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  • 1
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    Structural insight into precursor tRNA processing by yeast ribonuclease P (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018
    Description: 〈p〉Ribonuclease P (RNase P) is a universal ribozyme responsible for processing the 5'-leader of pre–transfer RNA (pre-tRNA). Here, we report the 3.5-angstrom cryo–electron microscopy structures of 〈i〉Saccharomyces cerevisiae〈/i〉 RNase P alone and in complex with pre-tRNA〈sup〉Phe〈/sup〉. The protein components form a hook-shaped architecture that wraps around the RNA and stabilizes RNase P into a "measuring device" with two fixed anchors that recognize the L-shaped pre-tRNA. A universally conserved uridine nucleobase and phosphate backbone in the catalytic center together with the scissile phosphate and the O3' leaving group of pre-tRNA jointly coordinate two catalytic magnesium ions. Binding of pre-tRNA induces a conformational change in the catalytic center that is required for catalysis. Moreover, simulation analysis suggests a two-metal-ion S〈sub〉N〈/sub〉2 reaction pathway of pre-tRNA cleavage. These results not only reveal the architecture of yeast RNase P but also provide a molecular basis of how the 5'-leader of pre-tRNA is processed by eukaryotic RNase P.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    Structural insight into precursor tRNA processing by yeast ribonuclease P (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2018
    Description: 〈p〉Ribonuclease P (RNase P) is a universal ribozyme responsible for processing the 5'-leader of pre-tRNA. Here we report the 3.5-Å cryo-EM structures of 〈i〉Saccharomyces cerevisiae〈/i〉 RNase P alone and in complex with pre-tRNA〈sup〉Phe〈/sup〉. The protein components form a hook-shaped architecture that wraps around the RNA and stabilizes RNase P into a "measuring device" with two fixed anchors that recognize the L-shaped pre-tRNA. A universally conserved uridine nucleobase and phosphate backbone in the catalytic center together with the scissile phosphate and the O3' leaving group of pre-tRNA jointly coordinate two catalytic magnesium ions. Binding of pre-tRNA induces a conformational change in the catalytic center that is required for catalysis. Moreover, simulation analysis suggests a two-metal-ion S〈sub〉N〈/sub〉2 reaction pathway of pre-tRNA cleavage. These results not only reveal the architecture of yeast RNase P but also provide a molecular basis of how the 5'-leader of pre-tRNA is processed by eukaryotic RNase P.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Structural insight into precursor tRNA processing by yeast ribonuclease P (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018-11-09
    Description: Ribonuclease P (RNase P) is a universal ribozyme responsible for processing the 5'-leader of pre–transfer RNA (pre-tRNA). Here, we report the 3.5-angstrom cryo–electron microscopy structures of Saccharomyces cerevisiae RNase P alone and in complex with pre-tRNA Phe . The protein components form a hook-shaped architecture that wraps around the RNA and stabilizes RNase P into a "measuring device" with two fixed anchors that recognize the L-shaped pre-tRNA. A universally conserved uridine nucleobase and phosphate backbone in the catalytic center together with the scissile phosphate and the O3' leaving group of pre-tRNA jointly coordinate two catalytic magnesium ions. Binding of pre-tRNA induces a conformational change in the catalytic center that is required for catalysis. Moreover, simulation analysis suggests a two-metal-ion S N 2 reaction pathway of pre-tRNA cleavage. These results not only reveal the architecture of yeast RNase P but also provide a molecular basis of how the 5'-leader of pre-tRNA is processed by eukaryotic RNase P.
    Keywords: Biochemistry, Online Only
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    A swarm of slippery micropropellers penetrates the vitreous body of the eye (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2018
    Description: 〈p〉The intravitreal delivery of therapeutic agents promises major benefits in the field of ocular medicine. Traditional delivery methods rely on the random, passive diffusion of molecules, which do not allow for the rapid delivery of a concentrated cargo to a defined region at the posterior pole of the eye. The use of particles promises targeted delivery but faces the challenge that most tissues including the vitreous have a tight macromolecular matrix that acts as a barrier and prevents its penetration. Here, we demonstrate novel intravitreal delivery microvehicles—slippery micropropellers—that can be actively propelled through the vitreous humor to reach the retina. The propulsion is achieved by helical magnetic micropropellers that have a liquid layer coating to minimize adhesion to the surrounding biopolymeric network. The submicrometer diameter of the propellers enables the penetration of the biopolymeric network and the propulsion through the porcine vitreous body of the eye over centimeter distances. Clinical optical coherence tomography is used to monitor the movement of the propellers and confirm their arrival on the retina near the optic disc. Overcoming the adhesion forces and actively navigating a swarm of micropropellers in the dense vitreous humor promise practical applications in ophthalmology.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    miR-17~92 cluster represses arteriogenesis [Medical Sciences] (2015)
    National Academy of Sciences
    Details
    Publication Date: 2015-10-14
    Description: The contribution of endothelial-derived miR-17∼92 to ischemia-induced arteriogenesis has not been investigated in an in vivo model. In the present study, we demonstrate a critical role for the endothelial-derived miR-17∼92 cluster in shaping physiological and ischemia-triggered arteriogenesis. Endothelial-specific deletion of miR-17∼92 results in an increase in collateral density limbs and...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    Horizontal Transfers of Tc1 Elements between Teleost Fishes and Their Vertebrate Parasites, Lampreys (2012)
    Oxford University Press
    Details
    Publication Date: 2012-09-12
