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1.
IEEE Trans Image Process ; 31: 3399-3413, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35503831

RESUMO

Geometry-based point cloud compression (G-PCC) can achieve remarkable compression efficiency for point clouds. However, it still leads to serious attribute compression artifacts, especially under low bitrate scenarios. In this paper, we propose a Multi-Scale Graph Attention Network (MS-GAT) to remove the artifacts of point cloud attributes compressed by G-PCC. We first construct a graph based on point cloud geometry coordinates and then use the Chebyshev graph convolutions to extract features of point cloud attributes. Considering that one point may be correlated with points both near and far away from it, we propose a multi-scale scheme to capture the short- and long-range correlations between the current point and its neighboring and distant points. To address the problem that various points may have different degrees of artifacts caused by adaptive quantization, we introduce the quantization step per point as an extra input to the proposed network. We also incorporate a weighted graph attentional layer into the network to pay special attention to the points with more attribute artifacts. To the best of our knowledge, this is the first attribute artifacts removal method for G-PCC. We validate the effectiveness of our method over various point clouds. Objective comparison results show that our proposed method achieves an average of 9.74% BD-rate reduction compared with Predlift and 10.13% BD-rate reduction compared with RAHT. Subjective comparison results present that visual artifacts such as color shifting, blurring, and quantization noise are reduced.

2.
Molecules ; 27(9)2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35566338

RESUMO

Neuroinflammation characterized by microglia activation is the mechanism of the occurrence and development of various central nervous system diseases. ST2825, as a peptide-mimetic MyD88 homodimerization inhibitor, has been identified as crucial molecule with an anti-inflammatory role in several immune cells, especially microglia. The purpose of the study was to investigate the anti-neuroinflammatory effects and the possible mechanism of ST2825. Methods: Lipopolysaccharide (LPS) was used to stimulate neuroinflammation in male BALB/c mice and BV2 microglia cells. The NO level was determined by Griess Reagents. The levels of pro-inflammatory cytokines and chemokines were determined by ELISA. The expressions of inflammatory proteins were determined by real-time PCR and Western blotting analysis. The level of ROS was detected by DCFH-DA staining. Results: In vivo, the improved levels of LPS-induced pro-inflammatory factors, including TNF-α, IL-6, IL-1ß, MCP-1 and ICAM-1 in the cortex and hippocampus, were reduced after ST2825 treatment. In vitro, the levels of LPS-induced pro-inflammatory factors, including NO, TNF-α, IL-6, IL-1ß, MCP-1, iNOS, COX2 and ROS, were remarkably decreased after ST2825 treatment. Further research found that the mechanism of its anti-neuroinflammatory effects appeared to be associated with inhibition of NF-κB activation and down-regulation of the NLRP3/cleaved caspase-1 signaling pathway. Conclusions: The current findings provide new insights into the activity and molecular mechanism of ST2825 for the treatment of neuroinflammation.

3.
Transl Cancer Res ; 11(4): 823-834, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35571635

RESUMO

Background: Glioblastoma (GBM) is the most common and fatal tumor in the central nervous system. Recent studies have found that long non-coding RNAs (lncRNAs) serve as competitive endogenous RNAs (ceRNAs) and play an important role in GBM by regulating immune responses. The aim of the present study was to identify lncRNAs with immune relevance and functions in GBM. Methods: We analyzed GBM datasets from The Cancer Genome Atlas (TCGA) database to obtain 356 significantly differentially expressed lncRNAs (DE-lncRNAs), 4,951 DE-mRNAs, and 34 DE-miRNAs in GBM, respectively. For mRNAs, 369 DE-mRNAs were identified as immune-related genes in the ImmPort database. For DE-lncRNAs, univariate analysis identified 39 DE-lncRNAs with prognostic significance, and 9 DE-lncRNAs were included in the ImmLnc database. Combined analysis was then conducted by integrating 9 immune-related DE-lncRNAs, 369 immune-related DE-mRNAs, and 34 DE-miRNAs. A ceRNA network composed of 2 upregulated lncRNAs (LINC01268 and CTB-31O20.2), 3 downregulated miRNAs, and 5 upregulated mRNAs was generated. Results: Kaplan-Meier survival analysis and univariate and multivariate Cox regression analyses showed that LINC01268 and CTB-31O20.2 serve as independent favorable prognostic markers in GBM. LINC01268 and CTB-31O20.2 overexpression was conducted in GBM cell U251. Cell Counting Kit-8 (CCK8), Transwell assay, and scratch healing assay indicated that LINC01268 and CTB-31O20.2 inhibit GBM cell line, U251, proliferation, invasion, and migration. Conclusions: LINC01268 and CTB-31O20.2 are independent prognostic immune-related markers, and reduce cancer cell proliferation and metastasis in GBM.

