Publications

We study the dynamics of proliferating cell collectives whose microscopic constituents' growth is inhibited by macroscopic growth-induced stress. Discrete particle simulations of a growing collective show the emergence of concentric-ring patterns in cell size whose spatio-temporal structure is closely tied to the individual cell's stress response. Motivated by these observations, we derive a multiscale continuum theory whose parameters map directly to the discrete model. Analytical solutions of this theory show the concentric patterns arise from anisotropically accumulated resistance to growth over many cell cycles. This work shows how purely mechanical processes can affect the internal patterning and morphology of cell collectives, and provides a concise theoretical framework for connecting the micro- to macroscopic dynamics of proliferating matter.

Nearly all circadian clocks maintain a period that is insensitive to temperature changes, a phenomenon known as temperature compensation (TC). Yet, it is unclear whether there is any common feature among different systems that exhibit TC. From a general timescale invariance, we show that TC relies on the existence of certain period-lengthening reactions wherein the period of the system increases strongly with the rates in these reactions. By studying several generic oscillator models, we show that this counterintuitive dependence is nonetheless a common feature of oscillators in the nonlinear (far-from-onset) regime where the oscillation can be separated into fast and slow phases. The increase of the period with the period-lengthening reaction rates occurs when the amplitude of the slow phase in the oscillation increases with these rates while the progression speed in the slow phase is controlled by other rates of the system. The positive dependence of the period on the period-lengthening rates balances its inverse dependence on other kinetic rates in the system, which gives rise to robust TC in a wide range of parameters. We demonstrate the existence of such period-lengthening reactions and their relevance for TC in all four model systems we considered. Theoretical results for a model of the Kai system are supported by experimental data. A study of the energy dissipation also shows that better TC performance requires higher energy consumption. Our study unveils a general mechanism by which a biochemical oscillator achieves TC by operating in parameter regimes far from the onset where period-lengthening reactions exist.

Learning in living organisms is typically associated with networks of neurons. The use of large numbers of adjustable units has also been a crucial factor in the continued success of artificial neural networks. In light of the complexity of both living and artificial neural networks, it is surprising to see that very simple organisms -- even unicellular organisms that do not possess a nervous system -- are capable of certain forms of learning. Since in these cases learning may be implemented with much simpler structures than neural networks, it is natural to ask how simple the building blocks required for basic forms of learning may be. The purpose of this study is to discuss the simplest dynamical systems that model a fundamental form of non-associative learning, habituation, and to elucidate technical implementations of such systems, which may be used to implement non-associative learning in neuromorphic computing and related applications.

Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs.

A primary cilium, made of nine microtubule doublets enclosed in a cilium membrane, is a mechanosensing organelle that bends under an external mechanical load and sends an intracellular signal through transmembrane proteins activated by cilium bending. The nine microtubule doublets are the main load-bearing structural component, while the transmembrane proteins on the cilium membrane are the main sensing component. No distinction was made between these two components in all existing models, where the stress calculated from the structural component (nine microtubule doublets) was used to explain the sensing location, which may be totally misleading. For the first time, we developed a microstructure-based primary cilium model by considering these two components separately. First, we refined the analytical solution of bending an orthotropic cylindrical shell for individual microtubule, and obtained excellent agreement between finite element simulations and the theoretical predictions of a microtubule bending as a validation of the structural component in the model. Second, by integrating the cilium membrane with nine microtubule doublets and simulating the tip-anchored optical tweezer experiment on our computational model, we found that the microtubule doublets may twist significantly as the whole cilium bends. Third, besides being cilium-length-dependent, we found the mechanical properties of the cilium are also highly deformation-dependent. More important, we found that the cilium membrane near the base is not under pure in-plane tension or compression as previously thought, but has significant local bending stress. This challenges the traditional model of cilium mechanosensing, indicating that transmembrane proteins may be activated more by membrane curvature than membrane stretching. Finally, we incorporated imaging data of primary cilia into our microstructure-based cilium model, and found that comparing to the ideal model with uniform microtubule length, the imaging-informed model shows the nine microtubule doublets interact more evenly with the cilium membrane, and their contact locations can cause even higher bending curvature in the cilium membrane than near the base.

