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  • 1
    Keywords: POPULATION ; BREAST-CANCER ; adenocarcinoma ; AGGREGATION ; GLIOMA ; METAANALYSIS ; GENOTYPE DATA ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; COMMON GENETIC-VARIATION
    Abstract: BACKGROUND: Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed. METHODS: We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non-lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5x10(-5) was used to assign statistical significance. RESULTS: The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8x10(-6)). This association was strongest for women with adenocarcinoma (P = 1.2x10(-4)) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1x10(-8)) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5x10(-5)), respectively. CONCLUSIONS: Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.
    Type of Publication: Journal article published
    PubMed ID: 24681604
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  • 2
    Publication Date: 2012-06-09
    Description: A fundamental feature of the mammalian neocortex is its columnar organization. In the visual cortex, functional columns consisting of neurons with similar orientation preferences have been characterized extensively, but how these columns are constructed during development remains unclear. The radial unit hypothesis posits that the ontogenetic columns formed by clonally related neurons migrating along the same radial glial fibre during corticogenesis provide the basis for functional columns in adult neocortex. However, a direct correspondence between the ontogenetic and functional columns has not been demonstrated. Here we show that, despite the lack of a discernible orientation map in mouse visual cortex, sister neurons in the same radial clone exhibit similar orientation preferences. Using a retroviral vector encoding green fluorescent protein to label radial clones of excitatory neurons, and in vivo two-photon calcium imaging to measure neuronal response properties, we found that sister neurons preferred similar orientations whereas nearby non-sister neurons showed no such relationship. Interestingly, disruption of gap junction coupling by viral expression of a dominant-negative mutant of Cx26 (also known as Gjb2) or by daily administration of a gap junction blocker, carbenoxolone, during the first postnatal week greatly diminished the functional similarity between sister neurons, suggesting that the maturation of ontogenetic into functional columns requires intercellular communication through gap junctions. Together with the recent finding of preferential excitatory connections among sister neurons, our results support the radial unit hypothesis and unify the ontogenetic and functional columns in the visual cortex.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375857/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375857/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ye -- Lu, Hui -- Cheng, Pei-lin -- Ge, Shaoyu -- Xu, Huatai -- Shi, Song-Hai -- Dan, Yang -- R01 DA024681/DA/NIDA NIH HHS/ -- R01 EY018861/EY/NEI NIH HHS/ -- R01 NS065915/NS/NINDS NIH HHS/ -- R21NS072483/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 2;486(7401):118-21. doi: 10.1038/nature11110.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22678292" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Carbenoxolone/pharmacology ; *Cell Communication ; Clone Cells/cytology ; Connexins/genetics/metabolism ; Female ; Gap Junctions/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Neurons/*physiology ; Visual Cortex/*cytology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-07-31
    Description: Mammalian pre-implantation development is a complex process involving dramatic changes in the transcriptional architecture. We report here a comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos, using single-cell RNA sequencing. Based on single-nucleotide variants in human blastomere messenger RNAs and paternal-specific single-nucleotide polymorphisms, we identify novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25 to 53%). By weighted gene co-expression network analysis, we find that each developmental stage can be delineated concisely by a small number of functional modules of co-expressed genes. This result indicates