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  • 1
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    Structural and mechanical properties of individual human telomeric G-quadruplexes in molecularly crowded solutions (2013)
    Oxford University Press
    Details
    Publication Date: 2013-04-02
    Description: Recent experiments provided controversial observations that either parallel or non-parallel G-quadruplex exists in molecularly crowded buffers that mimic cellular environment. Here, we used laser tweezers to mechanically unfold structures in a human telomeric DNA fragment, 5'-(TTAGGG) 4 TTA, along three different trajectories. After the end-to-end distance of each unfolding geometry was measured, it was compared with PDB structures to identify the best-matching G-quadruplex conformation. This method is well-suited to identify biomolecular structures in complex settings not amenable to conventional approaches, such as in a solution with mixed species or at physiologically significant concentrations. With this approach, we found that parallel G-quadruplex coexists with non-parallel species (1:1 ratio) in crowded buffers with dehydrating cosolutes [40% w/v dimethyl sulfoxide (DMSO) or acetonitrile (ACN)]. In crowded solutions with steric cosolutes [40% w/v bovine serum albumin (BSA)], the parallel G-quadruplex constitutes only 10% of the population. This difference unequivocally supports the notion that dehydration promotes the formation of parallel G-quadruplexes. Compared with DNA hairpins that have decreased unfolding forces in crowded (9 pN) versus diluted (15 pN) buffers, those of G-quadruplexes remain the same (20 pN). Such a result implies that in a cellular environment, DNA G-quadruplexes, instead of hairpins, can stop DNA/RNA polymerases with stall forces often 〈20 pN.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Exploded view of higher order G-quadruplex structures through click-chemistry assisted single-molecule mechanical unfolding (2016)
    Oxford University Press
    Details
    Publication Date: 2016-01-09
    Description: Due to the long-range nature of high-order interactions between distal components in a biomolecule, transition dynamics of tertiary structures is often too complex to profile using conventional methods. Inspired by the exploded view in mechanical drawing, here, we used laser tweezers to mechanically dissect high-order DNA structures into two constituting G-quadruplexes in the promoter of the human telomerase reverse transcriptase (hTERT) gene. Assisted with click-chemistry coupling, we sandwiched one G-quadruplex with two dsDNA handles while leaving the other unit free. Mechanical unfolding through these handles revealed transition dynamics of the targeted quadruplex in a native environment, which is named as native mechanical segmentation (NMS). Comparison between unfolding of an NMS construct and that of truncated G-quadruplex constructs revealed a quadruplex–quadruplex interaction with 2 kcal/mol stabilization energy. After mechanically targeting the two G-quadruplexes together, the same interaction was observed during the first unfolding step. The unfolding then proceeded through disrupting the weaker G-quadruplex at the 5'-end, followed by the stronger G-quadruplex at the 3'-end via various intermediates. Such a pecking order in unfolding well reflects the hierarchical nature of nucleic acid structures. With surgery-like precisions, we anticipate this NMS approach offers unprecedented perspective to decipher dynamic transitions in complex biomacromolecules.
    Keywords: Nucleic acid structure, Phsyical and Biochemical Characterisation of DNA
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Human impact overwhelms long-term climate control of weathering and erosion in southwest China (2015)
    Geological Society of America (GSA)
    In: Geology
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    Publication Date: 2015-04-25
    Description: During the Holocene there has been a gradual increase in the influence of humans on Earth systems. High-resolution sedimentary records can help us to assess how erosion and weathering have evolved in response to recent climatic and anthropogenic disturbances. Here we present data from a high-resolution (~75 cm/k.y.) sedimentary archive from the South China Sea. Provenance data indicate that the sediment was derived from the Red River, and can be used to reconstruct the erosion and/or weathering history in this river basin. Accelerator mass spectrometry 14 C dating provides direct age control and reveals coherent variations in clay mineralogy, geochemistry, and terrigenous flux, indicative of strong chemical weathering and physical erosion during the mid-Holocene warm period (6400–4000 cal [calibrated] yr B.P.), followed by weakening from ca. 4000–1800 cal yr B.P., and renewed intensification since 1800 cal yr B.P.. Comparison with climatic records from China indicates that precipitation and temperature controlled both physical erosion and chemical weathering intensity before 1800 cal yr B.P.. However, weathering proxies in the offshore sediment indicate recent increased soil erosion. We suggest that enhanced human activity (deforestation, cultivation, and mining) since the end of the Chinese Han Dynasty (220 CE) has overwhelmed the natural climatic controls on erosion in the Red River.
