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Article ; Online: Molecular frustration: a hypothesis for regulation of viral infections.

Twarock, Reidun / Towers, Greg J / Stockley, Peter G

2023 Volume 32, Issue 1, Page(s) 17–26

Abstract: The recent revolution in imaging techniques and results from RNA footprinting in situ reveal how the bacteriophage MS2 genome regulates both particle assembly and genome release. We have proposed a model in which multiple packaging signal (PS) RNA-coat ... ...

Abstract	The recent revolution in imaging techniques and results from RNA footprinting in situ reveal how the bacteriophage MS2 genome regulates both particle assembly and genome release. We have proposed a model in which multiple packaging signal (PS) RNA-coat protein (CP) contacts orchestrate different stages of a viral life cycle. Programmed formation and release of specific PS contacts with CP regulates viral particle assembly and genome uncoating during cell entry. We hypothesize that molecular frustration, a concept introduced to understand protein folding, can be used to better rationalize how PSs function in both particle assembly and genome release. More broadly this concept may explain the directionality of viral life cycles, for example, the roles of host cofactors in HIV infection. We propose that this is a universal principle in virology that explains mechanisms of host-virus interaction and suggests diverse therapeutic interventions.
MeSH term(s)	Humans ; Capsid Proteins ; RNA, Viral/genetics ; RNA, Viral/metabolism ; HIV Infections ; Genome, Viral ; Virus Assembly/genetics
Chemical Substances	Capsid Proteins ; RNA, Viral
Language	English
Publishing date	2023-07-27
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1158963-2
ISSN	1878-4380 ; 0966-842X
ISSN (online)	1878-4380
ISSN	0966-842X
DOI	10.1016/j.tim.2023.07.003
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Article ; Online: Anti-type I interferon antibodies as a cause of severe COVID-19.

Fajgenbaum, David C / Hayday, Adrian C / Rogers, Angela J / Towers, Greg J / Wack, Andreas / Zanoni, Ivan

Faculty reviews

2022 Volume 11, Page(s) 15

Abstract: COVID-19 ranges from asymptomatic through to respiratory failure and death. Although specific pre-existing conditions such as age and male sex have been associated with poor outcomes, we remain largely ignorant of the mechanisms predisposing to severe ... ...

Abstract	COVID-19 ranges from asymptomatic through to respiratory failure and death. Although specific pre-existing conditions such as age and male sex have been associated with poor outcomes, we remain largely ignorant of the mechanisms predisposing to severe disease. In this study, the authors discovered that approximately 10% of 987 patients with life-threatening COVID-19 harbored neutralizing antibodies to Type I interferons (IFNs)
Language	English
Publishing date	2022-06-10
Publishing country	England
Document type	Journal Article ; Comment
ISSN	2732-432X
ISSN (online)	2732-432X
DOI	10.12703/r-01-0000010
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Article ; Online: Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure.

Faysal, K M Rifat / Walsh, James C / Renner, Nadine / Márquez, Chantal L / Shah, Vaibhav B / Tuckwell, Andrew J / Christie, Michelle P / Parker, Michael W / Turville, Stuart G / Towers, Greg J / James, Leo C / Jacques, David A / Böcking, Till

eLife

2024 Volume 13

Abstract: The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability ... ...

Abstract	The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.
MeSH term(s)	Humans ; Capsid ; HIV-1 ; Capsid Proteins ; Anti-HIV Agents/pharmacology ; HIV Infections
Chemical Substances	Capsid Proteins ; Anti-HIV Agents
Language	English
Publishing date	2024-02-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.83605
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Article ; Online: Identifying a nuclear passport for HIV.

Zuliani-Alvarez, Lorena / Towers, Greg J

eLife

2019 Volume 8

Abstract: Identification of a protein that pulls HIV into the nucleus explains a key step in HIV infection. ...

Abstract	Identification of a protein that pulls HIV into the nucleus explains a key step in HIV infection.
MeSH term(s)	Active Transport, Cell Nucleus ; Capsid ; HIV Infections ; HIV-1 ; Humans ; Macrophages ; Nuclear Pore ; mRNA Cleavage and Polyadenylation Factors
Chemical Substances	mRNA Cleavage and Polyadenylation Factors
Language	English
Publishing date	2019-03-05
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.45580
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Article ; Online: Plasmapheresis to remove amyloid fibrin(ogen) particles for treating the post-COVID-19 condition.