a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism, acting in a step-wise fashion from cleavage to morula. Cross-species comparisons with mouse pre-implantation embryos reveal that the majority of human stage-specific modules (7 out of 9) are notably preserved, but developmental specificity and timing differ between human and mouse. Furthermore, we identify conserved key members (or hub genes) of the human and mouse networks. These genes represent novel candidates that are likely to be key in driving mammalian pre-implantation development. Together, the results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xue, Zhigang -- Huang, Kevin -- Cai, Chaochao -- Cai, Lingbo -- Jiang, Chun-yan -- Feng, Yun -- Liu, Zhenshan -- Zeng, Qiao -- Cheng, Liming -- Sun, Yi E -- Liu, Jia-yin -- Horvath, Steve -- Fan, Guoping -- P01 HD006576/HD/NICHD NIH HHS/ -- P30 HD004612/HD/NICHD NIH HHS/ -- P50 DA005010/DA/NIDA NIH HHS/ -- England -- Nature. 2013 Aug 29;500(7464):593-7. doi: 10.1038/nature12364. Epub 2013 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China. xuezhigang75@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23892778" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Blastocyst/cytology/metabolism ; Cell Cycle/genetics ; Embryo, Mammalian/cytology/*embryology/*metabolism ; Embryonic Development/*genetics ; Gene Expression Profiling ; *Gene Expression Regulation, Developmental ; Humans ; Mice ; Morula/cytology/metabolism ; Oocytes/cytology/metabolism ; *Sequence Analysis, RNA ; *Single-Cell Analysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-10-06
    Description: Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Although previous studies have demonstrated that certain embryonic developmental programs are reactivated aberrantly in adult organs to drive repair and regeneration, it is not well understood how quiescence is maintained in organs such as the lung, which displays a remarkably low level of cellular turnover. Here we demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signalling. Epithelial-specific deletion of sonic hedgehog (Shh) during postnatal homeostasis in the murine lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signalling is initially downregulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signalling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog actively maintain postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713039/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713039/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peng, Tien -- Frank, David B -- Kadzik, Rachel S -- Morley, Michael P -- Rathi, Komal S -- Wang, Tao -- Zhou, Su -- Cheng, Lan -- Lu, Min Min -- Morrisey, Edward E -- HL087825/HL/NHLBI NIH HHS/ -- HL100405/HL/NHLBI NIH HHS/ -- HL110942/HL/NHLBI NIH HHS/ -- K08-HL121146/HL/NHLBI NIH HHS/ -- R01 HL087825/HL/NHLBI NIH HHS/ -- T32 HL007915/HL/NHLBI NIH HHS/ -- U01 HL100405/HL/NHLBI NIH HHS/ -- U01 HL110942/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Oct 22;526(7574):578-82. doi: 10.1038/nature14984. Epub 2015 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26436454" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Proliferation ; Down-Regulation ; Epithelial Cells/cytology/metabolism/pathology ; Feedback, Physiological ; Hedgehog Proteins/deficiency/genetics/*metabolism ; Homeostasis ; Lung/*cytology/*metabolism/pathology ; Lung Injury/*metabolism/*pathology ; Male ; Mesoderm/cytology/metabolism ; Mice ; Paracrine Communication ; *Regeneration ; *Wound Healing
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2016-03-17
    Description: Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a 'loss of heterozygosity' deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836395/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836395/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Yu -- Chen, Chong -- Xu, Zhengmin -- Scuoppo, Claudio -- Rillahan, Cory D -- Gao, Jianjiong -- Spitzer, Barbara -- Bosbach, Benedikt -- Kastenhuber, Edward R -- Baslan, Timour -- Ackermann, Sarah -- Cheng, Lihua -- Wang, Qingguo -- Niu, Ting -- Schultz, Nikolaus -- Levine, Ross L -- Mills, Alea A -- Lowe, Scott W -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA016042/CA/NCI NIH HHS/ -- R01 CA190261/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 24;531(7595):471-5. doi: 10.1038/nature17157. