bluuebunny/crossref_metadata_2025_split huggingface dataset:
USP49 participates in the DNA damage response by forming a positive feedback loop with p53
Authors: Tu Rongfu , Kang Wenqian , Yang Xuefei , Zhang Qi , Xie Xiaoyu , Liu Wenbin , Zhang Jinxiang , Zhang Xiao-Dong , Wang Hui , Du Run-Lei 
Published: May 2018

AbstractThe p53 tumor suppressor is a critical factor in the DNA damage response (DDR), and regulation of p53 stability has a key role in this process. In our study, we identified USP49 as a novel deubiquitinase (DUB) for p53 from a library consisting of 80 DUBs and found that USP49 has a positive effect on p53 transcriptional activity and protein stability. Investigation of the mechanism revealed that USP49 interacts with the N terminus of p53 and suppresses several types of p53 ubiquitination. Furthermore, USP49 rendered HCT116 cells more sensitive to etoposide (Eto)-induced DNA damage and was upregulated in response to several types of cell stress, including DNA damage. Remarkably, USP49 expression was regulated by p53 and USP49 in knockout mice, which are more susceptible to azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colon tumors. These findings suggest that USP49 has an important role in DDR and may act as a potential tumor suppressor by forming a positive feedback loop with p53.
p53 attenuates acetaminophen-induced hepatotoxicity by regulating drug-metabolizing enzymes and transporter expression
Authors: Sun Jiahong , Wen Yajie , Zhou Yanying , Jiang Yiming , Chen Yixin , Zhang Huizheng , Guan Lihuan , Yao Xinpeng , Huang Min , Bi Huichang 
Published: May 2018

AbstractAcetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Inhibition of APAP metabolic activation and promotion in APAP disposition are important to protect against APAP-induced liver injury. Tumor suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have emerged on discovering its functions in metabolic regulation. Our previous study reported that p53 promoted bile acid disposition and alleviated cholestastic syndrome. Here, we examined the effect of doxorubicin (Dox)-mediated p53 activation on APAP-induced hepatotoxicity in mice and revealed a novel role of p53 in regulating APAP metabolism and disposition. Histopathological and biochemical assessments demonstrated that administration of Dox (10 mg/kg/d) before APAP treatment (400 mg/kg) significantly alleviated APAP-induced hepatotoxicity. Dox treatment prevented APAP-induced GSH depletion and lipid peroxidation. p53-null mice were more susceptible to APAP-induced liver injury. Further, we found that the expression of drug-metabolizing enzymes and transporters CYPs, SULTs and MRPs was regulated by p53. Dox treatment also promoted Nrf2 activation and increased the expression of Nrf2 target genes including GSTα/μ and NQO1, which contribute to APAP detoxification. Overall, this study is the first to demonstrate the protective role of p53 in regulating APAP metabolism and disposition, which provides a potential new therapeutic target for APAP-induced liver injury.
Reducing protein regulator of cytokinesis 1 as a prospective therapy for hepatocellular carcinoma
Authors: Liu Xinran , Li Yangkai , Meng Lijing , Liu Xin-Yuan , Peng Anlin , Chen Yuchen , Liu Chengyu , Chen Hong , Sun Sheng , Miao Xiaoping , Zhang Yu , Zheng Ling , Huang Kun 
Published: May 2018

AbstractProteins that bind to microtubule are important for cell cycle, and some of these proteins show oncogenic characteristics with mechanisms not fully understood. Herein we demonstrate overexpression of protein regulator of cytokinesis 1 (PRC1), a microtubule-associated regulator of mitosis, in human hepatocellular carcinoma (HCC). Moreover, upregulated PRC1 is associated with lower survival rates of HCC patients. Mechanistically, reducing PRC1 blocks mitotic exit of HCC cells at telophase in a spindle assembly checkpoint independent manner, and acts synergistically with microtubule-associated agents (MTAs) to suppress p53-wt or p53-null HCC cells in a p53- or p14ARF-dependent manner; while overexpressing PRC1 increases the resistance of HCC to taxol. A combined treatment of taxol/shPRC1 results in 90% suppression of tumor growth in subcutaneous HCC xenograft models. In orthotopic xenograft mice, reducing PRC1 significantly alleviates HCC development and hepatic injury. Together, our results suggest a dual-mitotic suppression approach against HCC by combining MTAs with cytokinesis inhibition, which blocks mitosis at both metaphase and telophase.
Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation
Authors: Yang Fan , Wu Rongrong , Jiang Zhi , Chen Jinghai , Nan Jinliang , Su Sheng’an , Zhang Na , Wang Chen , Zhao Jing , Ni Cheng , Wang Yingchao , Hu Wangxing , Zeng Zhiru , Zhu Keyang , Liu Xianbao , Hu Xinyang , Zhu Wei , Yu Hong , Huang Jinyu , Wang Jian’an 
Published: May 2018

