Exploration of factors affecting hemodynamic stability following pheochromocytoma resection - cohort study.

Purpose: Surgery is the only way to cure pheochromocytoma; however, postoperative hemodynamic instability is one of the main causes of serious complications and even death. This study's findings provide some guidance for improved clinical management. Patients and methods: This study was to investigate the factors leading to postoperative hemodynamic instability in the postoperative pathology indicated pheochromocytoma from May 2016 to May 2022. They were divided into two groups according to whether vasoactive drugs were used for a median number of days or more postoperatively. The factors affecting the postoperative hemodynamics in the perioperative period (preoperative, intraoperative, and postoperative) were then evaluated. Results: The median number of days requiring vasoactive drug support postoperatively was three in 234 patients, while 118 (50.4%) patients required vasoactive drug support for three days or more postoperatively. The results of the multivariate analysis indicated more preoperative colloid use (odds ratio [OR]=1.834, confidence interval [CI]:1.265-2.659, P=0.001), intraoperative use of vasoactive drug (OR=4.174, CI:1.882-9.258, P<0.001), and more postoperative crystalloid solution input per unit of body weight per day (ml/kg/d) (OR=1.087, CI:1.062-1.112, P<0.001) were risk factors for predicting postoperative hemodynamic instability. The optimal cutoff point of postoperative crystalloid use were 42.37 ml/kg/d. Conclusion: Hemodynamic instability is a key issue for consideration in the perioperative period of pheochromocytoma. The amount of preoperative colloid use, the need for intraoperative vasoactive drugs, and postoperative crystalloid solution are risk factors for predicting postoperative hemodynamic instability (registration number: ChiCT2300071166).

Exosomes in Glioma: Unraveling Their Roles in Progression, Diagnosis, and Therapy.

Gliomas, the most prevalent primary malignant brain tumors, present a challenging prognosis even after undergoing surgery, radiation, and chemotherapy. Exosomes, nano-sized extracellular vesicles secreted by various cells, play a pivotal role in glioma progression and contribute to resistance against chemotherapy and radiotherapy by facilitating the transportation of biological molecules and promoting intercellular communication within the tumor microenvironment. Moreover, exosomes exhibit the remarkable ability to traverse the blood-brain barrier, positioning them as potent carriers for therapeutic delivery. These attributes hold promise for enhancing glioma diagnosis, prognosis, and treatment. Recent years have witnessed significant advancements in exosome research within the realm of tumors. In this article, we primarily focus on elucidating the role of exosomes in glioma development, highlighting the latest breakthroughs in therapeutic and diagnostic approaches, and outlining prospective directions for future research.

Blockade of the lncRNA-DOT1L-LAMP5 axis enhances autophagy and promotes degradation of MLL fusion proteins.

BACKGROUND: Mixed-lineage leukemia (MLL) fusion gene caused by chromosomal rearrangement is a dominant oncogenic driver in leukemia. Due to having diverse MLL rearrangements and complex characteristics, MLL leukemia treated by currently available strategies is frequently associated with a poor outcome. Therefore, there is an urgent need to identify novel therapeutic targets for hematological malignancies with MLL rearrangements. METHODS: qRT-PCR, western blot, and spearman correction analysis were used to validate the regulation of LAMP5-AS1 on LAMP5 expression. In vitro and in vivo experiments were conducted to assess the functional relevance of LAMP5-AS1 in MLL leukemia cell survival. We utilized chromatin isolation by RNA purification (ChIRP) assay, RNA pull-down assay, chromatin immunoprecipitation (ChIP), RNA fluorescence in situ hybridization (FISH), and immunofluorescence to elucidate the relationship among LAMP5-AS1, DOT1L, and the LAMP5 locus. Autophagy regulation by LAMP5-AS1 was evaluated through LC3B puncta, autolysosome observation via transmission electron microscopy (TEM), and mRFP-GFP-LC3 puncta in autophagic flux. RESULTS: The study shows the crucial role of LAMP5-AS1 in promoting MLL leukemia cell survival. LAMP5-AS1 acts as a novel autophagic suppressor, safeguarding MLL fusion proteins from autophagic degradation. Knocking down LAMP5-AS1 significantly induced apoptosis in MLL leukemia cell lines and primary cells and extended the survival of mice in vivo. Mechanistically, LAMP5-AS1 recruits the H3K79 histone methyltransferase DOT1L to LAMP5 locus, directly activating LAMP5 expression. Importantly, blockade of LAMP5-AS1-LAMP5 axis can represses MLL fusion proteins by enhancing their degradation. CONCLUSIONS: The findings underscore the significance of LAMP5-AS1 in MLL leukemia progression through the regulation of the autophagy pathway. Additionally, this study unveils the novel lncRNA-DOT1L-LAMP5 axis as promising therapeutic targets for degrading MLL fusion proteins.