Fox, Tilly / Hunt, Beverley J / Ariens, Robert As / Towers, Greg J / Lever, Robert / Garner, Paul / Kuehn, Rebecca

The Cochrane database of systematic reviews

2023 Volume 7, Page(s) CD015775

Abstract: Background: The post-COVID-19 condition (PCC) consists of a wide array of symptoms including fatigue and impaired daily living. People seek a wide variety of approaches to help them recover. A new belief, arising from a few laboratory studies, is that ' ... ...

Abstract	Background: The post-COVID-19 condition (PCC) consists of a wide array of symptoms including fatigue and impaired daily living. People seek a wide variety of approaches to help them recover. A new belief, arising from a few laboratory studies, is that 'microclots' cause the symptoms of PCC. This belief has been extended outside these studies, suggesting that to recover people need plasmapheresis (an expensive process where blood is filtered outside the body). We appraised the laboratory studies, and it was clear that the term 'microclots' is incorrect to describe the phenomenon being described. The particles are amyloid and include fibrin(ogen); amyloid is not a part of a thrombus which is a mix of fibrin mesh and platelets. Initial acute COVID-19 infection is associated with clotting abnormalities; this review concerns amyloid fibrin(ogen) particles in PCC only. We have reported here our appraisal of laboratory studies investigating the presence of amyloid fibrin(ogen) particles in PCC, and of evidence that plasmapheresis may be an effective therapy to remove amyloid fibrin(ogen) particles for treating PCC. Objectives: Laboratory studies review To summarize and appraise the research reports on amyloid fibrin(ogen) particles related to PCC. Randomized controlled trials review To assess the evidence of the safety and efficacy of plasmapheresis to remove amyloid fibrin(ogen) particles in individuals with PCC from randomized controlled trials. Search methods: Laboratory studies review We searched for all relevant laboratory studies up to 27 October 2022 using a comprehensive search strategy which included the search terms 'COVID', 'amyloid', 'fibrin', 'fibrinogen'. Randomized controlled trials review We searched the following databases on 21 October 2022: Cochrane COVID-19 Study Register; MEDLINE (Ovid); Embase (Ovid); and BIOSIS Previews (Web of Science). We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for trials in progress. Selection criteria: Laboratory studies review Laboratory studies that investigate the presence of amyloid fibrin(ogen) particles in plasma samples from patients with PCC were eligible. This included studies with or without controls. Randomized controlled trials review Studies were eligible if they were of randomized controlled design and investigated the effectiveness or safety of plasmapheresis for removing amyloid fibrin(ogen) particles for treating PCC. Data collection and analysis: Two review authors applied study inclusion criteria to identify eligible studies and extracted data. Laboratory studies review We assessed the risk of bias of included studies using pre-developed methods for laboratory studies. We planned to perform synthesis without meta-analysis (SWiM) as described in our protocol. Randomized controlled trials review We planned that if we identified any eligible studies, we would assess risk of bias and report results with 95% confidence intervals. The primary outcome was recovery, measured using the Post-COVID-19 Functional Status Scale (absence of symptoms related to the illness, ability to do usual daily activities, and a return to a previous state of health and mind). Main results: Laboratory studies review We identified five laboratory studies. Amyloid fibrin(ogen) particles were identified in participants across all studies, including those with PCC, healthy individuals, and those with diabetes. The results of three studies were based on visual images of amyloid fibrin(ogen) particles, which did not quantify the amount or size of the particles identified. Formal risk of bias assessment showed concerns in how the studies were conducted and reported. This means the results were insufficient to support the belief that amyloid fibrin(ogen) particles are associated with PCC, or to determine whether there is a difference in the amount or size of amyloid fibrin(ogen) particles in the plasma of people with PCC compared to healthy controls. Randomized controlled trials review We identified no trials meeting our inclusion criteria. Authors' conclusions: In the absence of reliable research showing that amyloid fibrin(ogen) particles contribute to the pathophysiology of PCC, there is no rationale for plasmapheresis to remove amyloid fibrin(ogen) particles in PCC. Plasmapheresis for this indication should not be used outside the context of a well-conducted randomized controlled trial.
MeSH term(s)	Humans ; COVID-19 ; Fibrin/therapeutic use ; Plasmapheresis
Chemical Substances	estropipate (SVI38UY019) ; Fibrin (9001-31-4)
Language	English
Publishing date	2023-07-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	1469-493X
ISSN (online)	1469-493X
DOI	10.1002/14651858.CD015775
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Article ; Online: ChromaClade: combined visualisation of phylogenetic and sequence data.

