Replication Kinetics Research Articles

Evolutionary Game Analysis on Sharing Bicycles and Metro Strategies: Impact of Phasing out Subsidies for Bicycle–Metro Integration Model

The rapid development of sharing bicycles has facilitated the last mile of travel and provided new opportunities for the sustainable development of metro transportation. However, there is still insufficient literature on how to promote the bicycle–metro integration mode. This paper designs a bicycle–metro integrated model based on evolutionary game theory and explores the evolutionary mechanism of the sharing of bicycles connection system and metro system under the subsidy phasing out. The conditions for achieving different equilibrium states were discussed based on the replication dynamics equation. In order to prove the evolutionary game analysis, the system dynamics simulation model was used to reveal the effects of the cost factor, subsidy factor, reward, and penalty factors on the equilibrium of the integrated model. Moreover, the values of the influence factors that make the system reach the optimal equilibrium were obtained through sensitivity analysis. The results show that by reasonably adjusting the values of the parameters, sharing bicycles connection systems, metro systems and connection travelers can reach an equilibrium state where they are willing to cooperate. Subsidy phasing-out policies for travelers were key to promoting the equilibrium of the model. The unit price of shared bicycles has a greater impact on users, and the irregular parking ratio changes have a greater impact on the benefits of travelers compared to the benefits of the metro system. In order to promote bicycle–metro integration and enhance the attractiveness of metro transportation, policies designed for participants should be integrated with dynamic evolution.

Social dilemmas of sociality due to beneficial and costly contagion.

Levels of sociality in nature vary widely. Some species are solitary; others live in family groups; some form complex multi-family societies. Increased levels of social interaction can allow for the spread of useful innovations and beneficial information, but can also facilitate the spread of harmful contagions, such as infectious diseases. It is natural to assume that these contagion processes shape the evolution of complex social systems, but an explicit account of the dynamics of sociality under selection pressure imposed by contagion remains elusive. We consider a model for the evolution of sociality strategies in the presence of both a beneficial and costly contagion. We study the dynamics of this model at three timescales: using a susceptible-infectious-susceptible (SIS) model to describe contagion spread for given sociality strategies, a replicator equation to study the changing fractions of two different levels of sociality, and an adaptive dynamics approach to study the long-time evolution of the population level of sociality. For a wide range of assumptions about the benefits and costs of infection, we identify a social dilemma: the evolutionarily-stable sociality strategy (ESS) is distinct from the collective optimum-the level of sociality that would be best for all individuals. In particular, the ESS level of social interaction is greater (respectively less) than the social optimum when the good contagion spreads more (respectively less) readily than the bad contagion. Our results shed light on how contagion shapes the evolution of social interaction, but reveals that evolution may not necessarily lead populations to social structures that are good for any or all.

The κ-Deformed Calogero-Leyvraz Lagrangians and Applications to Integrable Dynamical Systems.

The Calogero-Leyvraz Lagrangian framework, associated with the dynamics of a charged particle moving in a plane under the combined influence of a magnetic field as well as a frictional force, proposed by Calogero and Leyvraz, has some special features. It is endowed with a Shannon "entropic" type kinetic energy term. In this paper, we carry out the constructions of the 2D Lotka-Volterra replicator equations and the N=2 Relativistic Toda lattice systems using this class of Lagrangians. We take advantage of the special structure of the kinetic term and deform the kinetic energy term of the Calogero-Leyvraz Lagrangians using the κ-deformed logarithm as proposed by Kaniadakis and Tsallis. This method yields the new construction of the κ-deformed Lotka-Volterra replicator and relativistic Toda lattice equations.