4.
Int J Biol Sci ; 18(7): 2744-2758, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35541906

RESUMO

RNA can be modified by over 170 types of distinct chemical modifications, and the most abundant internal modification of mRNA in eukaryotes is N6-methyladenosine (m6A). The m6A modification accelerates mRNA process, including mRNA splicing, translation, transcript stability, export and decay. m6A RNA modification is installed by methyltransferase-like proteins (writers), and potentially removed by demethylases (erasers), and this process is recognized by m6A-binding proteins (readers). Notably, alterations of m6A-modified proteins (writers, erasers and readers) are involved in the tumorigenesis, progression and metastasis. Importantly, the fate of m6A-methylated mRNA is mediated mostly through m6A readers, and among these readers, insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) are unique RNA-binding proteins (RBPs) that stabilize their targets mRNA via m6A modification. In this review, we update the writers, erasers and readers, and their cross-talks in m6A modification, and briefly discuss the oncogenic role of IGF2BPs in cancer. Most importantly, we mainly review the up-to-date knowledges of IGF2BPs (IGF2BP1/2/3) as m6A readers in an m6A-modified manner in cancer progression.


Assuntos
Proteínas de Transporte , Neoplasias , Carcinogênese , Humanos , Neoplasias/metabolismo , RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
5.
J Extracell Vesicles ; 11(5): e12221, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35524442

RESUMO

Tumour-associated angiogenesis plays a critical role in metastasis, the main cause of malignancy-related death. Extracellular vesicles (EVs) can regulate angiogenesis to participate in tumour metastasis. Our previous study showed that EVs rich in HAX1 are associated with in metastasis of nasopharyngeal carcinoma (NPC). However, the mechanism by which HAX1 of EVs promotes metastasis and angiogenesis is unclear. In this study, we demonstrated that EVs rich in HAX1 promote angiogenesis phenotype by activating the FAK pathway in endothelial cells (ECs) by increasing expression level of ITGB6. The expression level of HAX1 is markedly correlated with microvessel density (MVDs) in NPC and head and neck cancers based on an analysis of IHC. In addition to a series of in vitro cellular analyses, in vivo models revealed that HAX1 was correlated with migration and blood vessel formation of ECs, and metastasis of NPC. Using ribosome profiling, we found that HAX1 regulates the FAK pathway to influence microvessel formation and promote NPC metastasis by enhancing the translation efficiency of ITGB6. Our findings demonstrate that HAX1 can be used as an important biomarker for NPC metastasis, providing a novel basis for antiangiogenesis therapy in clinical settings.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Vesículas Extracelulares , Neoplasias Nasofaríngeas , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Endoteliais/metabolismo , Vesículas Extracelulares/genética , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/metabolismo , Neovascularização Patológica/genética
6.
Light Sci Appl ; 11(1): 145, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35595724

