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Article: Predicting host-based, synthetic lethal antiviral targets from omics data.

Staheli, Jeannette P / Neal, Maxwell L / Navare, Arti / Mast, Fred D / Aitchison, John D

bioRxiv : the preprint server for biology

2023

Abstract: Traditional antiviral therapies often have limited effectiveness due to toxicity and development of drug resistance. Host-based antivirals, while an alternative, may lead to non-specific effects. Recent evidence shows that virus-infected cells can be ... ...

Abstract	Traditional antiviral therapies often have limited effectiveness due to toxicity and development of drug resistance. Host-based antivirals, while an alternative, may lead to non-specific effects. Recent evidence shows that virus-infected cells can be selectively eliminated by targeting synthetic lethal (SL) partners of proteins disrupted by viral infection. Thus, we hypothesized that genes depleted in CRISPR KO screens of virus-infected cells may be enriched in SL partners of proteins altered by infection. To investigate this, we established a computational pipeline predicting SL drug targets of viral infections. First, we identified SARS-CoV-2-induced changes in gene products via a large compendium of omics data. Second, we identified SL partners for each altered gene product. Last, we screened CRISPR KO data for SL partners required for cell viability in infected cells. Despite differences in virus-induced alterations detected by various omics data, they share many predicted SL targets, with significant enrichment in CRISPR KO-depleted datasets. Comparing data from SARS-CoV-2 and influenza infections, we found possible broad-spectrum, host-based antiviral SL targets. This suggests that CRISPR KO data are replete with common antiviral targets due to their SL relationship with virus-altered states and that such targets can be revealed from analysis of omics datasets and SL predictions.
Language	English
Publishing date	2023-08-16
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.15.553430
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Characterization of Peroxisomal Regulation Networks.

Mast, Fred D / Aitchison, John D

Sub-cellular biochemistry

2018 Volume 89, Page(s) 367–382

Abstract: Peroxisome proliferation involves signal recognition and computation by molecular networks that direct molecular events of gene expression, metabolism, membrane biogenesis, organelle proliferation, protein import, and organelle inheritance. Peroxisome ... ...

Abstract	Peroxisome proliferation involves signal recognition and computation by molecular networks that direct molecular events of gene expression, metabolism, membrane biogenesis, organelle proliferation, protein import, and organelle inheritance. Peroxisome biogenesis in yeast has served as a model system for exploring the regulatory networks controlling this process. Yeast is an outstanding model system to develop tools and approaches to study molecular networks and cellular responses and because the mechanisms of peroxisome biogenesis and key aspects of the transcriptional regulatory networks are remarkably conserved from yeast to humans. In this chapter, we focus on the complex regulatory networks that respond to environmental cues leading to peroxisome assembly and the molecular events of organelle assembly. Ultimately, understanding the mechanisms of the entire peroxisome biogenesis program holds promise for predictive modeling approaches and for guiding rational intervention strategies that could treat human conditions associated with peroxisome function.
MeSH term(s)	Humans ; Metabolic Networks and Pathways ; Models, Biological ; Peroxisomes/chemistry ; Peroxisomes/genetics ; Peroxisomes/metabolism ; Protein Transport ; Saccharomyces cerevisiae/cytology ; Saccharomyces cerevisiae/metabolism
Language	English
Publishing date	2018-10-30
Publishing country	United States
Document type	Journal Article ; Review
ISSN	0306-0225 ; 0096-8757
ISSN	0306-0225 ; 0096-8757
DOI	10.1007/978-981-13-2233-4_16
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Peroxisome prognostications: Exploring the birth, life, and death of an organelle.

Mast, Fred D / Rachubinski, Richard A / Aitchison, John D

The Journal of cell biology

2020 Volume 219, Issue 3

Abstract: Peroxisomes play a central role in human health and have biochemical properties that promote their use in many biotechnology settings. With a primary role in lipid metabolism, peroxisomes share a niche with lipid droplets within the endomembrane- ... ...

