Publications

Theranostic materials research is experiencing rapid growth driven by the interest in integrating both therapeutic and diagnostic modalities. These materials offer the unique capability to not only provide treatment but also track the progression of a disease. However, to create an ideal theranostic biomaterial without compromising drug encapsulation, diagnostic imaging must be optimized for improved sensitivity and spatial localization. Herein, we create a protein-engineered fluorinated coiled-coil fiber, Q2TFL, capable of improved sensitivity to 19F magnetic resonance spectroscopy (MRS) detection. Leveraging residue-specific noncanonical amino acid incorporation of trifluoroleucine (TFL) into the coiled-coil, Q2, which self-assembles into nanofibers, we generate Q2TFL. We demonstrate that fluorination results in a greater increase in thermostability and 19F magnetic resonance detection compared to the nonfluorinated parent, Q2. Q2TFL also exhibits linear ratiometric 19F MRS thermoresponsiveness, allowing it to act as a temperature probe. Furthermore, we explore the ability of Q2TFL to encapsulate the anti-inflammatory small molecule, curcumin (CCM), and its impact on the coiled-coil structure. Q2TFL also provides hyposignal contrast in 1H MRI, echogenic signal with high-frequency ultrasound and sensitive detection by 19F MRS in vivo illustrating fluorination of coiled-coils for supramolecular assembly and their use with 1H MRI, 19F MRS and high frequency ultrasound as multimodal theranostic agents.

To facilitate single cell multi-omics analysis and improve reproducibility, we present SPEEDI (Single-cell Pipeline for End to End Data Integration), a fully automated end-to-end framework for batch inference, data integration, and cell type labeling. SPEEDI introduces data-driven batch inference and transforms the often heterogeneous data matrices obtained from different samples into a uniformly annotated and integrated dataset. Without requiring user input, it automatically selects parameters and executes pre-processing, sample integration, and cell type mapping. It can also perform downstream analyses of differential signals between treatment conditions and gene functional modules. SPEEDI’s data-driven batch inference method works with widely used integration and cell-typing tools. By developing data-driven batch inference, providing full end-to-end automation, and eliminating parameter selection, SPEEDI improves reproducibility and lowers the barrier to obtaining biological insight from these valuable single-cell datasets. The SPEEDI interactive web application can be accessed at https://speedi.princeton.edu/.

Few techniques are available for studying the nature of forces that drive subcellular dynamics. Here we develop two complementary ones. The first is femtosecond stereotactic laser ablation, which rapidly creates complex cuts of subcellular structures and enables precise dissection of when, where and in what direction forces are generated. The second is an assessment of subcellular fluid flows by comparison of direct flow measurements using microinjected fluorescent nanodiamonds with large-scale fluid-structure simulations of different force transduction models. We apply these techniques to study spindle and centrosome positioning in early Caenorhabditis elegans embryos and to probe the contributions of microtubule pushing, cytoplasmic pulling and cortical pulling upon centrosomal microtubules. Based on our results, we construct a biophysical model to explain the dynamics of centrosomes. We demonstrate that cortical pulling forces provide a general explanation for many behaviours mediated by centrosomes, including pronuclear migration and centration, rotation, metaphase spindle positioning, asymmetric spindle elongation and spindle oscillations. This work establishes methodologies for disentangling the forces responsible for cell biological phenomena.

Transient receptor potential (TRP) ion channels are among the most well-studied classes of temperature-sensing molecules. Yet, the molecular mechanism and thermodynamic basis for the temperature sensitivity of TRP channels remains to this day poorly understood. One hypothesis is that the temperature-sensing mechanism can simply be described by a difference in heat capacity between the closed and open channel states. While such a two-state model may be simplistic it nonetheless has descriptive value, in the sense that it can be used to compare overall temperature sensitivity between different channels and mutants. Here, we introduce a mathematical framework based on the two-state model to reliably extract temperature-dependent thermodynamic potentials and heat capacities from measurements of equilibrium constants at different temperatures. Our framework is implemented in an open-source data analysis package that provides a straightforward way to fit both linear and nonlinear van ’t Hoff plots, thus avoiding some of the previous, potentially erroneous, assumptions when extracting thermodynamic variables from TRP channel electrophysiology data.

The extracellular signal–regulated kinase (ERK) controls multiple critical processes in the cell and is deregulated in human cancers, congenital abnormalities, immune diseases, and neurodevelopmental syndromes. Catalytic activity of ERK requires dual phosphorylation by an upstream kinase, in a mechanism that can be described by two sequential Michaelis-Menten steps. The estimation of individual reaction rate constants from kinetic data in the full mechanism has proved challenging. Here, we present an analytically tractable approach to parameter estimation that is based on the phase plane representation of ERK activation and yields two combinations of six reaction rate constants in the detailed mechanism. These combinations correspond to the ratio of the specificities of two consecutive phosphorylations and the probability that monophosphorylated substrate does not dissociate from the enzyme before the second phosphorylation. The presented approach offers a language for comparing the effects of mutations that disrupt ERK activation and function in vivo. As an illustration, we use phase plane representation to analyze dual phosphorylation under heterozygous conditions, when two enzyme variants compete for the same substrate.