RESUMO

A highly efficient on-chip acousto-optic modulator is as a key component and occupies an exceptional position in microwave-to-optical conversion. Homogeneous thin-film lithium niobate is preferentially employed to build the suspended configuration for the acoustic resonant cavity, with the aim of improving the modulation efficiency of the device. However, the limited cavity length and complex fabrication recipe of the suspended prototype restrain further breakthroughs in modulation efficiency and impose challenges for waveguide fabrication. In this work, based on a nonsuspended thin-film lithium niobate-chalcogenide glass hybrid Mach-Zehnder interferometer waveguide platform, we propose and demonstrate a built-in push-pull acousto-optic modulator with a half-wave-voltage-length product VπL as low as 0.03 V cm that presents a modulation efficiency comparable to that of a state-of-the-art suspended counterpart. A microwave modulation link is demonstrated using our developed built-in push-pull acousto-optic modulator, which has the advantage of low power consumption. The nontrivial acousto-optic modulation performance benefits from the superior photoelastic property of the chalcogenide membrane and the completely bidirectional participation of the antisymmetric Rayleigh surface acoustic wave mode excited by the impedance-matched interdigital transducer, overcoming the issue of low modulation efficiency induced by the incoordinate energy attenuation of acoustic waves applied to the Mach-Zehnder interferometer with two arms in traditional push-pull acousto-optic modulators.

7.
Sci Rep ; 12(1): 8579, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35595822

RESUMO

Stimulator of interferon genes (STING) activation induces type I interferons and pro-inflammatory cytokines which stimulate tumor antigen cross presentation and the adaptive immune responses against tumor. The first-generation of STING agonists, cyclic di-nucleotide (CDN), mimicked the endogenous STING ligand cyclic guanosine monophosphate adenosine monophosphate, and displayed limited clinical efficacy. Here we report the discovery of SHR1032, a novel small molecule non-CDN STING agonist. Compared to the clinical CDN STING agonist ADU-S100, SHR1032 has much higher activity in human cells with different STING haplotypes and robustly induces interferon ß (IFNß) production. When dosed intratumorally, SHR1032 induced strong anti-tumor effects in the MC38 murine syngeneic tumor model. Pharmacodynamic studies showed induction of IFNß, tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) in the tumors and, to a lower extent, in the plasma. More importantly, we found SHR1032 directly causes cell death in acute myeloid leukemia (AML) cells. In conclusion, our findings demonstrate that in addition to their established ability to boost anti-tumor immune responses, STING agonists can directly eradicate AML cells, and SHR1032 may present a new and promising therapeutic agent for cancer patients.


Assuntos
Leucemia Mieloide Aguda , Proteínas de Membrana , Animais , Apoptose , Citocinas/metabolismo , Humanos , Interferon beta/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas de Membrana/metabolismo , Camundongos
8.
Sheng Li Xue Bao ; 74(2): 165-176, 2022 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-35503064

RESUMO

This paper was aimed to clarify the effect of high-intensity interval training (HIIT) on depression. Animal running platforms were used to establish HIIT exercise models, depression models were prepared by chronic unpredictable mild stress (CUMS), and depression-related behaviors were detected by behavioral experiments. The results showed that HIIT exercise improved depression-related behavior in CUMS model mice. Western blot and ELISA results showed that in the hippocampus, medial prefrontal cortex (mPFC) and amygdala of the CUMS model mice, glucocorticoid receptor (GR) protein expression was down-regulated, and the content of tumor necrosis factor α (TNF-α) was increased, compared with those in the control group, whereas HIIT exercise could effectively reverse these changes in CUMS model mice. These results suggest that HIIT exercise can exert antidepressant effect, which brings new ideas and means for the clinical treatment of depressive diseases.


Assuntos
Depressão , Estresse Psicológico , Animais , Antidepressivos/farmacologia , Comportamento Animal , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo/metabolismo , Camundongos , Estresse Psicológico/tratamento farmacológico
10.
Cancers (Basel) ; 14(9)2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35565318

