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| Open AccessComprehensive analysis of antibody recognition in convalescent humans from highly pathogenic avian influenza H5N1 infection
Unravelling the mechanism of the recognition of the highly pathogenic influenza A viruses by antibodies is important for understanding their protective function. Zuo et al. characterise the mechanism of recognition of the H5N1 influenza virus by human monoclonal antibodies isolated from convalescent individuals.
- Teng Zuo
- , Jianfeng Sun
- & Linqi Zhang
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Article
| Open AccessSingle-cell analysis and stochastic modelling unveil large cell-to-cell variability in influenza A virus infection
Cell-to-cell variability in viral infection means that cell population measurements may not be an accurate representation of the process. Using both experimental and modelling approaches the authors confirm this notion showing that influenza virus infections are variable processes affected by intrinsic and extrinsic noise.
- Frank S. Heldt
- , Sascha Y. Kupke
- & Timo Frensing
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| Open AccessMatrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection
Proteases degrade extracellular matrix during inflammation, releasing peptides that can recruit neutrophils. Here the authors show that degradation of such bioactive peptide by the enzyme leukotriene A4 hydrolase is critical to limit pulmonary inflammation during bacterial infection in mice.
- Samia Akthar
- , Dhiren F. Patel
- & Robert J. Snelgrove
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| Open AccessDevelopment of high-yield influenza A virus vaccine viruses
The availability of high-yield virus strains remains an important bottleneck in the rapid production of influenza vaccines. Here, the authors report the development of influenza A vaccine backbone that improves the virus yield of various seasonal and pandemic influenza vaccine strains in cell culture.
- Jihui Ping
- , Tiago J.S. Lopes
- & Yoshihiro Kawaoka
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| Open AccessA potent broad-spectrum protective human monoclonal antibody crosslinking two haemagglutinin monomers of influenza A virus
Monoclonal antibodies with broadly neutralizing activity are being developed as potential treatment of influenza infections. Here, the authors describe a broadly neutralizing antibody with an unusual mode of binding to viral haemagglutinin, which has been isolated from patients convalescent from pandemic H1N1 influenza infection.
- Ying Wu
- , MyungSam Cho
- & Ruben O. Donis
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| Open AccessIdentification of mammalian-adapting mutations in the polymerase complex of an avian H5N1 influenza virus
Understanding the factors that enable some bird flu viruses to infect humans is important for the identification of circulating viruses with higher potential to infect us. Here, Taft et al.identify novel mutations in the polymerase of an avian H5N1 virus that help the virus to replicate in human cells and in mice
- Andrew S. Taft
- , Makoto Ozawa
- & Yoshihiro Kawaoka
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| Open AccessRecovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8+ T cells
H7N9 avian influenza viruses can cause severe human disease. Here, the authors analyse blood samples from hospitalized H7N9 patients and show that a diversity of immune mechanisms seem to influence disease length and outcome.
- Zhongfang Wang
- , Yanmin Wan
- & Jianqing Xu
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| Open AccessMammalian adaptation of influenza A(H7N9) virus is limited by a narrow genetic bottleneck
H7N9 bird flu viruses cause mild disease in poultry but can occasionally infect humans with fatal consequences. Here, the authors show that viral genetic diversification is low in ferrets and high in chickens, suggesting that a genetic bottleneck limits H7N9 adaptation to mammals
- Hassan Zaraket
- , Tatiana Baranovich
- & Richard J. Webby
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Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus
Treatment options for prevention and control of fatal H7N9 influenza infections remain limited. Here, the authors show that two human monoclonal antibodies protect mice against H7N9 strains when administered before or after H7N9 infection.
- Zhe Chen
- , Jianmin Wang
- & Qi Jin
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Global migration of influenza A viruses in swine
The 2009 H1N1 influenza pandemic exposed major gaps in our knowledge of the spatial ecology and evolution of swine influenza A viruses. Here Nelson et al. perform an extensive phylogenetic analysis of these viruses and show that the global trade of live swine strongly predicts their spatial dissemination.