Genome-Wide CRISPR Screen Reveals Dependency of PPM1D-mutant Cells on DNA Repair

PPM1D (Protein Phosphatase Mg2+/Mn2+ Dependent 1D) is a protein phosphatase frequently mutated in clonal hematopoiesis (CH), therapy-related myeloid neoplasms (t-MN), and solid tumors. PPM1D is best known for its role as a negative regulator of the DNA damage response. Mutations in the terminal exon of PPM1D are gain-of-function and lead to a truncated, dominant form of PPM1D with preserved phosphatase activity. This stabilized, mutant protein leads to persistent dephosphorylation of PPM1D-targets including p53 and other key DNA damage response proteins. Our lab previously demonstrated that mutant Ppm1d hematopoietic stem and progenitor cells (HSPCs) outcompete their wild type (WT) counterparts in vivo following bone marrow transplantation and repeated cisplatin exposure. Given the prevalence of PPM1D mutations in CH and cancer, PPM1D is an attractive therapeutic target and ongoing efforts are underway to develop a small molecular inhibitor. We have sought to identify genetic vulnerabilities of PPM1D mutant cells by performing a whole-genome CRISPR/Cas9 dropout screen in PPM1D WT and mutant leukemia cell lines. Analysis of gene candidates that were essential for mutant cell survival, but not WT, showed an enrichment for genes involved in DNA repair including the Fanconi Anemia (FA) pathway genes. Given the role of PPM1D in the inhibition of p53 and the DNA damage response, we hypothesized that mutant PPM1D cells have increased genomic instability and therefore, rely on the non-canonical FA DNA repair pathway for survival. Indeed, we have found that PPM1D mutant cells harbored more single- and double-stranded DNA breaks as well as chromosomal aberrations both without external stressors and after cisplatin treatment compared to their WT counterparts. We have also found that PPM1D mutant cells exhibit significantly more FANCD2 foci at baseline compared to WT cells, suggesting increased activation of the FA pathway. In addition to interstrand crosslink repair, the FA pathway also plays a critical role in replication fork protection during replication stress to prevent the accumulation of toxic double-stranded breaks. To assess replication stress and kinetics in WT and PPM1D mutant cells, we performed DNA fiber assays to visualize nascent DNA synthesis at the single-molecule resolution. Surprisingly, in comparison to WT cells, PPM1D mutant cells had increased replication fork speed. These results demonstrate that PPM1D mutant cells have more genome instability and activate the FA pathway for DNA repair and replication progression. Increased DNA damage often results in increased mutagenesis and accumulation of single-base substitutions. To validate our cell line findings and determine if Ppm1d-mutant HSPCs harbor more mutations, we performed whole-genome sequencing on WT and Ppm1d HSPCs from single-cell derived methocult colonies. Surprisingly, we did not find a significant increase in the overall mutation burden in the Ppm1d-mutant colonies compared to WT. This suggests that while Ppm1d-mutant cells have more genomic instability, the fidelity of repair is maintained. This may be due to a delay in the recruitment of DNA repair factors. Overall, our work identifies genetic candidates that give rise to opportunities for synthetic lethal approaches to target PPM1D-mutant clonal expansion in patients with PPM1D-mutated malignancies and those at high-risk for developing t-MN.

