Human Liver Organoids Culture as a Personalised Approach in Assessing HBV Infection and Cellular Responses

HBV is a hepatotropic, partially double-stranded DNA virus that has been associated with chronic liver diseases such as liver cirrhosis and hepatocellular carcinoma (HCC). It has eight genotypes and many subtypes, with different risks of disease progression. Risks of HCC development is especially high in certain ethnic groups, suggesting the importance of host genetics in the disease outcome. Despite the development of highly effective nucleoside and nucleotide analogues that can control HBV replication, there is currently no curative treatment. Pegylated IFN-a is able to achieve functional cure in a small proportion of patients, and the exact mechanism of how this phenomenon occurs in some and not the others, is not yet clear. A major problem with HBV study is the lack of in vitro or in vivo model system that can recapitulate clinical disease progression. Many in vitro model systems utilise hepatomaderived cell lines that suffer from significant physiological and immunological limitations that restrict understanding of complex viral-host interactions. Primary hepatocytes have been considered the “gold standard” for in vitro studies but suffer from major limitations, for instance, they rapidly dedifferentiate in culture, have limited lifespan and are labour intensive to isolate and maintain. Stem-cell derived hepatocyte-like cells (HLCs) have gain significant research interest in recent years due to their ability to self-replenish in their stem cell stage and following differentiation, are able to achieve mature hepatocyte-like metabolic phenotypes. Studies using induced pluripotent stem cells (iPSC) derived HLCs have shown the ability of this model system to support HBV replication. iPSC, however, is not an ideal model system due to high rates of de novo mutations introduced during reprogramming process. Another stem cell-derived liver model system is the adult stem cell (AdSC) derived liver organoids that was first developed in the Hans Clevers laboratory by Meritxell Huch. This model system recapitulates liver regeneration from ductal stem cells following liver injuries. Following differentiation, the organoids can achieve metabolic phenotypes similar to liver tissue. Importantly, these organoids are genetically stable during culture and carry the genetic signatures of the original host. In this thesis, we developed and characterise the AdSC derived liver organoids as a novel model system for assessing HBV lifecycle, cellular responses and also demonstrate their utility in assessing antiviral response. We first characterise this culture system and the differentiation processes using mouse liver tissues. We subsequently adapted the culture system to generate human liver organoids from liver biopsy specimens to increase the applicability of this culture system as a personalised drug testing platform. We have shown in this thesis that the differentiated human liver organoids expressed higher levels of metabolic markers such as albumin and CYP3A4 expression. In addition, we demonstrated the importance of assessing functional HBV entry receptor (NTCP) expression during the course of differentiation to determine the optimal timing for HBV infection. Also arising from this thesis was the observation that the liver organoids can be infected with both cell culture and plasma derived HBV from different genotypes (B, C, D). In contrast to HepG2-NTCP, DMSO has no influence on the differentiation and infectivity of HBV in liver organoids. Importantly, we noticed that HBV infection in different donors resulted in very different viral dynamics, suggesting that individual host factors play an important role in HBV infection and replication. Antiviral response can also be assessed using the liver organoids culture system as demonstrated by lack of infection following treatment with Myrcludex B. Another novel discovery is that the interferon-stimulated genes (ISG) response to either RNA mimics or IFN-a stimulation is considerably different in their levels and timing of mRNA induction. These findings confirm our postulation that the liver organoids can demonstrate phenotypic donor variations in innate immunity. Having demonstrated that the liver organoids are immune competent, we assessed ISG induction in liver organoids following HBV infection. We noticed that although there were some donor variations in ISG expressions, the overall level of ISG induction following HBV infection was very poor. This result confirm that HBV is a poor inducer of ISGs and thus resolving some of the previous conflicting findings from studies using less physiological model system. In summary, we have developed a novel in vitro model system to evaluate HBV infection and the innate immune response. We have shown that the organoids demonstrate individualised HBV viral dynamics and ISG response and are responsive to antiviral treatment. We believe we have significantly improved our understanding of the innate immune response to HBV infection and the findings from this thesis will help pave the way for future development of a personalised antiviral platform for novel anti-HBV therapeutics.Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 202

