Time-dependent Strategies Research Articles

Nano-flow cytometry unveils mitochondrial permeability transition process and multi-pathway cell death induction for cancer therapy

Mitochondrial permeability transition (mPT)-mediated mitochondrial dysfunction plays a pivotal role in various human diseases. However, the intricate details of its mechanisms and the sequence of events remain elusive, primarily due to the interference caused by Bax/Bak-induced mitochondrial outer membrane permeabilization (MOMP). To address these, we have developed a methodology that utilizes nano-flow cytometry (nFCM) to quantitatively analyze the opening of mitochondrial permeability transition pore (mPTP), dissipation of mitochondrial membrane potential (Δ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\Delta$$\\end{document}Ψm), release of cytochrome c (Cyt c), and other molecular alternations of isolated mitochondria in response to mPT induction at the single-mitochondrion level. It was identified that betulinic acid (BetA) and antimycin A can directly induce mitochondrial dysfunction through mPT-mediated mechanisms, while cisplatin and staurosporine cannot. In addition, the nFCM analysis also revealed that BetA primarily induces mPTP opening through a reduction in Bcl-2 and Bcl-xL protein levels, along with an elevation in ROS content. Employing dose and time-dependent strategies of BetA, for the first time, we experimentally verified the sequential occurrence of mPTP opening and Δ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\Delta$$\\end{document}Ψm depolarization prior to the release of Cyt c during mPT-mediated mitochondrial dysfunction. Notably, our study uncovers a simultaneous release of cell-death-associated factors, including Cyt c, AIF, PNPT1, and mtDNA during mPT, implying the initiation of multiple cell death pathways. Intriguingly, BetA induces caspase-independent cell death, even in the absence of Bax/Bak, thereby overcoming drug resistance. The presented findings offer new insights into mPT-mediated mitochondrial dysfunction using nFCM, emphasizing the potential for targeting such dysfunction in innovative cancer therapies and interventions.

Optimal control and bifurcation analysis of SEIHR model for COVID-19 with vaccination strategies and mask efficiency

Abstract In this article, we present a susceptible, exposed, infected, hospitalized and recovered compartmental model for COVID-19 with vaccination strategies and mask efficiency. Initially, we established the positivity and boundedness of the solutions to ensure realistic predictions. To assess the epidemiological relevance of the system, an examination is conducted to ascertain the local stability of the endemic equilibrium and the global stability across two equilibrium points are carried out. The global stability of the system is demonstrated using Lyapunov’s direct method. The disease-free equilibrium is globally asymptotically stable when the basic reproduction number (BRN) is less than one, whereas the endemic equilibrium is globally asymptotically stable when BRN is greater than one. A sensitivity analysis is performed to identify the influential factors in the BRN. The impact of various time-dependent strategies for managing and regulating the dynamic transmission of COVID-19 is investigated. In this study, Pontryagin’s maximum principle for optimal control analysis is used to identify the most effective strategy for controlling the disease, including single, coupled, and threefold interventions. Single-control interventions reveal physical distancing as the most effective strategy, coupled measures reduce exposed populations, and implementing all controls reduces susceptibility and infections.

Developing computationally efficient optimal control strategies to eradicate Rubella disease

The threat of Rubella virus disease looms large, posing significant risks to public health and emphasizing the urgent need for comprehensive prevention, control, and awareness strategies. We conducted an extensive analysis of a newly developed SEITR deterministic model for the lethal Rubella virus disease. The main objective of our study is to gain deep insights into the disease dynamics and devise an optimal control strategy for the model, utilizing vaccination and treatment as preventive measures. We employed various mathematical techniques to establish the positivity and bounded nature of solutions. The value of threshold parameter is computed using the next-generation method to anticipate future dynamical behavior of the epidemic. The local and global stability of the equilibrium points was successfully assessed. Additionally, we utilized the well-known Non-Standard Finite Difference (NSFD) method to obtain numerical solutions for the Rubella model. A numerical analysis is carried out to assess the efficacy of a constant treatment strategy, and the results are presented through graphical illustrations. The developed model is subjected to sensitivity analysis and the most sensitive parameters are identified. In addition, the bifurcation nature of the model is examined. Subsequently, an optimal control problem is introduced for the model, aiming to determine the best time-dependent strategies for treatment and vaccination. The main goal is to reduce the number of individuals infected within the human population and the cost of controls. Designed optimal control problem and its corresponding optimality conditions of Pontryagin type have been derived. An important aspect of this study is the utilization of the NSFD method, implemented backward in time, to solve the optimal control problem, as opposed to other conventional methods. Numerical simulations were carried out to assess the impact of the applied controls on the dynamics of all classes, both before and after optimization.

