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Article: Abolished frameshifting for predicted structure-stabilizing SARS-CoV-2 mutants: Implications to alternative conformations and their statistical structural analyses.

Dey, Abhishek / Yan, Shuting / Schlick, Tamar / Laederach, Alain

bioRxiv : the preprint server for biology

2024

Abstract: The SARS-CoV-2 frameshifting element (FSE) has been intensely studied and explored as a therapeutic target for coronavirus diseases including COVID-19. Besides the intriguing virology, this small RNA is known to adopt many length-dependent conformations, ...

Abstract	The SARS-CoV-2 frameshifting element (FSE) has been intensely studied and explored as a therapeutic target for coronavirus diseases including COVID-19. Besides the intriguing virology, this small RNA is known to adopt many length-dependent conformations, as verified by multiple experimental and computational approaches. However, the role these alternative conformations play in the frameshifting mechanism and how to quantify this structural abundance has been an ongoing challenge. Here, we show by DMS and dual-luciferase functional assays that previously predicted FSE mutants (using the RAG graph theory approach) suppress structural transitions and abolish frameshifting. Furthermore, correlated mutation analysis of DMS data by three programs (DREEM, DRACO, and DANCE-MaP) reveals important differences in their estimation of specific RNA conformations, suggesting caution in the interpretation of such complex conformational landscapes. Overall, the abolished frameshifting in three different mutants confirms that all alternative conformations play a role in the pathways of ribosomal transition.
Language	English
Publishing date	2024-03-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.28.586935
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Article ; Online: Abolished frameshifting for predicted structure-stabilizing SARS-CoV-2 mutants: Implications to alternative conformations and their statistical structural analyses

Dey, Abhishek / Yan, Shuting / Schlick, Tamar / Laederach, Alain

bioRxiv

Abstract	The SARS-CoV-2 frameshifting element (FSE) has been intensely studied and explored as a therapeutic target for coronavirus diseases including COVID-19. Besides the intriguing virology, this small RNA is known to adopt many length-dependent conformations, as verified by multiple experimental and computational approaches. However, the role these alternative conformations play in the frameshifting mechanism and how to quantify this structural abundance has been an ongoing challenge. Here, we show by DMS and dual-luciferase functional assays that previously predicted FSE mutants (using the RAG graph theory approach) suppress structural transitions and abolish frameshifting. Furthermore, correlated mutation analysis of DMS data by three programs (DREEM, DRACO, and DANCE-MaP) reveals important differences in their estimation of specific RNA conformations, suggesting caution in the interpretation of such complex conformational landscapes. Overall, the abolished frameshifting in three different mutants confirms that all alternative conformations play a role in the pathways of ribosomal transition.
Keywords	covid19
Language	English
Publishing date	2024-03-29
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2024.03.28.586935
Database	COVID19

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Article ; Online: Evolution of coronavirus frameshifting elements: Competing stem networks explain conservation and variability.

Yan, Shuting / Zhu, Qiyao / Hohl, Jenna / Dong, Alex / Schlick, Tamar

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 20, Page(s) e2221324120

Abstract: The frameshifting RNA element (FSE) in coronaviruses (CoVs) regulates the programmed -1 ribosomal frameshift (-1 PRF) mechanism common to many viruses. The FSE is of particular interest as a promising drug candidate. Its associated pseudoknot or stem ... ...

Abstract	The frameshifting RNA element (FSE) in coronaviruses (CoVs) regulates the programmed -1 ribosomal frameshift (-1 PRF) mechanism common to many viruses. The FSE is of particular interest as a promising drug candidate. Its associated pseudoknot or stem loop structure is thought to play a large role in frameshifting and thus viral protein production. To investigate the FSE structural evolution, we use our graph theory-based methods for representing RNA secondary structures in the RNA-As-Graphs (RAG) framework to calculate conformational landscapes of viral FSEs with increasing sequence lengths for representative 10 Alpha and 13 Beta-CoVs. By following length-dependent conformational changes, we show that FSE sequences encode many possible competing stems which in turn favor certain FSE topologies, including a variety of pseudoknots, stem loops, and junctions. We explain alternative competing stems and topological FSE changes by recurring patterns of mutations. At the same time, FSE topology robustness can be understood by shifted stems within different sequence contexts and base pair coevolution. We further propose that the topology changes reflected by length-dependent conformations contribute to tuning the frameshifting efficiency. Our work provides tools to analyze virus sequence/structure correlations, explains how sequence and FSE structure have evolved for CoVs, and provides insights into potential mutations for therapeutic applications against a broad spectrum of CoV FSEs by targeting key sequence/structural transitions.
MeSH term(s)	Humans ; RNA, Viral/metabolism ; Coronavirus/genetics ; Coronavirus/metabolism ; Base Sequence ; Nucleic Acid Conformation ; Frameshifting, Ribosomal/genetics ; Coronavirus Infections/genetics
Chemical Substances	RNA, Viral
Language	English
Publishing date	2023-05-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2221324120
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Article ; Online: Which Specific Exercise Models Are Most Effective on Global Cognition in Patients with Cognitive Impairment? A Network Meta-Analysis.

