Publications by authors named "Yuting Liu"

249 Publications

Utilizing structure based drug design and metabolic soft spot identification to optimize the in vitro potency and in vivo pharmacokinetic properties leading to the discovery of novel reversible Bruton's tyrosine kinase inhibitors.

Bioorg Med Chem 2021 Jun 15;44:116275. Epub 2021 Jun 15.

Sunesis Pharmaceuticals, Inc. 395 Oyster Point Boulevard, South San Francisco, CA 94080, USA.

Bruton's tyrosine kinase (BTK) is an essential node on the BCR signaling in B cells, which are clinically validated to play a critical role in B-cell lymphomas and various auto-immune diseases such as Multiple Sclerosis (MS), Pemphigus, and rheumatoid arthritis (RA). Although non-selective irreversible BTK inhibitors have been approved for oncology, due to the emergence of drug resistance in B-cell lymphoma associated with covalent inhibitor, there an unmet medical need to identify reversible, selective, potent BTK inhibitor as viable therapeutics for patients. Herein, we describe the identification of Hits and subsequence optimization to improve the physicochemical properties, potency and kinome selectivity leading to the discovery of a novel class of BTK inhibitors. Utilizing Met ID and structure base design inhibitors were synthesized with increased in vivo metabolic stability and oral exposure in rodents suitable for advancing to lead optimization.
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http://dx.doi.org/10.1016/j.bmc.2021.116275DOI Listing
June 2021

Azithromycin "ghost peak": A solution degradation product of azithromycin via leaching from borosilicate glass volumetric flasks and vials.

J Pharm Biomed Anal 2021 Jul 9;204:114248. Epub 2021 Jul 9.

Dongguan HEC Generic Drug R&D Co., Ltd, Dongguan, 523871, China; Ruyuan HEC Pharmaceutical Glass Technology, Shaoguan, 512700, China. Electronic address:

An interference peak was found while detecting related substances of azithromycin. It is impressive that the degradation peak occurred at about 70 min in the next injection of the test solution (4 mg/mL or higher). Once the degradation peak was observed, it would keep growing. By using a strategy that Q-TOF high resolution mass spectrometry with mechanism-based stress studies, followed by preparative subsequent structure characterization by 1D and 2D NMR, the unknown peak was identified as azithromycin hydrogen borate. It apparently results from azithromycin and residual boron leaching out of the inner surface of the glass volumetric flasks and vials used in the sample preparation. By simulating the above chemical process, boric acid and azithromycin were dissolved in the same extraction diluent and a big interference peak occurred. It was found that boron-free flasks and vials, such as PMP or PP flasks and PTFE or PP vials could be used for the detection of azithromycin related substances to avoid the production of azithromycin hydrogen borate.
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http://dx.doi.org/10.1016/j.jpba.2021.114248DOI Listing
July 2021

Human pluripotent stem cell-derived eosinophils reveal potent cytotoxicity against solid tumors.

Stem Cell Reports 2021 Jul 1;16(7):1697-1704. Epub 2021 Jul 1.

School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100191, China. Electronic address:

Eosinophils are attractive innate immune cells to use to potentiate T cell antitumor efficacy because they are capable of infiltrating tumors at early stages and modulating the tumor microenvironment. However, the limited number of functional eosinophils caused by the scarcity and short life of primary eosinophils in peripheral blood has greatly impeded the development of eosinophil-based immunotherapy. In this study, we established an efficient chemically defined protocol to generate a large quantity of functional eosinophils from human pluripotent stem cells (hPSCs) with nearly 100% purity expressing eosinophil peroxidase. These hPSC-derived eosinophils transcriptionally resembled their primary counterpart. Moreover, hPSC-derived eosinophils showed competent tumor killing capacity in established solid tumors. Furthermore, the combination of hPSC-derived eosinophils with CAR-T cells exhibited potential synergistic effects, inhibiting tumor growth and enhancing mouse survival. Our study opens up new avenues for the development of eosinophil-based immunotherapies to treat cancer.
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http://dx.doi.org/10.1016/j.stemcr.2021.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282466PMC
July 2021

AP-1 activity is a major barrier of human somatic cell reprogramming.

Cell Mol Life Sci 2021 Aug 28;78(15):5847-5863. Epub 2021 Jun 28.

CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.

Human induced pluripotent stem cells (iPSCs) technology has been widely applied to cell regeneration and disease modeling. However, most mechanism of somatic reprogramming is studied on mouse system, which is not always generic in human. Consequently, the generation of human iPSCs remains inefficient. Here, we map the chromatin accessibility dynamics during the induction of human iPSCs from urine cells. Comparing to the mouse system, we found that the closing of somatic loci is much slower in human. Moreover, a conserved AP-1 motif is highly enriched among the closed loci. The introduction of AP-1 repressor, JDP2, enhances human reprogramming and facilitates the reactivation of pluripotent genes. However, ESRRB, KDM2B and SALL4, several known pluripotent factors promoting mouse somatic reprogramming fail to enhance human iPSC generation. Mechanistically, we reveal that JDP2 promotes the closing of somatic loci enriching AP-1 motifs to enhance human reprogramming. Furthermore, JDP2 can rescue reprogramming deficiency without MYC or KLF4. These results indicate AP-1 activity is a major barrier to prevent chromatin remodeling during somatic cell reprogramming.
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http://dx.doi.org/10.1007/s00018-021-03883-xDOI Listing
August 2021

Aggravated ozone pollution in the strong free convection boundary layer.

Sci Total Environ 2021 Sep 15;788:147740. Epub 2021 May 15.

State Key Laboratory of Atmospheric Boundary Layer Physics and Atmospheric Chemistry, Institute of Atmospheric Physics, Chinese Academy of Sciences, Beijing 100029, China; Center for Excellence in Urban Atmospheric Environment, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Clarifying the relationship between meteorological factors and ozone can provide scientific support for ozone pollution prediction, but the effects of boundary layer meteorology, especially boundary layer height and turbulence, on ozone pollution are rarely studied. Here, ozone and its related meteorological factors were observed in summer in Shijiazhuang, a city with the most serious ozone pollution on the North China Plain. The forced and free convection boundary layers were classified using ground remote observations. After eliminating the forced convection condition, strong free convection conditions, exhibiting a high boundary layer height, high wind speed, strong turbulence and large-scale free convection velocity, were found to be beneficial for the aggravation of ozone pollution. Combined with the ozone profile detected by a tethered balloon, the ozone chemical budget was calculated using the differences in the column ozone concentrations between the morning and afternoon, and the results confirmed the impact of free convection intensity on ozone pollution. The change in ozone sensitivity from VOCs sensitivity to NOx sensitivity driven by strong free convection was the main reason for the deterioration of ozone pollution. This study clarified the impact of boundary layer meteorology on ozone and its sensitivity and has important practical significance for ozone pollution prevention and early warning.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147740DOI Listing
September 2021

Comprehensive Profiling Reveals Distinct Microenvironment and Metabolism Characterization of Lung Adenocarcinoma.