Research on ultrasonic bone cutting mechanism based on extended finite element method.

The research on the crack propagation mechanism of bone has important research significance and clinical medical value for the selection of cutting parameters and the development of new surgical tools. In this paper, an extended finite element method (X-FEM) model of ultrasonic bone cutting considering microstructure was developed to further study the ultrasonic bone cutting mechanism and to quantitatively analyze the effects of cutting direction, ultrasonic parameters, and cutting parameters on the mechanism of ultrasonic bone cutting crack propagation. The results show that ultrasonic bone cutting is essentially a controlled crack propagation process, in which brittle crack and fatigue crack are the main crack propagation mechanisms. In order to improve the efficiency of ultrasonic bone cutting, large amplitude and high-frequency ultrasonic vibration are preferred. Compared with the other two cutting directions, the crack propagation deflection angle in the transverse cutting direction is the largest, resulting in the worst cutting surface. Therefore, in the path planning of orthopedic surgical robots, the transverse cutting direction should be avoided as much as possible. Frequency only has a significant effect on the crack propagation rate and has a positive correlation. There is a positive correlation between the deflection angle, propagation length, propagation rate, and amplitude, which provides the possibility to control the direction and length of crack propagation by controlling the amplitude of ultrasonic. The feed speed is much lower than the ultrasonic vibration speed, which makes the influence of ultrasonic vibration speed on the crack propagation characteristics dominant. The X-FEM model of ultrasonic bone cutting provides an effective method for selecting reasonable machining parameters of orthopedic robot and optimize the design of ultrasonic osteotome.

A convenient and robust design for diamond-based scanning probe microscopes.

Nitrogen-vacancy centers in diamond have been developed as a sensitive magnetic sensor and broadly applied on condensed matter physics. We present a design of a scanning probe microscope based on a nitrogen-vacancy center that can operate under various experimental conditions, including a broad temperature range (20-500 K) and a high-vacuum condition (1 × 10-7 mbar). The design of a compact and robust scanning head and vacuum chamber system is presented, which ensures system stability while enabling the convenience of equipment operations. By showcasing the temperature control performance and presenting confocal images of a single-layer graphene and a diamond probe, along with images of a ferromagnetic strip and an epitaxial BiFeO3 film on the SrTiO3 substrate, we demonstrate the reliability of the instrument. Our study proposes a method and a corresponding design for this microscope that extends its potential applications in nanomagnetism and spintronics.

Abnormal and Changing Information Interaction in Adults with Attention-Deficit/Hyperactivity Disorder Based on Network Motifs.

Network motif analysis approaches provide insights into the complexity of the brain's functional network. In recent years, attention-deficit/hyperactivity disorder (ADHD) has been reported to result in abnormal information interactions in macro- and micro-scale functional networks. However, most existing studies remain limited due to potentially ignoring meso-scale topology information. To address this gap, we aimed to investigate functional motif patterns in ADHD to unravel the underlying information flow and analyze motif-based node roles to characterize the different information interaction methods for identifying the abnormal and changing lesion sites of ADHD. The results showed that the interaction functions of the right hippocampus and the right amygdala were significantly increased, which could lead patients to develop mood disorders. The information interaction of the bilateral thalamus changed, influencing and modifying behavioral results. Notably, the capability of receiving information in the left inferior temporal and the right lingual gyrus decreased, which may cause difficulties for patients in processing visual information in a timely manner, resulting in inattention. This study revealed abnormal and changing information interactions based on network motifs, providing important evidence for understanding information interactions at the meso-scale level in ADHD patients.

Carotid massive intraplaque hemorrhage, lipid-rich necrotic core, and heavy circumferential calcification were associated with new ipsilateral ischemic cerebral lesions after carotid artery stenting: high-resolution magnetic resonance vessel wall imaging study.

