Gliomas, a common type of brain tumor, are characterized by aggressive infiltration, making it difficultly to cure by surgery. Netrin-1, an extracellular guidance cue critical for neuronal axon ...path-finding, has been reported to play an important role in cell invasion and migration in several types of cancers. However, the role of netrin-1 in glioma remains largely unknown. Here, we provide evidence suggested that Netrin-1 has a critical role in glioma growth. We found that netrin-1 was significantly increased in glioma samples and positively correlated with cell proliferation, tumor grade and malignancy. Netrin-1 knockdown reduced cell proliferation and attenuated tumor growth in a xenograft mouse model. Further studies found that netrin-1 induced NF-κB p65
phosphorylation and c-Myc expression in vitro and in vivo. Interestingly, activation of NF-κB by netrin-1 was dependent on UNC5A receptor, because suppression of UNC5A significantly inhibited NF-κB p65
phosphorylation, c-Myc up-regulation and reduced cell proliferation. Taken together, these results suggested netrin-1 promotes glioma cell proliferation by activating NF-κB signaling via UNC5A, netrin-1 may be a potential therapeutic target for the treatment of glioma.
The underlying complexity of urban space can be manifested by its fractal forms and scaling statistics. This paper examines these characteristics at the intra-urban scale through the lens of ...clustered street junctions (including road ends) in two Chinese metropolitan areas: Beijing and Shenzhen. We derived the cluster sets with Euclidean distance thresholds starting at 100 meters (m) and ending at 1000 m, and outlined each cluster using a concave-hull method to maintain their original irregular shapes. Within each delimited cluster, we examined four urban attributes: gross domestic product, number of street nodes, polygon area, and population. Our analysis revealed that power law distribution applied to almost every cluster set in terms of the four attributes, but varied from one attribute to another or from city to city, represented primarily by fluctuated power law exponents and ht-index values whose profiles along with the cluster growth can effectively characterize the urban structure. Additionally, we computed the spectrum of intra-urban scaling exponents with cluster size increments, contributing new insights into the allometric relationships between urban configuration and function.
Fe3O4/Polyvinylidene fluoride (PVDF) three-channel hollow fiber catalytic membrane was successfully fabricated via non-solvent induced phase inversion and used for organic wastewater degradation in ...this work. The effects of Fe3O4 nanoparticles addition on the surface and cross-section morphologies, hydrophilicity and thermal properties of the catalytic membrane were characterized by the field emission scanning electron microscopy (SEM), water contact angle and thermogravimetric analysis (TGA), respectively. The obtained catalytic membrane exhibited good hydrophilicity, a high pure water flux of 175.8 L m−2 h−1 and a high removal of methylene blue (up to 97.6%) with Fenton catalytic reaction. Meanwhile, the catalytic membrane shows excellent anti-fouling property due to the presence of Fenton reaction. Our results show that Fe3O4/PVDF three-channel hollow fiber catalytic membrane was a promising alternative for the degradation of organic contaminants.
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•Fe3O4/PVDF three-channel hollow fiber catalytic membrane was fabricated.•Fe3O4 endows the membrane with good Fenton catalytic performance.•Catalytic membrane has a good improvement in hydrophilia and stability.•Different additions of Fe3O4 were studied in this work.
Phosphatidylinositol‐3‐kinase gamma (PI3Kγ) is a leukocyte‐specific lipid kinase with signaling function downstream of G protein‐coupled receptors to regulate cell trafficking, but its role in ...T cells remains unclear. To investigate the requirement of PI3Kγ kinase activity in T‐cell function, we studied T cells from PI3Kγ kinase‐dead knock‐in (PI3KγKD/KD) mice expressing the kinase‐inactive PI3Kγ protein. We show that CD4+ and CD8+ T cells from PI3KγKD/KD mice exhibit impaired TCR/CD28‐mediated activation that could not be rescued by exogenous IL‐2. The defects in proliferation and cytokine production were also evident in naïve and memory T cells. Analysis of signaling events in activated PI3KγKD/KD T cells revealed a reduction in phosphorylation of protein kinase B (AKT) and ERK1/2, a decrease in lipid raft formation, and a delay in cell cycle progression. Furthermore, PI3KγKD/KD CD4+ T cells displayed compromised differentiation toward Th1, Th2, Th17, and induced Treg cells. PI3KγKD/KD mice also exhibited an impaired response to immunization and a reduced delayed‐type hypersensitivity to Ag challenge. These findings indicate that PI3Kγ kinase activity is required for optimal T‐cell activation and differentiation, as well as for mounting an efficient T cell‐mediated immune response. The results suggest that PI3Kγ kinase inhibitors could be beneficial in reducing the undesirable immune response in autoimmune diseases.