Abstract	Peroxisomes play a central role in human health and have biochemical properties that promote their use in many biotechnology settings. With a primary role in lipid metabolism, peroxisomes share a niche with lipid droplets within the endomembrane-secretory system. Notably, factors in the ER required for the biogenesis of peroxisomes also impact the formation of lipid droplets. The dynamic interface between peroxisomes and lipid droplets, and also between these organelles and the ER and mitochondria, controls their metabolic flux and their dynamics. Here, we review our understanding of peroxisome biogenesis to propose and reframe models for understanding how peroxisomes are formed in cells. To more fully understand the roles of peroxisomes and to take advantage of their many properties that may prove useful in novel therapeutics or biotechnology applications, we recast mechanisms controlling peroxisome biogenesis in a framework that integrates inference from these models with experimental data.
MeSH term(s)	Animals ; Endoplasmic Reticulum/metabolism ; Endosomal Sorting Complexes Required for Transport/metabolism ; Energy Metabolism ; Humans ; Lipid Droplets/metabolism ; Mitochondria/metabolism ; Organelle Biogenesis ; Peroxins/metabolism ; Peroxisomes/metabolism ; Peroxisomes/pathology ; Protein Transport ; Signal Transduction
Chemical Substances	Endosomal Sorting Complexes Required for Transport ; Peroxins
Language	English
Publishing date	2020-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201912100
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Article ; Online: Predicting host-based, synthetic lethal antiviral targets from omics data

Staheli, Jeannette P. / Neal, Maxwell L. / Navare, Arti / Mast, Fred D. / Aitchison, John D.

bioRxiv

Abstract	Traditional antiviral therapies often have limited effectiveness due to toxicity and development of drug resistance. Host-based antivirals, while an alternative, may lead to non-specific effects. Recent evidence shows that virus-infected cells can be selectively eliminated by targeting synthetic lethal (SL) partners of proteins disrupted by viral infection. Thus, we hypothesized that genes depleted in CRISPR KO screens of virus-infected cells may be enriched in SL partners of proteins altered by infection. To investigate this, we established a computational pipeline predicting SL drug targets of viral infections. First, we identified SARS-CoV-2-induced changes in gene products via a large compendium of omics data. Second, we identified SL partners for each altered gene product. Last, we screened CRISPR KO data for SL partners required for cell viability in infected cells. Despite differences in virus-induced alterations detected by various omics data, they share many predicted SL targets, with significant enrichment in CRISPR KO-depleted datasets. Comparing data from SARS-CoV-2 and influenza infections, we found possible broad-spectrum, host-based antiviral SL targets. This suggests that CRISPR KO data are replete with common antiviral targets due to their SL relationship with virus-altered states and that such targets can be revealed from analysis of omics datasets and SL predictions.
Keywords	covid19
Language	English
Publishing date	2023-08-16
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.08.15.553430
Database	COVID19

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Article: Nanobody repertoire generated against the spike protein of ancestral SARS-CoV-2 remains efficacious against the rapidly evolving virus.

Ketaren, Natalia E / Mast, Fred D / Fridy, Peter C / Olivier, Jean Paul / Sanyal, Tanmoy / Sali, Andrej / Chait, Brian T / Rout, Michael P / Aitchison, John D

bioRxiv : the preprint server for biology

2024

Abstract: To date, all major modes of monoclonal antibody therapy targeting SARS-CoV-2 have lost significant efficacy against the latest circulating variants. As SARS-CoV-2 omicron sublineages account for over 90% of COVID-19 infections, evasion of immune ... ...

Abstract	To date, all major modes of monoclonal antibody therapy targeting SARS-CoV-2 have lost significant efficacy against the latest circulating variants. As SARS-CoV-2 omicron sublineages account for over 90% of COVID-19 infections, evasion of immune responses generated by vaccination or exposure to previous variants poses a significant challenge. A compelling new therapeutic strategy against SARS-CoV-2 is that of single domain antibodies, termed nanobodies, which address certain limitations of monoclonal antibodies. Here we demonstrate that our high-affinity nanobody repertoire, generated against wild-type SARS-CoV-2 spike protein (Mast, Fridy et al. 2021), remains effective against variants of concern, including omicron BA.4/BA.5; a subset is predicted to counter resistance in emerging XBB and BQ.1.1 sublineages. Furthermore, we reveal the synergistic potential of nanobody cocktails in neutralizing emerging variants. Our study highlights the power of nanobody technology as a versatile therapeutic and diagnostic tool to combat rapidly evolving infectious diseases such as SARS-CoV-2.
Language	English
Publishing date	2024-01-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.07.14.549041
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Article: Automated, image-based quantification of peroxisome characteristics with

Neal, Maxwell L / Shukla, Nandini / Mast, Fred D / Farré, Jean-Claude / Pacio, Therese M / Raney-Plourde, Katelyn E / Prasad, Sumedh / Subramani, Suresh / Aitchison, John D

bioRxiv : the preprint server for biology

2024

Abstract: perox-per- ... ...

