Biology subjects

Esmaeili, S.

Publications and source records attributed to Esmaeili, S..

5 recordsLinked to original sources

bioRxiv2025

Plasma nirmatrelvir and molnupiravir concentrations required for inhibition of SARS CoV-2 replication differ between rhesus macaques and humans

Early during the COVID-19 pandemic, non-human primate (NHP) infection models emerged as highly useful tools for preclinical screening of antiviral drugs. However, it is uncertain whether NHP models can be used to precisely inform optimal dosing in humans. We previously established and validated mathematical models which were fit to SARS-CoV-2 viral loads from human clinical trials. These models identified that plasma drug concentrations required to inhibit viral replication by 50% in humans (in vivo EC50) differ substantially from in vitro EC50 estimates in cell culture systems. Here we apply models to sequential viral load data from SARS-CoV-2 infected rhesus macaques (RM) that were untreated or treated with nirmatrelvir/ritonavir, molnupiravir, or both drugs. We identify that equivalent plasma drug concentrations correspond to greater antiviral potency in lungs compared to nasal passages for nirmatrelvir and molnupiravir. Average nirmatrelvir antiviral efficacy in RM (30% in nasal passages and 46% in lungs) was estimated to be less than in humans (82%) due to shorter plasma drug half-life. Molnupiravir efficacy in RM (95% in nasal and 99% in lungs) is estimated to be similar to efficacy in humans against omicron variants. Our model estimates that 10-fold higher plasma nirmatelvir concentrations are needed in humans versus RM to achieve 50% reduction in viral replication, whereas 20-fold lower plasma molnupiravir concentrations are needed. Our results suggest that dose optimization in humans based on modeling of NHP viral loads is limited by drug-specific differences in pharmacokinetic, pharmacodynamic and virologic profiles, and that data from human phase 1 and 2 trials is better suited for this task.

systems biology↗

bioRxiv2025

A bipartite, mutation-tolerant NLS regulates interaction of ΔNp63α with importin alpha, nuclear transport and transcriptional activity

{Delta}Np63 is a master regulator of epithelial development, driving the expansion of progenitor cells in stratified epithelia. Mutations in {Delta}Np63 are linked to squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs), as well as to ectodermal dysplasia syndromes such as ectrodactyly-ectodermal dysplasia-clefting (EEC) and ankyloblepharon-ectodermal dysplasia-clefting (AEC). Although {Delta}Np63 functions as a nuclear transcription factor, the mechanisms underlying its nuclear import remain incompletely understood. By combining imaging, biochemical, structural and functional assays, we have thoroughly characterized {Delta}Np63 nuclear import, as mediated by the importin (IMP) /{beta}1 heterodimer. We also show here that {Delta}Np63 has evolved a peculiar strategy to ensure mutation tolerant nuclear localization, which is essential for DNA binding and transcriptional regulation. Despite a canonical bipartite NLS formed by two stretches of basic amino acids was identified between the DNA binding and oligomerization domains, each of them in sufficient to bind both IMP binding sites upon homodimerization. Therefore, in contrast to most known bipartite NLSs, only simultaneous substitution of both basic stretches of amino acids ablated nuclear localization, interaction with IMP, and decreased transcriptional activity. Since several {Delta}Np63 isoforms which lack the N-terminal basic stretch of amino acids have been described, and a number of mutations in the {Delta}Np63 NLS region have been identified in the Genome Aggregation Database, {Delta}Np63 has specifically evolved to tolerate mutations in its NLS without significantly compromising its ability to localize in the nucleus. GRAPHICAL ABSTRACT

cell biology↗

bioRxiv2025

Intracellular and extracellular dynamics of herpes simplex virus 1 DNA and infectious particles in epithelial and neuronal cells