Inhibitors of angiogenic factors are known to be upregulated, and their levels increase in the maternal circulation before the onset of preeclampsia. We reproduced a previously characterized model of ...preeclampsia by adenoviral overexpression of the soluble vascular endothelial growth factor (VEGF) receptor sFlt-1 (also referred to as sVEGFR-1) in pregnant and nonpregnant Sprague-Dawley rats. Animals were treated with VEGF121 at 0, 100, 200, or 400 microg/kg once or twice daily (n=8 per group; 64 total) and compared with normal control animals (n=4 per group) by examination of systolic blood pressure, urinary albumin and creatinine, renal histopathology, and glomerular gene expression profiling. sFlt-1 expression induced hypertension with proteinuria and glomerular endotheliosis and significant changes in gene expression. VEGF121 treatment alleviated these symptoms and reversed 125 of 268 sFlt-1-induced changes in gene expression. VEGF121 had beneficial effects in this rat model of preeclampsia without apparent harm to the fetus. Further study of VEGF121 as a potential therapeutic agent for preeclampsia is warranted.
Comprehensive molecular characterization of myriad somatic alterations and aberrant gene expressions at personal level is key to precision cancer therapy, yet limited by current short-read sequencing ...technology, individualized catalog of complete genomic and transcriptomic features is thus far elusive. Here, we integrated second- and third-generation sequencing platforms to generate a multidimensional dataset on a patient affected by metastatic epithelial ovarian cancer. Whole-genome and hybrid transcriptome dissection captured global genetic and transcriptional variants at previously unparalleled resolution. Particularly, single-molecule mRNA sequencing identified a vast array of unannotated transcripts, novel long noncoding RNAs and gene chimeras, permitting accurate determination of transcription start, splice, polyadenylation and fusion sites. Phylogenetic and enrichment inference of isoform-level measurements implicated early functional divergence and cytosolic proteostatic stress in shaping ovarian tumorigenesis. A complementary imaging-based high-throughput drug screen was performed and subsequently validated, which consistently pinpointed proteasome inhibitors as an effective therapeutic regime by inducing protein aggregates in ovarian cancer cells. Therefore, our study suggests that clinical application of the emerging long-read full-length analysis for improving molecular diagnostics is feasible and informative. An in-depth understanding of the tumor transcriptome complexity allowed by leveraging the hybrid sequencing approach lays the basis to reveal novel and valid therapeutic vulnerabilities in advanced ovarian malignancies.
Ru-based electrocatalysts have demonstrated excellent electrocatalytic performance toward hydrogen evolution reaction (HER). However, designing Ru nanoparticles/nanoclusters (Ru NPs/NCs) with ...abundant accessible active sites is challenging. Herein, a selective facile hydrothermal in situ polymerization strategy is described to accurately control the anchoring point of Ru in hollow mesoporous carbon spheres (HMCs) (outer surface, HMCs@Ru; cavity, Ru@HMCs; and pore channels, Ru/S-HMCs). The HER mechanisms of the three catalysts over a wide pH range were revealed by analyzing the loading position, content, dispersion, particle size, and valence state of Ru. HMCs@Ru shows excellent area activity, with overpotentials of 64.3, 2.8, and 78.1 mV at 10 mA·cm
−2
in 0.5 mol⋅L
−1
H
2
SO
4
, 1 mol⋅L
−1
KOH, and 0.5 mol⋅L
−1
phosphate buffer saline (PBS) solutions, respectively. Ru/S-HMCs exhibit high mass activity, with values 43.3, 2.9, and 12.7 times those of Pt/C in alkaline, acidic, and neutral media, respectively, at − 50 mV (vs. reversible hydrogen electrode (RHE)). After 2000 cyclic voltammetry cycles, the performances of HMCs@Ru and Ru/S-HMCs hardly decrease, indicating good stability. The excellent electrocatalytic activity can be attributed to two main factors: (1) the confinement effect, which not only promotes high Ru dispersion but also prevents the leaching of active metal under harsh conditions, and (2) their excellent structural characteristics. The catalyst structure features a large hollow located in the center (~ 160 nm in diameter) and an ultrathin monolayer of mesopores (~ 6 nm) uniformly distributed on the hollow shells, ensuring fast mass diffusion and electron transfer kinetics, as well as complete accessibility of catalytic sites.
