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Longitudinal Sequence and Functional Evolution within Glycoprotein E2 in Hepatitis C Virus Genotype 3a Infection

PLOS ONE, 2015

The E2 glycoprotein of Hepatitis C virus (HCV) is a major target of the neutralizing antibody (NA... more The E2 glycoprotein of Hepatitis C virus (HCV) is a major target of the neutralizing antibody (NAb) response with the majority of epitopes located within its receptor binding domain (RBD; 384-661). Within E2 are three variable regions located at the N-terminus (HVR1; 384-411), and internally at 460-480 (HVR2) and 570-580 [intergenotypic variable region (igVR)], all of which lie outside a conserved core domain that contains the CD81 binding site, essential for attachment of virions to host cells and a major target of NAbs. In this study, we examined the evolution of the E1 and E2 region in two patients infected with genotype 3a virus. Whereas one patient was able to clear the acute infection, the other developed a chronic infection. Mutations accumulated at multiple positions within the N-terminal HVR1 as well as within the igVR in both patients over time, whereas mutations in HVR2 were observed only in the chronically infected patient. Mutations within or adjacent to the CD81 contact site were observed in both patients but were less frequent and more conservative in the patient that cleared his/her infection. The evolution of CD81 binding function and antigenicity was examined with longitudinal E2 RBD sequences. The ability of the RBD to bind CD81 was completely lost by week 108 in the patient that developed chronic HCV. In the second patient, the ability of the week 36 RBD, just prior to viral clearance, to bind CD81 was reduced~50% relative to RBD sequences obtained earlier. The binding of a NAb specific to a conserved epitope located within E2 residues 411-428 was significantly reduced by week 108 despite complete conservation of its epitope suggesting that E2 antigenicity is allosterically modulated. The exposure of non-neutralizing antibody epitopes was similarly explored and we observed that the epitope of 3 out of 4 non-NAbs were significantly more exposed in the RBDs representing the late timepoints in the chronic patient. By contrast, the exposure of non-neutralizing epitopes was reduced in the patient that cleared his/ her infection and could in part be attributed to sequence changes in the igVR. These studies reveal that during HCV infection, the exposure of the CD81 binding site on E2 becomes PLOS ONE |

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Method-specific variations in the calibration of a new immunoglobulin standard suitable for use in nephelometric techniques

Clinical chemistry, 1978

The putative International Federation of Clinical Chemistry immunoglobulin standard, IFCC 74/1, w... more The putative International Federation of Clinical Chemistry immunoglobulin standard, IFCC 74/1, was calibrated against the World Health Organization (WHO) immunoglobulin standard 67/99 by three different methods: automated immunoprecipitation, Laurell rocket immunoelectrophoresis, and radial immunodiffusion. The same antisera were used in all the assays, which were performed in five expert laboratories. With the aid of linearizing transformations for the dilution curves of both materials and use of a carefully weighted statistical evaluation, values in International Units for IgG, IgA, and IgM were ascribed to IFCC 74/1. The values achieved by the three different methods were not statistically different, except in the case of IgA. IgM assays by automated immunoprecipitation were excluded owing to a high degree of imprecision.

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Norovirus GII.4 variant 2006b caused epidemics of acute gastroenteritis in Australia during 2007 and 2008

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Accounting for occurrences: An explanation for some novel tendencies in causal judgment from contingency information

Contingency information is information about empirical associations between possible causes and o... more Contingency information is information about empirical associations between possible causes and outcomes. In the present research, it is shown that, under some circumstances, there is a tendency for negative contingencies to lead to positive causal judgments and for positive contingencies to lead to negative causal judgments. If there is a high proportion of instances in which a candidate cause (CC) being judged is present, these tendencies are predicted by weighted averaging models of causal judgment. If the proportion of such instances is low, the predictions of weighted averaging models break down. It is argued that one of the main aims of causal judgment is to account for occurrences of the outcome. Thus, a CC is not given a high causal judgment if there are few or no occurrences of it, regardless of the objective contingency. This argument predicts that, if there is a low proportion of instances in which a CC is present, causal judgments are determined mainly by the number of Cell A instances (i.e., CC present, outcome occurs), and that this explains why weighted averaging models fail to predict judgmental tendencies under these circumstances. Experimental results support this argument.

Naive analysis of food web dynamics: a study of causal judgment about complex physical systems

Causal judgements about temporal sequences of events in single individuals

Quarterly journal of experimental psychology (2006), Jan 2, 2015

Stimuli were presented in which values of an outcome variable for a single individual were record... more Stimuli were presented in which values of an outcome variable for a single individual were recorded over 24 time periods, and an intervention was introduced at one of the time periods. Participants judged whether and how much the intervention affected the outcome. Judgements were affected by manipulations of the temporal relation between the intervention and a gradual increase in values on the outcome variable, by the size of the increase, by the time taken for the increase to occur, and by variance in the preincrease data. Most results were predicted by a simple model in which the mean outcome value for the preintervention time periods is subtracted from the mean outcome value for the postintervention time periods, though there was also an effect of temporal contiguity that is not predicted by the simple model. This form of information, which is a kind of quasiexperimental design, is more representative of the kind of information generally available for causal judgement than the mo...

