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188 results on '"Sherer, Nathan M."'

1. Author Correction: Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV± cancer

Author

Ayuso, Jose M., Farooqui, Mehtab, Virumbrales-Muñoz, María, Denecke, Katheryn, Rehman, Shujah, Schmitz, Rebecca, Guerrero, Jorge F., Sanchez-de-Diego, Cristina, Campo, Sara Abizanda, Maly, Elizabeth M., Forsberg, Matthew H., Kerr, Sheena C., Striker, Robert, Sherer, Nathan M., Harari, Paul M., Capitini, Christian M., Skala, Melissa C., and Beebe, David J.

Published
2023
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2. Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV± cancer

Author

Ayuso, Jose M., Farooqui, Mehtab, Virumbrales-Muñoz, María, Denecke, Katheryn, Rehman, Shujah, Schmitz, Rebecca, Guerrero, Jorge F., Sanchez-de-Diego, Cristina, Campo, Sara Abizanda, Maly, Elizabeth M., Forsberg, Matthew H., Kerr, Sheena C., Striker, Robert, Sherer, Nathan M., Harari, Paul M., Capitini, Christian M., Skala, Melissa C., and Beebe, David J.

Published
2023
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3. Spatially Adaptive Colocalization Analysis in Dual-Color Fluorescence Microscopy

Author

Wang, Shulei, Arena, Ellen T., Becker, Jordan T., Bement, William M., Sherer, Nathan M., Eliceiri, Kevin W., and Yuan, Ming

Subjects
Statistics - Methodology, Electrical Engineering and Systems Science - Image and Video Processing, Quantitative Biology - Quantitative Methods
Abstract

Colocalization analysis aims to study complex spatial associations between bio-molecules via optical imaging techniques. However, existing colocalization analysis workflows only assess an average degree of colocalization within a certain region of interest and ignore the unique and valuable spatial information offered by microscopy. In the current work, we introduce a new framework for colocalization analysis that allows us to quantify colocalization levels at each individual location and automatically identify pixels or regions where colocalization occurs. The framework, referred to as spatially adaptive colocalization analysis (SACA), integrates a pixel-wise local kernel model for colocalization quantification and a multi-scale adaptive propagation-separation strategy for utilizing spatial information to detect colocalization in a spatially adaptive fashion. Applications to simulated and real biological datasets demonstrate the practical merits of SACA in what we hope to be an easily applicable and robust colocalization analysis method. In addition, theoretical properties of SACA are investigated to provide rigorous statistical justification.

Published
2017

10. Exploiting a rodent cell block for intrinsic resistance to HIV-1 gene expression in human T cells

Author

Behrens, Ryan T., primary, Rajashekar, Jyothi Krishnaswamy, additional, Bruce, James W., additional, Evans, Edward L., additional, Hansen, Amelia M., additional, Salazar-Quiroz, Natalia, additional, Simons, Lacy M., additional, Ahlquist, Paul, additional, Hultquist, Judd F., additional, Kumar, Priti, additional, and Sherer, Nathan M., additional

Published
2023
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15. Microphysiological model reveals the promise of memory-like natural killer cell immunotherapy for HIV± cancer.

Author

Ayuso, Jose M., Farooqui, Mehtab, Virumbrales-Muñoz, María, Denecke, Katheryn, Rehman, Shujah, Schmitz, Rebecca, Guerrero, Jorge F., Sanchez-de-Diego, Cristina, Campo, Sara Abizanda, Maly, Elizabeth M., Forsberg, Matthew H., Kerr, Sheena C., Striker, Robert, Sherer, Nathan M., Harari, Paul M., Capitini, Christian M., Skala, Melissa C., and Beebe, David J.

Subjects
KILLER cells, HIV, T cells, CELL populations, HEAD & neck cancer, CANCER cells
Abstract

Numerous studies are exploring the use of cell adoptive therapies to treat hematological malignancies as well as solid tumors. However, there are numerous factors that dampen the immune response, including viruses like human immunodeficiency virus. In this study, we leverage human-derived microphysiological models to reverse-engineer the HIV-immune system interaction and evaluate the potential of memory-like natural killer cells for HIV+ head and neck cancer, one of the most common tumors in patients living with human immunodeficiency virus. Here, we evaluate multiple aspects of the memory-like natural killer cell response in human-derived bioengineered environments, including immune cell extravasation, tumor penetration, tumor killing, T cell dependence, virus suppression, and compatibility with retroviral medication. Overall, these results suggest that memory-like natural killer cells are capable of operating without T cell assistance and could simultaneously destroy head and neck cancer cells as well as reduce viral latency. Current biological models for examining cancer immunobiology in a HIV infected context are lacking. Here the authors use a human-derived microphysiological model to represent the HIV immune system and assess the ability of transferred populations of NK cells in the targeting of tumours. [ABSTRACT FROM AUTHOR]

