bluuebunny/crossref_metadata_2025 huggingface dataset:
Homocysteine activates autophagy by inhibition of CFTR expression via interaction between DNA methylation and H3K27me3 in mouse liver
Authors: Yang Anning , Jiao Yun , Yang Songhao , Deng Mei , Yang Xiaoling , Mao Caiyan , Sun Yue , Ding Ning , Li Nan , Zhang Minghao , Jin Shaoju , Zhang Huiping , Jiang Yideng
Published: February 2018

Elevated homocysteine (Hcy) levels have been reported to be involved in liver injury, and autophagy plays an important role in normal hepatic physiology and pathophysiology, but the mechanism underlying Hcy regulated autophagy is currently unknown. In this study, CBS+/- mice were fed with regular diet for 12 weeks to establish a hyperhomocysteinemia (HHcy) model and HL-7702 cells were treated with Hcy, we found that Hcy increases autophagy and aggravates liver injury by downregulation of cystic fibrosis transmembrane conductance regulator (CFTR) expression in vivo and in vitro. Overexpression of CFTR inhibited the formation of autophagosomes and the expression of autophagy-related proteins BECN1, LC3-II/I and Atg12, while the expression of p62 increased in Hcy-treated hepatocytes and CBS+/- mice injected with lentivirus expressing CFTR. Further study showed that CFTR expression is regulated by the interaction of DNA methyltransferase 1 (DNMT1) and enhancer of zeste homolog 2 (EZH2), which, respectively, regulate DNA methylation and histone H3 lysine 27 trimethylation (H3K27me3). In conclusion, our study showed that Hcy activates autophagy by inhibition of CFTR expression via interaction between H3K27me3 and DNA methylation in the mouse liver. These findings provide new insight into the mechanism of Hcy-induced autophagy in liver injury.
MicroRNA-1253 suppresses cell proliferation and invasion of non-small-cell lung carcinoma by targeting WNT5A
Authors: Liu Meiyue , Zhang Yue , Zhang Jie , Cai Haifeng , Zhang Chao , Yang Zhao , Niu Yi , Wang Huan , Wei Xiaomei , Wang Wei , Gao Peng , Li Hongmin , Zhang Jinghua , Sun Guogui
Published: February 2018

MicroRNAs (miRNA) are a class of small, noncoding RNA molecules that regulate the expression of target genes. miRNA dysregulation is involved in carcinogenesis and tumor progression. In this study, we identified microRNA-1253 (miR-1253) as being significantly down-regulated in non-small-cell lung carcinoma (NSCLC) tissues and associated with advanced clinical stage, lymph node metastasis, and poor survival. The enhanced expression of miR-1253 significantly inhibited the proliferation, migration, and invasion of NSCLC cells in vitro. Bioinformatics analyses showed that miR-1253 directly targeted WNT5A (long isoform), which was confirmed using the dual-luciferase reporter assay. The inhibitory effects of miR-1253 on the growth and metastasis of NSCLC cells were attenuated and phenocopied by WNT5A (long) overexpression and knockdown, respectively. Consistent with the in vitro results, subcutaneous tumor and metastatic NSCLC mouse models showed that miR-1253 functions as a potent suppressor of NSCLC in vivo. Taken together, our findings indicated that miR-1253 inhibited the proliferation and metastasis of NSCLC cells by targeting WNT5A (long isoform) and provided new evidence of miR-1253 as a potential therapeutic target in NSCLC.
Osteopontin promotes metastasis of intrahepatic cholangiocarcinoma through recruiting MAPK1 and mediating Ser675 phosphorylation of β-Catenin
Authors: Zheng Yan , Zhou Chuang , Yu Xin-Xin , Wu Chao , Jia Hu-Liang , Gao Xiao-Mei , Yang Ji-Meng , Wang Chao-Qun , Luo Qin , Zhu Ying , Zhang Yu , Wei Jin-Wang , Sheng Yuan-Yuan , Dong Qiong-Zhu , Qin Lun-Xiu
Published: February 2018

The incidence and mortality of intrahepatic cholangiocarcinoma (ICC) are increasing worldwide in recent decades. Osteopontin (OPN) plays an important role in cancer metastasis, but its functional mechanism in ICC is not clear yet. In this study, we found that OPN level was elevated both in plasma and tumor tissues of ICC patients, which was closely related to a shorter overall survival (OS) and high probability of tumor relapse after curative resection. The gain- and loss-of-function studies determined that OPN could promote ICC growth and metastasis. OPN selectively interacted with β-Catenin and knockdown of β-Catenin abrogated the effects induced by OPN. OPN recruited MAPK1 and activated MEK–MAPK1 pathway to mediate the S675 phosphorylation of β-Catenin and nucleus accumulation, which induced the activation of Wnt signaling. Moreover, a significant correlation between OPN and β-Catenin was found in ICC tissues. OPN, β-Catenin, and their combination were independent prognostic indicator for ICC patients. In conclusion, OPN promotes ICC progression through recruiting MAPK1 and activating the Wnt/β-Catenin pathway and can serve as a novel prognostic marker and therapeutic target for ICC.
Antitumor activity of EGFR-specific CAR T cells against non-small-cell lung cancer cells in vitro and in mice
Authors: Li He , Huang Yao , Jiang Du-Qing , Cui Lian-Zhen , He Zhou , Wang Chao , Zhang Zhi-Wei , Zhu Hai-Li , Ding Yong-Mei , Li Lin-Fang , Li Qiang , Jin Hua-Jun , Qian Qi-Jun
Published: February 2018