RESUMO

BACKGROUND AND AIMS: Perihilar cholangiocarcinoma (pCCA) is a hepatobiliary malignancy, with a dismal prognosis. Nerve fiber density (NFD)-a novel prognostic biomarker-describes the density of small nerve fibers without cancer invasion and is categorized into high numbers and low numbers of small nerve fibers (high vs low NFD). NFD is different than perineural invasion (PNI), defined as nerve fiber trunks invaded by cancer cells. Here, we aim to explore differences in immune cell populations and survival between high and low NFD patients. APPROACH AND RESULTS: We applied multiplex immunofluorescence (mIF) on 47 pCCA patients and investigated immune cell composition in the tumor microenvironment (TME) of high and low NFD. Group comparison and oncological outcome analysis was performed. CD8+PD-1 expression was higher in the high NFD than in the low NFD group (12.24 × 10-6 vs. 1.38 × 10-6 positive cells by overall cell count, p = 0.017). High CD8+PD-1 expression was further identified as an independent predictor of overall (OS; Hazard ratio (HR) = 0.41; p = 0.031) and recurrence-free survival (RFS; HR = 0.40; p = 0.039). Correspondingly, the median OS was 83 months (95% confidence interval (CI): 18-48) in patients with high CD8+PD-1+ expression compared to 19 months (95% CI: 5-93) in patients with low CD8+PD-1+ expression (p = 0.018 log rank). Furthermore, RFS was significantly lower in patients with low CD8+PD-1+ expression (14 months (95% CI: 6-22)) compared to patients with high CD8+PD-1+ expression (83 months (95% CI: 17-149), p = 0.018 log rank). CONCLUSIONS: PD-1+ T-cells correlate with high NFD as a prognostic biomarker and predict good survival; the biological pathway needs to be investigated.

11.
Front Mol Neurosci ; 15: 844668, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35600071

RESUMO

Cingulin, a cytoplasmic element of tight junctions (TJs), is involved in maintenance of the integrity of epithelial and endothelial cells. However, the role of cingulin in the development of auditory organs remains unclear. Zebrafish is popular as a model organism for hearing research. Using the whole mount in situ hybridization (WISH) experiment, we detected the expression of cingulin b in the posterior lateral line system (PLLs) of zebrafish. We traced the early development progress of zebrafish PLLs from 36 hpf to 72 hpf, and found that inhibition of cingulin b by target morpholinos resulted in severe developmental obstruction, including decreased number of neuromasts, reduced proliferative cells in the primordium, and repressed hair cell differentiation in the neuromasts. To examine the potential mechanism of cingulin b in the development of zebrafish PLL neuromasts, we performed RNA-seq analysis to compare the differently expressed genes (DEGs) between cingulin b knockdown samples and the controls. The KEGG enrichment analysis revealed that MAPK signaling pathway and cellular senescence were the key pathways with most DEGs in cingulin b-MO morphants compared to the Control-MO embryos. Furthermore, quantitative RT-PCR analysis confirmed the findings by RNA-seq that the transcript levels of cell cycle negative regulators such as tp53 and cdkn1a, were remarkably upregulated after inhibition of cingulin b. Our results therefore indicated an important role of cingulin b in the development of auditory organs, and MAPK signaling pathway was inhibited while cellular senescence pathway was activated after downregulation of cingulin b. We bring forward new insights of cingulin by exploring its function in auditory system.

12.
Endocrinology ; 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35511048

RESUMO

Ovulation is a dramatic remodeling process that includes rupture of blood capillaries and clotting, but coagulation is not thought to directly regulate this process. Herein, we report remarkable increases of coagulation factors V (f5, ~3145-fold) and tissue factor (f3a, ~120-fold) in zebrafish ovarian follicle cells during ovulation. This increase was mediated through the nuclear progestin receptor (Pgr), which is essential for ovulation in zebrafish, and was totally abolished in ovarian follicular cells from pgr-/- mutants. In addition, promoter activities of f5 and f3a were significantly enhanced by progestin (DHP) via Pgr. Similar regulation of human F5 promoter activity was induced via human PGRB, suggesting a conserved mechanism. Site-directed mutagenesis of the zebrafish f5 promoter further demonstrated a direct regulation of coagulation factors via progestin response elements. Moreover, a stark increase of erythrocytes occurred in capillaries meshed in wildtype preovulatory follicles but was absent in pgr-/- mutants. Interestingly, anticoagulants significantly inhibited ovulation both in vitro and in vivo, respectively. Furthermore, reduced fecundity was observed in f5+/- female zebrafish. Taken together, our study provides plausible evidence for steroid regulation of coagulation factors, and a new hypothesis for blood clotting triggered ovulation in vertebrates.