The Cause and Consequence of Replication Stress in Adult T-Cell Leukemia

EP300 and its homolog CBP are transcriptional co-activators of genes involved in a broad range of cellular processes, including proliferation, differentiation, apoptosis and DNA repair. Inactivating mutations in both EP300 and CBP have been reported in developmental disorders, such as Rubinstein-Taybi Syndrome, and several hematological malignancies. Most recently, somatic hypermutations in EP300 (but not CBP) were identified in Adult T-cell leukemia/lymphoma (ATLL) patients, diagnosed in Northern America. The mechanistic contribution of EP300 dysregulation to NA-ATLL etiology is currently unknown. ATLL is caused by infection by the Human T-cell Lymphotrophic Virus Type-1 (HTLV-1), that is endemic to Japan, the Caribbean basin, South America, southern parts of North America, Eastern Europe and certain areas of Africa. Unlike patients diagnosed in Japan (J-ATLL), NA-ATLL patient display a severe case of chemo-refractory disease with very poor prognosis. While prominent differences in the transcriptional and epigenetic landscape, particularly the p300 mutational status, has been identified between J-ATLL and NA-ATLL patients, the mechanistic contribution of p300 dysregulation to disease severity is yet to be established. Studies have revealed that the independent inhibition of EP300 in human cells results in a unique transcriptional landscape, involving the differential expression of genes involved in regulating the cell cycle, DNA replication and DNA damage response. Here, we show that EP300-mutated ATLL cells display a protracted S-phase, extensive genomic instability, dysregulations in DNA replication and repair dynamics. Using a powerful locus specific single molecule assay and genome-wide DNA fiber analysis, we show that perturbed DNA replication in EP300-mutated ATLL cells is characterized by elevated origin firing, increased replisome pausing and prominent nucleolytic degradation of nascent DNA at collapsed forks. The elevated origin firing in the absence of EP300 is likely driven by the inherent endogenous increase in c-MYC expression, which has been previously seen in EP300-mutated MCF7 cells. The striking replication pausing, fork collapse and nascent strand degradation observed in EP300-deficient NA-ATLL cells results in the persistence of single stranded DNA (ssDNA) genome-wide, resulting in the hyperphosphorylation of RPA at Ser4/8. Inhibition of Mre11 nuclease partially rescued the ssDNA accumulation indicating a dysregulation in downstream mechanisms that restrain nuclease activity at stalled forks. Elevated endogenous genomic instability, observed in ATLL cells during the S-phase is exacerbated by EP300 deficiency, even in the absence of exogenous stress/damage. Analysis of the consequences of S-phase abnormalities and genomic instability revealed elevated micronuclei and cytosolic DNA in ATLL cells exposed to DNA damage. Preliminary studies evaluating the innate immune system activation (cGAS-STING-pIRF3) by immunoblotting, in response to stress, has led to some intriguing results. There is a clear separation in the ability of J-ATLL versus NA-ATLL cells in activating the innate immune system, a response that appears to be EP300 independent. These results raise the possibility of the contribution of a suppressed innate immune response, a phenomenon seen in many fast-progressing cancers, to the etiology of NA-ATLL. In addition to increasing our understanding of the mechanisms contributing to ATLL in general, the results from this study have helped identify new mechanism-based treatment regimens that could target the replicative and innate immune system vulnerabilities observed in North American ATLL patients.

General non-linear imitation leads to limit cycles in eco-evolutionary dynamics

Eco-evolutionary dynamics is crucial to understand how individuals’ behaviors and the surrounding environment interplay with each other. Typically, it is assumed that individuals update their behaviors via linear imitation function, i.e., the replicator dynamics. It has been proved that there cannot be limit circles in such eco-evolutionary dynamics. It suggests that eco-evolutionary dynamics alone is not sufficient to explain the widely observed fluctuating behavior in both the biological and social systems. We extrapolate from the linear imitation function to general imitation function, which can be non-linear. It is shown that the general imitation does not change the internal equilibrium and its local stability. It however leads to limit cycles, which are never present in classical eco-evolutionary dynamics. Moreover, the average cooperation level and average environment state agree with the first and the second component of the internal fixed point. Furthermore, we estimate the location of the emergent limit cycle. On the one hand, our results provide an alternative mechanism to make cooperators and defectors coexist in a periodic way in the “tragedy of the commons” and indicates the global eco-evolutionary dynamics is sensitive to the imitation function. Our work indicates that the way of imitation, i.e., the imitation function, is crucial in eco-evolutionary dynamics, which is not true for evolutionary dynamics with a static environment.

EXTH-77. TARGETING CD73 IN GBM SENSITIZES TUMORS TO ONCOLYTIC VIRUS THERAPY

Abstract Glioblastoma Multiforme (GBM) is the most aggressive malignant primary brain tumor and has abysmal 5-year overall survival. With the approval of oHSV Imlygic by FDA for metastatic melanoma and more recently, conditional approval of G47Δ, marketed by Daiichi Sankyo for GBM treatment in Japan, oncolytic viral therapy has emerged as a promising biological approach to treat solid tumors. Our laboratory has previously shown that oHSV expressing long isoform of PTEN (PTENα), HSV-P10, has faster kinetics of virus replication associated with enhanced killing of the glioma cells compared to control HSV. Additionally, HSVP-10 is known to increase mitochondrial membrane potential and cellular ATP production while stimulating anti-tumor immune responses in vivo. RNA sequencing of primary GBM cells infected with HSV-P10 shows altered metabolic pathways relative to control HSV infected cells. 13C metabolic flux analysis in uninfected and control or HSV-P10 infected primary GBM cells reveals that while HSV-P10 infection shuttles most of the glutamine towards citrate by reductive carboxylation of α-ketoglutarate resulting in faster replication of HSV-P10, simultaneously it increased glucose utilization and shuttling towards TCA cycle. This corroborates with enhanced mitochondrial activity leading to increased oxidative phosphorylation and increased cellular and extracellular ATP (eATP). eATP binds to purinergic receptors on tumor and immune cells and boosts anti-tumor immunity. However, the use of extracellular ATP in cancer therapy is limited owing to its short half-life and rapid hydrolysis by ectoenzymes CD39 and CD73 into immune-suppressing adenosine. CD73 carries out the conversion of AMP to adenosine, making it a key regulator of this pathway. Using mice with CD73 knocked out globally (CD73KO), we show that combination of CD73 inhibition with HSV-P10 imparts significant survival benefit compared to WT mice treated with HSV-P10. Our findings will further the understanding of oHSV therapy and the role of the ATP/adenosine in the tumor microenvironment.