Monit, Christopher / Goldstein, Richard A / Towers, Greg J

BMC evolutionary biology

2019 Volume 19, Issue 1, Page(s) 186

Abstract: Background: Studying site-specific amino acid frequencies by eye can reveal biologically significant variability and lineage-specific adaptation. This so-called 'sequence gazing' often informs bioinformatics and experimental research. But it is ... ...

Abstract	Background: Studying site-specific amino acid frequencies by eye can reveal biologically significant variability and lineage-specific adaptation. This so-called 'sequence gazing' often informs bioinformatics and experimental research. But it is important to also account for the underlying phylogeny, since similarities may be due to common descent rather than selection pressure, and because it is important to distinguish between founder effects and convergent evolution. We set out to combine phylogenetic and sequence data to produce evolutionarily insightful visualisations. Results: We present ChromaClade, a convenient tool with a graphical user-interface that works in concert with popular tree viewers to produce colour-annotated phylogenies highlighting residues found in each taxon and at each site in a sequence alignment. Colouring branches according to residues found at descendent tips also quickly identifies lineage-specific residues and those internal branches where key substitutions have occurred. We demonstrate applications of ChromaClade to human immunodeficiency virus and influenza A virus datasets, illustrating cases of conservative, adaptive and convergent evolution. Conclusions: We find this to be a powerful approach for visualising site-wise residue distributions and detecting evolutionary patterns, especially in large datasets. ChromaClade is available for Windows, macOS and Unix or Linux; program executables and source code are available at github.com/chrismonit/chroma_clade .
MeSH term(s)	Computational Biology/methods ; HIV-1/genetics ; Humans ; Phylogeny ; Sequence Analysis, DNA ; Software
Language	English
Publishing date	2019-10-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041493-6
ISSN	1471-2148 ; 1471-2148
ISSN (online)	1471-2148
ISSN	1471-2148
DOI	10.1186/s12862-019-1518-9
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Article ; Online: Identifying a nuclear passport for HIV

Lorena Zuliani-Alvarez / Greg J Towers

eLife, Vol

2019 Volume 8

Abstract: Identification of a protein that pulls HIV into the nucleus explains a key step in HIV infection. ...

Abstract	Identification of a protein that pulls HIV into the nucleus explains a key step in HIV infection.
Keywords	Human immunodeficiency virus ; CPSF6 ; macrophages ; capsid ; nuclear pore complex ; nuclear import ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evolution of enhanced innate immune suppression by SARS-CoV-2 Omicron subvariants.

Reuschl, Ann-Kathrin / Thorne, Lucy G / Whelan, Matthew V X / Ragazzini, Roberta / Furnon, Wilhelm / Cowton, Vanessa M / De Lorenzo, Giuditta / Mesner, Dejan / Turner, Jane L E / Dowgier, Giulia / Bogoda, Nathasha / Bonfanti, Paola / Palmarini, Massimo / Patel, Arvind H / Jolly, Clare / Towers, Greg J

Nature microbiology

2024 Volume 9, Issue 2, Page(s) 451–463

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human adaptation resulted in distinct lineages with enhanced transmissibility called variants of concern (VOCs). Omicron is the first VOC to evolve distinct globally dominant subvariants. Here ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human adaptation resulted in distinct lineages with enhanced transmissibility called variants of concern (VOCs). Omicron is the first VOC to evolve distinct globally dominant subvariants. Here we compared their replication in human cell lines and primary airway cultures and measured host responses to infection. We discovered that subvariants BA.4 and BA.5 have improved their suppression of innate immunity when compared with earlier subvariants BA.1 and BA.2. Similarly, more recent subvariants (BA.2.75 and XBB lineages) also triggered reduced innate immune activation. This correlated with increased expression of viral innate antagonists Orf6 and nucleocapsid, reminiscent of VOCs Alpha to Delta. Increased Orf6 levels suppressed host innate responses to infection by decreasing IRF3 and STAT1 signalling measured by transcription factor phosphorylation and nuclear translocation. Our data suggest that convergent evolution of enhanced innate immune antagonist expression is a common pathway of human adaptation and link Omicron subvariant dominance to improved innate immune evasion.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Cell Line ; Immune Evasion ; Immunity, Innate
Language	English
Publishing date	2024-01-16
Publishing country	England
Document type	Journal Article
ISSN	2058-5276
ISSN (online)	2058-5276
DOI	10.1038/s41564-023-01588-4
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Article ; Online: SARS-CoV-2 variant biology: immune escape, transmission and fitness.