Yang, Junchao / Dong, Yunfeng / Yan, Shuting / Yi, Longyan / Qiu, Junqiang

International journal of environmental research and public health

2023 Volume 20, Issue 4

Abstract: 1) Introduction: Physical exercise interventions can impart significant cognitive benefits to older adults suffering from cognitive impairment (CI). However, the efficacy of these interventions can vary widely, depending on the type, intensity, duration ...

Abstract	(1) Introduction: Physical exercise interventions can impart significant cognitive benefits to older adults suffering from cognitive impairment (CI). However, the efficacy of these interventions can vary widely, depending on the type, intensity, duration and frequency of exercise. (2) Aim: To systematically review the efficacy of exercise therapy on global cognition in patients with CI using a network meta-analysis (NMA). (3) Methods: The PubMed, Embase, Sport Discus (EBSCO) and Cochrane Library databases were electronically searched to collect randomized controlled trials (RCTs) on exercise for patients with CI from inception to 7 August 2022. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. The NMA was performed using the consistency model. (4) Results: A total of 29 RCTs comprising 2458 CI patients were included. The effects of different types of exercise on patients with CI were ranked as follows: multicomponent exercise (SMD = 0.84, 95% CI 0.31 to 1.36,
MeSH term(s)	Humans ; Aged ; Network Meta-Analysis ; Exercise ; Cognition ; Cognitive Dysfunction ; Exercise Therapy
Language	English
Publishing date	2023-02-04
Publishing country	Switzerland
Document type	Meta-Analysis ; Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2175195-X
ISSN	1660-4601 ; 1661-7827
ISSN (online)	1660-4601
ISSN	1661-7827
DOI	10.3390/ijerph20042790
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Article ; Online: Length-dependent motions of SARS-CoV-2 frameshifting RNA pseudoknot and alternative conformations suggest avenues for frameshifting suppression.

Yan, Shuting / Zhu, Qiyao / Jain, Swati / Schlick, Tamar

Nature communications

2022 Volume 13, Issue 1, Page(s) 4284

Abstract: The SARS-CoV-2 frameshifting element (FSE), a highly conserved mRNA region required for correct translation of viral polyproteins, defines an excellent therapeutic target against Covid-19. As discovered by our prior graph-theory analysis with SHAPE ... ...

Abstract	The SARS-CoV-2 frameshifting element (FSE), a highly conserved mRNA region required for correct translation of viral polyproteins, defines an excellent therapeutic target against Covid-19. As discovered by our prior graph-theory analysis with SHAPE experiments, the FSE adopts a heterogeneous, length-dependent conformational landscape consisting of an assumed 3-stem H-type pseudoknot (graph motif 3_6), and two alternative motifs (3_3 and 3_5). Here, for the first time, we build and simulate, by microsecond molecular dynamics, 30 models for all three motifs plus motif-stabilizing mutants at different lengths. Our 3_6 pseudoknot systems, which agree with experimental structures, reveal interconvertible L and linear conformations likely related to ribosomal pausing and frameshifting. The 3_6 mutant inhibits this transformation and could hamper frameshifting. Our 3_3 systems exhibit length-dependent stem interactions that point to a potential transition pathway connecting the three motifs during ribosomal elongation. Together, our observations provide new insights into frameshifting mechanisms and anti-viral strategies.
MeSH term(s)	Base Sequence ; COVID-19 ; Frameshifting, Ribosomal ; Humans ; Nucleic Acid Conformation ; RNA, Viral/chemistry ; RNA, Viral/genetics ; SARS-CoV-2/genetics
Chemical Substances	RNA, Viral
Language	English
Publishing date	2022-07-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-31353-w
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Article: Length-dependent motions of SARS-CoV-2 frameshifting RNA pseudoknot and alternative conformations suggest avenues for frameshifting suppression.

