bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative analyses shed new light on human ribosomal protein gene regulation
Authors: Li Xin , Zheng Yiyu , Hu Haiyan , Li Xiaoman 
Published: June 2016

AbstractRibosomal protein genes (RPGs) are important house-keeping genes that are well-known for their coordinated expression. Previous studies on RPGs are largely limited to their promoter regions. Recent high-throughput studies provide an unprecedented opportunity to study how human RPGs are transcriptionally modulated and how such transcriptional regulation may contribute to the coordinate gene expression in various tissues and cell types. By analyzing the DNase I hypersensitive sites under 349 experimental conditions, we predicted 217 RPG regulatory regions in the human genome. More than 86.6% of these computationally predicted regulatory regions were partially corroborated by independent experimental measurements. Motif analyses on these predicted regulatory regions identified 31 DNA motifs, including 57.1% of experimentally validated motifs in literature that regulate RPGs. Interestingly, we observed that the majority of the predicted motifs were shared by the predicted distal and proximal regulatory regions of the same RPGs, a likely general mechanism for enhancer-promoter interactions. We also found that RPGs may be differently regulated in different cells, indicating that condition-specific RPG regulatory regions still need to be discovered and investigated. Our study advances the understanding of how RPGs are coordinately modulated, which sheds light to the general principles of gene transcriptional regulation in mammals.
Negative reciprocal regulation between Sirt1 and Per2 modulates the circadian clock and aging
Authors: Wang Rui-Hong , Zhao Tingrui , Cui Kairong , Hu Gangqing , Chen Qiang , Chen Weiping , Wang Xin-Wei , Soto-Gutierrez Alejandro , Zhao Keji , Deng Chu-Xia 
Published: June 2016

AbstractSirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. Using Sirt1-deficient mice, we found that Sirt1 and Period 2 (Per2) constitute a reciprocal negative regulation loop that plays important roles in modulating hepatic circadian rhythmicity and aging. Sirt1-deficient mice exhibited profound premature aging and enhanced acetylation of histone H4 on lysine16 (H4K16) in the promoter of Per2, the latter of which leads to its overexpression; in turn, Per2 suppresses Sirt1 transcription through binding to the Sirt1 promoter at the Clock/Bmal1 site. This negative reciprocal relationship between SIRT1 and PER2 was also observed in human hepatocytes. We further demonstrated that the absence of Sirt1 or the ectopic overexpression of Per2 in the liver resulted in a dysregulated pace of the circadian rhythm. The similar circadian rhythm was also observed in aged wild type mice. The interplay between Sirt1 and Per2 modulates aging gene expression and circadian-clock maintenance.
Stress-induced nuclear translocation of CDK5 suppresses neuronal death by downregulating ERK activation via VRK3 phosphorylation
Authors: Song Haengjin , Kim Wanil , Choi Jung-Hyun , Kim Sung-Hoon , Lee Dohyun , Park Choon-Ho , Kim Sangjune , Kim Do-Yeon , Kim Kyong-Tai 
Published: June 2016

AbstractAlthough extracellular signal-related kinase 1/2 (ERK 1/2) activity is generally associated with cell survival, prolonged ERK activation induced by oxidative stress also mediates neuronal cell death. Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation. Overexpression of VRK3 protected human neuroblastoma SH-SY5Y cells against hydrogen peroxide (H2O2)-induced apoptosis. However the CDK5 was unable to phosphorylate mutant VRK3, and thus the mutant forms of VRK3 could not attenuate apoptotic process. Suppression of CDK5 activity results in increase of ERK activation and elevation of proapoptotic protein Bak expression in mouse cortical neurons. Results from VRK3-deficient neurons were further confirmed the role of VRK3 phosphorylation in H2O2-evoked ERK regulation. Importantly, we showed an association between phospho-VRK3 levels and the progression of human Alzheimer’s disease (AD) and Parkinson’s disease (PD). Together our work reveals endogenous protective mechanism against oxidative stress-induced neuronal cell death and suggest VRK3 as a potential therapeutic target in neurodegenerative diseases.
DDX3 Represses Stemness by Epigenetically Modulating Tumor-suppressive miRNAs in Hepatocellular Carcinoma
Authors: Li Hao-Kang , Mai Ru-Tsun , Huang Hsien-Da , Chou Chih-Hung , Chang Yi-An , Chang Yao-Wen , You Li-Ru , Chen Chun-Ming , Lee Yan-Hwa Wu 
Published: June 2016