Effective control of non-small-cell lung cancer (NSCLC) remains clinically challenging, especially during advanced stages of the disease. This study developed an adoptive T-cell treatment through expression of a chimeric antigen receptor (CAR) to target human epidermal growth factor receptor (EGFR) in NSCLC. We optimized the non-viral piggyBac transposon system to engineer human T cells for the expression of EGFR-CAR, consisting of EGFR scFv, transmembrane domain, and intracellular 4-1BB-CD3ζ signaling domains. The modified CAR T cells exhibited expansion capability and anticancer efficacy in a time- and antigen-dependent manner in vitro as well as regression of EGFR-positive human lung cancer xenografts in vivo. EGFR-CAR T therapy is a promising strategy to improve the efficacy and potency of the adoptive immunotherapy in NSCLC. Moreover, EGFR-CAR T therapy could become a clinical application for NSCLC patients in the future.
The binding landscape of a partially-selective isopeptidase inhibitor with potent pro-death activity, based on the bis(arylidene)cyclohexanone scaffold
Authors: Ciotti Sonia , Sgarra Riccardo , Sgorbissa Andrea , Penzo Carlotta , Tomasella Andrea , Casarsa Federico , Benedetti Fabio , Berti Federico , Manfioletti Guidalberto , Brancolini Claudio
Published: February 2018

Diaryldienone derivatives with accessible β-carbons show strong anti-neoplastic properties, related to their ability to make covalent adducts with free thiols by Michael addition, and low toxicity in vivo. Accumulation of poly-ubiquitylated proteins, activation of the unfolded protein response (UPR) and induction of cell death are universal hallmarks of their activities. These compounds have been characterized as inhibitors of isopeptidases, a family of cysteine-proteases, which de-conjugate ubiquitin and ubiquitin-like proteins from their targets. However, it is unclear whether they can also react with additional proteins. In this work, we utilized the biotin-conjugated diaryldienone-derivative named 2c, as a bait to purify novel cellular targets of these small molecules. Proteomic analyses have unveiled that, in addition to isopeptidases, these inhibitors can form stable covalent adducts with different intracellular proteins, thus potentially impacting on multiple functions of the cells, from cytoskeletal organization to metabolism. These widespread activities can explain the ability of diaryldienone derivatives to efficiently trigger different cell death pathways.
Detecting RNA base methylations in single cells by in situ hybridization
Authors: Ranasinghe Rohan T. , Challand Martin R. , Ganzinger Kristina A. , Lewis Benjamin W. , Softley Charlotte , Schmied Wolfgang H. , Horrocks Mathew H. , Shivji Nadia , Chin Jason W. , Spencer James , Klenerman David
Published: February 2018

Methylated bases in tRNA, rRNA and mRNA control a variety of cellular processes, including protein synthesis, antimicrobial resistance and gene expression. Currently, bulk methods that report the average methylation state of ~104–107 cells are used to detect these modifications, obscuring potentially important biological information. Here, we use in situ hybridization of Molecular Beacons for single-cell detection of three methylations (m62A, m1G and m3U) that destabilize Watson–Crick base pairs. Our method—methylation-sensitive RNA fluorescence in situ hybridization—detects single methylations of rRNA, quantifies antibiotic-resistant bacteria in mixtures of cells and simultaneously detects multiple methylations using multicolor fluorescence imaging.
Toward a consistent modeling framework to assess multi-sectoral climate impacts
Authors: Monier Erwan , Paltsev Sergey , Sokolov Andrei , Chen Y.-H. Henry , Gao Xiang , Ejaz Qudsia , Couzo Evan , Schlosser C. Adam , Dutkiewicz Stephanie , Fant Charles , Scott Jeffery , Kicklighter David , Morris Jennifer , Jacoby Henry , Prinn Ronald , Haigh Martin
Published: February 2018

Efforts to estimate the physical and economic impacts of future climate change face substantial challenges. To enrich the currently popular approaches to impact analysis—which involve evaluation of a damage function or multi-model comparisons based on a limited number of standardized scenarios—we propose integrating a geospatially resolved physical representation of impacts into a coupled human-Earth system modeling framework. Large internationally coordinated exercises cannot easily respond to new policy targets and the implementation of standard scenarios across models, institutions and research communities can yield inconsistent estimates. Here, we argue for a shift toward the use of a self-consistent integrated modeling framework to assess climate impacts, and discuss ways the integrated assessment modeling community can move in this direction. We then demonstrate the capabilities of such a modeling framework by conducting a multi-sectoral assessment of climate impacts under a range of consistent and integrated economic and climate scenarios that are responsive to new policies and business expectations.
Conductance quantization suppression in the quantum Hall regime
Authors: Caridad José M. , Power Stephen R. , Lotz Mikkel R. , Shylau Artsem A. , Thomsen Joachim D. , Gammelgaard Lene , Booth Timothy J. , Jauho Antti-Pekka , Bøggild Peter
Published: February 2018

Conductance quantization is the quintessential feature of electronic transport in non-interacting mesoscopic systems. This phenomenon is observed in quasi one-dimensional conductors at zero magnetic field B, and the formation of edge states at finite magnetic fields results in wider conductance plateaus within the quantum Hall regime. Electrostatic interactions can change this picture qualitatively. At finite B, screening mechanisms in narrow, gated ballistic conductors are predicted to give rise to an increase in conductance and a suppression of quantization due to the appearance of additional conduction channels. Despite being a universal effect, this regime has proven experimentally elusive because of difficulties in realizing one-dimensional systems with sufficiently hard-walled, disorder-free confinement. Here, we experimentally demonstrate the suppression of conductance quantization within the quantum Hall regime for graphene nanoconstrictions with low edge roughness. Our findings may have profound impact on fundamental studies of quantum transport in finite-size, two-dimensional crystals with low disorder.
Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models
Authors: Sokhi Upneet K. , Liber Mark P. , Frye Laura , Park Sungho , Kang Kyuho , Pannellini Tania , Zhao Baohong , Norinsky Rada , Ivashkiv Lionel B. , Gong Shiaoching
Published: February 2018

