ORCID Profile
0000-0002-9384-2447
Current Organisations
University of New South Wales
,
Hong Kong University of Science and Technology
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Publisher: IEEE
Date: 06-2014
Publisher: IEEE
Date: 06-2014
Publisher: IEEE
Date: 06-2009
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2010
Publisher: IEEE
Date: 11-2010
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 08-2009
Publisher: IEEE
Date: 2010
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 02-2010
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 05-2013
Publisher: IEEE
Date: 06-2013
Publisher: IEEE
Date: 2010
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 09-2015
Publisher: Oxford University Press (OUP)
Date: 18-12-2019
DOI: 10.1093/BIOINFORMATICS/BTZ925
Abstract: Learning underlying correlation patterns in data is a central problem across scientific fields. Maximum entropy models present an important class of statistical approaches for addressing this problem. However, accurately and efficiently inferring model parameters are a major challenge, particularly for modern high-dimensional applications such as in biology, for which the number of parameters is enormous. Previously, we developed a statistical method, minimum probability flow–Boltzmann Machine Learning (MPF–BML), for performing fast and accurate inference of maximum entropy model parameters, which was applied to genetic sequence data to estimate the fitness landscape for the surface proteins of human immunodeficiency virus and hepatitis C virus. To facilitate seamless use of MPF–BML and encourage more widespread application to data in erse fields, we present a standalone cross-platform package of MPF–BML which features an easy-to-use graphical user interface. The package only requires the input data (protein sequence data or data of multiple configurations of a complex system with large number of variables) and returns the maximum entropy model parameters. The MPF–BML software is publicly available under the MIT License at hmedaq/MPF-BML-GUI. Supplementary data are available at Bioinformatics online.
Publisher: Wiley
Date: 28-01-2021
DOI: 10.1111/IMCB.12432
Publisher: IEEE
Date: 11-2009
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2010
Publisher: IEEE
Date: 12-2012
Publisher: Wiley
Date: 12-2022
DOI: 10.1111/IMCB.12607
Abstract: The long‐term health consequences of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection are still being understood. The molecular and phenotypic properties of SARS‐CoV‐2 antigen–specific T cells suggest a dysfunctional profile that persists in convalescence in those who were severely ill. By contrast, the antigen‐specific memory B‐cell (MBC) population has not yet been analyzed to the same degree, but phenotypic analysis suggests differences following recovery from mild or severe coronavirus disease 2019 (COVID‐19). Here, we performed single‐cell molecular analysis of the SARS‐CoV‐2 receptor‐binding domain (RBD)–specific MBC population in three patients after severe COVID‐19 and four patients after mild/moderate COVID‐19. We analyzed the transcriptomic and B‐cell receptor repertoire profiles at ~2 months and ~4 months after symptom onset. Transcriptomic analysis revealed a higher level of tumor necrosis factor‐alpha (TNF‐α) signaling via nuclear factor‐kappa B in the severe group, involving CD80 , FOS , CD83 and TNFAIP3 genes that was maintained over time. We demonstrated the presence of two distinct activated MBCs subsets based on expression of CD80 hi TNFAIP3 hi and CD11c hi CD95 hi at the transcriptome level. Both groups revealed an increase in somatic hypermutation over time, indicating progressive evolution of humoral memory. This study revealed distinct molecular signatures of long‐term RBD‐specific MBCs in convalescence, indicating that the longevity of these cells may differ depending on acute COVID‐19 severity.
Publisher: IEEE
Date: 06-2011
Publisher: IEEE
Date: 2008
Publisher: IEEE
Date: 2008
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 03-2013
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2009
Publisher: IEEE
Date: 06-2012
Publisher: IEEE
Date: 12-2010
Publisher: IEEE
Date: 11-2013
Publisher: IEEE
Date: 05-2010
Publisher: IEEE
Date: 06-2009
Publisher: IEEE
Date: 04-2012
Publisher: Cold Spring Harbor Laboratory
Date: 23-07-2019
DOI: 10.1101/711861
Abstract: Identifying the genetic drivers of adaptation is a necessary step in understanding the dynamics of rapidly evolving pathogens and cancer. However, signals of selection are obscured by the complex, stochastic nature of evolution. Pervasive effects of genetic linkage, including genetic hitchhiking and clonal interference between beneficial mutants, challenge our ability to distinguish the selective effect of in idual mutations. Here we describe a method to infer selection from genetic time series data that systematically resolves the confounding effects of genetic linkage. We applied our method to investigate patterns of selection in intrahost human immunodeficiency virus (HIV)-1 evolution, including a case in an in idual who develops broadly neutralizing antibodies (bnAbs). Most variants that arise are observed to have negligible effects on inferred selection at other sites, but a small minority of highly influential variants have strong and far-reaching effects. In particular, we found that accounting for linkage is crucial for estimating selection due to clonal interference between escape mutants and other variants that sweep rapidly through the population. We observed only modest selection for antibody escape, in contrast with strong selection for escape from CD8+ T cell responses. Weak selection for escape from antibody responses may facilitate bnAb development by ersifying the viral population. Our results provide a quantitative description of the evolution of HIV-1 in response to host immunity, including selection on the viral population that accompanies bnAb development. More broadly, our analysis argues for the importance of resolving linkage effects in studies of natural selection.