Front Genet 2021 28;12:619821. Epub 2021 May 28.

Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Lung adenocarcinoma has entered into an era of immunotherapy with the development of immune checkpoint inhibitors (ICIs). The identification of immune subtype is crucial to prolonging survival in patients. The tumor microenvironment (TME) and metabolism have a profound impact on prognosis and therapy. The majority of previous studies focused on only one aspect, while both of them are essential to the understanding of tumorigenesis and development. We hypothesized that lung adenocarcinoma can be stratified into immune subgroups with alterations in the TME infiltration. We aimed to explore the "TME-Metabolism-Risk" patterns in each subtypes and the mechanism behind. Glycolysis and cholesterol were selected for the analysis of metabolic states based on the first half of the study. Bioinformatic analysis was performed to investigate the transcriptomic and clinical data integrated by three lung adenocarcinoma cohorts (GSE30219, GSE31210, GSE37745, = 415). The results were validated in an independent cohort (GSE50081, = 127). In total, 415 lung adenocarcinoma samples were integrated and analyzed. Four major immune subtypes were indentified using bioinformatic analysis. Subtype NC1, characterized by a high level of glycolysis, with extremely low microenvironment cell infiltration. Subtype NC2, characterized by the "Silence" and "Cholesterol biosynthesis Predominant" metabolic states, with a middle degree infiltration of microenvironment cell. Subtype NC3, characterized by the lack of "Cholesterol biosynthesis Predominant" metabolic state, with abundant microenvironment cell infiltration. Subtype NC4, characterized by "Mixed" metabolic state, with a relatively low microenvironment cell infiltration. Least absolute shrinkage and selection operator (LASSO) regression and multivariate analyses were performed to calculate the risk of each sample, and we attempted to find out the potential immune escape mechanism in different subtypes. The result revealed that the lack of immune cells infiltration might contribute to the immune escape in subtypes NC1 and NC4. NC3 was characterized by the high expression of immune checkpoint molecules and fibroblasts. NC2 had defects in activation of innate immune cells. There existed an obviously survival advantage in subtype NC2. Gene set enrichment analysis (GSEA) and Gene Ontology analysis indicated that the PI3K-AKT-mTOR, TGF-β, MYC-related pathways might be correlated with this phenomenon. In addition, some differentially expressed genes (DEGs) were indentified in subtype NC3, which might be potential targets for survival phenotype transformation.
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http://dx.doi.org/10.3389/fgene.2021.619821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193848PMC
May 2021

Integrative Analysis of Genome, 3D Genome, and Transcriptome Alterations of Clinical Lung Cancer Samples.

Genomics Proteomics Bioinformatics 2021 Jun 8. Epub 2021 Jun 8.

Center for Bioinformatics, School of Life Sciences, Center for Statistical Science, Peking University, Beijing 100871, China. Electronic address:

Genomic studies of cancer cell alterations, such as mutations, copy number variations (CNVs), and translocations, greatly promote our understanding of the genesis and development of cancer. However, the 3D genome architecture of cancers remains less studied due to the complexity of cancer genomes and technical difficulties. To explore the 3D genome structure in clinical lung cancer, we performed Hi-C experiments using paired normal and tumor cells harvested from patients with lung cancer, combining with RNA-seq analysis. We demonstrated the feasibility of studying 3D genome of clinical lung cancer samples with a small number of cells (1 × 10), compared the genome architecture between clinical samples and cell lines of lung cancer, and identified conserved and changed spatial chromatin structures between normal and cancer samples. We also showed that Hi-C data can be used to infer CNVs and point mutations in cancer. By integrating those different types of cancer alterations, we showed significant associations between CNVs, 3D genome, and gene expression. We propose that 3D genome mediates the effects of cancer genomic alterations on gene expression through altering regulatory chromatin structures. Our study highlights the importance of analyzing 3D genomes of clinical cancer samples in addition to cancer cell lines and provides an integrative genomic analysis pipeline for future larger-scale studies in lung cancer and other cancers.
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http://dx.doi.org/10.1016/j.gpb.2020.05.007DOI Listing
June 2021

Preparation of Room Temperature Vulcanized Silicone Rubber Foam with Excellent Flame Retardancy.

Scanning 2021 20;2021:9976005. Epub 2021 May 20.

School of Material Science and Engineering, Jiangsu University of Science and Technology, Zhenjiang, Jiangsu 212003, China.

To retard the spread of fire in many cases with sealing materials is significant. A series of silicone rubber foam materials were prepared with room temperature vulcanization and foaming reactions. The morphology, chemical structure, cell structure, and thermal stability were investigated and results proved that the synthesis of silicone rubber was successful in a wide range of feed ratios. The fire-retardant tests were carried out to study the fire-proof property of the composite materials, and the excellent performance showed a promising prospect for wide application in sealing materials.
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http://dx.doi.org/10.1155/2021/9976005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163528PMC
May 2021

Mechanisms for potential Pb immobilization by hydroxyapatite in a soil-rice system.

Sci Total Environ 2021 Aug 18;783:147037. Epub 2021 Apr 18.

College of Resource and Environmental Science, Fujian Agriculture and Forestry University, Fuzhou 350002, PR China. Electronic address:

This study aimed to investigate the mechanism of lead (Pb) immobilization by hydroxyapatite (HAP) in a soil-rice system, a pot experiment was conducted using Pb-contaminated soil amended with various rates of HAP and planted with rice (Oryza sativa L.). The Pb species in the soil and rice roots were determined using Pb L3-edge X-ray absorption near edge structure (XANES). Application of HAP increased soil pH and induced the dissolution of phosphate, subsequently promoting the formation of chloropyromorphite, an insoluble Pb species, in the soil. Therefore, the acid soluble and DTPA-extractable Pb concentrations decreased significantly with increasing levels of applied HAP. HAP reduced the retention of Pb in the iron plaque on the root surface at maturity, thereby alleviating Pb uptake by rice roots. The amount of phosphate in roots were increased with increasing rate of application of HAP, but was negatively correlated with Pb in rice stems and leaves. Application of 32 g kg of HAP triggered the precipitation of PbPOCl in roots, limiting Pb translocation from roots to shoots. In addition, HAP may induce the redistribution of Pb in rice nodes, lowering the transfer factor of Pb from the stem (or leaf) to rice grains. When the rate of application of HAP exceeds 4 g kg, the Pb concentration in brown rice could be reduced to less than the Chinese National Standard of 0.2 mg kg (GB2762-2017).
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http://dx.doi.org/10.1016/j.scitotenv.2021.147037DOI Listing
August 2021

Cognitive Neural Mechanism of Social Anxiety Disorder: A Meta-Analysis Based on fMRI Studies.

