Model discovery approach enables noninvasive measurement of intra-tumoral fluid transport in dynamic MRI.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a routine method to noninvasively quantify perfusion dynamics in tissues. The standard practice for analyzing DCE-MRI data is to fit an ordinary differential equation to each voxel. Recent advances in data science provide an opportunity to move beyond existing methods to obtain more accurate measurements of fluid properties. Here, we developed a localized convolutional function regression that enables simultaneous measurement of interstitial fluid velocity, diffusion, and perfusion in 3D. We validated the method computationally and experimentally, demonstrating accurate measurement of fluid dynamics in situ and in vivo. Applying the method to human MRIs, we observed tissue-specific differences in fluid dynamics, with an increased fluid velocity in breast cancer as compared to brain cancer. Overall, our method represents an improved strategy for studying interstitial flows and interstitial transport in tumors and patients. We expect that our method will contribute to the better understanding of cancer progression and therapeutic response.

Neuronal branching is increasingly asymmetric near synapses, potentially enabling plasticity while minimizing energy dissipation and conduction time.

Neurons' primary function is to encode and transmit information in the brain and body. The branching architecture of axons and dendrites must compute, respond and make decisions while obeying the rules of the substrate in which they are enmeshed. Thus, it is important to delineate and understand the principles that govern these branching patterns. Here, we present evidence that asymmetric branching is a key factor in understanding the functional properties of neurons. First, we derive novel predictions for asymmetric scaling exponents that encapsulate branching architecture associated with crucial principles such as conduction time, power minimization and material costs. We compare our predictions with extensive data extracted from images to associate specific principles with specific biophysical functions and cell types. Notably, we find that asymmetric branching models lead to predictions and empirical findings that correspond to different weightings of the importance of maximum, minimum or total path lengths from the soma to the synapses. These different path lengths quantitatively and qualitatively affect energy, time and materials. Moreover, we generally observe that higher degrees of asymmetric branching-potentially arising from extrinsic environmental cues and synaptic plasticity in response to activity-occur closer to the tips than the soma (cell body).

Model discovery approach enables non-invasive measurement of intra-tumoral fluid transport in dynamic MRI.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a routine method to non-invasively quantify perfusion dynamics in tissues. The standard practice for analyzing DCE-MRI data is to fit an ordinary differential equation to each voxel. Recent advances in data science provide an opportunity to move beyond existing methods to obtain more accurate measurements of fluid properties. Here, we developed a localized convolutional function regression that enables simultaneous measurement of interstitial fluid velocity, diffusion, and perfusion in 3D. We validated the method computationally and experimentally, demonstrating accurate measurement of fluid dynamics in situ and in vivo. Applying the method to human MRIs, we observed tissue-specific differences in fluid dynamics, with an increased fluid velocity in breast cancer as compared to brain cancer. Overall, our method represents an improved strategy for studying interstitial flows and interstitial transport in tumors and patients. We expect that it will contribute to the better understanding of cancer progression and therapeutic response.

Neuronal Branching is Increasingly Asymmetric Near Synapses, Potentially Enabling Plasticity While Minimizing Energy Dissipation and Conduction Time.

Neurons' primary function is to encode and transmit information in the brain and body. The branching architecture of axons and dendrites must compute, respond, and make decisions while obeying the rules of the substrate in which they are enmeshed. Thus, it is important to delineate and understand the principles that govern these branching patterns. Here, we present evidence that asymmetric branching is a key factor in understanding the functional properties of neurons. First, we derive novel predictions for asymmetric scaling exponents that encapsulate branching architecture associated with crucial principles such as conduction time, power minimization, and material costs. We compare our predictions with extensive data extracted from images to associate specific principles with specific biophysical functions and cell types. Notably, we find that asymmetric branching models lead to predictions and empirical findings that correspond to different weightings of the importance of maximum, minimum, or total path lengths from the soma to the synapses. These different path lengths quantitatively and qualitatively affect energy, time, and materials. Moreover, we generally observe that higher degrees of asymmetric branching- potentially arising from extrinsic environmental cues and synaptic plasticity in response to activity- occur closer to the tips than the soma (cell body).

