bluuebunny/crossref_metadata_2025 huggingface dataset:
HCC-derived exosomes elicit HCC progression and recurrence by epithelial-mesenchymal transition through MAPK/ERK signalling pathway
Authors: Chen Lu , Guo Piao , He Yuchao , Chen Ziye , Chen Liwei , Luo Yi , Qi Lisha , Liu Yuanyuan , Wu Qiang , Cui Yunlong , Fang Feng , Zhang Xiaofang , Song Tianqiang , Guo Hua
Published: May 2018

Liver cancer is the second most common cause of cancer-related death worldwide. Approximately 70–90% of primary liver cancers are hepatocellular carcinoma (HCC). Currently, HCC patient prognosis is unsatisfactory due to high metastasis and/or post-surgical recurrence rates. Therefore, new therapeutic methods for inhibiting metastasis and recurrence are urgently needed. Exosomes are small lipid-bilayer vesicles that are implicated in tumour development and metastasis. Rab27a, a small GTPase, regulates exosome secretion by mediating multivesicular endosome docking at the plasma membrane. However, whether Rab27a participates in HCC cell-derived exosome exocytosis is unclear. Epithelial-mesenchymal transition (EMT) frequently initiates metastasis. The role of HCC cell-derived exosomes in EMT remains unknown. We found that exosomes from highly metastatic MHCC97H cells could communicate with low metastatic HCC cells, increasing their migration, chemotaxis and invasion. Rab27a knockdown inhibited MHCC97H-derived exosome secretion, which consequently promoted migration, chemotaxis and invasion in parental MHCC97H cells. Mechanistic studies showed that the biological alterations in HCC cells treated with MHCC97H-derived exosomes or MHCC97H cells with reduced self-derived exosome secretion were caused by inducing EMT via MAPK/ERK signalling. Animal experiments indicated that exosome secretion blockade was associated with enhanced lung and intrahepatic metastasis of parental MHCC97H cells, while ectopic overexpression of Rab27a in MHCC97H cells could rescue this enhancement of metastasis in vivo. Injection of MHCC97H cell-derived exosomes through the tail vein promoted intrahepatic recurrence of HLE tumours in vivo. Clinically, Rab27a was positively associated with serum alpha-fetoprotein (AFP) level, vascular invasion and liver cirrhosis. Our study elucidated the role of exosomes in HCC metastasis and recurrence, suggesting that they are promising therapeutic and prognostic targets for HCC patients.
BRD7 inhibits the Warburg effect and tumor progression through inactivation of HIF1α/LDHA axis in breast cancer
Authors: Niu Weihong , Luo Yanwei , Wang Xinye , Zhou Yao , Li Hui , Wang Heran , Fu Yaojie , Liu Shanshan , Yin Shanghelin , Li Jianglei , Zhao Ran , Liu Yukun , Fan Songqing , Li Zheng , Xiong Wei , Li Xiaoling , Li Guiyuan , Ren Caiping , Tan Ming , Zhou Ming
Published: May 2018

The bromodomain-containing protein 7 (BRD7) was first identified as a tumor suppressor in nasopharyngeal carcinoma and has critical roles in cancer development and progression. However, the regulatory roles and mechanisms of BRD7 in cancer metabolism are still unknown. In this study, we demonstrated that BRD7 was lowly expressed in breast cancer tissues and was identified as a poor prognostic factor in breast cancer. Meanwhile, BRD7 could suppress cell proliferation, initiate cell apoptosis and reduce aerobic glycolysis, suggesting that BRD7 plays a tumor suppressive roles in breast cancer. Mechanistically, BRD7 could negatively regulate a critical glycolytic enzyme LDHA through directly interaction with its upstream transcription factor, HIF1α, facilitating degradation of HIF1α mediated by ubiquitin–proteasome pathway. Moreover, restoring the expression of LDHA in breast cancer cells could reverse the effect of BRD7 on aerobic glycolysis, cell proliferation, and tumor formation, as well as the expression of cell cycle and apopotosis related molecules such as cyclin D1, CDK4, P21, and c-PARP both in vitro and in vivo. Taken together, these results indicate that BRD7 acts as a tumor suppressor in breast cancer and represses the glycolysis and tumor progression through inactivation of HIF1α/LDHA transcription axis.
MiR-422a regulates cellular metabolism and malignancy by targeting pyruvate dehydrogenase kinase 2 in gastric cancer
Authors: He Zhongyuan , Li Zheng , Zhang Xuan , Yin Kai , Wang Weizhi , Xu Zhipeng , Li Bowen , Zhang Lei , Xu Jianghao , Sun Guangli , Wang Lu , Li Qing , Huang Xiaoxu , Zhang Lu , Zhang Diancai , Xu Hao , Xu Zekuan
Published: May 2018

Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays a crucial role in human malignancies. Here, we showed that microRNA-422a (miR-422a) expression was dramatically downregulated in gastric cancer (GC) samples and cell lines compared with normal controls, and that its expression level was inversely related to tumor size and depth of infiltration. Functional studies revealed that the overexpression of miR-422a in GC tumor cells suppressed cell proliferation and migration, and drove a metabolic shift from aerobic glycolysis to oxidative phosphorylation. Mechanistic analysis suggested that miR-422a repressed pyruvate dehydrogenase kinase 2 (PDK2) to restore activity of the pyruvate dehydrogenase (PDH), the gatekeeping enzyme that catalyzes the decarboxylation of pyruvate to produce acetyl-CoA. Importantly, we further demonstrated that the mir-422a–PDK2 axis also influenced another metabolic pathway, de novo lipogenesis in cancer cells, and that it subsequently affected reactive oxygen species (ROS) and RB phosphorylation levels, ultimately resulting in cell cycle arrest in G1 phase. Our findings show that the miR-422a–PDK2 axis is an important mediator in metabolic reprogramming and a promising therapeutic target for antitumor treatment.
Femtosecond X-ray coherent diffraction of aligned amyloid fibrils on low background graphene
Authors: Seuring Carolin , Ayyer Kartik , Filippaki Eleftheria , Barthelmess Miriam , Longchamp Jean-Nicolas , Ringler Philippe , Pardini Tommaso , Wojtas David H. , Coleman Matthew A. , Dörner Katerina , Fuglerud Silje , Hammarin Greger , Habenstein Birgit , Langkilde Annette E. , Loquet Antoine , Meents Alke , Riek Roland , Stahlberg Henning , Boutet Sébastien , Hunter Mark S. , Koglin Jason , Liang Mengning , Ginn Helen M. , Millane Rick P. , Frank Matthias , Barty Anton , Chapman Henry N.
Published: May 2018

