor of the central nervous system (CNS) with high recurrence and low survival rates that is often misdiagnosed. MicroRNAs (miRNAs) are involved in the tumorigenesis of numerous pediatric cancers, but their roles in AT/RT remain unclear. METHODS: In this study, we used miRNA sequencing and gene expression microarrays from patient tissue to study both the miRNAome and transcriptome traits of AT/RT. RESULTS: Our findings demonstrate that 5 miRNAs were up-regulated, 16 miRNAs were down-regulated, 179 mRNAs were up-regulated and 402 mRNAs were down-regulated in AT/RT. qPCR revealed that hsa-miR-17-5p and MAP7 mRNA were the most significantly differentially expressed miRNA and mRNA in AT/RT tissues. Furthermore, the results from analyses using the miRTarBase database identified MAP7 mRNA as a target gene of hsa-miR-17-5p. CONCLUSIONS: Our findings suggest that the dysregulation of hsa-miR-17-5p may be a pivotal event in AT/RT and miRNAs that may represent potential therapeutic targets and diagnostic biomarkers.

Design and error calibration of an on-axis deflectometric microscope system.

An on-axis deflectometric microscope system (ODMS) is proposed for the microscopic surface measurement with high accuracy and a large slope dynamic range. To reduce the geometry sensitivity, a beam splitter is employed to build the coaxial configuration among the illumination screen, camera, and tested sample, which facilitates the calibration of system geometrical parameters. Due to the small working distance, the system model miscalibration in the model-ray-tracing-based "null" testing could cause obvious geometrical aberrations. In this paper, the geometrical aberrations due to the system model miscalibration are analyzed, and the corresponding calibration method based on computer-aided reverse optimization is applied to achieve accurate measurement. In addition, the systematic error introduced by the system components in the ODMS are also discussed. Both the simulation and experiment have been carried out to demonstrate the feasibility and high accuracy of the proposed measurement method. The proposed system is compact in structure, large in measurable slope range, and high in spatial resolution, providing a viable metrological tool for the microscopic testing of various freeform surfaces, microstructural elements, and micro-devices.

Sevoflurane Induces Ferroptosis of Glioma Cells Through Activating the ATF4-CHAC1 Pathway.

Objective: To clarify the function and mechanisms of sevoflurane (Sev) on ferroptosis in glioma cells. Methods: Different concentrations of Sev were used to treat glioma cells U87 and U251. Ferroptosis inducer Erastin was used to incubate glioma cells combined with Sev and ATF4 siRNA transfection treatment. CCK-8 assay and colorimetric assay were performed to analyze cell viability and Fe+ concentration, respectively. The releases of reactive oxygen species (ROS) were determined by flow cytometry analysis. Transcriptional sequencing was used to screen the differential genes affected by Sev in U251 cells. The mRNA and protein expression of ferroptosis-associated genes was detected by qRT-PCR and Western blotting. Results: Sev could suppress cell viability, increase ROS levels and Fe+ concentration, downregulate the protein expression levels of GPX4, and upregulate transferrin, ferritin, and Beclin-1 in a dose-dependent manner in U87 and U251 cells. The expression of ferroptosis and mitophagy-related gene activating transcription factor 4 (ATF4) was identified to be enhanced by Sev analyzed by transcriptional sequencing. ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1), which is involved in ferroptosis, is a downstream gene of ATF4. Inhibition of ATF4 could interrupt the expression of CHAC1 induced by Sev in U87 and U251 cells. Ferroptosis inducer Erastin treatment obviously inhibited the cell viability, elevated the Fe2+ concentration, and promoted ROS generation in U87 and U251 cells. The protein level of ATF4 and CHAC1 was increased in Erastin-treated U87 and U251 cells. Moreover, the interruption of Sev-induced ferroptosis and CHAC1 activating induced by ATF4 suppression could be reversed by Erastin. Conclusions: In summary, this study suggested that Sev exposure-induced ferroptosis by the ATF4-CHAC1 pathway in glioma cells.