Circadian Clock-Controlled Checkpoints in the Pathogenesis of Complex Disease.

The circadian clock coordinates physiology, metabolism, and behavior with the 24-h cycles of environmental light. Fundamental mechanisms of how the circadian clock regulates organ physiology and metabolism have been elucidated at a rapid speed in the past two decades. Here we review circadian networks in more than six organ systems associated with complex disease, which cluster around metabolic disorders, and seek to propose critical regulatory molecules controlled by the circadian clock (named clock-controlled checkpoints) in the pathogenesis of complex disease. These include clock-controlled checkpoints such as circadian nuclear receptors in liver and muscle tissues, chemokines and adhesion molecules in the vasculature. Although the progress is encouraging, many gaps in the mechanisms remain unaddressed. Future studies should focus on devising time-dependent strategies for drug delivery and engagement in well-characterized organs such as the liver, and elucidating fundamental circadian biology in so far less characterized organ systems, including the heart, blood, peripheral neurons, and reproductive systems.

Dynamic load shifting for the abatement of GHG emissions, power demand, energy use, and costs in metropolitan hybrid wastewater treatment systems

The installation of satellite water resource recovery facilities (WRRFs) has strengthened the ability to provide cheap and reliable recycled water to meet the increasing water demand of expanding cities. As a result, recent studies have attempted to address the problem of how to optimally integrate satellite systems with other sectors of the urban sphere, such as the local economy, the power supply, and the regional carbon footprint. However, such studies are merely based on the spatial domain, thus neglecting potential time-dependent strategies that could further improve the sustainability of metropolitan water systems. Therefore, in this study a new conceptual framework is proposed for the dynamic management of hybrid systems comprised of both centralized and satellite WRRFs. Furthermore, a novel set of integrated real-time control (RTC) strategies are considered to analyze three different scenarios: 1) demand response, 2) flow equalization of the centralized WRRF and 3) reduction of greenhouse gas emissions. Data from a case study in California is used to develop an integrated dynamic model of a system of 8 facilities. Our results show that by dynamically shifting the dry-weather influent wastewater flows between hydraulically connected WRRFs, a reduction in power demand (up to 25%), energy use (4%), operating costs (8.5%) and indirect carbon emissions (4.5%) can be achieved. Therefore, this study suggests that a certain degree of hydraulic interconnection coupled with dynamic load-shifting strategies, can broaden the operational flexibility and overall sustainability of hybrid WRRF systems.

A mathematical modeling of rabies with vaccination and culling

Rabies is a fatal contagious disease but preventable. It is a major public health problem in developing countries. Most of the rabies deaths around the world are caused by dog bites. If a person does not receive appropriate treatment after being exploded to rabies, the virus can damage the brain resulting in death. Since most of the deaths due to the transmission from dogs to humans, therefore, in this study, we will formulate a mathematical model that describes the dynamics of rabies virus transmission between dogs and humans. Also, we conduct both epidemic and endemic analysis. Optimal control theory is applied to seek cost-effective solutions for time-dependent vaccination and culling strategies against rabies outbreaks. Our results show that using vaccination during rabies outbreaks at the very beginning of the onset and culling infected dogs can reduce the number of infections significantly.

Time-dependent Cues Encode the Minimum Exploration Time in Discriminating Naturalistic Compliances.

