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  • 1
    Publication Date: 2012-10-06
    Description: Journal of the American Chemical Society DOI: 10.1021/ja3085115
    Print ISSN: 0002-7863
    Electronic ISSN: 1520-5126
    Topics: Chemistry and Pharmacology
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  • 2
    Publication Date: 2012-08-22
    Description: Ray-finned fishes make up half of all living vertebrate species. Nearly all ray-finned fishes are teleosts, which include most commercially important fish species, several model organisms for genomics and developmental biology, and the dominant component of marine and freshwater vertebrate faunas. Despite the economic and scientific importance of ray-finned fishes,...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 3
    Publication Date: 2012-04-15
    Description: The solvent dependency of the ground-state distribution as well as the electrochemical switching behavior in a redox-active bistable donor–acceptor [2]catenane, containing bisthiotetrathiafulvalene (STTFS) and 1,5-dioxynaphthalene (DNP) recognition sites incorporated within a macrocyclic polyether encircled by the cyclobis(paraquat- p -phenylene) (CBPQT 4+ ) ring, has been investigated. There are two translational isomers: (i) the ground-state co-conformation (GSCC) in which the CBPQT 4+ ring encircles the STTFS unit and (ii) the metastable-state co-conformation (MSCC) in which the CBPQT 4+ ring encircles the DNP unit. 1 H NMR spectroscopy indicates that the ground-state distribution of GSCC to MSCC varies from approximately 1:1 in MeCN to 7:1 in MeCN : H 2 O (1:1, v/v) at 283 K. The reversible electrochemical switching behavior of the [2]catenane was confirmed by 1 H NMR and UV−Vis spectroscopies, as well as by cyclic voltammetry (CV). Additionally, variable scan-rate CV studies were compared with simulated CV data and show that the ground-state distribution of GSCC to MSCC is about 30:1 in MeCN : H 2 O (1:1, v/v) at 298 K. With the assistance of isothermal titration calorimetry of model compounds, it was found that the changing ground-state distribution in differing solvent systems is driven entropically rather than enthalpically. Copyright © 2012 John Wiley & Sons, Ltd. The solvent dependency of the ground state distribution and the electrochemical switching behavior in a redox-active bistable donor-acceptor [2]catenane, containing bisthiotetrathia fulvalene (STTFS) and 1,5-dioxynaphthalene (DNP) recognition sites incorporated within a macrocyclic polyether encircled by the cyclobis(paraquat-p-phenylene) (CBPQT 4+ ) ring, has been investigated. In aqueous solvent, CBPQT 4+ prefers to reside upon the STTFS unit, while in organic solvent the cyclophane shows little selectivity between the two stations. Entropy, rather than enthalpy, drives the changing ground-state distribution in differing solvent systems.
    Print ISSN: 0894-3230
    Electronic ISSN: 1099-1395
    Topics: Chemistry and Pharmacology , Physics
    Published by Wiley
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  • 4
    Publication Date: 2012-05-16
    Description: The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 5
    Publication Date: 2012-01-05
    Description: The solvent dependency of the ground-state distribution as well as the electrochemical switching behavior in a redox-active bistable donor–acceptor [2]catenane, containing bisthiotetrathiafulvalene (STTFS) and 1,5-dioxynaphthalene (DNP) recognition sites incorporated within a macrocyclic polyether encircled by the cyclobis(paraquat- p -phenylene) (CBPQT 4+ ) ring, has been investigated. There are two translational isomers: (i) the ground-state co-conformation (GSCC) in which the CBPQT 4+ ring encircles the STTFS unit and (ii) the metastable-state co-conformation (MSCC) in which the CBPQT 4+ ring encircles the DNP unit. 1 H NMR spectroscopy indicates that the ground-state distribution of GSCC to MSCC varies from approximately 1:1 in MeCN to 7:1 in MeCN : H 2 O (1:1, v/v) at 283 K. The reversible electrochemical switching behavior of the [2]catenane was confirmed by 1 H NMR and UV−Vis spectroscopies, as well as by cyclic voltammetry (CV). Additionally, variable scan-rate CV studies were compared with simulated CV data and show that the ground-state distribution of GSCC to MSCC is about 30:1 in MeCN : H 2 O (1:1, v/v) at 298 K. With the assistance of isothermal titration calorimetry of model compounds, it was found that the changing ground-state distribution in differing solvent systems is driven entropically rather than enthalpically. Copyright © 2012 John Wiley & Sons, Ltd. The solvent dependency of the ground state distribution and the electrochemical switching behavior in a redox-active bistable donor-acceptor [2]catenane, containing bisthiotetrathia fulvalene (STTFS) and 1,5-dioxynaphthalene (DNP) recognition sites incorporated within a macrocyclic polyether encircled by the cyclobis(paraquat-p-phenylene) (CBPQT 4+ ) ring, has been investigated. In aqueous solvent, CBPQT 4+ prefers to reside upon the STTFS unit, while in organic solvent the cyclophane shows little selectivity between the two stations. Entropy, rather than enthalpy, drives the changing ground-state distribution in differing solvent systems.
