Publications

Achieving macroscopic directed migration of microscale swimmers in a fluid is an
important step towards utilizing their autonomous motion. It has been experimentally shown that
directed motion can be induced, without any external fields, by certain geometrically asymmetric
obstacles due to interaction between their boundaries and the swimmers. In this paper, we propose
a kinetic-type model to study swimming and directional migration of microscale bimetallic rods in
a periodic array of posts with noncircular cross-sections. Both rod position and orientation are
taken into account; rod trapping and release on the post boundaries are modeled by empirically
characterizing curvature and orientational dependence of the boundary absorption and desorption.
Intensity of the directed rod migration, which we call the normalized net flux, is then defined and
computed given the geometry of the post array. We numerically study the effect of post spacings on
the flux; we also apply shape optimization to find better post shapes that can induce stronger flux.
Inspired by preliminary numerical results on two candidate posts, we perform an approximate analysis
on a simplified model to show the key geometric features that a good post should have. Based on
this, three new candidate shapes are proposed which give rise to large fluxes. This approach provides
an effective tool and guidance for experimentally designing new devices that induce strong directed
migration of microscale swimmers.

We study how a suspended liquid film is deformed by an external flow en route to forming a bubble through experiments and a model. We identify a family of nonminimal but stable equilibrium shapes for flow speeds up to a critical value beyond which the film inflates unstably, and the model accounts for the observed nonlinear deformations and forces. A saddle-node or fold bifurcation in the solution diagram suggests that bubble formation at high speeds results from the loss of equilibrium and at low speeds from the loss of stability for overly inflated shapes.

The mammalian kidney develops through reciprocal interactions between the ureteric bud and the metanephric mesenchyme to give rise to the entire collecting system and the nephrons. Most of our knowledge of the developmental regulators driving this process arises from the study of gene expression and functional genetics in mice and other animal models. In order to shed light on human kidney development, we have used single-cell transcriptomics to characterize gene expression in different cell populations, and to study individual cell dynamics and lineage trajectories during development. Single-cell transcriptome analyses of 6414 cells from five individual specimens identified 11 initial clusters of specific renal cell types as defined by their gene expression profile. Further subclustering identifies progenitors, and mature and intermediate stages of differentiation for several renal lineages. Other lineages identified include mesangium, stroma, endothelial and immune cells. Novel markers for these cell types were revealed in the analysis, as were components of key signaling pathways driving renal development in animal models. Altogether, we provide a comprehensive and dynamic gene expression profile of the developing human kidney at the single-cell level.

It is well-known that by placing judiciously chosen image point forces and doublets to the Stokeslet above a flat wall, the no-slip boundary condition can be conveniently imposed on the wall [Blake, J. R. Math. Proc. Camb. Philos. Soc. 70(2), 1971: 303.]. However, to further impose periodic boundary conditions on directions parallel to the wall usually involves tedious derivations because single or double periodicity in Stokes flow may require the periodic unit to have no net force, which is not satisfied by the well-known image system. In this work we present a force-neutral image system. This neutrality allows us to represent the Stokes image system in a universal formulation for non-periodic, singly periodic and doubly periodic geometries. This formulation enables the black-box style usage of fast kernel summation methods. We demonstrate the efficiency and accuracy of this new image method with the periodic kernel independent fast multipole method in both non-periodic and doubly periodic geometries. We then extend this new image system to other widely used Stokes fundamental solutions, including the Laplacian of the Stokeslet and the Rotne-Prager-Yamakawa tensor.

The biology and behavior of adults differ substantially from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific isolation to identify the transcriptomes of C. elegans' four major tissues (or "tissue-ome"), identifying ubiquitously expressed and tissue-specific "enriched" genes. These data newly reveal the hypodermis' metabolic character, suggest potential worm-human tissue orthologies, and identify tissue-specific changes in the Insulin/IGF-1 signaling pathway. Tissue-specific alternative splicing analysis identified a large set of collagen isoforms. Finally, we developed a machine learning-based prediction tool for 76 sub-tissue cell types, which we used to predict cellular expression differences in IIS/FOXO signaling, stage-specific TGF-β activity, and basal vs. memory-induced CREB transcription. Together, these data provide a rich resource for understanding the biology governing multicellular adult animals.

