Reliable ligand discrimination in stochastic multistep kinetic proofreading: First passage time vs. product counting strategies.

Cellular signaling, crucial for biological processes like immune response and homeostasis, relies on specificity and fidelity in signal transduction to accurately respond to stimuli amidst biological noise. Kinetic proofreading (KPR) is a key mechanism enhancing signaling specificity through time-delayed steps, although its effectiveness is debated due to intrinsic noise potentially reducing signal fidelity. In this study, we reformulate the theory of kinetic proofreading (KPR) by convolving multiple intermediate states into a single state and then define an overall "processing" time required to traverse these states. This simplification allows us to succinctly describe kinetic proofreading in terms of a single waiting time parameter, facilitating a more direct evaluation and comparison of KPR performance across different biological contexts such as DNA replication and T cell receptor (TCR) signaling. We find that loss of fidelity for longer proofreading steps relies on the specific strategy of information extraction and show that in the first-passage time (FPT) discrimination strategy, longer proofreading steps can exponentially improve the accuracy of KPR at the cost of speed. Thus, KPR can still be an effective discrimination mechanism in the high noise regime. However, in a product concentration-based discrimination strategy, longer proofreading steps do not necessarily lead to an increase in performance. However, by introducing activation thresholds on product concentrations, can we decompose the product-based strategy into a series of FPT-based strategies to better resolve the subtleties of KPR-mediated product discrimination. Our findings underscore the importance of understanding KPR in the context of how information is extracted and processed in the cell.

Forecasting drug-overdose mortality by age in the United States at the national and county levels.

The drug-overdose crisis in the United States continues to intensify. Fatalities have increased 5-fold since 1999 reaching a record high of 108,000 deaths in 2021. The epidemic has unfolded through distinct waves of different drug types, uniquely impacting various age, gender, race, and ethnic groups in specific geographical areas. One major challenge in designing interventions and efficiently delivering treatment is forecasting age-specific overdose patterns at the local level. To address this need, we develop a forecasting method that assimilates observational data obtained from the CDC WONDER database with an age-structured model of addiction and overdose mortality. We apply our method nationwide and to three select areas: Los Angeles County, Cook County, and the five boroughs of New York City, providing forecasts of drug-overdose mortality and estimates of relevant epidemiological quantities, such as mortality and age-specific addiction rates.

A probabilistic model of relapse in drug addiction.

More than 60% of individuals recovering from substance use disorder relapse within one year. Some will resume drug consumption even after decades of abstinence. The cognitive and psychological mechanisms that lead to relapse are not completely understood, but stressful life experiences and external stimuli that are associated with past drug-taking are known to play a primary role. Stressors and cues elicit memories of drug-induced euphoria and the expectation of relief from current anxiety, igniting an intense craving to use again; positive experiences and supportive environments may mitigate relapse. We present a mathematical model of relapse in drug addiction that draws on known psychiatric concepts such as the "positive activation; negative activation" paradigm and the "peak-end" rule to construct a relapse rate that depends on external factors (intensity and timing of life events) and individual traits (mental responses to these events). We analyze which combinations and ordering of stressors, cues, and positive events lead to the largest relapse probability and propose interventions to minimize the likelihood of relapse. We find that the best protective factor is exposure to a mild, yet continuous, source of contentment, rather than large, episodic jolts of happiness.

Order-of-Mutation Effects on Cancer Progression: Models for Myeloproliferative Neoplasm.

In some patients with myeloproliferative neoplasms (MPN), two genetic mutations are often found: JAK2 V617F and one in the TET2 gene. Whether one mutation is present influences how the other subsequent mutation will affect the regulation of gene expression. In other words, when a patient carries both mutations, the order of when they first arose has been shown to influence disease progression and prognosis. We propose a nonlinear ordinary differential equation, the Moran process, and Markov chain models to explain the non-additive and non-commutative mutation effects on recent clinical observations of gene expression patterns, proportions of cells with different mutations, and ages at diagnosis of MPN. Combined, these observations are used to shape our modeling framework. Our key proposal is that bistability in gene expression provides a natural explanation for many observed order-of-mutation effects. We also propose potential experimental measurements that can be used to confirm or refute predictions of our models.

Overcompensation of transient and permanent death rate increases in age-structured models with cannibalistic interactions.

