Publications

Gametes in many species develop in cysts—clusters of germ cells formed by incomplete cytokinesis—that remain connected through intercellular bridges (ICBs). These connections enable sharing of cytoplasmic components between germ cells and, in the female germ line, enrich select cells in the cyst to become the oocyte(s). In mice, germline cysts of variable sizes are generated during embryonic development, thought to result from cyst fractures. Studies of fixed samples failed to capture fracture events, and thus, the mechanism remained elusive. Here, we use high-resolution live imaging of germ cells within their native tissue environment to visualize germline cyst dynamics. With this novel approach, we reveal a striking motile phenotype of gonad-resident germ cells and show that this randomly oriented cell-autonomous motile behavior during cyst formation underlies fracture events. Conversely, we show that stabilized ICBs help resist excessive fracturing. Additionally, we find that motility and thus fracture rates gradually decrease during development in a sex-dependent manner, completely ceasing by the end of cyst-forming divisions. These results lead to a model where the opposing activities of developmentally regulated cell motility and stable ICBs give rise to cysts of variable sizes. We corroborate these results by developing a model that uses experimentally measured fracture rates to simulate cyst formation and fracture and show that it can reproduce experimentally measured cyst sizes in both male and female. Understanding how variable cysts form will enable further studies of mammalian oocyte selection and establishment of the ovarian reserve.

Abstract We introduce a new class of multilevel, adaptive, dual-space methods for computing fast convolutional transformations. These methods can be applied to a broad class of kernels, from the Green's functions for classical partial differential equations (PDEs) to power functions and radial basis functions such as those used in statistics and machine learning. The DMK (dual-space multilevel kernel-splitting) framework uses a hierarchy of grids, computing a smoothed interaction at the coarsest level, followed by a sequence of corrections at finer and finer scales until the problem is entirely local, at which point direct summation is applied. Unlike earlier multilevel summation schemes, DMK exploits the fact that the interaction at each scale is diagonalized by a short Fourier transform, permitting the use of separation of variables, but without relying on the FFT. This requires careful attention to the discretization of the Fourier transform at each spatial scale. Like multilevel summation, we make use of a recursive (telescoping) decomposition of the original kernel into the sum of a smooth far-field kernel, a sequence of difference kernels, and a residual kernel, which plays a role only in leaf boxes in the adaptive tree. At all higher levels in the grid hierarchy, the interaction kernels are designed to be smooth in both physical and Fourier space, admitting efficient Fourier spectral approximations. The DMK framework substantially simplifies the algorithmic structure of the fast multipole method (FMM) and unifies the FMM, Ewald summation, and multilevel summation, achieving speeds comparable to the FFT in work per gridpoint, even in a fully adaptive context. For continuous source distributions, the evaluation of local interactions is further accelerated by approximating the kernel at the finest level as a sum of Gaussians (SOG) with a highly localized remainder. The Gaussian convolutions are calculated using tensor product transforms, and the remainder term is calculated using asymptotic methods. We illustrate the performance of DMK for both continuous and discrete sources with extensive numerical examples in two and three dimensions.

This paper briefly reprises, with added commentary, a talk I gave on transport and flows within living cells at an APS-DFD meeting. Directed transport is especially important in large cells, such as eggs where developmental factors need to be properly localized, and early embryos whose organelles and genetic material must be properly positioned before cell division. I discuss two cases—a nematode single-cell embryo and a fruit fly egg cell—where advances in mathematical modeling and large-scale simulation of fluid-structure interactions have helped us understand fundamental mechanisms of force transduction and self-organization within the cell.

We introduce multiple physics pretraining (MPP), an autoregressive task-agnostic pretraining approach for physical surrogate modeling of spatiotemporal systems with transformers. In MPP, rather than training one model on a specific physical system, we train a backbone model to predict the dynamics of multiple heterogeneous physical systems simultaneously in order to learn features that are broadly useful across systems and facilitate transfer. In order to learn effectively in this setting, we introduce a shared embedding and normalization strategy that projects the fields of multiple systems into a shared embedding space. We validate the efficacy of our approach on both pretraining and downstream tasks over a broad fluid mechanics-oriented benchmark. We show that a single MPP-pretrained transformer is able to match or outperform task-specific baselines on all pretraining sub-tasks without the need for finetuning. For downstream tasks, we demonstrate that finetuning MPP-trained models results in more accurate predictions across multiple time-steps on systems with previously unseen physical components or higher dimensional systems compared to training from scratch or finetuning pretrained video foundation models. We open-source our code and model weights trained at multiple scales for reproducibility.