Enhancers regulate gene expression and have been linked with disease pathogenesis. Little is known about enhancers that regulate human disease-associated genes in primary cells relevant for pathogenesis. Here we use BAC transgenics and genome editing to dissect, in vivo and in primary immune cells, enhancers that regulate human TNFAIP3, which encodes A20 and is linked with autoimmune diseases. A20 expression is dependent on a topologically associating subdomain (sub-TAD) that harbors four enhancers, while another >20 enhancers in the A20 locus are redundant. This sub-TAD contains cell- and activation-specific enhancers, including an enhancer (termed TT>A) harboring a proposed causal SLE-associated SNV. Deletion of the sub-TAD or the TT>A enhancer results in enhanced inflammatory responses, autoantibody production, and inflammatory arthritis, thus establishing functional importance in vivo and linking enhancers with a specific disease phenotype. These findings provide insights into enhancers that regulate human A20 expression to prevent inflammatory pathology and autoimmunity.
A defensin-like protein drives cadmium efflux and allocation in rice
Authors: Luo Jin-Song , Huang Jing , Zeng Da-Li , Peng Jia-Shi , Zhang Guo-Bin , Ma Hai-Ling , Guan Yuan , Yi Hong-Ying , Fu Yan-Lei , Han Bin , Lin Hong-Xuan , Qian Qian , Gong Ji-Ming
Published: February 2018

Pollution by heavy metals limits the area of land available for cultivation of food crops. A potential solution to this problem might lie in the molecular breeding of food crops for phytoremediation that accumulate toxic metals in straw while producing safe and nutritious grains. Here, we identify a rice quantitative trait locus we name cadmium (Cd) accumulation in leaf 1 (CAL1), which encodes a defensin-like protein. CAL1 is expressed preferentially in root exodermis and xylem parenchyma cells. We provide evidence that CAL1 acts by chelating Cd in the cytosol and facilitating Cd secretion to extracellular spaces, hence lowering cytosolic Cd concentration while driving long-distance Cd transport via xylem vessels. CAL1 does not appear to affect Cd accumulation in rice grains or the accumulation of other essential metals, thus providing an efficient molecular tool to breed dual-function rice varieties that produce safe grains while remediating paddy soils.
Emerging risks from marine heat waves
Authors: Frölicher Thomas L. , Laufkötter Charlotte
Published: February 2018

Recent marine heat waves have caused devastating impacts on marine ecosystems. Substantial progress in understanding past and future changes in marine heat waves and their risks for marine ecosystems is needed to predict how marine systems, and the goods and services they provide, will evolve in the future.
Demonstration of Einstein–Podolsky–Rosen steering with enhanced subchannel discrimination
Authors: Sun Kai , Ye Xiang-Jun , Xiao Ya , Xu Xiao-Ye , Wu Yu-Chun , Xu Jin-Shi , Chen Jing-Ling , Li Chuan-Feng , Guo Guang-Can
Published: February 2018

Einstein–Podolsky–Rosen (EPR) steering describes a quantum nonlocal phenomenon in which one party can nonlocally affect the other’s state through local measurements. It reveals an additional concept of quantum non-locality, which stands between quantum entanglement and Bell nonlocality. Recently, a quantum information task named as subchannel discrimination (SD) provides a necessary and sufficient characterization of EPR steering. The success probability of SD using steerable states is higher than using any unsteerable states, even when they are entangled. However, the detailed construction of such subchannels and the experimental realization of the corresponding task are still technologically challenging. In this work, we designed a feasible collection of subchannels for a quantum channel and experimentally demonstrated the corresponding SD task where the probabilities of correct discrimination are clearly enhanced by exploiting steerable states. Our results provide a concrete example to operationally demonstrate EPR steering and shine a new light on the potential application of EPR steering.
Integrated-optics heralded controlled-NOT gate for polarization-encoded qubits
Authors: Zeuner Jonas , Sharma Aditya N. , Tillmann Max , Heilmann René , Gräfe Markus , Moqanaki Amir , Szameit Alexander , Walther Philip
Published: February 2018

Recent progress in integrated-optics technology has made photonics a promising platform for quantum networks and quantum computation protocols. Integrated optical circuits are characterized by small device footprints and unrivalled intrinsic interferometric stability. Here, we take advantage of femtosecond-laser-written waveguides’ ability to process polarization-encoded qubits and present an implementation of a heralded controlled-NOT gate on chip. We evaluate the gate performance in the computational basis and a superposition basis, showing that the gate can create polarization entanglement between two photons. Transmission through the integrated device is optimized using thermally expanded core fibers and adiabatically reduced mode-field diameters at the waveguide facets. This demonstration underlines the feasibility of integrated quantum gates for all-optical quantum networks and quantum repeaters.
A meta-analysis of diffusion tensor imaging of substantia nigra in patients with Parkinson’s disease
Authors: Deng Xiao-Yan , Wang Li , Yang Ting-Ting , Li Rui , Yu Gang
Published: February 2018