AbstractAccumulating evidence revealed that mesenchymal stem cells (MSCs) confer cardioprotection against myocardial infarction (MI). However, the poor survival and engraftment rate of the transplanted cells limited their therapeutic efficacy in the heart. The enhanced leptin production associated with hypoxia preconditioning contributed to the improved MSCs survival. Mitochondrial integrity determines the cellular fate. Thus, we aimed to investigate whether leptin can enhance mitochondrial integrity of human MSCs (hMSCs) to protect against various stress. In vivo, transplantation of leptin-overexpressing hMSCs into the infarcted heart resulted in improved cell viability, leading to enhanced angiogenesis and cardiac function. In vitro, pretreatment of hMSCs with recombinant leptin (hMSCs-Leppre) displayed improved cell survival against severe ischemic condition (glucose and serum deprivation under hypoxia), which was associated with increased mitochondrial fusion. Subsequently, Optic atrophy 1 (OPA1), a mitochondrial inner membrane protein that regulates fusion and cristae structure, was significantly elevated in the hMSCs-Leppre group, and the protection of leptin was abrogated by targeting OPA1 with a selective siRNA. Furthermore, OMA1, a mitochondrial protease that cleaves OPA1, decreased in a leptin-dependent manner. Pretreatment of cells with an inhibitor of the proteasome (MG132), prevented leptin-induced OMA1 degradation, implicating the ubiquitination/proteasome system as a part of the protective leptin pathway. In addition, GSK3 inhibitor (SB216763) was also involved in the degradation of OMA1. In conclusion, in the hostile microenvironment caused by MI, (a) leptin can maintain the mitochondrial integrity and prolong the survival of hMSCs; (b) leptin-mediated mitochondrial integrity requires phosphorylation of GSK3 as a prerequisite for ubiquitination-depended degradation of OMA1 and attenuation of long-OPA1 cleavage. Thus, leptin targeting the GSK3/OMA1/OPA1 signaling pathway can optimize hMSCs therapy for cardiovascular diseases such as MI.
Targeting circular RNA-ZRANB1 for therapeutic intervention in retinal neurodegeneration
Authors: Wang Jia-Jian , Shan Kun , Liu Bai-Hui , Liu Chang , Zhou Rong-Mei , Li Xiu-Miao , Dong Rui , Zhang Shu-Jie , Zhang Sheng-Hai , Wu Ji-Hong , Yan Biao 
Published: May 2018

AbstractGlaucoma is a neurodegenerative disease characterized by retinal ganglion cell (RGC) loss, optic disc excavation, and progressive visual field loss. Direct or indirect ameliorating retinal neurodegeneration is a promising therapeutic therapy for glaucoma. Circular RNAs (circRNAs) are a class of covalently closed circular RNA transcripts and have emerged as potential regulators in several neurodegenerative diseases. In this study, we show that cZRANB1 expression is significantly upregulated in retinal neurodegeneration induced by glaucoma. cZRANB1 knockdown decreases retinal reactive gliosis, glial cell activation, and facilitates RGC survival in vivo. cZRANB1 knockdown directly regulates Müller cell function and indirectly regulates RGC function in vitro. cZRANB1 acts as miRNA sponge to regulate Müller cell function through cZRANB1/miR-217/RUNX2 network. Intervention of cZRANB1 expression would become an effective strategy for treating retinal neurodegeneration.
RXRα provokes tumor suppression through p53/p21/p16 and PI3K-AKT signaling pathways during stem cell differentiation and in cancer cells
Authors: Zhang Rui , Li Hui , Zhang Shuangshuang , Zhang Yujie , Wang Nan , Zhou Hao , He Hongpeng , Hu Guang , Zhang Tong-Cun , Ma Wenjian 
Published: May 2018