Deep-learning-based deflectometry for freeform surface measurement.

We propose a deep-learning based deflectometric method for freeform surface measurement, in which a deep neural network is devised for freeform surface reconstruction. Full-scale skip connections are adopted in the network architecture to extract and incorporate multi-scale feature maps from different layers, enabling the accuracy and robustness of the testing system to be greatly enhanced. The feasibility of the proposed method is numerically and experimentally validated, and its excellent performance in terms of accuracy and robustness is also demonstrated. The proposed method provides a feasible way to achieve the general measurement of freeform surfaces while minimizing the measurement errors due to noise and system geometry calibration.

Error Analysis of the Combined-Scan High-Speed Atomic Force Microscopy.

A combined tip-sample scanning architecture can improve the imaging speed of atomic force microscopy (AFM). However, the nonorthogonality between the three scanners and the nonideal response of each scanner cause measurement errors. In this article, the authors systematically analyze the influence of the installation and response errors of the combined scanning architecture. The experimental results show that when the probe in the homemade high-speed AFM moves with the Z-scanner, the spot position on the four-quadrant detector changes, thus introducing measurement error. Comparing the experimental results with the numerical and theoretical results shows that the undesired motion of the Z-scanner introduces a large error. The authors believe that this significant error occurs because the piezoelectric actuator not only stretches along the polarization direction but also swings under nonuniform multifield coupling. This article proposes a direction for further optimizing the instrument and provides design ideas for similar high-speed atomic force microscopes.

Clinical characteristics and therapeutic outcomes of mediastinal neuroblastoma with intraspinal extension: a retrospective study.

BACKGROUND: Mediastinal neuroblastoma (NB) can invade the spinal canal and result in spinal cord compression. Some patients go on to develop severe spinal deformities after decompression of the spinal cord. The optimal therapeutic strategy for mediastinal NB with intraspinal extension is still unclear. Our study is to assess the therapeutic strategies for such patients. METHODS: A total of 77 patients suffered mediastinal tumors with intraspinal extension between March 2015 and Aug 2019 were enrolled in the study. According to the primary therapy, NB were classified into 4 groups: chemotherapy, video-assisted thoracoscopic surgery (VATS)/thoracotomy, neurosurgical decompression, and a combined thoracic-neurosurgical approach. Clinical features, including patient demographics, neurologic recovery and survival rate, were assessed. RESULTS: Among the 77 patients suffered mediastinal tumors with intraspinal extension, neurological symptoms were present in 44 patients. Neurological deficits improved in 76.5% of patients who underwent neurosurgical intervention and 50% of the other patients (P=0.094). Compression manifestations of ≤4 weeks duration showed an improved outcome compared to a longer compression time, with complete recovery of neurological function in 60% of patients versus 28.6% for patients with a longer symptom duration (P=0.04). NB constituted 49.4% of the 77 patients. An overall survival rate of 90.0%±9.5% was achieved for patients in the combined thoracic-neurosurgical group, 59.5%±15.0% in the thoracotomy group, 40.0%±29.7% in laminectomy group, and 37.0%±20.2% in the chemotherapy group. Complete regression of the tumor was demonstrated in 80% of combined group, which was greater than that of patients in the other groups (P=0.001). CONCLUSIONS: Neurological recovery was correlated with the type of initial treatment and the duration of neurological symptoms. Mediastinal NB with intraspinal extension can be effectively managed with a combined neurosurgical and thoracic surgical approach.

Frequency modulation nonlinear correction and range-extension method based on laser frequency scanning interference.

A phase spread frequency sampling method is proposed. This method can be used to correct the nonlinearity in the beat frequency of a measurement signal. The proposed method expands the phase of the auxiliary interference beat signal, thereby satisfying the Nyquist sampling theorem, correcting the nonlinearity in the beat frequency of the measured signal, and solving the problem of limited range. The conditions over which the frequency sampling method can be applied are expanded. The measurement range is flexibly expanded by performing multiple phase expansions.

Calibration of geometrical aberration in transmitted wavefront testing of refractive optics with deflectometry.