13.
J Colloid Interface Sci ; 622: 261-271, 2022 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-35512590

RESUMO

Core-shell structure has been receiving extensive attention to enhance the electromagnetic wave (EMW) absorption performance due to its unique interface effect. In this paper, a micro-flower like ZnCo@C@1T-2H-MoS2 was prepared through MOF self-template method. The introduction 1T-2H-MoS2 shell helps optimize impedance matching of the CoZn@C particles to improve the EMW absorption ability. The minimal reflection loss (RLmin) value of ZnCo@C@1T-2H-MoS2 is -35.83 dB with a thickness of 5.0 mm at 5.83 GHz and the effective absorption (RL < -10 dB) bandwidth up to 4.56 GHz at 2.0 mm thickness. Meanwhile, the overall effective absorption bandwidth (OEAB) can reach up to 13.44 GHz from 4.56 to 18.0 GHz. Moreover, ultrafast photothermal performances are also achieved, which can guarantee the normal functioning of ZnCo@C@1T-2H-MoS2 materials in cold conditions. The excellent EMW absorption and photothermal performance are attributed to the unique structure designed with the core of magnetic ZnCo@C rhombic dodecahedral and the shell of dielectric micro-flower like 1T-2H-MoS2 optimize impedance matching.

14.
Front Bioeng Biotechnol ; 10: 822392, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35519609

RESUMO

Identification of protein-ligand binding sites plays a critical role in drug discovery. However, there is still a lack of targeted drug prediction for DNA-binding proteins. This study aims at the binding sites of DNA-binding proteins and drugs, by mining the residue interaction network features, which can describe the local and global structure of amino acids, combined with sequence feature. The predictor of DNA-binding protein-drug-binding sites is built by employing the Extreme Gradient Boosting (XGBoost) model with random under-sampling. We found that the residue interaction network features can better characterize DNA-binding proteins, and the binding sites with high betweenness value and high closeness value are more likely to interact with drugs. The model shows that the residue interaction network features can be used as an important quantitative indicator of drug-binding sites, and this method achieves high predictive performance for the binding sites of DNA-binding protein-drug. This study will help in drug discovery research for DNA-binding proteins.

15.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 36(4): 431-438, 2022 Apr 15.
Artigo em Chinês | MEDLINE | ID: mdl-35426282

RESUMO

Objective: To analyze the biomechanical properties of the rod-screw prosthesis based on a pelvic three-dimensional finite element model including muscle and ligament, and evaluate the effectiveness of zoneⅠ+Ⅱ+Ⅲ reconstruction of hemipelvis with rod-screw prosthesis in combination with clinical applications. Methods: A total of 21 patients who underwent hemipelvic tumor resection (zoneⅠ+Ⅱ+Ⅲ) and rod-screw prosthesis reconstruction between January 2015 and December 2020 were selected as the research subjects. Among them, there were 11 males and 10 females; the age ranged from 16 to 64 years, with an average age of 39.2 years. There were 9 cases of chondrosarcoma, 7 cases of osteosarcoma, 3 cases of Ewing sarcoma, and 2 cases of undifferentiated pleomorphic sarcoma. According to the Musculoskeletal Tumor Society Score (MSTS) staging, there were 19 cases of stage ⅡB and 2 cases of stage Ⅲ. Preoperative Harris Hip Score (HHS) and MSTS score were 54.4±3.1 and 14.1±2.0, respectively. Intraoperative 15 cases underwent extensive resection, 5 cases underwent marginal resection, and 1 case underwent intralesional resection. The CT image of 1 patient after reconstruction was used to establish a three-dimensional solid model of the pelvis via Mimics23Suite and 3-matic softwares. At the same time, a mirror operation was used to obtain a normal pelvis model, then the two solid models were imported into the finite element analysis software Workbench 2020R1 to establish three-dimensional finite element models, and the biomechanical properties of the standing position were analyzed. The operation time, intraoperative blood loss, and operation-related complications were recorded, and the postoperative evaluation was carried out with HHS and MSTS scores. Finally, the local recurrence and metastasis were reviewed. Results: Finite element analysis showed that the peak stress of the reconstructed pelvis appeared at the fixed S1, 2 rod-screw connections; the peak stress without muscles was higher than that after muscle construction, but much smaller than the yield strength of titanium alloy. The operation time was 250-370 minutes, with an average of 297 minutes; the amount of intraoperative blood loss was 3 200-5 500 mL, with an average of 4 009 mL. All patients were followed up 8-72 months, with an average of 42 months. There were 7 cases of pulmonary metastasis, of which 2 cases were preoperative metastasis; 5 cases died, 16 cases survived, and the 5-year survival rate was 72.1%. There were 3 cases of local recurrence, all of whom did not achieve extensive resection during operation. The function of the affected limbs significantly improved, and the walking function was restored. The HHS and MSTS scores were 75.2±3.0 and 20.4±2.0 at last follow-up, respectively, and the differences were significant when compared with those before operation (t=22.205, P<0.001; t=11.915, P<0.001). During follow-up, 2 cases of delayed incision healing, 2 cases of deep infection, 1 case of screw loosening, and 1 case of prosthesis dislocation occurred, and no other complication such as prosthesis or screw fracture occurred. Conclusion: The stress and deformation distribution of the reconstructed pelvis are basically the same as normal pelvis. The rod-screw prosthesis is an effective reconstruction method for pelvic malignant tumors.


