September 2
Speaker: Tin Phan (Los Alamos National Laboratories)
Title: Mathematical modeling reveals that latently infected cells reactivated by AZD5582 differ substantially from productively infected cells
Abstract: AZD5582 (AZD) is a promising latency reversing agent to enable the “shock-and-kill” strategy in HIV-1 cure research, due to its potent ability to reactivate latently infected cells while maintaining high specificity by targeting the non-canonical NF-κB pathway. Previous studies in rhesus macaques have demonstrated that AZD can promote the reactivation of latently infected cells, which can lead to a viral load increase of 2-3 logs. However, the resulting reduction of the latent reservoir is less robust. Quantitative analysis of this phenomenon is difficult due to limited and fluctuating low amplitude longitudinal viral load data. To overcome this obstacle, we developed an ensemble of mechanistic models and fit it to a data set obtained from 23 macaques treated with AZD in combination with other therapies. The model ensemble recapitulates the reactivation patterns observed in SIV RNA, the change in SIV CA-DNA, and provides robust estimates of key parameters related to the reactivated cells. We find that the reactivated cells produce fewer viruses, are less susceptible to viral cytotoxicity, and do not interact strongly with the immune response compared to productively infected cells. Reactivated cells likely enter a temporary state that is refractory to drug effects, prior to their return to latency. This refractory phase causes a diminishing return effect on the effectiveness of AZD. Thus, introducing a waiting time in between treatment periods to bypass this refractory phase may enhance the overall effect of AZD. Altogether, our results suggest the difference between AZD-reactivated cells and productively infected cells as the underlying mechanism responsible for the lack of reservoir reduction.
September 9
Speaker: Maliha Ahmed (Massachusetts Institute of Technology)
Title: Multiscale Modelling of Neurosteroid-mediated Seizure Trajectories in Childhood Absence Epilepsy
Abstract: Childhood absence epilepsy (CAE) is a pediatric generalized epilepsy disorder characterized by brief episodes of impaired consciousness and distinctive 2.5–5 Hz spike-wave discharges (SWDs) on electroencephalography. With a well-established genetic aetiology, this condition tends to resolve spontaneously during adolescence in most cases. While several mechanisms have been proposed for remission, understanding remains insufficient to guide early intervention practices. In this work, we first utilize a conductance-based thalamocortical network model that exhibits characteristic SWDs, to demonstrate that allopregnanolone, a progesterone metabolite known to enhance GABAa receptor-mediated inhibition, has an ameliorating effect on SWDs. To investigate the divergence between this finding and clinical observations, we developed an enhanced thalamocortical model that incorporates a layered cortical structure to explore regional cortical heterogeneity and frontocortical connectivity as potential resistance factors to ALLO-mediated recovery. Our results suggest that non-resolving CAE may be due not only to increased frontocortical connectivity but also to the composition of cell types within the network. We extended our investigation to examine whether these findings apply to CAE caused by different genetic mechanisms, particularly mutations in sodium channel genes by modelling their effects at the individual neuron level. Furthermore, we examined the degree to which these alterations lead to network-level pathological activity, as well as the influence of ALLO on these genetically distinct networks. Our results demonstrate that ALLO facilitates recovery from SWDs regardless of the underlying mutation type. However, enhanced frontocortical connectivity prevents recovery in some mutation types, particularly when mutation effects are severe. Altogether, our multi-scale computational framework demonstrates that CAE remission is determined by complex interactions between hormonal influences, genetic factors, and network connectivity patterns. These approaches not only advance our understanding of CAE specifically, but offer generalizable insights into the mathematical modelling of neurological conditions characterized by spontaneous shifts in brain dynamics.
September 16
Speaker: Peter Thomas (Case Western Reserve University)
Title: Stochastic Oscillators
Abstract: Phase reduction and isostable (or amplitude) reduction are important tools for studying synchronization, entrainment, and control of nonlinear limit cycle oscillators that arise throughout mathematical biology. Phase and amplitude coordinates were introduced classically for deterministic oscillators. The definitions of asymptotic phase, isochron, and isostable break down when oscillators are subject to stochastic forcing (noise). At the same time, there are models for biological oscillations in which the oscillations cease in the absence of noise. (Examples include excitable systems, quasicycle systems, and noisy heteroclinic cycles). In this talk I will review an approach to defining the asymptotic phase of a stochastic oscillator, as well as its isostable coordinates, by diagonalizing the stochastic Koopman operator. The talk will include a brief tutorial introduction to a stochastic oscillator toolbox developed with Max Kreider, who completed his PhD under my supervision last spring (https://github.com/MaxKreider/Stochastic_Oscillator_Workshop). The talk will also set the stage for Max Kreider's talk on synchronization and Arnold tongues for coupled stochastic oscillators scheduled for the Midwest Mathematical Biology Seminar for September 23, 2025.