- Martha I. Nelson
- , Cécile Viboud
- & Philippe Lemey
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| Open AccessMulti-spectral fluorescent reporter influenza viruses (Color-flu) as powerful tools for in vivo studies
Animal models are important to study organismal immune responses to infection with influenza viruses. Here, Fukuyama et al.report a new generation of fluorescently labelled influenza viruses that facilitate the study of viral infections in animal models at cellular level.
- Satoshi Fukuyama
- , Hiroaki Katsura
- & Yoshihiro Kawaoka
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| Open AccessVisualizing real-time influenza virus infection, transmission and protection in ferrets
Ferrets are the main animal model used for research on influenza transmission. Here, the authors investigate the dynamics of infection and transmission in ferrets using a replication-competent influenza reporter virus and real-time bioluminescence imaging.
- Erik A. Karlsson
- , Victoria A. Meliopoulos
- & Stacey Schultz-Cherry
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IL-10 inhibits neuraminidase-activated TGF-β and facilitates Th1 phenotype during early phase of infection
The role of IL-10 in influenza infection is controversial. Here the authors show that early during infection, IL-10 promotes Th1 immunity by inhibiting viral neuraminidase-mediated release of TGF-β, but later acts as an immunosuppressive cytokine to inhibit immunopathology and promote recovery.
- Avijit Dutta
- , Ching-Tai Huang
- & Yueh-Chia He
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Article
| Open AccessStructural characterization of a protective epitope spanning A(H1N1)pdm09 influenza virus neuraminidase monomers
Neuraminidase inhibitors offer a line of defence against flu infections, but resistance can occur even in the absence of prior exposure. Here Wan et al. describe the mode of action of CD6, a monoclonal antibody that protects against a common influenza strain, as a new therapeutic intervention model.
- Hongquan Wan
- , Hua Yang
- & Maryna C. Eichelberger
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Structural basis for preferential avian receptor binding by the human-infecting H10N8 avian influenza virus
Avian strains of the influenza virus sometimes infect human hosts with severe consequences. Here, Wang et al.report that the H10N8 avian influenza virus, for which two lethal human infections have been reported, possesses restricted affinity towards the human receptor and suggest a structural basis for H10N8’s limited virulence.
- Min Wang
- , Wei Zhang
- & George F. Gao
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Article
| Open AccessViral suppressors of the RIG-I-mediated interferon response are pre-packaged in influenza virions
It is unclear how incoming influenza viruses counteract the cells’ first line of defence, the interferon (IFN) response. Here Liedmann et al.show that a distinct amino-acid motif in polymerases PB1 and PA, which are packaged in the viral particles, inhibit early IFN induction.
- Swantje Liedmann
- , Eike R. Hrincius
- & Christina Ehrhardt
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| Open AccessThe K526R substitution in viral protein PB2 enhances the effects of E627K on influenza virus replication
Mutations in the viral polymerase, such as PB2-E627K, contribute to adaptation of avian influenza strains to mammalian hosts. Here the authors show that another mutation, PB2-K526R, is found in seasonal H3N2 and avian-origin human influenza isolates, and facilitates replication of these viruses in mammals.
- Wenjun Song
- , Pui Wang
- & Honglin Chen
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Effector CD4 T-cell transition to memory requires late cognate interactions that induce autocrine IL-2
The role of IL-2 signalling in the transition of T cells from effector to memory cells is not well defined. Here, the authors show that T-cell receptor interactions with cognate antigen elicit IL-2 secretion from effector cells, which rescues cells from apoptosis and upregulates IL-7 receptor expression, supporting CD4 T-cell memory formation.
- K. Kai McKinstry
- , Tara M. Strutt
- & Susan L. Swain
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Novel residues in avian influenza virus PB2 protein affect virulence in mammalian hosts
Avian influenza viruses can mutate and become infectious to humans, sometimes causing high mortality. Here, Fan et al.identify three mutations in viral protein PB2 that affect virulence in mammalian hosts.
- Shufang Fan
- , Masato Hatta
- & Yoshihiro Kawaoka
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Conserved and host-specific features of influenza virion architecture
Influenza-infected cells produce viral particles that incorporate a mixture of viral and host proteins. Here the authors analyse by mass spectrometry the protein composition of such particles and show that the host species determines certain characteristics of an otherwise conserved architecture.
