Publications

Tissue deformations during morphogenesis can be active, driven by internal processes, or passive, resulting from stresses applied at their boundaries. Here, we introduce the Drosophila hindgut primordium as a model for studying boundary-driven tissue morphogenesis. We characterize its deformations and show that its complex shape changes can be a passive consequence of the deformations of the active regions of the embryo that surround it. First, we find an intermediate characteristic triangular shape in the 3D deformations of the hindgut. We construct a minimal model of the hindgut primordium as an elastic ring deformed by active midgut invagination and germ band extension on an ellipsoidal surface, which robustly captures the symmetry-breaking into this triangular shape. We then quantify the 3D kinematics of the tissue by a set of contours and discover that the hindgut deforms in two stages: an initial translation on the curved embryo surface followed by a rapid breaking of shape symmetry. We extend our model to show that the contour kinematics in both stages are consistent with our passive picture. Our results suggest that the role of in-plane deformations during hindgut morphogenesis is to translate the tissue to a region with anisotropic embryonic curvature and show that uniform boundary conditions are sufficient to generate the observed nonuniform shape change. Our work thus provides a possible explanation for the various characteristic shapes of blastopore-equivalents in different organisms and a framework for the mechanical emergence of global morphologies in complex developmental systems.

Using a state-of-the-art numerical scheme, we show that the Higgs mode under excitation exhibits chirped oscillations and exponential decay when fluctuations are included. This is in stark contrast to conventional BCS collisionless dynamics which predict power-law decay and the absence of chirping. The chirped amplitude mode enables us to determine the local modification of the effective potential even when the system is in a long-lived prethermal state. We then show that this chirped amplitude mode is an experimentally observable quantity since the photoinduced (super)current in pump-probe experiments serves as an efficient proxy for the order parameter dynamics, including the chirped dynamics. Our result is based on the attractive Hubbard model using dynamical mean-field theory within the symmetry-broken state after a excitation across the superconducting gap. Since the collective response involves long timescales, we extend the hierarchical low-rank compression method for nonequilibrium Green's functions to symmetry-broken states and show that it serves as an efficient representation despite long-lived memory kernels.

Humans and monkeys can rapidly recognize objects in everyday scenes. While it is known that this ability relies on neural computations in the ventral stream of visual cortex, it is not well understood where this computation first arises. Previous work suggests selectivity for object shape first emerges in area V4. To explore the mechanisms of this selectivity, we generated a continuum of images between “scrambled” textures and photographic images of both natural and man-made environments, using techniques that preserve the local statistics of the original image while discarding information about scene and shape. We measured image responses from single units in area V4 from two awake macaque monkeys. Neuronal populations in V4 could reliably distinguish photographic from scrambled images, could more reliably discriminate between photographic images than between scrambled images, and responded with greater dynamic range to photographic images than scrambled images. Responses to partially scrambled images were more similar to fully scrambled responses than photographic responses, even for perceptually subtle changes. This same pattern emerged when these images were analyzed with an image-computable similarity metric that predicts human judgements of image degradation (DISTS - Deep Image Structure and Texture Similarity). Finally, analysis of response dynamics showed that sensitivity to differences between photographic and scrambled responses grew slowly, peaked 190 ms after response onset, and persisted for hundreds of milliseconds following response offset, suggesting that this signal may arise from recurrent mechanisms.

Biological and artificial neural systems form high-dimensional neural representations that underpin their computational capabilities. Methods for quantifying geometric similarity in neural representations have become a popular tool for identifying computational principles that are potentially shared across neural systems. These methods generally assume that neural responses are deterministic and static. However, responses of biological systems, and some artificial systems, are noisy and dynamically unfold over time. Furthermore, these characteristics can have substantial influence on a system’s computational capabilities. Here, we demonstrate that existing metrics can fail to capture key differences between neural systems with noisy dynamic responses. We then propose a metric for comparing the geometry of noisy neural trajectories, which can be derived as an optimal transport distance between Gaussian processes. We use the metric to compare models of neural responses in different regions of the motor system and to compare the dynamics of latent diffusion models for text-to-image synthesis.

Accurately placing macromolecular assemblies in the cellular context is important in understanding their mechanistic role inside the cell. Previously, we developed a 2D template-matching (2DTM) approach (Rickgauer et al., 2017[Rickgauer, J. P., Grigorieff, N. & Denk, W. (2017). eLife, 6, e25648.]; Lucas et al., 2021[Lucas, B. A., Himes, B. A., Xue, L., Grant, T., Mahamid, J. & Grigorieff, N. (2021). eLife, 10, e68946.]) in cisTEM (Grant et al., 2018[Grant, T., Rohou, A. & Grigorieff, N. (2018). eLife, 7, e35383.]) to detect targets in cellular cryo-EM images with high positional and orientational accuracy. 2DTM not only detects targets such as ribosomes in cryo-EM images but also provides data that enable the in situ classification and high-resolution reconstruction of these targets (Lucas et al., 2022[Lucas, B. A., Zhang, K., Loerch, S. & Grigorieff, N. (2022). eLife, 11, e79272.], 2023[Lucas, B. A., Himes, B. A. & Grigorieff, N. (2023). eLife, 12, 12RP90486.]; Elferich et al., 2022[Elferich, J., Schiroli, G., Scadden, D. T. & Grigorieff, N. (2022). eLife, 11, e80980.]). Building on these successes, this work aims to improve the 2DTM framework to detect more challenging targets in various environments.