Publisher: IEEE
Date: 2008
DOI: 10.1109/ICC.2008.854
Publisher: Proceedings of the National Academy of Sciences
Date: 08-01-2018
Abstract: An effective vaccine for HIV is still not available, although recent hope has emerged through the discovery of antibodies capable of neutralizing erse HIV strains. Nonetheless, there exist mutational pathways through which HIV can evade known broadly neutralizing antibody responses. An ideal vaccine would elicit broadly neutralizing antibodies that target parts of the virus’s spike proteins where mutations severely compromise the virus’s fitness. Here, we employ a computational approach that allows estimation of the fitness landscape (fitness as a function of sequence) of the polyprotein that comprises HIV’s spike. We validate the inferred landscape through comparisons with erse experimental measurements. The availability of this fitness landscape will aid the rational design of immunogens for effective vaccines.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2010
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2014
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 06-2009
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 07-2014
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2011
Publisher: IEEE
Date: 04-2010
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2012
Publisher: IEEE
Date: 11-2007
Publisher: IEEE
Date: 2008
DOI: 10.1109/ICC.2008.167
Publisher: Springer Science and Business Media LLC
Date: 02-08-2022
DOI: 10.1038/S41467-019-09819-1
Abstract: Isolation of broadly neutralizing human monoclonal antibodies (HmAbs) targeting the E2 glycoprotein of Hepatitis C virus (HCV) has sparked hope for effective vaccine development. Nonetheless, escape mutations have been reported. Ideally, a potent vaccine should elicit HmAbs that target regions of E2 that are most difficult to escape. Here, aimed at addressing this challenge, we develop a predictive in-silico evolutionary model for E2 that identifies one such region, a specific antigenic domain, making it an attractive target for a robust antibody response. Specific broadly neutralizing HmAbs that appear difficult to escape from are also identified. By providing a framework for identifying vulnerable regions of E2 and for assessing the potency of specific antibodies, our results can aid the rational design of an effective prophylactic HCV vaccine.
Publisher: Wiley
Date: 29-05-2013
DOI: 10.1002/ETT.2663
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 08-2014
Publisher: American Society of Hematology
Date: 21-10-2021
Abstract: We performed a phase 1 clinical trial to evaluate outcomes in patients receiving donor-derived CD19-specific chimeric antigen receptor (CAR) T cells for B-cell malignancy that relapsed or persisted after matched related allogeneic hemopoietic stem cell transplant. To overcome the cost and transgene-capacity limitations of traditional viral vectors, CAR T cells were produced using the piggyBac transposon system of genetic modification. Following CAR T-cell infusion, 1 patient developed a gradually enlarging retroperitoneal tumor due to a CAR-expressing CD4+ T-cell lymphoma. Screening of other patients led to the detection, in an asymptomatic patient, of a second CAR T-cell tumor in thoracic para-aortic lymph nodes. Analysis of the first lymphoma showed a high transgene copy number, but no insertion into typical oncogenes. There were also structural changes such as altered genomic copy number and point mutations unrelated to the insertion sites. Transcriptome analysis showed transgene promoter–driven upregulation of transcription of surrounding regions despite insulator sequences surrounding the transgene. However, marked global changes in transcription predominantly correlated with gene copy number rather than insertion sites. In both patients, the CAR T-cell–derived lymphoma progressed and 1 patient died. We describe the first 2 cases of malignant lymphoma derived from CAR gene–modified T cells. Although CAR T cells have an enviable record of safety to date, our results emphasize the need for caution and regular follow-up of CAR T recipients, especially when novel methods of gene transfer are used to create genetically modified immune therapies. This trial was registered at www.anzctr.org.au as ACTRN12617001579381.