Data driven model discovery and interpretation for CAR T-cell killing using sparse identification and latent variables.

In the development of cell-based cancer therapies, quantitative mathematical models of cellular interactions are instrumental in understanding treatment efficacy. Efforts to validate and interpret mathematical models of cancer cell growth and death hinge first on proposing a precise mathematical model, then analyzing experimental data in the context of the chosen model. In this work, we present the first application of the sparse identification of non-linear dynamics (SINDy) algorithm to a real biological system in order discover cell-cell interaction dynamics in in vitro experimental data, using chimeric antigen receptor (CAR) T-cells and patient-derived glioblastoma cells. By combining the techniques of latent variable analysis and SINDy, we infer key aspects of the interaction dynamics of CAR T-cell populations and cancer. Importantly, we show how the model terms can be interpreted biologically in relation to different CAR T-cell functional responses, single or double CAR T-cell-cancer cell binding models, and density-dependent growth dynamics in either of the CAR T-cell or cancer cell populations. We show how this data-driven model-discovery based approach provides unique insight into CAR T-cell dynamics when compared to an established model-first approach. These results demonstrate the potential for SINDy to improve the implementation and efficacy of CAR T-cell therapy in the clinic through an improved understanding of CAR T-cell dynamics.

How axon and dendrite branching are guided by time, energy, and spatial constraints.

Neurons are connected by complex branching processes-axons and dendrites-that process information for organisms to respond to their environment. Classifying neurons according to differences in structure or function is a fundamental part of neuroscience. Here, by constructing biophysical theory and testing against empirical measures of branching structure, we develop a general model that establishes a correspondence between neuron structure and function as mediated by principles such as time or power minimization for information processing as well as spatial constraints for forming connections. We test our predictions for radius scale factors against those extracted from neuronal images, measured for species that range from insects to whales, including data from light and electron microscopy studies. Notably, our findings reveal that the branching of axons and peripheral nervous system neurons is mainly determined by time minimization, while dendritic branching is determined by power minimization. Our model also predicts a quarter-power scaling relationship between conduction time delay and body size.

Dose-dependent thresholds of dexamethasone destabilize CAR T-cell treatment efficacy.

Chimeric antigen receptor (CAR) T-cell therapy is potentially an effective targeted immunotherapy for glioblastoma, yet there is presently little known about the efficacy of CAR T-cell treatment when combined with the widely used anti-inflammatory and immunosuppressant glucocorticoid, dexamethasone. Here we present a mathematical model-based analysis of three patient-derived glioblastoma cell lines treated in vitro with CAR T-cells and dexamethasone. Advanced in vitro experimental cell killing assay technologies allow for highly resolved temporal dynamics of tumor cells treated with CAR T-cells and dexamethasone, making this a valuable model system for studying the rich dynamics of nonlinear biological processes with translational applications. We model the system as a nonautonomous, two-species predator-prey interaction of tumor cells and CAR T-cells, with explicit time-dependence in the clearance rate of dexamethasone. Using time as a bifurcation parameter, we show that (1) dexamethasone destabilizes coexistence equilibria between CAR T-cells and tumor cells in a dose-dependent manner and (2) as dexamethasone is cleared from the system, a stable coexistence equilibrium returns in the form of a Hopf bifurcation. With the model fit to experimental data, we demonstrate that high concentrations of dexamethasone antagonizes CAR T-cell efficacy by exhausting, or reducing the activity of CAR T-cells, and by promoting tumor cell growth. Finally, we identify a critical threshold in the ratio of CAR T-cell death to CAR T-cell proliferation rates that predicts eventual treatment success or failure that may be used to guide the dose and timing of CAR T-cell therapy in the presence of dexamethasone in patients.

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy.

Targeted radionuclide therapy (TRT) has recently seen a surge in popularity with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results, an example being chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies. Moreover, TRT and CAR-T therapies possess unique features that require special consideration when determining how to dose as well as the timing and sequence of combination treatments including the distribution of the TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate the additive or synergistic effects of combination therapies and warrant a mathematical treatment that includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here, we combine two previously published mathematical models to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell-based therapies in a multiple myeloma setting. We find that, for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR-T therapies.

