Publications by authors named "Ning Liu"

1,758 Publications

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Exploring the Tunability and Dynamic Properties of MarR-PmarO Sensor System in .

ACS Synth Biol 2021 Jul 28. Epub 2021 Jul 28.

School of Chemical, Materials and Biomedical Engineering, College of Engineering, The University of Georgia, Athens, Georgia 30602, United States.

Transcriptional factor-based biosensors (TFBs) have been widely used in dynamic pathway control or high-throughput screening. Here, we systematically explored the tunability of a salicylic acid responsive regulator MarR from aiming to explore its engineering potential. The effect of endogenous MarR in on the MarR-PmarO biosensor system was investigated. Furthermore, to investigate the function of marO binding boxes in this biosensor system, a series of hybrid promoters were constructed by placing the marO binding boxes in the strong constitutive pL promoter. The engineered hybrid promoters became responsive to MarR and salicylic acid. To further study the influence of each nucleotide in the marO box on MarR binding, we employed dynamic modeling to simulate the interaction and binding energy between each nucleotide in the marO boxes with the corresponding residues on MarR. Guided by the results of the simulation, we introduced mutations to key positions on the hybrid promoters and investigated corresponding dynamic performance. Two promoter variants I12AII4T and I12AII14T that exhibited improved responsive strengths and shifted dynamic ranges were obtained, which can be beneficial for future metabolic engineering research.
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http://dx.doi.org/10.1021/acssynbio.1c00245DOI Listing
July 2021

self-assembled peptide nanofibers for cancer theranostics.

Biomater Sci 2021 Jul 28. Epub 2021 Jul 28.

State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, P. R. China.

Self-assembled nanofibers hold tremendous promise for cancer theranostics owing to their in situ assembly, spatiotemporal responsiveness, and diverse bioactivity. Herein, this review summarizes the recent advances of self-assembled peptide nanofibers and their applications in biological systems, focusing on the dynamic process of capturing cancer cells from the outside-in. (1) In situ self-assembly in response to pathological or physiological changes. (2) Diverse functions at different locations of tumors, such as forming thrombus in tumor vasculature, constructing a barrier on the cancer cell membrane, and disrupting the cancer organelles. Of note, with the assembly/aggregation induced residence (AIR) effect, the nanofibers could form a drug depot in situ for sustained release of chemotherapeutic drugs to increase their local concentration and prolong the residence time. Finally, perspectives toward future directions and challenges are presented to further understand and expand this exciting field.
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http://dx.doi.org/10.1039/d1bm00782cDOI Listing
July 2021

PSMC2/CCND1 axis promotes development of ovarian cancer through regulating cell growth, apoptosis and migration.

Cell Death Dis 2021 Jul 22;12(8):730. Epub 2021 Jul 22.

Department of Obstetrics and Gynaecology, Shengjing Hospital of China Medical University, Heping District, Shenyang, 110004, Liaoning, China.

Ovarian cancer is known as one of the most common malignancies of the gynecological system, whose treatment is still not satisfactory because of the unclear understanding of molecular mechanism. PSMC2 is an essential component of 19 S regulatory granules in 26 S proteasome and its relationship with ovarian cancer is still not clear. In this study, we found that PSMC2 was upregulated in ovarian cancer tissues, associated with tumor grade and could probably predict poor prognosis. Knocking down the endogenous PSMC2 expression in ovarian cancer cells could decrease colony formation ability, cell motility and cell proliferation rate, along with increasing cell apoptosis rate. Cells models or xenografts formed by cells with relatively lower expression of PSMC2 exhibited weaker oncogenicity and slower growth rate in vivo. Moreover, gene microarray was used to analyze the alteration of gene expression profiling of ovarian cancer induced by PSMC2 knockdown and identify CCND1 as a potential downstream of PSMC2. Further study revealed the mutual regulation between PSMC2 and CCND1, and demonstrated that knockdown of CCND1 could enhance the regulatory effects induced by PSMC2 knockdown and overexpression of CCND1 reverses it. In summary, PSMC2 may promote the development of ovarian cancer through CCND1, which may predict poor prognosis of ovarian cancer patients.
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http://dx.doi.org/10.1038/s41419-021-03981-5DOI Listing
July 2021

Geometrical Nonlinear Elasticity of Axon Under Tension: A Coarse-grained Computational Study.

Biophys J 2021 Jul 23. Epub 2021 Jul 23.

College of Engineering, University of Georgia, Athens, GA 30602. Electronic address:

Axons bundles cross-linked by microtubule (MT) associate proteins (MAP) and bounded by a shell skeleton are critical for normal function of neurons. Understanding effects of the complexly geometrical parameters on their mechanical properties can help gain a biomechanical perspective on the neurological functions of axons and thus brain disorders caused by the structural failure of axons. Here, the tensile mechanical properties of MT bundles cross-linked by tau proteins are investigated by systematically tuning MT length, axonal cross-section radius, and tau protein spacing in a bead-spring coarse-grained model. Our results indicate that the stress-strain curves of axons can be divided into two regimes, a nonlinear elastic regime dominated by rigid-body like inter-MT sliding, and a linear elastic regime dominated by affine deformation of both tau proteins and MTs. From the energetic analyses, first, the tau proteins dominate the mechanical performance of axons under tension. In the nonlinear regime, tau proteins undergo a rigid-body like rotating motion rather than elongating, while in the nonlinear elastic regime, tau proteins undergo a flexible elongating deformation along the MT axis. Second, as the average spacing between adjacent tau proteins along the MT axial direction increases from 25 nm to 125 nm, the Young's modulus of axon experiences a linear decrease while with the average space varying from 125 nm to 175 nm, and later reaches a plateau value with a stable fluctuation. Third, the increment of the cross-section radius of the MT bundle leads to a decrease in Young's modulus of axon, which is possibly attributed to the decrease in MT numbers per cross section. Overall, our research findings offer a new perspective into understanding the effects of geometrical parameters on the mechanics of MT bundles as well as serving as a theoretical basis for the development of artificial MT complexes potentially towards medical applications.
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http://dx.doi.org/10.1016/j.bpj.2021.07.019DOI Listing
July 2021

Intraperitoneal Chemotherapy Using Fluorouracil Implants Combined With Radical Resection and Postoperative Adjuvant Chemotherapy for Stage III Gastric Cancer: A Multi-Center, Randomized, Open-Label, Controlled Clinical Study.

Front Oncol 2021 8;11:670651. Epub 2021 Jul 8.

Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China.