Int J Environ Res Public Health 2021 05 22;18(11). Epub 2021 May 22.

Key Laboratory of Adolescent Cyberpsychology and Behavior, Ministry of Education, Key Laboratory of Human Development and Mental Health of Hubei Province, School of Psychology, Central China Normal University, Wuhan 430056, China.

Objective: The present meta-analysis aimed to explore the cognitive and neural mechanism of social anxiety disorder (SAD) from a whole-brain view, and compare the differences in brain activations under different task paradigms.

Methods: We searched Web of Science Core Collection and other databases with the keywords related to social anxiety, social phobia, and functional magnetic resonance imaging (fMRI) for comparing persons with SAD to healthy controls and used the activation likelihood estimation method. Thirty-seven papers met the inclusion criteria, including 15 with emotional faces as stimuli, 8 presenting specific situations as stimuli, and 14 using other types of tasks as stimuli. Among these papers, 654 participants were in the SAD group and 594 participants were in the control group with 335 activation increase points and 115 activation decrease points.

Results: Whole-brain analysis showed that compared with healthy controls, persons with SAD showed significantly lower activation of the left anterior cingulate gyrus (MNI coordinate: x = -6, y = 22, z = 38; 0.001). Sub-group analysis based on task indicated that when performing tasks with emotional faces as stimuli, persons with SAD showed significantly lower activation of the left cerebellar slope and fusiform gyrus (MNI coordinate: x = -26, y = -68, z = -12; 0.001), and significantly higher activation of the right supramarginal gyrus and angular gyrus, than healthy controls (MNI coordinate: x = 58, y = -52, z = 30; 0.001).

Conclusion: Individuals with social anxiety disorder show abnormal activation in the cingulate gyrus, which is responsible for the process of attention control, and task type can influence the activation pattern.
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http://dx.doi.org/10.3390/ijerph18115556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196988PMC
May 2021

PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization.

Front Pharmacol 2021 8;12:643215. Epub 2021 Apr 8.

Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, China.

Ulcerative colitis (UC) is a form of inflammatory bowel disease, which manifests as irritation or swelling and sores in the large intestine in a relapsing and remitting manner. In a dextran sulfate sodium sulfate (DSS)-induced UC model in female mice, we found that the levels of cyclic guanosine monophosphate (cGMP) are reduced, while the expression of phosphodiesterase 9A (PDE9A) is highest among all phosphodiesterase (PDEs). Since PDE9 has the highest affinity toward cGMP, we evaluated the selective PDE9 inhibitor PF-04447943 (PF) as a potential candidate for UC treatment. PF has been extensively studies in cognitive function and in sickle cell disease, but not in models for inflammatory bowel disease (IBD). Therefore, we used female C57BL/6 mice treated with 3% DSS alone or co-treated with PF or sulfasalazine (SASP) to study the body weight, colon length, histopathology, and measure superoxide dismutase (SOD), malondialdehyde (MDA), and cGMP level, as well as cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-12/23 (IL-12/23), interleukin-10 (IL-10), and pathways including nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and inflammasome activation. In addition, the number of dendritic cells (DC) and regulatory T cells (Treg cell) was assessed in the spleen, lymph node, and colon using flow cytometry. DSS reduced the number of goblet cells, decreased colon lengths and body weights, all of them were attenuated by PF treatment. It also suppressed the elevated level of inflammatory cytokines and increased level the anti-inflammatory cytokine, IL-10. PF treatment also reduced the DSS-induced inflammation by suppressing oxidative stress, NF-κB, STAT3, and inflammasome activation, by upregulating nuclear factor erythroid 2-related factor 2 (Nrf-2) and its downstream proteins via extracellular signal-regulated kinase (ERK) phosphorylation. Importantly, PF reversed imbalance in Treg/T helper 17 cells (Th17) cells ratio, possibly by regulating dendritic cells and Treg developmental process. In summary, this study shows the protective effect of a PDE9A inhibitor in ulcerative colitis by suppressing oxidative stress and inflammation as well as reversing the Treg/Th17 cells imbalance.
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http://dx.doi.org/10.3389/fphar.2021.643215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098793PMC
April 2021

Enterococcus faecalis contributes to hypertension and renal injury in Sprague-Dawley rats by disturbing lipid metabolism.

J Hypertens 2021 Jun;39(6):1112-1124

School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine.

Objective: Increasing studies have demonstrated that gut microbiota play vital roles in the development of hypertension. However, the underlying mechanism is not fully understood.

Methods: The relative abundance of Enterococcus faecalis was determined in the faecal samples of angiotensin II or deoxycorticosterone acetate/salt-induced hypertensive rats. Then, E. faecalis culture was administered orally to rats for 6 weeks. Blood pressure (BP) was measured, renal injury was estimated and a serum metabolomic analysis was performed.

Results: Compared with control, E. faecalis was markedly enriched in the faecal samples of hypertensive rats. The rats receiving live E. faecalis but not dead bacteria exhibited higher BP and enhanced renal injury. The serum metabolomic data showed that the E. faecalis treatment resulted in 35 variable metabolites including 16 (46%) lipid/lipid-like molecules, suggesting significant disturbance of lipid metabolism. Furthermore, the mRNA levels of 18 lipid metabolic enzymes in the renal medulla and cortex presented distinct and dynamic changes in response to 3 or 6-week E. faecalis treatment. Consistently, the protein levels of lysophospholipases A1 (LYPLA1) and phospholipase A2 group 4 A (PLA2G4) were enhanced only by live E. faecalis, which thus may have decreased the nitric oxide production in the renal medulla and elevated BP.