Yan, Shuting / Zhu, Qiyao / Jain, Swati / Schlick, Tamar

Research square

2022

Abstract: Conserved SARS-CoV-2 RNA regions of critical biological functions define excellent targets for anti-viral therapeutics against Covid-19 variants. One such region is the frameshifting element (FSE), responsible for correct translation of viral ... ...

Abstract	Conserved SARS-CoV-2 RNA regions of critical biological functions define excellent targets for anti-viral therapeutics against Covid-19 variants. One such region is the frameshifting element (FSE), responsible for correct translation of viral polyproteins. Here, we analyze molecular-dynamics motions of three FSE conformations, discovered by graph-theory analysis, and associated mutants designed by graph-based inverse folding: two distinct 3-stem H-type pseudoknots and a 3-way junction. We find that the prevalent H-type pseudoknot in literature adopts ring-like conformations, which in combination with 5' end threading could promote ribosomal pausing. An inherent shape switch from "L" to linear that may help trigger the frameshifting is suppressed in our designed mutant. The alternative conformation trajectories suggest a stable intermediate structure with mixed stem interactions of all three conformations, pointing to a possible transition pathway during ribosomal translation. These observations provide new insights into anti-viral strategies and frameshifting mechanisms.
Language	English
Publishing date	2022-01-04
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-1160075/v1
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Article ; Online: Influence of the Urban Built Environment on Physical and Mental Health of the Elderly under the Background of Big Data.

Yan, Shuting / Shi, Lei / Wang, Li

Computational intelligence and neuroscience

2022 Volume 2022, Page(s) 4266723

Abstract: With the advent of the information technology revolution and the Internet era, information technology is gradually occupying an important position and becoming an important strategic factor in economic development. As an emerging technology that has been ...

Abstract	With the advent of the information technology revolution and the Internet era, information technology is gradually occupying an important position and becoming an important strategic factor in economic development. As an emerging technology that has been developing continuously in recent years, big data is becoming an important industry to improve the innovation and development of the urban economy. Like AI technology, cloud computing, and the Internet, big data has become an important application technology for economic growth and economic efficiency improvement in today's world. It is an effective means of progress and development in a region and an important strategic resource. As a new technology, big data has attracted more and more attention from all walks of life. Many companies have turned their attention to developing big data for economic benefits. "Enjoy your old age" is the yearning of every old man and his family. In recent years, the national level has been committed to "creating an urban built environment for the elderly to achieve healthy aging." From the perspective of promoting the physical and mental health of the elderly, this paper analyzes the impact of the urban built environment on the physical and mental health of the elderly based on the needs of the elderly and puts forward countermeasures and suggestions based on the current status and existing problems of the urban built environment for the elderly. Based on the combined data analysis method and technology in big data, this paper conducted a field questionnaire survey on a total of 4,000 elderly people in urban and rural areas by means of the questionnaire survey. It is found that the existing problems of the built environment in the old cities include scattered content, one-sided understanding, and rigid design. According to the problems, the solutions of building consensus, paying attention to planning, combining urban characteristics, and the joint efforts of all sectors of society are put forward. And programming tools are used to combine formulas and analyze related data in detail. The analysis results show that the physical and mental health index of the elderly is highly correlated with factors such as changes in the consensus degree of the urban built environment, urban built environment planning, urban built environment policy support, and multiparty efforts in the urban built environment. Changes show a positive change.
MeSH term(s)	Aged ; Big Data ; Built Environment ; Cities ; City Planning ; Humans ; Male ; Mental Health
Language	English
Publishing date	2022-07-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2388208-6
ISSN	1687-5273 ; 1687-5273
ISSN (online)	1687-5273
ISSN	1687-5273
DOI	10.1155/2022/4266723
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Article ; Online: Computational Modeling of RNA Aptamers: Structure Prediction of the Apo State.

Yan, Shuting / Ilgu, Muslum / Nilsen-Hamilton, Marit / Lamm, Monica H

The journal of physical chemistry. B

2022 Volume 126, Issue 37, Page(s) 7114–7125

Abstract: RNA aptamers are single-stranded oligonucleotides that bind to specific molecular targets with high affinity and specificity. To design aptamers for new applications, it is critical to understand the ligand binding mechanism in terms of the structure and ...