Published
2023
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19. Perturbing HIV-1 Ribosomal Frameshifting Frequency Reveals a cis Preference for Gag-Pol Incorporation into Assembling Virions

Author

Universidad de Sevilla. Departamento de Fisiología, National Institutes of Health. United States, Benner, Bayleigh E., Bruce, James W., Kentala, Jacob R., Murray, Magdalena, Becker, Jordan T., García Miranda, Pablo, Ahlquist, Paul, Butcher, Samuel E., Sherer, Nathan M., Universidad de Sevilla. Departamento de Fisiología, National Institutes of Health. United States, Benner, Bayleigh E., Bruce, James W., Kentala, Jacob R., Murray, Magdalena, Becker, Jordan T., García Miranda, Pablo, Ahlquist, Paul, Butcher, Samuel E., and Sherer, Nathan M.

Abstract

HIV-1 virion production is driven by Gag and Gag-Pol (GP) proteins, with Gag forming the bulk of the capsid and driving budding, while GP binds Gag to deliver the essential virion enzymes protease, reverse transcriptase, and integrase. Virion GP levels are traditionally thought to reflect the relative abundances of GP and Gag in cells (;1:20), dictated by the frequency of a 21 programmed ribosomal frameshifting (PRF) event occurring in gag-pol mRNAs. Here, we exploited a panel of PRF mutant viruses to show that mechanisms in addition to PRF regulate GP incorporation into virions. First, we show that GP is enriched ;3-fold in virions relative to cells, with viral infectivity being better maintained at subphysiological levels of GP than when GP levels are too high. Second, we report that GP is more efficiently incorporated into virions when Gag and GP are synthesized in cis (i.e., from the same gag-pol mRNA) than in trans, suggesting that Gag/GP translation and assembly are spatially coupled processes. Third, we show that, surprisingly, virions exhibit a strong upper limit to trans-delivered GP incorporation; an adaptation that appears to allow the virus to temper defects to GP/Gag cleavage that may negatively impact reverse transcription. Taking these results together, we propose a "weighted Goldilocks"scenario for HIV-1 GP incorporation, wherein combined mechanisms of GP enrichment and exclusion buffer virion infectivity over a broad range of local GP concentrations. These results provide new insights into the HIV-1 virion assembly pathway relevant to the anticipated efficacy of PRF-targeted antiviral strategies.

Published
2022

25. [Ca.sup.2+] and synaptotagmin VII-dependent delivery of lysosomal membrane to nascent phagosomes

Author

Czibener, Cecilia, Sherer, Nathan M., Becker, Steven M., Pypaert, Marc, Hui, Enfu, Chapman, Edwin R., Mothes, Walther, and Andrews, Norma W.

Subjects
Exocytosis -- Research, Phagocytosis -- Research, Lysosomes -- Research, Biological sciences
Abstract

Synaptotagmin (Syt) VII is a ubiquitously expressed member of the Syt family of [Ca.sup.2+] sensors. It is present on lysosomes in several cell types, where it regulates [Ca.sup.2+]-dependent exocytosis. Because [[Ca.sup.2+].sub.i] and exocytosis have been associated with phagocytosis, we investigated the phagocytic ability of macrophages from Syt [VII.sup.-/-] mice. Syt [VII.sup.-/-] macrophages phagocytose normally at low particle/cell ratios but show a progressive inhibition in particle uptake under high load conditions. Complementation with Syt VII rescues this phenotype, but only when functional [Ca.sup.2+]-binding sites are retained. Reinforcing a role for Syt VII in [Ca.sup.2+]-dependent phagocytosis, particle uptake in Syt [VII.sup.-/-] macrophages is significantly less dependent on [[Ca.sup.2+].sub.i]. Syt VII is concentrated on peripheral domains of lysosomal compartments, from where it is recruited to nascent phagosomes. Syt VII recruitment is rapidly followed by the delivery of Lamp1 to phagosomes, a process that is inhibited in Syt [VII.sup.-/-] macrophages. Thus, Syt VII regulates the [Ca.sup.2+]-dependent mobilization of lysosomes as a supplemental source of membrane during phagocytosis.

