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  • Cell Research
    also abrogates Parkin mitochondrial translocation indicating that E3 activity is essential for Parkin translocation We found that Parkin can bind to K63 linked ubiquitin chains and that targeting K63 mimicking ubiquitin chains to mitochondria restores Parkin C431S localization We propose that Parkin translocation is achieved through a novel catalytic activity coupled mechanism ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor associated macrophages Yan Zhang 1 Swati Choksi 1 Kun Chen 1 2 Yelena Pobezinskaya 1 Ilona Linnoila 1 and Zheng Gang Liu 1 10 1038 cr 2013 75 Full Text PDF Differentiation to different types of macrophages determines their distinct functions Tumor associated macrophages TAMs promote tumorigenesis owing to their proangiogenic and immune suppressive functions similar to those of alternatively activated M2 macrophages We report that reactive oxygen species ROS production is critical for macrophage differentiation and that inhibition of superoxide O2 production specifically blocks the differentiation of M2 macrophages We found that when monocytes are triggered to differentiate O2 is generated and is needed for the biphasic ERK activation which is critical for macrophage differentiation We demonstrated that ROS elimination by butylated hydroxyanisole BHA and other ROS inhibitors blocks macrophage differentiation However the inhibitory effect of ROS elimination on macrophage differentiation is overcome when cells are polarized to classically activated M1 but not M2 macrophages More importantly the continuous administration of the ROS inhibitor BHA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models Targeting TAMs by blocking ROS can be a potentially effective method for cancer treatment ALDH2 protects against stroke by clearing 4 HNE Jin Min Guo 1 2 Ai Jun Liu 1 Pu Zang1 Wen Zhe Dong1 Li Ying 3 Wei Wang 1 Pu Xu 1 Xu Rui Song 1 Jun Cai 4 She Qing Zhang 5 Jun Li Duan 6 Jawahar L Mehta 7 and Ding Feng Su 1 10 1038 cr 2013 69 Full Text PDF Aldehyde dehydrogenase 2 ALDH2 is a mitochondrial enzyme that metabolizes ethanol and toxic aldehydes such as 4 hydroxy 2 nonenal 4 HNE Using an unbiased proteomic search we identified ALDH2 deficiency in stroke prone spontaneously hypertensive rats SHR SP as compared with spontaneously hypertensive rats SHR We concluded the causative role of ALDH2 deficiency in neuronal injury as overexpression or activation of ALDH2 conferred neuroprotection by clearing 4 HNE in in vitro studies Further ALDH2 knockdown rats revealed the absence of neuroprotective effects of PKCε Moderate ethanol administration that is known to exert protection against stroke was shown to enhance the detoxification of 4 HNE and to protect against ischemic cerebral injury through the PKCε ALDH2 pathway In SHR SP serum 4 HNE level was persistently elevated and correlated inversely with the lifespan The role of 4 HNE in stroke in humans was also suggested by persistent elevation of its plasma levels for at least 6 months after stroke Lastly we observed that 21 of 1 242 subjects followed for 8 years who developed

    Original URL path: http://www.cell-research.com/artsmore.asp?id=157 (2016-02-14)
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  • Cell Research
    and found Mlkl to be dispensable for normal mouse development as well as immune cell development Mlkl deficient mouse embryonic fibroblasts MEFs and macrophages both showed resistance to necrotic but not apoptotic stimuli Mlkl deficient MEFs and macrophages were indistinguishable from wild type cells in their ability to activate NF κB ERK JNK and p38 in response to TNF and lipopolysaccharides LPS respectively Consistently Mlkl deficient macrophages and mice exhibited normal interleukin 1β IL 1β IL 6 and TNF production after LPS treatment Mlkl deficiency protects mice from cerulean induced acute pancreatitis a necrosis related disease but has no effect on polymicrobial septic shock induced animal death Our results provide genetic evidence for the role of Mlkl in necroptosis Production of ACAT1 56 kDa isoform in human cells via trans splicing involving the ampicillin resistance gene Guang Jing Hu 1 Jia Chen 1 Xiao Nan Zhao 1 Jia Jia Xu 1 Dong Qing Guo 1 Ming Lu 1 