Abstract
The retinoid X receptor alpha (RXRα) is an important therapeutic target impacting diverse biological processes. Activation of RXRα is known to suppress cancer cell growth. However, the cellular mechanism has been elusive. In the present study, we addressed its role during stem cell differentiation and the underlying connections with carcinogenesis. RXRα was significantly upregulated following the differentiation of human mesenchymal stem cell (hMSC) toward the formation of endothelial cell (EC). However, overexpression of RXRα in hMSC provoked a senescence-like phenotype accompanied by the elevation of tumor suppressor p53, p21, and p16. Consistently, RXRα level was suppressed in cancer cells (~five times lower compared to differentiated hMSC), and its elevation could inhibit the proliferation, migration, and angiogenesis of cancer cells. We further demonstrated that these inhibitory effects were related to RXRα’s interaction with estrogen receptor α (ERα) as well as EGF and ANGPTL3 through modulating PI3K/AKT signaling pathway by AKT and FAK phosphorylation. Moreover, RXRα inhibited glycolytic metabolism in cancer cells, which might be underlying its inhibition of differentiation and carcinogenic features. These data suggest that RXRα acts as a suppressor rather than a driving force during stem cell differentiation, and unbalanced RXRα can trigger multiple yet connected signaling pathways in preventing carcinogenesis.
NVP-BEZ235, a dual PI3K-mTOR inhibitor, suppresses the growth of FaDu hypopharyngeal squamous cell carcinoma and has a synergistic effect with Cisplatin
Authors: Hsu Cheng-Ming , Lin Pai-Mei , Tsai Yao-Te , Tsai Ming-Shao , Tseng Chun-Han , Lin Sheng-Fung , Yang Ming-Yu 
Published: May 2018

AbstractNVP-BEZ235 is a dual phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor. A dual approach targeting more than one downstream effector is a promising strategy for treating cancers. The aim of this study was to evaluate the effect of NVP-BEZ235 in treating FaDu hypopharyngeal squamous cell carcinoma (HSCC), either alone or in combination with cisplatin. We found mTOR expression was higher in patients with HSCC. In the in vitro study, treatment with NVP-BEZ235 alone attenuated cell proliferation and suppressed p-p70S6K and p-4E-BP1 expression in FaDu cells. When NVP-BEZ235 was combined with Cisplatin, apoptosis was induced more effectively than with either drug alone. In mice with a FaDu xenograft, cotreatment with NVP-BEZ235 and Cisplatin engendered synergistic effects and produced a greater antitumor response than did treatment with either drug alone. Resected tumor samples also showed decreased p-p70S6K expression. Collectively, these data demonstrate that NVP-BEZ235 inhibits HSCC growth through phospho-p70S6K suppression and has a synergistic effect with Cisplatin in treating HSCC. The data also provide a strategy for more effective HSCC treatment.
In vitro DNA SCRaMbLE
Authors: Wu Yi , Zhu Rui-Ying , Mitchell Leslie A. , Ma Lu , Liu Rui , Zhao Meng , Jia Bin , Xu Hui , Li Yun-Xiang , Yang Zu-Ming , Ma Yuan , Li Xia , Liu Hong , Liu Duo , Xiao Wen-Hai , Zhou Xiao , Li Bing-Zhi , Yuan Ying-Jin , Boeke Jef D. 
Published: May 2018

AbstractThe power of synthetic biology has enabled the expression of heterologous pathways in cells, as well as genome-scale synthesis projects. The complexity of biological networks makes rational de novo design a grand challenge. Introducing features that confer genetic flexibility is a powerful strategy for downstream engineering. Here we develop an in vitro method of DNA library construction based on structural variation to accomplish this goal. The “in vitro SCRaMbLE system” uses Cre recombinase mixed in a test tube with purified DNA encoding multiple loxPsym sites. Using a β-carotene pathway designed for expression in yeast as an example, we demonstrate top-down and bottom-up in vitro SCRaMbLE, enabling optimization of biosynthetic pathway flux via the rearrangement of relevant transcription units. We show that our system provides a straightforward way to correlate phenotype and genotype and is potentially amenable to biochemical optimization in ways that the in vivo system cannot achieve.
Author Correction: Fermiology and electron dynamics of trilayer nickelate La4Ni3O10
Authors: Li Haoxiang , Zhou Xiaoqing , Nummy Thomas , Zhang Junjie , Pardo Victor , Pickett Warren E. , Mitchell J. F. , Dessau D. S. 
Published: May 2018