Published
2006

30. Integration of the ImageJ Ecosystem in KNIME Analytics Platform

Author

Dietz, Christian, primary, Rueden, Curtis T., additional, Helfrich, Stefan, additional, Dobson, Ellen T. A., additional, Horn, Martin, additional, Eglinger, Jan, additional, Evans, Edward L., additional, McLean, Dalton T., additional, Novitskaya, Tatiana, additional, Ricke, William A., additional, Sherer, Nathan M., additional, Zijlstra, Andries, additional, Berthold, Michael R., additional, and Eliceiri, Kevin W., additional

Published
2020
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31. B cells infected with Type 2 Epstein-Barr virus (EBV) have increased NFATc1/NFATc2 activity and enhanced lytic gene expression in comparison to Type 1 EBV infection

Author

Romero-Masters, James C., primary, Huebner, Shane M., additional, Ohashi, Makoto, additional, Bristol, Jillian A., additional, Benner, Bayleigh E., additional, Barlow, Elizabeth A., additional, Turk, Gail L., additional, Nelson, Scott E., additional, Baiu, Dana C., additional, Van Sciver, Nicholas, additional, Ranheim, Erik A., additional, Gumperz, Jenny, additional, Sherer, Nathan M., additional, Farrell, Paul J., additional, Johannsen, Eric C., additional, and Kenney, Shannon C., additional

Published
2020
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32. HIV-1 genome trafficking initiates APOBEC3G packaging in the cytosol

Author

Becker, Jordan T, Evans III, Edward L, Benner, Bayleigh E, Fricke, Stephanie L, Smith, Laura E, Bates, Andra E, and Sherer, Nathan M

Subjects
viruses
Abstract

HIV-1 RNA genomes interact with diverse RNA binding proteins in the cytoplasm including antiviral factor APOBEC3G (A3G) that, in the absence of viral Vif proteins, is packaged into virions. When and where genome-A3G interactions are initiated in the host cell is unknown. Here we use quantitative long-term (>24 h) live cell fluorescence video microscopy and a new in-cell RNA-protein interaction assay (the "IC-IP") to describe subcellular viral and A3G trafficking behaviors over the entire HIV-1 productive phase. Among other findings, we demonstrate that genome-A3G interactions are initiated in the cytosol soon if not immediately after genome nuclear export; that A3G-genome interactions are sufficiently strong so that tethering either factor to membranes inhibits trafficking of the reciprocal binding partner; and that selective recognition of genomes promotes consistent delivery of A3G to sites of virion assembly. Further elucidation of RNA signature(s) detected by A3G may inform development of RNA-targeted antivirals.

Published
2019
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33. Antigen structure affects cellular routing through DC-SIGN

Author

Massachusetts Institute of Technology. Department of Chemistry, Jarvis, Cassie M., Zwick, Daniel B., Grim, Joseph C., Alam, Mohammad Murshid, Prost, Lynne R., Gardiner, Jaye C., Park, Soyeong, Zimdars, Laraine L., Sherer, Nathan M., Kiessling, Laura L, Massachusetts Institute of Technology. Department of Chemistry, Jarvis, Cassie M., Zwick, Daniel B., Grim, Joseph C., Alam, Mohammad Murshid, Prost, Lynne R., Gardiner, Jaye C., Park, Soyeong, Zimdars, Laraine L., Sherer, Nathan M., and Kiessling, Laura L

Abstract

Dendritic cell (DC) lectins mediate the recognition, uptake, and processing of antigens, but they can also be coopted by pathogens for infection. These distinct activities depend upon the routing of antigens within the cell. Antigens directed to endosomal compartments are degraded, and the peptides are presented on major histocompatibility complex class II molecules, thereby promoting immunity. Alternatively, HIV-1 can avoid degradation, as virus engagement with C-type lectin receptors (CLRs), such as DC-SIGN (DC-specific ICAM-3–grabbing nonintegrin) results in trafficking to surface-accessible invaginated pockets. This process appears to enable infection of T cells in trans. We sought to explore whether antigen fate upon CLR-mediated internalization was affected by antigen physical properties. To this end, we employed the ring-opening metathesis polymerization to generate glycopolymers that each display multiple copies of mannoside ligand for DC-SIGN, yet differ in length and size. The rate and extent of glycopolymer internalization depended upon polymer structure—longer polymers were internalized more rapidly and more efficiently than were shorter polymers. The trafficking, however, did not differ, and both short and longer polymers colocalized with transferrin-labeled early endosomes. To explore how DC-SIGN directs larger particles, such as pathogens, we induced aggregation of the polymers to access particulate antigens. Strikingly, these particulate antigens were diverted to the invaginated pockets that harbor HIV-1. Thus, antigen structure has a dramatic effect on DC-SIGN–mediated uptake and trafficking. These findings have consequences for the design of synthetic vaccines. Additionally, the results suggest strategies for targeting DC reservoirs that harbor viral pathogens., National Institutes of Health (U.S.) (Grant AI055258)