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by severe, selective loss of pigmented neurons in the substantial nigra (SN). Previous studies have indicated that such loss could be detected by diffusion tensor imaging (DTI). Here, we try to consolidate current DTI data to both quantitatively determine the imaging changes in SN, as well as explore the potential use of DTI for PD diagnosis. Fourteen research articles are included in this meta-analysis, each obtained by searching PubMed, EMBASE, or Cochrane library database dated until July 2017. The articles contain 14 trials with 298 total PD patients and 283 healthy controls (HCs). The results show not only significantly lower FA values of SN in PD compared to that of HCs (WMD = −0.02, 95% CI = [−0.03, −0.02], p < 0.00001), but also a significantly higher MD in PD compared to HCs (WMD = 0.05, 95% CI = [0.03, 0.07], P < 0.0001). This indicates that the sharp difference detected between PD patients and HCs can be detected by DTI. By further analyzing the heterogeneity, we found that FA measurement of SN could be potentially used as a surrogate, noninvasive diagnostic marker toward PD diagnosis.
Mammalian Cells Undergo Endoreduplication in Response to Lactic Acidosis
Authors: Tan Zhihao , Chu De Zhi Valerie , Chan Yong Jie Andrew , Lu Yi Ena , Rancati Giulia
Published: February 2018

Polyploidization, a common event during the evolution of different tumours, has been proposed to confer selective advantages to tumour cells by increasing the occurrence of mutations promoting cancer progression and by conferring chemotherapy resistance. While conditions leading to polyploidy in cancer cells have been described, a general mechanism explaining the incidence of this karyotypic change in tumours is still missing. In this study, we tested whether a widespread tumour microenvironmental condition, low pH, could induce polyploidization in mammalian cells. We found that an acidic microenvironment, in the range of what is commonly observed in tumours, together with the addition of lactic acid, induced polyploidization in transformed and non-transformed human cell lines in vitro. In addition, we provide evidence that polyploidization was mainly driven through the process of endoreduplication, i.e. the complete skipping of mitosis in-between two S-phases. These findings suggest that acidic environments, which characterize solid tumours, are a plausible path leading to polyploidization of cancer cells.
Ultrasensitive optical biosensor for detection of miRNA-155 using positively charged Au nanoparticles
Authors: Hakimian Fatemeh , Ghourchian Hedayatollah , Hashemi Azam sadat , Arastoo Mohammad Reza , Behnam Rad Mohammad
Published: February 2018

An ultrasensitive optical biosensor for microRNA-155 (miR-155) was developed to diagnose breast cancer at early stages. At first, the probe DNA covalently bind to the negatively charged gold nanoparticles (citrate-capped AuNPs). Then, the target miR-155 electrostatically adsorb onto the positively charged gold nanoparticles (polyethylenimine-capped AuNP) surface. Finally, by mixing citrate-capped AuNP/probe and polyethylenimine-capped AuNP/miR-155, hybridization occurs and the optical signal of the mixture give a measure to quantify the miR-155 content. The proposed biosensor is able to specify 3-base-pair mismatches and genomic DNA from target miR-155. The novelty of this biosensor is in its ability to trap the label-free target by its branched positively charged polyethylenimine. This method increases loading the target on the polyethylenimine-capped AuNPs’ surface. So, proposed sensor enables miR-155 detection at very low concentrations with the detection limit of 100 aM and a wide linear range from 100 aM to 100 fM.
Panton–Valentine Leukocidin Colocalizes with Retinal Ganglion and Amacrine Cells and Activates Glial Reactions and Microglial Apoptosis
Authors: Liu XuanLi , Heitz Pauline , Roux Michel , Keller Daniel , Bourcier Tristan , Sauer Arnaud , Prévost Gilles , Gaucher David
Published: February 2018

Experimental models have established Panton–Valentine leukocidin (PVL) as a potential critical virulence factor during Staphylococcus aureus endophthalmitis. In the present study, we aimed to identify retinal cell targets for PVL and to analyze early retinal changes during infection. After the intravitreous injection of PVL, adult rabbits were euthanized at different time points (30 min, 1, 2, 4 and 8 h). PVL location in the retina, expression of its binding receptor C5a receptor (C5aR), and changes in Müller and microglial cells were analyzed using immunohistochemistry, Western blotting and RT-qPCR. In this model of PVL eye intoxication, only retinal ganglion cells (RGCs) expressed C5aR, and PVL was identified on the surface of two kinds of retinal neural cells. PVL-linked fluorescence increased in RGCs over time, reaching 98% of all RGCs 2 h after PVL injection. However, displaced amacrine cells (DACs) transiently colocalized with PVL. Müller and microglial cells were increasingly activated after injection over time. IL-6 expression in retina increased and some microglial cells underwent apoptosis 4 h and 8 h after PVL infection, probably because of abnormal nitrotyrosine production in the retina.
Genetic and morphological support for possible sympatric origin of fish from subterranean habitats
Authors: Hashemzadeh Segherloo Iraj , Normandeau Eric , Benestan Laura , Rougeux Clément , Coté Guillaume , Moore Jean-Sébastien , Ghaedrahmati NabiAllah , Abdoli Asghar , Bernatchez Louis
Published: February 2018