Here we present a new approach to diffraction imaging of amyloid fibrils, combining a free-standing graphene support and single nanofocused X-ray pulses of femtosecond duration from an X-ray free-electron laser. Due to the very low background scattering from the graphene support and mutual alignment of filaments, diffraction from tobacco mosaic virus (TMV) filaments and amyloid protofibrils is obtained to 2.7 Å and 2.4 Å resolution in single diffraction patterns, respectively. Some TMV diffraction patterns exhibit asymmetry that indicates the presence of a limited number of axial rotations in the XFEL focus. Signal-to-noise levels from individual diffraction patterns are enhanced using computational alignment and merging, giving patterns that are superior to those obtainable from synchrotron radiation sources. We anticipate that our approach will be a starting point for further investigations into unsolved structures of filaments and other weakly scattering objects.
A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum
Authors: Roth Alison , Maher Steven P. , Conway Amy J. , Ubalee Ratawan , Chaumeau Victor , Andolina Chiara , Kaba Stephen A. , Vantaux Amélie , Bakowski Malina A. , Thomson-Luque Richard , Adapa Swamy Rakesh , Singh Naresh , Barnes Samantha J. , Cooper Caitlin A. , Rouillier Mélanie , McNamara Case W. , Mikolajczak Sebastian A. , Sather Noah , Witkowski Benoît , Campo Brice , Kappe Stefan H. I. , Lanar David E. , Nosten François , Davidson Silas , Jiang Rays H. Y. , Kyle Dennis E. , Adams John H.
Published: May 2018

Malaria liver stages represent an ideal therapeutic target with a bottleneck in parasite load and reduced clinical symptoms; however, current in vitro pre-erythrocytic (PE) models forPlasmodium vivaxandP.falciparumlack the efficiency necessary for rapid identification and effective evaluation of new vaccines and drugs, especially targeting late liver-stage development and hypnozoites. Herein we report the development of a 384-well plate culture system using commercially available materials, including cryopreserved primary human hepatocytes. Hepatocyte physiology is maintained for at least 30 days and supports development ofP.vivaxhypnozoites and complete maturation ofP.vivaxandP.falciparumschizonts. Our multimodal analysis in antimalarial therapeutic research identifies important PE inhibition mechanisms: immune antibodies against sporozoite surface proteins functionally inhibit liver stage development and ion homeostasis is essential for schizont and hypnozoite viability. This model can be implemented in laboratories in disease-endemic areas to accelerate vaccine and drug discovery research.
NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence
Authors: Parry Aled J. , Hoare Matthew , Bihary Dóra , Hänsel-Hertsch Robert , Smith Stephen , Tomimatsu Kosuke , Mannion Elizabeth , Smith Amy , D’Santos Paula , Russell I. Alasdair , Balasubramanian Shankar , Kimura Hiroshi , Samarajiwa Shamith A. , Narita Masashi
Published: May 2018

Senescent cells interact with the surrounding microenvironment achieving diverse functional outcomes. We have recently identified that NOTCH1 can drive ‘lateral induction’ of a unique senescence phenotype in adjacent cells by specifically upregulating the NOTCH ligand JAG1. Here we show that NOTCH signalling can modulate chromatin structure autonomously and non-autonomously. In addition to senescence-associated heterochromatic foci (SAHF), oncogenic RAS-induced senescent (RIS) cells exhibit a massive increase in chromatin accessibility. NOTCH signalling suppresses SAHF and increased chromatin accessibility in this context. Strikingly, NOTCH-induced senescent cells, or cancer cells with high JAG1 expression, drive similar chromatin architectural changes in adjacent cells through cell–cell contact. Mechanistically, we show that NOTCH signalling represses the chromatin architectural protein HMGA1, an association found in multiple human cancers. Thus, HMGA1 is involved not only in SAHFs but also in RIS-driven chromatin accessibility. In conclusion, this study identifies that the JAG1–NOTCH–HMGA1 axis mediates the juxtacrine regulation of chromatin architecture.
Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis
Authors: Karouzakis Emmanuel , Raza Karim , Kolling Christoph , Buckley Christopher D. , Gay Steffen , Filer Andrew , Ospelt Caroline
Published: May 2018