- Edward C. Hutchinson
- , Philip D. Charles
- & Ervin Fodor
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Respiratory transmission of an avian H3N8 influenza virus isolated from a harbour seal
Avian influenza viruses constantly threaten human health as evidenced by the outbreaks of human H7N9 infections. Here, Karlsson et al. show that an avian H3N8 virus isolated from harbour seals has the potential to infect, cause disease and transmit in mammalian models of influenza virus infection.
- Erik A. Karlsson
- , Hon S. Ip
- & Stacey Schultz-Cherry
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Generation and characterization of influenza A viruses with altered polymerase fidelity
The inherent inaccuracy of viral RNA polymerases promotes viral evolution, but the importance of viral genetic diversity during infection is unclear. Here, Cheung et al.show that influenza strains with enhanced polymerase fidelity and low mutational frequency display reduced pathogenicity in mice.
- Peter P. H. Cheung
- , Simon J. Watson
- & Hui-Ling Yen
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An infectious bat-derived chimeric influenza virus harbouring the entry machinery of an influenza A virus
An uncharacterized influenza A-like virus (H17N10) has been detected in bats. Here the authors show that flu viruses containing certain H17N10 genes can infect human cells and mice, but do not exchange genes with other viruses, indicating that H17N10 transmission to humans is not very likely.
- Mindaugas Juozapaitis
- , Étori Aguiar Moreira
- & Martin Schwemmle
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A micro-sterile inflammation array as an adjuvant for influenza vaccines
There is a need of improved adjuvants for influenza vaccines. Here, the authors describe an adjuvant strategy using micro-fractional laser treatment combined with a topical cream containing a TLR 7 ligand that can enhance the immune response to intradermal vaccination with transient, constrained local inflammation.
- Ji Wang
- , Dilip Shah
- & Mei X. Wu
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| Open AccessPredicting the risk of avian influenza A H7N9 infection in live-poultry markets across Asia
An avian influenza virus of the H7N9 type, associated with live-poultry markets, has caused two human epidemics in China. Here, the authors develop a statistical model that predicts the risk of H7N9 infection in live-poultry markets across Asia, as a tool for disease surveillance and control.
- Marius Gilbert
- , Nick Golding
- & Hongjie Yu
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| Open AccessPathogenic potential of interferon αβ in acute influenza infection
Interferon αβ(IFNαβ) is known as a potent anti-viral factor, yet its role in influenza infection remains controversial. Here, the authors show that the IFNαβ response is a critical host factor, which, when excessive, causes strong inflammation and severe disease in a mouse model of acute influenza infection.
- Sophia Davidson
- , Stefania Crotta
- & Andreas Wack
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Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients
An avian influenza H7N9 virus causes severe human disease, including acute and often lethal respiratory failure. Here, the authors report that plasma levels of angiotensin II, a regulatory peptide of the renin–angiotensin system, are associated with disease severity and fatal outcome in infected patients.
- Fengming Huang
- , Jing Guo
- & Lanjuan Li
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Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections
H5N1 avian influenza viruses can be highly pathogenic. Here, the authors show that H5N1 infection leads to increased serum levels of angiotensin II in patients and mice, and that administration of angiotensin-converting enzyme 2 ameliorates lung injury in infected mice.
- Zhen Zou
- , Yiwu Yan
- & Chengyu Jiang
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Receptor mimicry by antibody F045–092 facilitates universal binding to the H3 subtype of influenza virus
Influenza A H3 viruses circulate in humans and bind host cells using the haemagglutinin (HA) glycoprotein. Here, Lee et al.perform a structural analysis of antibody F045–092 with broadly neutralizing activity against the H3 subtype and reveal its interaction with the HA receptor binding site.
- Peter S. Lee
- , Nobuko Ohshima
- & Ian A. Wilson
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FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability
Regulatory T cells (Tregs) are mainly known to suppress effector T cell and B-cell responses. Here, the authors demonstrate that Tregs are able to promote T follicular helper and germinal centre B-cell responses to influenza by sequestering IL-2, the negative regulator of T follicular helper cell differentiation.