Score-based diffusion models have significantly advanced high-dimensional data generation across various domains, by learning a denoising oracle (or score) from datasets. From a Bayesian perspective, they offer a realistic modeling of data priors and facilitate solving inverse problems through posterior sampling. Although many heuristic methods have been developed recently for this purpose, they lack the quantitative guarantees needed in many scientific applications. This work addresses the topic from two perspectives. We first present a hardness result indicating that a generic method leveraging the prior denoising oracle for posterior sampling becomes infeasible as soon as the measurement operator is mildly ill-conditioned. We next develop the tilted transport technique, which leverages the quadratic structure of the log-likelihood in linear inverse problems in combination with the prior denoising oracle to exactly transform the original posterior sampling problem into a new one that is provably easier to sample from. We quantify the conditions under which the boosted posterior is strongly log-concave, highlighting how task difficulty depends on the condition number of the measurement matrix and the signal-to-noise ratio. The resulting general scheme is shown to match the best-known sampling methods for Ising models, and is further validated on high-dimensional Gaussian mixture models.

Cells modified outside of the body and then reintroduced provide an advantage over most small-molecule therapeutics in that cells can be designed to recognize target molecules in specific tissues and then act locally. Two studies now demonstrate advances in cell engineering for treating human disease (see the Perspective by Davila and Brentjens). Reddy et al. engineered human T cells to make a synthetic receptor that recognized overactive T cells such as those causing autoimmune disease and organ rejection. The most effective modified cells tested were ones in which the synthetic receptor initiated a program causing the production of both an anti-inflammatory cytokine and a receptor that acted as sink for a locally produced proinflammatory cytokine. In mouse models, such cells could be designed with logic programs that protect the desired tissues without detrimental systemic immunosuppression. Simic et al. modified T cells to produce a synthetic receptor that recognized an antigen localized to the extracellular matrix of the brain. The synthetic receptor activated a circuit stimulating the production of chimeric antigen receptors that targeted and killed cancer cells in the brain but not those implanted elsewhere in the mouse. A mouse model of neuroinflammatory brain disease could be treated with cells engineered to locally produce an anti-inflammatory cytokine.

Extracellular-signal-regulated kinase (ERK) signaling controls development and homeostasis and is genetically deregulated in human diseases, including neurocognitive disorders and cancers. Although the list of ERK functions is vast and steadily growing, the full spectrum of processes controlled by any specific ERK activation event remains unknown. Here, we show how ERK functions can be systematically identified using targeted perturbations and global readouts of ERK activation. Our experimental model is the Drosophila embryo, where ERK signaling at the embryonic poles has thus far only been associated with the transcriptional patterning of the future larva. Through a combination of live imaging and phosphoproteomics, we demonstrated that ERK activation at the poles is also critical for maintaining the speed and synchrony of embryonic cleavages. The presented approach to interrogating phosphorylation networks identifies a hidden function of a well-studied signaling event and sets the stage for similar studies in other organisms.

Earth introduces strong attenuation and dispersion to propagating waves. The time-fractional wave equation with very small fractional exponent, based on Kjartansson's constant-Q theory, is widely recognized in the field of geophysics as a reliable model for frequency-independent Q anelastic behavior. Nonetheless, the numerical resolution of this equation poses considerable challenges due to the requirement of storing a complete time history of wavefields. To address this computational challenge, we present a novel approach: a nearly optimal sum-of-exponentials (SOE) approximation to the Caputo fractional derivative with very small fractional exponent, utilizing the machinery of generalized Gaussian quadrature. This method minimizes the number of memory variables needed to approximate the power attenuation law within a specified error tolerance. We establish a mathematical equivalence between this SOE approximation and the continuous fractional stress-strain relationship, relating it to the generalized Maxwell body model. Furthermore, we prove an improved SOE approximation error bound to thoroughly assess the ability of rheological models to replicate the power attenuation law. Numerical simulations on constant-Q viscoacoustic equation in 3D homogeneous media and variable-order P- and S- viscoelastic wave equations in 3D inhomogeneous media are performed. These simulations demonstrate that our proposed technique accurately captures changes in amplitude and phase resulting from material anelasticity. This advancement provides a significant step towards the practical usage of the time-fractional wave equation in seismic inversion.

Two-particle response functions are a centerpiece of both experimental and theoretical quantum many-body physics. Yet, due to their size and discontinuity structure, they are challenging to handle numerically. Recently, two advances were made to tackle this problem: first, the overcomplete intermediate representation (OIR), which provides a highly efficient compression of Green's functions in imaginary frequency, and second, partial spectral functions (PSFs), which allow for an efficient evaluation in real frequency. We show that there is a two-to-one correspondence between PSFs and OIR coefficients and exploit this fact to construct the OIR for three-or-more-particle propagators. We then use OIR to fit and compress imaginary-frequency data obtained from the numerical renormalization group (NRG), reaching a compression ratio of more than 400. Finally, we attempt to match the OIR data to partial Green's functions from this http URL to the overcompleteness, we achieve only qualitative agreement.