Abstract	perox-per-cell
Language	English
Publishing date	2024-04-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.08.588597
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Article ; Online: SARS-CoV-2 Orf6 is positioned in the nuclear pore complex by Rae1 to inhibit nucleocytoplasmic transport.

Makio, Tadashi / Zhang, Ke / Love, Nicole / Mast, Fred D / Liu, Xue / Elaish, Mohamed / Hobman, Tom / Aitchison, John D / Fontoura, Beatriz M A / Wozniak, Richard W

Molecular biology of the cell

2024 Volume 35, Issue 5, Page(s) ar62

Abstract: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) accessory protein Orf6 works as an interferon antagonist, in part, by inhibiting the nuclear import activated p-STAT1, an activator of interferon-stimulated genes, and the export of the ... ...

Abstract	The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) accessory protein Orf6 works as an interferon antagonist, in part, by inhibiting the nuclear import activated p-STAT1, an activator of interferon-stimulated genes, and the export of the poly(A) RNA. Insight into the transport regulatory function of Orf6 has come from the observation that Orf6 binds to the nuclear pore complex (NPC) components: Rae1 and Nup98. To gain further insight into the mechanism of Orf6-mediated transport inhibition, we examined the role of Rae1 and Nup98. We show that Rae1 alone is not necessary to support p-STAT1 import or nuclear export of poly(A) RNA. Moreover, the loss of Rae1 suppresses the transport inhibitory activity of Orf6. We propose that the Rae1/Nup98 complex strategically positions Orf6 within the NPC where it alters FG-Nup interactions and their ability to support nuclear transport. In addition, we show that Rae1 is required for normal viral protein production during SARS-CoV-2 infection presumably through its role in supporting Orf6 function.
MeSH term(s)	Humans ; Active Transport, Cell Nucleus ; COVID-19/metabolism ; Interferons/metabolism ; Nuclear Pore/metabolism ; Nuclear Pore Complex Proteins/metabolism ; Nucleocytoplasmic Transport Proteins/metabolism ; RNA, Messenger/metabolism ; SARS-CoV-2/metabolism ; Viral Proteins/metabolism ; Nuclear Matrix-Associated Proteins/metabolism
Chemical Substances	Interferons (9008-11-1) ; Nuclear Pore Complex Proteins ; Nucleocytoplasmic Transport Proteins ; RNA, Messenger ; ORF6 protein, SARS-CoV-2 ; Viral Proteins ; RAE1 protein, human ; Nuclear Matrix-Associated Proteins
Language	English
Publishing date	2024-03-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E23-10-0386
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Article ; Online: Multiple receptor tyrosine kinases regulate dengue infection of hepatocytes.

Bourgeois, Natasha M / Wei, Ling / Ho, Nhi N T / Neal, Maxwell L / Seferos, Denali / Tongogara, Tinotenda / Mast, Fred D / Aitchison, John D / Kaushansky, Alexis

Frontiers in cellular and infection microbiology

2024 Volume 14, Page(s) 1264525

Abstract: Introduction: Dengue is an arboviral disease causing severe illness in over 500,000 people each year. Currently, there is no way to constrain dengue in the clinic. Host kinase regulators of dengue virus (DENV) infection have the potential to be ... ...

Abstract	Introduction: Dengue is an arboviral disease causing severe illness in over 500,000 people each year. Currently, there is no way to constrain dengue in the clinic. Host kinase regulators of dengue virus (DENV) infection have the potential to be disrupted by existing therapeutics to prevent infection and/or disease progression. Methods: To evaluate kinase regulation of DENV infection, we performed kinase regression (KiR), a machine learning approach that predicts kinase regulators of infection using existing drug-target information and a small drug screen. We infected hepatocytes with DENV Results: Thirty-six kinases were predicted to have a functional role. Intriguingly, seven of the predicted kinases - EPH receptor A4 (EPHA4), EPH receptor B3 (EPHB3), EPH receptor B4 (EPHB4), erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 2 (FGFR2), Insulin like growth factor 1 receptor (IGF1R), and ret proto-oncogene (RET) - belong to the receptor tyrosine kinase (RTK) family, which are already therapeutic targets in the clinic. We demonstrate that predicted RTKs are expressed at higher levels in DENV infected cells. Knockdown of EPHB4, ERBB2, FGFR2, or IGF1R reduces DENV infection in hepatocytes. Finally, we observe differential temporal induction of ERBB2 and IGF1R following DENV infection, highlighting their unique roles in regulating DENV. Discussion: Collectively, our findings underscore the significance of multiple RTKs in DENV infection and advocate further exploration of RTK-oriented interventions against dengue.
MeSH term(s)	Humans ; Dengue ; Dengue Virus/physiology ; Receptor, EphA1 ; Hepatocytes/metabolism ; Tyrosine ; Virus Replication
Chemical Substances	Receptor, EphA1 (EC 2.7.10.1) ; Tyrosine (42HK56048U)
Language	English
Publishing date	2024-03-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2024.1264525
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Article ; Online: Nanobody repertoire generated against the spike protein of ancestral SARS-CoV-2 remains efficacious against the rapidly evolving virus.