There has been renewed interest in understanding the mathematical structure of ecological population models that lead to overcompensation, the process by which a population recovers to a higher level after suffering a permanent increase in predation or harvesting. Here, we apply a recently formulated kinetic population theory to formally construct an age-structured single-species population model that includes a cannibalistic interaction in which older individuals prey on younger ones. Depending on the age-dependent structure of this interaction, our model can exhibit transient or steady-state overcompensation of an increased death rate as well as oscillations of the total population, both phenomena that have been observed in ecological systems. Analytic and numerical analysis of our model reveals sufficient conditions for overcompensation and oscillations. We also show how our structured population partial integrodifferential equation (PIDE) model can be reduced to coupled ODE models representing piecewise constant parameter domains, providing additional mathematical insight into the emergence of overcompensation.

Stochastic nucleosome disassembly mediated by remodelers and histone fragmentation.

We construct and analyze monomeric and multimeric models of the stochastic disassembly of a single nucleosome. Our monomeric model predicts the time needed for a number of histone-DNA contacts to spontaneously break, leading to dissociation of a non-fragmented histone from DNA. The dissociation process can be facilitated by DNA binding proteins or processing molecular motors that compete with histones for histone-DNA contact sites. Eigenvalue analysis of the corresponding master equation allows us to evaluate histone detachment times under both spontaneous detachment and protein-facilitated processes. We find that competitive DNA binding of remodeling proteins can significantly reduce the typical detachment time but only if these remodelers have DNA-binding affinities comparable to those of histone-DNA contact sites. In the presence of processive motors, the histone detachment rate is shown to be proportional to the product of the histone single-bond dissociation constant and the speed of motor protein procession. Our simple intact-histone model is then extended to allow for multimeric nucleosome kinetics that reveal additional pathways of disassembly. In addition to a dependence of complete disassembly times on subunit-DNA contact energies, we show how histone subunit concentrations in bulk solutions can mediate the disassembly process by rescuing partially disassembled nucleosomes. Moreover, our kinetic model predicts that remodeler binding can also bias certain pathways of nucleosome disassembly, with higher remodeler binding rates favoring intact-histone detachment.

The role of APOBEC3-induced mutations in the differential evolution of monkeypox virus.

Recent studies show that newly sampled monkeypox virus (MPXV) genomes exhibit mutations consistent with Apolipoprotein B mRNA Editing Catalytic Polypeptide-like3 (APOBEC3)-mediated editing compared to MPXV genomes collected earlier. It is unclear whether these single-nucleotide polymorphisms (SNPs) result from APOBEC3-induced editing or are a consequence of genetic drift within one or more MPXV animal reservoirs. We develop a simple method based on a generalization of the General-Time-Reversible model to show that the observed SNPs are likely the result of APOBEC3-induced editing. The statistical features allow us to extract lineage information and estimate evolutionary events.

Mathematical Characterization of Private and Public Immune Receptor Sequences.

Diverse T and B cell repertoires play an important role in mounting effective immune responses against a wide range of pathogens and malignant cells. The number of unique T and B cell clones is characterized by T and B cell receptors (TCRs and BCRs), respectively. Although receptor sequences are generated probabilistically by recombination processes, clinical studies found a high degree of sharing of TCRs and BCRs among different individuals. In this work, we use a general probabilistic model for T/B cell receptor clone abundances to define "publicness" or "privateness" and information-theoretic measures for comparing the frequency of sampled sequences observed across different individuals. We derive mathematical formulae to quantify the mean and the variances of clone richness and overlap. Our results can be used to evaluate the effect of different sampling protocols on abundances of clones within an individual as well as the commonality of clones across individuals. Using synthetic and empirical TCR amino acid sequence data, we perform simulations to study expected clonal commonalities across multiple individuals. Based on our formulae, we compare these simulated results with the analytically predicted mean and variances of the repertoire overlap. Complementing the results on simulated repertoires, we derive explicit expressions for the richness and its uncertainty for specific, single-parameter truncated power-law probability distributions. Finally, the information loss associated with grouping together certain receptor sequences, as is done in spectratyping, is also evaluated. Our approach can be, in principle, applied under more general and mechanistically realistic clone generation models.