Ming Zhu 1 Ying Xiong 1 Qin Li 1 Catherine CY Chang 2 Bao Liang Song 1 Ta Yuan Chang 2 and Bo Liang Li 1 10 1038 cr 2013 86 Full Text PDF Trans splicing a process involving the cleavage and joining of two separate transcripts can expand the transcriptome and proteome in eukaryotes Chimeric RNAs generated by trans splicing are increasingly described in literatures The widespread presence of antibiotic resistance genes in natural environments and human intestines is becoming an important challenge for public health Certain antibiotic resistance genes such as ampicillin resistance gene Ampr are frequently used in recombinant plasmids Until now trans splicing involving recombinant plasmid derived exogenous transcripts and endogenous cellular RNAs has not been reported Acyl CoA cholesterol acyltransferase 1 ACAT1 is a key enzyme involved in cellular cholesterol homeostasis The 4 3 kb human ACAT1 chimeric mRNA can produce 50 kDa and 56 kDa isoforms with different enzymatic activities Here we show that human ACAT1 56 kDa isoform is produced from an mRNA species generated through the trans splicing of an exogenous transcript encoded by the antisense strand of Ampr asAmp present in common Ampr plasmids and the 4 3 kb endogenous ACAT1 chimeric mRNA which is presumably processed through a prior event of interchromosomal trans splicing Strikingly DNA fragments containing the asAmp with an upstream recombined cryptic promoter and the corresponding exogenous asAmp transcripts have been detected in human cells Our findings shed lights on the mechanism of human ACAT1 56 kDa isoform production reveal an exogenous endogenous trans splicing system in which recombinant plasmid derived exogenous transcripts are linked with endogenous cellular RNAs in human cells and suggest that exogenous DNA might affect human gene expression at both DNA and RNA levels Viral degradasome hijacks mitochondria to suppress innate immunity Ramansu Goswami 1 Tanmay Majumdar 1 Jayeeta Dhar 1 Saurabh Chattopadhyay 2 Sudip K Bandyopadhyay 2 Valentina Verbovetskaya 1 Ganes C Sen 2 and Sailen Barik 1 10 1038 cr 2013 98 Full Text PDF The balance between the innate immunity of the

    Original URL path: http://www.cell-research.com/artsmore.asp?id=158 (2016-02-14)
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  • Cell Research
    coronary arteries and veins Collectively these data suggested that subepicardial ECs are the major source of intramyocardial coronary arteries in the ventricle wall and that coronary arteries and veins have a common origin in the developing heart Genome analysis and signature discovery for diving and sensory properties of the endangered Chinese alligator Qiu Hong Wan 1 Sheng Kai Pan 2 Li Hu 2 Ying Zhu 1 Peng Wei Xu 2 Jin Quan Xia 2 Hui Chen 1 Gen Yun He 2 Jing He 2 Xiao Wei Ni 1 Hao Long Hou 2 Sheng Guang Liao 2 Hai Qiong Yang 1 Ying Chen 2 Shu Kun Gao 2 Yun Fa Ge 1 Chang Chang Cao 2 Peng Fei Li 2 Li Ming Fang 3 Li Liao 2 Shu Zhang 2 Meng Zhen Wang 1 Wei Dong 2 and Sheng Guo Fang 1 10 1038 cr 2013 104 Full Text PDF Crocodilians are diving reptiles that can hold their breath under water for long periods of time and are crepuscular animals with excellent sensory abilities They comprise a sister lineage of birds and have no sex chromosome Here we report the genome sequence of the endangered Chinese alligator Alligator sinensis and describe its unique features The next generation sequencing generated 314 Gb of raw sequence yielding a genome size of 2 3 Gb A total of 22 200 genes were predicted in Alligator sinensis using a de novo homology and RNA based combined model The genetic basis of long diving behavior includes duplication of the bicarbonate binding hemoglobin gene co functioning of routine phosphate binding and special bicarbonate binding oxygen transport and positively selected energy metabolism ammonium bicarbonate excretion and cardiac muscle contraction Further we elucidated the robust Alligator sinensis sensory system including a significantly expanded olfactory receptor repertoire rapidly evolving nerve related cellular components and visual perception and positive selection of the night vision related opsin and sound detection associated otopetrin We also discovered a well developed immune system with a considerable number of lineage