Publications

Active fluids consume fuel at the microscopic scale, converting this energy into forces that can drive macroscopic motions over scales far larger than their microscopic constituents. In some cases, the mechanisms that give rise to this phenomenon have been well characterized, and can explain experimentally observed behaviors in both bulk fluids and those confined in simple stationary geometries. More recently, active fluids have been encapsulated in viscous drops or elastic shells so as to interact with an outer environment or a deformable boundary. Such systems are not as well understood. In this work, we examine the behavior of droplets of an active nematic fluid. We study their linear stability about the isotropic equilibrium over a wide range of parameters, identifying regions in which different modes of instability dominate. Simulations of their full dynamics are used to identify their nonlinear behavior within each region. When a single mode dominates, the droplets behave simply: as rotors, swimmers, or extensors. When parameters are tuned so that multiple modes have nearly the same growth rate, a pantheon of modes appears, including zigzaggers, washing machines, wanderers, and pulsators.

Developing oocytes need large supplies of macromolecules and organelles. A conserved strategy for accumulating these products is to pool resources of oocyte-associated germline nurse cells. In Drosophila, these cells grow more than 100-fold to boost their biosynthetic capacity. No previously known mechanism explains how nurse cells coordinate growth collectively. Here, we report a cell cycle-regulating mechanism that depends on bidirectional communication between the oocyte and nurse cells, revealing the oocyte as a critical regulator of germline cyst growth. Transcripts encoding the cyclin-dependent kinase inhibitor, Dacapo, are synthesized by the nurse cells and actively localized to the oocyte. Retrograde movement of the oocyte-synthesized Dacapo protein to the nurse cells generates a network of coupled oscillators that controls the cell cycle of the nurse cells to regulate cyst growth. We propose that bidirectional nurse cell-oocyte communication establishes a growth-sensing feedback mechanism that regulates the quantity of maternal resources loaded into the oocyte.

Standard workflows for analyzing microbiomes often include the creation and curation of phylogenetic trees. Here we present EMPress, an interactive web tool for visualizing trees in the context of microbiome, metabolome, and other community data scalable to trees with well over 500,000 nodes. EMPress provides novel functionality—including ordination integration and animations—alongside many standard tree visualization features and thus simplifies exploratory analyses of many forms of ‘omic data.

Sedimentation in active fluids has come into focus due to the ubiquity of swimming micro-organisms in natural and industrial processes. Here, we investigate sedimentation dynamics of passive particles in a fluid as a function of bacteria E. coli concentration. Results show that the presence of swimming bacteria significantly reduces the speed of the sedimentation front even in the dilute regime, in which the sedimentation speed is expected to be independent of particle concentration. Furthermore, bacteria increase the dispersion of the passive particles, which determines the width of the sedimentation front. For short times, particle sedimentation speed has a linear dependence on bacterial concentration. Mean square displacement data shows, however, that bacterial activity decays over long experimental (sedimentation) times. An advection-diffusion equation coupled to bacteria population dynamics seems to capture concentration profiles relatively well. A single parameter, the ratio of single particle speed to the bacteria flow speed can be used to predict front sedimentation speed.

Convolutional neural networks (CNNs) have become a standard for analysis of biological sequences. Tuning of network architectures is essential for a CNN’s performance, yet it requires substantial knowledge of machine learning and commitment of time and effort. This process thus imposes a major barrier to broad and effective application of modern deep learning in genomics. Here we present Automated Modelling for Biological Evidence-based Research (AMBER), a fully automated framework to efficiently design and apply CNNs for genomic sequences. AMBER designs optimal models for user-specified biological questions through the state-of-the-art neural architecture search (NAS). We applied AMBER to the task of modelling genomic regulatory features and demonstrated that the predictions of the AMBER-designed model are significantly more accurate than the equivalent baseline non-NAS models and match or even exceed published expert-designed models. Interpretation of AMBER architecture search revealed its design principles of utilizing the full space of computational operations for accurately modelling genomic sequences. Furthermore, we illustrated the use of AMBER to accurately discover functional genomic variants in allele-specific binding and disease heritability enrichment. AMBER provides an efficient automated method for designing accurate deep learning models in genomics.