DNA methylation is an important epigenetic modification that is known to be altered in rheumatoid arthritis synovial fibroblasts (RASF). Here, we compared the status of promoter DNA methylation of SF from patients with very early RA with SF from patients with resolving arthritis, fully established RA and from non-arthritic patients. DNA was hybridized to Infinium Human methylation 450k and 850k arrays and differential methylated genes and pathways were identified. We could identify a significant number of CpG sites that differed between the SF of different disease stages, showing that epigenetic changes in SF occur early in RA development. Principal component analysis confirmed that the different groups of SF were separated according to their DNA methylation state. Furthermore, pathway analysis showed that important functional pathways were altered in both very early and late RASF. By focusing our analysis on CpG sites in CpG islands within promoters, we identified genes that have significant hypermethylated promoters in very early RASF. Our data show that changes in DNA methylation differ in RASF compared to other forms of arthritis and occur at a very early, clinically yet unspecific stage of disease. The identified differential methylated genes might become valuable prognostic biomarkers for RA development.
Screen and Verification for Transgene Integration Sites in Pigs
Authors: Ma Linyuan , Wang Yuzhe , Wang Haitao , Hu Yiqing , Chen Jingyao , Tan Tan , Hu Man , Liu Xiaojuan , Zhang Ran , Xing Yiming , Zhao Yiqiang , Hu Xiaoxiang , Li Ning
Published: May 2018

Efficient transgene expression in recipient cells constitutes the primary step in gene therapy. However, random integration in host genome comprises too many uncertainties. Our study presents a strategy combining bioinformatics and functional verification to find transgene integration sites in pig genome. Using an in silico approach, we screen out two candidate sites, namely, Pifs302 and Pifs501, located in actively transcribed intergenic regions with low nucleosome formation potential and without potential non-coding RNAs. After CRISPR/Cas9-mediated site-specific integration on Pifs501, we detected high EGFP expression in different pig cell types and ubiquitous EGFP expression in diverse tissues of transgenic pigs without adversely affecting 600 kb neighboring gene expression. Promoters integrated on Pifs501 exhibit hypomethylated modification, which suggest a permissive epigenetic status of this locus. We establish a versatile master cell line on Pifs501, which allows us to achieve site-specific exchange of EGFP to Follistatin with Cre/loxP system conveniently. Through in vitro and in vivo functional assays, we demonstrate the effectiveness of this screening method, and take Pifs501 as a potential site for transgene insertion in pigs. We anticipate that Pifs501 will have useful applications in pig genome engineering, though the identification of genomic safe harbor should over long-term various functional studies.
Genetic mapping identifies loci that influence tomato resistance against Colorado potato beetles
Authors: Vargas-Ortiz Erandi , Gonda Itay , Smeda John R. , Mutschler Martha A. , Giovannoni James J. , Jander Georg
Published: May 2018

The Colorado potato beetle (CPB; Leptinotarsa decemlineata Say), the most economically important insect pest on potato (Solanum tuberosum L.), also feeds on other Solanaceae, including cultivated tomato (Solanum lycopersicum L.). We used tomato genetic mapping populations to investigate natural variation in CPB resistance. CPB bioassays with 74 tomato lines carrying introgressions of Solanum pennellii in S. lycopersicum cv. M82 identified introgressions from S. pennellii on chromosomes 1 and 6 conferring CPB susceptibility, whereas introgressions on chromosomes 1, 8 and 10 conferred higher resistance. Mapping of CPB resistance using 113 recombinant inbred lines derived from a cross between S. lycopersicum cv UC-204B and Solanum galapagense identified significant quantitative trait loci on chromosomes 6 and 8. In each case, the S. galapagense alleles were associated with lower leaf damage and reduced larval growth. Results of both genetic mapping approaches converged on the same region of chromosome 6, which may have important functions in tomato defense against CPB herbivory. Although genetic mapping identified quantitative trait loci encompassing known genes for tomato acyl sugar and glycoalkaloid biosynthesis, experiments with acyl sugar near-isogenic lines and transgenic GAME9 glycoalkaloid-deficient and overproducing lines showed no significant effect of these otherwise insect-defensive metabolites on CPB performance.
Unexpectedly rapid evolution of mandibular shape in hominins
Authors: Raia P. , Boggioni M. , Carotenuto F. , Castiglione S. , Di Febbraro M. , Di Vincenzo F. , Melchionna M. , Mondanaro A. , Papini A. , Profico A. , Serio C. , Veneziano A. , Vero V. A. , Rook L. , Meloro C. , Manzi G.
Published: May 2018

Members of the hominins – namely the so-called ‘australopiths’ and the species of the genus Homo – are known to possess short and deep mandibles and relatively small incisors and canines. It is commonly assumed that this suite of traits evolved in early members of the clade in response to changing environmental conditions and increased consumption of though food items. With the emergence of Homo, the functional meaning of mandible shape variation is thought to have been weakened by technological advancements and (later) by the control over fire. In contrast to this expectation, we found that mandible shape evolution in hominins is exceptionally rapid as compared to any other primate clade, and that the direction and rate of shape change (from the ape ancestor) are no different between the australopiths and Homo. We deem several factors including the loss of honing complex, canine reduction, and the acquisition of different diets may have concurred in producing such surprisingly high evolutionary rates. This study reveals the evolution of mandibular shape in hominins has strong morpho-functional and ecological significance attached.
The relation between natural variations in ocean heat uptake and global mean surface temperature anomalies in CMIP5
Authors: Drijfhout Sybren
Published: May 2018

It is still unclear whether a hiatus period arises due to a vertical redistribution of ocean heat content (OHC) without changing ocean heat uptake (OHU), or whether the increasing radiative forcing is associated with an increase in OHU when global mean surface temperature (GMST) rise stalls. By isolating natural variability from forced trends and performing a more precise lead-lag analysis, we show that in climate models TOA radiation and OHU do anti-correlate with natural variations in GMST, when GMST leads or when they coincide, but the correlation changes sign when OHU leads. Surface latent and sensible heat fluxes always force GMST-variations, whilst net surface longwave and solar radiation fluxes have a damping effect, implying that natural GMST-variations are caused by oceanic heat redistribution. In the models an important trigger for a hiatus period on decadal timescales is increased reflection of solar radiation, by increased sea-ice cover over deep-water formation areas. On inter-annual timescales, reflection of solar radiation in the tropics by increased cloud cover associated with La Niña is most important and the subsequent reduction in latent heat release becomes the dominant cause for a hiatus.
A single amino acid substitution in the Bombyx-specific mucin-like membrane protein causes resistance to Bombyx mori densovirus
Authors: Ito Katsuhiko , Kidokoro Kurako , Katsuma Susumu , Sezutsu Hideki , Uchino Keiro , Kobayashi Isao , Tamura Toshiki , Yamamoto Kimiko , Mita Kazuei , Shimada Toru , Kadono-Okuda Keiko
Published: May 2018