    Print ISSN: 0894-3230
    Electronic ISSN: 1099-1395
    Topics: Chemistry and Pharmacology , Physics
    Published by Wiley
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  • 6
    Publication Date: 2008-02-12
    Description: Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2577037/" 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/PMC2577037/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sakai, Wataru -- Swisher, Elizabeth M -- Karlan, Beth Y -- Agarwal, Mukesh K -- Higgins, Jake -- Friedman, Cynthia -- Villegas, Emily -- Jacquemont, Celine -- Farrugia, Daniel J -- Couch, Fergus J -- Urban, Nicole -- Taniguchi, Toshiyasu -- K08 CA096610/CA/NCI NIH HHS/ -- K08 CA096610-01/CA/NCI NIH HHS/ -- P50 CA083636/CA/NCI NIH HHS/ -- P50 CA083636-10/CA/NCI NIH HHS/ -- R01 CA125636/CA/NCI NIH HHS/ -- R01 CA125636-02/CA/NCI NIH HHS/ -- England -- Nature. 2008 Feb 28;451(7182):1116-20. doi: 10.1038/nature06633. Epub 2008 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18264087" target="_blank"〉PubMed〈/a〉
    Keywords: Azulenes/pharmacology ; BRCA2 Protein/genetics/metabolism ; Benzodiazepines/pharmacology ; Breast Neoplasms/drug therapy/genetics/pathology ; Cell Line, Tumor ; Cisplatin/*pharmacology ; Drug Resistance, Neoplasm/*drug effects/*genetics ; Female ; *Genes, BRCA2 ; Humans ; Middle Aged ; Mutation/*genetics ; Neoplasms/*drug therapy/*genetics ; Ovarian Neoplasms/drug therapy/genetics ; Pancreatic Neoplasms/drug therapy/genetics/pathology ; Poly(ADP-ribose) Polymerase Inhibitors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2010-01-15
    Description: The human Y chromosome began to evolve from an autosome hundreds of millions of years ago, acquiring a sex-determining function and undergoing a series of inversions that suppressed crossing over with the X chromosome. Little is known about the recent evolution of the Y chromosome because only the human Y chromosome has been fully sequenced. Prevailing theories hold that Y chromosomes evolve by gene loss, the pace of which slows over time, eventually leading to a paucity of genes, and stasis. These theories have been buttressed by partial sequence data from newly emergent plant and animal Y chromosomes, but they have not been tested in older, highly evolved Y chromosomes such as that of humans. Here we finished sequencing of the male-specific region of the Y chromosome (MSY) in our closest living relative, the chimpanzee, achieving levels of accuracy and completion previously reached for the human MSY. By comparing the MSYs of the two species we show that they differ radically in sequence structure and gene content, indicating rapid evolution during the past 6 million years. The chimpanzee MSY contains twice as many massive palindromes as the human MSY, yet it has lost large fractions of the MSY protein-coding genes and gene families present in the last common ancestor. We suggest that the extraordinary divergence of the chimpanzee and human MSYs was driven by four synergistic factors: the prominent role of the MSY in sperm production, 'genetic hitchhiking' effects in the absence of meiotic crossing over, frequent ectopic recombination within the MSY, and species differences in mating behaviour. Although genetic decay may be the principal dynamic in the evolution of newly emergent Y chromosomes, wholesale renovation is the paramount theme in the continuing evolution of chimpanzee, human and perhaps other older MSYs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653425/" 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/PMC3653425/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hughes, Jennifer F -- Skaletsky, Helen -- Pyntikova, Tatyana -- Graves, Tina A -- van Daalen, Saskia K M -- Minx, Patrick J -- Fulton, Robert S -- McGrath, Sean D -- Locke, Devin P -- Friedman, Cynthia -- Trask, Barbara J -- Mardis, Elaine R -- Warren, Wesley C -- Repping, Sjoerd -- Rozen, Steve -- Wilson, Richard K -- Page, David C -- R01 HG000257/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jan 28;463(7280):536-9. doi: 10.1038/nature08700. Epub 2010 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Whitehead Institute, and Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20072128" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromosomes, Human, Pair 21/genetics ; Chromosomes, Human, Y/*genetics ; DNA/chemistry/genetics ; Genes/*genetics ; Humans ; Male ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Pan troglodytes/*genetics ; Sequence Homology, Nucleic Acid ; Y Chromosome/*genetics