Convolutional neural networks (CNN) have become a standard approach for modeling genomic sequences. CNNs can be effectively built by Neural Architecture Search (NAS) by trading computing power for accurate neural architectures. Yet, the consumption of immense computing power is a major practical, financial, and environmental issue for deep learning. Here, we present a novel NAS framework,
AMBIENT, that generates highly accurate CNN architectures for biological sequences of diverse functions, while substantially reducing the computing cost of conventional NAS.

Chromosome segregation—the partitioning of genetic material into two daughter cells—is one of the most crucial processes in cell division. In all Eukaryotes, chromosome segregation is driven by the spindle, a microtubule-based, self-organizing subcellular structure. Extensive research performed over the past 150 years has identified numerous commonalities and contrasts between spindles in different systems. In this review, we use simple coarse-grained models to organize and integrate previous studies of chromosome segregation. We discuss sites of force generation in spindles and fundamental mechanical principles that any understanding of chromosome segregation must be based upon. We argue that conserved sites of force generation may interact differently in different spindles, leading to distinct mechanical mechanisms of chromosome segregation. We suggest experiments to determine which mechanical mechanism is operative in a particular spindle under study. Finally, we propose that combining biophysical experiments, coarse-grained theories, and evolutionary genetics will be a productive approach to enhance our understanding of chromosome segregation in the future.

Chromosome segregation—the partitioning of genetic material into two daughter cells—is one of the most crucial processes in cell division. In all Eukaryotes, chromosome segregation is driven by the spindle, a microtubule-based, self-organizing subcellular structure. Extensive research performed over the past 150 years has identified numerous commonalities and contrasts between spindles in different systems. In this review, we use simple coarse-grained models to organize and integrate previous studies of chromosome segregation. We discuss sites of force generation in spindles and fundamental mechanical principles that any understanding of chromosome segregation must be based upon. We argue that conserved sites of force generation may interact differently in different spindles, leading to distinct mechanical mechanisms of chromosome segregation. We suggest experiments to determine which mechanical mechanism is operative in a particular spindle under study. Finally, we propose that combining biophysical experiments, coarse-grained theories, and evolutionary genetics will be a productive approach to enhance our understanding of chromosome segregation in the future

Evaluating microbial community composition through next-generation sequencing has become increasingly accessible. However, metagenomic sequencing data sets provide researchers with only a snapshot of a dynamic ecosystem and do not provide information about the total microbial number, or load, of a sample. Additionally, DNA can be detected long after a microorganism is dead, making it unsafe to assume that all microbial sequences detected in a community came from living organisms. By combining relic DNA removal by propidium monoazide (PMA) with microbial quantification with flow cytometry, we present a novel workflow to quantify live microbial load in parallel with metagenomic sequencing. We applied this method to unstimulated saliva samples, which can easily be collected longitudinally and standardized by passive collection time. We found that the number of live microorganisms detected in saliva was inversely correlated with salivary flow rate and fluctuated by an order of magnitude throughout the day in healthy individuals. In an acute perturbation experiment, alcohol-free mouthwash resulted in a massive decrease in live bacteria, which would have been missed if we did not consider dead cell signal. While removing relic DNA from saliva samples did not greatly impact the microbial composition, it did increase our resolution among samples collected over time. These results provide novel insight into the dynamic nature of host-associated microbiomes and underline the importance of applying scale-invariant tools in the analysis of next-generation sequencing data sets.

The rise of antibiotic resistance calls for new therapeutics targeting resistance factors such as the New Delhi metallo-β-lactamase 1 (NDM-1), a bacterial enzyme that degrades β-lactam antibiotics. We present structure-guided computational methods for designing peptide macrocycles built from mixtures of L- and D-amino acids that are able to bind to and inhibit targets of therapeutic interest. Our methods explicitly consider the propensity of a peptide to favor a binding-competent conformation, which we found to predict rank order of experimentally observed IC50 values across seven designed NDM-1- inhibiting peptides. We were able to determine X-ray crystal structures of three of the designed inhibitors in complex with NDM-1, and in all three the conformation of the peptide is very close to the computationally designed model. In two of the three structures, the binding mode with NDM-1 is also very similar to the design model, while in the third, we observed an alternative binding mode likely arising from internal symmetry in the shape of the design combined with flexibility of the target. Although challenges remain in robustly predicting target backbone changes, binding mode, and the effects of mutations on binding affinity, our methods for designing ordered, bindingcompetent macrocycles should have broad applicability to a wide range of therapeutic targets.