Herpes simplex virus 1 (HSV-1) infection of epithelial cells is lytic, while infection of neurons typically results in long-term latency. However, the rates at which HSV-1 replicates and spreads in epithelial cells versus neurons under low and high multiplicity of infection (MOI) conditions remain undefined. Identifying these rates requires the application of mathematical models to carefully designed viral kinetic experiments. It is also critical to differentiate the dynamics of infectious viral particles versus viral DNA, as both quantities are routinely measured in in vitro experiments and human studies using plaque assays and polymerase chain reactions, respectively. Here, we developed mechanistic mathematical models to describe HSV-1 dynamics after infection of epithelial Vero cells and neuronal N2A cells, at high (3) and low (0.01) MOI. Our model recapitulates the dynamics of cell-free and cell-associated viral DNA and plaque-forming units (PFU). In epithelial cells, the model describes a pre-productive eclipse phase with a mean duration of 10.9 and 12.8 hours prior to HSV DNA replication and PFU production, respectively. Cells exited the eclipse phase as early and late as 2.5 and 32 hours, respectively. Infected cells produced a single PFU for every 224 HSV DNA genomes. PFU egressed at a constant rate, whereas the HSV DNA egress rate increased over time, before saturating at a 15 times higher rate. Under low relative to high MOI conditions, Vero cells spent 7 hours longer in the eclipse phase, had a 12-hour delay prior to egress, and had a longer mean duration of productive infection (14 versus 3.5-hour half-life). Secondary epithelial cell infection in low MOI experiments was overwhelmingly due to cell-to-cell viral spread and originated from a small number of early-producer cells. Neuronal cells produced viruses at a 5-fold lower rate and had a longer (mean: 42 hours) and more variable eclipse phase, with some neurons remaining in eclipse for more than a week. Our results highlighted large differences in HSV egress rates, as well as infected cell eclipse phase duration and death rates, in epithelial cells versus neurons during low and high MOI infection. The observed viral dynamics in neurons reflect a balance between active replication and latency.

microbiology↗

bioRxiv2020

Dynamical Ising model of spatially-coupled ecological oscillators

Long-range synchrony from short-range interactions is a familiar pattern in biological and physical systems, many of which share a common set of "universal" properties at the point of synchronization. Common biological systems of coupled oscillators have been shown to be members of the Ising universality class, meaning that the very simple Ising model replicates certain spatial statistics of these systems at stationarity. This observation is useful because it reveals which aspects of spatial pattern arise independently of the details governing local dynamics, resulting in both deeper understanding of and a simpler baseline model for biological synchrony. However, in many situations a systems dynamics are of greater interest than their static spatial properties. Here, we ask whether a dynamical Ising model can replicate universal and non-universal features of ecological systems, using noisy coupled metapopulation models with two-cycle dynamics as a case study. The standard Ising model makes unrealistic dynamical predictions, but the Ising model with memory corrects this by using an additional parameter to reflect the tendency for local dynamics to maintain their phase of oscillation. By fitting the two parameters of the Ising model with memory to simulated ecological dynamics, we assess the correspondence between the Ising and ecological models in several of their features (location of the critical boundary in parameter space between synchronous and asynchronous dynamics, probability of local phase changes, and ability to predict future dynamics). We find that the Ising model with memory is reasonably good at representing these properties of ecological metapopulations. The correspondence between these models creates the potential for the simple and well-known Ising class of models to become a valuable tool for understanding complex biological systems.

ecology↗

bioRxiv2020

Density Dependent Resource Budget Model for Alternate Bearing

Alternate bearing, seen in many types of plants, is the variable yield with a strongly biennial pattern. In this paper, we introduce a new model for alternate bearing behavior. Similar to the well-known Resource Budget Model, our model is based on the balance between photosynthesis (carbon accumulation) and reproduction processes. We consider two novel features with our model, 1) the existence of a finite capacity in the trees resource reservoir and 2) the possibility of having low (but non-zero) yield when the trees energy level is low. We achieve the former using a density dependent resource accumulation function, and the latter by removing the concept of the well-defined threshold used in the Resource Budget Model. At the level of an individual tree, our model has a stable two-cycle solution, which is suitable to model plants in which the alternate bearing behavior is pronounced. We incorporate environmental stochasticity by adding two uncorrelated noise terms to the parameters of the model associated with the carbon accumulation and reproduction processes. Furthermore, we examine the models behavior on a system of two coupled trees with direct coupling. Unlike the coupled Resource Budget Model, for which the only stable solution is the out-of-phase solution, our model with diffusive coupling has stable in-phase period-2 solutions. This suggests that our model might serve to explain spatial synchrony on a larger scale.

ecology↗