Bombyx mori densovirus type 1 (BmDV) is a pathogen that causes flacherie disease in the silkworm. The absolute nonsusceptibility to BmDV among certain silkworm strains is determined independently by two genes, nsd-1 and Nid-1. However, neither of these genes has been molecularly identified to date. Here, we isolated the nsd-1 gene by positional cloning and characterized the properties of its product, NSD-1. Sequence and biochemical analyses revealed that this gene encodes a Bombyx-specific mucin-like glycoprotein with a single transmembrane domain. The NSD-1 protein was specifically expressed in the larval midgut epithelium, the known infection site of BmDV. Sequence analysis of the nsd-1 gene from 13 resistant and 12 susceptible strains suggested that a specific arginine residue in the extracellular tail of the NSD-1 protein was common among susceptible strains. Germline transformation of the susceptible-type nsd-1 (with a single nucleotide substitution) conferred partial susceptibility to resistant larvae, indicating that the + 
nsd-1
gene is required for the susceptibility of B. mori larvae to BmDV and the susceptibility is solely a result of the substitution of a single amino acid with arginine. Taken together, our results provide striking evidence that a novel membrane-bound mucin-like protein functions as a cell-surface receptor for a densovirus.
Calretinin Participates in Regulating Steroidogenesis by PLC-Ca2+-PKC Pathway in Leydig Cells
Authors: Xu Wendan , Zhu Qian , Liu Shan , Dai Xiaonan , Zhang Bei , Gao Chao , Gao Li , Liu Jiayin , Cui Yugui
Published: May 2018

Calretinin, a Ca2+-binding protein, participates in many cellular events. Our previous studies found the high expression of calretinin in testicular Leydig cells. In this study, (MLTC-1 cells were infected with LV-calb2, R2C cells with LV-siRNA-calb2. The primary mouse Leydig cells were also used to confirm those data from cell lines. Testosterone level was significantly higher in the MLTC-1 cells with over-expressed calretinin than in the control, while progesterone was lower in the R2C cells in which down-regulated calretinin. The expressions of StAR changed in synchrony with hormones. Cytoplasmic Ca2+ level was significantly increased when calretinin was over-expressed. When MLTC-1 cells were infected with LV-calb2 and then stimulated using Clopiazonic, a Ca2+-releasing agent, testosterone was significantly increased. Interestingly, the expression levels of PLC, p-PKCµ (PKD), p-MARCKS and CREB, were significantly increased in the MLTC-1 cells with over-expressed calretinin, while PLC, p-PKD, p-MARCKS, MARCKS and CREB were decreased in the R2C cells with down-regulated calretinin. We also observed the increased expression of calretinin up-regulated testosterone production and the expressions of StAR and PLC in primary mouse Leydig cells. So, calretinin as a Ca2+-binding protein participates in the regulation of steroidogenesis via the PLC-Ca2+-PKC pathway in Leydig cells.
Spin valley and giant quantum spin Hall gap of hydrofluorinated bismuth nanosheet
Authors: Gao Heng , Wu Wei , Hu Tao , Stroppa Alessandro , Wang Xinran , Wang Baigeng , Miao Feng , Ren Wei
Published: May 2018

Spin-valley and electronic band topological properties have been extensively explored in quantum material science, yet their coexistence has rarely been realized in stoichiometric two-dimensional (2D) materials. We theoretically predict the quantum spin Hall effect (QSHE) in the hydrofluorinated bismuth (Bi2HF) nanosheet where the hydrogen (H) and fluorine (F) atoms are functionalized on opposite sides of bismuth (Bi) atomic monolayer. Such Bi2HF nanosheet is found to be a 2D topological insulator with a giant band gap of 0.97 eV which might host room temperature QSHE. The atomistic structure of Bi2HF nanosheet is noncentrosymmetric and the spontaneous polarization arises from the hydrofluorinated morphology. The phonon spectrum and ab initio molecular dynamic (AIMD) calculations reveal that the proposed Bi2HF nanosheet is dynamically and thermally stable. The inversion symmetry breaking together with spin-orbit coupling (SOC) leads to the coupling between spin and valley in Bi2HF nanosheet. The emerging valley-dependent properties and the interplay between intrinsic dipole and SOC are investigated using first-principles calculations combined with an effective Hamiltonian model. The topological invariant of the Bi2HF nanosheet is confirmed by using Wilson loop method and the calculated helical metallic edge states are shown to host QSHE. The Bi2HF nanosheet is therefore a promising platform to realize room temperature QSHE and valley spintronics.
Unbiased estimation of an optical loss at the ultimate quantum limit with twin-beams
Authors: Losero Elena , Ruo-Berchera Ivano , Meda Alice , Avella Alessio , Genovese Marco
Published: May 2018