Two blind Iran cave barbs, Garra typhlops and Garra lorestanensis, exist in sympatry in a single subterranean habitat, raising the hypothesis that they may represent a case of sympatric speciation following a colonization event. Their different mental disc forms have prompted some authors to propose the alternative hypothesis of two separate colonization events. In this study, we analysed a genome-wide panel of 11,257 SNPs genotyped by means of genotyping-by-sequencing combined with mitochondrial cytochrome c oxidase sub-unit I sequence data, field observations and morphological traits to test these two hypotheses. Field data suggest some degree of ecological divergence despite some possible niche overlap such that hybridization is possible. According to both nuclear and mtDNA data, the cave barb species are monophyletic with close phylogenetic relationships with Garra gymnothorax from the Karun-Dez and Karkheh river basins. The historical demography analysis revealed that a model of Isolation-with-Migration (IM) best fitted the data, therefore better supporting a scenario of sympatric origin than that of allopatric isolation followed by secondary contact. Overall, our results offer stronger support to the hypothesis that speciation in the subterranean habitat could have occurred in sympatry following a colonization event from the Karun-Dez-Karkheh basins in the Zagros Mountains of Iran.
Structural properties of apolipoprotein A-I mimetic peptides that promote ABCA1-dependent cholesterol efflux
Authors: Islam Rafique M. , Pourmousa Mohsen , Sviridov Denis , Gordon Scott M. , Neufeld Edward B. , Freeman Lita A. , Perrin B. Scott , Pastor Richard W. , Remaley Alan T.
Published: February 2018

Peptides mimicking the major protein of highdensity lipoprotein (HDL), apolipoprotein A-I (apoA-I), are promising therapeutics for cardiovascular diseases. Similar to apoA-I, their atheroprotective property is attributed to their ability to form discoidal HDL-like particles by extracting cellular cholesterol and phospholipids from lipid microdomains created by the ABCA1 transporter in a process called cholesterol efflux. The structural features of peptides that enable cholesterol efflux are not well understood. Herein, four synthetic amphipathic peptides denoted ELK, which only contain Glu, Leu, Lys, and sometimes Ala, and which have a wide range of net charges and hydrophobicities, were examined for cholesterol efflux. Experiments show that ELKs with a net neutral charge and a hydrophobic face that subtends an angle of at least 140° are optimal for cholesterol efflux. All-atom molecular dynamics simulations show that peptides that are effective in promoting cholesterol efflux stabilize HDL nanodiscs formed by these peptides by the orderly covering of the hydrophobic acyl chains on the edge of the disc. In contrast to apoA-I, which forms an anti-parallel double belt around the HDL, active peptides assemble in a mostly anti-parallel “picket fence” arrangement. These results shed light on the efflux ability of apoA-I mimetics and inform the future design of such therapeutics.
Zinc ions have a potential to attenuate both Ni ion uptake and Ni ion-induced inflammation
Authors: Onodera Ryo , Asakawa Sanki , Segawa Ryosuke , Mizuno Natsumi , Ogasawara Kouetsu , Hiratsuka Masahiro , Hirasawa Noriyasu
Published: February 2018

Nickel ions (Ni2+) are eluted from various metallic materials, such as medical devices implanted in human tissues. Previous studies have shown that Ni2+enters inflammatory cells inducing inflammation. However, the regulation of Ni2+uptake in cells has not yet been reported in detail. In the present study, we investigated the effects of various divalent cations on Ni2+uptake and Ni2+-induced interleukin (IL)-8 production in the human monocytic cell line, THP-1. We demonstrated that ZnCl2,MnCl2, and CoCl2inhibited the Ni2+uptake, while CuCl2, FeCl2, MgCl2, and divalent metal transporter (DMT)-1 inhibitor, Chlorazol Black, did not. Furthermore, ZnCl2inhibited Ni2+-induced IL-8 production, correlating with the inhibition of Ni2+uptake. These results suggested that Ni2+uptake occurred through Zn2+, Mn2+, and Co2+-sensitive transporters and that the inhibition of Ni2+uptake resulted in the inhibition of IL-8 production. Furthermore, using an Ni wire-implanted mouse model, we found that Ni wire-induced expression of mouse macrophage inflammatory protein-2 (MIP-2) and cyclooxygenase-2 (COX-2) mRNA in the skin tissue surrounding the wire were enhanced by low Zn conditions. These results suggested that the physiological concentration of Zn2+modulates Ni2+uptake by inflammatory cells, and a Zn deficient state might increase sensitivity to Ni.
Grassland dynamics in response to climate change and human activities in Xinjiang from 2000 to 2014
Authors: Zhang Renping , Liang Tiangang , Guo Jing , Xie Hongjie , Feng Qisheng , Aimaiti Yusupujiang
Published: February 2018

Climate change and human activities are two key factors that affect grassland ecosystem. Accurately estimating the effects of these two factors on grassland dynamics and understanding the driving forces of the dynamics are important in controlling grassland degradation. In this study, the potential Net Primary productivity (NPPP) and the difference between NPPP and actual NPP (NPPA) are used as indicators of climate change and human activities on grassland ecosystem in Xinjiang. An overall grassland NPPA increase than decrease (69.7% vs 30.3%) is found over the study period of 2000 to 2014. While human activities played a dominant role for such a NPPA increase, both human activities and climate change contributed almost equally to the grassland NPPA decrease. Within the three types of grasslands in Xinjiang, the desert grassland showed the greatest NPPA increasing trend that mostly attributed to human activities; the meadow showed an overall NPPA decreasing trend that was mainly caused by human activities; the steppe showed similar NPPA decreasing and increasing trend in terms of area percentage. Based on this study, our recommendations are (1) to continue the grazing prohibition policy in desert grassland and (2) to extensively implement the rest grazing policy in steppe and meadow grasslands.
WDR1 is a novel EYA3 substrate and its dephosphorylation induces modifications of the cellular actin cytoskeleton
Authors: Mentel Mihaela , Ionescu Aura E. , Puscalau-Girtu Ioana , Helm Martin S. , Badea Rodica A. , Rizzoli Silvio O. , Szedlacsek Stefan E.
Published: February 2018