Stochastic nucleosome disassembly mediated by remodelers and histone fragmentation.

We construct and analyze monomeric and multimeric models of the stochastic disassembly of a single nucleosome. Our monomeric model predicts the time needed for a number of histone-DNA contacts to spontaneously break, leading to dissociation of a non-fragmented histone from DNA. The dissociation process can be facilitated by DNA binding proteins or processing molecular motors that compete with histones for histone-DNA contact sites. Eigenvalue analysis of the corresponding master equation allows us to evaluate histone detachment times under both spontaneous detachment and protein-facilitated processes. We find that competitive DNA binding of remodeling proteins can significantly reduce the typical detachment time but only if these remodelers have DNA-binding affinities comparable to those of histone-DNA contact sites. In the presence of processive motors, the histone detachment rate is shown to be proportional to the product of the histone single-bond dissociation constant and the speed of motor protein procession. Our simple intact-histone model is then extended to allow for multimeric nucleosome kinetics that reveal additional pathways of disassembly. In addition to a dependence of complete disassembly times on subunit-DNA contact energies, we show how histone subunit concentrations in bulk solution can mediate the disassembly process by rescuing partially disassembled nucleosomes. Moreover, our kinetic model predicts that remodeler binding can also bias certain pathways of nucleosome disassembly, with higher remodeler binding rates favoring intact-histone detachment.

Order-of-mutation effects on cancer progression: models for myeloproliferative neoplasm.

In some patients with myeloproliferative neoplasms (MPN), two genetic mutations are often found, JAK2 V617F and one in the TET2 gene. Whether or not one mutation is present will influence how the other subsequent mutation affects the regulation of gene expression. When both mutations are present, the order of their occurrence has been shown to influence disease progression and prognosis. We propose a nonlinear ordinary differential equation (ODE), Moran process, and Markov chain models to explain the non-additive and non-commutative mutation effects on recent clinical observations of gene expression patterns, proportions of cells with different mutations, and ages at diagnosis of MPN. These observations consistently shape our modeling framework. Our key proposal is that bistability in gene expression provides a natural explanation for many observed order-of-mutation effects. We also propose potential experimental measurements that can be used to confirm or refute predictions of our models.

The role of APOBEC3-induced mutations in the differential evolution of monkeypox virus.

Recent studies show that newly sampled monkeypox virus (MPXV) genomes exhibit mutations consistent with Apolipoprotein B mRNA Editing Catalytic Polypeptide-like3 (APOBEC3)-mediated editing, compared to MPXV genomes collected earlier. It is unclear whether these single nucleotide polymorphisms (SNPs) result from APOBEC3-induced editing or are a consequence of genetic drift within one or more MPXV animal reservoirs. We develop a simple method based on a generalization of the General-Time-Reversible (GTR) model to show that the observed SNPs are likely the result of APOBEC3-induced editing. The statistical features allow us to extract lineage information and estimate evolutionary events.

Order-of-mutation effects on cancer progression: models for myeloproliferative neoplasm.

In some patients with myeloproliferative neoplasms (MPN), two genetic mutations are often found, JAK2 V617F and one in the TET2 gene. Whether or not one mutation is present will influence how the other subsequent mutation affects the regulation of gene expression. When both mutations are present, the order of their occurrence has been shown to influence disease progression and prognosis. We propose a nonlinear ordinary differential equation (ODE), Moran process, and Markov chain models to explain the non-additive and non-commutative mutation effects on recent clinical observations of gene expression patterns, proportions of cells with different mutations, and ages at diagnosis of MPN. These observations consistently shape our modeling framework. Our key proposal is that bistability in gene expression provides a natural explanation for many observed order-of-mutation effects. We also propose potential experimental measurements that can be used to confirm or refute predictions of our models.

Modeling and forecasting age-specific drug overdose mortality in the United States.

Drug overdose deaths continue to increase in the United States for all major drug categories. Over the past two decades the total number of overdose fatalities has increased more than fivefold; since 2013 the surge in overdose rates is primarily driven by fentanyl and methamphetamines. Different drug categories and factors such as age, gender, and ethnicity are associated with different overdose mortality characteristics that may also change in time. For example, the average age at death from a drug overdose has decreased from 1940 to 1990 while the overall mortality rate has steadily increased. To provide insight into the population-level dynamics of drug overdose mortality, we develop an age-structured model for drug addiction. Using an augmented ensemble Kalman filter (EnKF), we show through a simple example how our model can be combined with synthetic observation data to estimate mortality rate and an age-distribution parameter. Finally, we use an EnKF to combine our model with observation data on overdose fatalities in the United States from 1999 to 2020 to forecast the evolution of overdose trends and estimate model parameters.