Assuntos
Neoplasias Ósseas , Ossos Pélvicos , Adolescente , Adulto , Perda Sanguínea Cirúrgica , Neoplasias Ósseas/cirurgia , Parafusos Ósseos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ossos Pélvicos/cirurgia , Implantação de Prótese , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
16.
Front Mol Neurosci ; 15: 848257, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35431796

RESUMO

Nexmif is mainly expressed in the central nervous system (CNS) and plays important roles in cell migration, cell to cell and cell-matrix adhesion, and maintains normal synaptic formation and function. Nevertheless, it is unclear how nexmif is linked to motor neuron morphogenesis. Here, we provided in situ hybridization evidence that nexmifa (zebrafish paralog) was localized to the brain and spinal cord and acted as a vital regulator of motor neuron morphogenesis. Nexmifa deficiency in zebrafish larvae generated abnormal primary motor neuron (PMN) development, including truncated Cap axons and decreased branches in Cap axons. Importantly, RNA-sequencing showed that nexmifa-depleted zebrafish embryos caused considerable CNS related gene expression alterations. Differentially expressed genes (DEGs) were mainly involved in axon guidance and several synaptic pathways, including glutamatergic, GABAergic, dopaminergic, cholinergic, and serotonergic synapse pathways, according to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation. In particular, when compared with other pathways, DEGs were highest (84) in the axon guidance pathway, according to Organismal Systems. Efna5b, bmpr2b, and sema6ba were decreased markedly in nexmifa-depleted zebrafish embryos. Moreover, both overexpression of efna5b mRNA and sema6ba mRNA could partially rescued motor neurons morphogenesis. These observations supported nexmifa as regulating axon morphogenesis of motor neurons in zebrafish. Taken together, nexmifa elicited crucial roles during motor neuron development by regulating the morphology of neuronal axons.

17.
Eur J Neurosci ; 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35481869

RESUMO

Although it is well recognized that the circadian timing system profoundly influences cognitive performance, the underlying molecular mechanisms remain poorly defined. Our previous work has found that the mitogen-activated protein kinase-interacting kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis, a conserved cellular signalling pathway regulating mRNA translation, modulates the function of the suprachiasmatic nucleus (SCN), the master circadian clock. Here, with the use of a combination of genetic, biochemical and behavioural approaches, we investigated the distribution and temporal regulation of eIF4E phosphorylation in the brain and its role in regulating the diurnal oscillations of some aspects of cognition in mice. We found that activities of the MNK-eIF4E axis, as indicated by the level of eIF4E phosphorylation at Ser209, exhibited significant circadian oscillations in a variety of brain regions, including but not limited to the prefrontal cortex, the hippocampus, the amygdala and the cerebellum. Phosphorylated eIF4E was enriched in neurons but not in astrocytes or microglia. Mice lacking eIF4E phosphorylation (eIF4ES209A/S209A ) or the MNKs (Mnk1-/-,2-/- ), the kinases that phosphorylate eIF4E, exhibited impaired diurnal variations of novel object recognition, object location memory, Barnes maze learning and ambulatory activities. Together, these results suggest that circadian activities of the MNK-eIF4E axis contribute to the diurnal rhythms of some cognitive functions, highlighting a role for rhythmic translational control in circadian regulation of cognitive performance.

