Biophysical Model Research Articles

Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors

Ketamine is an N-methyl-D-aspartate (NMDA)-receptor antagonist that produces sedation, analgesia, and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1 to 4 Hz) at high doses. Ketamine's primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and nonhuman primate local field potential recordings. We have identified how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported and provides important insights into ketamine's mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.

Unravelling the role of oceanographic connectivity in the distribution of genetic diversity of marine forests at the global scale

AbstractAimGenetic diversity of marine forests results from complex interactions of eco‐evolutionary processes. Among them, oceanographic connectivity driven by dispersal through water transport is hypothesized to play a pivotal role, yet its relative contribution has not been addressed at the global scale. Here, we test how present‐day oceanographic connectivity is correlated with the distribution of genetic diversity of marine forests across the ocean.LocationGlobal.Time periodContemporary.Major taxa studiedMarine forests of brown macroalgae (order: Fucales, Ishigeales, Laminariales and Tilopteridales).MethodsThrough literature review, we compiled a comprehensive dataset of genetic differentiation, encompassing 699 populations of 30 species. A biophysical model coupled with network analyses estimated multigenerational oceanographic connectivity and centrality across the marine forest global distribution. This approach integrated propagule dispersive capacity and long‐distance dispersal events. Linear mixed models tested the relative contribution of site‐specific processes, connectivity and centrality in explaining genetic differentiation.ResultsWe show that spatiality‐dependent eco‐evolutionary processes, as described by our models, are prominent drivers of genetic differentiation in marine forests (significant models in 91.43% of the cases with an average R2 of 0.50 ± 0.07). Specifically, we reveal that 18.7% of genetic differentiation variance is explicitly induced by predicted contemporary connectivity and centrality. Moreover, we demonstrate that long‐distance dispersal is key in connecting populations of species distributed across large water masses and continents.Main conclusionsOur findings highlight the role of present‐day oceanographic connectivity in shaping the extant distribution of genetic diversity of marine forests on a global scale, with significant implications for biogeography and evolution. This understanding can pave the way for future research aimed at guiding conservation efforts, including the designation of well‐connected marine protected areas, which is particularly relevant for sessile ecosystems structuring species such as brown macroalgae.

Influence of Magnetic Field Strength on Intravoxel Incoherent Motion Parameters in Diffusion MRI of the Calf

Background: The purpose of this study was to investigate the dependence of Intravoxel Incoherent Motion (IVIM) parameters measured in the human calf on B0. Methods: Diffusion-weighted image data of eight healthy volunteers were acquired using five b-values (0–600 s/mm2) at rest and after muscle activation at 0.55 and 7 T. The musculus gastrocnemius mediale (GM, activated) was assessed. The perfusion fraction f and diffusion coefficient D were determined using segmented fits. The dependence on field strength was assessed using Student’s t-test for paired samples and the Wilcoxon signed-rank test. A biophysical model built on the three non-exchanging compartments of muscle, venous blood, and arterial blood was used to interpret the data using literature relaxation times. Results: The measured perfusion fraction of the GM was significantly lower at 7 T, both for the baseline measurement and after muscle activation. For 0.55 and 7 T, the mean f values were 7.59% and 3.63% at rest, and 14.03% and 6.92% after activation, respectively. The biophysical model estimations for the mean proton-density-weighted perfusion fraction were 3.37% and 6.50% for the non-activated and activated states, respectively. Conclusions: B0 may have a significant effect on the measured IVIM parameters. The blood relaxation times suggest that 7 T IVIM may be arterial-weighted whereas 0.55 T IVIM may exhibit an approximately equal weighting of arterial and venous blood.

Quantifying marine larval dispersal to assess MPA network connectivity and inform future national and transboundary planning efforts

A marine protected area (MPA) network of multiple reserves can protect biodiversity across space, but to be effective, network configuration should support dispersal among MPAs as well as spillover to unprotected habitats. The ability of MPAs to function as an interacting network of populations connected by dispersal, however, is difficult to estimate at broad spatial scales, and therefore, connectivity is often not integrated in MPA design. Here, we simulate passive larval dispersal using a biophysical model to estimate potential transboundary network connectivity of MPAs in western Canada and United States. Drift time was varied to represent generic functional groups of nearshore species with planktonic larvae and sedentary adult stages. We found that MPAs potentially act as an interacting network and meet connectivity design criteria for nearshore invertebrate species, many MPAs (65%–90%) possibly exchange individuals, and a third of larvae from MPAs (25%–32%) source areas of the unprotected coast. This analysis provides a first approximation of multispecies connectivity to inform ongoing transboundary MPA design, and it can be used as a foundation for future model development.