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Hematology and Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu 610041, China. ; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA. ; Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Human Oncology &Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Hematology &Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu 610041, China. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Howard Hughes Medical Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982726" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Cell Transformation, Neoplastic/genetics ; Chromosomes, Human, Pair 17/genetics ; Chromosomes, Mammalian/genetics ; Disease Models, Animal ; Disease Progression ; Female ; Genes, p53/*genetics ; Heterozygote ; Humans ; Leukemia, Myeloid, Acute/genetics/pathology ; Lymphoma/genetics/pathology ; Male ; Mice ; Neoplasms/*genetics/*pathology ; Peptide Initiation Factors/genetics/metabolism ; RNA-Binding Proteins/genetics/metabolism ; Sequence Deletion/*genetics ; Synteny/genetics ; Tumor Suppressor Protein p53/*deficiency
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2015-09-19
    Description: Double-stranded RNA (dsRNA) viruses possess a segmented dsRNA genome and a number of RNA-dependent RNA polymerases (RdRps) enclosed in a capsid. Until now, the precise structures of genomes and RdRps within the capsids have been unknown. Here we report the structures of RdRps and associated RNAs within nontranscribing and transcribing cypoviruses (NCPV and TCPV, respectively), using a combination of cryo-electron microscopy (cryo-EM) and a symmetry-mismatch reconstruction method. The RdRps and associated RNAs appear to exhibit a pseudo-D3 symmetric organization in both NCPV and TCPV. However, the molecular interactions between RdRps and the genomic RNA were found to differ in these states. Our work provides insight into the mechanisms of the replication and transcription in dsRNA viruses and paves a way for structural determination of lower-symmetry complexes enclosed in higher-symmetry structures.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Hongrong -- Cheng, Lingpeng -- New York, N.Y. -- Science. 2015 Sep 18;349(6254):1347-50. doi: 10.1126/science.aaa4938.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉College of Physics and Information Science, Hunan Normal University, Changsha, Hunan 410081, China. hrliu@hunnu.edu.cn lingpengcheng@mail.tsinghua.edu.cn. ; School of Life Sciences, Tsinghua University, Beijing 100084, China. hrliu@hunnu.edu.cn lingpengcheng@mail.tsinghua.edu.cn.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26383954" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Capsid/enzymology/ultrastructure ; Capsid Proteins/*ultrastructure ; Cryoelectron Microscopy ; Genome, Viral ; Humans ; Protein Conformation ; RNA Replicase/*ultrastructure ; RNA, Double-Stranded/genetics/*ultrastructure ; RNA, Viral/genetics/*ultrastructure ; *Reoviridae/enzymology/genetics/ultrastructure ; Transcription, Genetic ; Virus Assembly
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2010-12-17
    Description: Classical non-homologous DNA end-joining (NHEJ) is a major mammalian DNA double-strand-break (DSB) repair pathway. Deficiencies for classical NHEJ factors, such as XRCC4, abrogate lymphocyte development, owing to a strict requirement for classical NHEJ to join V(D)J recombination DSB intermediates. The XRCC4-like factor (XLF; also called NHEJ1) is mutated in certain immunodeficient human patients and has been implicated in classical NHEJ; however, XLF-deficient mice have relatively normal lymphocyte development and their lymphocytes support normal V(D)J recombination. The ataxia telangiectasia-mutated protein (ATM) detects DSBs and activates DSB responses by phosphorylating substrates including histone H2AX. However, ATM deficiency causes only modest V(D)J recombination and lymphocyte developmental defects, and H2AX deficiency does not have a measurable impact on these processes. Here we show that XLF, ATM and H2AX all have fundamental roles in processing and joining DNA ends during V(D)J recombination, but that these roles have been masked by unanticipated functional redundancies. Thus, combined deficiency of ATM and XLF nearly blocks mouse lymphocyte development due to an