Macromolecular interactions and geometrical confinement determine the 3D diffusion of ribosome-sized particles in live cells.

The crowded bacterial cytoplasm is composed of biomolecules that span several orders of magnitude in size and electrical charge. This complexity has been proposed as the source of the rich spatial organization and apparent anomalous diffusion of intracellular components, although this has not been tested directly. Here, we use biplane microscopy to track the 3D motion of self-assembled bacterial genetically encoded multimeric nanoparticles (bGEMs) with tunable size (20 to 50 nm) and charge (-3,240 to +2,700 e) in live cells.

Mapping the topography of spatial gene expression with interpretable deep learning.

Spatially resolved transcriptomics technologies provide high-throughput measurements of gene expression in a tissue slice, but the sparsity of these data complicates analysis of spatial gene expression patterns. We address this issue by deriving a topographic map of a tissue slice-analogous to a map of elevation in a landscape-using a quantity called the isodepth. Contours of constant isodepths enclose domains with distinct cell type composition, while gradients of the isodepth indicate spatial directions of maximum change in expression.

Local polar order controls mechanical stress and triggers layer formation in Myxococcus xanthus colonies.

Colonies of the social bacterium Myxococcus xanthus go through a morphological transition from a thin colony of cells to three-dimensional droplet-like fruiting bodies as a strategy to survive starvation. The biological pathways that control the decision to form a fruiting body have been studied extensively. However, the mechanical events that trigger the creation of multiple cell layers and give rise to droplet formation remain poorly understood.

measurements of receptor tyrosine kinase activity reveal feedback regulation of a developmental gradient.

A lack of tools for detecting receptor activity has limited our ability to fully explore receptor-level control of developmental patterning. Here, we extend a new class of biosensors for receptor tyrosine kinase (RTK) activity, the pYtag system, to visualize endogenous RTK activity in . We build biosensors for three RTKs that function across developmental stages and tissues.

Morphogenesis of bacterial cables in polymeric environments.

Many bacteria live in polymeric fluids, such as mucus, environmental polysaccharides, and extracellular polymers in biofilms. However, laboratory studies typically focus on cells in polymer-free fluids. Here, we show that interactions with polymers shape a fundamental feature of bacterial life-how they proliferate in space in multicellular colonies.

Resolving tissue complexity by multimodal spatial omics modeling with MISO.

Spatial molecular profiling has provided biomedical researchers valuable opportunities to better understand the relationship between cellular localization and tissue function. Effectively modeling multimodal spatial omics data is crucial for understanding tissue complexity and underlying biology. Furthermore, improvements in spatial resolution have led to the advent of technologies that can generate spatial molecular data with subcellular resolution, requiring the development of computationally efficient methods that can handle the resulting large-scale datasets.

Biological sex matters in brain aging.

Every cell in the body has a biological sex. The expansion of aging research to investigate female- and male-specific biology heralds a major advance for human health. Unraveling and harnessing mechanistic etiologies of sex differences may reveal new diagnostics and therapeutics for the aging brain.

Coancestry superposed on admixed populations yields measures of relatedness at individual-level resolution.

The admixture model is widely applied to estimate and interpret population structure among individuals. Here we consider a "standard admixture" model that assumes the admixed populations are unrelated and also a generalized model, where the admixed populations themselves are related via coancestry (or covariance) of allele frequencies. The generalized model yields a potentially more realistic and substantially more flexible model that we call "super admixture".

Dietary or pharmacological inhibition of insulin-like growth factor-1 protects from renal ischemia-reperfusion injury in mice.

One-week protein restriction (PR) limits ischemia-reperfusion (IR) damages and improves metabolic fitness. Similarly, longer-term calory restriction results in increased lifespan, partly via reduced insulin-like growth factor (IGF)-1. However, the influence of short-term PR on IGF-1 and its impact on IR are unknown.

Deriving a genetic regulatory network from an optimization principle.

Many biological systems operate near the physical limits to their performance, suggesting that aspects of their behavior and underlying mechanisms could be derived from optimization principles. However, such principles have often been applied only in simplified models. Here, we explore a detailed mechanistic model of the gap gene network in the embryo, optimizing its 50+ parameters to maximize the information that gene expression levels provide about nuclear positions.