Conclusion: Our results suggest that E. faecalis in the gut contributes to hypertension and renal injury in rats by disturbing the lipid metabolism. The information provided here could shed new light on the pathologic mechanisms and potential intervention targets for the treatment of gut dysbiosis-induced hypertension.
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http://dx.doi.org/10.1097/HJH.0000000000002767DOI Listing
June 2021

Pseudorabies virus pUL16 assists the nuclear import of VP26 through protein-protein interaction.

Vet Microbiol 2021 Jun 20;257:109080. Epub 2021 Apr 20.

Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, China; Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonoses, Yangzhou University, Yangzhou, 225009, China. Electronic address:

Pseudorabies virus (PRV) is related to alphaherpesvirus and varicellovirus. pUL16 is a conserved protein in all herpesviruses, and studies have shown that UL16 can interact with the viral proteins pUL11, pUL49, pUL21, gD, and gE. In this study, we found that pUL16 interacted with the viral capsid protein VP26, which could not translocate into the nucleus itself but did appear in the nucleus. We further determined whether pUL16 assists the translocation of VP26 into the nucleus. We found that pUL16 interacted with VP26 with or without viral proteins, and since VP26 itself did not contain a nuclear location signal, we concluded that pUL16 assisted the translocation of VP26 into the nucleus. Deletion of UL16 and UL35 significantly reduced the 50 % tissue culture infective dose, virulence, attachment, and internalization of PRV in cells. These results show that the interaction between pUL16 and VP26 influences the growth and virulence of pseudorabies virus. Our research is the first study to show that pUL16 interacts with VP26, which may explain the targeting site of UL16 and viral capsids. It is also the first to show that UL16 assists the transport of other viral proteins to organelles. Previous researches on pUL16 usually emphasized its interaction with pUL11, pUL21, and gE, and sometimes commented on pUL49 and gD. Our research focuses on the novel interaction between pUL16 and VP26, thereby enriching the studies on herpesviruses and possibly providing different directions for researchers.
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http://dx.doi.org/10.1016/j.vetmic.2021.109080DOI Listing
June 2021

Computational Image Analysis Identifies Histopathological Image Features Associated With Somatic Mutations and Patient Survival in Gastric Adenocarcinoma.

Front Oncol 2021 31;11:623382. Epub 2021 Mar 31.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States.

Computational analysis of histopathological images can identify sub-visual objective image features that may not be visually distinguishable by human eyes, and hence provides better modeling of disease phenotypes. This study aims to investigate whether specific image features are associated with somatic mutations and patient survival in gastric adenocarcinoma (sample size = 310). An automated image analysis pipeline was developed to extract quantitative morphological features from H&E stained whole-slide images. We found that four frequently somatically mutated genes (TP53, ARID1A, OBSCN, and PIK3CA) were significantly associated with tumor morphological changes. A prognostic model built on the image features significantly stratified patients into low-risk and high-risk groups (log-rank test p-value = 2.6e-4). Multivariable Cox regression showed the model predicted risk index was an additional prognostic factor besides tumor grade and stage. Gene ontology enrichment analysis showed that the genes whose expressions mostly correlated with the contributing features in the prognostic model were enriched on biological processes such as cell cycle and muscle contraction. These results demonstrate that histopathological image features can reflect underlying somatic mutations and identify high-risk patients that may benefit from more precise treatment regimens. Both the image features and pipeline are highly interpretable to enable translational applications.
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http://dx.doi.org/10.3389/fonc.2021.623382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045755PMC
March 2021

Cross-Species Metabolic Profiling of Floral Specialized Metabolism Facilitates Understanding of Evolutional Aspects of Metabolism Among Brassicaceae Species.

Front Plant Sci 2021 31;12:640141. Epub 2021 Mar 31.

Graduate School of Biological Science, Nara Institute of Science and Technology (NAIST), Ikoma, Japan.

Plants produce a variety of floral specialized (secondary) metabolites with roles in several physiological functions, including light-protection, attraction of pollinators, and protection against herbivores. Pigments and volatiles synthesized in the petal have been focused on and characterized as major chemical factors influencing pollination. Recent advances in plant metabolomics have revealed that the major floral specialized metabolites found in land plant species are hydroxycinnamates, phenolamides, and flavonoids albeit these are present in various quantities and encompass diverse chemical structures in different species. Here, we analyzed numerous floral specialized metabolites in 20 different Brassicaceae genotypes encompassing both different species and in the case of crop species different cultivars including self-compatible (SC) and self-incompatible (SI) species by liquid chromatography-mass spectrometry (LC-MS). Of the 228 metabolites detected in flowers among 20 Brassicaceae species, 15 metabolite peaks including one phenylacyl-flavonoids and five phenolamides were detected and annotated as key metabolites to distinguish SC and SI plant species, respectively. Our results provide a family-wide metabolic framework and delineate signatures for compatible and incompatible genotypes thereby providing insight into evolutionary aspects of floral metabolism in Brassicaceae species.
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http://dx.doi.org/10.3389/fpls.2021.640141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045754PMC
March 2021

Imaging, clinical, and pathologic findings of Sertoli-leydig cell tumors.

Sci Prog 2021 Apr-Jun;104(2):368504211009668

Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China.

To explore the clinical features, imaging findings, and pathological manifestations of ovarian Sertoli-Leydig cell tumors (SLCTs). The clinical and pathological manifestations, tumor location, size, morphology, vascularity, computed tomography (CT) density, magnetic resonance imaging (MRI) signal intensity, and contrast enhancement patterns in five cases with SLCTs were retrospectively reviewed. SLCTs most commonly occurred in young women. Virilization was observed in three cases (60%). All five tumors were unilateral and oval or round, with a clear boundary. The solid part of the tumor was isoattenuated on the conventional CT scan, and showed isoattenuation or slight hypoattenuation relative to adjacent myometrium on T1 weighted imaging (T1WI) and T2 weighted imaging (T2WI). On contrast-enhanced images, three tumors showed marked enhancement. DICER1 hotspot mutations were commonly seen in SLCTs. A highly vascularized mass with low signal intensity (SI) of the solid part on T2WI and androgen overproduction symptoms may suggest an SLCT.
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http://dx.doi.org/10.1177/00368504211009668DOI Listing
April 2021

Mechanism of Cdk5-synaptophysin-SNARE pathway in acute and chronic inflammatory pain.

Am J Transl Res 2021 15;13(3):1075-1084. Epub 2021 Mar 15.

Department of Pain Management, Hebei General Hospital Shijiazhuang 050051, Hebei Province, China.