Correlative single molecule lattice light sheet imaging reveals the dynamic relationship between nucleosomes and the local chromatin environment

In the nucleus, biological processes are driven by proteins that diffuse through and bind to a meshwork of nucleic acid polymers. To better understand this interplay, we present an imaging platform to simultaneously visualize single protein dynamics together with the local chromatin environment in live cells. Together with super-resolution imaging, new fluorescent probes, and biophysical modeling, we demonstrate that nucleosomes display differential diffusion and packing arrangements as chromatin density increases whereas the viscoelastic properties and accessibility of the interchromatin space remain constant. Perturbing nuclear functions impacts nucleosome diffusive properties in a manner that is dependent both on local chromatin density and on relative location within the nucleus. Our results support a model wherein transcription locally stabilizes nucleosomes while simultaneously allowing for the free exchange of nuclear proteins. Additionally, they reveal that nuclear heterogeneity arises from both active and passive processes and highlight the need to account for different organizational principles when modeling different chromatin environments.

AIUPred: combining energy estimation with deep learning for the enhanced prediction of protein disorder.

Intrinsically disordered proteins and protein regions (IDPs/IDRs) carry out important biological functions without relying on a single well-defined conformation. As these proteins are a challenge to study experimentally, computational methods play important roles in their characterization. One of the commonly used tools is the IUPred web server which provides prediction of disordered regions and their binding sites. IUPred is rooted in a simple biophysical model and uses a limited number of parameters largely derived on globular protein structures only. This enabled an incredibly fast and robust prediction method, however, its limitations have also become apparent in light of recent breakthrough methods using deep learning techniques. Here, we present AIUPred, a novel version of IUPred which incorporates deep learning techniques into the energy estimation framework. It achieves improved performance while keeping the robustness of the original method. Based on the evaluation of recent benchmark datasets, AIUPred scored amongst the top three single sequence based methods. With a new web server we offer fast and reliable visual analysis for users as well as options to analyze whole genomes in mere seconds with the downloadable package. AIUPred is available at https://aiupred.elte.hu.

Allosteric Cholesterol Site in Glycine Receptors Characterized through Molecular Simulations.

Glycine receptors are pentameric ligand-gated ion channels that conduct chloride ions across postsynaptic membranes to facilitate fast inhibitory neurotransmission. In addition to gating by the glycine agonist, interactions with lipids and other compounds in the surrounding membrane environment modulate their function, but molecular details of these interactions remain unclear, in particular, for cholesterol. Here, we report coarse-grained simulations in a model neuronal membrane for three zebrafish glycine receptor structures representing apparent resting, open, and desensitized states. We then converted the systems to all-atom models to examine detailed lipid interactions. Cholesterol bound to the receptor at an outer-leaflet intersubunit site, with a preference for the open and desensitized versus resting states, indicating that it can bias receptor function. Finally, we used short atomistic simulations and iterative amino acid perturbations to identify residues that may mediate allosteric gating transitions. Frequent cholesterol contacts in atomistic simulations clustered with residues identified by perturbation analysis and overlapped with mutations influencing channel function and pathology. Cholesterol binding at this site was also observed in a recently reported pig heteromeric glycine receptor. These results indicate state-dependent lipid interactions relevant to allosteric transitions of glycine receptors, including specific amino acid contacts applicable to biophysical modeling and pharmaceutical design.

Biophysics of frequency-dependent variation in paresthesia and pain relief during spinal cord stimulation.