Evolution of cooperation in multigame with environmental space and delay

Replicator dynamics is widely used in evolutionary game theory, however, most previous studies on replicator dynamics focus on single games and ignore multiple social dilemmas encountered by individuals in a population. This paper uses replicator dynamics to construct a multigame system with environmental space and delay based on three social dilemmas. For the non-delayed and delayed multigame systems, rich dynamics for stability, bistability, transcritical bifurcation, Hopf bifurcation, and the direction, stability and periodic variation of periodic solutions are comprehensively investigated. Accordingly, we use numerical simulations to assist in exploring the effects of multigame, environmental space, and time delay on strategic dynamics. The results show that large proportions of snowdrift game and stag hunt game are conducive to the prosperity of cooperators, and defectors are easy to survive when the proportion of prisoner’s dilemma is large. The cooperator gains the advantage of benefit distribution from environmental space, or the defector gets less benefit distribution as punishment, which will make pure cooperation the dominant strategy. Furthermore, environmental space can allow cooperation and defection to coexist oscillatingly. Interestingly, large delays reverse the coexistence of cooperation and defection to a situation dominated by the purely cooperative strategy.

Influenza A virus reassortment in mammals gives rise to genetically distinct within-host subpopulations

Influenza A virus (IAV) genetic exchange through reassortment has the potential to accelerate viral evolution and has played a critical role in the generation of multiple pandemic strains. For reassortment to occur, distinct viruses must co-infect the same cell. The spatio-temporal dynamics of viral dissemination within an infected host therefore define opportunity for reassortment. Here, we used wild type and synonymously barcoded variant viruses of a pandemic H1N1 strain to examine the within-host viral dynamics that govern reassortment in guinea pigs, ferrets and swine. The first two species are well-established models of human influenza, while swine are a natural host and a frequent conduit for cross-species transmission and reassortment. Our results show reassortment to be pervasive in all three hosts but less frequent in swine than in ferrets and guinea pigs. In ferrets, tissue-specific differences in the opportunity for reassortment are also evident, with more reassortants detected in the nasal tract than the lower respiratory tract. While temporal trends in viral diversity are limited, spatial patterns are clear, with heterogeneity in the viral genotypes detected at distinct anatomical sites revealing extensive compartmentalization of reassortment and replication. Our data indicate that the dynamics of viral replication in mammals allow diversification through reassortment but that the spatial compartmentalization of variants likely shapes their evolution and onward transmission.

An analysis of cross-channel return processing with return-freight insurance for live streaming platforms

Live streaming has witnessed a steady growth with advances in E-commerce, many offline manufacturers have adopted live streaming as a tool to improve online sales performance. However, one of the challenges faced by the manufacturer is return problem, such as cross-channel return, return cost sharing. To address this, offline manufacturers, nowadays, are adopting return-freight insurance. This study uses evolutionary game theory to investigate the dynamic evolution process for the decision of return-freight insurance and cross-channel return between the offline manufacturer and consumers in live streaming. In the modeling process, the payoff matrices and replicator dynamics equations between the manufacturer and consumers are constructed. The following two issues are addressed: who bears the cost of return-freight insurance and whether there is a stable strategy choice for the return mode of consumers. Further, the selection of an evolutionary stable strategy (ESS) for the entire system is explored. Numerical simulation is conducted to validate the effects of the parameters on the decisions of both players. The results show that the final ESS for the entire system can be changed by adjusting relevant parameters and the initial strategy combinations of both players. Thus, this study contributes by generalizing the application of return-freight insurance in trade processing and highlighting the importance of return-freight insurance in return behavior.