Deflectometry, with its noticeable advantages such as simple structure, large dynamic range, and high accuracy comparable to interferometry, has been one of the powerful metrological techniques for optical surfaces in recent years. In the "null" deflectometric transmitted wavefront testing of refractive optics, ray tracing of the test system model is required, in which both the miscalibration of system geometrical parameters and optical tolerances on tested optics could introduce significant geometrical aberrations in the testing results. In this paper, the geometrical aberration introduced by a system modeling error in the transmitted wavefront testing is discussed. Besides, a calibration method based on polynomial optimization of geometrical aberration is presented for the geometrical aberration calibration. Both simulation and experiment have been performed to validate the feasibility of the proposed calibration method. The proposed method can calibrate the optical tolerances on tested optics effectively, and it is feasible even with a large geometric error, providing a viable way to address the uncertainty in system modeling in transmitted wavefront testing of freeform refractive optics with large dynamic range.

The CXCL12/CXCR4 axis confers temozolomide resistance to human glioblastoma cells via up-regulation of FOXM1.

Glioblastoma multiforme (GBM) is the most common primary malignancy in the adult central nervous, and is characterized by high aggressiveness and a high mortality rate. The high mortality rate is largely due to the development of drug resistance. Temozolomide (TMZ) resistance is considered to be one of the major reasons responsible for GBM therapy failure. CXCL12/CXCR4 has been demonstrated to be involved in cell proliferation, migration, invasion, angiogenesis, and radioresistance in GBM. However, its role in TMZ resistance in GBM is unknown. In this study, we aimed to evaluate the role of CXCL12/CXCR4 in mediating the TMZ resistance to GBM cells and explore the underlying mechanisms. We found that the CXCL12/CXCR4 axis enhanced TMZ resistance in GBM cells. Further study showed that CXCL12/CXCR4 conferred TMZ resistance and promoted the migration and invasion of GBM cells by up-regulating FOXM1. This resistance was partially reversed by suppressing CXCL12/CXCR4 and FOXM1 silencing. Our study revealed the vital role of CXCL12/CXCR4 in mediating the resistance of GBM cells to TMZ, and suggested that targeting CXCL12/CXCR4 axis may attenuate the resistance to TMZ in GBM.

Integrative genomic analyses identify WDR12 as a novel oncogene involved in glioblastoma.

Glioblastoma (GBM) is the most malignant primary brain tumor in adults. Due to its invasive nature, it cannot be thoroughly eliminated. WD repeat domain 12 (WDR12) processes the 32S precursor rRNA but cannot affect the synthesis of the 45S/47S primary transcript. In this study, we found that WDR12 is highly expressed in GBM according to the analysis results of mRNA expression by The Cancer Genome Atlas database. The high expression level of WDR12 is dramatically related to shorter overall survival and reduced disease-free survival. Next, we knocked down WDR12 and found that knockdown of WDR12 promoted the apoptosis and inhibited the proliferation by cell biology experiments. Differential expression genes in gene-chip revealed that WDR12 knockdown mainly inhibited cell cycle. Finally, we also found that WDR12 is associated with PLK1 and EZH2 in cell proliferation of GBM. Resumptively, this report showed a possible evidence that WDR12 drove malignant behavior of GBM, whose expression may present a neoteric independent prognostic biomarker in GBM.

Pediatric primary diffuse leptomeningeal melanomatosis: Case report and review of the literature.