The neurophysiological effects of spinal cord stimulation (SCS) for chronic pain are poorly understood, resulting in inefficient failure-prone programming protocols and inadequate pain relief. Nonetheless, novel stimulation patterns are regularly introduced and adopted clinically. Traditionally, paresthetic sensation is considered necessary for pain relief, although novel paradigms provide analgesia without paresthesia. However, like pain relief, the neurophysiological underpinnings of SCS-induced paresthesia are unknown. Here, we paired biophysical modeling with clinical paresthesia thresholds (of both sexes) to investigate how stimulation frequency affects the neural response to SCS relevant to paresthesia and analgesia. Specifically, we modeled the dorsal column (DC) axonal response, dorsal column nucleus (DCN) synaptic transmission, conduction failure within DC fiber collaterals, and dorsal horn network output. Importantly, we found that high-frequency stimulation reduces DC fiber activation thresholds, which in turn accurately predicts clinical paresthesia perception thresholds. Furthermore, we show that high-frequency SCS produces asynchronous DC fiber spiking and ultimately asynchronous DCN output, offering a plausible biophysical basis for why high-frequency SCS is less comfortable and produces qualitatively different sensation than low-frequency stimulation. Finally, we demonstrate that model dorsal horn network output is sensitive to SCS-inherent variations in spike timing, which could contribute to heterogeneous pain relief across patients. Importantly, we show that model DC fiber collaterals cannot reliably follow high-frequency stimulation, strongly affecting network output and typically producing anti-nociceptive effects at high frequencies. Altogether, these findings clarify how SCS affects the nervous system and provide insight into the biophysics of paresthesia generation and pain relief.Significance Statement The effects of spinal cord stimulation (SCS) on the nervous system are poorly understood, resulting in inadequate clinical success rates. Here, we use a biophysical modeling approach to investigate the neural response to SCS. We demonstrate that low- and high-frequency stimulation produce contrasting responses in the dorsal columns, brainstem, and dorsal horn. Importantly, our modeling approach was able to accurately predict clinical paresthesia thresholds as a function of frequency, as well as provide plausible biophysical explanations for frequency-dependent effects on paresthesia quality and pain relief. Overall, our results greatly enhance our understanding of the neural response to SCS, thereby offering context for interpreting clinical observations and crucial insight for development of future SCS systems.

Inferring Stochastic Rates from Heterogeneous Snapshots of Particle Positions.

Many imaging techniques for biological systems-like fixation of cells coupled with fluorescence microscopy-provide sharp spatial resolution in reporting locations of individuals at a single moment in time but also destroy the dynamics they intend to capture. These snapshot observations contain no information about individual trajectories, but still encode information about movement and demographic dynamics, especially when combined with a well-motivated biophysical model. The relationship between spatially evolving populations and single-moment representations of their collective locations is well-established with partial differential equations (PDEs) and their inverse problems. However, experimental data is commonly a set of locations whose number is insufficient to approximate a continuous-in-space PDE solution. Here, motivated by popular subcellular imaging data of gene expression, we embrace the stochastic nature of the data and investigate the mathematical foundations of parametrically inferring demographic rates from snapshots of particles undergoing birth, diffusion, and death in a nuclear or cellular domain. Toward inference, we rigorously derive a connection between individual particle paths and their presentation as a Poisson spatial process. Using this framework, we investigate the properties of the resulting inverse problem and study factors that affect quality of inference. One pervasive feature of this experimental regime is the presence of cell-to-cell heterogeneity. Rather than being a hindrance, we show that cell-to-cell geometric heterogeneity can increase the quality of inference on dynamics for certain parameter regimes. Altogether, the results serve as a basis for more detailed investigations of subcellular spatial patterns of RNA molecules and other stochastically evolving populations that can only be observed for single instants in their time evolution.

AAPM Task Group Report 267: A joint AAPM GEC-ESTRO report on biophysical models and tools for the planning and evaluation of brachytherapy.