A study of the MAYV replication cycle: Correlation between the kinetics of viral multiplication and viral morphogenesis

Mayaro virus (MAYV) is mainly found in Central and South America and causes a febrile illness followed by debilitating arthritis and arthralgia similar to chikungunya virus (CHIKV). Infection leads to long-term sequelae with a direct impact on the patient's productive capacity, resulting in economic losses. Mayaro fever is a neglected disease due to the limited epidemiological data. In Brazil, it is considered a potential public health risk with the number of cases increasing every year. Most of our knowledge about MAYV biology is inferred from data obtained from other alphaviruses as well as more recent studies on MAYV. Here, we analyzed the kinetics of viral replication through standard growth curves, quantification of intracellular and extracellular particles, and RNA quantification. We compared transmission electron microscopy data during different stages of infection. This approach allowed us to establish a chronological order of events during MAYV replication and its respective timepoints including cell entry through clathrin-mediated endocytosis occurring at 15-30 min, genome replication at 2-3 h, morphogenesis at 4 hpi, and release at 4-6 hpi. We also present evidence of uncharacterized events such as ribosome reorganization as well as clusters of early viral precursors and release through exocytosis in giant forms. Our work sheds new and specific light on the MAYV replication cycle and may contribute to future studies on the field

Recovery of Siniperca chuatsi rhabdovirus from cloned cDNA.

Siniperca chuatsi rhabdovirus (SCRV) is an important pathogen that infects mandarin fish. A reverse genetics system is an important technical platform for virus research. In this study, the minigenome in which the enhanced green fluorescent protein gene is flanked by the viral genomic ends of SCRV and transcribed using a T7 promoter-terminator cassette was constructed. Co-transfection of the minigenome construct with SCRV-supporting plasmids of N, P, and L in BSRT7 cells resulted in the expression of the reporter gene. Transcription of a positive-strand RNA copy from cDNA of the SCRV genome along with the viral N, P, and L proteins resulted in the recovery of infectious SCRV in cells. Viral titre up to 108 PFU/ml was achieved. Recombinant SCRV was verified by the detection of a unique restriction site engineered into the SCRV genome. The phenotypes of the recombinant SCRV and the parental virus were evaluated by plaque size, replication kinetics in vitro, and pathogenicity in vivo. The recovered SCRV from cDNA showed similar phenotypes compared to the parental virus. The established reverse genetics system is of great significance and value for the functional genome study of SCRV and for laying a foundation for the development of the viral vector and SCRV vaccine.

The Impact of Environmental Protection Requirements on the Development of Green Animal Husbandry: An Evolutionary Game between Local Governments and Breeding Companies

The enhancement of green animal husbandry has a significant effect on carbon emissions, carbon neutrality, and ecological development. Promoting the production transformation of polluting enterprises has caught the attention of local governments, and breeding companies are faced with either maintaining current practices or green development. This study investigated the evolution of decision-making processes between local governments and breeding companies from the perspective of evolutionary game theory, offering an evolutionarily stable strategy (ESS) for both parties, based on replicator dynamics. Within the model, the static rewards and punishments were framed by conventional environmental protection requirements, and the dynamic rewards and punishments were based on stricter environmental standards. Numerical simulation and sensitivity analyses were then performed. We found that when environmental protection policy was not considered, no ESS emerged in the replicator dynamic system. When tightening of environmental protection policy was considered, the system spirally converged to a stable equilibrium point. Hence, more demanding environmental protection requirements facilitated the development of green animal husbandry. Reasonable reward and punishment mechanisms can achieve the goal of the green development of enterprises under the premise of reducing regulatory costs. This study provides guidance for optimizing government decision-making and promoting the green development of animal husbandry.

Modeling the Dynamics of Eukaryotic DNA Synthesis in Remembrance of Tunde Ogunnaike.