Computers, as well as most neuromorphic hardware systems, use central processing and top-down algorithmic control to train for machine learning tasks. In contrast, brains are ensembles of 100 billion neurons working in tandem, giving them tremendous advantages in power efficiency and speed. Many physical systems `learn' through history dependence, but training a physical system to perform arbitrary nonlinear tasks without a processor has not been possible. Here we demonstrate the successful implementation of such a system - a learning meta-material. This nonlinear analog circuit is comprised of identical copies of a single simple element, each following the same local update rule. By applying voltages to our system (inputs), inference is performed by physics in microseconds. When labels are properly enforced (also via voltages), the system's internal state evolves in time, approximating gradient descent. Our system; it requires no processor. Once trained, it performs inference passively, requiring approximately 100~W of total power dissipation across its edges. We demonstrate the flexibility and power efficiency of our system by solving nonlinear 2D classification tasks. Learning meta-materials have immense potential as fast, efficient, robust learning systems for edge computing, from smart sensors to medical devices to robotic control.

The prospect of substantial reductions in the power consumption of AI is a major motivation for the development of neuromorphic hardware. Less attention has been given to the complementary research of power-efficient learning rules for such systems. Here we study self-learning physical systems trained by local learning rules based on contrastive learning. We show how the physical learning rule can be biased toward finding power-efficient solutions to learning problems, and demonstrate in simulations and laboratory experiments the emergence of a trade-off between power-efficiency and task performance.

Nearly, all dense suspensions undergo dramatic and abrupt thickening transitions in their flow behavior when sheared at high stresses. Such transitions occur when the dominant interactions between the suspended particles shift from hydrodynamic to frictional. Here, we interpret abrupt shear thickening as a precursor to a rigidity transition and give a complete theory of the viscosity in terms of a universal crossover scaling function from the frictionless jamming point to a rigidity transition associated with friction, anisotropy, and shear. Strikingly, we find experimentally that for two different systems—cornstarch in glycerol and silica spheres in glycerol—the viscosity can be collapsed onto a single universal curve over a wide range of stresses and volume fractions. The collapse reveals two separate scaling regimes due to a crossover between frictionless isotropic jamming and frictional shear jamming, with different critical exponents. The material-specific behavior due to the microscale particle interactions is incorporated into a scaling variable governing the proximity to shear jamming, that depends on both stress and volume fraction. This reformulation opens the door to importing the vast theoretical machinery developed to understand equilibrium critical phenomena to elucidate fundamental physical aspects of the shear thickening transition.

Many stellarator coil design problems are plagued by multiple minima, where the locally optimal coil sets can sometimes vary substantially in performance. As a result, solving a coil design problem a single time with a local optimization algorithm is usually insufficient and better optima likely do exist. To address this problem, we propose a global optimization algorithm for the design of stellarator coils and outline how to apply box constraints to the physical positions of the coils. The algorithm has a global exploration phase that searches for interesting regions of design space and is followed by three local optimization algorithms that search in these interesting regions (a "global-to-local" approach). The first local algorithm (phase I), following the globalization phase, is based on near-axis expansions and finds stellarator coils that optimize for quasisymmetry in the neighborhood of a magnetic axis. The second local algorithm (phase II) takes these coil sets and optimizes them for nested flux surfaces and quasisymmetry on a toroidal volume. The final local algorithm (phase III) polishes these configurations for an accurate approximation of quasisymmetry. Using our global algorithm, we study the trade-off between coil length, aspect ratio, rotational transform, and quality of quasi-axisymmetry. The database of stellarators, which comprises almost 140,000 coil sets, is available online and is called QUASR, for "QUAsi-symmetric Stellarator Repository".

Inferring dynamical models from low-resolution temporal data continues to be a significant challenge in biophysics, especially within transcriptomics, where separating molecular programs from noise remains an important open problem. We explore a common scenario in which we have access to an adequate amount of cross-sectional samples at a few time-points, and assume that our samples are generated from a latent diffusion process. We propose an approach that relies on the probability flow associated with an underlying diffusion process to infer an autonomous, nonlinear force field interpolating between the distributions. Given a prior on the noise model, we employ score-matching to differentiate the force field from the intrinsic noise. Using relevant biophysical examples, we demonstrate that our approach can extract non-conservative forces from non-stationary data, that it learns equilibrium dynamics when applied to steady-state data, and that it can do so with both additive and multiplicative noise models.