Purpose: Currently, there is no favorable treatment plan for inflammatory pain, so exploring new analgesics is still a research hotspot in this area. Cyclin-dependent protein kinase 5 (Cdk5) is a pain-related protein kinase, but its mechanism in inflammatory pain has not been clarified. This research aimed to explore the mechanism of Cdk5-synaptophysin (Syn)-soluble N-ethylmaleimide-sensitivity factor (NSF) attachment protein receptor (SNARE) in acute and chronic inflammatory pain.

Methods: Rat models of acute and chronic inflammatory pain were induced by formalin and complete Freund's adjuvant (CFA), separately, and some rats injected with normal saline through intraplantar injection were divided into a control group. Thirty minutes before modeling, rats were given Cdk5 inhibitor (Roscovitine, Ros), SNARE scavenger (botulinum toxin A, BTTA), glutamate receptor inhibitor (MK801), and dimethyl sulfoxide (DMSO) through spinal canals, and the paw withdrawal threshold (PWT) and thermal withdrawal latency (PWL) at difference time points were compared.

Results: Compared with rats in the control group, those in the rat models of acute and chronic inflammatory pain showed lower PWT and PWL, higher Cdk5 enzyme level, tight correlation of Cdk5 with Syn, SNARE, p25 proteins, and higher levels of Cdk5, Syn and SNARE. And the above situation was dramatically reversed under intervention of Ros, BTTA and MK801.

Conclusion: Cdk5-Syn-SNARE pathway is a therapeutic target for inflammatory pain. Blocking the activation of this pathway is beneficial to exert analgesic effect.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014406PMC
March 2021

GSK3β rephosphorylation rescues ALPL deficiency-induced impairment of odontoblastic differentiation of DPSCs.

Stem Cell Res Ther 2021 04 6;12(1):225. Epub 2021 Apr 6.

National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, Precision Medicine Institute, The Second Affiliated Hospital of Xi'an Jiaotong University, No.157 Xiwu Road, Xi'an, 710004, China.

Background: Premature exfoliation of the deciduous teeth is a common manifestation in childhood patients with hypophosphatasia (HPP), which is an autosomal inherited disease caused by ALPL mutations. Dysplasia of the cementum, dentin, and alveolar bone has been proposed to be the main reasons for the exfoliation of teeth, while the extraordinarily complex intracellular mechanisms remain elusive. Dental pulp stem cells (DPSCs) have been demonstrated to successfully regenerate functional pulp-dentin-like tissue. Dental pulp cells derived from HPP patients impaired mineralization; however, insight into the deeper mechanism is still unclear.

Methods: The effects of ALPL on odontoblastic differentiation of DPSCs from HPP patient were assessed by Alizarin Red staining, immunofluorescent staining, Western blot and RT-PCR, and micro-CT assays.

Result: Here, we found DPSCs from HPP patient exhibited low ALP activity and impaired odontoblastic differentiation. Meanwhile, we found that loss of function of ALPL reduced phosphorylation of GSK3β in DPSCs. While GSK3β rephosphorylation improved odontoblastic differentiation of HPP DPSCs with LiCl treatment. Finally, we demonstrated systemic LiCl injection ameliorated tooth-associated defects in ALPL mice by enhanced phosphorylation of GSK3β in the teeth.

Conclusions: Our study indicates that ALPL regulates odontoblastic differentiation of DPSCs and provides useful information for understanding how ALPL deficiency led to tooth dysplasia and, ultimately, may inform efforts at improvement tooth defects in HPP patients.
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http://dx.doi.org/10.1186/s13287-021-02235-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022410PMC
April 2021

Omega-3 fatty acid protects cardiomyocytes against hypoxia-induced injury through targeting MiR-210-3p/CASP8AP2 axis.

Mol Cell Biochem 2021 Aug 31;476(8):2999-3007. Epub 2021 Mar 31.

Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, 510632, China.

MicroRNAs (miRs) regulate diverse biological functions in both normal and pathological cellular conditions by post-transcriptional regulation of various genes expression. Nevertheless, the role of miRs in regulating the protective functions of omega-3 fatty acid in relation to hypoxia in cardiomyocytes remains unknown. The aim of this study was to investigate the effects of omega-3 fatty acid supplementation on cardiomyocyte apoptosis and further delineate the mechanisms underlying microRNA-210 (miRNA-210)-induced cardiomyocyte apoptosis in vitro. H9C2 cultured cells were first subjected to hypoxia followed by a subsequent treatment with main component of the Omega-3 fatty acid, Docosahexaenoic Acid (DHA). Cell apoptosis were detected by flow cytometry and the expression of miR-210-3p were detected by RT-qPCR and caspase-8-associated protein 2 (CASP8AP2) at protein levels by immunoblotting. Dual luciferase assay was used to verify the mutual effect between miR-210-3p and the 3'-untranslated region (UTR) of CASP8AP2 gene. DHA was shown to reduce apoptosis in H9C2 cells subjected to hypoxia. While DHA caused a significant increase in the expression of miR-210-3p, there was a marked reduction in the protein expression of CASP8AP2. MiR-210-3p and CASP8AP2 were significantly increased in H9C2 cardiomyocyte subjected to hypoxia. Overexpression of miR-210-3p could ameliorate hypoxia-induced apoptosis in H9C2 cells. MiR-210-3p negatively regulated CASP8AP2 expression at the transcriptional level. Both miR-210-3p mimic and CASP8AP2 siRNA could efficiently inhibit apoptosis in H9C2 cardiomyocyte subjected to hypoxia. We provide strong evidence showing that Omega-3 fatty acids can attenuate apoptosis in cardiomyocyte under hypoxic conditions via the up-regulation of miR-210-3p and targeting CASP8AP2 signaling pathway.
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http://dx.doi.org/10.1007/s11010-021-04141-1DOI Listing
August 2021

Analysis of mRNA expression differences in bladder cancer metastasis based on TCGA datasets.

J Int Med Res 2021 Mar;49(3):300060521996929

Department of Urology, the First Affiliated Hospital of the Third Military Medical University, Chongqing, China.

Objective: To investigate the metastatic mechanism of muscle invasive bladder cancer (MIBC), which accounts for approximately 30% of all bladder cancer cases, and is a considerable medical problem with high metastatic and mortality rates.