Modeling and forecasting age-specific drug overdose mortality in the United States.

Drug overdose deaths continue to increase in the United States for all major drug categories. Over the past two decades the total number of overdose fatalities has increased more than five-fold; since 2013 the surge in overdose rates is primarily driven by fentanyl and methamphetamines. Different drug categories and factors such as age, gender, and ethnicity are associated with different overdose mortality characteristics that may also change in time. For example, the average age at death from a drug overdose has decreased from 1940 to 1990 while the overall mortality rate has steadily increased. To provide insight into the population-level dynamics of drug-overdose mortality, we develop an age-structured model for drug addiction. Using an augmented ensemble Kalman filter (EnKF), we show through a simple example how our model can be combined with synthetic observation data to estimate mortality rate and an age-distribution parameter. Finally, we use an EnKF to combine our model with observation data on overdose fatalities in the United States from 1999 to 2020 to forecast the evolution of overdose trends and estimate model parameters.

Impact of random and targeted disruptions on information diffusion during outbreaks.

Outbreaks are complex multi-scale processes that are impacted not only by cellular dynamics and the ability of pathogens to effectively reproduce and spread, but also by population-level dynamics and the effectiveness of mitigation measures. A timely exchange of information related to the spread of novel pathogens, stay-at-home orders, and other measures can be effective at containing an infectious disease, particularly during the early stages when testing infrastructure, vaccines, and other medical interventions may not be available at scale. Using a multiplex epidemic model that consists of an information layer (modeling information exchange between individuals) and a spatially embedded epidemic layer (representing a human contact network), we study how random and targeted disruptions in the information layer (e.g., errors and intentional attacks on communication infrastructure) impact the total proportion of infections, peak prevalence (i.e., the maximum proportion of infections), and the time to reach peak prevalence. We calibrate our model to the early outbreak stages of the SARS-CoV-2 pandemic in 2020. Mitigation campaigns can still be effective under random disruptions, such as failure of information channels between a few individuals. However, targeted disruptions or sabotage of hub nodes that exchange information with a large number of individuals can abruptly change outbreak characteristics, such as the time to reach the peak of infection. Our results emphasize the importance of the availability of a robust communication infrastructure during an outbreak that can withstand both random and targeted disruptions.

Fentanyl-driven acceleration of racial, gender and geographical disparities in drug overdose deaths in the United States.

We examine trends in drug overdose deaths by race, gender, and geography in the United States during the period 2013-2020. Race and gender specific crude rates were extracted from the final National Vital Statistics System multiple cause-of-death mortality files for several jurisdictions and used to calculate the male-to-female ratios of crude rates between 2013 and 2020. We established 2013-2019 temporal trends for four major drug types: psychostimulants with addiction potential (T43.6, such as methamphetamines); heroin (T40.1); natural and semi-synthetic opioids (T40.2, such as those contained in prescription pain-killers); synthetic opioids (T40.4, such as fentanyl and its derivatives) through a quadratic regression and determined whether changes in the pandemic year 2020 were statistically significant. We also identified which race, gender and states were most impacted by drug overdose deaths. Nationwide, the year 2020 saw statistically significant increases in overdose deaths from all drug categories except heroin, surpassing predictions based on 2013-2019 trends. Crude rates for Black individuals of both genders surpassed those for White individuals for fentanyl and psychostimulants in 2018, creating a gap that widened through 2020. In some regions, mortality among White persons decreased while overdose deaths for Black persons kept rising. The largest 2020 mortality statistic is for Black males in the District of Columbia, with a record 134 overdose deaths per 100,000 due to fentanyl, 9.4 times more than the fatality rate among White males. Male overdose crude rates in 2020 remain larger than those of females for all drug categories except in Idaho, Utah and Arkansas where crude rates of overdose deaths by natural and semisynthetic opioids for females exceeded those of males. Drug prevention, mitigation and no-harm strategies should include racial, geographical and gender-specific efforts, to better identify and serve at-risk groups.

