ORCID Profile
0000-0001-9806-5125
Current Organisation
University of New South Wales
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Publisher: Elsevier BV
Date: 08-2014
Publisher: Oxford University Press (OUP)
Date: 11-06-2013
DOI: 10.1093/JAC/DKT205
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-04-2013
Abstract: The envelope of influenza virus contains two immunodominant glycoproteins: hemagglutinin and neuraminidase (NA). Existing antivirals like zanamivir (Relenza) and oseltamivir (Tamiflu) target NA however, the development of drug resistance is a problem. Kim et al. (p. 71 , published online 21 February) now report a different class of NA inhibitors. NA catalyzes the removal of sialic acids from the surface of host cells to initiate entry. Discovery of a NA–sialic acid intermediate led to the production of sialic acid analogs that bound covalently to NA and inhibited its enzymatic activity. These compounds showed activity against a wide variety of influenza strains, inhibited viral replication in cell culture, and were able to protect mice against influenza infection. Protection of mice was equivalent to protection seen from zanamivir. Moreover, the compounds showed activity against drug-resistant strains in vitro. These compounds represent a potentially useful addition to the arsenal of antivirals used to treat influenza infection.
Publisher: MIT Press
Date: 03-2021
DOI: 10.1162/REST_A_00895
Abstract: A substantial proportion of in iduals who complete the widely used multiple price list (MPL) instrument switch back and forth between the safe and the risky choice columns, behavior that is believed to indicate low-quality decision making. We develop a conceptual framework to formally define decision-making quality, test explanations for the nature of low-quality decision making, and introduce a novel “nudge” treatment that reduced multiple switching behavior and increased decision-making quality. We find evidence in support of task-specific miscomprehension of the MPL and that non-multiple switchers and relatively high-cognitive-ability in iduals are not immune to low-quality decision making.
Publisher: American Chemical Society (ACS)
Date: 03-02-2018
DOI: 10.1021/ACS.JMEDCHEM.7B01467
Abstract: Competitive inhibitors of the influenza neuraminidase (NA) were discovered almost 20 years ago, with zanamivir and oseltamivir licensed globally. These compounds are based on a transition state analogue of the sialic acid substrate. We recently showed that 5- N-(acetylamino)-2,3,5-trideoxy-2,3-difluoro-d-erythro-β-l-manno-2-nonulopyranosonic acid (DFSA) and its derivatives are also potent inhibitors of the influenza NA. They are mechanism based inhibitors, forming a covalent bond between the C2 of the sugar ring and Y406 in the NA active site, thus inactivating the enzyme. We have now synthesized a series of deoxygenated DFSA derivatives in order to understand the contribution of each hydroxyl in DFSA to binding and inhibition of the influenza NA. We have investigated their relative efficacy in enzyme assays in vitro, in cell culture, and by X-ray crystallography. We found loss of the 8- and 9-OH had the biggest impact on the affinity of binding and antiviral potency.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.ANTIVIRAL.2014.12.004
Abstract: The neuraminidase (NA) inhibitors oseltamivir and zanamivir are administered twice daily for 5days for treatment of influenza. Laninamivir is a 7-methoxy derivative of zanamivir, but a single dose is effective when taken as the laninamivir octanoate prodrug. We show here in IC50 kinetics assays and a solid phase reactivation assay that compared to zanamivir laninamivir also demonstrates slow binding to but slower dissociation from multiple wild type NAs. A D197E mutation in an influenza B and an E119G in an N9 neuraminidase which confer 15- and 150-fold resistance to laninamivir result in faster binding and dissociation. Despite similar IC50s our assays demonstrate more rapid dissociation of laninamivir from clade 1 compared to 2 H5N1 NAs.
