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Article ; Online: The endoplasmic reticulum: structure, function and response to cellular signaling.

Schwarz, Dianne S / Blower, Michael D

Cellular and molecular life sciences : CMLS

2016 Volume 73, Issue 1, Page(s) 79–94

Abstract: The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, ... ...

Abstract	The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, sheets and the nuclear envelope. Several proteins that contribute to the overall architecture and dynamics of the ER have been identified, but many questions remain as to how the ER changes shape in response to cellular cues, cell type, cell cycle state and during development of the organism. Here we discuss what is known about the dynamics of the ER, what questions remain, and how coordinated responses add to the layers of regulation in this dynamic organelle.
MeSH term(s)	Animals ; Calcium/metabolism ; Endoplasmic Reticulum/chemistry ; Endoplasmic Reticulum/metabolism ; Endoplasmic Reticulum/ultrastructure ; Fertilization ; Humans ; Lipid Metabolism ; Mitosis ; Protein Biosynthesis ; Protein Folding ; Proteins/chemistry ; Proteins/metabolism ; Signal Transduction ; Unfolded Protein Response
Chemical Substances	Proteins ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2016-01
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-015-2052-6
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Article ; Online: The calcium-dependent ribonuclease XendoU promotes ER network formation through local RNA degradation.

Schwarz, Dianne S / Blower, Michael D

The Journal of cell biology

2014 Volume 207, Issue 1, Page(s) 41–57

Abstract: How cells shape and remodel organelles in response to cellular signals is a poorly understood process. Using Xenopus laevis egg extract, we found that increases in cytosolic calcium lead to the activation of an endogenous ribonuclease, XendoU. A fraction ...

Abstract	How cells shape and remodel organelles in response to cellular signals is a poorly understood process. Using Xenopus laevis egg extract, we found that increases in cytosolic calcium lead to the activation of an endogenous ribonuclease, XendoU. A fraction of XendoU localizes to the endoplasmic reticulum (ER) and is required for nuclear envelope assembly and ER network formation in a catalysis-dependent manner. Using a purified vesicle fusion assay, we show that XendoU functions on the surface of ER membranes to promote RNA cleavage and ribonucleoprotein (RNP) removal. Additionally, RNA removal from the surface of vesicles by RNase treatment leads to increased ER network formation. Using human tissue culture cells, we found that hEndoU localizes to the ER, where it promotes the formation of ER tubules in a catalysis-dependent manner. Together, these results demonstrate that calcium-activated removal of RNA from membranes by XendoU promotes and refines ER remodeling and the formation of tubular ER.
MeSH term(s)	Animals ; Calcium/metabolism ; Calcium Signaling ; Cell Line ; Cell Membrane/enzymology ; Cell Membrane/metabolism ; Endoplasmic Reticulum/metabolism ; Endoribonucleases/metabolism ; HeLa Cells ; Humans ; Nuclear Envelope/metabolism ; Ovum/metabolism ; RNA Interference ; RNA Stability ; RNA, Messenger/metabolism ; RNA, Small Interfering/genetics ; Ribonucleoproteins/metabolism ; Signal Transduction/genetics ; Xenopus Proteins/metabolism ; Xenopus laevis/genetics ; Xenopus laevis/metabolism
Chemical Substances	RNA, Messenger ; RNA, Small Interfering ; Ribonucleoproteins ; Xenopus Proteins ; Endoribonucleases (EC 3.1.-) ; ENDOU protein, Xenopus (EC 3.1.26.-) ; Calcium (SY7Q814VUP)
Keywords	covid19
Language	English
Publishing date	2014-10-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201406037
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Article ; Online: Combining different mRNA capture methods to analyze the transcriptome: analysis of the Xenopus laevis transcriptome.

Blower, Michael D / Jambhekar, Ashwini / Schwarz, Dianne S / Toombs, James A

PloS one

2013 Volume 8, Issue 10, Page(s) e77700

Abstract: mRNA sequencing (mRNA-seq) is a commonly used technique to survey gene expression from organisms with fully sequenced genomes. Successful mRNA-seq requires purification of mRNA away from the much more abundant ribosomal RNA, which is typically ... ...