Background: Reducing peritoneal recurrence after radical surgery is an important choice to improve the prognosis of patients with advanced gastric cancer. Intraoperative intraperitoneal chemotherapy has the potential to be a promising treatment strategy. In the present study, we conducted a multi-center, randomized, controlled clinical study to evaluate the efficacy and safety of intraoperative intraperitoneal chemotherapy using sustained-release fluorouracil implants plus radical gastrectomy and adjuvant chemotherapy for cTNM stage III gastric cancer.

Methods: The patients were randomized into intraperitoneal chemotherapy group (sustained-release fluorouracil implants administration after standard D2 radical gastrectomy, and followed by XELOX adjuvant chemotherapy) and control group (standard D2 radical gastrectomy, and followed by XELOX adjuvant chemotherapy). A total of 122 patients from three centers were enrolled from September 2015 to February 2017.

Results: One hundred and two eligible patients completed the treatment course. The median follow-up time was 41.7 months (36.1-52.9 months). The 3-year progression-free survival rate and overall survival of patients in the intraperitoneal chemotherapy group were 43.9% and 49.1%, respectively, which were significantly better than those of the control group, 31.0% and 38.4%. In the intraperitoneal chemotherapy group, the number of cases with peritoneal recurrence was significantly less than that of the control group, 9 cases (17.3%) 19 cases (44.2%). There were neither significant differences between the groups in the incidence of hematogenous metastasis, lymph node metastasis, nor local metastasis.

Conclusion: For cTNM stage III gastric cancer, intraoperative sustained-release fluorouracil implants after radical resection combined with postoperative adjuvant chemotherapy, could significantly reduce the risk of peritoneal recurrence and prolong PFS. https://clinicaltrials.gov/, identifier (NCT02269904).
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http://dx.doi.org/10.3389/fonc.2021.670651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298064PMC
July 2021

Expression of TCF7L2 in Glioma and Its Relationship With Clinicopathological Characteristics and Patient Overall Survival.

Front Neurol 2021 8;12:627431. Epub 2021 Jul 8.

Sanbo Brain Hospital, Capital Medical University, Beijing, China.

The TCF7L2 gene is known as transcription factor 7-like 2 which has been identified as a novel transcription factor epithelial-mesenchymal transition (EMT) in tumor cells at 10q25.3. TCF7L2 may affect cancer progression and plays a central role in cancer proliferation, migration, and invasion. However, its clinical and prognostic value have not been researched in glioma. The purpose of our study was to research TCF7L2 expression and evaluate the clinical value of prognosis. We collected glioma specimens including low-grade glioma ( = 46) and glioblastoma ( = 51) from September 2015 to September 2017. Expression of TCF7L2 in 97 specimens was detected by quantitative real-time PCR (qRT-PCR). The chi-square test was applied to analyze the relationship between TCF7L2 expression and clinicopathological characteristics. The overall survival (OS) was estimated by log-rank tests among strata, and the survival curves were drawn by Kaplan-Meier. Univariate and multivariate analysis were utilized to analyze the relationship between prognosis and clinicopathological characteristics including TCF7L2 expression. Compared with the low-grade glioma group, the expression of TCF7L2 was significantly increased in the glioblastoma group ( = 0.001). TCF7L2 overexpression was associated with higher WHO grade ( = 0.001), isocitrate dehydrogenase (IDH) wild-type ( = 0.001), and lack of O(6)-methylguanine-DNA methyltransferase (MGMT) methylation ( = 0.001). Moreover, Kaplan-Meier analysis proved that overexpressed TCF7L2 was associated with poor OS ( = 0.010). The multivariate analysis suggested that TCF7L2 expression was an independent prognostic factor ( = 0.020). Our research proved that TCF7L2 was overexpressed in glioblastoma, and related with tumor long-term prognosis, which, therefore, could be an independent prognostic factor for glioma patients.
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http://dx.doi.org/10.3389/fneur.2021.627431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296806PMC
July 2021

Effect of RNAi targeting CYP6CY3 on the growth, development and insecticide susceptibility of Aphis gossypii by using nanocarrier-based transdermal dsRNA delivery system.

Pestic Biochem Physiol 2021 Aug 24;177:104878. Epub 2021 May 24.

Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830046, Xinjiang, China. Electronic address:

RNA interference (RNAi) has been proved to be a viable method for agricultural pest control. Due to the limited uptake of dsRNA in hemiptera insects, this study used nanocarrier SPc (star polycation) transdermal delivery systems to deliver two truncated fragments (P1/P2) dsRNA of the CYP6CY3 for silencing this target gene in Aphis gossypii. After the cotton aphid was sprayed with the SPc + dsP1/P2 mixture, the expression level of target gene in SPc + dsP1 treatment group was not different from that in dsP1 group at 24 h, 48 h, and significantly lower than that in dsP1 group at 60 h, 72 h, respectively; and the expression level of target gene in SPc + dsP2 treatment group was not different from that in dsP2 group at 24 h, and significantly lower than that in dsP2 group from 48 h, 60 h, 72 h, respectively. In addition, the expression level was continuously silenced after spraying the SPc + dsP1/P2 mixture and significant reduced by 79.7% and 84.3% at 48 h compared with the HO control group, the mortality rate reached 48.09% and 43.18% at 84 h, respectively. And the cumulative reproduction number of cotton aphids also decreased, but the cumulative death number of newborn nymphs had an increase trend, compared with the control groups. Bioassays after RNAi showed that the silencing of CYP6CY3 increased the susceptibility of the 4 instar aphid to imidacloprid, and increased mortality by 67.21% and 58.69% at 96 h, respectively. The life table parameters of the offspring from the 4 instar cotton aphids from the SPc + dsP1/P2 treatment groups showed that the offspring had a longer pre-reproductive period and post-reproductive period. The intrinsic growth rate was 0.231 ± 0.005, 0.210 ± 0.013 and the finite growth rate was 1.260 ± 0.007 and 1.234 ± 0.016 in the SPc + dsP1/P2 treatment group, these two parameters of the two groups were lower than that of the corresponding control,the population doubling time of the two groups was prolonged and the developmental duration was delayed. These results indicate that CYP6CY3 plays a key role in the growth, development, reproduction and detoxification ability in cotton aphids, and may be as a potential RNAi target for controlling aphids, laying the foundation for the development of new environmentally-friendly RNA pesticides in this field.
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http://dx.doi.org/10.1016/j.pestbp.2021.104878DOI Listing
August 2021

FBXW7 induces apoptosis in glioblastoma cells by regulating HDAC7.

Cell Biol Int 2021 Jul 19. Epub 2021 Jul 19.

Department of Neurosurgery, Huzhou Central Hospital, Affiliated Cent Hospital HuZhou University, Huzhou, China.