    Description: Horizontal gene transfer (HGT) has been recognized to be an important mechanism that shaped the evolution and genomes of prokaryotes and unicellular eukaryotes. However, HGT is regarded to be exceedingly rare among eukaryotes. We discovered massive transfers of a DNA transposon, a Tc1 element encoding a transposase, between multiple teleost fishes and lampreys that last shared a common ancestor over 500 Ma. Members of this group of Tc1 elements were found to exhibit a mosaic phylogenetic distribution, yet their sequences were highly similar even between distantly related lineages (95%–99% identity). Our molecular phylogenetic analyses suggested that horizontal transfers of this element happened repeatedly, involving multiple teleost fishes that are phylogenetically only distantly related. Interestingly, almost all the affected teleost lineages are also known to be subject to lamprey parasitism, suggesting that the horizontal transfers between vertebrates might have occurred through parasite–host interaction. The genomes of several northern hemisphere lamprey species, including that of the sea lamprey ( Petromyzon marinus ), were found to contain thousands of copies of the foreign elements. Impact of this event is discussed in relation to other peculiar genomic features of lampreys.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome (2012)
    Oxford University Press
    Details
    Publication Date: 2012-06-13
    Description: The impact of cigarette smoking can persist for extended periods following smoking cessation and may involve epigenetic reprogramming. Changes in DNA methylation associated with smoking may help to identify molecular pathways that contribute to the latency between exposure and disease onset. Cross-sectional cohort data from subjects in the International COPD Genetics Network ( n = 1085) and the Boston Early-Onset COPD study ( n = 369) were analyzed as the discovery and replication cohorts, respectively. Genome-wide methylation data on 27 578 CpG sites in 14 475 genes were obtained on DNA from peripheral blood leukocytes using the Illumina HumanMethylation27K Beadchip in both cohorts. We identified 15 sites significantly associated with current smoking, 2 sites associated with cumulative smoke exposure, and, within the subset of former smokers, 3 sites associated with time since quitting cigarettes. Two loci, factor II receptor-like 3 ( F2RL3 ) and G-protein-coupled receptor 15 ( GPR15 ), were significantly associated in all three analyses and were validated by pyrosequencing. These findings (i) identify a novel locus ( GPR15 ) associated with cigarette smoking and (ii) suggest the existence of dynamic, site-specific methylation changes in response to smoking which may contribute to the extended risks associated with cigarette smoking that persist after cessation.
    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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    Piezo1 in vascular development [Physiology] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-07-16
    Description: Mechanosensation is perhaps the last sensory modality not understood at the molecular level. Ion channels that sense mechanical force are postulated to play critical roles in a variety of biological processes including sensing touch/pain (somatosensation), sound (hearing), and shear stress (cardiovascular physiology); however, the identity of these ion channels has...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 9
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    PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel (2019)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2019
    Description: 〈p〉Severe local acidosis causes tissue damage and pain, and is one of the hallmarks of many diseases including ischemia, cancer, and inflammation. However, the molecular mechanisms of the cellular response to acid are not fully understood. We performed an unbiased RNA interference screen and identified 〈i〉PAC (TMEM206)〈/i〉 as being essential for the widely observed proton-activated Cl〈sup〉–〈/sup〉 (PAC) currents (〈i〉I〈/i〉〈sub〉Cl,H〈/sub〉). Overexpression of human PAC in 〈i〉PAC〈/i〉 knockout cells generated 〈i〉I〈/i〉〈sub〉Cl,H〈/sub〉 with the same characteristics as the endogenous ones. Zebrafish PAC encodes a PAC channel with distinct properties. Knockout of mouse 〈i〉Pac〈/i〉 abolished 〈i〉I〈/i〉〈sub〉Cl,H〈/sub〉 in neurons and attenuated brain damage after ischemic stroke. The wide expression of PAC suggests a broad role for this conserved Cl〈sup〉–〈/sup〉 channel family in physiological and pathological processes associated with acidic pH.〈/p〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 10
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    A swarm of slippery micropropellers penetrates the vitreous body of the eye (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2018-11-03
    Description: The intravitreal delivery of therapeutic agents promises major benefits in the field of ocular medicine. Traditional delivery methods rely on the random, passive diffusion of molecules, which do not allow for the rapid delivery of a concentrated cargo to a defined region at the posterior pole of the eye. The use of particles promises targeted delivery but faces the challenge that most tissues including the vitreous have a tight macromolecular matrix that acts as a barrier and prevents its penetration. Here, we demonstrate novel intravitreal delivery microvehicles—slippery micropropellers—that can be actively propelled through the vitreous humor to reach the retina. The propulsion is achieved by helical magnetic micropropellers that have a liquid layer coating to minimize adhesion to the surrounding biopolymeric network. The submicrometer diameter of the propellers enables the penetration of the biopolymeric network and the propulsion through the porcine vitreous body of the eye over centimeter distances. Clinical optical coherence tomography is used to monitor the movement of the propellers and confirm their arrival on the retina near the optic disc. Overcoming the adhesion forces and actively navigating a swarm of micropropellers in the dense vitreous humor promise practical applications in ophthalmology.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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