specific antigen presentation genes for adaptive immunity as well as expansion of the tripartite motif containing C type lectin and butyrophilin genes for innate immunity and expression of antibacterial peptides Multifluorescence in situ hybridization showed that alligator chromosome 3 which encodes DMRT1 exhibits significant synteny with chicken chromosome Z Finally population history analysis indicated population admixture 0 60 1 05 million years ago when the Qinghai Tibetan Plateau was uplifted The gating charge pathway of an epilepsy associated potassium channel accommodates chemical ligands Ping Li 1 Zhuxi Chen 2 Haiyan Xu 1 Haifeng Sun 2 Hao Li 2 Hong Liu 2 Huaiyu Yang 2 Zhaobing Gao 1 Hualiang Jiang 2 and Min Li 1 3 10 1038 cr 2013 82 Full Text PDF Voltage gated potassium Kv channels derive their voltage sensitivity from movement of gating charges in voltage sensor domains VSDs The gating charges translocate through a physical pathway in the VSD to open or close the channel Previous studies showed that the gating charge

    Original URL path: http://www.cell-research.com/artsmore.asp?id=159 (2016-02-14)
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  • Cell Research
    high specificity of the system Driving vascular endothelial cell fate of human multipotent Isl1 heart progenitors with VEGF modified mRNA Kathy O Lui1 2 3 Lior Zangi 1 2 4 Eduardo A Silva 5 6 Lei Bu 1 2 3 Makoto Sahara 1 2 Ronald A Li 3 7 David J Mooney 5 and Kenneth R Chien 1 2 8 10 1038 cr 2013 112 Full Text PDF Distinct families of multipotent heart progenitors play a central role in the generation of diverse cardiac smooth muscle and endothelial cell lineages during mammalian cardiogenesis The identification of precise paracrine signals that drive the cell fate decision of these multipotent progenitors and the development of novel approaches to deliver these signals in vivo are critical steps towards unlocking their regenerative therapeutic potential Herein we have identified a family of human cardiac endothelial intermediates located in outflow tract of the early human fetal hearts OFT ECs characterized by coexpression of Isl1 and CD144 vWF By comparing angiocrine factors expressed by the human OFT ECs and non cardiac ECs vascular endothelial growth factor VEGF A was identified as the most abundantly expressed factor and clonal assays documented its ability to drive endothelial specification of human embryonic stem cell ESC derived Isl1 progenitors in a VEGF receptor dependent manner Human Isl1 ECs endothelial cells differentiated from hESC derived ISL1 progenitors resemble OFT ECs in terms of expression of the cardiac endothelial progenitor and endocardial cell specific genes confirming their organ specificity To determine whether VEGF A might serve as an in vivo cell fate switch for human ESC derived Isl1 ECs we established a novel approach using chemically modified mRNA as a platform for transient yet highly efficient expression of paracrine factors in cardiovascular progenitors Overexpression of VEGF A promotes not only the endothelial specification but also engraftment proliferation and survival reduced apoptosis of the human Isl1 progenitors in vivo The large scale derivation of cardiac specific human Isl1 ECs from human pluripotent stem cells coupled with the ability to drive endothelial specification engraftment and survival following transplantation suggest a novel strategy for vascular regeneration in the heart Generation of haploid embryonic stem cells from Macaca fascicularis monkey parthenotes Hui Yang 1 Zhen Liu 2 Yu Ma 3 Cuiqing Zhong 1 Qi Yin 1 Chikai Zhou 1 4 Linyu Shi 1 Yijun Cai 2 Hanzhi Zhao 3 Hui Wang 5 Fan Tang 3 Yan Wang 2 Chenchen Zhang 2 Xin yuan Liu 4 Dongmei Lai 5 Ying Jin 3 Qiang Sun 2 and Jinsong Li 1 10 1038 cr 2013 93 Full Text PDF Recent success in the derivation of haploid embryonic stem cells haESCs from mouse via parthenogenesis and androgenesis has enabled genetic screening in mammalian cells and generation of gene modified animals However whether haESCs can be derived from primates remains unknown Here we report the derivation of haESCs from parthenogenetic blastocysts of Macaca fascicularis monkeys These cells termed as PG haESCs are pluripotent and can differentiate to cells of three embryonic germ