Abstract	mRNA sequencing (mRNA-seq) is a commonly used technique to survey gene expression from organisms with fully sequenced genomes. Successful mRNA-seq requires purification of mRNA away from the much more abundant ribosomal RNA, which is typically accomplished by oligo-dT selection. However, mRNAs with short poly-A tails are captured poorly by oligo-dT based methods. We demonstrate that combining mRNA capture via oligo-dT with mRNA capture by the 5' 7-methyl guanosine cap provides a more complete view of the transcriptome and can be used to assay changes in mRNA poly-A tail length on a genome-wide scale. We also show that using mRNA-seq reads from both capture methods as input for de novo assemblers provides a more complete reconstruction of the transcriptome than either method used alone. We apply these methods of mRNA capture and de novo assembly to the transcriptome of Xenopus laevis, a well-studied frog that currently lacks a finished sequenced genome, to discover transcript sequences for thousands of mRNAs that are currently absent from public databases. The methods we describe here will be broadly applicable to many organisms and will provide insight into the transcriptomes of organisms with sequenced and unsequenced genomes.
MeSH term(s)	Animals ; Gene Expression Profiling/methods ; Oligodeoxyribonucleotides/genetics ; Poly A/genetics ; RNA, Messenger/genetics ; RNA, Messenger/isolation & purification ; Sequence Analysis, RNA ; Xenopus laevis/genetics
Chemical Substances	Oligodeoxyribonucleotides ; RNA, Messenger ; oligo (dT) ; Poly A (24937-83-5)
Language	English
Publishing date	2013-10-15
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0077700
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Article ; Online: Combining different mRNA capture methods to analyze the transcriptome

Michael D Blower / Ashwini Jambhekar / Dianne S Schwarz / James A Toombs

PLoS ONE, Vol 8, Iss 10, p e

analysis of the Xenopus laevis transcriptome.

2013 Volume 77700

Abstract	mRNA sequencing (mRNA-seq) is a commonly used technique to survey gene expression from organisms with fully sequenced genomes. Successful mRNA-seq requires purification of mRNA away from the much more abundant ribosomal RNA, which is typically accomplished by oligo-dT selection. However, mRNAs with short poly-A tails are captured poorly by oligo-dT based methods. We demonstrate that combining mRNA capture via oligo-dT with mRNA capture by the 5' 7-methyl guanosine cap provides a more complete view of the transcriptome and can be used to assay changes in mRNA poly-A tail length on a genome-wide scale. We also show that using mRNA-seq reads from both capture methods as input for de novo assemblers provides a more complete reconstruction of the transcriptome than either method used alone. We apply these methods of mRNA capture and de novo assembly to the transcriptome of Xenopus laevis, a well-studied frog that currently lacks a finished sequenced genome, to discover transcript sequences for thousands of mRNAs that are currently absent from public databases. The methods we describe here will be broadly applicable to many organisms and will provide insight into the transcriptomes of organisms with sequenced and unsequenced genomes.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article: Why do miRNAs live in the miRNP?

Schwarz, Dianne S / Zamore, Phillip D

Genes & development

2002 Volume 16, Issue 9, Page(s) 1025–1031

MeSH term(s)	Animals ; Argonaute Proteins ; DEAD Box Protein 20 ; DEAD-box RNA Helicases ; Drosophila Proteins ; Endoribonucleases/metabolism ; Humans ; Proteins/genetics ; Proteins/metabolism ; RNA/genetics ; RNA/metabolism ; RNA Helicases/genetics ; RNA Helicases/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Induced Silencing Complex ; Ribonuclease III ; Ribonucleoproteins/genetics ; Ribonucleoproteins/metabolism ; Untranslated Regions
Chemical Substances	Argonaute Proteins ; Drosophila Proteins ; PIWIL1 protein, human ; Proteins ; RNA, Messenger ; RNA-Induced Silencing Complex ; Ribonucleoproteins ; Untranslated Regions ; piwi protein, Drosophila ; RNA (63231-63-0) ; Endoribonucleases (EC 3.1.-) ; Ribonuclease III (EC 3.1.26.3) ; DDX20 protein, human (EC 3.6.1.-) ; DEAD Box Protein 20 (EC 3.6.1.-) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2002-05-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.992502
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Zs.A 2292: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: The RNA-induced silencing complex is a Mg2+-dependent endonuclease.

Schwarz, Dianne S / Tomari, Yukihide / Zamore, Phillip D

Current biology : CB

2004 Volume 14, Issue 9, Page(s) 787–791

Abstract: In the Drosophila and mammalian RNA interference (RNAi) pathways, target RNA destruction is catalyzed by the siRNA-guided, RNA-induced silencing complex (RISC). RISC has been proposed to be an siRNA-directed endonuclease, catalyzing cleavage of a single ... ...