Methods: The mRNA levels of patients with metastatic MIBC and nonmetastatic MIBC from The Cancer Genome Atlas dataset were compared. An integrated bioinformatics analysis was performed of the differentially expressed genes (DEGs), and analyses of Gene Ontology, Kyoto Encyclopaedia of Genes and Genomes pathway, protein-protein interaction, and survival were performed to investigate differences between metastatic and nonmetastatic MIBC.

Results: Data from 264 patients were included (131 with, and 133 without, metastasis). A total of 385 significantly DEGs were identified, including 209 upregulated genes and 176 downregulated genes. Based on results using the STRING database and the MCODE plugin of Cytoscape software, two clusters were obtained. Moreover, two genes were identified that may be valuable for prognostic analysis: Keratin 38, type I () and Histone cluster 1, H3f ().

Conclusion: The and genes may be important in metastasis of MIBC.
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http://dx.doi.org/10.1177/0300060521996929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020247PMC
March 2021

Long-term trends of surface and canopy layer urban heat island intensity in 272 cities in the mainland of China.

Sci Total Environ 2021 Jun 4;772:145607. Epub 2021 Feb 4.

School of Computer Science, China University of Geosciences, Wuhan 430074, China; Hubei Key Laboratory of Intelligent Geo-Information Processing, China University of Geosciences, Wuhan 430074, China.

The canopy layer urban heat island (CLUHI) and surface urban heat island (SUHI) refer to higher canopy layer and land surface temperatures in urban areas than in rural areas, respectively. The long-term trends of CLUHIs are poorly understood at the regional scale. In this study, 1 km resolution air temperature (Ta) data for the 2001-2018 period in the mainland of China were mapped using satellite data and station-based Ta data. Subsequently, the temporal trends of the CLUHI and SUHI intensities (CLUHII and SUHII, respectively) were investigated in 272 cities in the mainland of China. The Ta was estimated with high accuracy, with a root mean square error ranging from 0.370 °C to 0.592 °C. The CLUHII and SUHII increased significantly in over half of the cities in spring and summer, over one-third of the cities in autumn, and over one-fifth of the cities in winter. The trends of the nighttime SUHII were strongly related to the CLUHII calculated using mean and minimum Ta (correlation coefficients ranging from 0.613 to 0.770), whereas the relationships between the trends of the daytime SUHII and CLUHII were relatively weak. Human activities were the major driving forces for the increase in the CLUHII and SUHII. The difference in impervious surfaces between urban and rural areas was significantly correlated with the CLUHII and SUHII in approximately half of the cities. Meteorological factors were significantly correlated with the CLUHII and SUHII in few cities. This study highlights the trends of the significant increase in the CLUHII and SUHII in the mainland of China, which may have negative effects on humans and the environment.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145607DOI Listing
June 2021

The Efficacy of First-Generation EGFR-TKI Combined With Brain Radiotherapy as the First-Line Treatment for Lung Adenocarcinoma Patients With Brain Metastases and EGFR Sensitive Mutations: A Retrospective study.

Technol Cancer Res Treat 2021 Jan-Dec;20:1533033821997819

Cancer Center, Union Hospital, Tongji Medical College, 12443Huazhong University of Science and Technology, Wuhan, China.

Background: It was controversial that whether LUAD patients with brain metastases (BMs) and EGFR sensitive mutations should be conducted using brain radiotherapy when treated with first-generation EGFR-TKI. Herein, a retrospective study was designed to compare the efficacy of first-generation EGFR-TKI combined with brain radiotherapy and EGFR-TKI alone as first-line treatment for these LUAD patients.

Patients And Methods: We retrospectively analyzed the status of patients with advanced LUAD carrying EGFR sensitive mutations who received first-generation EGFR-TKI treatment in our center. iPFS was the first time of intracranial progression or death from the diagnosis of BMs, PFS was the time of progression of any site or death from the diagnosis of BMs, and OS was the time of confirmed BMs to death or the last follow-up time. Differences in characteristics between groups were compared using the Chi-square test. The Kaplan-Meier method was used to calculate the iPFS, PFS, and OS. Univariate analysis, multivariate analysis, and subgroup analysis were conducted by Cox regression model.

Results: There were 77 patients (77/134, 57.5%) in the TKI + RT group and 57 patients (57/134, 42.5%) in the TKI group. TKI + RT group had a significant higher intracranial ORR and DCR, and the combination therapy was independently significantly associated with a longer iPFS (18.9 10.5 months, = 0.0009), systematic PFS (12.5 8.4 months, = 0.0071) and OS (30.8 . 22.7 months, = 0.0183). Females, non-smokers, and younger patients benefited more from the combination therapy. Subgroup analysis demonstrated that the combination therapy could improve the iPFS in patients with more than 3 BMs ( = 0.005); however, it couldn't improve the OS for these patients.

Conclusion: Our study confirmed the effect of the combination of EGFR-TKI and brain radiotherapy as first-line treatment for LUAD patients with BMs and EGFR sensitive mutations.
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http://dx.doi.org/10.1177/1533033821997819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958186PMC
March 2021

Differences in the gut microbiomes of dogs and wolves: roles of antibiotics and starch.

BMC Vet Res 2021 Mar 6;17(1):112. Epub 2021 Mar 6.

Institute of Pet Sciences, College of Animal Science and Veterinary Medicine, Shenyang Agricultural University, Shenyang, China.

Background: Dogs are domesticated wolves. Change of living environment, such as diet and veterinary care may affect the gut bacterial flora of dogs. The aim of this study was to assess the gut bacterial diversity and function in dogs compared with captive wolves. We surveyed the gut bacterial diversity of 27 domestic dogs, which were fed commercial dog food, and 31 wolves, which were fed uncooked meat, by 16S rRNA sequencing. In addition, we collected fecal samples from 5 dogs and 5 wolves for shotgun metagenomic sequencing to explore changes in the functions of their gut microbiome.

Results: Differences in the abundance of core bacterial genera were observed between dogs and wolves. Together with shotgun metagenomics, the gut microbiome of dogs was found to be enriched in bacteria resistant to clinical drugs (P < 0.001), while wolves were enriched in bacteria resistant to antibiotics used in livestock (P < 0.001). In addition, a higher abundance of putative α-amylase genes (P < 0.05; P < 0.01) was observed in the dog samples.

Conclusions: Living environment of dogs and domestic wolves has led to increased numbers of bacteria with antibiotic resistance genes, with exposure to antibiotics through direct and indirect methods. In addition, the living environment of dogs has allowed the adaptation of their microbiota to a starch-rich diet. These observations align with a domestic lifestyle for domestic dogs and captive wolves, which might have consequences for public health.
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http://dx.doi.org/10.1186/s12917-021-02815-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937242PMC
March 2021

ZmSPL10/14/26 are required for epidermal hair cell fate specification on maize leaf.