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Interpretation of Coastal HF Radar Derived Surface Currents with High-Resolution Drifter Data

Journal of Atmospheric and Oceanic Technology, 2007

Dense arrays of surface drifters are used to quantify the flow field on time and space scales ove... more Dense arrays of surface drifters are used to quantify the flow field on time and space scales over which high-frequency (HF) radar observations are measured. Up to 13 drifters were repetitively deployed off the Santa Barbara and San Diego coasts on 7 days during 18 months. Each day a regularly spaced grid overlaid on a 1-km2 (San Diego) or 4-km2

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The area of break crops on farm: What farmers are doing compared to estimates based on maximising profit

• Break crops increase farm profit, although in some cases the optimal area for break crops on th... more

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Prehistoric Settlement on Norfolk Island and its Oceanic Context

The likelihood of Polynesian settlement of Norfolk Island was recognized in the eighteenth centur... more The likelihood of Polynesian settlement of Norfolk Island was recognized in the eighteenth century, but archaeological remains of a settlement site were only discovered in 1995. The excavation history of the Emily Bay site is summarized, its date put at about the thirteenth to fourteenth century A.D. and its East Polynesian nature, especially its contacts with the Kermadecs and New

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The population pharmacokinetics of rapacuronium

Clinical Pharmacology & Therapeutics, 1999

Foundation, Cleveland, OH and Columbia Univ, New York, NY. Rapacuronium (R) is a new rapid onset ... more Foundation, Cleveland, OH and Columbia Univ, New York, NY. Rapacuronium (R) is a new rapid onset short acting neuromuscular blocking agent. We determined the pharmacokinetics (PK) of R in 37 surgical patients during desflurane, sevoflurane, isoflurane, or propofol anesthesia. Patients received an IV bolus dose of 1.5 mg/kg of R followed by a maintenance infusion. Blood samples were collected 10-15 min before the end of infusion and at 1, 3, 6, 10, 20, 40, 90, 120 and 240 rain after administration. NONMEM was used to determine the PK and covariate effects such as anesthesia type, age, weight, height, lean body mass (LBM), hematocrit, gender and study site. A three compartment model described the PK. LBM (kg) was a significant covariate for V2, V3 and C11. The parameters of the population model were: V1=4.39 L, V2=0.108 (LBM-48.6) + 2.17 L, V3=0.119 (LBM-48.6) + 10.3 L, CLI=0.0071 (LBM-48.6) + 0.373 L*min -1, CL2=0.197 L*min -1 and CL3=0.087 L*min -1.

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Singular clues to causality and their use in human causal judgment

Cognitive science

It is argued that causal understanding originates in experiences of acting on objects. Such exper... more It is argued that causal understanding originates in experiences of acting on objects. Such experiences have consistent features that can be used as clues to causal identification and judgment. These are singular clues, meaning that they can be detected in single instances. A catalog of 14 singular clues is proposed. The clues function as heuristics for generating causal judgments under uncertainty and are a pervasive source of bias in causal judgment. More sophisticated clues such as mechanism clues and repeated interventions are derived from the 14. Research on the use of empirical information and conditional probabilities to identify causes has used scenarios in which several of the clues are present, and the use of empirical association information for causal judgment depends on the presence of singular clues. It is the singular clues and their origin that are basic to causal understanding, not multiple instance clues such as empirical association, contingency, and conditional p...

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Viral niche construction alters hosts and ecosystems at multiple scales

Trends in ecology & evolution, 2014

The classical picture of viruses focuses on pathogenic viruses damaging the host's cells and ... more The classical picture of viruses focuses on pathogenic viruses damaging the host's cells and physiology and host-pathogen immune coevolution. However, a broader picture of viruses is emerging that includes weakly pathogenic, commensal, or even mutualistic viruses and includes gross behavioural manipulations and viral effects on ecosystems. In this paper, we argue for niche construction as a unifying perspective on viral evolution. As obligate intracellular parasites, viruses are always modifying their environment, and these modifications drive evolutionary feedback between the virus and its environment across multiple scales from cells to ecosystems. We argue that niche construction will provide new insights into viral evolution, and that virology is a powerful source of empirical tests for niche construction.

An outbreak of norovirus genogroup II associated with New South Wales oysters

Communicable diseases intelligence quarterly report, 2014

Currently available antigen tests for norovirus (NoV) have excellent specificity but negative res... more Currently available antigen tests for norovirus (NoV) have excellent specificity but negative results do not always rule out infection. Real-time reverse transcription polymerase chain reaction (RT-PCR) is a useful method for detecting and genotyping NoV in humans and oysters. An outbreak of NoV associated with oyster consumption in northern New South Wales confirmed the value of real-time RT-PCR where immunochromatography (ICT) tests were negative. Eight cases of gastrointestinal illness in northern NSW, clinically suggestive of NoV infection, were associated with consumption of oysters. A joint environmental investigation was conducted by the New South Wales Food Authority and local council. One human sample was collected and tested for NoV using ICT and real-time RT-PCR. Oyster samples were tested for NoV utilising real-time RT-PCR. The patient with a stool sample had NoV genogroup II (GII) confirmed by real-time RT-PCR after testing negative by ICT. Illness in all cases was cons...