Abstract	In the Drosophila and mammalian RNA interference (RNAi) pathways, target RNA destruction is catalyzed by the siRNA-guided, RNA-induced silencing complex (RISC). RISC has been proposed to be an siRNA-directed endonuclease, catalyzing cleavage of a single phosphodiester bond on the RNA target. Although 5' cleavage products are readily detected for RNAi in vitro, only 3' cleavage products have been observed in vivo. Proof that RISC acts as an endonuclease requires detection of both 5' and 3' cleavage products in a single experimental system. Here, we show that siRNA-programmed RISC generates both 5' and 3' cleavage products in vitro; cleavage requires Mg(2+), but not Ca(2+), and the cleavage product termini suggest a role for Mg(2+) in catalysis. Moreover, a single phosphorothioate in place of the scissile phosphate blocks cleavage; the phosphorothioate effect can be rescued by the thiophilic cation Mn(2+), but not by Ca(2+) or Mg(2+). We propose that during catalysis, a Mg(2+) ion is bound to the RNA substrate through a nonbridging oxygen of the scissile phosphate. The mechanism of endonucleolytic cleavage is not consistent with the mechanisms of the previously identified RISC nuclease, Tudor-SN. Thus, the RISC-component that mediates endonucleolytic cleavage of the target RNA remains to be identified.
MeSH term(s)	Animals ; Catalysis ; DNA Primers ; Drosophila/enzymology ; Drosophila/metabolism ; Drosophila Proteins/metabolism ; Endonucleases/metabolism ; Endonucleases/physiology ; Luciferases/metabolism ; Magnesium/metabolism ; Membrane Transport Proteins/metabolism ; Phosphates/metabolism ; RNA Interference/physiology ; RNA, Small Interfering/metabolism ; RNA-Induced Silencing Complex/metabolism ; RNA-Induced Silencing Complex/physiology
Chemical Substances	DNA Primers ; Drosophila Proteins ; Membrane Transport Proteins ; Phosphates ; RNA, Small Interfering ; RNA-Induced Silencing Complex ; tud protein, Drosophila ; Luciferases (EC 1.13.12.-) ; Endonucleases (EC 3.1.-) ; Magnesium (I38ZP9992A)
Language	English
Publishing date	2004-05-04
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2004.03.008
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Article: Evidence that siRNAs function as guides, not primers, in the Drosophila and human RNAi pathways.

Schwarz, Dianne S / Hutvágner, György / Haley, Benjamin / Zamore, Phillip D

Molecular cell

2002 Volume 10, Issue 3, Page(s) 537–548

Abstract: In Drosophila, two features of small interfering RNA (siRNA) structure--5' phosphates and 3' hydroxyls--are reported to be essential for RNA interference (RNAi). Here, we show that as in Drosophila, a 5' phosphate is required for siRNA function in human ... ...

Abstract	In Drosophila, two features of small interfering RNA (siRNA) structure--5' phosphates and 3' hydroxyls--are reported to be essential for RNA interference (RNAi). Here, we show that as in Drosophila, a 5' phosphate is required for siRNA function in human HeLa cells. In contrast, we find no evidence in flies or humans for a role in RNAi for the siRNA 3' hydroxyl group. Our in vitro data suggest that in both flies and mammals, each siRNA guides endonucleolytic cleavage of the target RNA at a single site. We conclude that the underlying mechanism of RNAi is conserved between flies and mammals and that RNA-dependent RNA polymerases are not required for RNAi in these organisms.
MeSH term(s)	Animals ; Drosophila melanogaster/embryology ; Drosophila melanogaster/genetics ; Endoribonucleases/metabolism ; Gene Expression Regulation ; Genes, Insect ; HeLa Cells ; Humans ; Phosphates/metabolism ; RNA Interference/physiology ; RNA, Double-Stranded/chemistry ; RNA, Double-Stranded/metabolism ; RNA, Small Interfering/chemistry ; RNA, Small Interfering/metabolism ; Ribonuclease III
Chemical Substances	Phosphates ; RNA, Double-Stranded ; RNA, Small Interfering ; Endoribonucleases (EC 3.1.-) ; Ribonuclease III (EC 3.1.26.3)
Language	English
Publishing date	2002-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/s1097-2765(02)00651-2
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Article: The Listening Network and Cochlear Implant Benefits in Hearing-Impaired Adults.

James, Chris J / Graham, Petra L / Betances Reinoso, Frank A / Breuning, Silvia N / Durko, Marcin / Huarte Irujo, Alicia / Royo López, Juan / Müller, Lida / Perenyi, Adam / Jaramillo Saffon, Rafael / Salinas Garcia, Sandra / Schüssler, Mark / Schwarz Langer, Margarita J / Skarzynski, Piotr H / Mecklenburg, Dianne J

Frontiers in aging neuroscience

2021 Volume 13, Page(s) 589296

Abstract: Older adults with mild or no hearing loss make more errors and expend more effort listening to speech. Cochlear implants (CI) restore hearing to deaf patients but with limited fidelity. We hypothesized that patient-reported hearing and health-related ... ...