Glioblastoma is an aggressive type of brain cancer with an extremely poor prognosis. Additionally, the F-box WD repeat-containing protein 7 (FBXW7) is a component of the ubiquitin-proteasome system that has been widely implicated in human cancers. In this study, we investigated the role and mechanism of FBXW7 in glioblastoma. FBXW7 expression was analyzed in normal and glioblastoma tissue samples using The Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) database. Then, quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to examine mRNA expression, whereas, western blot analysis was conducted to determine protein levels of the samples. Furthermore, cell apoptosis was assessed using the Annexin V staining method, followed by flow cytometry analysis. Immunoprecipitation (IP) assay was conducted as well to test protein-protein interactions. Lastly, protein expression in tissues was examined by conducting immunohistochemistry (IHC). Results showed that the glioblastoma tissue samples displayed an FBXW7 downregulation compared with normal tissues. In vitro, the overexpression of FBXW7 in glioblastoma cells induced apoptosis, whereas, its knockdown displayed the opposite effect. Mechanistically, FBXW7 interacted with HDAC7 to promote HDAC7 ubiquitination, however, the overexpression of HDAC7 in glioblastoma cells blocked FBXW7-induced apoptosis. Finally, FBXW7 and HDAC7 displayed an inverse correlation in glioblastoma tissues in vivo. Therefore, our data demonstrated an important function of FBXW7 in promoting glioblastoma apoptosis by interacting with HDAC7 and promoting HDAC7 ubiquitination.
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http://dx.doi.org/10.1002/cbin.11668DOI Listing
July 2021

Comparative Secretome Analysis of Magnaporthe oryzae Identified Proteins Involved in Virulence and Cell Wall Integrity.

Genomics Proteomics Bioinformatics 2021 Jul 17. Epub 2021 Jul 17.

State Key Laboratory of Agrobiotechnology and MOA Key Laboratory of Pest Monitoring and Green Management, China Agricultural University, Beijing 100193, China. Electronic address:

Plant fungal pathogens secrete numerous proteins into the apoplast at the plant-fungus contact sites to facilitate colonization. Only a few secretory proteins were functionally characterized in Magnaporthe oryzae, the fungal pathogen causing rice blast disease worldwide. Asparagine-linked glycosylation 3 (Alg3) is an α-1, 3-mannosyltransferase functioning in the N-glycan synthesis of N-glycosylated secretory proteins. Fungal pathogenicity and cell wall integrity are impaired in Δalg3 mutants, but the secreted proteins affected in Δalg3 mutants are largely unknown. In this study, we compared the secretome of wild-type and Δalg3 mutants and identified 51 proteins that require Alg3 for proper secretion. These proteins are predicted to be involved in metabolic processes, interspecies interactions, cell wall organization, and response to chemicals. Nine proteins were selected for further validation. We found that these proteins were localized at the apoplastic region surrounding the fungal infection hyphae. Moreover, the N-glycosylation of these proteins was significantly changed in the Δalg3 mutant, leading to the decreased protein secretion and abnormal protein localization. Furthermore, we tested the biological function of two genes, INV1 encoding invertase 1, a secreted invertase and AMCase encoding acid mammalian chinitase, a secreted chitinase. The fungal virulence was significantly reduced, and the cell wall integrity was altered in the Δinv1 and Δamcase mutant strains. Moreover, the N-glycosylation is essential for the function and secretion of AMCase. Comparative secretome analysis of M. oryzae identified N-glycosylated secretory proteins that function in fungal virulence and cell wall integrity.
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http://dx.doi.org/10.1016/j.gpb.2021.02.007DOI Listing
July 2021

Occurrence of postharvest snow rot caused by on Asian ginseng in China.

Plant Dis 2021 Jul 20. Epub 2021 Jul 20.

Chinese Academy of Agricultural Sciences, 12661, Institute of Special Wild Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, Changchun, Jilin, China;

Asian ginseng () is a valuable medicinal plant that is commercially cultivated in China. A long postharvest storage period is required before ginseng is processed. From October 2019 to May 2020, snow rot was observed on the roots of 4- and 5-year-old fresh ginseng stored in three cold storage facilities located in Tonghua and Changbai cities in northeastern China, which are the most important regions for Asian ginseng production. We sampled 1,000 ginseng roots from the three cold storage facilities, and the average disease incidence was 21%. Initially, sparse hyphae and microsclerotia appeared on the root epidermis. Lesions gradually softened and the epidermis detached easily. Multiple infected sites slowly converged, resulting in the formation of a dense complex of multiple sclerotia and thick hyphae on the surface of the ginseng root as well as internal decay. The infection eventually spread to the adjacent ginseng roots (Fig. 1). Sixteen diseased ginseng roots were collected and then sclerotia were removed from the root surface, immersed in 1% NaClO for 2 min, rinsed three times with sterile water, and placed on potato dextrose agar (PDA) containing streptomycin (40 μg/mL) in Petri dishes. After a 3-day incubation at 20 °C in darkness, 22 suspected Sclerotinia isolates were obtained. Isolates SN1 and SN2 were randomly selected for identification. On PDA, fast-growing colonies produced white, sparse, powdery, and cotton-like aerial mycelia, and the reverse side showed the same color (Fig. 2). Small and white sclerotial primordia formed 3 days later and a ring of sclerotia was detected at the plate periphery. At 7 to 10 days after incubation, the mature sclerotia were black, spherical-to-subspherical, and elongated or fused to form irregular shapes. Each Petri dish produced 55-65 sclerotia, measuring 1.1 × 1.2 to 3.2 × 3.9 mm (n = 100). The sclerotia were firmly attached to the agar surface. The isolates were initially identified as sp. (Saito 1997). After sequencing the nuclear ribosomal internal transcribed spacer region (MW927134 and MW927135) and the β-tubulin gene (MW929179 and MW929180) (White et al. 1990; Glass and Donaldson 1995), BLAST searches revealed 100% homology with JX262268 and JX296007 of the published strain KGC-S0601, respectively. The pathogenicity of the two isolates was tested using detached ginseng roots. Briefly, healthy roots were washed, surface-disinfested with 75% alcohol, and rinsed with sterile water. Mycelial plugs (5 mm diameter) removed from the margin of actively growing colonies on PDA were placed on the ginseng roots. For each isolate, four roots were inoculated, with two plugs per root. Additionally, PDA plugs without mycelia were used as the negative control. The roots were placed in a fresh-keeping box at 20 °C in darkness and evaluated after 7 days. The pathogenicity test was repeated twice. The symptoms on the inoculated roots were the same as those observed on the roots during cold storage, whereas the control roots remained symptomless. The same fungus was reisolated consistently from all infected roots and its identity was confirmed by resequencing, thereby fulfilling Koch's postulates. To the best of our knowledge, this is the first report of causing postharvest snow rot on Asian ginseng in China. The occurrence of this disease threatens the postharvest storage of Asian ginseng. Hence, effective management strategies must be developed.
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http://dx.doi.org/10.1094/PDIS-04-21-0868-PDNDOI Listing
July 2021

Potential of thrombospondin-1 in treatment of polycystic ovary syndrome rat model: a preliminary study.