Eyes absent (EYA) proteins are unusual proteins combining in a single polypeptide chain transactivation, threonine phosphatase, and tyrosine phosphatase activities. They play pivotal roles in organogenesis and are involved in a variety of physiological and pathological processes including innate immunity, DNA damage repair or cancer metastasis. The molecular targets of EYA tyrosine phosphatase activity are still elusive. Therefore, we sought to identify novel EYA substrates and also to obtain further insight into the tyrosine-dephosphorylating role of EYA proteins in various cellular processes. We show here that Src kinase phosphorylates tyrosine residues in two human EYA family members, EYA1 and EYA3. Both can autodephosphorylate these residues and their nuclear and cytoskeletal localization seems to be controlled by Src phosphorylation. Next, using a microarray of phosphotyrosine-containing peptides, we identified a phosphopeptide derived from WD-repeat-containing protein 1 (WDR1) that is dephosphorylated by EYA3. We further demonstrated that several tyrosine residues on WDR1 are phosphorylated by Src kinase, and are efficiently dephosphorylated by EYA3, but not by EYA1. The lack of phosphorylation generates major changes to the cellular actin cytoskeleton. We, therefore, conclude that WDR1 is an EYA3-specific substrate, which implies that EYA3 is a key modulator of the cytoskeletal reorganization.
Aldehyde Dehydrogenases Function in the Homeostasis of Pyridine Nucleotides in Arabidopsis thaliana
Authors: Missihoun Tagnon D. , Kotchoni Simeon O. , Bartels Dorothea
Published: February 2018

Aldehyde dehydrogenase enzymes (ALDHs) catalyze the oxidation of aliphatic and aromatic aldehydes to their corresponding carboxylic acids using NAD+ or NADP+ as cofactors and generating NADH or NADPH. Previous studies mainly focused on the ALDH role in detoxifying toxic aldehydes but their effect on the cellular NAD(P)H contents has so far been overlooked. Here, we investigated whether the ALDHs influence the cellular redox homeostasis. We used a double T-DNA insertion mutant that is defective in representative members of Arabidopsis thaliana ALDH families 3 (ALDH3I1) and 7 (ALDH7B4), and we examined the pyridine nucleotide pools, glutathione content, and the photosynthetic capacity of the aldh mutants in comparison with the wild type. The loss of function of ALDH3I1 and ALDH7B4 led to a decrease of NAD(P)H, NAD(P)H/NAD(P) ratio, and an alteration of the glutathione pools. The aldh double mutant had higher glucose-6-phosphate dehydrogenase activity than the wild type, indicating a high demand for reduced pyridine nucleotides. Moreover, the mutant had a reduced quantum yield of photosystem II and photosynthetic capacity at relatively high light intensities compared to the wild type. Altogether, our data revealed a role of ALDHs as major contributors to the homeostasis of pyridine nucleotides in plants.
The effect of TiO2 on nucleation and crystallization of a Li2O-Al2O3-SiO2 glass investigated by XANES and STEM
Authors: Kleebusch Enrico , Patzig Christian , Krause Michael , Hu Yongfeng , Höche Thomas , Rüssel Christian
Published: February 2018

Glass ceramics based on Li2O/Al2O3/SiO2 are of high economic importance, as they often show very low coefficients of thermal expansion. This enables a number of challenging applications, such as cooktop panels, furnace windows or telescope mirror blanks. Usually, the crystallization of the desired LAS crystal phases within the glasses must be tailored by a careful choice of crystallization schedule and type of nucleation agents to be used. The present work describes the formation of nanocrystalline TiO2 within an LAS base composition that contains solely TiO2 as nucleating agent. Using a combination of scanning transmission electron microscopy as well as X-ray absorption spectroscopy, it is found that a mixture of four- and six-fold coordinated Ti4+ ions exists already within the glass. Heating of the glass to 740 °C immediately changes this ratio towards a high content of six-fold coordinated Ti, which accumulates in liquid-liquid phase-separation droplets. During the course of thermal treatment, these droplets eventually evolve into nanocrystalline TiO2 precipitations, in which Ti4+ is six-fold coordinated. Thus, it is shown that the nucleation of nanocrystalline TiO2 is initiated by a gradual re-arrangement of the Ti ions in the amorphous, glassy matrix, from a four-fold towards a six-fold coordination.
Electro-optic spatial decoding on the spherical-wavefront Coulomb fields of plasma electron sources
Authors: Huang K. , Esirkepov T. , Koga J. K. , Kotaki H. , Mori M. , Hayashi Y. , Nakanii N. , Bulanov S. V. , Kando M.
Published: February 2018

Detections of the pulse durations and arrival timings of relativistic electron beams are important issues in accelerator physics. Electro-optic diagnostics on the Coulomb fields of electron beams have the advantages of single shot and non-destructive characteristics. We present a study of introducing the electro-optic spatial decoding technique to laser wakefield acceleration. By placing an electro-optic crystal very close to a gas target, we discovered that the Coulomb field of the electron beam possessed a spherical wavefront and was inconsistent with the previously widely used model. The field structure was demonstrated by experimental measurement, analytic calculations and simulations. A temporal mapping relationship with generality was derived in a geometry where the signals had spherical wavefronts. This study could be helpful for the applications of electro-optic diagnostics in laser plasma acceleration experiments.
A new method to optimize root order classification based on the diameter interval of fine root
Authors: Liu Ying , Wang Guoliang , Yu Kunxia , Li Peng , Xiao Lie , Liu Guobin
Published: February 2018