    Original URL path: http://www.cell-research.com/artsmore.asp?id=160 (2016-02-14)
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  • Cell Research
    recruitment of HDACs MicroRNA 124 mediates the cholinergic anti inflammatory action through inhibiting the production of pro inflammatory cytokines OPEN Yang Sun 1 Qi Li 1 Huan Gui 1 Dong Ping Xu 1 Yi Li Yang 2 Ding Feng Su 1 and Xia Liu 1 10 1038 cr 2013 116 Full Text PDF The vagus nerve can control inflammatory response through a cholinergic anti inflammatory pathway which is mediated by the α7 nicotinic acetylcholine receptor α7nAChR on macrophages However the intracellular mechanisms that link α7nAChR activation and pro inflammatory cytokine production remain not well understood In this study we found that miR 124 is upregulated by cholinergic agonists in LPS exposed cells and mice Utilizing miR 124 mimic and siRNA knockdown we demonstrated that miR 124 is a critical mediator for the cholinergic anti inflammatory action Furthermore our data indicated that miR 124 modulates LPS induced cytokine production by targeting signal transducer and activator of transcription 3 STAT3 to decrease IL 6 production and TNF α converting enzyme TACE to reduce TNF α release These results also indicate that miR 124 is a potential therapeutic target for the treatment of inflammatory diseases Centrosomal protein FOR20 is essential for S phase progression by recruiting Plk1 to centrosomes FREE Minhong Shen 1 2 Yuqi Cai 1 2 Yuehong Yang 1 2 Xiaoyi Yan 1 2 Xiaoqi Liu 3 and Tianhua Zhou 1 2 10 1038 cr 2013 127 Full Text PDF Centrosomes are required for efficient cell cycle progression mainly by orchestrating microtubule dynamics and facilitating G1 S and G2 M transitions However the role of centrosomes in S phase progression is largely unknown Here we report that depletion of FOR20 FOP related protein of 20 kDa a conserved centrosomal protein inhibits S phase progression and prevents targeting of Plk1 polo like kinase 1 to centrosomes where FOR20 interacts with Plk1 Ablation of Plk1 also significantly induces S phase defects which are reversed by ectopic expression of Plk1 even a kinase dead mutant but not a mutant that fails to localize to centrosomes Exogenous expression of centrosome tethered Plk1 but not wild type Plk1 overrides FOR20 depletion induced S phase defects independently of its kinase activity Thus these data indicate that recruitment of Plk1 to centrosomes by FOR20 may act as a signal to license efficient progression of S phase This represents a hitherto uncharacterized role of centrosomes in cell cycle regulation Crystal structures of isoorotate decarboxylases reveal a novel catalytic mechanism of 5 carboxyl uracil decarboxylation and shed light on the search for DNA decarboxylase FREE Shutong Xu 1 2 Wenjing Li 1 2 Junjun Zhu 1 2 Rong Wang 1 2 Zheng Li 1 2 Guo Liang Xu 1 and Jianping Ding 1 10 1038 cr 2013 107 Full Text PDF DNA methylation and demethylation regulate many crucial biological processes in mammals and are linked to many diseases Active DNA demethylation is believed to be catalyzed by TET proteins and a putative DNA decarboxylase that may share some similarities in

    Original URL path: http://www.cell-research.com/artsmore.asp?id=161 (2016-02-14)
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  • Cell Research
    results in reduced NA catalytic efficiency along with lower viral fitness This helps to explain why K294 has predominantly been found in clinical cases of H7N9 infection under the selective pressure of oseltamivir treatment and not in the dominant human infecting viruses This implies that oseltamivir can still be efficiently used in the treatment of H7N9 infections miR 142 3p regulates the formation and differentiation of hematopoietic stem cells in vertebrates FREE Xinyan Lu 1 Xiajuan Li 1 Qiuping He 1 Jiao Gao 2 Ya Gao 1 Bing Liu 2 and Feng Liu 1 10 1038 cr 2013 145 Full Text PDF Previous studies on developmental hematopoiesis have mainly focused on signaling and transcription factors while the appreciation of epigenetic regulation including that of microRNAs is recent Here we show that in zebrafish and mouse miR 142 3p is specifically expressed in hematopoietic stem cells HSCs Knockdown of miR 142a 3p in zebrafish led to a reduced population of