Background: Following carotid artery stenting (CAS), new ipsilateral ischemic lesions (NIILs) in the brain are frequently seen using diffusion-weighted imaging (DWI). This study's goal was to identify the imaging characteristics associated with NIILs after CAS by high-resolution magnetic resonance vessel wall imaging (HR-VWI). Methods: This was a case-control study. 109 patients who received CAS for atherosclerotic carotid stenosis were retrospectively collected and categorized into NIILs positive and NIILs negative groups. Based on the existence or absence of stroke symptoms after CAS, the NIILs positive group was split into two subgroups: the NIILs symptomatic group and the NIILs asymptomatic group. Patients underwent preoperative HR-VWI and brain magnetic resonance imaging (MRI) within 7 days preoperatively and within 3 days postoperatively. Quantitatively assess carotid plaque burden and components using HR-VWI. The baseline and HR-VWI imaging characteristics of all patients were retrospectively analyzed. To ascertain the imaging characteristics connected with NIILs after CAS, logistic regression analysis was carried out. Results: Among 109 patients, 38 patients (34.9%) developed NIILs after CAS. Six patients (5.5%) developed symptomatic stroke with NIILs. The logistic regression analysis revealed that maximum wall thickness (Max WT) [odds ratio (OR), 1.53; 95% confidence interval (CI): 1.20-1.96; P=0.001], the maximum area percentage of lipid-rich necrotic core (LRNC) (OR, 1.05; 95% CI: 1.03-1.07; P<0.001), the volume of LRNC (OR, 1.004; 95% CI: 1.002-1.005; P<0.001), the maximum area percentage of intraplaque hemorrhage (IPH) (OR, 1.17; 95% CI: 1.11-1.24; P<0.001), the volume of IPH (OR, 1.06; 95% CI: 1.03-1.08; P<0.001), and maximum circumference score of calcification in a single slice (OR, 1.66; 95% CI: 1.04-2.63; P=0.03) were linked with NIILs following CAS. Conclusions: The massive IPH, LRNC, and heavy circumferential calcification were associated with NIILs after CAS. Preoperative quantitative assessment of carotid plaque using HR-VWI may be useful for predicting NIILs following CAS.

Calcification circumference, area, and location are associated with carotid stent expansion rate: high-resolution magnetic resonance vessel wall imaging study.

Background: The plaque imaging findings associated with the stent expansion rate (SER) of the carotid artery are not well known. The purpose of this study was to investigate the imaging findings associated with SER. Methods: It was a retrospective investigation. Based on the kind of carotid stents used, retrospective data from 89 patients who had carotid artery stenting (CAS) for atherosclerotic carotid stenosis were gathered and divided into two groups: open-cell stents and closed-cell stents. Patients underwent preoperative carotid high-resolution magnetic resonance vessel wall imaging (HR-VWI). Use HR-VWI to quantitatively evaluate carotid wall thickness and plaque components. Calculate SER using digital subtraction angiography (DSA). All patients' baseline and HR-VWI imaging features were retrospectively analyzed. Simple and multivariable linear regression analysis was used to determine the imaging findings associated with SER of open-cell and closed-cell stents. Results: A total of 89 patients (mean age, 70±8 years; 69 men) were included in the final analysis. Among 89 patients, 35 patients were treated with open-cell stents. Fifty-four patients were treated with closed-cell stents. In the open-cell stents group, the Maximum single-slice calcification circumference score, maximum wall thickness (WTmax), and total calcification location score with P<0.10 in the simple linear regression analysis were included in the multivariable linear regression analysis. The results of the multivariable linear regression revealed that only the Maximum single-slice calcification circumference score (ß=-9.35; 95% CI: -18.15 to -0.56; P=0.03) was associated with SER of open-cell stents. In the closed-cell stents group, the Maximum single-slice calcification circumference score, WTmax, maximum area percentage of calcification, calcification volume, and total calcification location score with P<0.10 in the simple linear regression analysis were included in the multivariable linear regression analysis. The results of the multivariable linear regression revealed that the Maximum area percentage of calcification (ß=-0.67; 95% CI: -1.29 to -0.05; P=0.03), Maximum single-slice calcification circumference score (ß=-8.43; 95% CI: -13.36 to -3.49; P=0.001) and total calcification location score (ß=-0.37; 95% CI: -1.08 to 0.09; P=0.02) were associated with SER of closed-cell stents. Conclusions: Calcified plaques are associated with SER of the carotid artery. Calcification circumference correlates with SER of open-cell stents. Calcification circumference, calcification area, and calcification location are related to SER of closed-cell stents, which may provide a new consideration for clinicians when choosing carotid artery stents.