A 2DTM search yields a signal-to-noise ratio (SNR) for every location in the cryo-EM image that depends on the cross-correlation between the template and the image (Rickgauer et al., 2017[Rickgauer, J. P., Grigorieff, N. & Denk, W. (2017). eLife, 6, e25648.]). A target is detected when the SNR value exceeds a statistically defined threshold that limits the average false positives to one per image, based on the assumption that the cryo-EM image is dominated by noise and cellular background and that the cross-correlation values observed across the image after whitening the noise/background follow a Gaussian distribution. The 2DTM SNR can be further normalized by subtracting the mean and dividing by the standard deviation of cross-correlations calculated across all sampled orientations at each location in the image (Rickgauer et al., 2017[Rickgauer, J. P., Grigorieff, N. & Denk, W. (2017). eLife, 6, e25648.]). This step is often referred to as `z-score' normalization (Spiegel & Stephens, 1999[Spiegel, M. R. & Stephens, L. J. (1999). Schaum's Outline of Theory and Problems of Statistics, 3rd ed. New York: McGraw-Hill.]). Using the z-score instead of the SNR improves the detection of capsomers in rotavirus double-layered particles (DLPs; Rickgauer et al., 2017[Rickgauer, J. P., Grigorieff, N. & Denk, W. (2017). eLife, 6, e25648.]) and ribosomes in a crowded cellular environment (Lucas et al., 2022[Lucas, B. A., Zhang, K., Loerch, S. & Grigorieff, N. (2022). eLife, 11, e79272.]). In the following, we will refer to the outputs of 2DTM as the 2DTM SNR and 2DTM z-score, respectively.

Previous applications of 2DTM have shown that the 2DTM SNR and z-score function differently depending on the characteristics of the sample and target. For example, when low-resolution features were suppressed by using a near-focus image setting (70 nm), the 2DTM SNR map showed a flat background with sharp peaks indicating the locations of apoferritins, even in a dense protein (bovine serum albumin) background (Rickgauer et al., 2017[Rickgauer, J. P., Grigorieff, N. & Denk, W. (2017). eLife, 6, e25648.]). On the other hand, low-resolution features from the target itself when strongly defocused (>2000 nm), or from the background structural noise, can result in broader peaks or an uneven background in the SNR map, complicating target detection (Rickgauer et al., 2017[Rickgauer, J. P., Grigorieff, N. & Denk, W. (2017). eLife, 6, e25648.]; Lucas et al., 2022[Lucas, B. A., Zhang, K., Loerch, S. & Grigorieff, N. (2022). eLife, 11, e79272.]). The misleading low-resolution background can be suppressed by calculating the 2DTM z-score (Rickgauer et al., 2017[Rickgauer, J. P., Grigorieff, N. & Denk, W. (2017). eLife, 6, e25648.]), which removes spurious correlations between the template and the structural noise in the image, thereby flattening the background and improving the detectability of targets in cellular environments (Rickgauer et al., 2020[Rickgauer, J. P., Choi, H., Lippincott-Schwartz, J. & Denk, W. (2020). bioRxiv, 2020.04.22.053868.]; Lucas et al., 2022[Lucas, B. A., Zhang, K., Loerch, S. & Grigorieff, N. (2022). eLife, 11, e79272.]). In Fig. 1[link](a), a segment of a previously published micrograph of a yeast lamella near the nucleus is presented (Lucas et al., 2022[Lucas, B. A., Zhang, K., Loerch, S. & Grigorieff, N. (2022). eLife, 11, e79272.]). This image section contains various cellular compartments located from left to right, including the vacuole, cytoplasm and nucleus. Using the mature 60S as a search template, 2DTM outputs a 2DTM SNR map and a 2DTM z-score map [Figs. 1[link](b) and 1[link](c)]. The bright spots in the 2DTM SNR map are locations with high correlation values, indicating 60S ribosomes. However, the peaks are surrounded by halos of increased SNR values extending to other low-resolution features in the image, such as membranes. The z-score map removes these halos and spurious matches of high-contrast features, thereby reducing the number of false detections (membranes or partial overlap with ribosomes) while preserving locations with high-resolution matches from the riboso