AbstractStudies indicate that the presence of cancer stem cells (CSCs) is responsible for poor prognosis of hepatocellular carcinoma (HCC) patients. In this study, the functional role of DDX3 in regulation of hepatic CSCs was investigated. Our results demonstrated that reduced DDX3 expression was not only inversely associated with tumor grade, but also predicted poor prognosis of HCC patients. Knockdown of DDX3 in HCC cell line HepG2 induced stemness gene signature followed by occurrence of self-renewal, chemoreisistance, EMT, migration as well as CSC expansion and most importantly, DDX3 knockdown promotes tumorigenesis. Moreover, we found positive correlations between DDX3 level and expressions of tumor-suppressive miR-200b, miR-200c, miR-122 and miR-145, but not miR-10b and miR-519a, implying their involvement in DDX3 knockdown-induced CSC phenotypes. In addition, DDX3 reduction promoted up-regulation of DNA methyltransferase 3A (DNMT3A), while neither DNMT3B nor DNMT1 expression was affected. Enriched DNMT3A binding along with hypermethylation on promoters of these tumor-suppressive miRNAs reflected their transcriptional repressions in DDX3-knockdown cells. Furthermore, individual restoration of these tumor-suppressive miRNAs represses DDX3 knockdown-induced CSC phenotypes. In conclusion, our study suggested that DDX3 prevents generation of CSCs through epigenetically regulating a subset of tumor-suppressive miRNAs expressions, which strengthens tumor suppressor role of DDX3 in HCC.
Quantitative analysis of co-oligomer formation by amyloid-beta peptide isoforms
Authors: Iljina Marija , Garcia Gonzalo A. , Dear Alexander J. , Flint Jennie , Narayan Priyanka , Michaels Thomas C. T. , Dobson Christopher M. , Frenkel Daan , Knowles Tuomas P. J. , Klenerman David 
Published: June 2016

AbstractMultiple isoforms of aggregation-prone proteins are present under physiological conditions and have the propensity to assemble into co-oligomers with different properties from self-oligomers, but this process has not been quantitatively studied to date. We have investigated the amyloid-β (Aβ) peptide, associated with Alzheimer’s disease, and the aggregation of its two major isoforms, Aβ40 and Aβ42, using a statistical mechanical modelling approach in combination with in vitro single-molecule fluorescence measurements. We find that at low concentrations of Aβ, corresponding to its physiological abundance, there is little free energy penalty in forming co-oligomers, suggesting that the formation of both self-oligomers and co-oligomers is possible under these conditions. Our model is used to predict the oligomer concentration and size at physiological concentrations of Aβ and suggests the mechanisms by which the ratio of Aβ42 to Aβ40 can affect cell toxicity. An increased ratio of Aβ42 to Aβ40 raises the fraction of oligomers containing Aβ42, which can increase the hydrophobicity of the oligomers and thus promote deleterious binding to the cell membrane and increase neuronal damage. Our results suggest that co-oligomers are a common form of aggregate when Aβ isoforms are present in solution and may potentially play a significant role in Alzheimer’s disease.
RETRACTED ARTICLE: High Expression of RIOK2 and NOB1 Predict Human Non-small Cell Lung Cancer Outcomes
Authors: Liu Kun , Chen Hong-Lin , Wang Shuo , Gu Ming-Ming , Chen Xin-Ming , Zhang Shuang-Long , Yu Kang-Jun , You Qing-Sheng 
Published: June 2016

AbstractNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. However, there is a shortage of suitable diagnostic markers for early stages of NSCLC and therapeutic targets are limited. Right open reading frame (Rio) kinase 2 (RIOK2) and Nin one binding (NOB1) protein are important accessory factors in ribosome assembly and are highly expressed in malignant tumours; moreover, they interact with each other. However, the RIOK2 expression profile and its clinical significance as well as NOB1’s mechanism in NSCLC remain unknown. In this study, NSCLC cell lines and 15 NSCLC tumour tissues (paired with adjacent normal lung tissues) were collected for a real-time quantitative PCR (RT-qPCR) analysis. In addition, 153 NSCLC cases and 27 normal lung tissues were used in an immunohistochemical analysis to evaluate the RIOK2 and NOB1 expression profiles, their clinicopathological factors in NSCLC and their correlations with prognoses. RIOK2 and NOB1 were highly expressed in NSCLC cells and tissues and their expression profiles were significantly associated with the Tumour Node Metastasis (TNM) clinical stage, lymph node metastasis and differentiation. RIOK2 expression was correlated with NOB1. The results suggested that simultaneously determining the expression of RIOK2 and NOB1 will improve the diagnostic rate in early stages of NSCLC. Moreover, RIOK2 and NOB1 might be potential targets for NSCLC therapy.
Ndk, a novel host-responsive regulator, negatively regulates bacterial virulence through quorum sensing in Pseudomonas aeruginosa
Authors: Yu Hua , Xiong Junzhi , Zhang Rong , Hu Xiaomei , Qiu Jing , Zhang Di , Xu Xiaohui , Xin Rong , He Xiaomei , Xie Wei , Sheng Halei , Chen Qian , Zhang Le , Rao Xiancai , Zhang Kebin 
Published: June 2016