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Radiotherapy is the first‐line treatment for locally advanced cervical squamous cell cancer (CSCC). However, ≈50% of patients fail to respond to therapy and, in some cases, tumors progress after ...radical radiotherapy. Here, single‐nucleus RNA‐seq is performed to construct high‐resolution molecular landscapes of various cell types in CSCC before and during radiotherapy, to better understand radiotherapy related molecular responses within tumor microenvironment. The results show that expression levels of a neural‐like progenitor (NRP) program in tumor cells are significantly higher after radiotherapy and these are enriched in the tumors of nonresponding patients. The enrichment of the NRP program in malignant cells from the tumors of nonresponders in an independent cohort analyzed by bulk RNA‐seq is validated. In addition, an analysis of The Cancer Genome Atlas dataset shows that NRP expression is associated with poor prognosis in CSCC patients. In vitro experiments on the CSCC cell line demonstrate that downregulation of neuregulin 1 (NRG1), a key gene from NRP program, is associated with decreased cell growth and increased sensitivity to radiation. Immunohistochemistry staining in cohort 3 validated key genes, NRG1 and immediate early response 3 from immunomodulatory program, as radiosensitivity regulators. The findings reveal that the expression of NRP in CSCC can be used to predict the efficacy of radiotherapy.
About half of locally advanced cervical squamous cell cancer (CSCC) patients receiving radiotherapy experience radioresistance. This study reveals that the expression levels of a neural‐like progenitor (NRP) program in malignant cells are significantly elevated in the tumors from nonresponders or after radiotherapy, and higher NRP expression is associated with poor prognosis in CSCC patients.
A common perception is that oxidized magma is critical for the formation of a porphyry Cu ± Mo ± Au ore deposit. We have used an ore-bearing pluton (Tongchang) and an ore-barren pluton (Shilicun) in ...the western rim of the South China block to test this idea and to determine other important controls on ore genesis. Zircon UPb ages indicate that the Tongchang and Shilicun plutons were emplaced at 36.3 ± 0.2 Ma and 35.2 ± 0.4 Ma, respectively, broadly coinciding with strike-slip faulting in the region and continental collision that occurred ~300 km to the west. These two plutons are all characterized by significant light REE enrichments and pronounced negative NbTa anomalies, similar to the bulk crust. Apatite separates from these two plutons all have elevated initial 87Sr/86Sr (Tongchang, 0.70690 to 0.70796; Shilicun, 0.70703 to 0.70726) and negative εNd(t) (Tongchang, −6.2 to −7.3; Shilicun, −4.5 to −5.8). The mean εHf(t) and δ18O of zircon from these plutons are −1.4 and 6.8‰ for Tongchang, and −0.3 and 6.5‰ for Shilicun. The Sr-Nd-Hf isotope compositions are all within the ranges of the Neoproterozoic mafic arc lower crust in the region. Whole-rock U-Nb-Ta systematics indicate that the Tongchang and Shilicun plutons originated from an amphibole-bearing source and a garnet-bearing source, respectively, implying a shallower and more H2O-rich mafic source for the former than the latter. Quartz trace element data indicate that the Tongchang pluton was emplaced at a shallower depth than the Shilicun pluton. Zircon Ce4+/Ce3+ and whole-rock V/Sc ratios, and apatite SO3 and MnO contents indicate that the parental magmas of both plutons are as oxidized as those of some porphyry Cu deposits in northern Chile, but the parental magma of the Tongchang pluton is less oxidized than that of the Shilicun pluton. Apatite Cl-F-OH systematics and higher abundant hydrous silicate minerals such as amphibole and biotite in the Tongchang pluton than the Shilicun pluton indicate that the parental magma of the Tongchang pluton has higher Cl and H2O content than that of the Shilicun pluton. Our results show that oxidized magma is important but this alone cannot make a porphyry Cu ± Mo ± Au ore deposit. High contents of H2O-Cl in magma and shallow depth of emplacement are also important.
•Both plutons are different in magmatic fO2, H2O-Cl contents, and emplacement depth.•Oxidized magma is important but this alone cannot make a porphyry Cu deposit.•High H2O-Cl contents and shallow emplacement depth of magma are also important.
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