Quasi-2D Coulomb systems are of fundamental importance and have attracted much attention in many areas nowadays. Their reduced symmetry gives rise to interesting collective behaviors, but also brings great challenges for particle-based simulations. Here, we propose a novel algorithm framework to address the O(N2) simulation complexity associated with the long-range nature of Coulomb interactions. First, we introduce an efficient Sum-of-Exponentials (SOE) approximation for the long-range kernel associated with Ewald splitting, achieving uniform convergence in terms of inter-particle distance, which reduces the complexity to O(N7/5). We then introduce a random batch sampling method in the periodic dimensions, the stochastic approximation is proven to be both unbiased and with reduced variance via a tailored importance sampling strategy, further reducing the computational cost to O(N). The performance of our algorithm is demonstrated via various numerical examples. Notably, it achieves a speedup of 2∼3 orders of magnitude comparing with Ewald2D method, enabling molecular dynamics (MD) simulations with up to 106 particles on a single core. The present approach is therefore well-suited for large-scale particle-based simulations of Coulomb systems under confinement, making it possible to investigate the role of Coulomb interaction in many practical situations.

Large language models have demonstrated an impressive ability to perform factual recall. Prior work has found that transformers trained on factual recall tasks can store information at a rate proportional to their parameter count. In our work, we show that shallow transformers can use a combination of associative memories to obtain such near optimal storage capacity. We begin by proving that the storage capacities of both linear and MLP associative memories scale linearly with parameter count. We next introduce a synthetic factual recall task, and prove that a transformer with a single layer of self-attention followed by an MLP can obtain 100% accuracy on the task whenever either the total number of self-attention parameters or MLP parameters scales (up to log factors) linearly with the number of facts. In particular, the transformer can trade off between using the value matrices or the MLP as an associative memory to store the dataset of facts. We complement these expressivity results with an analysis of the gradient flow trajectory of a simplified linear attention model trained on our factual recall task, where we show that the model exhibits sequential learning behavior.

Macrocycles are a promising therapeutic class. The incorporation of heterochiral and non-natural chemical building-blocks presents challenges for rational design, however. With no existing machine learning methods tailored for heterochiral macrocycle design, we developed a novel convolutional autoencoder model to rapidly generate energetically favorable macrocycle backbones for heterochiral design and structure prediction. Our approach surpasses the current state-of-the-art method, Generalized Kinematic loop closure (GenKIC) in the Rosetta software suite. Given the absence of large, available macrocycle datasets, we created a custom dataset in-house and in silico. Our model, CyclicCAE, produces energetically stable backbones and designable structures more rapidly than GenKIC. It enables users to perform energy minimization, generate structurally similar or diverse inputs via MCMC, and conduct inpainting with fixed anchors or motifs. We propose that this novel method will accelerate the development of stable macrocycles, speeding up macrocycle drug design pipelines.

This paper provides an explicit formula for the approximate solution of the static London equations. These equations describe the currents and magnetic fields in a Type-I superconductor. We represent the magnetic field as a 2-form and the current as a 1-form, and assume that the superconducting material is contained in a bounded, connected set, Ω, with smooth boundary. The London penetration depth gives an estimate for the thickness of the layer near ∂Ω where the current is largely carried. In an earlier paper, we introduced a system of Fredholm integral equations of second kind, on ∂Ω, for solving the physically relevant scattering problems in this context. In real Type-I superconductors the penetration depth is very small, typically about 100nm, which often renders the integral equation approach computationally intractable. In this paper we provide an explicit formula for approximate solutions, with essentially optimal error estimates, as the penetration depth tends to zero. Our work makes extensive use of the Hodge decomposition of differential forms on manifolds with boundary, and thus evokes Kohn's work on the tangential Cauchy-Riemann equations.

Granular flows in small-outlet hoppers exhibit several characteristic but poorly understood behaviors: temporary clogs (pauses) where flow stops before later spontaneously restarting, permanent clogs that last indefinitely, and non-Gaussian, nonmonotonic flow-rate statistics. These aspects have been studied independently, but a model of hopper flow that explains all three has not been formulated. Here, we introduce a phenomenological model that provides a unifying dynamical mechanism for all three behaviors: coupling between the flow rate and a hidden mode that controls the stability of clogs. In the theory, flow rate evolves according to Langevin dynamics with multiplicative noise and an absorbing state at zero flow, conditional on the hidden mode. The model fully reproduces the statistics of pause and clog events of a large (>40000 flows) experimental dataset, including nonexponentially distributed clogging times and non-Gaussian flow rate distribution, and explains the stretched-exponential growth of the average clogging time with outlet size. Further, we identify the physical nature of the hidden mode in microscopic configurational features, including size and smoothness of the static arch structure formed during pauses and clogs. Our work provides a unifying framework for several poorly understood clogging phenomena, and suggests numerous new paths toward further understanding of this complex system.