Novel Insights on 6:6 Perfluoroalkyl Phosphonic Acid-Induced Melanin Synthesis Disorders Leading to Pigmentation in Tadpoles.

As alternatives to traditional per- and polyfluoroalkyl substances, perfluoroalkyl phosphonic acids (PFPiAs) are widely present in aquatic environments and can potentially harm aquatic organisms. Pigmentation affects the probability of aquatic organisms being preyed on and serves as an important toxic endpoint of development, but little is known about the impacts of PFPiAs on the development of aquatic organisms. In this study, Xenopus laevis embryos were exposed to 6:6 PFPiA (1, 10, and 100 nM) for 14 days. The developed tadpoles exhibited evident pigmentation with increased melanin particle size and density on the skin. Pathological and behavioral experiments revealed that the retinal layers became thinner, reducing the photosensitivity and disturbing the circadian rhythm of the tadpoles. Compared to the control group, the exposed tadpoles showed higher levels but less changes of melanin throughout the light/dark cycle, as well as distinct oxidative damage. Consequently, the expression level of microphthalmia-associated transcription factor (MITF), a key factor inducing melanin synthesis, increased significantly. Molecular docking analysis suggested that 6:6 PFPiA forms strong interactions in the binding pocket of MITF, implying that it could activate MITF directly. The activation of MITF ultimately promotes melanin synthesis, resulting in pigmentation on tadpoles.

Automatic renal mass segmentation and classification on CT images based on 3D U-Net and ResNet algorithms.

Purpose: To automatically evaluate renal masses in CT images by using a cascade 3D U-Net- and ResNet-based method to accurately segment and classify focal renal lesions. Material and Methods: We used an institutional dataset comprising 610 CT image series from 490 patients from August 2009 to August 2021 to train and evaluate the proposed method. We first determined the boundaries of the kidneys on the CT images utilizing a 3D U-Net-based method to be used as a region of interest to search for renal mass. An ensemble learning model based on 3D U-Net was then used to detect and segment the masses, followed by a ResNet algorithm for classification. Our algorithm was evaluated with an external validation dataset and kidney tumor segmentation (KiTS21) challenge dataset. Results: The algorithm achieved a Dice similarity coefficient (DSC) of 0.99 for bilateral kidney boundary segmentation in the test set. The average DSC for renal mass delineation using the 3D U-Net was 0.75 and 0.83. Our method detected renal masses with recalls of 84.54% and 75.90%. The classification accuracy in the test set was 86.05% for masses (<5 mm) and 91.97% for masses (≥5 mm). Conclusion: We developed a deep learning-based method for fully automated segmentation and classification of renal masses in CT images. Testing of this algorithm showed that it has the capability of accurately localizing and classifying renal masses.

Age-related morphometrics of normal adrenal glands based on deep learning-aided segmentation.

OBJECTIVE: This study aims to evaluate the morphometrics of normal adrenal glands in adult patients semiautomatically using a deep learning-based segmentation model. MATERIALS AND METHODS: A total of 520 abdominal CT image series with normal findings, from January 1, 2016, to March 14, 2019, were retrospectively collected for the training of the adrenal segmentation model. Then, 1043 portal venous phase image series of inpatient contrast-enhanced abdominal CT examinations with normal adrenal glands were included for analysis and grouped by every 10-year gap. A 3D U-Net-based segmentation model was used to predict bilateral adrenal labels followed by manual modification of labels as appropriate. Quantitative parameters (volume, CT value, and diameters) of the bilateral adrenal glands were then analyzed. RESULTS: In the study cohort aged 18-77 years old (554 males and 489 females), the left adrenal gland was significantly larger than the right adrenal gland [all patients, 2867.79 (2317.11-3499.89) mm3 vs. 2452.84 (1983.50-2935.18) mm3, P < 0.001]. Male patients showed a greater volume of bilateral adrenal glands than females in all age groups (all patients, left: 3237.83 ± 930.21 mm3 vs. 2646.49 ± 766.42 mm3, P < 0.001; right: 2731.69 ± 789.19 mm3 vs. 2266.18 ± 632.97 mm3, P = 0.001). Bilateral adrenal volume in male patients showed an increasing then decreasing trend as age increased that peaked at 38-47 years old (left: 3416.01 ± 886.21 mm3, right: 2855.04 ± 774.57 mm3). CONCLUSIONS: The semiautomated measurement revealed that the adrenal volume differs as age increases. Male patients aged 38-47 years old have a peaked adrenal volume.