inability to process and join chromosomal V(D)J recombination DSB intermediates. Combined XLF and ATM deficiency also severely impairs classical NHEJ, but not alternative end-joining, during IgH class switch recombination. Redundant ATM and XLF functions in classical NHEJ are mediated by ATM kinase activity and are not required for extra-chromosomal V(D)J recombination, indicating a role for chromatin-associated ATM substrates. Correspondingly, conditional H2AX inactivation in XLF-deficient pro-B lines leads to V(D)J recombination defects associated with marked degradation of unjoined V(D)J ends, revealing that H2AX has a role in this process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058373/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058373/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zha, Shan -- Guo, Chunguang -- Boboila, Cristian -- Oksenych, Valentyn -- Cheng, Hwei-Ling -- Zhang, Yu -- Wesemann, Duane R -- Yuen, Grace -- Patel, Harin -- Goff, Peter H -- Dubois, Richard L -- Alt, Frederick W -- AI007376/AI/NIAID NIH HHS/ -- AI020047/AI/NIAID NIH HHS/ -- AI076210/AI/NIAID NIH HHS/ -- K08 AI089972/AI/NIAID NIH HHS/ -- K08 AI089972-01/AI/NIAID NIH HHS/ -- P01 AI076210/AI/NIAID NIH HHS/ -- P01 AI076210-03/AI/NIAID NIH HHS/ -- R01 AI020047/AI/NIAID NIH HHS/ -- R01 AI020047-28/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jan 13;469(7329):250-4. doi: 10.1038/nature09604. Epub 2010 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The Children's Hospital, the Immune Disease Institute and the Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21160472" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line, Transformed ; Chromatin/metabolism ; Chromosomes, Mammalian/genetics/metabolism ; *DNA Breaks, Double-Stranded ; *DNA Repair ; DNA-Binding Proteins/deficiency/genetics/*metabolism ; Embryo, Mammalian/embryology/metabolism ; *Gene Rearrangement, B-Lymphocyte/genetics ; Histones/*metabolism ; Mice ; Precursor Cells, B-Lymphoid/cytology/metabolism ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; *Recombination, Genetic ; Tumor Suppressor Proteins/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2014-08-19
    Description: Dysregulated neurodevelopment with altered structural and functional connectivity is believed to underlie many neuropsychiatric disorders, and 'a disease of synapses' is the major hypothesis for the biological basis of schizophrenia. Although this hypothesis has gained indirect support from human post-mortem brain analyses and genetic studies, little is known about the pathophysiology of synapses in patient neurons and how susceptibility genes for mental disorders could lead to synaptic deficits in humans. Genetics of most psychiatric disorders are extremely complex due to multiple susceptibility variants with low penetrance and variable phenotypes. Rare, multiply affected, large families in which a single genetic locus is probably responsible for conferring susceptibility have proven invaluable for the study of complex disorders. Here we generated induced pluripotent stem (iPS) cells from four members of a family in which a frameshift mutation of disrupted in schizophrenia 1 (DISC1) co-segregated with major psychiatric disorders and we further produced different isogenic iPS cell lines via gene editing. We showed that mutant DISC1 causes synaptic vesicle release deficits in iPS-cell-derived forebrain neurons. Mutant DISC1 depletes wild-type DISC1 protein and, furthermore, dysregulates expression of many genes related to synapses and psychiatric disorders in human forebrain neurons. Our study reveals that a psychiatric disorder relevant mutation causes synapse deficits and transcriptional dysregulation in human neurons and our findings provide new insight into the molecular and synaptic etiopathology of psychiatric disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501856/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501856/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wen, Zhexing -- Nguyen, Ha Nam -- Guo, Ziyuan -- Lalli, Matthew A -- Wang, Xinyuan -- Su, Yijing -- Kim, Nam-Shik -- Yoon, Ki-Jun -- Shin, Jaehoon -- Zhang, Ce -- Makri, Georgia -- Nauen, David -- Yu, Huimei -- Guzman, Elmer -- Chiang, Cheng-Hsuan -- Yoritomo, Nadine -- Kaibuchi, Kozo -- Zou, Jizhong -- Christian, Kimberly M -- Cheng, Linzhao -- Ross, Christopher A -- Margolis, Russell L -- Chen, Gong -- Kosik, Kenneth S -- Song, Hongjun -- Ming, Guo-li -- AG045656/AG/NIA NIH HHS/ -- F31 MH102978/MH/NIMH NIH HHS/ -- MH087874/MH/NIMH NIH HHS/ -- MH102978/MH/NIMH NIH HHS/ -- NS047344/NS/NINDS NIH HHS/ -- NS048271/NS/NINDS NIH HHS/ -- R01 AG024984/AG/NIA NIH HHS/ -- R01 AG045656/AG/NIA NIH HHS/ -- R01 MH083911/MH/NIMH NIH HHS/ -- R01 MH105128/MH/NIMH NIH HHS/ -- R01 NS047344/NS/NINDS NIH HHS/ -- R01 NS048271/NS/NINDS NIH HHS/ -- R21 ES021957/ES/NIEHS NIH HHS/ -- R21 MH092740/MH/NIMH NIH HHS/ -- T32 GM008752/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):414-8. doi: 10.1038/nature13716. Epub 2014 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3]. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3]. ; 1] Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA [2]. ; Neuroscience Research Institute, Department of Molecular Cellular and Developmental Biology, Biomolecular Science and Engineering Program, University of California, Santa Barbara, California 93106, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8550, Japan. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Biology, Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; 1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [4] The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25132547" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Fibroblasts ; Glutamine/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism/*pathology ; Male ; Mental Disorders/genetics/metabolism/*pathology ; Mice ; Mutant Proteins/genetics/metabolism ; Mutation/genetics ; Nerve Tissue Proteins/genetics/metabolism ; Neurons/cytology/metabolism/pathology ; Pedigree ; Presynaptic Terminals/metabolism/pathology ; Prosencephalon/metabolism/pathology ; Protein Binding ; Synapses/metabolism/*pathology ; Transcriptome
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2012-04-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheng, Likwan -- New York, N.Y. -- Science. 2012 Apr 13;336(6078):155, 157. doi: 10.1126/science.336.6078.155-c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22499924" target="_blank"〉PubMed〈/a〉
    Keywords: *International Cooperation ; *Science
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2012-06-30
    Description: Modern tomato (Solanum lycopersicum) varieties are bred for uniform ripening (u) light green fruit phenotypes to facilitate harvests of evenly ripened fruit. U encodes a Golden 2-like (GLK) transcription factor, SlGLK2, which determines chlorophyll accumulation and distribution in developing fruit. In tomato, two GLKs--SlGLK1 and SlGLK2--are expressed in leaves, but only SlGLK2 is expressed in fruit. Expressing GLKs increased the chlorophyll content of fruit, whereas SlGLK2 suppression recapitulated the u mutant phenotype. GLK overexpression enhanced fruit photosynthesis gene expression and chloroplast development, leading to elevated carbohydrates and carotenoids in ripe fruit. SlGLK2 influences photosynthesis in developing fruit, contributing to mature fruit characteristics and suggesting that selection of u inadvertently compromised ripe fruit quality in exchange for desirable production traits.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Powell, Ann L T -- Nguyen, Cuong V -- Hill, Theresa -- Cheng, Kalai Lam -- Figueroa-Balderas, Rosa -- Aktas, Hakan -- Ashrafi, Hamid -- Pons, Clara -- Fernandez-Munoz, Rafael -- Vicente, Ariel -- Lopez-Baltazar, Javier -- Barry, Cornelius S -- Liu, Yongsheng -- Chetelat, Roger -- Granell, Antonio -- Van Deynze, Allen -- Giovannoni, James J -- Bennett, Alan B -- New York, N.Y. -- Science. 2012 Jun 29;336(6089):1711-5. doi: 10.1126/science.1222218.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plant Sciences Department, University of California, Davis, CA 95616, USA. alpowell@ucdavis.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22745430" target="_blank"〉PubMed〈/a〉
    Keywords: Chloroplasts/*genetics/physiology ; Chromosome Mapping ; Chromosomes, Plant ; Fruit/genetics/growth & development ; Lycopersicon esculentum/*genetics/*growth & development ; Phenotype ; Plant Proteins/*genetics/physiology ; Transcription Factors/*genetics/physiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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