The original version of this Article contained errors in Fig. 2, Fig. 3a–c and Supplementary Fig. 2. In Fig. 2g and Supplementary Fig. 2, the band structure plot calculated from density function theory (DFT) had a missing band of mainly z2 character that starts at about – 0.25 eV at the Y point and disperses downwards towards the Γ point. This band was inadvertently neglected when transferring the lines from the original band plot to the enhanced version for publication. Also in Fig. 2g, the points labelled M and Y were not exactly at (1/2 1/2 0) and (0 1/2 0), but rather (0.52 0.48 0) and (0 0.48 0) due to a bug in XCrysDen for low-symmetry structures that the authors failed to identify before publication. Thus, the bands presented were slightly off the true M–Y direction and additional splitting incorrectly appeared (in particular for the highly dispersive bands of x2–y2 character). The correct versions of Fig. 2g (cited as Fig. 1) and Supplementary Fig. 2 (cited as Fig. 2) are:which replaces the previous incorrect version, cited here as Fig. 3 and Fig. 4:Neither of these errors in Fig. 2g or Supplementary Fig. 2 affects either the discussion or any of the interpretations of the ARPES data provided in the paper. The authors discussed the multilayer band splitting along the Γ–M direction (δ band and α band as assigned in the paper), and ARPES did not see any split band. The authors did not discuss the further splitting that arises due to back folding along the M–Y direction.In Fig. 3a–c, the errors in the M and Y points in Fig. 2g cause subtle changes to the DFT dispersions. The correct version of Fig. 3a–c is cited here as Fig 5:which replaces the previous incorrect version (Fig. 6):However, the influence on the effective mass results of Fig. 3d is negligible.These errors have now been corrected in both the PDF and HTML versions of the Article. The authors acknowledge James Rondinelli and Danilo Puggioni from Northwestern University for calling our attention to these issues.
A joint view on genetic variants for adiposity differentiates subtypes with distinct metabolic implications
Authors: Winkler Thomas W , Günther Felix , Höllerer Simon , Zimmermann Martina , Loos Ruth JF , Kutalik Zoltán , Heid Iris M 
Published: May 2018

AbstractThe problem of the genetics of related phenotypes is often addressed by analyzing adjusted-model traits, but such traits warrant cautious interpretation. Here, we adopt a joint view of adiposity traits in ~322,154 subjects (GIANT consortium). We classify 159 signals associated with body mass index (BMI), waist-to-hip ratio (WHR), or WHR adjusted for BMI (WHRadjBMI) at P < 5 × 10−8, into four classes based on the direction of their effects on BMI and WHR. Our classes help differentiate adiposity genetics with respect to anthropometry, fat depots, and metabolic health. Class-specific Mendelian randomization reveals that variants associated with both WHR-decrease and BMI increase are linked to metabolically rather favorable adiposity through beneficial hip fat. Class-specific enrichment analyses implicate digestive systems as a pathway in adiposity genetics. Our results demonstrate that WHRadjBMI variants capture relevant effects of “unexpected fat distribution given the BMI” and that a joint view of the genetics underlying related phenotypes can inform on important biology.
Hollow organic capsules assemble into cellular semiconductors
Authors: Zhang Boyuan , Hernández Sánchez Raúl , Zhong Yu , Ball Melissa , Terban Maxwell W. , Paley Daniel , Billinge Simon J. L. , Ng Fay , Steigerwald Michael L. , Nuckolls Colin 
Published: May 2018

AbstractSelf-assembly of electroactive molecules is a promising route to new types of functional semiconductors. Here we report a capsule-shaped molecule that assembles itself into a cellular semiconducting material. The interior space of the capsule with a volume of ~415 Å3 is a nanoenvironment that can accommodate a guest. To self-assemble these capsules into electronic materials, we functionalize the thiophene rings with bromines, which encode self-assembly into two-dimensional layers held together through halogen bonding interactions. In the solid state and in films, these two-dimensional layers assemble into the three-dimensional crystalline structure. This hollow material is able to form the active layer in field effect transistor devices. We find that the current of these devices has strong response to the guest’s interaction within the hollow spaces in the film. These devices are remarkable in their ability to distinguish, through their electrical response, between small differences in the guest.
A multistage rotational speed changing molecular rotor regulated by pH and metal cations
Authors: Wu Yingying , Wang Guangxia , Li Qiaolian , Xiang Junfeng , Jiang Hua , Wang Ying 
Published: May 2018