Enhancer-driven transcription of MCM8 by E2F4 promotes ATR pathway activation and glioma stem cell characteristics.

BACKGROUND: Glioma stem cells (GSCs) are responsible for glioma recurrence and drug resistance, yet the mechanisms underlying their maintenance remains unclear. This study aimed to identify enhancer-controlled genes involved in GSCs maintenance and elucidate the mechanisms underlying their regulation. METHODS: We analyzed RNA-seq data and H3K27ac ChIP-seq data from GSE119776 to identify differentially expressed genes and enhancers, respectively. Gene Ontology analysis was performed for functional enrichment. Transcription factors were predicted using the Toolkit for Cistrome Data Browser. Prognostic analysis and gene expression correlation was conducted using the Chinese Glioma Genome Atlas (CGGA) data. Two GSC cell lines, GSC-A172 and GSC-U138MG, were isolated from A172 and U138MG cell lines. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to detect H3K27ac of enhancers, and binding of E2F4 to target gene enhancers. Western blot was used to analyze protein levels of p-ATR and γH2AX. Sphere formation, limiting dilution and cell growth assays were used to analyze GSCs growth and self-renewal. RESULTS: We found that upregulated genes in GSCs were associated with ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) pathway activation, and that seven enhancer-controlled genes related to ATR pathway activation (LIN9, MCM8, CEP72, POLA1, DBF4, NDE1, and CDKN2C) were identified. Expression of these genes corresponded to poor prognosis in glioma patients. E2F4 was identified as a transcription factor that regulates enhancer-controlled genes related to the ATR pathway activation, with MCM8 having the highest hazard ratio among genes positively correlated with E2F4 expression. E2F4 bound to MCM8 enhancers to promote its transcription. Overexpression of MCM8 partially restored the inhibition of GSCs self-renewal, cell growth, and the ATR pathway activation caused by E2F4 knockdown. CONCLUSION: Our study demonstrated that E2F4-mediated enhancer activation of MCM8 promotes the ATR pathway activation and GSCs characteristics. These findings offer promising targets for the development of new therapies for gliomas.

Association between childhood trauma and affective lability among adolescents: A moderated mediation model.

BACKGROUND: Affective lability is an important feature of psychopathology. However, there is limited relevant research involving adolescents. To fill this research gap, the present study assessed the relationship between childhood trauma and affective lability among adolescents using a moderated mediation model. METHODS: A total of 3738 students were recruited from four high schools in Shenzhen, China, between September and December 2019. The participants completed self-reported questionnaires measuring childhood trauma, affective lability, body image dissatisfaction, and the experience of being bullied. Linear regression and moderated mediation analyses were used in this study. RESULTS: Linear regression analysis showed that emotional abuse and body image dissatisfaction positively predicted affective lability in boys and girls (all p < 0.001). Body image dissatisfaction mediated the relationship between emotional abuse and affective lability. In the moderated mediation model, being bullied moderated the direct path from emotional abuse to affective lability (p = 0.0236, p = 0.0188), and gender did not have a significant moderating effect on any direct or indirect path (all p > 0.05). LIMITATIONS: A causal relationship could not be ascertained due to the cross-sectional design, and the results cannot be generalized to other populations. CONCLUSIONS: The findings support that childhood trauma has an impact on affective lability in adolescents. Specifically, body image dissatisfaction and being bullied affect the relationship between emotional abuse and affective lability.

A novel photoelectrochemical strategy for sequence-spot bispecific analysis of N6-methyladenosine modification based on proximity ligation-triggered cascade amplification.