New Phytol 2021 05 24;230(4):1533-1549. Epub 2021 Mar 24.

State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, South China Agricultural University, Guangzhou, 510642, China.

The epidermal hair and stomata are two types of specialized structures on the surface of plant leaves. On mature maize leaves, stomatal complexes and three types of hairs are distributed in a stereotyped pattern on the adaxial epidermis. However, the spatiotemporal relationship between epidermal hair and stomata development and the regulatory mechanisms governing their formation in maize remain largely unknown. Here, we report that three homologous ZmSPL transcription factors, ZmSPL10, ZmSPL14 and ZmSPL26, act in concert to promote epidermal hair fate on maize leaf. Cytological analyses revealed that Zmspl10/14/26 triple mutants are completely glabrous, but possess ectopic stomatal files. Strikingly, the precursor cells for prickle and bicellular hairs are transdifferentiated into ectopic stomatal complexes in the Zmspl10/14/26 mutants. Molecular analyses demonstrated that ZmSPL10/14/26 bind directly to the promoter of a WUSCHEL-related homeobox gene, ZmWOX3A, and upregulate its expression in the hair precursor cells. Moreover, several auxin-related genes are downregulated in the Zmspl10/14/26 triple mutants. Our results suggest that ZmSPL10/14/26 play a key role in promoting epidermal hair fate on maize leaves, possibly through regulating ZmWOX3A and auxin-related gene expression, and that the fates of epidermal hairs and stomata are switchable.
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http://dx.doi.org/10.1111/nph.17293DOI Listing
May 2021

Spatial Analysis and Clinical Significance of HLA Class-I and Class-II Subunit Expression in Non-Small Cell Lung Cancer.

Clin Cancer Res 2021 May 18;27(10):2837-2847. Epub 2021 Feb 18.

Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.

Purpose: To analyze the distribution, associated immune contexture, and clinical significance of human leukocyte antigen (HLA) class-I and HLA class-II subunits in non-small cell lung cancer (NSCLC).

Experimental Design: Using spatially resolved and quantitative multiplexed immunofluorescence we studied the tumor/stromal tissue distribution, cancer cell-specific defects, and clinicopathologic/survival associations of β2 microglobulin (β2M), HLA-A, and HLA-B,-C heavy chains, as well as HLA class-II β chain in >700 immunotherapy-naïve NSCLCs from four independent cohorts. Genomic analysis of HLA genes in NSCLC was performed using two publicly available cohorts.

Results: Cancer cell-specific downregulation of HLA markers was identified in 30.4% of cases. β2M was downregulated in 9.8% (70/714), HLA-A in 9% (65/722), HLA-B,-C in 12.1% (87/719), and HLA class-II in 17.7% (127/717) of evaluable samples. Concurrent downregulation of β2M, HLA-B,-C, and HLA class-II was commonly identified. Deleterious mutations in HLA genes were detected in <5% of lung malignancies. Tumors with cancer cell-specific β2M downregulation displayed reduced T cells and increased natural killer (NK)-cell infiltration. Samples with cancer cell HLA-A downregulation displayed modest increase in CD8 T cells and NK-cell infiltration. Samples with cancer cell-selective HLA-B,-C or HLA class-II downregulation displayed reduced T cells and NK-cell infiltration. There was limited association of the markers with clinicopathologic variables and KRAS/EGFR mutations. Cancer cell-selective downregulation of the HLA subunits was associated with shorter overall survival.

Conclusions: Our results reveal frequent and differential defects in HLA class-I and HLA class-II protein subunit expression in immunotherapy-naïve NSCLCs associated with distinct tumor microenvironment composition and patient survival.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3655DOI Listing
May 2021

Time-course observation of the reconstruction of stem cell niche in the intact root.

Plant Physiol 2021 Apr;185(4):1652-1665

College of Life Sciences, College of Horticulture, Fujian Agriculture and Forestry University, Fuzhou 350002, China.

The stem cell niche (SCN) is critical in maintaining continuous postembryonic growth of the plant root. During their growth in soil, plant roots are often challenged by various biotic or abiotic stresses, resulting in damage to the SCN. This can be repaired by the reconstruction of a functional SCN. Previous studies examining the SCN's reconstruction often introduce physical damage including laser ablation or surgical excision. In this study, we performed a time-course observation of the SCN reconstruction in pWOX5:icals3m roots, an inducible system that causes non-invasive SCN differentiation upon induction of estradiol on Arabidopsis (Arabidopsis thaliana) root. We found a stage-dependent reconstruction of SCN in pWOX5:icals3m roots, with division-driven anatomic reorganization in the early stage of the SCN recovery, and cell fate specification of new SCN in later stages. During the recovery of the SCN, the local accumulation of auxin was coincident with the cell division pattern, exhibiting a spatial shift in the root tip. In the early stage, division mostly occurred in the neighboring stele to the SCN position, while division in endodermal layers seemed to contribute more in the later stages, when the SCN was specified. The precise re-positioning of SCN seemed to be determined by mutual antagonism between auxin and cytokinin, a conserved mechanism that also regulates damage-induced root regeneration. Our results thus provide time-course information about the reconstruction of SCN in intact Arabidopsis roots, which highlights the stage-dependent re-patterning in response to differentiated quiescent center.
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http://dx.doi.org/10.1093/plphys/kiab006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133607PMC
April 2021

A Robust PtNi Nanoframe/N-Doped Graphene Aerogel Electrocatalyst with Both High Activity and Stability.

Angew Chem Int Ed Engl 2021 Apr 17;60(17):9590-9597. Epub 2021 Mar 17.

The Key Laboratory of Low-Carbon Chemistry & Energy Conservation of Guangdong Province, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, State Key Laboratory of Optoelectronic Materials and Technologies, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, 510275, P. R. China.