Publisher: Elsevier BV
Date: 05-2022
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.ANTIVIRAL.2019.104542
Abstract: An influenza A(H1N1)pdm09 and an influenza B virus were passaged in 3-fluoro(eq)-4-guanidino difluoro sialic acid (3Feq4Gu DFSA), an inhibitor of the influenza neuraminidase (NA) to determine whether resistant variants could be selected. 3Feq4Gu DFSA is a mechanism-based inhibitor, forming a covalent link to Y406 in the NA active site. Given its similarity to the natural substrate, sialic acid, we predicted resistant variants would be difficult to select. Yields of both viruses decreased with passaging, so that after 12 passages both viruses were only growing to low titers. Drug concentrations were decreased for another three passages. There was no difference in NA sensitivity in the MUNANA fluorescence-based assay, nor in plaque assays for the passaged virus stocks. All influenza B plaques were still wild type in all assays. There were isolated small diffuse plaques in the P15 pdm09 stock, which after purification had barely detectable NA or hemagglutinin (HA) activity. These had a novel non-active site I106M substitution in the NA gene, but unexpectedly no HA changes. The I106M may impact NA function through steric effects on the movement of the 150 and 430-loops. The I106M viruses had similar replication kinetics in MDCK cells as wild type viruses, but their ability to bind to and infect CHO-K1 cells expressing high levels of cell-bound mucin was compromised. The I106M substitution was unstable, with progeny rapidly reverting to wild type by three different mechanisms. Some had reverted to I106, some had V106, both with wild type NA and HA properties. A third group retained the I106M, but had a compensating R363K substitution, which regained almost wild type NA properties. These viruses now agglutinated chicken red blood cells (CRBCs) but unlike the I/V106, they rebound after elution at 37 °C. There were no mutations in the HA, but each phenotype correlated with the NA sequence. We propose that the activity in the I106M mutant is insufficient to remove carbohydrates from the virion HA and NA, sterically limiting HA access to CRBC receptors, thus resulting in poor HA binding.
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.ANTIVIRAL.2018.03.007
Abstract: We have tested the in vitro susceptibility to the neuraminidase (NA) inhibitors of 96 highly pathogenic clade 2.1 A(H5N1) viruses from Indonesia, isolated between 2008 and 2011. HPAI virus s les obtained through the Influenza Virus Monitoring (IVM) surveillance program in Indonesia were tested for susceptibility to oseltamivir and zanamivir. The NAs of four viruses were identified as extreme outliers to oseltamivir, based on statistical analysis by box plots, with IC
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.ANTIVIRAL.2015.08.014
Abstract: The human parainfluenza virus type 3 (hPIV3) hemagglutinin-neuraminidase (HN) has opposing functions of binding sialic acid receptors and cleaving them, facilitating virus release. The crystal structure of hPIV3 HN complexed with the substrate analogue difluorosialic acid (DFSA) revealed that catalysis by HN involves the formation of a covalently linked sialosyl-enzyme intermediate which was trapped along with a transition-state analogue resembling an oxocarbenium ion. This mechanism of enzyme catalysis was also confirmed in the crystal structure of the influenza N9 neuraminidase complexed with DFSA. Additionally, novel secondary receptor binding sites were identified in the hPIV3 HN-DFSA complex including one near the catalytic cavity which upon binding DFSA imposes subtle changes and may help the HN balance the opposing functions. Multiple receptor binding sites may increase avidity to facilitate cell binding and fusion promotion. The secondary receptor binding sites in the paramyxoviruses are so far unique to each virus type.