Stochastic dynamics and ribosome-RNAP interactions in transcription-translation coupling.

Under certain cellular conditions, transcription and mRNA translation in prokaryotes appear to be "coupled," in which the formation of mRNA transcript and production of its associated protein are temporally correlated. Such transcription-translation coupling (TTC) has been evoked as a mechanism that speeds up the overall process, provides protection against premature termination, and/or regulates the timing of transcript and protein formation. What molecular mechanisms underlie ribosome-RNAP coupling and how they can perform these functions have not been explicitly modeled. We develop and analyze a continuous-time stochastic model that incorporates ribosome and RNAP elongation rates, initiation and termination rates, RNAP pausing, and direct ribosome and RNAP interactions (exclusion and binding). Our model predicts how distributions of delay times depend on these molecular features of transcription and translation. We also propose additional measures for TTC: a direct ribosome-RNAP binding probability and the fraction of time the translation-transcription process is "protected" from attack by transcription-terminating proteins. These metrics quantify different aspects of TTC and differentially depend on parameters of known molecular processes. We use our metrics to reveal how and when our model can exhibit either acceleration or deceleration of transcription, as well as protection from termination. Our detailed mechanistic model provides a basis for designing new experimental assays that can better elucidate the mechanisms of TTC.

Discrete stochastic models of SELEX: Aptamer capture probabilities and protocol optimization.

Antibodies are important biomolecules that are often designed to recognize target antigens. However, they are expensive to produce and their relatively large size prevents their transport across lipid membranes. An alternative to antibodies is aptamers, short (∼15-60 bp) oligonucleotides (and amino acid sequences) with specific secondary and tertiary structures that govern their affinity to specific target molecules. Aptamers are typically generated via solid phase oligonucleotide synthesis before selection and amplification through Systematic Evolution of Ligands by EXponential enrichment (SELEX), a process based on competitive binding that enriches the population of certain strands while removing unwanted sequences, yielding aptamers with high specificity and affinity to a target molecule. Mathematical analyses of SELEX have been formulated in the mass action limit, which assumes large system sizes and/or high aptamer and target molecule concentrations. In this paper, we develop a fully discrete stochastic model of SELEX. While converging to a mass-action model in the large system-size limit, our stochastic model allows us to study statistical quantities when the system size is small, such as the probability of losing the best-binding aptamer during each round of selection. Specifically, we find that optimal SELEX protocols in the stochastic model differ from those predicted by a deterministic model.

Modelling the impact of birth control policies on China's population and age: effects of delayed births and minimum birth age constraints.

We consider age-structured models with an imposed refractory period between births. These models can be used to formulate alternative population control strategies to China's one-child policy. By allowing any number of births, but with an imposed delay between births, we show how the total population can be decreased and how a relatively older age distribution can be generated. This delay represents a more 'continuous' form of population management for which the strict one-child policy is a limiting case. Such a policy approach could be more easily accepted by society. Our analyses provide an initial framework for studying demographics and how social constraints influence population structure.

A mathematical model of reward-mediated learning in drug addiction.

Substances of abuse are known to activate and disrupt neuronal circuits in the brain reward system. We propose a simple and easily interpretable dynamical systems model to describe the neurobiology of drug addiction that incorporates the psychiatric concepts of reward prediction error, drug-induced incentive salience, and opponent process theory. Drug-induced dopamine releases activate a biphasic reward response with pleasurable, positive "a-processes" (euphoria, rush) followed by unpleasant, negative "b-processes" (cravings, withdrawal). Neuroadaptive processes triggered by successive intakes enhance the negative component of the reward response, which the user compensates for by increasing drug dose and/or intake frequency. This positive feedback between physiological changes and drug self-administration leads to habituation, tolerance, and, eventually, to full addiction. Our model gives rise to qualitatively different pathways to addiction that can represent a diverse set of user profiles (genetics, age) and drug potencies. We find that users who have, or neuroadaptively develop, a strong b-process response to drug consumption are most at risk for addiction. Finally, we include possible mechanisms to mitigate withdrawal symptoms, such as through the use of methadone or other auxiliary drugs used in detoxification.