Plant roots are a highly heterogeneous and hierarchical system. Although the root-order method is superior to the root diameter method for revealing differences in the morphology and physiology of fine roots, its complex partitioning limits its application. Whether root order can be determined by partitioning the main root based on its diameter remains uncertain. Four methods were employed for studying the morphological characteristics of seedling roots of twoPinusspecies in a natural and nitrogen-enriched environment. The intrinsic relationships among categories of roots by root order and diameter were systematically compared to explore the possibility of using the latter to describe root morphology. The normal transformation method proved superior to the other three in that the diameter intervals corresponded most closely (at least 68.3%) to the morphological characteristics. The applied methods clearly distinguished the results from the natural and nitrogen-rich environments. Considering both root diameter and order simplified the classification of fine roots, and improved the estimation of root lifespan and the data integrity of field collection, but failed to partition all roots into uniform diameter intervals.
Spontaneous oscillation in cell adhesion and stiffness measured using atomic force microscopy
Authors: Sanyour Hanna , Childs Josh , Meininger Gerald A. , Hong Zhongkui
Published: February 2018

Atomic force microscopy (AFM) is an attractive technique for studying biomechanical and morphological changes in live cells. Using real-time AFM monitoring of cellular mechanical properties, spontaneous oscillations in cell stiffness and cell adhesion to the extracellular matrix (ECM) have been found. However, the lack of automated analytical approaches to systematically extract oscillatory signals, and noise filtering from a large set of AFM data, is a significant obstacle when quantifying and interpreting the dynamic characteristics of live cells. Here we demonstrate a method that extends the usage of AFM to quantitatively investigate live cell dynamics. Approaches such as singular spectrum analysis (SSA), and fast Fourier transform (FFT) were introduced to analyze a real-time recording of cell stiffness and the unbinding force between the ECM protein-decorated AFM probe and vascular smooth muscle cells (VSMCs). The time series cell adhesion and stiffness data were first filtered with SSA and the principal oscillatory components were isolated from the noise floor with the computed eigenvalue from the lagged-covariance matrix. Following the SSA, the oscillatory parameters were detected by FFT from the noise-reduced time series data sets and the sinusoidal oscillatory components were constructed with the parameters obtained by FFT.
Blood biomarkers of Hikikomori, a severe social withdrawal syndrome
Authors: Hayakawa Kohei , Kato Takahiro A. , Watabe Motoki , Teo Alan R. , Horikawa Hideki , Kuwano Nobuki , Shimokawa Norihiro , Sato-Kasai Mina , Kubo Hiroaki , Ohgidani Masahiro , Sagata Noriaki , Toda Hiroyuki , Tateno Masaru , Shinfuku Naotaka , Kishimoto Junji , Kanba Shigenobu
Published: February 2018

Hikikomori, a severe form of social withdrawal syndrome, is a growing social issue in Japan and internationally. The pathophysiology of hikikomori has not yet been elucidated and an effective treatment remains to be established. Recently, we revealed that avoidant personality disorder is the most common comorbidity of hikikomori. Thus, we have postulated that avoidant personality is the personality underpinning hikikomori. First, we herein show relationships between avoidant personality traits, blood biomarkers, hikikomori-related psychological features, and behavioural characteristics assessed by a trust game in non-hikikomori volunteers. Avoidant personality traits were negatively associated with high-density lipoprotein cholesterol (HDL-C) and uric acid (UA) in men, and positively associated with fibrin degeneration products (FDP) and high sensitivity C-reactive protein (hsCRP) in women. Next, we recruited actual individuals with hikikomori, and compared avoidant personality traits, blood biomarkers, and psychological features between individuals with hikikomori and age-matched healthy controls. Individuals with hikikomori had higher avoidant personality scores in both sexes, and showed lower serum UA levels in men and lower HDL-C levels in women compared with healthy controls. This is the first report showing possible blood biomarkers for hikikomori, and opens the door to clarify the underlying biological pathophysiology of hikikomori.
Tracing ultrahigh-pressure metamorphism at the catchment scale
Authors: Schönig Jan , Meinhold Guido , von Eynatten Hilmar , Lünsdorf Nils K.
Published: February 2018

Finding traces of ultrahigh-pressure (UHP) metamorphism in the geological record has huge implications for unravelling Earth’s geodynamic evolution, such as the onset of deep subduction. Usually, UHP rocks are identified by specific mineral inclusions like coesite and characteristic petrographic features resulting from its (partial) transformation to the lower-pressure polymorph quartz in thin sections of crystalline rocks. This approach relies on very small sample size and is thus limited to a few points within large regions. Here we present the first findings of coesite inclusions in detrital mineral grains. The intact monomineralic inclusions were detected in garnets from a modern sand sample from the Western Gneiss Region, SW Norway. They represent the first known intact monomineralic coesite inclusions in the Western Gneiss Region, and their presence is suggested to indicate the erosion of UHP rocks in the sampled catchment area. The novel approach introduced here allows for tracing UHP metamorphic rocks and their erosional products at the catchment scale instead of being limited to outcrops of crystalline rocks. It opens new avenues for the prospective exploration of UHP metamorphism in Earth’s geological record.
Candidate-gene based GWAS identifies reproducible DNA markers for metabolic pyrethroid resistance from standing genetic variation in East African Anopheles gambiae
Authors: Weetman David , Wilding Craig S. , Neafsey Daniel E. , Müller Pie , Ochomo Eric , Isaacs Alison T. , Steen Keith , Rippon Emily J. , Morgan John C. , Mawejje Henry D. , Rigden Daniel J. , Okedi Loyce M. , Donnelly Martin J.
Published: February 2018