AbstractPathogenic bacteria could adjust gene expression to enable their survival in the distinct host environment. However, the mechanism by which bacteria adapt to the host environment is not well described. In this study, we demonstrated that nucleoside diphosphate kinase (Ndk) of Pseudomonas aeruginosa is critical for adjusting the bacterial virulence determinants during infection. Ndk expression was down-regulated in the pulmonary alveoli of a mouse model of acute pneumonia. Knockout of ndk up-regulated transcription factor ExsA-mediated T3S regulon expression and decreased exoproduct-related gene expression through the inhibition of the quorum sensing hierarchy. Moreover, in vitro and in vivo studies demonstrated that the ndk mutant exhibits enhanced cytotoxicity and host pathogenicity by increasing T3SS proteins. Taken together, our data reveal that ndk is a critical novel host-responsive gene required for coordinating P. aeruginosa virulence upon acute infection.
Bivalent vaccine platform based on Japanese encephalitis virus (JEV) elicits neutralizing antibodies against JEV and hepatitis C virus
Authors: Saga Ryohei , Fujimoto Akira , Watanabe Noriyuki , Matsuda Mami , Hasegawa Makoto , Watashi Koichi , Aizaki Hideki , Nakamura Noriko , Tajima Shigeru , Takasaki Tomohiko , Konishi Eiji , Kato Takanobu , Kohara Michinori , Takeyama Haruko , Wakita Takaji , Suzuki Ryosuke 
Published: June 2016

AbstractDirectly acting antivirals recently have become available for the treatment of hepatitis C virus (HCV) infection, but there is no prophylactic vaccine for HCV. In the present study, we took advantage of the properties of Japanese encephalitis virus (JEV) to develop antigens for use in a HCV vaccine. Notably, the surface-exposed JEV envelope protein is tolerant of inserted foreign epitopes, permitting display of novel antigens. We identified 3 positions that permitted insertion of the HCV E2 neutralization epitope recognized by HCV1 antibody. JEV subviral particles (SVP) containing HCV-neutralization epitope (SVP-E2) were purified from culture supernatant by gel chromatography. Sera from mice immunized with SVP-E2 inhibited infection by JEV and by trans-complemented HCV particles (HCVtcp) derived from multi-genotypic viruses, whereas sera from mice immunized with synthetic E2 peptides did not show any neutralizing activity. Furthermore, sera from mice immunized with SVP-E2 neutralized HCVtcp with N415K escape mutation in E2. As with the SVP-E2 epitope-displaying particles, JEV SVPs with HCV E1 epitope also elicited neutralizing antibodies against HCV. Thus, this novel platform harboring foreign epitopes on the surface of the particle may facilitate the development of a bivalent vaccine against JEV and other pathogens.
Evidence of extensive non-allelic gene conversion among LTR elements in the human genome
Authors: Trombetta Beniamino , Fantini Gloria , D’Atanasio Eugenia , Sellitto Daniele , Cruciani Fulvio 
Published: June 2016

AbstractLong Terminal Repeats (LTRs) are nearly identical DNA sequences found at either end of Human Endogenous Retroviruses (HERVs). The high sequence similarity that exists among different LTRs suggests they could be substrate of ectopic gene conversion events. To understand the extent to which gene conversion occurs and to gain new insights into the evolutionary history of these elements in humans, we performed an intra-species phylogenetic study of 52 LTRs on different unrelated Y chromosomes. From this analysis, we obtained direct evidence that demonstrates the occurrence of ectopic gene conversion in several LTRs, with donor sequences located on both sex chromosomes and autosomes. We also found that some of these elements are characterized by an extremely high density of polymorphisms, showing one of the highest nucleotide diversities in the human genome, as well as a complex patchwork of sequences derived from different LTRs. Finally, we highlighted the limits of current short-read NGS studies in the analysis of genetic diversity of the LTRs in the human genome. In conclusion, our comparative re-sequencing analysis revealed that ectopic gene conversion is a common event in the evolution of LTR elements, suggesting complex genetic links among LTRs from different chromosomes.
Hybrid-Actuating Macrophage-Based Microrobots for Active Cancer Therapy
Authors: Han Jiwon , Zhen Jin , Du Nguyen Van , Go Gwangjun , Choi Youngjin , Ko Seong Young , Park Jong-Oh , Park Sukho 
Published: June 2016