Publisher: American Economic Association
Date: 06-2021
Abstract: We study the causes of sustained participation in political movements. To identify the persistent effect of protest participation, we randomly indirectly incentivize Hong Kong university students into participation in an antiauthoritarian protest. To identify the role of social networks, we randomize this treatment’s intensity across major-cohort cells. We find that incentives to attend one protest within a political movement increase subsequent protest attendance but only when a sufficient fraction of an in idual’s social network is also incentivized to attend the initial protest. One-time mobilization shocks have dynamic consequences, with mobilization at the social network level important for sustained political engagement. (JEL D72, D74, I23, Z13)
Publisher: Public Library of Science (PLoS)
Date: 11-06-2013
Publisher: University of Chicago Press
Date: 04-2017
DOI: 10.1086/690951
Publisher: Oxford University Press (OUP)
Date: 21-01-2019
DOI: 10.1093/QJE/QJZ002
Publisher: American Chemical Society (ACS)
Date: 09-08-2010
DOI: 10.1021/JM100621S
Publisher: Oxford University Press (OUP)
Date: 04-05-2012
DOI: 10.1093/JAC/DKS150
Abstract: Pandemic H1N1/09 viruses with the neuraminidase H274Y mutation have emerged in untreated patients or following oseltamivir therapy or prophylaxis. There have been no reports yet of zanamivir-resistant H1N1/09 viruses in previously healthy patients. We wanted to determine whether we could select for neuraminidase mutations conferring high-level resistance to zanamivir by in vitro passage of the virus. We also wanted to investigate if passaging in a combination of zanamivir and oseltamivir could prevent the emergence of the H274Y mutation. An H1N1/09 virus was passaged in cell culture in increasing concentrations of either zanamivir or a combination of zanamivir and oseltamivir. Passage in zanamivir selected a virus with N146S neuraminidase and G158E haemagglutinin mutations. The neuraminidase mutation only reduced drug susceptibility by 2-fold in enzyme assays. The haemagglutinin mutation conferred drug dependence and drug resistance in cells to oseltamivir and zanamivir and reduced binding to red blood cells. After four passages in zanamivir and oseltamivir, virus with a D198G neuraminidase mutation was selected with around 10-fold reduced susceptibility to oseltamivir, zanamivir and peramivir in the enzyme assay. Further passaging selected a virus with both D198G and H274Y mutations that was highly resistant to oseltamivir and peramivir, but not zanamivir. All mutations affected growth in cell culture and decreased affinities of the neuraminidases for substrate. We did not select a virus with a neuraminidase mutation conferring high-level resistance to zanamivir. Dual exposure to zanamivir and oseltamivir was not sufficient to prevent selection of the H274Y mutation.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 21-12-2022
Abstract: The consequences of crowding on the dynamic conformational ensembles of intrinsically disordered proteins (IDPs) remain unresolved because of their ultrafast motion. Here, we report crowder-induced interactions and conformational dynamics of a prototypical multistimuli-responsive IDP, Rec1-resilin. The effects of a range of crowders of varying sizes, forms, topologies, and concentrations were examined using spectroscopic, spectrofluorimetric, and contrast-matching small- and ultrasmall-angle neutron scattering investigation. To achieve sufficient neutron contrast against the crowders, deuterium-labeled Rec1-resilin was biosynthesized successfully. Moreover, the ab initio “shape reconstruction” approach was used to obtain three-dimensional models of the conformational assemblies. The IDP revealed crowder-specific systematic extension and compaction with the level of macromolecular crowding. Last, a robust extension-contraction model has been postulated to capture the fundamental phenomena governing the observed behavior of IDPs. The study provides insights and fresh perspectives for understanding the interactions and structural dynamics of IDPs in crowded states.
Publisher: Proceedings of the National Academy of Sciences
Date: 25-04-2016
Abstract: Despite Darwin’s recognition of the importance of intrasexual competition, the topic of female competition has been largely ignored. Economists, looking for reasons why women are rarely found in top jobs, have accumulated experimental evidence pointing to women’s lower desire to compete than men. Consistent with newer interdisciplinary hypotheses about female competition, our experimental results show that women can compete as much as men once we change the experimental reward medium to something more in line with women’s goal: the benefit of one’s children. Our results have important policy implications: a change in the workplace incentive structure could induce more women to enter workplace competitions. Such findings matter for a broader group of scientists including biologists, anthropologists, psychologists, economists, and sociologists.
Publisher: Oxford University Press (OUP)
Date: 20-12-2018
DOI: 10.1111/ECOJ.12596
Location: United States of America
No related grants have been discovered for Y. Jane Zhang.