Biomolecular recruitment by phase separated condensates has emerged as a key organising principle of biological processes. One such process is the RNA silencing pathway, which regulates gene expression and genomic defense against foreign nucleic acids. In C. elegans, this pathway involves siRNA amplification at perinuclear germ granules named Mutator foci. The formation of Mutator foci depends on the phase separation of MUT-16, acting as a scaffolding protein to recruit other components of the Mutator complex. Earlier studies have indicated a crucial role for an exoribonuclease, MUT-7, in RNA silencing. The recruitment of MUT-7 to Mutator foci is facilitated by a bridging protein, MUT-8. However, how MUT-8 binds to MUT-16 remains elusive. We resolved the molecular drivers of MUT-16 phase separation and the recruitment of MUT-8 using multi-scale molecular dynamics simulations and in vitro experiments. Residue-level coarse-grained simulations predicted the relative phase separation propensities of MUT-16 disordered regions, which we validated by experiments.

Coarse-grained simulations at residue-level and near atomic-resolution also indicated the essential role of aromatic amino acids (Tyr and Phe) in MUT-16 phase separation. Furthermore, coarse-grained and atomistic simulations of MUT-8 N-terminal prion-like domain with phase separated MUT-16 condensate revealed the importance of cation-π interaction between Tyr residues of MUT-8 and Arg/Lys residues of MUT-16. By re-introducing atomistic detail to condensates from coarse-grained and 350 µs all-atom simulations in explicit solvent on Folding@Home, we demonstrate Arg-Tyr interaction surpasses the strength of Lys-Tyr interactions in the recruitment of MUT-8. The atomistic simulations show that the planar guanidinium group of Arg also engages in sp2-π interaction, and hydrogen bonds with the Tyr residues and these additional favorable contacts are missing in the Lys-Tyr interactions. In agreement with simulations, the mutation of seven Arg residues in MUT-16 to Lys and Ala weakens MUT-8 binding in vitro.

Coiled-coil protein motifs have become widely employed in the design of biomaterials. Some of these designs have been studied for use in drug delivery due to the unique ability of coiled-coils to impart stability, oligomerization, and supramolecular assembly. To leverage these properties and improve drug delivery, release, and targeting, a variety of nano- to mesoscale architectures have been adopted. Coiled-coil drug delivery and therapeutics have been developed by using the coiled-coil alone, designing for higher-order assemblies such as fibers and hydrogels, and combining coiled-coil proteins with other biocompatible structures such as lipids and polymers. We review the recent development of these structures and the design criteria used to generate functional proteins of varying sizes and morphologies.

Nucleocytoplasmic transport is essential for cellular function, presenting a canonical example of rapid molecular sorting inside cells. It consists of a coordinated interplay between import/export of molecules in/out the cell nucleus. Here, we investigate the role of spatio-temporal dynamics of the nucleocytoplasmic transport and its regulation. We develop a biophysical model that captures the main features of the nucleocytoplasmic transport, in particular, its regulation through the Ran cycle. Our model yields steady-state profiles for the molecular components of the Ran cycle, their relaxation times, as well as the nuclear-to-cytoplasmic molecule ratio. We show that these quantities are affected by their spatial dynamics and heterogeneity within the nucleus. Specifically, we find that the spatial nonuniformity of Ran Guanine Exchange Factor (RanGEF) -- particularly its proximity to the nuclear envelope -- enhances the Ran cycle's efficiency. We further show that RanGEF's accumulation near the nuclear envelope results from its intrinsic dynamics as a nuclear cargo, transported by the Ran cycle itself. Overall, our work highlights the critical role of molecular spatial dynamics in cellular processes, and proposes new avenues for theoretical and experimental inquiries into the nucleocytoplasmic transport.

Deciphering the regulatory code of gene expression and interpreting the transcriptional effects of genome variation are critical challenges in human genetics. Modern experimental technologies have resulted in an abundance of data, enabling the development of sequence-based deep learning models that link patterns embedded in DNA to the biochemical and regulatory properties contributing to transcriptional regulation, including modeling epigenetic marks, 3D genome organization, and gene expression, with tissue and cell-type specificity. Such methods can predict the functional consequences of any noncoding variant in the human genome, even rare or never-before-observed variants, and systematically characterize their consequences beyond what is tractable from experiments or quantitative genetics studies alone. Recently, the development and application of interpretability approaches have led to the identification of key sequence patterns contributing to the predicted tasks, providing insights into the underlying biological mechanisms learned and revealing opportunities for improvement in future models.

Can the BlastAssist deep learning pipeline perform comparably to or outperform human experts and embryologists at measuring interpretable, clinically relevant features of human embryos in IVF?