AbstractDespite having significant applications in building nanomachines, molecular rotors with the rotational speed modulations to multiple stages in a wide range of frequency have not yet been well established. Here, we report the discovery of a stimuli-responsive molecular rotor, the rotational speed of which in the slow-to-fast range could be modulated to at least four stages triggered by acid/base and metal cations. The rotor itself rotates rapidly at ambient or elevated temperature but displays a restricted rotation after deprotonation due to the produced intramolecular electrostatic repulsion. Subsequent addition of Li+ or Na+ cations introduces an electrostatic bridge to stabilize the transition state of the deprotonated rotor, thus giving a cation-radius-dependent acceleration of the rotation to render the rotor running at a mid-speed. All the stimuli are highly reversible. Our studies provide a conceptual approach for constructing multistage rotational-speed-changing molecular rotors, and further, the practical nanomachines.
Organic matter loading by hippopotami causes subsidy overload resulting in downstream hypoxia and fish kills
Authors: Dutton Christopher L. , Subalusky Amanda L. , Hamilton Stephen K. , Rosi Emma J. , Post David M. 
Published: May 2018

AbstractOrganic matter and nutrient loading into aquatic ecosystems affects ecosystem structure and function and can result in eutrophication and hypoxia. Hypoxia is often attributed to anthropogenic pollution and is not common in unpolluted rivers. Here we show that organic matter loading from hippopotami causes the repeated occurrence of hypoxia in the Mara River, East Africa. We documented 49 high flow events over 3 years that caused dissolved oxygen decreases, including 13 events resulting in hypoxia, and 9 fish kills over 5 years. Evidence from experiments and modeling demonstrates a strong mechanistic link between the flushing of hippo pools and decreased dissolved oxygen in the river. This phenomenon may have been more widespread throughout Africa before hippopotamus populations were severely reduced. Frequent hypoxia may be a natural part of tropical river ecosystem function, particularly in rivers impacted by large wildlife.
A cell-penetrating artificial metalloenzyme regulates a gene switch in a designer mammalian cell
Authors: Okamoto Yasunori , Kojima Ryosuke , Schwizer Fabian , Bartolami Eline , Heinisch Tillmann , Matile Stefan , Fussenegger Martin , Ward Thomas R. 
Published: May 2018

AbstractComplementing enzymes in their native environment with either homogeneous or heterogeneous catalysts is challenging due to the sea of functionalities present within a cell. To supplement these efforts, artificial metalloenzymes are drawing attention as they combine attractive features of both homogeneous catalysts and enzymes. Herein we show that such hybrid catalysts consisting of a metal cofactor, a cell-penetrating module, and a protein scaffold are taken up into HEK-293T cells where they catalyze the uncaging of a hormone. This bioorthogonal reaction causes the upregulation of a gene circuit, which in turn leads to the expression of a nanoluc-luciferase. Relying on the biotin–streptavidin technology, variation of the biotinylated ruthenium complex: the biotinylated cell-penetrating poly(disulfide) ratio can be combined with point mutations on streptavidin to optimize the catalytic uncaging of an allyl-carbamate-protected thyroid hormone triiodothyronine. These results demonstrate that artificial metalloenzymes offer highly modular tools to perform bioorthogonal catalysis in live HEK cells.
A Five-microRNA Signature for Survival Prognosis in Pancreatic Adenocarcinoma based on TCGA Data
Authors: Shi Xiu-Hui , Li Xu , Zhang Hang , He Rui-Zhi , Zhao Yan , Zhou Min , Pan Shu-Tao , Zhao Chun-Le , Feng Ye-Chen , Wang Min , Guo Xing-Jun , Qin Ren-Yi 
Published: May 2018

AbstractNovel biomarkers for pancreatic adenocarcinoma are urgently needed because of its poor prognosis. Here, by using The Cancer Genome Atlas (TCGA) RNA-seq data, we evaluated the prognostic values of the differentially expressed miRNAs and constructed a five-miRNA signature that could effectively predict patient overall survival (OS). The Kaplan-Meier overall survival curves of two groups based on the five miRNAs were notably different, showing overall survival in 10.2% and 47.8% at five years for patients in high-risk and low-risk groups, respectively. The ROC curve analysis achieved AUC of 0.775, showing good sensitivity and specificity of the five-miRNA signature model in predicting pancreatic adenocarcinoma patient survival risk. The functional enrichment analysis suggested that the target genes of the miRNA signature may be involved in various pathways related to cancer, including PI3K-Akt, TGF-β, and pluripotent stem cell signaling pathways. Finally, we analyzed expression of the five specific miRNAs in the miRNA signature, and validated the reliability of the results in 20 newly diagnosed pancreatic adenocarcinoma patients using qRT-PCR. The expression results of qRT-PCR were consistent with the TCGA results. Taken together, these findings suggested that the five-miRNA signature (hsa-miR-203, hsa-miR-424, hsa-miR-1266 hsa-miR-1293, and hsa-miR-4772) could be used as a prognostic marker for pancreatic adenocarcinoma.