18.
Front Mol Neurosci ; 15: 854556, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35465091

RESUMO

Vessels and nerves are closely associated in anatomy as well as functions. Accumulating evidences have demonstrated that axon-guiding signals may affect endothelial cells migration and path finding, which is crucial for the patterning of both the complex vascular network and neural system. However, studies regarding the functional overlap between vascular and neuronal orchestrating are still incomplete. Semaphorin6D (Sema6D) belongs to the Semaphorin family and has been identified as an important regulating factor in diverse biological processes. Its roles in vascular development are still unclear. Here, we confirmed that sema6D is enriched in neural system and blood vessels of zebrafish embryos by in situ hybridization. Then, the deficiency of sema6D caused by specific antisense morpholino-oligonucleotides (MO) led to dramatic path finding defects in both intersegmental vessels (ISVs) and primary motor neurons (PMNs) of spinal cord in zebrafish embryos. Furthermore, these defective phenotypes were confirmed in F0 generation of sema6D knockouts and rescue experiments by overexpression of sema6D mRNA in sema6D morphants. These data collectively indicate that sema6D regulates zebrafish vascular patterning and motor neuronal axon growth in the spinal cord, which might be of great therapeutical use to regulate vessel and nerve guidance in the relevant diseases that affect both systems.

19.
Cell Death Discov ; 8(1): 208, 2022 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-35436989

RESUMO

Identifying the mechanism of glioma progression is critical for diagnosis and treatment. Although studies have shown that guanylate-binding protein 2(GBP2) has critical roles in various cancers, its function in glioma is unclear. In this work, we demonstrate that GBP2 has high expression levels in glioma tissues. In glioma cells, depletion of GBP2 impairs proliferation and migration, whereas overexpression of GBP2 enhances proliferation and migration. Regarding the mechanism, we clarify that epidermal growth factor receptor (EGFR) signaling is regulated by GBP2, and also demonstrate that GBP2 interacts directly with kinesin family member 22(KIF22) and regulates glioma progression through KIF22/EGFR signaling in vitro and in vivo. Therefore, our study provides new insight into glioma progression and paves the way for advances in glioma treatment.

20.
Open Biol ; 12(4): 210315, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35382569

RESUMO

A precise guiding signal is crucial to orchestrate directional migration and patterning of the complex vascular network and neural system. So far, limited studies have reported the discovery and functions of microRNAs (miRNAs) in guiding vascular and neural pathfinding. Currently, we showed that the deficiency of miRNA-22a, an endothelial-enriched miRNA, caused dramatic pathfinding defects both in intersegmental vessels (ISVs) and primary motor neurons (PMNs) in zebrafish embryos. Furthermore, we found the specific inhibition of miR-22a in endothelial cells (ECs) resulted in patterning defects of both ISVs and PMNs. Neuronal block of miR-22a mainly led to axonal defects of PMN. Sema4c was identified as a potential target of miR-22a through transcriptomic analysis and in silico analysis. Additionally, a luciferase assay and EGFP sensor assay confirmed the binding of miR-22a with 3'-UTR of sema4c. In addition, downregulation of sema4c in the miR-22a morphants significantly neutralized the aberrant patterning of vascular and neural networks. Then we demonstrated that endothelial miR-22a regulates PMNs axonal navigation. Our study revealed that miR-22a acted as a dual regulatory cue coordinating vascular and neuronal patterning, and expanded the repertoire of regulatory molecules, which might be of use therapeutically to guide vessels and nerves in the relevant diseases.


Assuntos
MicroRNAs , Semaforinas , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Orientação de Axônios , Células Endoteliais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neurônios Motores , Semaforinas/genética , Semaforinas/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
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