Published
2020

35. Endogenous MOV10 inhibits the retrotransposition of endogenous retroelements but not the replication of exogenous retroviruses

Author

Arjan-Odedra Shetal, Swanson Chad M, Sherer Nathan M, Wolinsky Steven M, and Malim Michael H

Subjects
MOV10, Retrovirus, Retrotransposon, APOBEC3, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background The identification of cellular factors that regulate the replication of exogenous viruses and endogenous mobile elements provides fundamental understanding of host-pathogen relationships. MOV10 is a superfamily 1 putative RNA helicase that controls the replication of several RNA viruses and whose homologs are necessary for the repression of endogenous mobile elements. Here, we employ both ectopic expression and gene knockdown approaches to analyse the role of human MOV10 in the replication of a panel of exogenous retroviruses and endogenous retroelements. Results MOV10 overexpression substantially decreased the production of infectious retrovirus particles, as well the propagation of LTR and non-LTR endogenous retroelements. Most significantly, RNAi-mediated silencing of endogenous MOV10 enhanced the replication of both LTR and non-LTR endogenous retroelements, but not the production of infectious retrovirus particles demonstrating that natural levels of MOV10 suppress retrotransposition, but have no impact on infection by exogenous retroviruses. Furthermore, functional studies showed that MOV10 is not necessary for miRNA or siRNA-mediated mRNA silencing. Conclusions We have identified novel specificity for human MOV10 in the control of retroelement replication and hypothesise that MOV10 may be a component of a cellular pathway or process that selectively regulates the replication of endogenous retroelements in somatic cells.

Published
2012
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40. HIV-1gag-polmRNA localization regulates the site of virion assembly

Author

Becker, Jordan T. and Sherer, Nathan M.

Subjects
Messenger RNA, Capsid, Chemistry, viruses, Gene expression, Guide RNA, Nucleic acid structure, Subcellular localization, Nuclear export signal, Actin cytoskeleton, Cell biology
Abstract

HIV-1 full-length, unspliced genomic RNAs (gRNAs) serve both as mRNAs encoding the Gag and Gag-Pol capsid proteins as well as the genetic material packaged by Gag into virions that assemble at the plasma membrane (PM). Whether localized Gag synthesis contributes to assembly at the PM is unknown. Here we show that artificially tethering gRNAs or surrogategag-pol mRNAs to non-PM membranes or the actin cytoskeleton can markedly affect Gag’s distribution in the cytoplasm, causing aberrant subcellular sites of assembly and severe reductions to virus particle output. Onlygag-polmRNAs competent for translation were capable of altering Gag’s distribution within the cell, and the activity mapped to twocis-acting RNA regulatory elements; the 5’ packaging signal (Psi) bound by Gag and, unexpectedly, the Rev response element (RRE) that regulates the nuclear export of gRNAs and other intron-retaining viral RNAs. Taken together, our results suggest a model wherein localized translation of gRNAs at the PM helps to compartmentalize Gag-gRNA interactions, thereby promoting efficient genome encapsidation.AUTHOR SUMMARYThe spatial distribution of messenger RNAs (mRNAs) within the cytoplasm can be a crucial determinant of gene expression. Here we provide evidence that a devastating viral pathogen, human immunodeficiency virus type 1 (HIV-1), exploits localized translation to favor the formation of infectious, transmissible virions at the surface of infected cells. Artificially tethering viral mRNAs encoding the Gag and Gag-Pol capsid proteins (gag-polmRNAs) to alternative regions of the cell such as cytoplasmic vesicles or the actin cytoskeletion markedly alters Gag subcellular distribution, perturbs sites of assembly, and reduces virus particle production. These and additional findings suggest a model for HIV-1 assembly wherein localized Gag/Gag-Pol translation coupled to confined interactions between Gag and viral genomes ensures infectious virion production at the right place and the right time. Perturbing HIV-1 mRNA subcellular localization could represent a novel antiviral strategy.

Published
2016
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47. Human iNKT Cells Promote Protective Inflammation by Inducing Oscillating Purinergic Signaling in Monocyte-Derived DCs

Author

Xu, Xuequn, primary, Pocock, Ginger M., additional, Sharma, Akshat, additional, Peery, Stephen L., additional, Fites, J. Scott, additional, Felley, Laura, additional, Zarnowski, Robert, additional, Stewart, Douglas, additional, Berthier, Erwin, additional, Klein, Bruce S., additional, Sherer, Nathan M., additional, and Gumperz, Jenny E., additional

Published
2016
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