Abstract	Older adults with mild or no hearing loss make more errors and expend more effort listening to speech. Cochlear implants (CI) restore hearing to deaf patients but with limited fidelity. We hypothesized that patient-reported hearing and health-related quality of life in CI patients may similarly vary according to age. Speech Spatial Qualities (SSQ) of hearing scale and Health Utilities Index Mark III (HUI) questionnaires were administered to 543 unilaterally implanted adults across Europe, South Africa, and South America. Data were acquired before surgery and at 1, 2, and 3 years post-surgery. Data were analyzed using linear mixed models with visit, age group (18-34, 35-44, 45-54, 55-64, and 65+), and side of implant as main factors and adjusted for other covariates. Tinnitus and dizziness prevalence did not vary with age, but older groups had more preoperative hearing. Preoperatively and postoperatively, SSQ scores were significantly higher (Δ0.75-0.82) for those aged <45 compared with those 55+. However, gains in SSQ scores were equivalent across age groups, although postoperative SSQ scores were higher in right-ear implanted subjects. All age groups benefited equally in terms of HUI gain (0.18), with no decrease in scores with age. Overall, younger adults appeared to cope better with a degraded hearing before and after CI, leading to better subjective hearing performance.
Language	English
Publishing date	2021-02-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2021.589296
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Article: Asymmetry in the assembly of the RNAi enzyme complex.

Schwarz, Dianne S / Hutvágner, György / Du, Tingting / Xu, Zuoshang / Aronin, Neil / Zamore, Phillip D

Cell

2003 Volume 115, Issue 2, Page(s) 199–208

Abstract: A key step in RNA interference (RNAi) is assembly of the RISC, the protein-siRNA complex that mediates target RNA cleavage. Here, we show that the two strands of an siRNA duplex are not equally eligible for assembly into RISC. Rather, both the absolute ... ...

Abstract	A key step in RNA interference (RNAi) is assembly of the RISC, the protein-siRNA complex that mediates target RNA cleavage. Here, we show that the two strands of an siRNA duplex are not equally eligible for assembly into RISC. Rather, both the absolute and relative stabilities of the base pairs at the 5' ends of the two siRNA strands determine the degree to which each strand participates in the RNAi pathway. siRNA duplexes can be functionally asymmetric, with only one of the two strands able to trigger RNAi. Asymmetry is the hallmark of a related class of small, single-stranded, noncoding RNAs, microRNAs (miRNAs). We suggest that single-stranded miRNAs are initially generated as siRNA-like duplexes whose structures predestine one strand to enter the RISC and the other strand to be destroyed. Thus, the common step of RISC assembly is an unexpected source of asymmetry for both siRNA function and miRNA biogenesis.
MeSH term(s)	Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Base Pair Mismatch ; Base Pairing ; Base Sequence ; Drosophila melanogaster/embryology ; Hydrogen Bonding ; Kinetics ; MicroRNAs/chemistry ; MicroRNAs/metabolism ; Models, Biological ; Phosphorylation ; RNA Helicases/metabolism ; RNA Interference ; RNA, Antisense/chemistry ; RNA, Antisense/metabolism ; RNA, Double-Stranded/chemistry ; RNA, Double-Stranded/metabolism ; RNA, Messenger/chemistry ; RNA, Messenger/metabolism ; RNA, Small Interfering/chemistry ; RNA, Small Interfering/metabolism ; RNA, Untranslated/chemistry ; RNA, Untranslated/metabolism ; RNA-Induced Silencing Complex/chemistry ; RNA-Induced Silencing Complex/metabolism ; Superoxide Dismutase/chemistry ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1
Chemical Substances	MicroRNAs ; RNA, Antisense ; RNA, Double-Stranded ; RNA, Messenger ; RNA, Small Interfering ; RNA, Untranslated ; RNA-Induced Silencing Complex ; Adenosine Diphosphate (61D2G4IYVH) ; Adenosine Triphosphate (8L70Q75FXE) ; Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1) ; RNA Helicases (EC 3.6.4.13)
Language	English
Publishing date	2003-10-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/s0092-8674(03)00759-1
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Discovery and characterization of a novel dihydroisoxazole class of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiators.

Journal of medicinal chemistry

2013 Volume 56, Issue 22, Page(s) 9180–9191

Abstract: Positive allosteric modulators ("potentiators") of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. ... ...

Abstract	Positive allosteric modulators ("potentiators") of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors. Subsequent structure-based drug design using X-ray crystal structures of the ligand-binding domain of human GluA2 led to the discovery of both PF-04725379 (11), which in tritiated form became a novel ligand for characterizing the binding affinities of subsequent AMPAR potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.
MeSH term(s)	Absorption ; Allosteric Regulation/drug effects ; Animals ; Drug Discovery ; High-Throughput Screening Assays ; Humans ; Isoxazoles/chemistry ; Isoxazoles/metabolism ; Isoxazoles/pharmacokinetics ; Isoxazoles/pharmacology ; Male ; Mice ; Models, Molecular ; Protein Structure, Tertiary ; Rats ; Receptors, AMPA/chemistry ; Receptors, AMPA/metabolism ; Structure-Activity Relationship
Chemical Substances	Isoxazoles ; Receptors, AMPA
Language	English
Publishing date	2013-11-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm401274b
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