Our perception of compliance is informed by multi-dimensional tactile cues. Compared with stationary cues at terminal contact, time-dependent cues may afford optimal efficiency, speed, and fidelity. In this work, we investigate strategies by which temporal cues may encode compliances by modulating our exploration time. Two potential perceptual strategies are considered, inspired by memory representations within and between explorations. For either strategy, we introduce a unique computational approach. First, a curve similarity analysis, of accumulating touch force between sequentially explored compliances, generates a minimum time for discrimination. Second, a Kalman filtering approach derives a recognition time from progressive integration of stiffness estimates over time within a single exploration. Human-subjects experiments are conducted for both single finger touch and pinch grasp. The results indicate that for either strategy, by employing a more natural pinch grasp, time-dependent cues afford greater efficiency by reducing the exploration time, especially for harder objects. Moreover, compared to single finger touch, pinch grasp improves discrimination rates in judging plum ripeness. The time-dependent strategies as defined here appear promising, and may tie with the time-scales over which we make perceptual judgments.

An EOQ model for non-instantaneous deteriorating items with time-dependent quadratic demand and two-level pricing strategies under trade credit policy.

An EOQ model for non-instantaneous deteriorating items with time-dependent quadratic demand and two-level pricing strategies under trade credit policy.

Optimal deployment for anti-submarine operations with time-dependent strategies

In this paper, we consider the optimal deployment of multiple assets in anti-submarine warfare (ASW) operations with time-dependent strategies. We model this as a zero-sum game that takes place over a finite time horizon. An agent, representing multiple assets, in an ASW operation, decides on the allocation of these assets (e.g., one or more frigates and helicopters) to prevent an intruder, an enemy submarine, from attacking a moving high-value unit (HVU), e.g., a tanker ship. Hereby, the agent aims to prevent an intruder, an enemy submarine, from attacking a moving HVU, e.g., a tanker ship. The intruder is deciding on a route that minimizes the detection probability given the agent’s strategy. We first consider a game model where a part of the agent’s strategy, namely the complete strategy of a frigate, is known to the intruder; and second, we consider a sequential game approach where the exact location of the frigate becomes known to the intruder at the start of each time interval. For both approaches, we construct (integer) linear programs, give complexity results, and use an algorithmic approach to determine optimal strategies. Finally, we explore the added value of this approach in comparison to a traditional ASW simulation model.

Couple-Group Consensus for Multiagent Systems via Time-Dependent Event-Triggered Control

This paper investigates couple-group consensus problems for multiagent first-order and second-order systems. Several consensus protocols are proposed based on the time-dependent distributed event-triggered control. For the case of no communication delays, the time-dependent event-triggered strategies are applied to couple-group consensus problems. Based on the matrix theory, algebraic conditions for couple-group consensus are established. For the system with communication delays, based on event-triggered strategies, a Lyapunov-Krasovskii functional is constructed to prove the input-to-state stability of the systems. Moreover, Zeno behavior is excluded. Finally, numeral examples are given to illustrate the effectiveness of these results.

The quality of cortical network function recovery depends on localization and degree of axonal demyelination

Myelin loss is a severe pathological hallmark common to a number of neurodegenerative diseases, including multiple sclerosis (MS). Demyelination in the central nervous system appears in the form of lesions affecting both white and gray matter structures. The functional consequences of demyelination on neuronal network and brain function are not well understood. Current therapeutic strategies for ameliorating the course of such diseases usually focus on promoting remyelination, but the effectiveness of these approaches strongly depends on the timing in relation to the disease state. In this study, we sought to characterize the time course of sensory and behavioral alterations induced by de- and remyelination to establish a rational for the use of remyelination strategies. By taking advantage of animal models of general and focal demyelination, we tested the consequences of myelin loss on the functionality of the auditory thalamocortical system: a well-studied neuronal network consisting of both white and gray matter regions. We found that general demyelination was associated with a permanent loss of the tonotopic cortical organization in vivo, and the inability to induce tone-frequency-dependent conditioned behaviors, a status persisting after remyelination. Targeted, focal lysolecithin-induced lesions in the white matter fiber tract, but not in the gray matter regions of cortex, were fully reversible at the morphological, functional and behavioral level. These findings indicate that remyelination of white and gray matter lesions have a different functional regeneration potential, with the white matter being able to regain full functionality while cortical gray matter lesions suffer from permanently altered network function. Therefore therapeutic interventions aiming for remyelination have to consider both region- and time-dependent strategies.