Carabelli, Alessandro M / Peacock, Thomas P / Thorne, Lucy G / Harvey, William T / Hughes, Joseph / Peacock, Sharon J / Barclay, Wendy S / de Silva, Thushan I / Towers, Greg J / Robertson, David L

Nature reviews. Microbiology

2023 Volume 21, Issue 3, Page(s) 162–177

Abstract: In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. These highly mutated forms of SARS-CoV-2 had enhanced rates ...

Abstract	In late 2020, after circulating for almost a year in the human population, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibited a major step change in its adaptation to humans. These highly mutated forms of SARS-CoV-2 had enhanced rates of transmission relative to previous variants and were termed 'variants of concern' (VOCs). Designated Alpha, Beta, Gamma, Delta and Omicron, the VOCs emerged independently from one another, and in turn each rapidly became dominant, regionally or globally, outcompeting previous variants. The success of each VOC relative to the previously dominant variant was enabled by altered intrinsic functional properties of the virus and, to various degrees, changes to virus antigenicity conferring the ability to evade a primed immune response. The increased virus fitness associated with VOCs is the result of a complex interplay of virus biology in the context of changing human immunity due to both vaccination and prior infection. In this Review, we summarize the literature on the relative transmissibility and antigenicity of SARS-CoV-2 variants, the role of mutations at the furin spike cleavage site and of non-spike proteins, the potential importance of recombination to virus success, and SARS-CoV-2 evolution in the context of T cells, innate immunity and population immunity. SARS-CoV-2 shows a complicated relationship among virus antigenicity, transmission and virulence, which has unpredictable implications for the future trajectory and disease burden of COVID-19.
MeSH term(s)	Humans ; SARS-CoV-2/genetics ; COVID-19 ; Immunity, Innate ; Biology
Language	English
Publishing date	2023-01-18
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2139054-X
ISSN	1740-1534 ; 1740-1526
ISSN (online)	1740-1534
ISSN	1740-1526
DOI	10.1038/s41579-022-00841-7
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Article ; Online: HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65.

Fink, Douglas L / Cai, James / Whelan, Matthew V X / Monit, Christopher / Maluquer de Motes, Carlos / Towers, Greg J / Sumner, Rebecca P

Retrovirology

2022 Volume 19, Issue 1, Page(s) 2

Abstract: Background: The NF-κB family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-κB transcription factors by viral pathogen-associated molecular patterns, such as viral RNA ... ...

Abstract	Background: The NF-κB family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-κB transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-κB and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins targeting the NF-κB pathway to mitigate the anti-viral effects of NF-κB-dependent host immunity. Results: In this study we have demonstrated using a variety of assays, in a number of different cell types including primary cells, that plasmid-encoded or virus-delivered simian immunodeficiency virus (SIV) accessory protein Vpx is a broad antagonist of NF-κB signalling active against diverse innate NF-κB agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-κB transcription factor p65, but not NF-κB family members p50 or p100, preventing nuclear translocation of p65. We found that broad antagonism of NF-κB activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity. Conclusions: We have discovered a novel mechanism by which lentiviruses antagonise NF-κB activation by targeting p65. These findings extend our knowledge of how lentiviruses manipulate universal regulators of immunity to avoid the anti-viral sequelae of pro-inflammatory gene expression stimulated by both viral and extra-viral agonists. Importantly our findings are also relevant to the gene therapy field where virus-like particle associated Vpx is routinely used to enhance vector transduction through antagonism of SAMHD1, and perhaps also through manipulation of NF-κB.
MeSH term(s)	Animals ; HIV-2/genetics ; NF-kappa B/metabolism ; SAM Domain and HD Domain-Containing Protein 1/metabolism ; Simian Immunodeficiency Virus/genetics ; Viral Regulatory and Accessory Proteins/genetics ; Viral Regulatory and Accessory Proteins/metabolism
Chemical Substances	NF-kappa B ; Viral Regulatory and Accessory Proteins ; SAM Domain and HD Domain-Containing Protein 1 (EC 3.1.5.-)
Language	English
Publishing date	2022-01-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2142602-8
ISSN	1742-4690 ; 1742-4690
ISSN (online)	1742-4690
ISSN	1742-4690
DOI	10.1186/s12977-021-00586-w
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