HSCs in the aorta gonad mesonephros AGM region as well as T cell defects in the thymus Mechanistically miR 142a 3p regulates HSC formation and differentiation through the repression of interferon regulatory factor 7 irf7 mediated inflammation signaling Finally we show that miR 142 3p is also involved in the development of HSCs in mouse AGM suggesting that it has a highly conserved role in vertebrates Together these findings unveil the pivotal roles that miR 142a 3p plays in the formation and differentiation of HSCs by repressing irf7 signaling Molecular basis for the selective and ABA independent inhibition of PP2CA by PYL13 FREE Wenqi Li 1 2 3 Li Wang 3 Xinlei Sheng 1 2 3 Chuangye Yan 1 2 3 Rui Zhou 1 2 3 Jing Hang 1 2 3 Ping Yin 1 2 3 and Nieng Yan 1 2 3 10 1038 cr 2013 143 Full Text PDF PYR1 PYL RCAR family proteins PYLs are well characterized abscisic acid ABA receptors Among the 14 PYL members in Arabidopsis thaliana PYL13 is ABA irresponsive and its function has remained elusive Here we show that PYL13 selectively inhibits the phosphatase activity of PP2CA independent of ABA The crystal structure of PYL13 PP2CA complex which was determined at 2 4 Å resolution elucidates the molecular basis for the specific recognition between PP2CA and PYL13 In addition to the canonical interactions between PYLs and PP2Cs an extra interface is identified involving an element in the vicinity of a previously uncharacterized CCCH zinc finger ZF motif in PP2CA Sequence blast identified another 56 ZF containing PP2Cs all of which are from plants The structure also reveals the molecular determinants for the ABA irresponsiveness of PYL13 Finally biochemical analysis suggests that PYL13 may hetero oligomerize with PYL10 These two PYLs antagonize each other in their respective ABA independent inhibitions of PP2Cs The biochemical and structural studies provide important insights into the function of PYL13 in the stress response of plant and set up a foundation for future biotechnological applications of PYL13 ORIGINAL ARTICLE The unique

    Original URL path: http://www.cell-research.com/artsmore.asp?id=162 (2016-02-14)
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  • Cell Research
    amino acids ATP and oxygen levels are intimately tied to the cellular balance of anabolic and catabolic processes Signaling from key nutrient sensitive kinases mTORC1 and AMP activated protein kinase AMPK is essential for the nutrient sensing of the autophagy pathway Recent advances have shown that the nutrient status of the cell is largely passed on to the autophagic machinery through the coordinated regulation of the ULK and VPS34 kinase complexes Identification of extensive crosstalk and feedback loops converging on the regulation of ULK and VPS34 can be attributed to the importance of these kinases in autophagy induction and maintaining cellular homeostasis A current perspective of autophagosome biogenesis FREE Shusaku T Shibutani 1 2 and Tamotsu Yoshimori 1 2 10 1038 cr 2013 159 Full Text PDF Autophagy is a bulk degradation system induced by cellular stresses such as nutrient starvation Its function relies on the formation of double membrane vesicles called autophagosomes Unlike other organelles that appear to stably exist in the cell autophagosomes are formed on demand and once their formation is initiated it proceeds surprisingly rapidly How and where this dynamic autophagosome formation takes place has been a long standing question but the discovery of Atg proteins in the 1990 s significantly accelerated our understanding of autophagosome biogenesis In this review we will briefly introduce each Atg functional unit in relation to autophagosome biogenesis and then discuss the origin of the autophagosomal membrane with an introduction to selected recent studies addressing this problem Autophagy and human diseases FREE Peidu Jiang 1 2 and Noboru Mizushima 1 2 10 1038 cr 2013 161 Full Text PDF Autophagy is a major intracellular degradative process that delivers cytoplasmic materials to the lysosome for degradation Since the discovery of autophagy related Atg genes in the 1990s there has been a proliferation of studies on the physiological and pathological roles of autophagy in a variety of autophagy knockout models However direct evidence of the connections