Metabolic resistance to pyrethroid insecticides is widespread in Anopheles mosquitoes and is a major threat to malaria control. DNA markers would aid predictive monitoring of resistance, but few mutations have been discovered outside of insecticide-targeted genes. Isofemale family pools from a wild Ugandan Anopheles gambiae population, from an area where operational pyrethroid failure is suspected, were genotyped using a candidate-gene enriched SNP array. Resistance-associated SNPs were detected in three genes from detoxification superfamilies, in addition to the insecticide target site (the Voltage Gated Sodium Channel gene, Vgsc). The putative associations were confirmed for two of the marker SNPs, in the P450 Cyp4j5 and the esterase Coeae1d by reproducible association with pyrethroid resistance in multiple field collections from Uganda and Kenya, and together with the Vgsc-1014S (kdr) mutation these SNPs explained around 20% of variation in resistance. Moreover, the >20 Mb 2La inversion also showed evidence of association with resistance as did environmental humidity. Sequencing of Cyp4j5 and Coeae1d detected no resistance-linked loss of diversity, suggesting selection from standing variation. Our study provides novel, regionally-validated DNA assays for resistance to the most important insecticide class, and establishes both 2La karyotype variation and humidity as common factors impacting the resistance phenotype.
Reverse Engineering the Intracellular Self-Assembly of a Functional Mechanopharmaceutical Device
Authors: Woldemichael Tehetina , Keswani Rahul K. , Rzeczycki Phillip M. , Murashov Mikhail D. , LaLone Vernon , Gregorka Brian , Swanson Joel A. , Stringer Kathleen A. , Rosania Gus R.
Published: February 2018

Weakly basic, poorly soluble chemical agents could be exploited as building blocks for constructing sophisticated molecular devices inside the cells of living organisms. Here, using experimental and computational approaches, we probed the relationship between the biological mechanisms mediating lysosomal ion homeostasis and the self-assembly of a weakly basic small molecule building block (clofazimine) into a functional, mechanopharmaceutical device (intracellular Crystal-Like Drug Inclusions – “CLDIs”) in macrophage lysosomes. Physicochemical considerations indicate that the intralysosomal stabilization of the self-assembled mechanopharmaceutical device depends on the pHmax of the weakly basic building block and its affinity for chloride, both of which are consistent with the pH and chloride content of a physiological lysosomal microenvironment. Most importantly, in vitro and in silico studies revealed that high expression levels of the vacuolar ATPase (V-ATPase), irrespective of the expression levels of chloride channels, are necessary and sufficient to explain the cell-type dependent formation, stabilization, and biocompatibility of the self-assembled mechanopharmaceutical device within macrophages.
Analyzing the genes related to nicotine addiction or schizophrenia via a pathway and network based approach
Authors: Hu Ying , Fang Zhonghai , Yang Yichen , Rohlsen-Neal Dekai , Cheng Feng , Wang Ju
Published: February 2018

The prevalence of tobacco use in people with schizophrenia is much higher than in general population, which indicates a close relationship between nicotine addiction and schizophrenia. However, the molecular mechanism underlying the high comorbidity of tobacco smoking and schizophrenia remains largely unclear. In this study, we conducted a pathway and network analysis on the genes potentially associated with nicotine addiction or schizophrenia to reveal the functional feature of these genes and their interactions. Of the 276 genes associated with nicotine addiction and 331 genes associated with schizophrenia, 52 genes were shared. From these genes, 12 significantly enriched pathways associated with both diseases were identified. These pathways included those related to synapse function and signaling transduction, and drug addiction. Further, we constructed a nicotine addiction-specific and schizophrenia-specific sub-network, identifying 11 novel candidate genes potentially associated with the two diseases. Finally, we built a schematic molecular network for nicotine addiction and schizophrenia based on the results of pathway and network analysis, providing a systematic view to understand the relationship between these two disorders. Our results illustrated that the biological processes underlying the comorbidity of nicotine addiction and schizophrenia was complex, and was likely induced by the dysfunction of multiple molecules and pathways.
Microarray profile of circular RNAs identifies hsa_circ_0014130 as a new circular RNA biomarker in non-small cell lung cancer
Authors: Zhang Shaoyan , Zeng Xiaoli , Ding Ting , Guo Lin , Li Yulong , Ou Songlei , Yuan Hui
Published: February 2018

Accumulating evidence has revealed that aberrant Circular RNAs (circRNAs) expression plays important roles in carcinogenesis and tumor progression. However, their role in non-small cell lung cancer (NSCLC) remains unclear. In this study, we first used circRNA microarrays to screen for tumour-specific circRNA candidates in between NSCLC (n = 3) and adjacent lung (n = 3) tissue. Among the circRNA expression profile, two circRNAs (hsa_circ_0014130 and hsa_circ_0016760) were selected for validation in ten pairs of NSCLC and adjacent non-cancerous tissues by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Only hsa_circ_0014130 exhibited significantly overexpressed in NSCLC tissues (P < 0.001), which were further confirmed in another 36 matched tissue samples using qRT-PCR. Hsa_circ_0014130 expression significantly correlated with TNM stage (P = 0.001) and lymphatic metastasis (P = 0.004). The area under the receiver operating characteristic curve was 0.878 (95% confidence interval = 0.804–0.951; P < 0.001), which showed good diagnostic potential. Bioinformatics platforms predicted that hsa_circ_0014130 might interact with five miRNAs and their corresponding mRNAs. Gene oncology analysis and pathway analysis revealed that hsa_circ_0014130 could participate in NSCLC development. In summary, our findings indicated that hsa_circ_0014130 could be used as a potential NSCLC biomarker and might be closely related to the carcinogenesis of NSCLC.