Insufficient catalytic activity and stability and high cost are the barriers for Pt-based electrocatalysts in wide practical applications. Herein, a hierarchically porous PtNi nanoframe/N-doped graphene aerogel (PtNiNF-NGA) electrocatalyst with outstanding performance toward methanol oxidation reaction (MOR) in acid electrolyte has been developed via facile tert-butanol-assisted structure reconfiguration. The ensemble of high-alloying-degree-modulated electronic structure and correspondingly the optimum MOR reaction pathway, the structure superiorities of hierarchical porosity, thin edges, Pt-rich corners, and the anchoring effect of the NGA, endow the PtNiNF-NGA with both prominent electrocatalytic activity and stability. The mass and specific activity (1647 mA mg , 3.8 mA cm ) of the PtNiNF-NGA are 5.8 and 7.8 times higher than those of commercial Pt/C. It exhibits exceptional stability under a 5-hour chronoamperometry test and 2200-cycle cyclic voltammetry scanning.
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http://dx.doi.org/10.1002/anie.202015679DOI Listing
April 2021

Molecular simulation of zwitterionic polypeptides on protecting glucagon-like peptide-1 (GLP-1).

Int J Biol Macromol 2021 Mar 1;174:519-526. Epub 2021 Feb 1.

Shenzhen Key Laboratory of Environmental Chemistry and Ecological Remediation, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, Guangdong 518060, China. Electronic address:

Owing to their anti-fouling properties, zwitterionic polypeptides demonstrate great advantage on protecting protein drugs. When conjugated to glucagon-like peptide-1 (GLP-1), a drug for type-II diabetes, zwitterionic polypeptides confer better pharmacokinetics than uncharged counterparts. However, its microscopic mechanism is still unclear due to the complicated conformational space. To address this challenge, this work explored the interaction modes of GLP-1 with the unconnected repeat units, instead of the full-length polypeptides. The three repeat units are two zwitterionic pentapeptides VPKEG and VPREG, and one uncharged control VPGAG. Our molecular simulations revealed that the helical conformation of GLP-1 was stabilized by adding 40 polypeptides. Both VPGAG and VPREG formed dense packing shells around GLP-1, but the driving forces were hydrophobic and electrostatic interactions, respectively. In contrast, the packing shell composed of VPKEG was most loose, while could still stabilize GLP-1. The moderate electrostatic interactions endowed VPKEG an anti-fouling property, thereby avoiding non-specific interaction with other amino acids. The strong electrostatic interactions exerted by arginine promoted atomic contacts between VPREG and other residues, making it as "hydrophobic" as VPGAG. In summary, the combination of hydrophobic and moderate electrostatic interactions in VPKEG brings about a subtle balance between stabilizing GLP-1 and avoiding non-specific interaction.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.01.207DOI Listing
March 2021

Changes of Structural Brain Network Following Repetitive Transcranial Magnetic Stimulation in Children With Bilateral Spastic Cerebral Palsy: A Diffusion Tensor Imaging Study.

Front Pediatr 2020 15;8:617548. Epub 2021 Jan 15.

Department of Rehabilitation, Children's Hospital of Nanjing Medical University, Nanjing, China.

Bilateral spastic cerebral palsy (BSCP) is the most common subtype of cerebral palsy (CP), which is characterized by various motor and cognitive impairments, as well as emotional instability. However, the neural basis of these problems and how repetitive transcranial magnetic stimulation (rTMS) can make potential impacts on the disrupted structural brain network in BSCP remain unclear. This study was aimed to explore the topological characteristics of the structural brain network in BSCP following the treatment of rTMS. Fourteen children with BSCP underwent 4 weeks of TMS and 15 matched healthy children (HC) were enrolled. Diffusion tensor imaging (DTI) data were acquired from children with bilateral spastic cerebral palsy before treatment (CP1), children with bilateral spastic cerebral palsy following treatment (CP2) and HC. The graph theory analysis was applied to construct the structural brain network. Then nodal clustering coefficient ( ) and shortest path length ( ) were measured and compared among groups. Brain regions with significant group differences in were located in the left precental gyrus, middle frontal gyrus, calcarine fissure, cuneus, lingual gyrus, postcentral gyrus, inferior parietal gyri, angular gyrus, precuneus, paracentral lobule and the right inferior frontal gyrus (triangular part), insula, posterior cingulate gyrus, precuneus, paracentral lobule, pallidum. In addition, significant differences were detected in the of the left precental gyrus, lingual gyrus, superior occipital gyrus, middle occipital gyrus, superior parietal gyrus, precuneus and the right median cingulate gyrus, posterior cingulate gyrus, hippocampus, putamen, thalamus. -test revealed that the CP2 group exhibited increased in the right inferior frontal gyrus, pallidum and decreased in the right putamen, thalamus when compared with the CP1 group. Significant differences of node-level metrics were found in various brain regions of BSCP, which indicated a disruption in structural brain connectivity in BSCP. The alterations of the structural brain network provided a basis for understanding of the pathophysiological mechanisms of motor and cognitive impairments in BSCP. Moreover, the right inferior frontal gyrus, putamen, thalamus could potentially be biomarkers for predicting the efficacy of TMS.
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http://dx.doi.org/10.3389/fped.2020.617548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844328PMC
January 2021

Circular RNA hsa_circ_0004277 Stimulates Malignant Phenotype of Hepatocellular Carcinoma and Epithelial-Mesenchymal Transition of Peripheral Cells.

Front Cell Dev Biol 2020 12;8:585565. Epub 2021 Jan 12.

Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China.

Accumulating evidence shows that exosomal circRNAs reflect the physiological status of donor cells, and various cell reactions are induced after exosomal circRNAs are captured by recipient cells. In this study, qRT-PCR was performed to detect circ-0004277 expression in hepatocellular carcinoma (HCC) cell lines, tissues, and plasma exosomes. The effects of circ-0004277 on the proliferation and migration of HCC cells were assessed by cell counting, 5-ethynyl-2'-deoxyuridine assays, Transwell migration assays, and tumor formation in nude mice. We found that circ-0004277 was significantly upregulated in HCC cells, tissues, and plasma exosomes compared to that in normal controls. Overexpression of circ-0004277 enhanced the proliferation, migration, and epithelial-mesenchymal transition (EMT) of HCC cells and . Furthermore, exosomes from HCC cells enhanced circ-0004277 expression in surrounding normal cells and stimulated EMT progression. ZO-1, a tight junction adapter protein, was downregulated in HCC tissues. In conclusion, our findings suggest that circ-0004277 promotes the malignant phenotype of HCC cells via inhibition of and promotion of EMT progression. In addition, exosomal circ-0004277 from HCC cells stimulates EMT of peripheral cells through cellular communication to further promote the invasion of HCC into normal surrounding tissues.
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http://dx.doi.org/10.3389/fcell.2020.585565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835424PMC
January 2021
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