- Beatriz León
- , John E. Bradley
- & André Ballesteros-Tato
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Fragile X mental retardation protein stimulates ribonucleoprotein assembly of influenza A virus
To successfully replicate and propagate, viruses hijack different components of the host cell machinery. Here, Zhou et al.identify the RNA-binding protein Fragile X mental retardation protein as a host factor involved in influenza A virus replication in host cells.
- Zhuo Zhou
- , Mengmeng Cao
- & Tao Deng
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Dynamic reassortments and genetic heterogeneity of the human-infecting influenza A (H7N9) virus
H7N9 influenza A viruses capable of infecting humans have recently emerged in China. Here, the authors show that these viruses remain genetically diverse, suggesting that they are still in the process of adapting to human hosts.
- Lunbiao Cui
- , Di Liu
- & George F. Gao
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| Open AccessInfluenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility
Some clinical isolates of influenza A(H7N9) virus encode a mutation within neuraminidase that could confer resistance to the only class of drugs active against H7N9. Here, the authors show that this mutation does not affect viral replication and pathogenicity while mediating resistance to antivirals in vivo.
- Rong Hai
- , Mirco Schmolke
- & Nicole M. Bouvier
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Real-time influenza forecasts during the 2012–2013 season
Our ability to accurately predict the spread of infectious diseases is still in its infancy. Here, Shamanet al.develop a model framework that produces accurate real-time forecasts of influenza peak timing for over a hundred cities in the USA.
- Jeffrey Shaman
- , Alicia Karspeck
- & Marc Lipsitch
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A Ca2+-dependent signalling circuit regulates influenza A virus internalization and infection
Influenza virus can enter host cells through endocytosis, but the molecular pathways involved in this process are not fully understood. Here, the authors dissect these pathways and identify Ca2+as a key regulator of influenza A virus entry via both clathrin-mediated and clathrin-independent endocytosis.
- Yoichiro Fujioka
- , Masumi Tsuda
- & Yusuke Ohba
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Acute emergence and reversion of influenza A virus quasispecies within CD8+ T cell antigenic peptides
Cytotoxic CD8+ T cells provide one level of protection against influenza infection. Here, the authors present evidence, in mice and humans, for the emergence and reversion of influenza A virus escape mutants associated with the immune pressure from cytotoxic CD8+ T lymphocytes.
- Sophie A. Valkenburg
- , Sergio Quiñones-Parra
- & Katherine Kedzierska
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Selection on haemagglutinin imposes a bottleneck during mammalian transmission of reassortant H5N1 influenza viruses
Mutations in the haemagglutinin of H5N1 avian influenza viruses confer transmissibility in ferrets. Here, Wilker et al. show that while within host variability is high, transmitted virus diversity is low suggesting a genetic bottleneck acts during transmission, driven by selection on haemagglutinin genes.
- Peter R. Wilker
- , Jorge M. Dinis
- & Thomas C. Friedrich
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| Open AccessVisualizing influenza virus infection in living mice
Mouse models of influenza infection that permit monitoring of infection in living animals are scarce. Here Pan et al. describe an engineered influenza virus expressing luciferase, which enables real-time in vivovisualization of viral infection and assessment of antiviral drugs.
- Weiqi Pan
- , Zhenyuan Dong
- & Ling Chen
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Article
| Open Accessp53 increases MHC class I expression by upregulating the endoplasmic reticulum aminopeptidase ERAP1
The protein p53 is an important tumour suppressor. Here Wanget al.show that p53 can induce expression of MHC class I on the cell surface by promoting expression of the aminopeptidase ERAP1, and that this mechanism operates in cancer cells as well as those infected with influenza virus.
- Bei Wang
- , Dandan Niu
- & Ee Chee Ren
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Article
| Open AccessBacterial colonization dampens influenza-mediated acute lung injury via induction of M2 alveolar macrophages
Bacterial infections can influence disease outcome in influenza infection; however, the mechanisms mediating these complex interactions remain unclear. Wang et al. reveal how infection with a component of the airway microbiota enhances survival during influenza infection via induction of anti-inflammatory macrophages.