    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: 2010-11-19
    Description: Post-transcriptional gene regulation frequently occurs through elements in mRNA 3' untranslated regions (UTRs). Although crucial roles for 3'UTR-mediated gene regulation have been found in Caenorhabditis elegans, most C. elegans genes have lacked annotated 3'UTRs. Here we describe a high-throughput method for reliable identification of polyadenylated RNA termini, and we apply this method, called poly(A)-position profiling by sequencing (3P-Seq), to determine C. elegans 3'UTRs. Compared to standard methods also recently applied to C. elegans UTRs, 3P-Seq identified 8,580 additional UTRs while excluding thousands of shorter UTR isoforms that do not seem to be authentic. Analysis of this expanded and corrected data set suggested that the high A/U content of C. elegans 3'UTRs facilitated genome compaction, because the elements specifying cleavage and polyadenylation, which are A/U rich, can more readily emerge in A/U-rich regions. Indeed, 30% of the protein-coding genes have mRNAs with alternative, partially overlapping end regions that generate another 10,480 cleavage and polyadenylation sites that had gone largely unnoticed and represent potential evolutionary intermediates of progressive UTR shortening. Moreover, a third of the convergently transcribed genes use palindromic arrangements of bidirectional elements to specify UTRs with convergent overlap, which also contributes to genome compaction by eliminating regions between genes. Although nematode 3'UTRs have median length only one-sixth that of mammalian 3'UTRs, they have twice the density of conserved microRNA sites, in part because additional types of seed-complementary sites are preferentially conserved. These findings reveal the influence of cleavage and polyadenylation on the evolution of genome architecture and provide resources for studying post-transcriptional gene regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057491/" 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/PMC3057491/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jan, Calvin H -- Friedman, Robin C -- Ruby, J Graham -- Bartel, David P -- GM067031/GM/NIGMS NIH HHS/ -- R01 GM067031/GM/NIGMS NIH HHS/ -- R01 GM067031-06/GM/NIGMS NIH HHS/ -- R01 GM067031-07/GM/NIGMS NIH HHS/ -- R01 GM067031-08/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jan 6;469(7328):97-101. doi: 10.1038/nature09616. Epub 2010 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21085120" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/*genetics ; AT Rich Sequence/genetics ; Animals ; Caenorhabditis elegans/*genetics ; Conserved Sequence/genetics ; *Evolution, Molecular ; Gene Expression Profiling/methods ; Gene Expression Regulation/*genetics ; Genes, Helminth/genetics ; High-Throughput Nucleotide Sequencing/*methods ; Humans ; MicroRNAs/genetics ; Poly A ; Polyadenylation ; RNA, Helminth/genetics ; Regulatory Sequences, Ribonucleic Acid/genetics ; Sequence Alignment ; Sequence Analysis, RNA/methods
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2019
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 10
    Publication Date: 2017-07-22
    Description: While eukaryotic noncoding RNAs have recently received intense scrutiny, it is becoming clear that bacterial transcription is at least as pervasive. Bacterial small RNAs and antisense RNAs (sRNAs) are often as...
    Electronic ISSN: 1471-2164
    Topics: Biology
    Published by BioMed Central
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