Abstract	RNA aptamers are single-stranded oligonucleotides that bind to specific molecular targets with high affinity and specificity. To design aptamers for new applications, it is critical to understand the ligand binding mechanism in terms of the structure and dynamics of the ligand-bound and apo states. The problem is that most of the NMR or X-ray crystal structures available for RNA aptamers are for ligand-bound states. Available apo state structures, mostly characterized by crystallization under nonphysiological conditions or probed by low resolution techniques, might fail to represent the diverse structural variations of the apo state in solution. Here, we develop an approach to obtain a representative ensemble of apo structures that are based on
MeSH term(s)	Aptamers, Nucleotide/chemistry ; Computer Simulation ; Ligands ; Neomycin ; RNA/chemistry
Chemical Substances	Aptamers, Nucleotide ; Ligands ; RNA (63231-63-0) ; Neomycin (I16QD7X297)
Language	English
Publishing date	2022-09-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/acs.jpcb.2c04649
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Article: Computational Modeling of RNA Aptamers: Structure Prediction of the Apo State

Yan, Shuting / Ilgu, Muslum / Nilsen-Hamilton, Marit / Lamm, Monica H.

Journal of physical chemistry. 2022 Sept. 13, v. 126, no. 37

2022

Abstract	RNA aptamers are single-stranded oligonucleotides that bind to specific molecular targets with high affinity and specificity. To design aptamers for new applications, it is critical to understand the ligand binding mechanism in terms of the structure and dynamics of the ligand-bound and apo states. The problem is that most of the NMR or X-ray crystal structures available for RNA aptamers are for ligand-bound states. Available apo state structures, mostly characterized by crystallization under nonphysiological conditions or probed by low resolution techniques, might fail to represent the diverse structural variations of the apo state in solution. Here, we develop an approach to obtain a representative ensemble of apo structures that are based on in silico RNA 3D structure prediction and in vitro experiments that characterize base stacking. Using the neomycin-B aptamer as a case study, an ensemble of structures for the aptamer in the apo (unbound) state are validated and then used to investigate the ligand-binding mechanism for the aptamer in complex with neomycin-B.
Keywords	RNA ; X-radiation ; case studies ; computer simulation ; crystallization ; ligands ; nucleotide aptamers ; prediction
Language	English
Dates of publication	2022-0913
Size	p. 7114-7125.
Publishing place	American Chemical Society
Document type	Article
ISSN	1520-5207
DOI	10.1021/acs.jpcb.2c04649
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Structure-altering mutations of the SARS-CoV-2 frameshifting RNA element.

Schlick, Tamar / Zhu, Qiyao / Jain, Swati / Yan, Shuting

Biophysical journal

2020 Volume 120, Issue 6, Page(s) 1040–1053

Abstract: With the rapid rate of COVID-19 infections and deaths, treatments and cures besides hand washing, social distancing, masks, isolation, and quarantines are urgently needed. The treatments and vaccines rely on the basic biophysics of the complex viral ... ...

Abstract	With the rapid rate of COVID-19 infections and deaths, treatments and cures besides hand washing, social distancing, masks, isolation, and quarantines are urgently needed. The treatments and vaccines rely on the basic biophysics of the complex viral apparatus. Although proteins are serving as main drug and vaccine targets, therapeutic approaches targeting the 30,000 nucleotide RNA viral genome form important complementary approaches. Indeed, the high conservation of the viral genome, its close evolutionary relationship to other viruses, and the rise of gene editing and RNA-based vaccines all argue for a focus on the RNA agent itself. One of the key steps in the viral replication cycle inside host cells is the ribosomal frameshifting required for translation of overlapping open reading frames. The RNA frameshifting element (FSE), one of three highly conserved regions of coronaviruses, is believed to include a pseudoknot considered essential for this ribosomal switching. In this work, we apply our graph-theory-based framework for representing RNA secondary structures, "RAG (or RNA-As-Graphs)," to alter key structural features of the FSE of the SARS-CoV-2 virus. Specifically, using RAG machinery of genetic algorithms for inverse folding adapted for RNA structures with pseudoknots, we computationally predict minimal mutations that destroy a structurally important stem and/or the pseudoknot of the FSE, potentially dismantling the virus against translation of the polyproteins. Our microsecond molecular dynamics simulations of mutant structures indicate relatively stable secondary structures. These findings not only advance our computational design of RNAs containing pseudoknots, they pinpoint key residues of the SARS-CoV-2 virus as targets for antiviral drugs and gene editing approaches.
MeSH term(s)	Algorithms ; Frameshifting, Ribosomal/genetics ; Gene Editing ; Molecular Dynamics Simulation ; Mutation/genetics ; Nucleic Acid Conformation ; RNA, Viral/chemistry ; RNA, Viral/genetics ; SARS-CoV-2/chemistry ; SARS-CoV-2/genetics
Chemical Substances	RNA, Viral
Keywords	covid19
Language	English
Publishing date	2020-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2020.10.012
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