Brachytherapy utilizes a multitude of radioactive sources and treatment techniques that often exhibit widely different spatial and temporal dose delivery patterns. Biophysical models, capable of modeling the key interacting effects of dose delivery patterns with the underlying cellular processes of the irradiated tissues, can be a potentially useful tool for elucidating the radiobiological effects of complex brachytherapy dose delivery patterns and for comparing their relative clinical effectiveness. While the biophysical models have been used largely in research settings by experts, it has also been used increasingly by clinical medical physicists over the last two decades. A good understanding of the potentials and limitations of the biophysical models and their intended use is critically important in the widespread use of these models. To facilitate meaningful and consistent use of biophysical models in brachytherapy, Task Group 267 (TG-267) was formed jointly with the American Association of Physics in Medicine (AAPM) and The Groupe Européen de Curiethérapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO) to review the existing biophysical models, model parameters, and their use in selected brachytherapy modalities and to develop practice guidelines for clinical medical physicists regarding the selection, use, and interpretation of biophysical models. The report provides an overview of the clinical background and the rationale for the development of biophysical models in radiation oncology and, particularly, in brachytherapy; a summary of the results of literature review of the existing biophysical models that have been used in brachytherapy; a focused discussion of the applications of relevant biophysical models for five selected brachytherapy modalities; and the task group recommendations on the use, reporting, and implementation of biophysical models for brachytherapy treatment planning and evaluation. The report concludes with discussions on the challenges and opportunities in using biophysical models for brachytherapy and with an outlook for future developments.

Using biophysical modelling and marine connectivity to assess the risk of natural dispersal of non-indigenous species to comply with the Ballast Water Management Convention

AbstractThe introduction of Marine Non-Indigenous Species (NIS) poses a significant threat to global marine biodiversity and ecosystems. To mitigate this risk, the Ballast Water Management Convention (BWMC) was adopted by the UN International Maritime Organisation (IMO), setting strict criteria for discharges of ballast water. However, the BWMC permits exemptions for shipping routes operating within a geographical area, known as a Same-Risk-Area (SRA). An SRA can be established in areas where a risk assessment (RA) can conclude that the spread of NIS via ballast water is low relative to the predicted natural dispersal. Despite the BWMC's requirement for RAs to be based on modelling of the natural dispersal of NIS, no standard procedures have been established. This paper presents a methodology utilizing biophysical modelling and marine connectivity analyses to conduct SRA RA and delineation. Focusing on the Kattegat and Øresund connecting the North Sea and Baltic Sea, we examine two SRA candidates spanning Danish and Swedish waters. We provide an example on how to conduct an RA including an RA summary, and addressing findings, challenges, and prospects. Our study aims to advance the development and adoption of consistent, transparent, and scientifically robust SRA assessments for effective ballast water management.

Optimising seafood nutritional value and environmental sustainability in aquaculture through a novel integrated modelling tool applicable to IMTA and monoculture

Aquaculture policies that decrease the reliance on wild-caught fish and promote integrated multi-trophic aquaculture (IMTA) both aim to lessen the environmental footprint but often overlook economic-environmental trade-offs and neglect social, health, and broad-scale sustainability considerations. Here we present a new bio-physical model (FYNE) that bridges some of these gaps, by linking farm operational choices, such as feed choices and farm siting, with the nutritional value of the farm-gate seafood products and the resulting environmental eutrophication footprint at the farm level. The FYNE model operates both in conditions of monoculture or of IMTA production, and estimates feed composition effects on growth and omega-3 fatty acid content of Atlantic salmon (Salmo salar) and blue mussel (Mytilus edulis), and nitrogen and carbon concentrations, the latter being a measure of the environmental eutrophication footprint of the farm. The model here developed integrates for the first time (i) an ecosystem model of an IMTA and (ii) a fatty acid dynamics model, with new models for salmon feed digestibility and mussel ingestion. The outputs span (i) production analysis for simulation of biomass; (ii) farm mass-balance analysis on deposition analysis and environmental eutrophication footprint; and (iii) product nutritional quality, in terms of fatty acid content. An application of the model to an IMTA farm in Scotland (UK) demonstrates how fatty acid and environmental changes can be modelled in tandem and could be used to support the industry to optimize the nutritional value of cultured species and manage aquatic environmental eutrophication footprint at farm level, informing feed and siting decisions. The model effectively predicts changes in omega-3 fatty acids, particularly DHA and EPA, in response to variations in feed composition. Notably, our results confirm that salmon waste has limited influence on mussel growth due to the spatial separation within the IMTA system, which emphasizes the need for strategic siting to enhance system productivity through effective waste recycling. Additionally, results show that while increasing fishmeal in diets enhances environmental outcomes, it reduces levels of critical fatty acids like DHA and EPA, underscoring the need for balanced feed formulations. The method developed in this study described a novel integrated model (FYNE) that extend previous modelling work by incorporating the influence of farmed species feed composition on fatty acid dynamics as well as the farming environmental factors.