Publisher: IEEE
Date: 04-2009
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 11-2011
Publisher: IEEE
Date: 06-2014
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 04-2009
Publisher: IEEE
Date: 03-2012
Publisher: IEEE
Date: 2008
DOI: 10.1109/ICC.2008.809
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2016
Publisher: IEEE
Date: 06-2011
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 06-2008
Publisher: IEEE
Date: 06-2007
DOI: 10.1109/ICC.2007.859
Publisher: Springer Science and Business Media LLC
Date: 30-11-2020
Publisher: Springer Science and Business Media LLC
Date: 07-12-2022
DOI: 10.1038/S41467-022-35281-7
Abstract: T cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood s les from a unique cohort of in iduals with primary infection using single-cell multi-omics to identify the functions and phenotypes of HCV-specific CD8 + T cells. Early elevated IFN-γ response against the transmitted virus is associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome, we find heterogeneous subsets of progenitors of exhaustion, based on the level of PD-1 expression and loss of AP-1 transcription factors. Intra-clonal analysis shows distinct trajectories with multiple fates and evolutionary plasticity of precursor cells. These findings challenge the current paradigm on the contribution of CD8 + T cells to HCV disease outcome and provide data for future studies on T cell differentiation in human infections.
Publisher: IEEE
Date: 03-2008
Publisher: American Society for Microbiology
Date: 07-2014
DOI: 10.1128/JVI.03812-13
Abstract: Chronic hepatitis C virus (HCV) infection is one of the leading causes of liver failure and liver cancer, affecting around 3% of the world's population. The extreme sequence variability of the virus resulting from error-prone replication has thwarted the discovery of a universal prophylactic vaccine. It is known that vigorous and multispecific cellular immune responses, involving both helper CD4 + and cytotoxic CD8 + T cells, are associated with the spontaneous clearance of acute HCV infection. Escape mutations in viral epitopes can, however, abrogate protective T-cell responses, leading to viral persistence and associated pathologies. Despite the propensity of the virus to mutate, there might still exist substitutions that incur a fitness cost. In this paper, we identify groups of coevolving residues within HCV nonstructural protein 3 (NS3) by analyzing erse sequences of this protein using ideas from random matrix theory and associated methods. Our analyses indicate that one of these groups comprises a large percentage of residues for which HCV appears to resist multiple simultaneous substitutions. Targeting multiple residues in this group through vaccine-induced immune responses should either lead to viral recognition or elicit escape substitutions that compromise viral fitness. Our predictions are supported by published clinical data, which suggested that immune genotypes associated with spontaneous clearance of HCV preferentially recognized and targeted this vulnerable group of residues. Moreover, mapping the sites of this group onto the available protein structure provided insight into its functional significance. An epitope-based immunogen is proposed as an alternative to the NS3 epitopes in the peptide-based vaccine IC41. IMPORTANCE Despite much experimental work on HCV, a thorough statistical study of the HCV sequences for the purpose of immunogen design was missing in the literature. Such a study is vital to identify epistatic couplings among residues that can provide useful insights for designing a potent vaccine. In this work, ideas from random matrix theory were applied to characterize the statistics of substitutions within the erse publicly available sequences of the genotype 1a HCV NS3 protein, leading to a group of sites for which HCV appears to resist simultaneous substitutions possibly due to deleterious effect on viral fitness. Our analysis leads to completely novel immunogen designs for HCV. In addition, the NS3 epitopes used in the recently proposed peptide-based vaccine IC41 were analyzed in the context of our framework. Our analysis predicts that alternative NS3 epitopes may be worth exploring as they might be more efficacious.
Publisher: Cold Spring Harbor Laboratory
Date: 11-09-2021
DOI: 10.1101/2021.09.09.459584
Abstract: T-cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. Limited knowledge exists of the initial viral and immune dynamics that characterise exhaustion in humans. We studied longitudinal blood s les from a unique cohort of subjects with primary infection using single cell multi-omics to identify the functions and phenotypes of HCV-specific CD8 + T cells. Early elevated IFN-γ response against the transmitted virus was associated with the rate of immune escape, larger clonal expansion, and early onset of exhaustion. Irrespective of disease outcome we discovered progenitors of early-exhaustion with intermediate expression of PD-1. Intra clonal analysis revealed distinct trajectories with multiple fates suggesting evolutionary plasticity of precursor cells. These findings challenge current paradigm on the contribution of CD8 + T cells to HCV disease outcome and provide data for future studies on T-cell differentiation in human infections. Progenitors of T-cell exhaustion in acute HCV infection
No related grants have been discovered for Raymond Hall Yip Louie.