    Print ISSN: 0091-7613
    Electronic ISSN: 1943-2682
    Topics: Geosciences
    Published by Geological Society of America (GSA)
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  • 4
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    A fly model for the CCUG-repeat expansion of myotonic dystrophy type 2 reveals a novel interaction with MBNL1 (2015)
    Oxford University Press
    Details
    Publication Date: 2015-01-25
    Description: Expanded non-coding RNA repeats of CUG and CCUG are the underlying genetic causes for myotonic dystrophy type 1 (DM1) and type 2 (DM2), respectively. A gain-of-function of these pathogenic repeat expansions is mediated at least in part by their abnormal interactions with RNA-binding proteins such as MBNL1 and resultant loss of activity of these proteins. To study pathogenic mechanisms of CCUG-repeat expansions in an animal model, we created a fly model of DM2 that expresses pure, uninterrupted CCUG-repeat expansions ranging from 16 to 720 repeats in length. We show that this fly model for DM2 recapitulates key features of human DM2 including RNA repeat-induced toxicity, ribonuclear foci formation and changes in alternative splicing. Interestingly, expression of two isoforms of MBNL1, MBNL1 35 and MBNL1 40 , leads to cleavage and concurrent upregulation of the levels of the RNA-repeat transcripts, with MBNL1 40 having more significant effects than MBNL1 35 . This property is shared with a fly CUG-repeat expansion model. Our results suggest a novel mechanism for interaction between the pathogenic RNA repeat expansions of myotonic dystrophy and MBNL1.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 5
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    DeAnnCNV: a tool for online detection and annotation of copy number variations from whole-exome sequencing data (2015)
    Oxford University Press
    Details
    Publication Date: 2015-07-02
    Description: With the decrease in costs, whole-exome sequencing (WES) has become a very popular and powerful tool for the identification of genetic variants underlying human diseases. However, integrated tools to precisely detect and systematically annotate copy number variations (CNVs) from WES data are still in great demand. Here, we present an online tool, DeAnnCNV ( De tection and Ann otation of C opy N umber V ariations from WES data), to meet the current demands of WES users. Upon submitting the file generated from WES data by an in-house tool that can be downloaded from our server, DeAnnCNV can detect CNVs in each sample and extract the shared CNVs among multiple samples. DeAnnCNV also provides additional useful supporting information for the detected CNVs and associated genes to help users to find the potential candidates for further experimental study. The web server is implemented in PHP + Perl + MATLAB and is online available to all users for free at http://mcg.ustc.edu.cn/db/cnv/ .
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Responses of photosynthetic characters of Skeletonema costatum to different nutrient conditions (2012)
    Oxford University Press
    Details
    Publication Date: 2012-12-28
    Description: The photosynthetic capacity of phytoplankton is frequently limited by the availability of nutrients. To explore the mechanism of the effect of nutrient availability on photosynthesis, batch cultures of a marine diatom Skeletonema costatum (Greville) Cleve were carried out under different nitrate (N: 0–220.75 µM) and phosphate (P: 0–9.075 µM) concentrations. Changes of photosynthetic characters, including the photosynthetic rate (measured by O 2 evolution) and the rbcL mRNA content (encoding the large subunit of the Calvin cycle enzyme, RuBisCO), were both studied. Within the range tested, both the photosynthetic rate and rbcL transcript levels correlated significantly with N and P concentrations in the medium. Additionally, the photosynthetic rates and rbcL transcript levels were both growth dependent. Significant correlations were also found between the abundance of rbcL mRNA and the photosynthetic rate ( R 2 = 0.800), rbcL and growth rate ( R 2 = 0.855), the photosynthetic rate and growth rate ( R 2 = 0.815). These results are consistent with N and P nutrition-regulating photosynthesis from the transcriptional levels of rbcL . The rbcL transcript level has the potential to be a good marker of algal growth and primary productivity.