N6-methyladenosine (m6A) modification as the most prevalent mammalian RNA internal modification has been considered as the invasive biomarkers in clinical diagnosis and biological mechanism researches. It is still challenged to explore m6A functions due to technical limitations on base- and location-resolved m6A modification. Herein, we firstly proposed a sequence-spot bispecific photoelectrochemical (PEC) strategy based on in situ hybridization mediated proximity ligation assay for m6A RNA characterization with high sensitivity and accuracy. Firstly, the target m6A methylated RNA could be transferred to the exposed cohesive terminus of H1 based on the special self-designed auxiliary proximity ligation assay (PLA) with sequence-spot bispecific recognition. The exposed cohesive terminus of H1 could furtherly trigger the next catalytic hairpin assembly (CHA) amplification and in situ exponential nonlinear hyperbranched hybridization chain reaction for highly sensitive monitoring of m6A methylated RNA. Compared with conventional technologies, the proposed sequence-spot bispecific PEC strategy for m6A methylation of special RNA based on proximity ligation-triggered in situ nHCR performed improved sensitivity and selectivity with a detection limit of 53 fM, providing new insights into highly sensitive monitoring m6A methylation of RNA in bioassay, disease diagnosis and RNA mechanism.

Reduction of peritoneal cavity B1a cells in adult Slc7a5 knockdown mice via dysregulating the mTOR pathway.

Slc7a5 is an important amino acid transporter that is highly expressed in metabolically active and rapidly proliferating cells. To explore the effect of Slc7a5 on adult B cell development, we conditionally deleted Slc7a5 in murine B cells and observed a significant reduction of B1a cells. In contrast to PI3K-Akt pathway activation, activity of the mTOR pathway was decreased. This may result from intracellular amino acid starvation in Slc7a5 knockdown (Slc7a5 KD) bone marrow B cells, thereby dampening B1a development. RNA-seq analysis demonstrated increased translation and reduced proliferation in Slc7a5 KD bone marrow B cells. Overall, the results of our study highlight the importance of Slc7a5 in peritoneal B1a cell development.

Fibroblast-Generated Extracellular Matrix Guides Anastomosis during Wound Healing in an Engineered Lymphatic Skin Flap.

A healthy lymphatic system is required to return excess interstitial fluid back to the venous circulation. However, up to 49% of breast cancer survivors eventually develop breast cancer-related lymphedema due to lymphatic injuries from lymph node dissections or biopsies performed to treat cancer. While early-stage lymphedema can be ameliorated by manual lymph drainage, no cure exists for late-stage lymphedema when lymph vessels become completely dysfunctional. A viable late-stage treatment is the autotransplantation of functional lymphatic vessels. Here we report on a novel engineered lymphatic flap that may eventually replace the skin flaps used in vascularized lymph vessel transfers. The engineered flap mimics the lymphatic and dermal compartments of the skin by guiding multi-layered tissue organization of mesenchymal stem cells and lymphatic endothelial cells with an aligned decellularized fibroblast matrix. The construct was tested in a novel bilayered wound healing model and implanted into athymic nude rats. The in vitro model demonstrated capillary invasion into the wound gaps and deposition of extracellular matrix fibers, which may guide anastomosis and vascular integration of the graft during wound healing. The construct successfully anastomosed in vivo, forming chimeric vessels of human and rat cells. Overall, our flap replacement has high potential for treating lymphedema.

Novel Insight into the Mechanisms of Neurotoxicity Induced by 6:6 PFPiA through Disturbing the Gut-Brain Axis.

As alternatives to traditional per- and polyfluoroalkyl substances, perfluoroalkyl phosphonic acids (PFPiAs) are frequently detected in aquatic environments, but the neurotoxic effects and underlying mechanisms remain unclear. In this study, male zebrafish were exposed to 6:6 PFPiA (1 and 10 nM) for 28 days, which exhibited anxiety-like symptoms. Gut microbiome results indicated that 6:6 PFPiA significantly increased the abundance of Gram-negative bacteria, leading to enhanced levels of lipopolysaccharide (LPS) and inflammation in the gut. The LPS was delivered to the brain through the gut-brain axis (GBA), damaged the blood-brain barrier (BBB), stimulated neuroinflammation, and caused apoptosis as well as neural injury in the brain. This mechanism was verified by the fact that antibiotics reduced the LPS levels in the gut and brain, accompanied by reduced inflammatory responses and anxiety-like behavior. The BBB damage also resulted in the enhanced accumulation of 6:6 PFPiA in the brain, where it might bind strongly with and activate aryl hydrocarbon receptor (AhR) to induce brain inflammation directly. Additionally, as the fish received treatment with an inhibitor of AhR, the inflammation response and anxiety-like behavior decreased distinctly. This study sheds light on the new mechanisms of neurotoxicity-induced 6:6 PFPiA due to the interruption on GBA.