Optimal control solutions to sodic soil reclamation

We study the reclamation process of a sodic soil by irrigation with water amended with calcium cations. In order to explore the entire range of time-dependent strategies, this task is framed as an optimal control problem, where the amendment rate is the control and the total rehabilitation time is the quantity to be minimized. We use a minimalist model of vertically averaged soil salinity and sodicity, in which the main feedback controlling the dynamics is the nonlinear coupling of soil water and exchange complex, given by the Gapon equation. We show that the optimal solution is a bang–bang control strategy, where the amendment rate is discontinuously switched along the process from a maximum value to zero. The solution enables a reduction in remediation time of about 50%, compared with the continuous use of good-quality irrigation water. Because of its general structure, the bang–bang solution is also shown to work for the reclamation of other soil conditions, such as saline–sodic soils. The novelty in our modeling approach is the capability of searching the entire “strategy space” for optimal time-dependent protocols. The optimal solutions found for the minimalist model can be then fine-tuned by experiments and numerical simulations, applicable to realistic conditions that include spatial variability and heterogeneities.

Bounded memory Folk Theorem

We show that the Folk Theorem holds for n-player discounted repeated games with bounded memory (recall) strategies. Our main result demonstrates that any payoff profile that exceeds the pure minmax payoff profile can be approximately sustained by a pure strategy finite memory subgame perfect equilibrium of the repeated game if the players are sufficiently patient. We also show that the result can be extended to any payoff profile that exceeds the mixed minmax payoff profile if players can randomize at each stage of the repeated game. Our results requires neither time-dependent strategies, nor public randomization, nor any communication. The type of strategies we employ to establish our result turn out to have new features that may be important in understanding repeated interactions.

Practical Implementation of Evidence-Based Dentistry Into Daily Dental Practice Through a Short Time Dependent Searching Method

IntroductionDespite the fact that the benefits of implementation of Evidence-Based Dentistry (EBD) into clinical practice is increasingly being highlighted, there are still clear limitations in its implementation into daily dental practice. One potentially important barrier to effective implementation into practice is the perception of EBD as a time-consuming process. The aim of the present study is to increase the familiarity of dental practitioners with the benefits of different time-dependent ‘practical’ search strategies important to EBD using a clinical question from the field of dental implantology as an example. Materials and MethodsThe PICO (population, intervention, comparison, outcome) question used in this study was: “In young adults with anterior single-tooth implant what is the effect of immediate or delayed loading on success?” A bibliographic search according to the Haynes 5S pyramid, together with 3 different time-dependent strategies (5-min, 30-min and more than 60-min), were applied. ResultsBoth the Haynes 5S Pyramid and time-dependent search strategies revealed promising results for enhancing decision-making for determining the feasibility of immediate or conventional loading of anterior single dental implants. Results clearly showed that selection of the loading protocol would be case (patient)-specific and also indicated high primary implant stability and bone quality as the most important prerequisites for a successful immediate/early loading. From among the 3 different time-dependent strategies (5 min, 30 min and more than 60 min), the 60+ min search results were quite comparable with the Haynes pyramid search results. ConclusionIt is likely that the different time-dependent search strategies may have the potential to support the clinical decision making process and may improve the implementation of EBD into daily dental practice. Increased time spent searching naturally seems to increase the extent of this support. However, even with short time-dependent searches, busy dental clinicians may get an improved idea/opinion regarding a clinical question.

Distributed event‐triggered consensus in multi‐agent systems with non‐linear protocols

In this study, the distributed event-triggered consensus problem in multi-agent systems with non-linear protocols is discussed. In the proposed strategies, each agent adopts a local control based on a combination of non-linear functions of relative states, and the couplings among agents are not necessarily symmetric and constant. By using a graph-theoretical-reasoning based Lyapunov function, the authors present two kinds of distributed event-triggered strategies, namely state-dependent and time-dependent strategies. Through the transmission of states at discrete instants, the former can simultaneously reduce the updates of both control and communication. By virtue of global information such as the path between arbitrary two agents, the latter can decide the updating time sequence for each agent by its own state and a given time-dependent function. In both cases, a positive lower bound for inter-event times can be found such that the Zeno behaviour is eliminated. Numerical simulations show the effectiveness of the above two strategies.