Branching principles of animal and plant networks identified by combining extensive data, machine learning and modelling.

Branching in vascular networks and in overall organismic form is one of the most common and ancient features of multicellular plants, fungi and animals. By combining machine-learning techniques with new theory that relates vascular form to metabolic function, we enable novel classification of diverse branching networks-mouse lung, human head and torso, angiosperm and gymnosperm plants. We find that ratios of limb radii-which dictate essential biologic functions related to resource transport and supply-are best at distinguishing branching networks. We also show how variation in vascular and branching geometry persists despite observing a convergent relationship across organisms for how metabolic rate depends on body mass.

Improving Blood Vessel Tortuosity Measurements via Highly Sampled Numerical Integration of the Frenet-Serret Equations.

Measures of vascular tortuosity-how curved and twisted a vessel is-are associated with a variety of vascular diseases. Consequently, measurements of vessel tortuosity that are accurate and comparable across modality, resolution, and size are greatly needed. Yet in practice, precise and consistent measurements are problematic-mismeasurements, inability to calculate, or contradictory and inconsistent measurements occur within and across studies. Here, we present a new method of measuring vessel tortuosity that ensures improved accuracy. Our method relies on numerical integration of the Frenet-Serret equations. By reconstructing the three-dimensional vessel coordinates from tortuosity measurements, we explain how to identify and use a minimally-sufficient sampling rate based on vessel radius while avoiding errors associated with oversampling and overfitting. Our work identifies a key failing in current practices of filtering asymptotic measurements and highlights inconsistencies and redundancies between existing tortuosity metrics. We demonstrate our method by applying it to manually constructed vessel phantoms with known measures of tortuousity, and 9,000 vessels from medical image data spanning human cerebral, coronary, and pulmonary vascular trees, and the carotid, abdominal, renal, and iliac arteries.

Plant traits and vegetation data from climate warming experiments along an 1100 m elevation gradient in Gongga Mountains, China.

Functional trait data enhance climate change research by linking climate change, biodiversity response, and ecosystem functioning, and by enabling comparison between systems sharing few taxa. Across four sites along a 3000-4130 m a.s.l. gradient spanning 5.3 °C in growing season temperature in Mt. Gongga, Sichuan, China, we collected plant functional trait and vegetation data from control plots, open top chambers (OTCs), and reciprocally transplanted vegetation turfs. Over five years, we recorded vascular plant composition in 140 experimental treatment and control plots. We collected trait data associated with plant resource use, growth, and life history strategies (leaf area, leaf thickness, specific leaf area, leaf dry matter content, leaf C, N and P content and C and N isotopes) from local populations and from experimental treatments. The database consists of 6,671 plant records and 36,743 trait measurements (increasing the trait data coverage of the regional flora by 500%) covering 11 traits and 193 plant taxa (ca. 50% of which have no previous published trait data) across 37 families.

Derivations of the Core Functions of the Maximum Entropy Theory of Ecology.

The Maximum Entropy Theory of Ecology (METE), is a theoretical framework of macroecology that makes a variety of realistic ecological predictions about how species richness, abundance of species, metabolic rate distributions, and spatial aggregation of species interrelate in a given region. In the METE framework, "ecological state variables" (representing total area, total species richness, total abundance, and total metabolic energy) describe macroecological properties of an ecosystem. METE incorporates these state variables into constraints on underlying probability distributions. The method of Lagrange multipliers and maximization of information entropy (MaxEnt) lead to predicted functional forms of distributions of interest. We demonstrate how information entropy is maximized for the general case of a distribution, which has empirical information that provides constraints on the overall predictions. We then show how METE's two core functions are derived. These functions, called the "Spatial Structure Function" and the "Ecosystem Structure Function" are the core pieces of the theory, from which all the predictions of METE follow (including the Species Area Relationship, the Species Abundance Distribution, and various metabolic distributions). Primarily, we consider the discrete distributions predicted by METE. We also explore the parameter space defined by the METE's state variables and Lagrange multipliers. We aim to provide a comprehensive resource for ecologists who want to understand the derivations and assumptions of the basic mathematical structure of METE.