Two things Tunde loved were dynamics and probability. The work described herein combined them both, which explains why Tunde invariably asked me each time we talked how this work was proceeding. However, as I've come to appreciate as reminiscent of a surprisingly large amount of work in almost any researcher's career, I did not complete a peer-reviewed article on the matter while he could see it. We were broadly motivated by analysis of data for total DNA content in single cells, across thousands of cells. From such data one can estimate the proportions of cells in different phases of the cell cycle by fitting a mixture model for subpopulations of G0/G1 phase cells (1 relative copy of the genome), S phase cells (between 1 and 2 relative copies of the genome), and G2/M phase cells (2 relative copies of the genome). Given an asynchronously cycling population, Gaussian models are reasonable for the G0/G1 and G2/M subpopulations, but an appropriate functional form for the S-phase subpopulation was unclear. Since the probability of observing an S-phase cell is intimately related to the dynamics of DNA replication, we worked to derive a model for DNA replication dynamics from first principles, resulting in a closed-form, analytic expression for the dynamics of DNA synthesis. While quite arguably a somewhat superfluous effort, there is a certain satisfaction and academic beauty to modeling systems from a first-principles approach, and it can sometimes lead to unexpected scientific insights. Yet, while mathematically elegant, there was a fundamental issue with a key assumption that the so-called inter-origin distance distribution (distances between DNA replication initiation sites) was time-invariant. First, I present the model as developed previously. Then, to address the time-invariant inter-origin distance distribution issue, I provide a treatment of time-varying inter-origin distance distributions that, while mathematically simple, provides (i) mechanistic predictions for how all the DNA in a fertilized frog egg can be replicated "on time" despite some inter-origin distances initially exceeding the corresponding amount of allowable time and (ii) evidence that, based only on data from DNA content versus time and average inter-origin distances, somatic cell DNA is parsed into distinct regions whose replication is temporally separate.

Some examples for stable and historic behavior in replicator equations

The evolutionary dynamics of zero-sum and non zero-sum games under replicator equations could be drastically different from each other. In zero-sum games, heteroclinic cycles naturally occur whenever the species of the population supersede each other in cyclic fashion (like for the Rock–Paper–Scissors game). In this case, the highly erratic oscillations may cause the divergence of the time averages. In contrast, it is a common belief that all “reasonable” replicator equations of non-zero sum games satisfy “The Folk Theorem of Evolutionary Game Theory” which asserts that (i)a Nash equilibrium is a rest point; (ii)a stable rest point is a Nash equilibrium; (iii)a strictly Nash equilibrium is asymptotically stable; (iv)any interior convergent orbit evolves to a Nash equilibrium. In this paper, we propose two distinct classes of replicator equations generated by Schur-convex potential functions which exhibit two opposing phenomena: stable/predictable and historic/unpredictable behavior. In the latter case, the time averages of the orbit will slowly oscillate during the evolution of the system and do not converge to any limit. This will eventually cause the divergence of higher-order repeated time averages.

Eco-evolutionary dynamics of bimatrix games

Feedbacks between strategies and the environment are common in social-ecological, evolutionary ecological and even psychological-economic systems. Using common resources is always a dilemma for community members, like the tragedy of the commons. Here, we consider replicator dynamics with feedback-evolving games, where the pay-offs switch between two different matrices. Although each pay-off matrix on its own represents an environment where cooperators and defectors cannot coexist stably, we show that it is possible to design appropriate switching control laws and achieve persistent oscillations of strategy abundance. This result should help guide the widespread problem of population state control in microbial experiments and other social problems with eco-evolutionary feedback loops.

Longitudinal viral kinetic study of BK virus in renal transplant patients - A single-center study in Sri Lanka

BackgroundThere is a strong association between high-level BK viraemia and the development of BK virus-associated nephropathy. Therefore, understanding the kinetics of BK virus replication following transplantation would be helpful in predicting high-level viraemia and the development of BKVAN. ObjectivesThis study was aimed to assess the incidence of BKV infection and the BK viral kinetics among renal transplant recipients in their first year following the transplant. MethodsThis study was a retrospective descriptive study involving renal transplant recipients treated at National Hospital, Kandy, Sri Lanka. The patients were recruited from January 2018 to December 2019 and their demographic details and quantitative BKV PCR assay results were analysed during the first year following transplantation. Results297 patients were transplanted during the study period wherein, males predominated with 78.1% and 43.67 years old being the mean age (IQR: 35.50–53.0). The cumulative incidence of BK viraemia was 24.9% (n = 74). The mean age of the cohort with BK viraemia was 44.4 years (IQR: 36–54). Twenty percent (n = 13) of the female population had BKV viraemia, while 26.29% (n = 61) of the male population. Among patients with BK viraemia 12 had significant viraemia of 104IU/ml giving a cumulative incidence of significant viraemia was 4.04% and 10 of them (83.33%) had low levels of viraemia before showing significant viraemia. ConclusionThe presence of low-level viraemia in 83% of patients with significant viraemia proves the value of early routine screening to predict the development of significant BK viraemia and to take preventive measures.