Abstract WP280: Use of Strategies to Improve Door-to-Needle Times with Tissue Plasminogen Activator in Acute Ischemic Stroke by US Hospitals: Findings from the Target: Stroke Survey

Background: The benefits of intravenous tissue-plasminogen activator (tPA) in acute ischemic stroke are time-dependent and several strategies have been reported to be associated with more rapid door-to-needle (DTN) times. However, the extent to which hospitals are utilizing these strategies has not been well studied. Methods: We surveyed 304 hospitals joining Target: Stroke regarding their baseline use of strategies to reduce door-to-needle times in the 1/2008-2/2010 timeframe (prior to the initiation of Target: Stroke). The survey was developed based on literature review and expert consensus for strategies identified as being associated with shorter DTN times and further refined after pilot testing. Categorical responses are reported as frequencies. Results: Hospitals participating in the survey were 50% academic, median 163 (IQR 106-247) ischemic stroke admissions per year, median 10 (IQR 6-17) tPA treated patients per year, and had median 79 minute (IQR 71-89) DTN times. By survey, 214 of 304 hospitals (70%) reported initiating or revising strategies to reduce DTN times in the prior 2 years. Reported use of the different strategies varied in frequency, with use of ischemic stroke critical pathways, CT scanner located in the Emergency Department, and tPA being stored in the Emergency Department being the strategies least frequently employed (Table). As part of Target: Stroke participation, 279 of 304 hospitals (91.5%) indicated they planned to have a dedicated team focused on reducing DTN times. Conclusions: While most US hospitals participating in this survey report use of the strategies to improve the timeliness of tPA administration for acute ischemic stroke, significant variation exists. Further research is needed to understand which of these strategies are most effective in improving acute ischemic stroke care.

Stopping Inflations, Big and Small

Previous studies of disinflation work with models in which firms use time-dependent strategies, changing nominal prices at intervals of fixed length. These models may be criticized for failing to allow pricing behavior to adjust after a large shift in policy regime. Consequently, this paper develops a model that allows firms to adopt strategies that are partially state-dependent, changing nominal prices whenever they deviate sufficiently from their target values. The paper uses this model to examine how the welfare costs and benefits of disinflation vary with the initial inflation rate and the speed of disinflation.

Continuous-time evolutionary stock and bond markets with time-dependent strategies

This paper develops a general continuous-time evolutionary finance model with time-dependent strategies based on evolutionary game theory. We show that the continuous model, which is a limit of a general discrete model, is well-defined and if there exists one completely diversified strategy in the market, then there is no sudden bankruptcy. We study in detail, a deterministic evolutionary bond market and certify that a bond market is evolutionary stable if and only if the total returns across all assets are the same. By this way, we derive an explicit expression for the bond valuation and provide an approach to recover the benchmark interest rate from an effective bond market. Key words: Evolutionary finance, evolutionary bond market, continuous-time model, time-dependent strategies.

Continuous-Time Evolutionary Stock and Bond Markets with Time-Dependent Strategies

This paper develops a general continuous-time evolutionary finance model with time-dependent strategies. It is shown that the continuous model, which is a limit of a general discrete model, is well-defined and if there exists one completely diversified strategy in the market, then there is no sudden bankruptcy. After that a deterministic evolutionary bond market is studied in detail. It is certified that a bond market is evolutionary stable, which is equal to arbitrage-free if and only if the total returns defined in this paper across all the assets are the same, or each bond is evaluated by an improper integral in which the integrand is a discounted value of the dividend payoff with the discount rate being market consumption parameter. Last an approach to compute the benchmark interest rate is provided.

DYNAMIC PORTFOLIO SELECTION UNDER CAPITAL-AT-RISK WITH NO SHORT-SELLING CONSTRAINTS

Portfolio optimization under downside risk is of crucial importance to asset managers. In this article we consider one such particular measure given by the notion of Capital at Risk (CaR), closely related to Value at Risk. We consider portfolio optimization with respect to CaR in the Black-Scholes setting with time dependent parameters and investment strategies, i.e., continuous-time portfolio optimization. We review the results from our previous work in unconstrained portfolio optimization, and then investigate and solve the corresponding problems with the additional constraint of no-short-selling. Analytical formulae are derived for the optimal strategies, and numerical examples are presented.