RATIONALE: Primary melanocytic tumors of central nerve system (CNS) are rare, primary diffuse leptomeningeal melanomatosis (PDLM), a subtype of malignant melanomas of CNS, is extremely rare,especially in pediatrics. As the clinical manifestation of PDLM is not characteristic, It is often misdiagnosed as tubercular meningitis and hemorrhage. PATIENT CONCERNS: A 13-year-old boy was admitted to our department with symptoms of recurrent headache and vomiting twice. As the brain imaging revealed a lesion located in the left temporal lobe mimicked hemorrhage, so there was a misdiagnosis of hemorrhage in first hospitalization. He was admitted again for the recurrence of the headache and vomiting. Detailed physical examination showed multiple melanin changes in the skin of the whole body which were ignored in last hospitalization. Brain imaging showed the significantly enlarged lesion in the left temporal lobe and several smaller lesions in the left parietal lobe and cerebellum which indicated metastasis. DIAGNOSIS: According to the history,physical examination and the radiological finding, the patient was diagnosed with malignant melanoma of central never system possibly. INTERVENTIONS: The patient underwent left temporal and parietal lesions total resection with a craniotomy. OUTCOMES: The diagnosis of PDLM was established according to pathological characteristics and the negative finding of positron emission tomography (PET)-computed tomography (CT) outside CNS. The patient got no further treatment for economic reasons and experienced the progression and died 5 months after operation. LESSONS: PDLM is extremely rare in CNS, as the clinical manifestation, radiological changes are not special, early diagnosis is difficult. The confirmed diagnosis is established by leptomeningeal biospy or surgical tissue. PET-CT can help differential diagnosis with metastastic leptomeningeal melanomas. The prognosis is dismal due to the inefficiency of chemotherapy or radiotherapy.

Multiple Cavernous Malformations of Brain, Chest, and Skin: A Rare Case of an Infant and Literature Review.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular malformations that account for 5%-15% of all central nervous system vascular malformations. However, multiple CCMs, which can be sporadic or familial, are rare, with a prevalence of 0.1%-0.5%. CASE DESCRIPTION: Here, we presented a rare case of sporadic multiple CCMs in an infant, which were accompanied with multiple cavernous malformations of the chest and skin. CONCLUSIONS: CCMs were pathologically diagnosed through the total resection of the pineal regional lesion. We also observed a spontaneous regression of the remaining lesions during a follow-up period of 2 years. To our knowledge, this is the first case of CCMs in an infant in the English-language literature.

The PDK1/c­Jun pathway activated by TGF­ß induces EMT and promotes proliferation and invasion in human glioblastoma.

Glioblastoma multiforme (GBM) is the most common primary malignant tumor affecting the human brain. Despite improvements in therapeutic technologies, patients with GBM have a poor clinical result and the molecular mechanisms responsible for the development of GBM have not yet been fully elucidated. 3-phosphoinositide dependent protein kinase 1 (PDK1) is upregulated in various tumors and promotes tumor invasion. In glioma, transforming growth factor-ß (TGF­ß) promotes cell invasion; however, whether TGF­ß directly regulates PDK1 protein and promotes proliferation and invasion is not yet clear. In this study, PDK1 levels were measured in glioma tissues using tissue microarray (TMA) by immunohistochemistry (IHC) and RT­qPCR. Kaplan-Meier analyses were used to calculate the survival rate of patients with glioma. In vitro, U251 and U87 glioma cell lines were used for functional analyses. Cell proliferation and invasion were analyzed using siRNA transfection, MTT assay, RT­qPCR, western blot analysis, flow cytometry and invasion assay. In vivo, U251 glioma cell xenografts were established. The results revealed that PDK1 protein was significantly upregulated in glioma tissues compared with non-tumorous tissues. Furthermore, the higher PDK1 levels were associated with a large tumor size (>5.0 cm), a higher WHO grade and a shorter survival of patients with GBM. Univariate and multivariate analyses indicated that PDK1 was an independent prognostic factor. In vivo, PDK1 promoted glioma tumor xenograft growth. In vitro, functional analyses confirmed that TGF­ß upregulated PDK1 protein expression and PDK1 promoted cell migration and invasion, and functioned as an oncogene in GBM, by upregulating c­Jun protein and inducing epithelial-mesenchymal transition (EMT). c­Jun protein were overexpressed in glioma tissues and positively correlated with PDK1 levels. Moreover, our findings were further validated by the online Oncomine database. On the whole, the findings of this study indicate that in GBM, PDK1 functions as an oncogene, promoting proliferation and invasion.