Gynecol Endocrinol 2021 Jul 20:1-7. Epub 2021 Jul 20.

Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

Objective: Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disease in reproductive women, and the endocrine levels are also affected by diseases. The aim of this study was to determine the effect of thrombospondin-1 (TSP-1) on PCOS rat model.

Methods: We established the PCOS rat model, the serum hormones including TSP-1 expression were determined and morphological characteristics were investigated to evaluate the model. These above endocrine and morphological features were investigated again to evaluate the effect of TSP-1 treatment.

Results: In the PCOS model group, the serum hormones change (higher luteinizing hormone, testosterone and estrogen) and decreased TSP-1 expression levels were found compared with the control group. Besides, the morphological characteristics of PCOS were also observed in the model group. After TSP-1 treatment, the higher TSP-1, ANGPT2, PDGFB and PDGFD expression levels, the lower LH and T levels, decreased vessel density as well as VEGFA and ANGPT1 expression levels were found compared with the control group, and the ovary morphological changes were also observed in the TSP-1 experimental group.

Conclusions: TSP-1 delivery system might be an alternative therapy for PCOS treatment.
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http://dx.doi.org/10.1080/09513590.2021.1950682DOI Listing
July 2021

The zinc finger protein StMR1 affects the pathogenicity and melanin synthesis of Setosphaeria turcica and directly regulates the expression of DHN melanin synthesis pathway genes.

Mol Microbiol 2021 Jul 19. Epub 2021 Jul 19.

State Key Laboratory of North China Crop Improvement and Regulation/Key Laboratory of Hebei Province for Plant Physiology and Molecular Pathology, Hebei Agricultural University, Mycotoxin and Molecular Plant Pathology Laboratory, Hebei Agricultural University, Baoding, 071001, P.R.China.

The infection and colonization of pathogenic fungi are often regulated by transcription factors. In our previous study, the zinc finger protein-encoding gene StMR1 was found to be highly expressed during the infection process of Setosphaeria turcica, the pathogen causing northern corn leaf blight. Evolutionary tree analysis showed that this gene was associated with regulatory factors of melanin synthesis. However, the regulatory mechanism of melanin synthesis and its effect on pathogenicity remain unclear. In this study, the function of StMR1 was analyzed by gene knockout. When the expression level of StMR1 in the mutants was significantly reduced, the colony color became lighter, the mycelia were curved and transparent, and the mutant showed a significant loss of pathogenicity. In addition, compared with wild-type, the accumulation of melanin decreased significantly in △Stmr1. RNA-seq analysis revealed 1,981 differentially expressed genes between the wild-type and knockout mutant, among which 39 genes were involved in melanin metabolism. qPCR revealed that the expression levels of 6 key genes in the melanin synthesis pathway were significantly reduced. ChIP-PCR and yeast one-hybrid assays confirmed that StMR1 directly binds to the promoters of St3HNR, St4HNR, StPKS, and StLAC2 in the DHN melanin synthesis pathway and regulates gene expression. The C2H2-type zinc fingers and Zn(Ⅱ)2Cys6 binuclear cluster in StMR1 was important for the binding to targets.
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http://dx.doi.org/10.1111/mmi.14786DOI Listing
July 2021

Comparison of Untargeted Metabolomic Profiling vs Traditional Metabolic Screening to Identify Inborn Errors of Metabolism.

JAMA Netw Open 2021 Jul 1;4(7):e2114155. Epub 2021 Jul 1.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Importance: Recent advances in newborn screening (NBS) have improved the diagnosis of inborn errors of metabolism (IEMs); however, many potentially treatable IEMs are not included on NBS panels, nor are they covered in standard, first-line biochemical testing.

Objective: To examine the utility of untargeted metabolomics as a primary screening tool for IEMs by comparing the diagnostic rate of clinical metabolomics with the recommended traditional metabolic screening approach.

Design, Setting, And Participants: This cross-sectional study compares data from 4464 clinical samples received from 1483 unrelated families referred for trio testing of plasma amino acids, plasma acylcarnitine profiling, and urine organic acids (June 2014 to October 2018) and 2000 consecutive plasma samples from 1807 unrelated families (July 2014 to February 2019) received for clinical metabolomic screening at a College of American Pathologists and Clinical Laboratory Improvement Amendments-certified biochemical genetics laboratory. Data analysis was performed from September 2019 to August 2020.

Exposures: Metabolic and molecular tests performed at a genetic testing reference laboratory in the US and available clinical information for each patient were assessed to determine diagnostic rate.

Main Outcomes And Measures: The diagnostic rate of traditional metabolic screening compared with clinical metabolomic profiling was assessed in the context of expanded NBS.

Results: Of 1483 cases screened by the traditional approach, 912 patients (61.5%) were male and 1465 (98.8%) were pediatric (mean [SD] age, 4.1 [6.0] years; range, 0-65 years). A total of 19 families were identified with IEMs, resulting in a 1.3% diagnostic rate. A total of 14 IEMs were detected, including 3 conditions not included in the Recommended Uniform Screening Panel for NBS. Of the 1807 unrelated families undergoing plasma metabolomic profiling, 1059 patients (58.6%) were male, and 1665 (92.1%) were pediatric (mean [SD] age, 8.1 [10.4] years; range, 0-80 years). Screening identified 128 unique cases with IEMs, giving an overall diagnostic rate of 7.1%. In total, 70 different metabolic conditions were identified, including 49 conditions not presently included on the Recommended Uniform Screening Panel for NBS.

Conclusions And Relevance: These findings suggest that untargeted metabolomics provided a 6-fold higher diagnostic yield compared with the conventional screening approach and identified a broader spectrum of IEMs. Notably, with the expansion of NBS programs, traditional metabolic testing approaches identify few disorders beyond those covered on the NBS. These data support the capability of clinical untargeted metabolomics in screening for IEMs and suggest that broader screening approaches should be considered in the initial evaluation for metabolic disorders.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.14155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276086PMC
July 2021

Perfluorononanoic acid impedes mouse oocyte maturation by inducing mitochondrial dysfunction and oxidative stress.

Reprod Toxicol 2021 Jul 8;104:58-67. Epub 2021 Jul 8.

Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA. Electronic address:

Perfluorononanoic acid (PFNA), a member of PFAS, is frequently detected in human blood and tissues, even in follicular fluid of women. The exposure of PFNA, but not PFOA and PFOS, is positively correlated with miscarriage and increased time to pregnancy. Toxicological studies indicated that PFNA exposure is associated with immunotoxicity, hepatotoxicity, developmental toxicity, and reproductive toxicity in animals. However, there is little information regarding the toxic effects of PFNA on oocyte maturation. In this study, we investigated the toxic effects of PFNA exposure on mouse oocyte maturation in vitro. Our results showed that 600 μM PFNA significantly inhibited germinal vesicle breakdown (GVBD) and polar body extrusion (PBE) in mouse oocytes. Our further study revealed that PFNA induced abnormal metaphase I (MI) spindle assembly, evidenced by malformed spindles and mislocalization of p-ERK1/2 in PFNA-treated oocytes. We also found that PFNA induced abnormal mitochondrial distribution and increased mitochondrial membrane potential. Consequently, PFNA increased reactive oxygen species (ROS) levels, leading to oxidative stress, DNA damage, and eventually early-stage apoptosis in oocytes. In addition, after 14 h culture, PFNA disrupted the formation of metaphase II (MII) spindle in most PFNA-treated oocytes with polar bodies. Collectively, our results indicate that PFNA interferes with oocyte maturation in vitro via disrupting spindle assembly, damaging mitochondrial functions, and inducing oxidative stress, DNA damage, and early-stage apoptosis.
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http://dx.doi.org/10.1016/j.reprotox.2021.07.002DOI Listing
July 2021

Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury.

Nat Commun 2021 07 9;12(1):4220. Epub 2021 Jul 9.

Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Prokineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.
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http://dx.doi.org/10.1038/s41467-021-24469-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270965PMC
July 2021

Effect of Salvia miltiorrhiza aerial parts on growth performance, nutrient digestibility, and digestive enzymes in rabbits.

Anim Biosci 2021 Jun 23. Epub 2021 Jun 23.

Department of Animal Science, Henan University of Science and Technology, Luoyang 471023, China.

Objective: This study aimed to investigate the effect of Salvia miltiorrhiza (S.m.) aerial parts as an alternative ingredient on growth performance, nutrient digestibility, and digestive enzymes in growing rabbits.

Methods: Treatments included five tested diets: a control (basal diet), antibiotic (basal diet+enramycin at 5 mg/kg), and S.m. aerial parts powder added at 3.0, 6.0 and 9.0% of feed using 300 growing rabbits.

Results: The diets with S.m. aerial parts addition at 9.0% decreased (p<0.05) feed/gain compared to the control, but there were no differences in feed intake and body weight gain. In contrast with the control, the addition of antibiotic increased (p<0.05) digestibility of dry matter, crude protein, energy, fiber, and ash. The herb addition did not cause differences in the digestibility of most nutrients compared to the antibiotic, but fiber digestibility of the herb at 6.0 and 9.0% was lower (p<0.05) than that of the antibiotic. Moreover, the antibiotic and the herb also similarly increased (p<0.05) the activities of duodenal α-amylase, maltase, lipase, and trypsin, compared to the control, and the herb at 6.0 and 9.0% showed a greater (p<0.05) activity of elastase than the dose 3.0%.

Conclusion: The obtained data indicate that S.m. aerial parts can be a potential forage in rabbit's diet at 9.0% with a beneficial regulation on nutrition and digestion.
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http://dx.doi.org/10.5713/ab.21.0070DOI Listing
June 2021

Clinical Characteristics and Prognosis of Renal Cell Carcinoma With Spinal Bone Metastases.

Front Oncol 2021 16;11:659779. Epub 2021 Jun 16.

Department of Urology, Beijing Jishuitan Hospital, Beijing, China.

Background: The prognosis of renal cell carcinoma (RCC) with spinal bone metastasis (sBM) varies greatly. In this study, we aimed to define the clinical characteristics and prognostic factors of RCC with spinal bone metastasis (sBM) in our center.

Methods: The clinical and medical records of RCC patients with sBMs were collected. The gender, age, time of BM, the extent of BM, the number of BMs, the presence or absence of visceral metastasis, and the pathological type of BM were investigated. All patients were followed up regularly. Overall survival (OS) was calculated from the date of BMs diagnosis to death or last follow-up using Kaplan-Meier method and modelled with Cox regression analysis.

Results: Forty-three RCC patients with sBM were collected. sBM was found synchronously in 30 patients (70%) and metachronously in 13 patients (30%). The median survival time was 30 months in 13 patients (30%) with solitary sBM and 19 months in 30 patients (70%) with multiple sBMs ( = 0.002). Visceral metastasis occurred in 12 patients (28%) with the median survival time of 17 months, while the other 31 patients (72%) had no visceral metastasis with the median survival time of 29 months (<0.001). En-block resection was done in 10 patients with median survival time of 40.1 months. Non-en-block resection were done in 33 patients with median survival time of 19.7 months (<0.001). Multivariate COX regression analysis showed that MSKCC score, number of BM, visceral metastasis, and en-block resection are the independent prognosis factors of RCC patients with sBM.

Conclusions: MSKCC risk stratification, number of sBM, visceral metastasis and en-block resection are significant prognostic factors for OS in RCC patients with spinal BM. Therefore, for selected patients who has solitary spinal BM with no visceral metastasis, en-block resection of spinal BM can potentially prolong survival and is the treatment of choice.
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http://dx.doi.org/10.3389/fonc.2021.659779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242338PMC
June 2021

The Neurogenic Compound P7C3 Regulates the Aerobic Glycolysis by Targeting Phosphoglycerate Kinase 1 in Glioma.

Front Oncol 2021 18;11:644492. Epub 2021 Jun 18.

The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.

Background: P7C3 is a neurogenic compound that exhibits neuroprotective properties in neural cells. However, its target proteins and effects in glioma are unknown.

Methods: The candidate P7C3 target proteins were analyzed using a human protein microarray containing 23136 human proteins. A streptavidin agarose affinity assay was used to verify the direct interaction between P7C3 and phosphoglycerate kinase 1 (PGK1). Mass spectrometry was used to identify the binding sites of PGK1 for P7C3 binding. Seahorse XF96 extracellular flux analyzer was used to measure the cell oxygen consumption rate and extracellular acidification rate. Glycolytic metabolites were measured using the related kits. Protein level was detected by western blotting and immunohistochemical staining. Autophagy was analyzed using a transmission electron microscope and western blotting. The malignancy of tumor progression and was analyzed based on cell viability, apoptosis and proliferation, migration and invasion, and xenograft model. Glial cells were marked by antibodies immunohistochemical staining.