Repeat-Until-Success quantum computing using stationary and flying qubits

We introduce an architecture for robust and scalable quantum computation using both stationary qubits (e.g. single photon sources made out of trapped atoms, molecules, ions, quantum dots, or defect centers in solids) and flying qubits (e.g. photons). Our scheme solves some of the most pressing problems in existing non-hybrid proposals, which include the difficulty of scaling conventional stationary qubit approaches, and the lack of practical means for storing single photons in linear optics setups. We combine elements of two previous proposals for distributed quantum computing, namely the efficient photon-loss tolerant build up of cluster states by Barrett and Kok [Phys. Rev. A 71, 060310(R) (2005)] with the idea of Repeat-Until-Success (RUS) quantum computing by Lim et al. [Phys. Rev. Lett. 95, 030505 (2005)]. This idea can be used to perform eventually deterministic two-qubit logic gates on spatially separated stationary qubits via photon pair measurements. Under non-ideal conditions, where photon loss is a possibility, the resulting gates can still be used to build graph states for one-way quantum computing. In this paper, we describe the RUS method, present possible experimental realizations, and analyse the generation of graph states.Comment: 14 pages, 7 figures, minor changes, references and a discussion on the effect of photon dark counts adde

SandCanvas: A Multi-touch Art Medium Inspired by Sand Animation

10.1145/1978942.1979133Conference on Human Factors in Computing Systems - Proceedings1283-129

Maritime threat response

This report was prepared by Systems Engineering and Analysis Cohort Nine (SEA-9) Maritime Threat Response, (MTR) team members.Background: The 2006 Naval Postgraduate School (NPS) Cross-Campus Integrated Study, titled “Maritime Threat Response” involved the combined effort of 7 NPS Systems Engineering students, 7 Singaporean Temasek Defense Systems Institute (TDSI) students, 12 students from the Total Ship Systems Engineering (TSSE) curriculum, and numerous NPS faculty members from different NPS departments. After receiving tasking provided by the Wayne E. Meyer Institute of Systems Engineering at NPS in support of the Office of the Assistant Secretary of Defense for Homeland Defense, the study examined ways to validate intelligence and respond to maritime terrorist attacks against United States coastal harbors and ports. Through assessment of likely harbors and waterways to base the study upon, the San Francisco Bay was selected as a representative test-bed for the integrated study. The NPS Systems Engineering and Analysis Cohort 9 (SEA-9) Maritime Threat Response (MTR) team, in conjunction with the TDSI students, used the Systems Engineering Lifecycle Process (SELP) [shown in Figure ES-1, p. xxiii ] as a systems engineering framework to conduct the multi-disciplinary study. While not actually fabricating any hardware, such a process was well-suited for tailoring to the team’s research efforts and project focus. The SELP was an iterative process used to bound and scope the MTR problem, determine needs, requirements, functions, and to design architecture alternatives to satisfy stakeholder needs and desires. The SoS approach taken [shown in Figure ES-2, p. xxiv ]enabled the team to apply a systematic approach to problem definition, needs analysis, requirements, analysis, functional analysis, and then architecture development and assessment.In the twenty-first century, the threat of asymmetric warfare in the form of terrorism is one of the most likely direct threats to the United States homeland. It has been recognized that perhaps the key element in protecting the continental United States from terrorist threats is obtaining intelligence of impending attacks in advance. Enormous amounts of resources are currently allocated to obtaining and parsing such intelligence. However, it remains a difficult problem to deal with such attacks once intelligence is obtained. In this context, the Maritime Threat Response Project has applied Systems Engineering processes to propose different cost-effective System of Systems (SoS) architecture solutions to surface-based terrorist threats emanating from the maritime domain. The project applied a five-year time horizon to provide near-term solutions to the prospective decision makers and take maximum advantage of commercial off-the-shelf (COTS) solutions and emphasize new Concepts of Operations (CONOPS) for existing systems. Results provided insight into requirements for interagency interactions in support of Maritime Security and demonstrated the criticality of timely and accurate intelligence in support of counterterror operations.This report was prepared for the Office of the Assistant Secretary of Defense for Homeland DefenseApproved for public release; distribution is unlimited

