Author
Jeremy S. Rossman
Other affiliations: Uniformed Services University of the Health Sciences, Howard Hughes Medical Institute, Northwestern University
Bio: Jeremy S. Rossman is an academic researcher from University of Kent. The author has contributed to research in topics: Virus & Membrane curvature. The author has an hindex of 17, co-authored 35 publications receiving 1992 citations. Previous affiliations of Jeremy S. Rossman include Uniformed Services University of the Health Sciences & Howard Hughes Medical Institute.
Papers
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TL;DR: This review investigates the latest research on influenza virus budding in an attempt to provide a step-by-step analysis of the assembly and budding processes for influenza viruses.
613 citations
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TL;DR: It is shown that M2 localizes to the neck of budding virions and that mutation of the M2 amphipathic helix results in failure of the virus to undergo membrane scission and virion release, suggesting that M1 mediates the final steps of budding for influenza viruses, bypassing the need for host ESCRT proteins.
490 citations
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TL;DR: Data suggest that cyclic CPPs exit the endosome by binding to the endOSomal membrane and inducing CPP-enriched lipid domains to bud off as small vesicles, which should provide a powerful system for intracellular delivery of therapeutic agents and chemical probes.
Abstract: Previous cell-penetrating peptides (CPPs) generally have low cytosolic delivery efficiencies, because of inefficient endosomal escape. In this study, a family of small, amphipathic cyclic peptides was found to be highly efficient CPPs, with cytosolic delivery efficiencies of up to 120% (compared to 2.0% for Tat). These cyclic CPPs bind directly to the plasma membrane phospholipids and enter mammalian cells via endocytosis, followed by efficient release from the endosome. Their total cellular uptake efficiency correlates positively with the binding affinity for the plasma membrane, whereas their endosomal escape efficiency increases with the endosomal membrane-binding affinity. The cyclic CPPs induce membrane curvature on giant unilamellar vesicles and budding of small vesicles, which subsequently collapse into amorphous lipid/peptide aggregates. These data suggest that cyclic CPPs exit the endosome by binding to the endosomal membrane and inducing CPP-enriched lipid domains to bud off as small vesicles. Together with their high proteolytic stability, low cytotoxicity, and oral bioavailability, these cyclic CPPs should provide a powerful system for intracellular delivery of therapeutic agents and chemical probes.
207 citations
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TL;DR: It is found that an amphipathic helix located within the M2 cytoplasmic tail is able to bind cholesterol, and it is speculated that M2 cholesterol binding is essential for both filament formation and the stability of existing viral filaments.
Abstract: Influenza A virus buds from cells as spherical (∼100-nm diameter) and filamentous (∼100 nm × 2 to 20 μm) virions. Previous work has determined that the matrix protein (M1) confers the ability of the virus to form filaments; however, additional work has suggested that the influenza virus M2 integral membrane protein also plays a role in viral filament formation. In examining the role of the M2 protein in filament formation, we observed that the cytoplasmic tail of M2 contains several sites that are essential for filament formation. Additionally, whereas M2 is a nonraft protein, expression of other viral proteins in the context of influenza virus infection leads to the colocalization of M2 with sites of virus budding and lipid raft domains. We found that an amphipathic helix located within the M2 cytoplasmic tail is able to bind cholesterol, and we speculate that M2 cholesterol binding is essential for both filament formation and the stability of existing viral filaments.
188 citations
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TL;DR: It is found that filamentous influenza viruses use macropinocytosis as the primary entry mechanism, and low pH triggers a conformational change in the M2 ion channel protein, altering membrane curvature and leading to a fragmentation of the filamentous virions.
Abstract: Influenza virus is pleiomorphic, producing both spherical (100-nm-diameter) and filamentous (100-nm by 20-μm) virions. While the spherical virions are known to enter host cells through exploitation of clathrin-mediated endocytosis, the entry pathway for filamentous virions has not been determined, though the existence of an alternative, non-clathrin-, non-caveolin-mediated entry pathway for influenza virus has been known for many years. In this study, we confirm recent results showing that influenza virus utilizes macropinocytosis as an alternate entry pathway. Furthermore, we find that filamentous influenza viruses use macropinocytosis as the primary entry mechanism. Virions enter cells as intact filaments within macropinosomes and are trafficked to the acidic late-endosomal compartment. Low pH triggers a conformational change in the M2 ion channel protein, altering membrane curvature and leading to a fragmentation of the filamentous virions. This fragmentation may enable more-efficient fusion between the viral and endosomal membranes.
140 citations
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01 May 1993
TL;DR: Comparing the results to the fastest reported vectorized Cray Y-MP and C90 algorithm shows that the current generation of parallel machines is competitive with conventional vector supercomputers even for small problems.