Ketaren, Natalia E / Mast, Fred D / Fridy, Peter C / Olivier, Jean Paul / Sanyal, Tanmoy / Sali, Andrej / Chait, Brian T / Rout, Michael P / Aitchison, John D

eLife

2024 Volume 12

Abstract	To date, all major modes of monoclonal antibody therapy targeting SARS-CoV-2 have lost significant efficacy against the latest circulating variants. As SARS-CoV-2 omicron sublineages account for over 90% of COVID-19 infections, evasion of immune responses generated by vaccination or exposure to previous variants poses a significant challenge. A compelling new therapeutic strategy against SARS-CoV-2 is that of single-domain antibodies, termed nanobodies, which address certain limitations of monoclonal antibodies. Here, we demonstrate that our high-affinity nanobody repertoire, generated against wild-type SARS-CoV-2 spike protein (Mast et al., 2021), remains effective against variants of concern, including omicron BA.4/BA.5; a subset is predicted to counter resistance in emerging XBB and BQ.1.1 sublineages. Furthermore, we reveal the synergistic potential of nanobody cocktails in neutralizing emerging variants. Our study highlights the power of nanobody technology as a versatile therapeutic and diagnostic tool to combat rapidly evolving infectious diseases such as SARS-CoV-2.
MeSH term(s)	Single-Domain Antibodies/immunology ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Humans ; COVID-19/immunology ; COVID-19/virology ; Antibodies, Viral/immunology ; Antibodies, Viral/therapeutic use ; Antibodies, Neutralizing/immunology ; Animals
Chemical Substances	Single-Domain Antibodies ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Antibodies, Viral ; Antibodies, Neutralizing
Language	English
Publishing date	2024-05-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.89423
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Article ; Online: Dengue activates mTORC2 signaling to counteract apoptosis and maximize viral replication.

Carter, Christoph C / Mast, Fred D / Olivier, Jean Paul / Bourgeois, Natasha M / Kaushansky, Alexis / Aitchison, John D

Frontiers in cellular and infection microbiology

2022 Volume 12, Page(s) 979996

Abstract: The mechanistic target of rapamycin (mTOR) functions in two distinct complexes: mTORC1, and mTORC2. mTORC1 has been implicated in the pathogenesis of flaviviruses including dengue, where it contributes to the establishment of a pro-viral autophagic state. ...

Abstract	The mechanistic target of rapamycin (mTOR) functions in two distinct complexes: mTORC1, and mTORC2. mTORC1 has been implicated in the pathogenesis of flaviviruses including dengue, where it contributes to the establishment of a pro-viral autophagic state. Activation of mTORC2 occurs upon infection with some viruses, but its functional role in viral pathogenesis remains poorly understood. In this study, we explore the consequences of a physical protein-protein interaction between dengue non-structural protein 5 (NS5) and host cell mTOR proteins during infection. Using shRNA to differentially target mTORC1 and mTORC2 complexes, we show that mTORC2 is required for optimal dengue replication. Furthermore, we show that mTORC2 is activated during viral replication, and that mTORC2 counteracts virus-induced apoptosis, promoting the survival of infected cells. This work reveals a novel mechanism by which the dengue flavivirus can promote cell survival to maximize viral replication.
MeSH term(s)	Apoptosis ; Dengue ; Humans ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mechanistic Target of Rapamycin Complex 2/genetics ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; RNA, Small Interfering ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/metabolism ; Virus Replication
Chemical Substances	Multiprotein Complexes ; RNA, Small Interfering ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2022-09-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2022.979996
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