Non-repudiation in an agent-based e-commerce system

Abecos is an agent-based e-commerce system under development at the Nanyang Technological University. It aims to provide a software infrastructure for a large scale, distributed system whereby seller and buyer (software) agents engage in e-commerce activities on behalf of organizations and individuals. A key factor in making this system usable in practice is strict security controls. One aspect of security is the provision of non-repudiation services. As protocols for non-repudiation have focused on the singlemessage non-repudiation, its adaptation to afford non-repudiation in a communication session for two agents in Abecos is inefficient. In this work, we investigate and propose a protocol for enforcing non-repudiation in a session. We compare and show that it is more efficient than simple adaptations of existing protocols. Keywords: Electronic Commerce, Security, Non-Repudiation Protocol 1 Introduction Electronic commerce is an emerging paradigm of business on the fast g..

Tracking the international spread of SARS-CoV-2 lineages B.1.1.7 and B.1.351/501Y-V2

Publisher Copyright: © 2021 O'Toole Á et al.Late in 2020, two genetically-distinct clusters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with mutations of biological concern were reported, one in the United Kingdom and one in South Africa. Using a combination of data from routine surveillance, genomic sequencing and international travel we track the international dispersal of lineages B.1.1.7 and B.1.351 (variant 501Y-V2). We account for potential biases in genomic surveillance efforts by including passenger volumes from location of where the lineage was first reported, London and South Africa respectively. Using the software tool grinch (global report investigating novel coronavirus haplotypes), we track the international spread of lineages of concern with automated daily reports, Further, we have built a custom tracking website (cov-lineages.org/global_report.html) which hosts this daily report and will continue to include novel SARS-CoV-2 lineages of concern as they are detected.Peer reviewe

Economic value added as a predictor of stock returns

This research studies the effectiveness EVA as a predictor of superior stock returns and compares it against other indicators like P/E. The sample consists of 50 companies that are the largest in terms of market capitalisation as at June 1991. The period of the study is from 1991 to 1996. The 50 stocks are ranked according to EVA/Market Capitalisation (EVA/MktC). The annual returns of the top ten stocks in each year are then statistically tested against the annual returns of the bottom ten stocks. The overall results suggest that EVA is not an effective predictor of stocks with superior returns. Neither is it superior to P/E or P/B

International portfolio diversification : a factor analysis approach

This study looks at international p01tfolio diversification of the Asia-Pacific, and is based on indices or averages of six stock exchanges - Australian Stock Exchange, Stock Exchange of Hong Kong, Toh.yro Stock Exchange, Kuala Lumpur Stock Exchange, Stock Exchange of Singapore, and New York Stock Exchange. The Australia All-Industries Index, the Hang Seng Index, the Nikkei Stock Average (Nikkei-225), the Kuala Lumpur Composite Index, the SES AllSingapore Share Index and the Dow Jones Industrial Average are used in the statistical analysis, recognising the fact that stock indices and averages are widely used to monitor performance of stock markets. Factor Analysis is the main tool used to analyse the data. From here, two main factors are identified from the exchange rate-adjusted rate of returns of indices or averages. The fu·st factor relates to emerging markets and the second pertains to established markets. Given the six markets chosen, an efficient portfolio should consist of one emerging market (Singapore, Malaysia or Hong Kong) and one established market being the New York stock market. The results of the analysis support international portfolio diversification as a means of reducing risk. The project also confums the presence of intertemporal stability of the variables and this indicates the efficacy of factor analysis as a guide to future international diversification decisions. The exact portfolio to be undertaken by an investor is, however, dependent on his/her risk-return preference.ACCOUNTANC