Downscaled numerical weather predictions can improve forecasts of sugarcane irrigation indices

Efficient irrigation reduces energy and water costs, increases profit margins and delivers better environmental outcomes. Whilst many growers rely on weather forecasts to make decisions, few studies have sought to incorporate weather forecast uncertainty into the optimisation of irrigation management or to evaluate weather forecasts through the lens of irrigation indices. Therefore, in this study, we seek to generate and evaluate ensemble forecasts of irrigation indices produced by coupling numerical weather prediction (NWP) forecasts with a biophysical process model (APSIM). We investigate a case study application for sugarcane in northeastern Australia. As a first step, three and a half years of forecasts from the Australian Bureau of Meteorology’s ACCESS-G3 model are statistically post-processed to generate 7-day forecasts that are downscaled and calibrated to local climate zones. In addition, the forecast post-processor converts the deterministic forecasts into an ensemble, thus quantifying forecast uncertainty. The generated forecasts are then used as forcing for the APSIM crop model to produce ensemble forecasts of soil water deficit (SWD), crop water use (CWU) and crop stress (Stress) for a simulated sugarcane crop. Through cross-validation, the post-processed weather forecasts demonstrate improved forecast accuracy compared to naive climatology and raw NWP forecasts for daily rainfall, maximum and minimum temperature and solar radiation; with the added benefit of providing a reliable uncertainty estimate. Improvement to an even greater degree is observed for the derived irrigation indices, particularly CWU and Stress, for which the forecasts are also reliable. The developed irrigation indices based on NWP can be used directly for decision making or, alternatively, may be used further in machine learning for optimisation of irrigation schedules in conjunction with other remotely sensed variables.

Abstract PO1-01-05: Spatial PK/PD Model with HER2 Expression for Predicting Individual Tumor Response to T-DM1

Abstract Introduction: As new antibody drug conjugates are developed, the question of which specific patients will respond to these therapies remains. This work develops a spatial PK/PD model for the antibody drug conjugate trastuzumab emtansine, T-DM1, and explores the relationship between HER2 (target) expression and other individual features of the tumor microenvironment using a computational approach. Methods: We developed a spatial PK/PD model for T-DM1 based upon an allometrically-scaled mouse model (Jumbe, Nelson L., et al., 2010) and the reported outcomes from the KRISTINE trial, which investigated T-DM1 plus pertuzumab in the neoadjuvant early-stage breast cancer setting (Hurvitz, Sara A., et al., 2018). The T-DM1 spatial PK/PD model was then integrated into our previously described 4D biophysical simulation model (Howard, Frederick M., et al., 2022). The biophysical model leverages baseline breast MRI and clinicopathologic features and predicts the individual response to a treatment regimen. Using digital twin tumors from our TumorBank to simulate the KRISTINE trial cohort (n=40), the PD model was parameterized to achieve the trial response rate. To orthogonally validate the spatial PK/PD model, volumetric response and pCR were predicted in an independent cohort of ISPY2 trial patients (n=44) who received T-DM1 followed by dose-dense doxorubicin and cyclophosphamide. We then assessed the added value of the target expression data by developing logistic regression models to predict which patients would achieve pCR based upon HER2 expression alone or HER2 expression combined with the final tumor volume simulated using the spatial PK/PD model. Results: A logistic regression model based upon HER2 expression from transcriptomic data is a strong predictor of response to T-DM1 with an odds ratio of 9.6 and an area under the ROC curve (AUC) of 0.81. The tumorHER2 model, which combines the HER2 expression with the spatial PK/PD model, improves the predictive value of the model with an odds ratio of 34.0 and an AUC of 0.88. Conclusion: The spatial PK/PD improves prognostic predictions compared to HER2 gene expression data alone. In leveraging the SBS biophysical simulation platform, the spatial PK/PD model captures the individual variability in tumor growth rate, tumor perfusion, and drug disposition, all of which influence the treatment efficacy. The rate of target expression will highly influence response to an ADC, but the biophysical model demonstrates that features of the spatial tumor microenvironment also influence response. Table 1. Performance comparison between the SBS tumorHER2model and SBSHER2 Signature. Citation Format: Nicole Hobbs, Bradley Feiger, John Cole, Tricia Carrigan, Joseph Peterson, John Pfeiffer, Daniel Cook. Spatial PK/PD Model with HER2 Expression for Predicting Individual Tumor Response to T-DM1 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-05.

