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Article ; Online: Probabilistic integration of preceding responses explains response bias in perceptual decision making.

Schlunegger, Daniel / Mast, Fred W

iScience

2023 Volume 26, Issue 7, Page(s) 107123

Abstract: Expectations of sensory information change not only how well but also what we perceive. Even in an unpredictable environment, the brain is by default constantly engaged in computing probabilities between sensory events. These estimates are used to ... ...

Abstract	Expectations of sensory information change not only how well but also what we perceive. Even in an unpredictable environment, the brain is by default constantly engaged in computing probabilities between sensory events. These estimates are used to generate predictions about future sensory events. Here, we investigated the predictability of behavioral responses using three different learning models in three different one-interval two-alternative forced choice experiments with either auditory, vestibular, or visual stimuli. Results indicate that recent decisions, instead of the sequence of generative stimuli, cause serial dependence. By bridging the gap between sequence learning and perceptual decision making, we provide a novel perspective on sequential choice effects. We propose that serial biases reflect the tracking of statistical regularities of the decision variable, offering a broader understanding of this phenomenon.
Language	English
Publishing date	2023-06-14
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.107123
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Article ; Online: Executive functions in patients with bilateral and unilateral peripheral vestibular dysfunction.

Schöne, Corina G / Vibert, Dominique / Mast, Fred W

Journal of neurology

2024

Abstract: Previous research suggests that patients with peripheral vestibular dysfunction (PVD) suffer from nonspatial cognitive problems, including executive impairments. However, previous studies that assessed executive functions are conflicting, limited to ... ...

Abstract	Previous research suggests that patients with peripheral vestibular dysfunction (PVD) suffer from nonspatial cognitive problems, including executive impairments. However, previous studies that assessed executive functions are conflicting, limited to single executive components, and assessments are confounded by other cognitive functions. We compared performance in a comprehensive executive test battery in a large sample of 83 patients with several conditions of PVD (34 bilateral, 29 chronic unilateral, 20 acute unilateral) to healthy controls who were pairwise matched to patients regarding age, sex, and education. We assessed basic and complex executive functions with validated neuropsychological tests. Patients with bilateral PVD performed worse than controls in verbal initiation and working memory span, while other executive functions were preserved. Patients with chronic unilateral PVD had equal executive performance as controls. Patients with acute unilateral PVD performed worse than controls in the exact same tests as patients with bilateral PVD (verbal initiation, working memory span); however, this effect in patients with acute PVD diminished after correcting for multiple comparisons. Hearing loss and affective disorders did not influence our results. Vestibular related variables (disease duration, symptoms, dizziness handicap, deafferentation degree, and compensation) did not predict verbal initiation or working memory span in patients with bilateral PVD. The results suggest that bilateral PVD not only manifests in difficulties when solving spatial tasks but leads to more general neurocognitive deficits. This understanding is important for multidisciplinary workgroups (e.g., neurotologists, neurologists, audiologists) that are involved in diagnosing and treating patients with PVD. We recommend screening patients with PVD for executive impairments and if indicated providing them with cognitive training or psychoeducational support.
Language	English
Publishing date	2024-03-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	187050-6
ISSN	1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
ISSN (online)	1432-1459
ISSN	0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
DOI	10.1007/s00415-024-12267-7
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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: 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
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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
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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: 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: 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: ... Mast, Fridy et al. 2021), remains effective against variants of concern, including omicron BA.4/BA.5 ...

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 ; 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: 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: ... Mast et al., 2021), remains effective against variants of concern, including omicron BA.4/BA.5 ...

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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