between ATG gene dysfunction and human diseases has emerged only recently There are an increasing number of reports showing that mutations in the ATG genes were identified in various human diseases such as neurodegenerative diseases infectious diseases and cancers Here we review the major advances in identification of mutations or polymorphisms of the ATG genes in human diseases Current autophagy modulating compounds in clinical trials are also summarized You are what you eat multifaceted functions of autophagy during C elegans development FREE Peiguo Yang 1 and Hong Zhang 1 10 1038 cr 2013 154 Full Text PDF Autophagy involves the sequestration of a portion of the cytosolic contents in an enclosed double membrane autophagosomal structure and its subsequent delivery to lysosomes for degradation Autophagy activity functions in multiple biological processes during Caenorhabditis elegans development The basal level of autophagy in embryos removes aggregate prone proteins paternal mitochondria and spermatid specific membranous organelles MOs Autophagy also contributes to the efficient removal of embryonic apoptotic cell corpses by promoting phagosome maturation During larval development autophagy modulates miRNA mediated gene

    Original URL path: http://www.cell-research.com/artsmore.asp?id=164 (2016-02-14)
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  • Cell Research
    WTAP interacts with METTL3 and METTL14 and is required for their localization into nuclear speckles enriched with pre mRNA processing factors and for catalytic activity of the m6A methyltransferase in vivo The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif In the absence of WTAP the RNA binding capability of METTL3 is strongly reduced suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets Furthermore transcriptomic analyses in combination with photoactivatable ribonucleoside enhanced crosslinking and immunoprecipitation PAR CLIP illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing Morpholino mediated knockdown targeting WTAP and or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism Structural basis of PP2A activation by PTPA an ATP dependent activation chaperone OPEN Feng Guo 1 Vitali Stanevich 1 Nathan Wlodarchak 1 Rituparna Sengupta 1 Li Jiang 1 Kenneth A Satyshur 1 and Yongna Xing 1 10 1038 cr 2013 138 Full Text PDF Proper activation of protein phosphatase 2A PP2A catalytic subunit is central for the complex PP2A regulation and is crucial for broad aspects of cellular function The crystal structure of PP2A bound to PP2A phosphatase activator PTPA and ATPγS reveals that PTPA makes broad contacts with the structural elements surrounding the PP2A active site and the adenine moiety of ATP PTPA binding stabilizes the protein fold of apo PP2A required for activation and orients ATP phosphoryl groups to bind directly to the PP2A active site This allows ATP to modulate the metal binding preferences of the PP2A active site and utilize the PP2A active site for ATP hydrolysis In vitro ATP selectively and drastically enhances binding of endogenous catalytic metal ions which requires ATP hydrolysis and is crucial for acquisition of pSer Thr specific phosphatase activity Furthermore both PP2A and ATP binding are required for PTPA function in cell proliferation and survival Our results suggest novel mechanisms of PTPA in PP2A activation with structural economy and a unique ATP binding pocket that could potentially serve as a specific therapeutic target Amplification of MPZL1 PZR promotes tumor cell migration through Src mediated phosphorylation of cortactin in hepatocellular carcinoma Deshui Jia 1 2 Ying Jing 1 2 Zhenfeng Zhang 1 Li Liu 1 Jie Ding 1 Fangyu Zhao 1 Chao Ge 1 Qifeng Wang 3 Taoyang Chen 4 Ming Yao 1 Jinjun Li 1 Jianren Gu1 and Xianghuo He 1 10 1038 cr 2013 158 Full Text PDF We have previously identified 1 241 regions of somatic copy number alterations CNAs in hepatocellular carcinoma HCC In the present study we found that a novel recurrent focal amplicon 1q24 1 24 2 targets the MPZL1 gene in HCC Notably there is a positive correlation between the expression levels of MPZL1 and intrahepatic

    Original URL path: http://www.cell-research.com/artsmore.asp?id=165 (2016-02-14)
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