Unlocking the secret life of blue mussels: Exploring connectivity in the Skagerrak through biophysical modeling and population genomics.

Knowledge of functional dispersal barriers in the marine environment can be used to inform a wide variety of management actions, such as marine spatial planning, restoration efforts, fisheries regulations, and invasive species management. Locations and causes of dispersal barriers can be studied through various methods, including movement tracking, biophysical modeling, demographic models, and genetics. Combining methods illustrating potential dispersal, such as biophysical modeling, with realized dispersal through, e.g., genetic connectivity estimates, provides particularly useful information for teasing apart potential causes of observed barriers. In this study, we focus on blue mussels (Mytilus edulis) in the Skagerrak-a marginal sea connected to the North Sea in Northern Europe-and combine biophysical models of larval dispersal with genomic data to infer locations and causes of dispersal barriers in the area. Results from both methods agree; patterns of ocean currents are a major structuring factor in the area. We find a complex pattern of source-sink dynamics with several dispersal barriers and show that some areas can be isolated despite an overall high dispersal capability. Finally, we translate our finding into management advice that can be used to sustainably manage this ecologically and economically important species in the future.

Modeling attenuation of photosynthetically active radiation across the optical gradient in the Laurentian Great Lakes with application to Lake Erie

Representation of subsurface photosynthetically active radiation (PAR) in biophysical models of the Laurentian Great Lakes (LGL) is imperative to their utility as tools for research and management. Here we consolidated measured vertical profiles of subsurface PAR with concurrent water quality (WQ) data from four LGL. We estimated the diffuse attenuation coefficient of PAR (Kd(PAR)) by fitting an exponential function to measured PAR over depth, and evaluated 68 regressions predicting Kd(PAR) as a function of water quality variables (Kd-WQ regressions). We compare four of the top cross-lake calibrated regressions against two published regressions trained on western Lake Erie (WLE) data. Then, as a case study, we demonstrate the utility of our cross-lake calibrated Kd-WQ regressions with a simplified biophysical model of Lake Erie consisting of the Finite Volume Community Ocean Model with submodules for simulating suspended sediment and dissolved organic carbon (FVCOM-SS-DOC). Twenty-five Kd-WQ regressions were identified as candidates for use in biophysical models based on their skill determined via cross-validation. WLE-trained Kd-WQ regressions were less able to simulate Kd(PAR) and PAR in more transparent waters compared to cross-lake calibrated Kd-WQ regressions, which translated to considerable differences in primary production estimates for the central and eastern basins when using WQ data simulated by FVCOM-SS-DOC. A cross-lake calibrated Kd-WQ regression was installed into FVCOM-SS-DOC, which then simulated spatial patterns of suspended sediments and Kd(PAR). These calibrated Kd-WQ regressions can be used in a variety of biophysical models across optically-distinct waters of the LGL to support adaptive management of nutrient inputs and fisheries

Numerics with coordinate transforms for efficient Brownian dynamics simulations

Many stochastic processes in the physical and biological sciences can be modelled as Brownian dynamics with multiplicative noise. However, numerical integrators for these processes can lose accuracy or even fail to converge when the diffusion term is configuration-dependent. One remedy is to construct a transform to a constant-diffusion process and sample the transformed process instead. In this work, we explain how coordinate-based and time-rescaling-based transforms can be used either individually or in combination to map a general class of variable-diffusion Brownian motion processes into constant-diffusion ones. The transforms are invertible, thus allowing recovery of the original dynamics. We motivate our methodology using examples in one dimension before then considering multivariate diffusion processes. We illustrate the benefits of the transforms through numerical simulations, demonstrating how the right combination of integrator and transform can improve computational efficiency and the order of convergence to the invariant distribution. Notably, the transforms that we derive are applicable to a class of multibody, anisotropic Stokes-Einstein diffusion that has applications in biophysical modelling.