Results: The human protein microarray identified 577 candidate P7C3 target proteins. The global profile of P7C3 target proteins indicated that P7C3 regulates glycolysis. Metabolic experiments confirmed that P7C3 regulates aerobic glycolysis in glioma cells. The underlying mechanism of P7C3 was found to be direct targeting PGK1 at lysine residues and asparagine residues, and the specific P7C3-PGK1 interaction led to decreased protein level and total intracellular kinase activity of PGK1. The Cancer Genome Atlas and Chinese Glioma Genome Atlas databases indicated that the mRNA level of PGK1 is significantly increased in high-grade glioma, and the abnormally high mRNA level of PGK1 is associated with a poor prognosis in patients with glioma, suggesting that PGK1 is a promising target for glioma therapy. The inhibition of PGK1 and the subsequent suppression of aerobic glycolysis caused by P7C3 inhibited the malignant growth of glioma and . Furthermore, P7C3 did not damage normal glial cells under concentration, which exhibit an inhibitory effect on gliomas.

Conclusions: This study revealed that P7C3 suppresses glioma by regulating aerobic glycolysis directly targeting PGK1. Furthermore, we identified the P7C3 target proteins for the first time which is expected to provide scientific clues for future studies.
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http://dx.doi.org/10.3389/fonc.2021.644492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252887PMC
June 2021

Proximity Effect in Uranyl Coordination of the Cucurbit[6]uril-Bipyridinium Pseudorotaxane Ligand for Promoting Host-Guest Synergistic Chelating.

Inorg Chem 2021 Jul 2;60(14):10522-10534. Epub 2021 Jul 2.

Laboratory of Nuclear Energy Chemistry, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, P. R. China.

In the present work, we proposed regulating uranyl coordination behavior of cucurbituril-bipyridinium pseudorotaxane ligand by utilizing meta-functionalized bipyridinium dicarboxylate guest. A tailored pseudorotaxane precursor involving 1,1'-(hexane-1,6-diyl)bis(3-cyanopyridin-1-ium) bromide () and cucurbit[6]uril (CB[6]) has designed and synthesized. Through in situ hydrolysis of the pseudorotaxane ligands and their coordination assembly with uranyl cations, seven new uranyl-rotaxane coordination polymers have been obtained under hydrothermal conditions in the presence of different anions. It is demonstrated that the variation of carboxylate groups from para- to meta-position greatly affected the coordination behaviors of the meta-functionalized pseudorotaxane linkers, which are enriched from simple guest-only binding to host-guest simultaneous coordination and synergistic chelating. This effective regulation on uranyl coordination of supramolecular pseudorotaxane can be attributed to the proximity effect, which refers to the meta-position carboxyl group being spatially closer to the portal carbonyl group of CB[6]. Moreover, by combining other regulation methods such as introducing competing counterions and modulating solution acidity, the nuclearity of the uranyl center and the coordination patterns of the pseudorotaxane ligand can be diversely tuned, which subsequently exert great influence on the final dimensionality of resultant uranyl compounds. This work presents a large diversity of uranyl-based coordination polyrotaxane compounds with fascinating mechanically interlocked components and, most importantly, provides a feasible approach to adjust and control the metal coordination behavior of the pseudorotaxane ligand that might expand the scope of application of such supramolecular ligands.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01177DOI Listing
July 2021

Effects of Fermented Milk Containing Strain Shirota on Constipation in Patients with Depression: A Randomized, Double-Blind, Placebo-Controlled Trial.

Nutrients 2021 Jun 29;13(7). Epub 2021 Jun 29.

Department of Nutrition and Health, China Agricultural University, Beijing 100091, China.

Probiotics have been shown to benefit patients with constipation and depression, but whether they specifically alleviate constipation in patients with depression remains unclear. The aim of this study was to investigate the effect of strain Shirota (LcS), formerly strain Shirota, on constipation in patients with depression with specific etiology and gut microbiota and on depressive regimens. Eighty-two patients with constipation were recruited. The subjects consumed 100 mL of a LcS beverage (10 CFU/mL) or placebo every day for 9 weeks. After ingesting beverages for this period, we observed no significant differences in the total patient constipation-symptom (PAC-SYM) scores in the LcS group when compared with the placebo group. However, symptoms/scores in item 7 (rectal tearing or bleeding after a bowel movement) and items 8-12 (stool symptom subscale) were more alleviated in the LcS group than in the placebo group. The Beck Depression Index (BDI) and Hamilton Depression Rating Scale (HAMD) scores were all significantly decreased, and the degree of depression was significantly improved in both the placebo and LcS groups ( < 0.05), but there was no significant difference between the groups. The LcS intervention increased the beneficial , and levels and decreased the bacterial levels related to mental illness, such as , and Additionally, the interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) levels were significantly decreased in both the placebo and LcS groups ( < 0.05). In particular, the IL-6 levels were significantly lower in the LcS group than the placebo group after the ingestion period ( < 0.05). In conclusion, the daily consumption of LcS for 9 weeks appeared to relieve constipation and improve the potentially depressive symptoms in patients with depression and significantly decrease the IL-6 levels. In addition, the LcS supplementation also appeared to regulate the intestinal microbiota related to mental illness.
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http://dx.doi.org/10.3390/nu13072238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308326PMC
June 2021

Impact of Dietary Crude Protein Level on Hepatic Lipid Metabolism in Weaned Female Piglets.

Animals (Basel) 2021 Jun 18;11(6). Epub 2021 Jun 18.

State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, China Agricultural University, Beijing 100193, China.

Amino acids serve not only as building blocks for proteins, but also as substrates for the synthesis of low-molecular-weight substances involved in hepatic lipid metabolism. In the present study, eighteen weaned female piglets at 35 days of age were fed a corn- and soybean meal-based diet containing 20%, 17%, or 14% crude protein (CP), respectively. We found that 17% or 20% CP administration reduced the triglyceride and cholesterol concentrations, while enhanced high-density lipoprotein cholesterol (HDL-C) concentration in serum. Western blot analysis showed that piglets in the 20% CP group had higher protein abundance of hormone-sensitive triglyceride lipase (HSL) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), as compared with other groups. Moreover, the mRNA expression of sterol regulatory element binding transcription factor 1 (SREBPF1), fatty acid synthase (FASN), and stearoyl-CoA desaturase (SCD) were lower in the 17% or 20% CP group, compared with those of the piglets administered with 14% CP. Of note, the mRNA level of acetyl-CoA carboxylase alpha (ACACα) was lower in the 17% CP group, compared with other groups. Additionally, the mRNA level of lipoprotein lipase (LPL), peroxisome proliferator-activated receptor alpha α (PPARα), glucose-6-phosphatase catalytic subunit (G6PC), and phosphoenolpyruvate carboxykinase 1 (PKC1) in the liver of piglets in the 20% CP group were higher than those of the 14% CP group. Collectively, our results demonstrated that dietary CP could regulate hepatic lipid metabolism through altering hepatic lipid lipogenesis, lipolysis, oxidation, and gluconeogenesis.
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http://dx.doi.org/10.3390/ani11061829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235084PMC
June 2021

Boron nitride nanosheets decorated MIL-53(Fe) for efficient synergistic ibuprofen photocatalytic degradation by persulfate activation.