AbstractUsing macrophage recruitment in tumors, we develop active, transportable, cancer theragnostic macrophage-based microrobots as vector to deliver therapeutic agents to tumor regions. The macrophage-based microrobots contain docetaxel (DTX)-loaded poly-lactic-co-glycolic-acid (PLGA) nanoparticles (NPs) for chemotherapy and Fe3O4 magnetic NPs (MNPs) for active targeting using an electromagnetic actuation (EMA) system. And, the macrophage-based microrobots are synthesized through the phagocytosis of the drug NPs and MNPs in the macrophages. The anticancer effects of the microrobots on tumor cell lines (CT-26 and 4T1) are evaluated in vitro by cytotoxic assay. In addition, the active tumor targeting by the EMA system and macrophage recruitment, and the chemotherapeutic effect of the microrobots are evaluated using three-dimensional (3D) tumor spheroids. The microrobots exhibited clear cytotoxicity toward tumor cells, with a low survivability rate (<50%). The 3D tumor spheroid assay showed that the microrobots demonstrated hybrid actuation through active tumor targeting by the EMA system and infiltration into the tumor spheroid by macrophage recruitment, resulting in tumor cell death caused by the delivered antitumor drug. Thus, the active, transportable, macrophage-based theragnostic microrobots can be considered to be biocompatible vectors for cancer therapy.
New insights into salvianolic acid A action: Regulation of the TXNIP/NLRP3 and TXNIP/ChREBP pathways ameliorates HFD-induced NAFLD in rats
Authors: Ding Chunchun , Zhao Yan , Shi Xue , Zhang Ning , Zu Guo , Li Zhenlu , Zhou Junjun , Gao Dongyan , Lv Li , Tian Xiaofeng , Yao Jihong 
Published: June 2016

AbstractSalvianolic acid A (SalA), one of the most efficacious polyphenol compounds extracted from Radix Salvia miltiorrhiza (Danshen), has been shown to possess many potential pharmacological activities. This study aimed to investigate whether SalA has hepatoprotective effects against high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) and to further explore the mechanism underlying this process. SalA treatment significantly attenuated HFD-induced obesity and liver injury and markedly decreased lipid accumulation in HFD-fed rat livers. Moreover, SalA treatment ameliorated HFD-induced hepatic inflammation and oxidative stress by decreasing hepatotoxic levels of cytokines, suppressing the overproduction of reactive oxygen species (ROS) and methane dicarboxylic aldehyde (MDA) and preventing the decreased expression of superoxide dismutase (SOD). Importantly, SalA reversed the HFD- or palmitic acid (PA)-induced activation of the NLRP3 inflammasome, the nuclear translocation of ChREBP and the up-regulation of FAS and these effects were accompanied by TXNIP down-regulation. However, TXNIP siRNA treatment partially abrogated the above-mentioned effects of SalA in PA-treated HepG2 cells. Together, our results demonstrated, for the first time, that SalA protects against HFD-induced NAFLD by ameliorating hepatic lipid accumulation and inflammation and these protective effects may partially due to regulation of the TXNIP/NLRP3 and TXNIP/ChREBP pathways.
Transverse writing of three-dimensional tubular optical waveguides in glass with a slit-shaped femtosecond laser beam
Authors: Liao Yang , Qi Jia , Wang Peng , Chu Wei , Wang Zhaohui , Qiao Lingling , Cheng Ya 
Published: June 2016

AbstractWe report on fabrication of tubular optical waveguides buried in ZBLAN glass based on transverse femtosecond laser direct writing. Irradiation in ZBLAN with focused femtosecond laser pulses leads to decrease of refractive index in the modified region. Tubular optical waveguides of variable mode areas are fabricated by forming the four sides of the cladding with slit-shaped femtosecond laser pulses, ensuring single mode waveguiding with a mode field dimension as small as ~4 μm.
DJ-1 deficiency impairs glutamate uptake into astrocytes via the regulation of flotillin-1 and caveolin-1 expression
Authors: Kim Jin-Mo , Cha Seon-Heui , Choi Yu Ree , Jou Ilo , Joe Eun-Hye , Park Sang Myun 
Published: June 2016