The full spectrum of SLC22 OCT1 mutations illuminates the bridge between drug transporter biophysics and pharmacogenomics

Mutations in transporters can impact an individual's response to drugs and cause many diseases. Few variants in transporters have been evaluated for their functional impact. Here, we combine saturation mutagenesis and multi-phenotypic screening to dissect the impact of 11,213 missense single-amino-acid deletions, and synonymous variants across the 554 residues of OCT1, a key liver xenobiotic transporter. By quantifying in parallel expression and substrate uptake, we find that most variants exert their primary effect on protein abundance, a phenotype not commonly measured alongside function. Using our mutagenesis results combined with structure prediction and molecular dynamic simulations, we develop accurate structure-function models of the entire transport cycle, providing biophysical characterization of all known and possible human OCT1 polymorphisms. This work provides a complete functional map of OCT1 variants along with a framework for integrating functional genomics, biophysical modeling, and human genetics to predict variant effects on disease and drug efficacy.

Spectral neural approximations for models of transcriptional dynamics

The advent of high-throughput transcriptomics provides an opportunity to advance mechanistic understanding of transcriptional processes and their connections to cellular function at an unprecedented, genome-wide scale. These transcriptional systems, which involve discrete stochastic events, are naturally modeled using chemical master equations (CMEs), which can be solved for probability distributions to fit biophysical rates that govern system dynamics. While CME models have been used as standards in fluorescence transcriptomics for decades to analyze single-species RNA distributions, there are often no closed-form solutions to CMEs that model multiple species, such as nascent and mature RNA transcript counts. This has prevented the application of standard likelihood-based statistical methods for analyzing high-throughput, multi-species transcriptomic datasets using biophysical models. Inspired by recent work in machine learning to learn solutions to complex dynamical systems, we leverage neural networks and statistical understanding of system distributions to produce accurate approximations to a steady-state bivariate distribution for a model of the RNA life cycle that includes nascent and mature molecules. The steady-state distribution to this simple model has no closed-form solution and requires intensive numerical solving techniques: our approach reduces likelihood evaluation time by several orders of magnitude. We demonstrate two approaches, whereby solutions are approximated by 1) learning the weights of kernel distributions with constrained parameters or 2) learning both weights and scaling factors for parameters of kernel distributions. We show that our strategies, denoted by kernel weight regression and parameter-scaled kernel weight regression, respectively, enable broad exploration of parameter space and can be used in existing likelihood frameworks to infer transcriptional burst sizes, RNA splicing rates, and mRNA degradation rates from experimental transcriptomic data.

Proteolytic stability and aggregation in a key metabolic enzyme of bacteria

Proteins that are kinetically stable are thought to be less prone to both aggregation and proteolysis. We demonstrate that the classical lac system of Escherichia coli can be leveraged as a model system to study this relation. β-galactosidase (LacZ) plays a critical role in lactose metabolism and is an extremely stable protein that can persist in growing cells for multiple generations after expression has stopped. By attaching degradation tags to the LacZ protein, we find that LacZ can be transiently degraded during lac operon expression but once expression has stopped functional LacZ is protected from degradation. We reversibly destabilize its tetrameric assembly using α-complementation, and show that unassembled LacZ monomers and dimers can either be degraded or lead to formation of aggregates within cells, while the tetrameric state protects against proteolysis and aggregation. We show that the presence of aggregates is associated with cell death, and that these proteotoxic stress phenotypes can be alleviated by attaching an ssrA tag to LacZ monomers which leads to their degradation. We unify our findings using a biophysical model that enables the interplay of protein assembly, degradation, and aggregation to be studied quantitatively in vivo. This work may yield approaches to reversing and preventing protein-misfolding disease states, while elucidating the functions of proteolytic stability in constant and fluctuating environments.