J Colloid Interface Sci 2021 Jun 18;603:270-281. Epub 2021 Jun 18.

Key Laboratory of Organic Compound Pollution Control Engineering (MOE), Shanghai University, Shanghai 200444, PR China; School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China. Electronic address:

In this study, based on one-step hydrothermal method, boron nitride nanosheets (BNNs) and MIL-53(Fe) composites (BNFe-X) were successfully prepared and the catalytic performance of BNFe-X on persulfate (PS) activation for ibuprofen (IBP) photodegradation was investigated. The introduction of BNNs changed the morphology of MIL-53(Fe) to be a unique prism-like structure and enhanced the degradation efficiency of IBP, which followed the pseudo-first-order rate kinetics. Among the prepared composites, BNFe-3 (3% BNNs) exhibited the highest IBP degradation activity and possessed strong stability after four cycles. Over 99% IBP removal was achieved at the irradiation time of 60 min. The promoted decomposition rate of IBP could be ascribed to be the activation of PS and the enhanced electrons transfer efficiency between BNNs and MIL-53(Fe). The scavenger studies and electron spin-resonance spectroscopy (ESR) demonstrated the generation of SO, OH and O, and all these radicals had the different contributions in IBP degradation. Based on the LC-MS-MS and TOC results, the possible decomposition pathways of IBP in BNFe-3/PS system were proposed. This work suggested that the BNNs/Fe-based MOFs composites and PS system had great potential in organic pollutants degradation in aqueous solution.
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http://dx.doi.org/10.1016/j.jcis.2021.06.082DOI Listing
June 2021

Association between Palliative Care, Days at Home, and Health Care Use in Patients with Advanced COPD: A Cohort Study.

Ann Am Thorac Soc 2021 Jun 25. Epub 2021 Jun 25.

Sunnybrook Research Institute, 282299, Toronto, Ontario, Canada.

Rationale: Palliative care focuses on improving quality of life for patients with life-limiting conditions. While previous studies have shown palliative care to be associated with reduced acute health care use in people with cancer and other illnesses, these findings may not generalize to patients with COPD.

Objectives: We examined the association between palliative care and rates of days at home, location of death, and acute health care use in patients with COPD.

Methods: We used health administrative databases in Ontario, Canada to identify patients with advanced COPD hospitalized between April 2010 and March 2017 and followed until March 2018. Patients who received palliative care were matched 1:1 to those who did not on age, sex, long-term oxygen, previous COPD hospitalizations and propensity scores. Rate ratios (RR) were estimated using Poisson models with generalized estimating equations to account for matching.

Results: Among 35,492 patients, 1,788 (5%) received palliative care. In the matched cohort (1,721 pairs), people with COPD receiving palliative care had similar rates of days at home (RR=1.01, 95% CI [0.97, 1.05]) but were more likely to die at home (16.4% vs. 10.0%, p<0.001) compared to those who did not receive palliative care. Rates of healthcare utilization were similar except for increased hospitalizations in the palliative care group (RR=1.09, 95% CI [1.01, 1.18]).

Conclusions: Receipt of palliative care did not reduce days at home or healthcare utilization but was associated with a modest increase in proportion dying at home. Future work should evaluate palliative care strategies designed specifically for patients with COPD.
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http://dx.doi.org/10.1513/AnnalsATS.202007-859OCDOI Listing
June 2021

circMELK promotes glioblastoma multiforme cell tumorigenesis through the miR-593/EphB2 axis.

Mol Ther Nucleic Acids 2021 Sep 8;25:25-36. Epub 2021 May 8.

Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.

A number of studies indicate that circular RNAs (circRNAs) play paramount roles in regulating the biological behavior of glioblastoma multiforme (GBM). In this study, we investigated the underlying mechanism of circMELK in GBM. Real-time PCRs were used to examine the expression of circMELK in glioma tissues and normal brain tissues (NBTs). Localization of circMELK in GBM cells was estimated by fluorescence hybridization (FISH). Transwell migration and three-dimensional invasion assays were performed to examine glioma cell migration and invasion . Spheroid formation, clonogenicity, and cell viability assays were implemented to test the stemness of glioma stem cells (GSCs). The functions of circMELK were investigated in a xenograft nude-mouse model. We have proved that circMELK functions as a sponge for tumor suppressor microRNA-593 (miR-593) by RNA immunoprecipitation and circRNA precipitation assays, which targets the oncogenic gene Eph receptor B2 (EphB2). Dual-luciferase reporter assays were adopted to estimate the interactions between miR-593 and circMELK or EphB2. We demonstrated that circMELK was upregulated in GBM, acting as an oncogene and regulating GBM mesenchymal transition and GSC maintenance via sponging of miR-593. Furthermore, we found that EphB2 was involved in circMELK/miR-593 axis-induced GBM tumorigenesis. This function opens the opportunity for the development of a novel therapeutic target for the treatment of gliomas.
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http://dx.doi.org/10.1016/j.omtn.2021.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190146PMC
September 2021

Simple and efficient method for producing high radionuclidic purity In using enriched Cd target.

Appl Radiat Isot 2021 Jun 13;176:109828. Epub 2021 Jun 13.

Key Laboratory of Radiation Physics and Technology of Ministry of Education, Institute of Nuclear Science and Technology, Sichuan University, Chengdu, 610064, China. Electronic address:

In this work, a simple and efficient method for producing high radionuclidic purity In from an enriched Cd target was developed. The enriched Cd metal target formed by cyanide-free electroplating was bombarded with protons of 21 MeV in a CS-30 cyclotron. Then, we explored a purification scheme using CL-P204 cation exchange resin wherein 98% of the In in the bombarded target could be extracted in less than 1 h. The purified In in the form of [In]In-chloride had a high radionuclidic purity (99.9%) and a low impurity concentration (<1.2 ppm). The yield of In via the reaction of Cd (p, 2n) In was measured to be 222 ± 5 MBq/μA∙h. In addition, a chemical procedure for collecting the unreacted Cd at a recovery rate of 96.6% was explored.
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http://dx.doi.org/10.1016/j.apradiso.2021.109828DOI Listing
June 2021

Pathogen-associated molecular pattern active sites of GH45 endoglucanohydrolase from .

