Should a viral genome stay in the host cell or leave? A quantitative dynamics study of how hepatitis C virus deals with this dilemma

by Shoya Iwanami, Kosaku Kitagawa, Hirofumi Ohashi, Yusuke Asai, Kaho Shionoya, Wakana Saso, Kazane Nishioka, Hisashi Inaba, Shinji Nakaoka, Takaji Wakita, Odo Diekmann, Shingo Iwami, Koichi Watashi

Virus proliferation involves gene replication inside infected cells and transmission to new target cells. Once positive-strand RNA virus has infected a cell, the viral genome serves as a template for copying (“stay-strategy”) or is packaged into a progeny virion that will be released extracellularly (“leave-strategy”). The balance between genome replication and virion release determines virus production and transmission efficacy. The ensuing trade-off has not yet been well characterized. In this study, we use hepatitis C virus (HCV) as a model system to study the balance of the two strategies. Combining viral infection cell culture assays with mathematical modeling, we characterize the dynamics of two different HCV strains (JFH-1, a clinical isolate, and Jc1-n, a laboratory strain), which have different viral release characteristics. We found that 0.63% and 1.70% of JFH-1 and Jc1-n intracellular viral RNAs, respectively, are used for producing and releasing progeny virions. Analysis of the Malthusian parameter of the HCV genome (i.e., initial proliferation rate) and the number of de novo infections (i.e., initial transmissibility) suggests that the leave-strategy provides a higher level of initial transmission for Jc1-n, whereas, in contrast, the stay-strategy provides a higher initial proliferation rate for JFH-1. Thus, theoretical-experimental analysis of viral dynamics enables us to better understand the proliferation strategies of viruses, which contributes to the efficient control of virus transmission. Ours is the first study to analyze the stay-leave trade-off during the viral life cycle and the significance of the replication-release switching mechanism for viral proliferation.

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An extended and generalized framework for the calculation of metabolic intervention strategies based on minimal cut sets

by Philipp Schneider, Axel von Kamp, Steffen Klamt

The concept of minimal cut sets (MCS) provides a flexible framework for analyzing properties of metabolic networks and for computing metabolic intervention strategies. In particular, it has been used to support the targeted design of microbial strains for bio-based production processes. Herein we present a number of major extensions that generalize the existing MCS approach and broaden its scope for applications in metabolic engineering. We first introduce a modified approach to integrate gene-protein-reaction associations (GPR) in the metabolic network structure for the computation of gene-based intervention strategies. In particular, we present a set of novel compression rules for GPR associations, which effectively speedup the computation of gene-based MCS by a factor of up to one order of magnitude. These rules are not specific for MCS and as well applicable to other computational strain design methods. Second, we enhance the MCS framework by allowing the definition of multiple target (undesired) and multiple protected (desired) regions. This enables precise tailoring of the metabolic solution space of the designed strain with unlimited flexibility. Together with further generalizations such as individual cost factors for each intervention, direct combinations of reaction/gene deletions and additions as well as the possibility to search for substrate co-feeding strategies, the scope of the MCS framework could be broadly extended. We demonstrate the applicability and performance benefits of the described developments by computing (gene-based) Escherichia coli strain designs for the bio-based production of 2,3-butanediol, a chemical, that has recently received much attention in the field of metabolic engineering. With our extended framework, we could identify promising strain designs that were formerly unpredictable, including those based on substrate co-feeding.

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Projected impact of a reduction in sugar-sweetened beverage consumption on diabetes and cardiovascular disease in Argentina: A modeling study

by M. Victoria Salgado, Joanne Penko, Alicia Fernandez, Jonatan Konfino, Pamela G. Coxson, Kirsten Bibbins-Domingo, Raul Mejia

Background

Sugar-sweetened beverage (SSB) consumption is associated with obesity, diabetes, and hypertension. Argentina is one of the major consumers of SSBs per capita worldwide. Determining the impact of SSB reduction on health will inform policy debates.

Methods and findings

We used the Cardiovascular Disease Policy Model-Argentina (CVD Policy Model-Argentina), a local adaptation of a well-established computer simulation model that projects cardiovascular and mortality events for the population 35–94 years old, to estimate the impact of reducing SSB consumption on diabetes incidence, cardiovascular events, and mortality in Argentina during the period 2015–2024, using local demographic and consumption data. Given uncertainty regarding the exact amount of SSBs consumed by different age groups, we modeled 2 estimates of baseline consumption (low and high) under 2 different scenarios: a 10% and a 20% decrease in SSB consumption. We also included a range of caloric compensation in the model (0%, 39%, and 100%). We used Monte Carlo simulations to generate 95% uncertainty intervals (UIs) around our primary outcome measures for each intervention scenario. Over the 2015–2024 period, a 10% reduction in SSBs with a caloric compensation of 39% is projected to reduce incident diabetes cases by 13,300 (95% UI 10,800–15,600 [low SSB consumption estimate]) to 27,700 cases (95% UI 22,400–32,400 [high SSB consumption estimate]), i.e., 1.7% and 3.6% fewer cases, respectively, compared to a scenario of no change in SSB consumption. It would also reduce myocardial infarctions by 2,500 (95% UI 2,200–2,800) to 5,100 (95% UI 4,500–5,700) events and all-cause deaths by 2,700 (95% UI 2,200–3,200) to 5,600 (95% UI 4,600–6,600) for “low” and “high” estimates of SSB intake, respectively. A 20% reduction in SSB consumption with 39% caloric compensation is projected to result in 26,200 (95% UI 21,200–30,600) to 53,800 (95% UI 43,900–62,700) fewer cases of diabetes, 4,800 (95% UI 4,200–5,300) to 10,000 (95% UI 8,800–11,200) fewer myocardial infarctions, and 5,200 (95% UI 4,300–6,200) to 11,000 (95% UI 9,100–13,100) fewer deaths. The largest reductions in diabetes and cardiovascular events were observed in the youngest age group modeled (35–44 years) for both men and women; additionally, more events could be avoided in men compared to women in all age groups. The main limitations of our study are the limited availability of SSB consumption data in Argentina and the fact that we were only able to model the possible benefits of the interventions for the population older than 34 years.

