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Quantification of intrahepatic covalently closed circular DNA (cccDNA) is a key for evaluating an elimination of hepatitis B virus (HBV) in infected patients. However, quantifying cccDNA requires invasive methods such as a liver biopsy, which makes it impractical to access the dynamics of cccDNA in patients. Although HBV RNA and HBV core-related antigens (HBcrAg) have been proposed as surrogate markers for evaluating cccDNA activity, they do not necessarily estimate the amount of cccDNA. Here, we employed a recently developed multiscale mathematical model describing intra- and intercellular viral propagation and applied it in HBV-infected patients under treatment. We developed a model that can predict intracellular HBV dynamics by use of extracellular viral markers, including HBsAg, HBV DNA, and HBcrAg in peripheral blood. Importantly, the model prediction of the amount of cccDNA in patients over time was confirmed to be well correlated with the data for quantified cccDNA by paired liver biopsy. Thus, our method combining classic and emerging surrogate markers enables us to predict the decay dynamics of cccDNA in patients undergoing treatment. Author summary: Chronic hepatitis B (CHB) poses a major global health issue due to the persistence of covalently closed circular DNA (cccDNA) in the liver, which acts as a template for ongoing viral replication. Current therapies, such as PEG IFN-α, could reduce cccDNA levels but rarely achieve complete elimination. In this study, we developed and applied a multiscale mathematical model that combines data from in vitro, in vivo, and clinical studies to predict the dynamics of cccDNA in CHB patients during treatment. Our model uses extracellular viral markers—HBV DNA, HBsAg, and HBcrAg—to estimate cccDNA levels, potentially reducing the reliance on invasive liver biopsies. We demonstrated that our model may predict cccDNA turnover under treatment and can suggest options such as prolonging the duration of treatment to patients who get a large reduction in cccDNA to achieve a complete cure. This approach provides a new tool for personalizing CHB treatment strategies, aiming to achieve a complete cure by targeting and monitoring cccDNA dynamics more effectively. [ABSTRACT FROM AUTHOR]

Transactions in financial markets are not evenly spaced but can be concentrated within a short period of time. In this study, we investigated the factors that determine the transaction frequency in financial markets. Specifically, we employed the Hawkes process model to identify exogenous and endogenous forces governing transactions of individual stocks in the Tokyo Stock Exchange during the COVID-19 pandemic. To enhance the accuracy of our analysis, we introduced a novel EM algorithm for the estimation of exogenous and endogenous factors that specifically addresses the interdependence of the values of these factors over time. We detected a substantial change in the transaction frequency in response to policy change announcements. Moreover, there is significant heterogeneity in the transaction frequency among individual stocks. We also found a tendency where stocks with high market capitalization tend to significantly respond to external news, while their excitation relationship between transactions is weak. This suggests the capability of quantifying the market state from the viewpoint of the exogenous and endogenous factors generating transactions for various stocks. [ABSTRACT FROM AUTHOR]

Chronic infection with hepatitis B virus (HBV) is caused by the persistence of closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Despite available therapeutic anti-HBV agents, eliminating the cccDNA remains challenging. Thus, quantifying and understanding the dynamics of cccDNA are essential for developing effective treatment strategies and new drugs. However, such study requires repeated liver biopsy to measure the intrahepatic cccDNA, which is basically not accepted because liver biopsy is potentially morbid and not common during hepatitis B treatment. We here aimed to develop a noninvasive method for quantifying cccDNA in the liver using surrogate markers in peripheral blood. We constructed a multiscale mathematical model that explicitly incorporates both intracellular and intercellular HBV infection processes. The model, based on age-structured partial differential equations, integrates experimental data from in vitro and in vivo investigations. By applying this model, we roughly predicted the amount and dynamics of intrahepatic cccDNA within a certain range using specific viral markers in serum samples, including HBV DNA, HBsAg, HBeAg, and HBcrAg. Our study represents a significant step towards advancing the understanding of chronic HBV infection. The noninvasive quantification of cccDNA using our proposed method holds promise for improving clinical analyses and treatment strategies. By comprehensively describing the interactions of all components involved in HBV infection, our multiscale mathematical model provides a valuable framework for further research and the development of targeted interventions. Author summary: In viral infectious diseases, evaluating the quantity and dynamics of the virus within target cells is crucial for understanding disease progression caused by the virus and predicting the efficacy of anti-viral drugs. HBV, which infects the human liver, increases the risk of development of hepatocellular carcinoma with chronic infection. To avoid the risk, viral elimination by anti-viral treatment is needed. The final goal of HBV treatment is the elimination of cccDNA known as a viral reservoir, although it is challenging with current treatment. One of the barriers to this lies in the fact that cccDNA remains within the liver without entering the peripheral blood, making it difficult to assess the quantity and dynamics of cccDNA within the patient. To quantitate cccDNA, an invasive method called liver biopsy is necessary. This method involves inserting a large needle through the abdomen into the liver, which is basically not accepted. In this study, we constructed a multiscale mathematical model based on the experimental data, which allowed us to evaluate the quantity and dynamics of cccDNA using viral markers in the peripheral blood, if the baseline cccDNA amount prior to treatment has been quantified. The method we have developed is expected to significantly contribute to the improvement of future HBV treatment strategies. [ABSTRACT FROM AUTHOR]