Loss measurements are at the base of spectroscopy and imaging, thus permeating all the branches of science, from chemistry and biology to physics and material science. However, quantum mechanics laws set the ultimate limit to the sensitivity, constrained by the probe mean energy. This can be the main source of uncertainty, for example when dealing with delicate systems such as biological samples or photosensitive chemicals. It turns out that ordinary (classical) probe beams, namely with Poissonian photon number distribution, are fundamentally inadequate to measure small losses with the highest sensitivity. It is known that quantum-correlated pair of beams, named “twin-beam state”, allows surpassing this classical limit. Here we demonstrate they can reach the ultimate sensitivity for all energy regimes (even less than one photon per mode) with the simplest measurement strategy. One beam of the pair addresses the sample, while the second one is used as a reference to compensate both for classical drifts and for fluctuation at the most fundamental quantum level. This capability of selfcompensating for unavoidable instability of the sources and detectors allows also to strongly reduce the bias in practical measurement. Moreover, we report the best sensitivity per photon ever achieved in loss estimation experiments.
Expressional analysis of disease-relevant signalling-pathways in primary tumours and metastasis of head and neck cancers
Authors: Goesswein Dorothee , Habtemichael Negusse , Gerhold-Ay Aslihan , Mazur Johanna , Wünsch Désirée , Knauer Shirley K. , Künzel Julian , Matthias Christoph , Strieth Sebastian , Stauber Roland H.
Published: May 2018

Head and neck squamous cell carcinoma (HNSCC) often metastasize to lymph nodes resulting in poor prognosis for patients. Unfortunately, the underlying molecular mechanisms contributing to tumour aggressiveness, recurrences, and metastasis are still not fully understood. However, such knowledge is key to identify biomarkers and drug targets to improve prognosis and treatments. Consequently, we performed genome-wide expression profiling of 15 primary HNSSCs compared to corresponding lymph node metastases and non-malignant tissue of the same patient. Differentially expressed genes were bioinformatically exploited applying stringent filter criteria, allowing the discrimination between normal mucosa, primary tumours, and metastases. Signalling networks involved in invasion contain remodelling of the extracellular matrix, hypoxia-induced transcriptional modulation, and the recruitment of cancer associated fibroblasts, ultimately converging into a broad activation of PI3K/AKT-signalling pathway in lymph node metastasis. Notably, when we compared the diagnostic and prognostic value of sequencing data with our expression analysis significant differences were uncovered concerning the expression of the receptor tyrosine kinases EGFR and ERBB2, as well as other oncogenic regulators. Particularly, upregulated receptor tyrosine kinase combinations for individual patients varied, implying potential compensatory and resistance mechanisms against specific targeted therapies. Collectively, we here provide unique transcriptional profiles for disease predictions and comprehensively analyse involved signalling pathways in advanced HNSCC.
Colon Cancer-Upregulated Long Non-Coding RNA lincDUSP Regulates Cell Cycle Genes and Potentiates Resistance to Apoptosis
Authors: Forrest Megan E. , Saiakhova Alina , Beard Lydia , Buchner David A. , Scacheri Peter C. , LaFramboise Thomas , Markowitz Sanford , Khalil Ahmad M.
Published: May 2018

Long non-coding RNAs (lncRNAs) are frequently dysregulated in many human cancers. We sought to identify candidate oncogenic lncRNAs in human colon tumors by utilizing RNA sequencing data from 22 colon tumors and 22 adjacent normal colon samples from The Cancer Genome Atlas (TCGA). The analysis led to the identification of ~200 differentially expressed lncRNAs. Validation in an independent cohort of normal colon and patient-derived colon cancer cell lines identified a novel lncRNA, lincDUSP, as a potential candidate oncogene. Knockdown of lincDUSP in patient-derived colon tumor cell lines resulted in significantly decreased cell proliferation and clonogenic potential, and increased susceptibility to apoptosis. The knockdown of lincDUSP affects the expression of ~800 genes, and NCI pathway analysis showed enrichment of DNA damage response and cell cycle control pathways. Further, identification of lincDUSP chromatin occupancy sites by ChIRP-Seq demonstrated association with genes involved in the replication-associated DNA damage response and cell cycle control. Consistent with these findings, lincDUSP knockdown in colon tumor cell lines increased both the accumulation of cells in early S-phase and γH2AX foci formation, indicating increased DNA damage response induction. Taken together, these results demonstrate a key role of lincDUSP in the regulation of important pathways in colon cancer.
Anomalous Scaling of Gene Expression in Confined Cell-Free Reactions
Authors: Sakamoto Ryota , Noireaux Vincent , Maeda Yusuke T.
Published: May 2018

Cellular surface breaks the symmetry of molecular diffusion across membrane. Here, we study how steric interactions between the surface and the bulk of cell-sized emulsion droplets alters gene expression emulated by a cell-free transcription/translation (TXTL) system. The concentration of synthesized reporter proteins in droplets of radius R shows an anomalous geometric scaling of R4 different from the expected size-dependence of R3. Given that TXTL becomes less efficient at thin surface layer, a mathematical model explains the anomalous size-dependence found in experiment. The surface of cell-sized compartment can thus play a regulatory role for cell-free gene expression.
Radioprotective effect of Date syrup on radiation- induced damage in Rats
Authors: Abou-Zeid Shimaa M. , EL-bialy Badr E. , EL-borai Nermeen B. , AbuBakr Huda O. , Elhadary Abdel Monsef A.
Published: May 2018