Abstract: Three parallel algorithms for classical molecular dynamics are presented. The first assigns each processor a fixed subset of atoms; the second assigns each a fixed subset of inter-atomic forces to compute; the third assigns each a fixed spatial region. The algorithms are suitable for molecular dynamics models which can be difficult to parallelize efficiently—those with short-range forces where the neighbors of each atom change rapidly. They can be implemented on any distributed-memory parallel machine which allows for message-passing of data between independently executing processors. The algorithms are tested on a standard Lennard-Jones benchmark problem for system sizes ranging from 500 to 100,000,000 atoms on several parallel supercomputers--the nCUBE 2, Intel iPSC/860 and Paragon, and Cray T3D. Comparing the results to the fastest reported vectorized Cray Y-MP and C90 algorithm shows that the current generation of parallel machines is competitive with conventional vector supercomputers even for small problems. For large problems, the spatial algorithm achieves parallel efficiencies of 90% and a 1840-node Intel Paragon performs up to 165 faster than a single Cray C9O processor. Trade-offs between the three algorithms and guidelines for adapting them to more complex molecular dynamics simulations are also discussed.
29,323 citations
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TL;DR: Data shows that E is involved in critical aspects of the viral life cycle and that CoVs lacking E make promising vaccine candidates, which can aid in the production of effective anti-coronaviral agents for both human CoVs and enzootic CoVs.
Abstract: Coronaviruses (CoVs) primarily cause enzootic infections in birds and mammals but, in the last few decades, have shown to be capable of infecting humans as well. The outbreak of severe acute respiratory syndrome (SARS) in 2003 and, more recently, Middle-East respiratory syndrome (MERS) has demonstrated the lethality of CoVs when they cross the species barrier and infect humans. A renewed interest in coronaviral research has led to the discovery of several novel human CoVs and since then much progress has been made in understanding the CoV life cycle. The CoV envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus’ life cycle, such as assembly, budding, envelope formation, and pathogenesis. Recent studies have expanded on its structural motifs and topology, its functions as an ion-channelling viroporin, and its interactions with both other CoV proteins and host cell proteins. This review aims to establish the current knowledge on CoV E by highlighting the recent progress that has been made and comparing it to previous knowledge. It also compares E to other viral proteins of a similar nature to speculate the relevance of these new findings. Good progress has been made but much still remains unknown and this review has identified some gaps in the current knowledge and made suggestions for consideration in future research. The most progress has been made on SARS-CoV E, highlighting specific structural requirements for its functions in the CoV life cycle as well as mechanisms behind its pathogenesis. Data shows that E is involved in critical aspects of the viral life cycle and that CoVs lacking E make promising vaccine candidates. The high mortality rate of certain CoVs, along with their ease of transmission, underpins the need for more research into CoV molecular biology which can aid in the production of effective anti-coronaviral agents for both human CoVs and enzootic CoVs.
1,502 citations
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TL;DR: The results of a simulation study that opens some new research tensions on the impact of COVID-19 (SARS-CoV-2) on the global SCs are presented and an analysis for observing and predicting both short-term and long-term impacts of epidemic outbreaks on the SCs along with managerial insights are offered.
Abstract: Epidemic outbreaks are a special case of supply chain (SC) risks which is distinctively characterized by a long-term disruption existence, disruption propagations (i.e., the ripple effect), and high uncertainty. We present the results of a simulation study that opens some new research tensions on the impact of COVID-19 (SARS-CoV-2) on the global SCs. First, we articulate the specific features that frame epidemic outbreaks as a unique type of SC disruption risks. Second, we demonstrate how simulation-based methodology can be used to examine and predict the impacts of epidemic outbreaks on the SC performance using the example of coronavirus COVID-19 and anyLogistix simulation and optimization software. We offer an analysis for observing and predicting both short-term and long-term impacts of epidemic outbreaks on the SCs along with managerial insights. A set of sensitivity experiments for different scenarios allows illustrating the model's behavior and its value for decision-makers. The major observation from the simulation experiments is that the timing of the closing and opening of the facilities at different echelons might become a major factor that determines the epidemic outbreak impact on the SC performance rather than an upstream disruption duration or the speed of epidemic propagation. Other important factors are lead-time, speed of epidemic propagation, and the upstream and downstream disruption durations in the SC. The outcomes of this research can be used by decision-makers to predict the operative and long-term impacts of epidemic outbreaks on the SCs and develop pandemic SC plans. Our approach can also help to identify the successful and wrong elements of risk mitigation/preparedness and recovery policies in case of epidemic outbreaks. The paper is concluded by summarizing the most important insights and outlining future research agenda.
1,282 citations
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TL;DR: An antibody able to broadly neutralize both group 1 and group 2 influenza A viruses—and its target epitope—are identified and may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency.
Abstract: The isolation of broadly neutralizing antibodies against influenza A viruses has been a long-sought goal for therapeutic approaches and vaccine design. Using a single-cell culture method for screening large numbers of human plasma cells, we isolated a neutralizing monoclonal antibody that recognized the hemagglutinin (HA) glycoprotein of all 16 subtypes and neutralized both group 1 and group 2 influenza A viruses. Passive transfer of this antibody conferred protection to mice and ferrets. Complexes with HAs from the group 1 H1 and the group 2 H3 subtypes analyzed by x-ray crystallography showed that the antibody bound to a conserved epitope in the F subdomain. This antibody may be used for passive protection and to inform vaccine design because of its broad specificity and neutralization potency.
1,146 citations