Phytopathology 2021 Jun 24. Epub 2021 Jun 24.

Shandong Agricultural University, 34734, Tai'an, Shandong, China;

A 207-amino acid residue endoglucanohydrolase (EG1) belonging to the glycoside hydrolase 45 (GH45) from acts as a pathogen associated molecular pattern (PAMP). However, the mechanism of EG1 inducing plant immunity is unclear. Here, we found that EG1 contains two domains related to its PAMP function. Transient expression showed mutation deleting 60 amino acid residuesfrom the N-terminal; EG1-1, still reserved the PAMP function. Further truncation of EG1-1 obtained two truncating mutations, EG1-2 deleting seven amino acid residues from the N-terminal of EG1-1 (SPWAVND) and EG1-3 deleting five amino acid residues from the C-terminal of EG1-1 (GCSRK). Transient expression showed that the two truncating mutations EG1-2 and EG1-3 all lost the PAMP function. Site-directed mutagenesis of EG1-1 showed that the three amino acid residues (P, W, and D) in the region SPWAVND and the two amino acid residues (C and R) in the region GCSRK were involved in the PAMP function. The homology model showed that the two regions were located at a surface on the EG1 and structurally independent. These results demonstrate that there are two functional regions for the plant immune function of the EG1 released by , and the two functional regions are independent of each other.
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http://dx.doi.org/10.1094/PHYTO-04-21-0164-RDOI Listing
June 2021

Discovery and Optimization of a Novel 2-Pyrazolo[3,4-d]pyrimidine Derivative as a Potent Irreversible Pan-Fibroblast Growth Factor Receptor Inhibitor.

J Med Chem 2021 Jul 15;64(13):9078-9099. Epub 2021 Jun 15.

The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, P. R. China.

Fibroblast growth factor receptors (FGFRs) have become promising therapeutic targets in various types of cancers. In fact, several selective irreversible inhibitors capable of covalently reacting with the conserved cysteine of FGFRs are currently being evaluated in clinical trials. In this article, we optimized and discovered a novel lead compound with remarkable inhibitory effects against FGFR (1-3), which is a derivative of 2-pyrazolo[3,4-d]pyrimidine. The irreversible binding to FGFRs was characterized by LC-MS. This compound has been shown to exhibit significant anti-proliferation effects against NCI-H1581 and SNU-16 cancer cell lines both and . Compound has also demonstrated a low toxicity profile and adequate pharmacokinetic properties and is currently under validation as a potential drug candidate.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00174DOI Listing
July 2021

Methionine enkephalin (MENK) suppresses lung cancer by regulating the Bcl-2/Bax/caspase-3 signaling pathway and enhancing natural killer cell-driven tumor immunity.

Int Immunopharmacol 2021 Jun 8;98:107837. Epub 2021 Jun 8.

Department of Immunology, School of Basic Medical Science, China Medical University, Shenyang 110122, China. Electronic address:

The aim of this study was to investigate how methionine enkephalin (MENK) regulates the biological behavior of lung cancer cells and to further explore its anti-lung cancer mechanisms in vitro and in vivo. The results showed that MENK enhanced the expression of opioid receptor (OGFr) and induced apoptosis of lung cancer cells by activating the Bcl-1/Bax/caspase-3 signaling pathway in vitro and in vivo. However, the regulatory effects of MENK disappeared after blockade of the OGFr. This confirmed that a prerequisite for the anti-tumor action of MENK is binding to OGFr. Additionally, we observed that MENK treatment enhanced the immunogenicity of lung cancer by enhancing the exposure of calreticulin and high mobility group box 1, and increasing the expression of NKG2D ligands. Further studies showed that MENK treatment increased the expression of natural killer (NK) cell-related cytokines such as granzyme B and interferon-γ and NK cell activation. Thus, we concluded that MENK might inhibit the proliferation of lung cancer cells by activating the Bcl-2/Bax/caspase-3 signaling pathway and enhancing immunogenicity and NK cell-driven tumor immunity.
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http://dx.doi.org/10.1016/j.intimp.2021.107837DOI Listing
June 2021

[Application of extracorporeal membrane oxygenation in critically ill pregnant women].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2021 May;33(5):605-608

Department of Intensive Care Unit, Nanjing Drum Tower Hospital, the Affiliated Hospital to Nanjing University Medical School, Nanjing 210009, Jiangsu, China. Corresponding author: Gu Qin, Email:

Objective: To investigate the safety and effectiveness of extracorporeal membrane oxygenation (ECMO) in emergency treatment of critically ill pregnant women.

Methods: Clinical data of 8 pregnant women with severe cardiopulmonary dysfunction during the perinatal period treated by ECMO in the department of intensive care unit (ICU) of Nanjing Drum Tower Hospital, the Affiliated Hospital to Nanjing University Medical School from September 2017 to November 2020 were retrospectively analyzed.

Results: For the 8 pregnant women, the mean age was (32.5±6.3) years old. Body weight was (73.5±8.1) kg. Gestational age was (31.0±4.4) weeks. Acute physiology and chronic health evaluation II (APACHE II) score was 13.0±6.6, and sequential organ failure assessment (SOFA) score was 8.3±3.8. Among them, 5 pregnant women suffered from severe pneumonia and were treated with venous-venous ECMO (VV-ECMO). Another 3 pregnant women with heart failure underwent venous-arterial ECMO (VA-ECMO). The initial ECMO flow rate was set to 2.0-3.0 L/min. Then the highest flow rate was (3.1±0.6) L/min, and the average ECMO running time was (174±36) hours. The length of ICU stay was (16.0±5.4) days. Six pregnant women (5 with severe pneumonia and 1 with peripartum cardiomyopathy) successfully evacuated from ECMO and survived. Two pregnant women with pulmonary hypertension showed poor prognosis. In total, seven babies survived. Two of them were delivered after ECMO evacution, and one underwent emergency cesarean section with ECMO support. In another case, the fetus could not be delivered due to under-gestational weeks. During this period, there were no serious bleeding complications. One pregnant woman developed heparin-induced thrombocytopenia and thrombosis (HITT), then she received another anticoagulant treatment. One pregnant woman got sequential anticoagulation therapy for 3 months on account of thrombosis in the puncture vessel.

Conclusions: ECMO has played an active role in the rescue of critically ill pregnant women. For those with reversible severe cardiopulmonary dysfunction, it is necessary to evaluate the application of ECMO as early as possible to improve the survival rate of mothers and infants.
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http://dx.doi.org/10.3760/cma.j.cn121430-20201231-00784DOI Listing
May 2021
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