Ionizing radiation has cytotoxic and genotoxic effects caused mainly by the oxidative damage induced by free radical release. The need for radioprotectives is increasing to protect normal tissues during radiotherapy. In the present study, we investigated the radioprotective effect of Date syrup in rats subjected to whole body radiation at 6 Gy through biochemical, molecular and histopathological analysis. Significant elevations were recorded in the activities of serum ALT, AST, ALP and LDH and in the levels of all lipid profiles parameters, while the level of HDL-C was reduced. The concentration of liver MDA was elevated with depletion of hepatic glutathione (GSH) and catalase. DNA damage was evidenced by increased DNA strand breakage and DNA-protein crosslinks. Significant elevations were observed in the expression of liver TNF-α and serum activity of matrix metalloproteinase (MMP-9). Pretreatment of rats with Date syrup ameliorated the tissue damage induced by radiation as evidenced by the improvement of liver function, antioxidant status and reduction of DNA damage. Besides, liver TNF-α expression and serum MMP-9 activity were reduced. In conclusion, Date syrup could alleviate the toxic effects of ionizing radiation and thus is useful as a radioprotective in radiotherapy regimen.
Integrated analysis highlights APC11 protein expression as a likely new independent predictive marker for colorectal cancer
Authors: Drouet Youenn , Treilleux Isabelle , Viari Alain , Léon Sophie , Devouassoux-Shisheboran Mojgan , Voirin Nicolas , de la Fouchardière Christelle , Manship Brigitte , Puisieux Alain , Lasset Christine , Moyret-Lalle Caroline
Published: May 2018

After a diagnosis of colorectal cancer (CRC), approximately 50% of patients will present distant metastasis. Although significant progress has been made in treatments, most of them will die from the disease. We investigated the predictive and prognostic potential of APC11, the catalytic subunit of APC/C, which has never been examined in the context of CRC. The expression of APC11 was assessed in CRC cell lines, in tissue microarrays (TMAs) and in public datasets. Overexpression of APC11 mRNA was associated with chromosomal instability, lymphovascular invasion and residual tumor. Regression models accounting for the effects of well-known protein markers highlighted association of APC11 protein expression with residual tumor (odds ratio: OR = 6.51; 95% confidence intervals: CI = 1.54–27.59; P = 0.012) and metastasis at diagnosis (OR = 3.87; 95% CI = 1.20–2.45; P = 0.024). Overexpression of APC11 protein was also associated with worse distant relapse-free survival (hazard ratio: HR = 2.60; 95% CI = 1.26–5.37; P = 0.01) and worse overall survival (HR = 2.69; 95% CI = 1.31–5.51; P = 0.007). APC11 overexpression in primary CRC thus represents a potentially novel theranostic marker of metastatic CRC.
Drivers of demographic decline across the annual cycle of a threatened migratory bird
Authors: Wilson Scott , Saracco James F. , Krikun Richard , Flockhart D. T. Tyler , Godwin Christine M. , Foster Kenneth R.
Published: May 2018

Migratory species are rapidly declining but we rarely know which periods of the annual cycle are limiting for most species. This knowledge is needed to effectively allocate conservation resources to the periods of the annual cycle that best promote species recovery. We examined demographic trends and response to human footprint for Canada warblers (Cardellina canadensis), a threatened Neotropical migrant, using range-wide data (1993–2016) from the Monitoring Avian Productivity and Survivorship (MAPS) program on the breeding grounds. Declines in abundance were steepest in the eastern breeding region, followed by the western region. Breeding productivity did not decline in any region. In contrast, we observed declining recruitment in all regions, low apparent survival in the east and west, and a decline in apparent survival in the east. Abundance declined with increasing disturbance around MAPS stations. Between 1993 and 2009, the human footprint index on the breeding range increased by 0.11% in contrast to a 14% increase on the wintering range. Landscape-scale disturbance on the breeding grounds may influence abundance in some regions; however, the observed trends in demography and footprint suggests limitation during the non-breeding period as the likely driver of overall declines, particularly for eastern populations.
Replication study of polymorphisms associated with response to methotrexate in patients with rheumatoid arthritis
Authors: López-Rodríguez Rosario , Ferreiro-Iglesias Aida , Lima Aurea , Bernardes Miguel , Pawlik Andrzej , Paradowska-Gorycka Agnieszka , Świerkot Jerzy , Slezak Ryszard , Dolžan Vita , González-Álvaro Isidoro , Narváez Javier , Cáliz Rafael , Pérez-Pampín Eva , Mera-Varela Antonio , Vidal-Bralo Laura , Acuña Ochoa José Gorgonio , Conde Carmen , Gómez-Reino Juan J. , González Antonio
Published: May 2018

About 70 genetic studies have already addressed the need of biomarkers to predict the response of patients with rheumatoid arthritis (RA) to methotrexate (MTX) treatment. However, no genetic biomarker has yet been sufficiently validated. Here, we aimed to replicate a selection of 25 SNPs in the largest collection of patients up to date, which consisted of 915 patients treated with MTX. The change in disease activity (measured as ΔDAS28) from baseline was considered the primary outcome. In addition, response according to widely used criteria (EULAR) was taken as secondary outcome. We considered consistency between outcomes, P values accounting for the number of SNPs, and independence from potential confounders for interpretation of the results. Only the rs1801394 SNP in MTRR fulfilled the high association standards. Its minor allele was associated with less improvement than the major allele according to ΔDAS28 (p = 0.0016), and EULAR response (p = 0.004), with independence of sex, age, baseline DAS28, smoking, seropositivity, concomitant corticosteroid use or previous treatments. In addition, previous evidence suggests the association of this SNP with response to MTX in another autoimmune disease, juvenile idiopathic arthritis, and with high intracellular folate levels, which could contribute to poor response.
Low-Yellowing Phosphor-in-Glass for High-Power Chip-on-board White LEDs by Optimizing a Low-Melting Sn-P-F-O Glass Matrix
Authors: Yoon Hee Chang , Yoshihiro Kouhara , Yoo Heeyeon , Lee Seung Woo , Oh Ji Hye , Do Young Rag
Published: May 2018