Response to Rainsbury and Scott, and Lee

Clinical Otolaryngology, 2009

Dear Sir, Thank you for your interest in our paper. As stated in the discussion section of the pa... more Dear Sir, Thank you for your interest in our paper. As stated in the discussion section of the paper, whilst a significant result from the study would have provided evidence that nose picking was contributory to paediatric epistaxis, a non-significant result does not provide evidence that nose picking does not contribute. As such our paper does not provide any evidence that recurrent paediatric epistaxis is not caused by nose picking. It does, however, show no link between dominant hand and side of the epistaxis.

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A summary of the 20th International Symposium on Hepatitis C Virus and Related Viruses

Gastroenterology, 2014

The repertoire of host entry factors seems to be expanding with 2 new host cell molecules reporte... more The repertoire of host entry factors seems to be expanding with 2 new host cell molecules reported to play a role in HCV entry. Liang et al showed that E-cadherin is essential for HCV entry and Tang et al described the role of cell-death inducing DFFA-like effector b (CIDEB) in the entry of cell culture derived HCV, but not HCV glycoprotein pseudotyped particles. The 3-dimensional structure of the major cellular attachment protein of HCV, glycoprotein E2, has eluded researchers for many years. A major breakthrough was reported by the group of Law et al, who presented the first 2.65-Å structure of a minimized form of the E2 that retains the ability to bind neutralizing antibodies and CD81 and inhibits HCV pseudoparticle entry. The smaller size of glycoprotein E2, relative to glycoprotein E of the flaviviruses, is likely to be relevant to interpretation of the cryo-electron microscopy (EM) structures presented for cell-culture-derived infectious HCV particles by Meunier et al in the assembly session and recently published independently by Rice. 1 In these cryo-EM structures, there are far fewer glycoproteins embedded in the particles relative to the number of apolipoprotein (Apo)A, ApoB, and ApoE molecules. In addition, strong evidence emerged that ApoJ is also required for assembly of infectious HCV as presented by Chun-Chien-Lin in the assembly session. Finally, a major advance to our understanding of HCV entry in polarized hepatocytes was presented by Randall et al. Previous studies on the role of each HCV entry receptors/factors has been studied in nonpolarized Huh 7.5 cells, far removed from the complex polarized architecture of hepatocytes in the liver. The polarized cells are permissive to HCV infection, allowing the complete replication cycle to be examined providing a much-needed system in which to reexamine the role of each of the identified entry receptors and cofactors. In this system, CD81 and SR-B1 are found on the surface of cells, and claudin 1 and occludin localize exclusively to tight junctions. DiD-labelled HCV particles co-traffic with early entry receptors in association in an actin-dependent process to tight junctions and can be blocked by antibodies to CD81. In contrast with previous reports, no alteration in tight junction integrity was observed during HCV infection.

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Transport Studies Report

Novel genes identified by manual annotation and microarray expression analysis in the pancreas

Genomics, 2006

The mouse PancChip, a microarray developed for studying endocrine pancreatic development and diab... more The mouse PancChip, a microarray developed for studying endocrine pancreatic development and diabetes, represents over 13,000 cDNAs. After computationally assigning the cDNAs on the array to known genes, manual curation of the remaining sequences identified 211 novel transcripts. In microarray experiments, we found that 196 of these transcripts were expressed in total pancreas and/or pancreatic islets. Of 50 randomly selected clones

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Preparing System Security Policies

Continuous-time, stage-structured, multiple-species model with applications to amphibians

Applied Mathematics and Computation - AMC, 2010

Since the 1980s, biologists have noticed a major decline in amphibian population. The reason this... more Since the 1980s, biologists have noticed a major decline in amphibian population. The reason this is so alarming is because amphibians have been seen as a “Canary in the mine” when it comes to the world’s environmental changes. With global warming and CO2 emissions all over the news, we have become more aware of how we are impacting our world. If the decline of amphibians is a precursor to what is happening with the environment, then we need to find a good model to give us estimates on what is going to happen in the future. Here we used a predator–prey-competition model to help investigate how three amphibians might interact when confined to the same area.

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Archaeological fieldwork on Norfolk Island

Records of the Australian Museum, Supplement, 2001

Exploratory excavations in Cemetery, Emily and Slaughter Bays in search of a prehistoric settleme... more Exploratory excavations in Cemetery, Emily and Slaughter Bays in search of a prehistoric settlement site are outlined, along with small scale researches elsewhere on Norfolk Island and on adjacent islands. The archaeological excavations at the settlement site discovered in Emily Bay are described in detail and the taphonomy of the site discussed.

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