METTL3 protects METTL14 from STUB1-mediated degradation to maintain m6 A homeostasis.

N6 -Methyladenosine (m6 A) is an important RNA modification catalyzed by methyltransferase-like 3 (METTL3) and METTL14. m6 A homeostasis mediated by the methyltransferase (MTase) complex plays key roles in various biological processes. However, the mechanism underlying METTL14 protein stability and its role in m6 A homeostasis remain elusive. Here, we show that METTL14 stability is regulated by the competitive interaction of METTL3 with the E3 ligase STUB1. STUB1 directly interacts with METTL14 to mediate its ubiquitination at lysine residues K148, K156, and K162 for subsequent degradation, resulting in a significant decrease in total m6 A levels. The amino acid regions 450-454 and 464-480 of METTL3 are essential to promote METTL14 stabilization. Changes in STUB1 expression affect METTL14 protein levels, m6 A modification and tumorigenesis. Collectively, our findings uncover an ubiquitination mechanism controlling METTL14 protein levels to fine-tune m6 A homeostasis. Finally, we present evidence that modulating STUB1 expression to degrade METTL14 could represent a promising therapeutic strategy against cancer.

Combined Effects of Programmed Cell Death-1 Blockade and Endostar on Brain Metastases of Lung Cancer.

BACKGROUND: The blockade of programmed cell death-1 (PD-1) and recombinant human endostatin can be used for the treatment of non-small cell lung cancer (NSCLC) and its metastasis. This study aims to explore the therapeutically potential of PD-1 blockade plus Endostar in brain metastasis of NSCLC. METHODS: The mouse brain metastases model was established using Lewis lung carcinoma luciferase (LLC-Luc) and PC-9-Luc cells. Tumor metastasis in the brain and tumor burden were analyzed by using bioluminescence imaging (BLI), qRT-PCR and ELISA which were used to determine the mRNA and protein levels of biomarkers in tumor tissues. Immunohistochemical staining was used to determine the expression and location of CD31 in tumor tissues in the brain. RESULTS: Treatment with anti-PD-1 and Endostar suppressed tumor metastasis in the brain and prolonged overall survival rate in LLC-Luc and PC-9-Luc brain metastases mouse model. In addition, treatment with anti-PD-1 and Endostar inhibited the expressions of CD31 and VEGF in tumor tissues in the brain. Furthermore, treatment with anti-PD- 1 and Endostar significantly suppressed the levels of IL1ß, IFNγ, and TGFß in the tumor tissues. CONCLUSION: The combination of PD-1 blockade and endostar suppressed brain metastases of NSCLC.

Abnormal Spatial and Temporal Overlap of Time-Varying Brain Functional Networks in Patients with Schizophrenia.

Schizophrenia (SZ) is a complex psychiatric disorder with unclear etiology and pathological features. Neuroscientists are increasingly proposing that schizophrenia is an abnormality in the dynamic organization of brain networks. Previous studies have found that the dynamic brain networks of people with SZ are abnormal in both space and time. However, little is known about the interactions and overlaps between hubs of the brain underlying spatiotemporal dynamics. In this study, we aimed to investigate different patterns of spatial and temporal overlap of hubs between SZ patients and healthy individuals. Specifically, we obtained resting-state functional magnetic resonance imaging data from the public dataset for 43 SZ patients and 49 healthy individuals. We derived a representation of time-varying functional connectivity using the Jackknife Correlation (JC) method. We employed the Betweenness Centrality (BC) method to identify the hubs of the brain's functional connectivity network. We then applied measures of temporal overlap, spatial overlap, and hierarchical clustering to investigate differences in the organization of brain hubs between SZ patients and healthy controls. Our findings suggest significant differences between SZ patients and healthy controls at the whole-brain and subnetwork levels. Furthermore, spatial overlap and hierarchical clustering analysis showed that quasi-periodic patterns were disrupted in SZ patients. Analyses of temporal overlap revealed abnormal pairwise engagement preferences in the hubs of SZ patients. These results provide new insights into the dynamic characteristics of the network organization of the SZ brain.