We introduce a low-melting-point (MP) Sn-P-F-O glass ceramic material into the phosphor-in-glass (PIG) material to realize an ‘on-chip’ chip-on-board (COB) type of phosphor-converted (pc) white light-emitting diode (WLED) with green (BaSr)2SiO4:Eu2+ and red (SrCa)AlSiN3:Eu2+ (SCASN) phosphors. The optimum Sn-P-F-O-based ceramic components can be sintered into the glass phase with a facile one-step heating process at 285 °C for 1 min. Specifically, these soft-fabrication conditions can be optimized to minimize the degradation of the luminescent properties of the red SCASN phosphor as well as the green silicate phosphor in PIG-based white COB-type pc-LEDs owing to the low thermal loss of the phosphors at low fabrication temperatures below 300 °C. Moreover, the constituents of the COB package, in this case the wire bonding and plastic exterior, can be preserved simultaneously from thermal damage. That is, the low sintering temperature of the glass ceramic encapsulant is a very important factor to realize excellent optical qualities of white COB LEDs. The optical performances of low-MP Sn-P-F-O-based PIG on-chip COB-type pc-WLEDs exhibit low yellowing phenomena, good luminous efficacy of 70.9–86.0 lm/W, excellent color rendering index of 94–97 with correlated color temperatures from 2700 to 10000 K, and good long-term stability.
Clinical evaluation of silicone gel in the treatment of cleft lip scars
Authors: Chang Chun-Shin , Wallace Christopher Glenn , Hsiao Yen-Chang , Huang Jung-Ju , Chen Zung-Chung , Chang Chee-Jen , Lo Lun-Jou , Chen Philip Kuo-Ting , Chen Jyh-Ping , Chen Yu-Ray
Published: May 2018

Upper lip scars are at risk of hypertrophy. Our center therefore uses microporous tape and silicone sheeting for postoperative scar care following cleft lip repair. However, some babies have previously ingested their silicone sheeting, which has the potential for respiratory compromise or gastrointestinal obstruction. Self-dry silicone gel is reportedly also effective for preventing hypertrophic scars. Hence, we sought to test whether silicone gel, which cannot be ingested whole, might be non-inferior to silicone sheeting for controlling against upper lip scar hypertrophy. This was a mixed prospective and retrospective case-controlled clinical trial involving patients undergoing unilateral cleft lip repair, 29 of whom received standard postoperative silicone sheeting (control group) and another 33 age-matched consecutive patients who received self-dry silicone instead. The Vancouver scar scale, visual analogue scale and photographically assessed scar width assessments were the same in both groups at six months after surgery. In conclusion, silicone gel appears to be non-inferior to silicone sheeting for postoperative care of upper lip scars as judged by scar quality at six months, but silicone sheeting has the safety disadvantage that it can be swallowed whole by babies. It is thus recommended that silicone gel be used for upper lip scar management in babies.
Assessment of Pulmonary Gas Transport in Rabbits Using Hyperpolarized Xenon-129 Magnetic Resonance Imaging
Authors: Ruppert Kai , Hamedani Hooman , Amzajerdian Faraz , Xin Yi , Duncan Ian F. , Profka Harrilla , Siddiqui Sarmad , Pourfathi Mehrdad , Kadlecek Stephen , Rizi Rahim R.
Published: May 2018

Many forms of lung disease manifest themselves as pathological changes in the transport of gas to the circulatory system, yet the difficulty of imaging this process remains a central obstacle to the comprehensive diagnosis of lung disorders. Using hyperpolarized xenon-129 as a surrogate marker for oxygen, we derived the temporal dynamics of gas transport from the ratio of two lung images obtained with different timing parameters. Additionally, by monitoring changes in the total hyperpolarized xenon signal intensity in the left side of the heart induced by depletion of xenon signal in the alveolar airspaces of interest, we quantified the contributions of selected lung volumes to the total pulmonary gas transport. In a rabbit model, we found that it takes at least 200 ms for xenon gas to enter the lung tissue and travel the distance from the airspaces to the heart. Additionally, our method shows that both lungs contribute fairly equally to the gas transport in healthy rabbits, but that this ratio changes in a rabbit model of acid aspiration. These results suggest that hyperpolarized xenon-129 MRI may improve our ability to measure pulmonary gas transport and detect associated pathological changes.
Molecular mechanism of ER stress-induced pre-emptive quality control involving association of the translocon, Derlin-1, and HRD1
Authors: Kadowaki Hisae , Satrimafitrah Pasjan , Takami Yasunari , Nishitoh Hideki
Published: May 2018

The maintenance of endoplasmic reticulum (ER) homeostasis is essential for cell function. ER stress-induced pre-emptive quality control (ERpQC) helps alleviate the burden to a stressed ER by limiting further protein loading. We have previously reported the mechanisms of ERpQC, which includes a rerouting step and a degradation step. Under ER stress conditions, Derlin family proteins (Derlins), which are components of ER-associated degradation, reroute specific ER-targeting proteins to the cytosol. Newly synthesized rerouted polypeptides are degraded via the cytosolic chaperone Bag6 and the AAA-ATPase p97 in the ubiquitin-proteasome system. However, the mechanisms by which ER-targeting proteins are rerouted from the ER translocation pathway to the cytosolic degradation pathway and how the E3 ligase ubiquitinates ERpQC substrates remain unclear. Here, we show that ERpQC substrates are captured by the carboxyl-terminus region of Derlin-1 and ubiquitinated by the HRD1 E3 ubiquitin ligase prior to degradation. Moreover, HRD1 forms a large ERpQC-related complex composed of Sec61α and Derlin-1 during ER stress. These findings indicate that the association of the degradation factor HRD1 with the translocon and the rerouting factor Derlin-1 may be necessary for the smooth and effective clearance of ERpQC substrates.
Cloning and characterization of a pyrethroid pesticide decomposing esterase gene, Est3385, from Rhodopseudomonas palustris PSB-S
Authors: Luo Xiangwen , Zhang Deyong , Zhou Xuguo , Du Jiao , Zhang Songbai , Liu Yong
Published: May 2018