Conclusions

Our study finds that, even under conservative assumptions, a relatively small reduction in SSB consumption could lead to a substantial decrease in diabetes incidence, cardiovascular events, and mortality in Argentina.

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Predicting obesity reduction after implementing warning labels in Mexico: A modeling study

by Ana Basto-Abreu, Rossana Torres-Alvarez, Francisco Reyes-Sánchez, Romina González-Morales, Francisco Canto-Osorio, M. Arantxa Colchero, Simón Barquera, Juan A. Rivera, Tonatiuh Barrientos-Gutierrez

Background

In October 2019, Mexico approved a law to establish that nonalcoholic beverages and packaged foods that exceed a threshold for added calories, sugars, fats, trans fat, or sodium should have an “excess of” warning label. We aimed to estimate the expected reduction in the obesity prevalence and obesity costs in Mexico by introducing warning labels, over 5 years, among adults under 60 years of age.

Methods and findings

Baseline intakes of beverages and snacks were obtained from the 2016 Mexican National Health and Nutrition Survey. The expected impact of labels on caloric intake was obtained from an experimental study, with a 10.5% caloric reduction for beverages and 3.0% caloric reduction for snacks. The caloric reduction was introduced into a dynamic model to estimate weight change. The model output was then used to estimate the expected changes in the prevalence of obesity and overweight. To predict obesity costs, we used the Health Ministry report of the impact of overweight and obesity in Mexico 1999–2023. We estimated a mean caloric reduction of 36.8 kcal/day/person (23.2 kcal/day from beverages and 13.6 kcal/day from snacks). Five years after implementation, this caloric reduction could reduce 1.68 kg and 4.98 percentage points (pp) in obesity (14.7%, with respect to baseline), which translates into a reduction of 1.3 million cases of obesity and a reduction of US$1.8 billion in direct and indirect costs. Our estimate is based on experimental evidence derived from warning labels as proposed in Canada, which include a single label and less restrictive limits to sugar, sodium, and saturated fats. Our estimates depend on various assumptions, such as the transportability of effect estimates from the experimental study to the Mexican population and that other factors that could influence weight and food and beverage consumption remain unchanged. Our results will need to be corroborated by future observational studies through the analysis of changes in sales, consumption, and body weight.

Conclusions

In this study, we estimated that warning labels may effectively reduce obesity and obesity-related costs. Mexico is following Chile, Peru, and Uruguay in implementing warning labels to processed foods, but other countries could benefit from this intervention.

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Changes in the amount of nutrient of packaged foods and beverages after the initial implementation of the Chilean Law of Food Labelling and Advertising: A nonexperimental prospective study

by Marcela Reyes, Lindsey Smith Taillie, Barry Popkin, Rebecca Kanter, Stefanie Vandevijvere, Camila Corvalán

Background

In June 2016, the first phase of the Chilean Food Labelling and Advertising Law that mandated front-of-package warning labels and marketing restrictions for unhealthy foods and beverages was implemented. We assess foods and beverages reformulation after this initial implementation.

Methods and findings

A data set with the 2015 to 2017 nutritional information was developed collecting the information at 2 time periods: preimplementation (T0: January–February 2015 or 2016; n = 4,055) and postimplementation (T1: January–February 2017; n = 3,025). Quartiles of energy and nutrients of concern (total sugars, saturated fats, and sodium, per 100 g/100 mL) and the proportion of products with energy and nutrients exceeding the cutoffs of the law (i.e., products “high in”) were compared pre- and postimplementation of the law in cross-sectional samples of products with sales >1% of their specific food or beverage groups, according to the Euromonitor International Database; a longitudinal subsample (i.e., products collected in both the pre- and postimplementation periods, n = 1,915) was also analyzed. Chi-squared, McNemar tests, and quantile regressions (simple and multilevel) were used for comparing T0 and T1. Cross-sectional analysis showed a significant decrease (T0 versus T1) in the proportion of product with any “high in” (from 51% [95% confidence interval (CI) 49–52] to 44% [95% CI 42–45]), mostly in food and beverage groups in which regulatory cutoffs were below the 75th percentile of the nutrient or energy distribution. Most frequent reductions were in the proportion of “high in” sugars products (in beverages, milks and milk-based drinks, breakfast cereals, sweet baked products, and sweet and savory spreads; from 80% [95% CI 73–86] to 60% [95% CI 51–69]) and in “high in sodium” products (in savory spreads, cheeses, ready-to-eat meals, soups, and sausages; from 74% [95% CI 69–78] to 27% [95% CI 20–35]). Conversely, the proportion of products “high in” saturated fats only decreased in savory spreads (p p Conclusions

Our results show that, after initial implementation of the Chilean Law of Food Labelling and Advertising, there was a significant decrease in the amount of sugars and sodium in several groups of packaged foods and beverages. Further studies should clarify how food reformulation will impact dietary quality of the population.

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