    Print ISSN: 0142-7873
    Electronic ISSN: 1464-3774
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Deficiency of FRAS1-related extracellular matrix 1 (FREM1) causes congenital diaphragmatic hernia in humans and mice (2013)
    Oxford University Press
    Details
    Publication Date: 2013-02-02
    Description: Congenital diaphragmatic hernia (CDH) is a common life-threatening birth defect. Recessive mutations in the FRAS1-related extracellular matrix 1 ( FREM1 ) gene have been shown to cause bifid nose with or without anorectal and renal anomalies (BNAR) syndrome and Manitoba oculotrichoanal (MOTA) syndrome, but have not been previously implicated in the development of CDH. We have identified a female child with an isolated left-sided posterolateral CDH covered by a membranous sac who had no features suggestive of BNAR or MOTA syndromes. This child carries a maternally-inherited ~86 kb FREM1 deletion that affects the expression of FREM1 's full-length transcripts and a paternally-inherited splice site mutation that causes activation of a cryptic splice site, leading to a shift in the reading frame and premature termination of all forms of the FREM1 protein. This suggests that recessive FREM1 mutations can cause isolated CDH in humans. Further evidence for the role of FREM1 in the development of CDH comes from an N -ethyl- N -nitrosourea -derived mouse strain, eyes2 , which has a homozygous truncating mutation in Frem1. Frem1 eyes2 mice have eye defects, renal agenesis and develop retrosternal diaphragmatic hernias which are covered by a membranous sac. We confirmed that Frem1 is expressed in the anterior portion of the developing diaphragm and found that Frem1 eyes2 embryos had decreased levels of cell proliferation in their developing diaphragms when compared to wild-type embryos. We conclude that FREM1 plays a critical role in the development of the diaphragm and that FREM1 deficiency can cause CDH in both humans and mice.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    Requirement for human Mps1/TTK in oxidative DNA damage repair and cell survival through MDM2 phosphorylation (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-20
    Description: Human Mps1 (hMps1) is a protein kinase essential for mitotic checkpoints and the DNA damage response. Here, we present new evidence that hMps1 also participates in the repair of oxidative DNA lesions and cell survival through the MDM2-H2B axis. In response to oxidative stress, hMps1 phosphorylates MDM2, which in turn promotes histone H2B ubiquitination and chromatin decompaction. These events facilitate oxidative DNA damage repair and ATR-CHK1, but not ATM-CHK2 signaling. Depletion of hMps1 or MDM2 compromised H2B ubiquitination, DNA repair and cell survival. The impairment could be rescued by re-expression of WT but not the phospho-deficient MDM2 mutant, supporting the involvement of hMps1-dependent MDM2 phosphorylation in the oxidative stress response. In line with these findings, localization of RPA and base excision repair proteins to damage foci also requires MDM2 and hMps1. Significantly, like MDM2, hMps1 is upregulated in human sarcoma, suggesting high hMps1 and MDM2 expression may be beneficial for tumors constantly challenged by an oxidative micro-environment. Our study therefore identified an hMps1-MDM2-H2B signaling axis that likely plays a relevant role in tumor progression.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1 (2012)
    Oxford University Press
    Details
    Publication Date: 2012-08-28
    Description: Recurrent microdeletions of 8p23.1 that include GATA4 and SOX7 confer a high risk of both congenital diaphragmatic hernia (CDH) and cardiac defects. Although GATA4-deficient mice have both CDH and cardiac defects, no humans with cardiac defects attributed to GATA4 mutations have been reported to have CDH. We were also unable to identify deleterious GATA4 sequence changes in a CDH cohort. This suggested that haploinsufficiency of another 8p23.1 gene may contribute, along with GATA4 , to the development of CDH. To determine if haploinsufficiency of SOX7 —another transcription factor encoding gene—contributes to the development of CDH, we generated mice with a deletion of the second exon of Sox7 . A portion of these Sox7 ex2/+ mice developed retrosternal diaphragmatic hernias located in the anterior muscular portion of the diaphragm. Anterior CDH is also seen in Gata4 +/– mice and has been described in association with 8p23.1 deletions in humans. Immunohistochemistry revealed that SOX7 is expressed in the vascular endothelial cells of the developing diaphragm and may be weakly expressed in some diaphragmatic muscle cells. Sox7 ex2/ex2 embryos die prior to diaphragm development with dilated pericardial sacs and failure of yolk sac remodeling suggestive of cardiovascular failure. Similar to our experience screening GATA4 , no clearly deleterious SOX7 sequence changes were identified in our CDH cohort. We conclude that haploinsufficiency of Sox7 or Gata4 is sufficient to produce anterior CDH in mice and that haploinsufficiency of SOX7 and GATA4 may each contribute to the development of CDH in individuals with 8p23.1 deletions.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 10
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    A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability (2012)
    Oxford University Press
    Details
    Publication Date: 2012-09-14
    Description: Glutamine (Q) expansion diseases are a family of degenerative disorders caused by the lengthening of CAG triplet repeats present in the coding sequences of seemingly unrelated genes whose mutant proteins drive pathogenesis. Despite all the molecular evidence for the genetic basis of these diseases, how mutant poly-Q proteins promote cell death and drive pathogenesis remains controversial. In this report, we show a specific interaction between the mutant androgen receptor (AR), a protein associated with spinal and bulbar muscular atrophy (SBMA), and the nuclear protein PTIP (Pax Transactivation-domain Interacting Protein), a protein with an unusually long Q-rich domain that functions in DNA repair. Upon exposure to ionizing radiation, PTIP localizes to nuclear foci that are sites of DNA damage and repair. However, the expression of poly-Q AR sequesters PTIP away from radiation-induced nuclear foci. This results in sensitivity to DNA-damaging agents and chromosomal instabilities. In a mouse model of SBMA, evidence for DNA damage is detected in muscle cell nuclei and muscular atrophy is accelerated when one copy of the gene encoding PTIP is removed. These data provide a new paradigm for understanding the mechanisms of cellular degeneration observed in poly-Q expansion diseases.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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