Key challenges for human genetics, precision medicine and evolutionary biology include deciphering the regulatory code of gene expression and understanding the transcriptional effects of genome variation. However, this is extremely difficult because of the enormous scale of the noncoding mutation space. We developed a deep learning–based framework, ExPecto, that can accurately predict, ab initio from a DNA sequence, the tissue-specific transcriptional effects of mutations, including those that are rare or that have not been observed. We prioritized causal variants within disease- or trait-associated loci from all publicly available genome-wide association studies and experimentally validated predictions for four immune-related diseases. By exploiting the scalability of ExPecto, we characterized the regulatory mutation space for human RNA polymerase II–transcribed genes by in silico saturation mutagenesis and profiled > 140 million promoter-proximal mutations. This enables probing of evolutionary constraints on gene expression and ab initio prediction of mutation disease effects, making ExPecto an end-to-end computational framework for the in silico prediction of expression and disease risk.

GIANT2 (Genome-wide Integrated Analysis of gene Networks in Tissues) is an interactive web server that enables biomedical researchers to analyze their proteins and pathways of interest and generate hypotheses in the context of genome-scale functional maps of human tissues. The precise actions of genes are frequently dependent on their tissue context, yet direct assay of tissue-specific protein function and interactions remains infeasible in many normal human tissues and cell-types. With GIANT2, researchers can explore predicted tissue-specific functional roles of genes and reveal changes in those roles across tissues, all through interactive multi-network visualizations and analyses. Additionally, the NetWAS approach available through the server uses tissue-specific/cell-type networks predicted by GIANT2 to re-prioritize statistical associations from GWAS studies and identify disease-associated genes. GIANT2 predicts tissue-specific interactions by integrating diverse functional genomics data from now over 61 400 experiments for 283 diverse tissues and cell-types. GIANT2 does not require any registration or installation and is freely available for use at http://giant-v2.princeton.edu.

Abstract Spindles are self-organized microtubule-based structures that segregate chromosomes during cell division. The mass of the spindle is controlled by the balance between microtubule turnover and nucleation. The mechanisms that control the spatial regulation of microtubule nucleation remain poorly understood. While previous work found that microtubule nucleators bind to microtubules in the spindle, it is still unclear whether this binding regulates the activity of those nucleators. Here we use a combination of experiments and mathematical modeling to investigate this issue. We measured the concentration of microtubules and soluble tubulin in and around the spindle. We found a very sharp decay in the concentration of microtubules at the spindle interface. This is inconsistent with a model in which the activity of nucleators is independent of their association with microtubules but consistent with a model in which microtubule nucleators are only active when bound to preexisting microtubules. This argues that the activity of microtubule nucleators is greatly enhanced when bound to microtubules. Thus, microtubule nucleators are both localized and activated by the microtubules they generate.

We investigate the dynamics of hydrodynamically interacting motile and non-motile stress-generating swimmers or particles as they invade a surrounding viscous fluid. Colonies of aligned pusher particles are shown to elongate in the direction of particle orientation and undergo a cascade of transverse concentration instabilities. Colonies of aligned puller particles instead are found to elongate in the direction opposite the particle orientation and exhibit dramatic splay as the group moves into the bulk. A linear stability analysis of concentrated line distributions of particles is performed and growth rates are found, using an active slender-body approximation, to match the results of numerical simulations. Thin concentrated bands of aligned pusher particles are always unstable, while bands of aligned puller particles can either be stable (immotile particles) or unstable (motile particles) with a growth rate which is non-monotonic in the force dipole strength. We also prove a surprising "no-flow theorem": a distribution initially isotropic in orientation loses isotropy immediately but in such a way that results in no fluid flow anywhere at any time.