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Phillip A. Sharp

Bio: Phillip A. Sharp is an academic researcher from Massachusetts Institute of Technology. The author has contributed to research in topics: RNA & RNA splicing. The author has an hindex of 172, co-authored 614 publications receiving 117126 citations. Previous affiliations of Phillip A. Sharp include McGovern Institute for Brain Research & Medical Research Council.
Topics: RNA, RNA splicing, Gene, Transcription (biology), DNA


Papers
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Journal ArticleDOI
01 Jan 2001-RNA
TL;DR: The finding that lariat formation can be accomplished by a small RNA with sequences related to U6 snRNA indicates that the RNA available in the spliceosome may be involved in RNA-catalyzed branch formation.
Abstract: In vitro selection was used to sample SnRNA-related sequences for ribozyme activities, and several 2',5'-branch-forming ribozymes were isolated One such ribozyme is highly dependent upon an 11-nt motif that contains a conserved U6 snRNA sequence (ACAGAGA-box) known to be important for pre-mRNA splicing The ribozyme reaction is similar to the first step of splicing in that an internal 2'-hydroxyl of an unpaired adenosine attacks at the 5'-phosphate of a guanosine It differs in that the leaving group is diphosphate rather than a 5' exon The finding that lariat formation can be accomplished by a small RNA with sequences related to U6 snRNA indicates that the RNA available in the spliceosome may be involved in RNA-catalyzed branch formation

17 citations

Journal Article
TL;DR: In this article, the emergence of weak cooperative interactions for mediating specificity results in organisms that can evolve to accomplish new tasks with fewer, and likely less lethal, mutations, which makes the system more capable of undergoing evolutionary changes robustly, and thus this mechanism has been repeatedly positively selected in increasingly complex organisms.
Abstract: A hallmark of biological systems is that particular functions and outcomes are realized in specific contexts, such as when particular signals are received. One mechanism for mediating specificity is described by Fisher’s “lock and key” metaphor, exemplified by enzymes that bind selectively to a particular substrate via specific finely tuned interactions. Another mechanism, more prevalent in multicellular organisms, relies on multivalent weak cooperative interactions. Its importance has recently been illustrated by the recognition that liquid-liquid phase transitions underlie the formation of membraneless condensates that perform specific cellular functions. Based on computer simulations of an evolutionary model, we report that the latter mechanism likely became evolutionarily prominent when a large number of tasks had to be performed specifically for organisms to function properly. We find that the emergence of weak cooperative interactions for mediating specificity results in organisms that can evolve to accomplish new tasks with fewer, and likely less lethal, mutations. We argue that this makes the system more capable of undergoing evolutionary changes robustly, and thus this mechanism has been repeatedly positively selected in increasingly complex organisms. Specificity mediated by weak cooperative interactions results in some useful cross-reactivity for related tasks, but at the same time increases susceptibility to misregulation that might lead to pathologies.

17 citations

Journal ArticleDOI
18 Nov 2020-BMJ Open
TL;DR: The aim of this study is to examine the impact of consuming zinc biofortified flour (Zincol-2016) on biochemical and functional measures of status in adolescent girls and children living in a low-resource setting in Pakistan.
Abstract: Introduction: Micronutrient deficiencies, commonly referred to as “hidden hunger”, affect more than two billion people worldwide, with zinc and iron deficiency frequently reported. The aim of this study is to examine the impact of consuming zinc biofortified flour (Zincol-2016) on biochemical and functional measures of status in adolescent girls and children living in a low resource setting in Pakistan. Methods and analysis: We are conducting a pragmatic, cluster-randomised, double-blind, controlled trial. A total of 483 households have been recruited from two catchment areas approximately 30-40 km distance from Peshawar. Household inclusion criteria are the presence of both an adolescent girl, aged 10-16 years, and a child aged 2-5 years. The study duration is 12 months, divided into two 6-month phases. During phase 1, all households will be provided with locally procured flour from standard varieties of wheat. During phase 2, clusters will be paired, and randomised to either the control or intervention arm of the study. The intervention arm will be provided with zinc biofortified wheat flour, with a target zinc concentration of 40 mg/kg. The control arm will be provided with locally procured wheat flour from standard varieties with an expected zinc concentration of 20 mg/kg. The primary outcome measure is plasma zinc concentration. Secondary outcomes include anthropometric measurements, biomarkers of iron and zinc status, and the presence and duration of respiratory tract infections and diarrhoea. Ethics and dissemination: Ethical approval was granted from the University of Central Lancashire STEMH Ethics Committee (reference number: STEMH 1014) and Khyber Medical University Ethics Committee (DIR/KMU-EB/BZ/000683). The final study methods will be published in peer reviewed journals, alongside the study outcomes. In addition, findings will be disseminated to the scientific community via conference presentations and abstracts and communicated to the study participants through the village elders at an appropriate community forum. Registration details: The trial has been registered with the ISRCTN registry, study ID ISRCTN17107812.

17 citations

Journal ArticleDOI
TL;DR: Results suggest that many cell lines susceptible to simian virus 40 infection may be transiently converted to a suppressor-positive phenotype for use in the genetic study of mammalian viruses.
Abstract: A nonsense mutation (UAG) in the thymidine kinase gene of herpes simplex virus type 1 can be suppressed in vivo to produce active thymidine kinase by prior infection with a defective simian virus 40 stock which acts as a vector to introduce a functional suppressor tRNA gene into mammalian cells in culture. The suppression is specific for UAG, but not UGA or missense, mutants and restores thymidine kinase activity to 20 to 40% of the wild-type level. These results suggest that many cell lines susceptible to simian virus 40 infection may be transiently converted to a suppressor-positive phenotype for use in the genetic study of mammalian viruses.

17 citations

Journal ArticleDOI
01 May 1977-Gene
TL;DR: An attenuated bacteriophage lambda has been prepared for proposed use as an EK2 vector, and the rate of transfer of kanamycin resistance to permissive and nonpermissive strains of E. coli has been measured.

16 citations


Cited by
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Journal ArticleDOI
23 Jan 2004-Cell
TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

32,946 citations

Journal ArticleDOI
Eric S. Lander1, Lauren Linton1, Bruce W. Birren1, Chad Nusbaum1  +245 moreInstitutions (29)
15 Feb 2001-Nature
TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

22,269 citations

28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal ArticleDOI
23 Jan 2009-Cell
TL;DR: The current understanding of miRNA target recognition in animals is outlined and the widespread impact of miRNAs on both the expression and evolution of protein-coding genes is discussed.

18,036 citations

Journal ArticleDOI
TL;DR: In this paper, a procedure for extracting plasmid DNA from bacterial cells is described, which is simple enough to permit the analysis by gel electrophoresis of 100 or more clones per day, yet yields DNA which is pure enough to be digestible by restriction enzymes.
Abstract: A procedure for extracting plasmid DNA from bacterial cells is described. The method is simple enough to permit the analysis by gel electrophoresis of 100 or more clones per day yet yields plasmid DNA which is pure enough to be digestible by restriction enzymes. The principle of the method is selective alkaline denaturation of high molecular weight chromosomal DNA while covalently closed circular DNA remains double-stranded. Adequate pH control is accomplished without using a pH meter. Upon neutralization, chromosomal DNA renatures to form an insoluble clot, leaving plasmid DNA in the supernatant. Large and small plasmid DNAs have been extracted by this method.

13,805 citations