Computation Offloading for Partitionable Applications in Dense Networks: An Evolutionary Game Approach

Mobile-edge computing (MEC) is a burgeoning paradigm that performs computation close to the network edge. In MEC, computation offloading is an essential mechanism to alleviate the limitations of user equipment (UEs) by offloading computation-intensive and latency-sensitive tasks to edge servers deployed in base stations (BSs). For the partitionable task model, multi-BS offloading makes the parallel execution of tasks possible, which can further reduce the execution delay. In this article, we consider a MEC architecture in a dense network with multiple BSs and multiple UEs and formulate a computation offloading problem for partitionable tasks with the goal of minimizing the task completion time. We jointly optimize the computation and radio resources considering the heterogeneity of UEs’ geographic locations and task types. Specifically, we construct a task offloading game using the evolutionary game theory (EGT). We apply replicator dynamics to model the offloading decision process and obtain the evolutionary equilibrium, which is proved to be an evolutionary stable strategy. Based on the theoretical analysis, we propose an EGT-based offloading mechanism to achieve a suboptimal solution in the case of limited numbers of subtasks. The extensive evaluation results demonstrate the effectiveness of our proposed mechanism compared with the centralized optimal solution.

Effect of E23G/K, F36V, N37T, E119D, and E199G polymerase acidic protein substitutions on the replication and baloxavir susceptibility of influenza B viruses

Baloxavir marboxil (baloxavir) is a highly effective, single-dose influenza therapeutic. Identification of molecular markers in the target polymerase acidic (PA) protein that can diminish baloxavir efficacy is an ongoing goal of the scientific community. In this study, we generated recombinant Victoria-lineage and Yamagata-lineage influenza B viruses (IBVs) containing 6 substitutions (E23G/K, F36V, N37T, E119D, and E199G) spanning the endonuclease domain of the PA. Although 5 of these PA substitutions negatively impacted in vitro polymerase activity and replication kinetics, particularly in the Victoria-lineage IBV background, viruses with E119D exhibited activity levels comparable to those of wild-type viruses. Moreover, only E119D moderately decreased the susceptibility of IBVs to baloxavir (resulting in ∼2.0-fold to 2.6-fold elevated EC50s); viruses with the other substitutions exhibited normal drug inhibition. These results show that E119D may reduce the baloxavir susceptibility of IBVs without compromising their replicative fitness. Overall, this study expands the molecular landscape of PA substitutions potentially affecting baloxavir efficacy against IBV.

Competition between Variable–Supply and Fixed–Supply Currencies

For one variable–supply currency in isolation, one player’s Cobb–Douglas utility depends on the current supply divided by the initial supply, multiplied by the inverse of the accumulative inflation/deflation. With equal weight assigned to both factors, money printing outweighs inflation, and money withdrawal outweighs deflation. The study design is to analyze how competition between one variable–supply and one fixed–supply currency impacts the player’s choice of currency. Applying the 1959–2021 US M2 money supply data and the 1635–2021 US inflation data, the player’s utility increases over time when assigning high weight to money printing/withdrawal and increases less or decreases overall when assigning high weight to inflation/deflation. With different player support for the two currencies, depending on each currency’s backing, convenience, confidentiality, transaction efficiency, financial stability, and security, replicator dynamics is used to determine the player’s volume fraction of transactions in each currency. Low, high, increasing, and decreasing support of a currency are analyzed. Each fraction may increase, decrease, be inverse U–shaped, U–shaped, and approach low or high levels over time. For example, high weight assigned to money printing may cause the player to eventually prefer the variable–supply currency unless the player supports the fixed–supply currency highly and increasingly.