- Jian Wang
- , Fengqi Li
- & Zhigang Tian
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Aerosol transmission is an important mode of influenza A virus spread
Influenza A viruses spread through contact, large and small respiratory droplets (aerosols), but the relative importance of these modes of transmission is unclear. Cowling et al. model data from community trials of face masks and hand hygiene and find that aerosol transmission accounts for half of influenza occurrences.
- Benjamin J. Cowling
- , Dennis K. M. Ip
- & James Mark Simmerman
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The role and assembly mechanism of nucleoprotein in influenza A virus ribonucleoprotein complexes
The nucleoprotein of negative-strand RNA viruses forms a part of the ribonucleoprotein complex. Here Turrell et al.show that nucleoprotein does not regulate the initiation and termination of transcription and replication by the viral RNA polymerase, suggesting that nucleoprotein instead is an elongation factor.
- Lauren Turrell
- , Jon W. Lyall
- & Frank T. Vreede
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Influenza neuraminidase operates via a nucleophilic mechanism and can be targeted by covalent inhibitors
New influenza neuramidase inhibitors may increase preparedness against influenza outbreaks. Vavricka et al.confirm the catalytic mechanism of neuramidase and show that it can be inhibited irreversibly with covalent inhibitors.
- Christopher J. Vavricka
- , Yue Liu
- & George F. Gao
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Article
| Open AccessInterferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals
A variant in the IFITM3gene increases the risk of severe influenza, but homozygosity is rare in Caucasians. The authors show that the variant gene is homozygous in 25% of healthy Chinese people, and 69% of those with severe pandemic influenza, suggesting that this gene influences the epidemiology of influenza in South-East Asia.
- Yong-Hong Zhang
- , Yan Zhao
- & Tao Dong
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Mapping of H3N2 influenza antigenic evolution in China reveals a strategy for vaccine strain recommendation
Influenza vaccines are updated frequently to accommodate changing influenza antigenicity. Here, the authors develop a new computational method for predicting the antigenicity of H3N2 influenza strains based on the HA sequence.
- Xiangjun Du
- , Libo Dong
- & Taijiao Jiang
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| Open AccessModification of the carboxy-terminal flanking region of a universal influenza epitope alters CD4+ T-cell repertoire selection
Epitopes presented by MHC-II molecules bind to T-cell receptors to activate CD4+ T cells. In this study, changes in the carboxy-terminal region of the influenza hemagglutinin epitope HA305-320alters the strength of binding to the T-cell receptor, thus modulating T-cell receptor usage and activation.
- David K. Cole
- , Kathleen Gallagher
- & Andrew Godkin
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Article
| Open AccessThree-dimensional analysis of ribonucleoprotein complexes in influenza A virus
The influenza A virus genome consists of eight RNA segments, which permits genetic reassortment and contributes to the emergence of novel strains with pandemic potential. Here, electron tomography is used to study the three-dimensional structure of ribonucleoprotein complexes within progeny virions.
- Takeshi Noda
- , Yukihiko Sugita
- & Yoshihiro Kawaoka
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Location-specific patterns of exposure to recent pre-pandemic strains of influenza A in southern China
Population demographics affect influenza transmission at large spatial scales. Here, influenza immunity is shown to vary spatially in a way unexplained by differences in demographics, suggesting that there are aspects of locations that drive influenza transmission other than individual and household risk factors.
- Justin Lessler
- , Derek A.T. Cummings
- & Steven Riley
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| Open AccessMechanism of 150-cavity formation in influenza neuraminidase
Group-1 influenza A neuramidase proteins have a 150-cavity that can be targeted by drugs, but the 2009 H1N1 virus neuramidase is not thought to have a 150-cavity. Here, biophysical simulations show that the 2009 H1N1 neuramidase exists in solution with an open 150-cavity, which is stabilized by a salt bridge.
- Rommie E. Amaro
- , Robert V. Swift
- & Robin M. Bush