Full length open reading frame of pyrethroid detoxification gene, Est3385, contains 963 nucleotides. This gene was identified and cloned based on the genome sequence of Rhodopseudomonas palustris PSB-S available at the GneBank. The predicted amino acid sequence of Est3385 shared moderate identities (30–46%) with the known homologous esterases. Phylogenetic analysis revealed that Est3385 was a member in the esterase family I. Recombinant Est3385 was heterologous expressed in E. coli, purified and characterized for its substrate specificity, kinetics and stability under various conditions. The optimal temperature and pH for Est3385 were 35 °C and 6.0, respectively. This enzyme could detoxify various pyrethroid pesticides and degrade the optimal substrate fenpropathrin with a Km and Vmax value of 0.734 ± 0.013 mmol·l−1 and 0.918 ± 0.025 U·µg−1, respectively. No cofactor was found to affect Est3385 activity but substantial reduction of enzymatic activity was observed when metal ions were applied. Taken together, a new pyrethroid degradation esterase was identified and characterized. Modification of Est3385 with protein engineering toolsets should enhance its potential for field application to reduce the pesticide residue from agroecosystems.
Development of a lab-on-a-chip method for rapid assay of Xylella fastidiosa subsp. pauca strain CoDiRO
Authors: Chiriacò Maria Serena , Luvisi Andrea , Primiceri Elisabetta , Sabella Erika , De Bellis Luigi , Maruccio Giuseppe
Published: May 2018

Xylella fastidiosa subsp. pauca strain CoDiRO, a pathogen responsible for Olive Quick Decline Syndrome (OQDS), is strongly threatening the agricultural-based economy of South Italy and making its typical landscape collapse. The bacteria can also infect more than other twenty woody or shrub species and quarantine programs are carried out in Italy. Since symptoms of OQDS like leaf scorching and wilting of canopy may appear several months after infection and some hosts are asymptomatic, a tool for the rapid and early screening of plants is desirable, in order to plan a sudden control strategy and apply programs for pest management. X. fastidiosa detection is usually performed by ELISA and PCR methods. In this work, the two standard methods are compared with an innovative on-chip detection strategy for X. fastidiosa assay from leaves samples, based on an electrochemical transduction method. The realized lab-on-chip includes also a microfluidic module and its performances are competitive with conventional diagnostic methods in terms of reliability, but with further advantages of portability, low-costs and ease of use. Thus, the proposed technology has the potential to provide a useful assay method for large-scale monitoring programs.
MHD convective heat transfer in a discretely heated square cavity with conductive inner block using two-phase nanofluid model
Authors: Alsabery A. I. , Sheremet M. A. , Chamkha A. J. , Hashim I.
Published: May 2018

The problem of steady, laminar natural convection in a discretely heated and cooled square cavity filled by an alumina/water nanofluid with a centered heat-conducting solid block under the effects of inclined uniform magnetic field, Brownian diffusion and thermophoresis is studied numerically by using the finite difference method. Isothermal heaters and coolers are placed along the vertical walls and the bottom horizontal wall, while the upper horizontal wall is kept adiabatic. Water-based nanofluids with alumina nanoparticles are chosen for investigation. The governing parameters of this study are the Rayleigh number (103 ≤ Ra ≤ 106), the Hartmann number (0 ≤ Ha ≤ 50), thermal conductivity ratio (0.28 ≤ k
w
 ≤ 16), centered solid block size (0.1 ≤ D ≤ 0.7) and the nanoparticles volume fraction (0 ≤ ϕ ≤ 0.04). The developed computational code is validated comprehensively using the grid independency test and numerical and experimental data of other authors. The obtained results reveal that the effects of the thermal conductivity ratio, centered solid block size and the nanoparticles volume fraction are non-linear for the heat transfer rate. Therefore, it is possible to find optimal parameters for the heat transfer enhancement in dependence on the considered system. Moreover, high values of the Rayleigh number and nanoparticles volume fraction characterize homogeneous distributions of nanoparticles inside the cavity. High concentration of nanoparticles can be found near the centered solid block where thermal plumes from the local heaters interact.
Substrate specificity of human MCPIP1 endoribonuclease
Authors: Wilamowski Mateusz , Gorecki Andrzej , Dziedzicka-Wasylewska Marta , Jura Jolanta
Published: May 2018

MCPIP1, also known as Regnase-1, is a ribonuclease crucial for regulation of stability of transcripts related to inflammatory processes. Here, we report that MCPIP1 acts as an endonuclease by degrading several stem-loop RNA structures and single-stranded RNAs. Our studies revealed cleavage sites present in the stem-loops derived from the 3′ untranslated region of the interleukin-6 transcript. Furthermore, MCPIP1 induced endonuclease cleavage at the loop motif of stem-loop structures. Additionally, we observed that MCPIP1 could cleave single-stranded RNA fragments. However, RNA substrates shorter than 6 nucleotides were not further affected by MCPIP1 nucleolytic activity. In this study, we also determined the dissociation constants of full-length MCPIP1D141N and its ribonuclease domain PIN D141N with twelve oligonucleotides substrates. The equilibrium binding constants (Kd) for MCPIP1D141N and the RNA targets were approximately 10 nM. Interestingly, we observed that the presence of a zinc finger in the PIN domain increases the affinity of this protein fragment to 25-nucleotide-long stem-loop RNA but not to shorter ones. Furthermore, size exclusion chromatography of the MCPIP1 and PIN proteins suggested that MCPIP1 undergoes homooligomerization during interaction with RNA substrates. Our results provide insight into the mechanism of MCPIP1 substrate recognition and its affinity towards various oligonucleotides.