AbstractParkinson’s disease (PD) is a common chronic and progressive neurodegenerative disorder. Although the cause of PD is still poorly understood, mutations in many genes including SNCA, parkin, PINK1, LRRK2, and DJ-1 have been identified in the familial forms of PD. It was recently proposed that alterations in lipid rafts may cause the neurodegeneration shown in PD. Here, we observe that DJ-1 deficiency decreased the expression of flotillin-1 (flot-1) and caveolin-1 (cav-1), the main protein components of lipid rafts, in primary astrocytes and MEF cells. As a mechanism, DJ-1 regulated flot-1 stability by direct interaction, however, decreased cav-1 expression may not be a direct effect of DJ-1, but rather as a result of decreased flot-1 expression. Dysregulation of flot-1 and cav-1 by DJ-1 deficiency caused an alteration in the cellular cholesterol level, membrane fluidity, and alteration in lipid rafts-dependent endocytosis. Moreover, DJ-1 deficiency impaired glutamate uptake into astrocytes, a major function of astrocytes in the maintenance of CNS homeostasis, by altering EAAT2 expression. This study will be helpful to understand the role of DJ-1 in the pathogenesis of PD, and the modulation of lipid rafts through the regulation of flot-1 or cav-1 may be a novel therapeutic target for PD.
Structural and functional characterization of the CAP domain of pathogen-related yeast 1 (Pry1) protein
Authors: Darwiche Rabih , Kelleher Alan , Hudspeth Elissa M. , Schneiter Roger , Asojo Oluwatoyin A. 
Published: June 2016

AbstractThe production, crystal structure and functional characterization of the C-terminal cysteine-rich secretory protein/antigen 5/pathogenesis related-1 (CAP) domain of pathogen-related yeast protein-1 (Pry1) from Saccharomyces cerevisiae is presented. The CAP domain of Pry1 (Pry1CAP) is functional in vivo as its expression restores cholesterol export to yeast mutants lacking endogenous Pry1 and Pry2. Recombinant Pry1CAP forms dimers in solution, is sufficient for in vitro cholesterol binding and has comparable binding properties as full-length Pry1. Two crystal structures of Pry1CAP are reported, one with Mg2+ coordinated to the conserved CAP tetrad (His208, Glu215, Glu233 and His250) in spacegroup I41 and the other without divalent cations in spacegroup P6122. The latter structure contains four 1,4-dioxane molecules from the crystallization solution, one of which sits in the cholesterol binding site. Both structures reveal that the divalent cation and cholesterol binding sites are connected upon dimerization, providing a structural basis for the observed Mg2+-dependent sterol binding by Pry1.
Tunable optical properties of ternary non‐stoichiometric Cu–In–S nanocrystal emitters
Authors: Feng Guangwei , Feng Jian 
Published: June 2016

Low toxic, non‐stoichiometric colloidal copper–indium–sulphur [Cu–In–S (CIS)] ternary quantum dots with different Cu:In molar ratios by a hot‐injection method in octadecene was synthesised. The Cu:In precursor molar ratios were 1/10, 1/20 and 1/40. Varying the fraction of cationic and capping agents, the compositions of CIS nanocrystals were precisely controlled. The photoluminescence (PL) results reveal that, reducing the Cu:In ratio in the CIS is the feasible strategy for bandgap engineering. Tunable PL emissions have been observed. X‐ray powder diffraction and high‐resolution transmission electron microscopy results indicate that as‐prepared CIS nanocrystals are compositional homogeneity. The single‐crystal nature of CIS nanocrystals improves the relative PL quantum yield up to 12%, which exhibits substantial enhancement comparing with the stoichiometric CuInS2 and CIS‐based semiconductor core QDs. The PL decay curve of CIS has a triexponential feature. The value of τ 1, τ 2 and τ 3 of CIS sample agree well with CuInS2 core QDs. The average PL lifetime of CIS is reduced to 146.9 ns, which can be attributed to the reduction of surface‐related trap states.
The interpretation of metonymy by Japanese learners of English
Authors: Littlemore Jeannette , Arizono Satomi , May Alice 
Published: June 2016

Figurative language can present both difficulties and opportunities in cross-linguistic and cross-cultural communication. Previous studies have focused on difficulties in metaphor comprehension by speakers of different languages, but metonymy comprehension is a relatively under-researched area. In this paper, we describe a two-part study exploring metonymy comprehension by Japanese learners of English. In the first part of the study, ten Japanese learners of English were asked to explain the meanings of twenty expressions instantiating a range of metonymy types. Comprehension problems included: the missing of, or misuse of, contextual clues; positive and negative interference from Japanese; ‘underspecification’; and a tendency to interpret metonyms as if they were metaphors. The second part of the study focused on the functions performed by metonymy. Twenty-two Japanese learners of English were asked to interpret a set of twenty metonyms, each of which performed a particular function. Metonyms involving humour and irony appeared to be more difficult to understand than ones serving other functions, such as indirect reference and evaluation.