Transcription factor clusters as information transfer agents.

Deciphering how genes interpret information from transcription factor (TF) concentrations within the cell nucleus remains a fundamental question in gene regulation. Recent advancements have revealed the heterogeneous distribution of TF molecules, posing challenges to precisely decoding concentration signals. Using high-resolution single-cell imaging of the fluorescently tagged TF Bicoid in living embryos, we show that Bicoid accumulation in submicrometer clusters preserves the spatial information of the maternal Bicoid gradient.

Sensitive and accurate proteome profiling of embryogenesis using Real-Time Search and TMTproC quantification.

Multiplexed proteomics has become a powerful tool for investigating biological systems. Using balancer-peptide conjugates (e.g.

Identifying causal genotype-phenotype relationships for population-sampled parent-child trios.

The process by which genes are transmitted from parent to child provides a source of randomization preceding all other factors that may causally influence any particular child phenotype. Because of this, it is natural to consider genetic transmission as a source of experimental randomization. In this work, we show how parent-child trio data can be leveraged to identify causal genetic loci by modeling the randomization during genetic transmission.

The geometric basis of epithelial convergent extension.

Shape changes of epithelia during animal development, such as convergent extension, are achieved through the concerted mechanical activity of individual cells. While much is known about the corresponding large-scale tissue flow and its genetic drivers, fundamental questions regarding local control of contractile activity on the cellular scale and its embryo-scale coordination remain open. To address these questions, we develop a quantitative, model-based analysis framework to relate cell geometry to local tension in recently obtained time-lapse imaging data of gastrulating embryos.

Engineered extrachromosomal oncogene amplifications promote tumorigenesis.

Focal gene amplifications are among the most common cancer-associated mutations but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1 Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs) in a spatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures.

Membrane wetting by biomolecular condensates is facilitated by mobile tethers.

Biomolecular condensates frequently rely on membrane interactions for localization, recruitment, and chemical substrates. These interactions are often mediated by membrane-anchored tethers, a feature overlooked by traditional wetting models. Using a surface free-energy framework that couples surface tension with tether density, we solve for the contact angle and tether density in a spherical cap geometry, generalizing the Young-Dupré equation.

Neo-Sex Chromosome Evolution in Treehoppers Despite Long-Term X Chromosome Conservation.

Sex chromosomes follow distinct evolutionary trajectories compared to the rest of the genome. In many cases, sex chromosomes (X and Y or Z and W) significantly differentiate from one another resulting in heteromorphic sex chromosome systems. Such heteromorphic systems are thought to act as an evolutionary trap that prevents subsequent turnover of the sex chromosome system.

Hiding in plain sight: a research parasite's perspective on new lessons in old data.

High-throughput techniques that measure thousands of analytes at once have become ubiquitous features of biological research. The increasing expectation that the raw data generated by these techniques be deposited to public repositories creates rich opportunities for secondary analysis of these datasets. Such opportunities can take multiple forms.

Finding the last bits of positional information.

In a developing embryo, information about the position of cells is encoded in the concentrations of morphogen molecules. In the fruit fly, the local concentrations of just a handful of proteins encoded by the gap genes are sufficient to specify position with a precision comparable to the spacing between cells along the anterior-posterior axis. This matches the precision of downstream events such as the striped patterns of expression in the pair-rule genes, but is not quite sufficient to define unique identities for individual cells.

Characterizing the genetic architecture of drug response using gene-context interaction methods.

Identifying factors that affect treatment response is a central objective of clinical research, yet the role of common genetic variation remains largely unknown. Here, we develop a framework to study the genetic architecture of response to commonly prescribed drugs in large biobanks. We quantify treatment response heritability for statins, metformin, warfarin, and methotrexate in the UK Biobank.

Adult single-nucleus neuronal transcriptomes of insulin signaling mutants reveal regulators of behavior and learning.

Gene expression in individual neurons can change during development to adulthood and can have large effects on behavior. Additionally, the insulin/insulin-like signaling (IIS) pathway regulates many of the adult functions of Caenorhabditis elegans, including learning and memory, via transcriptional changes. We used the deep resolution of single-nucleus RNA sequencing to define the adult transcriptome of each neuron in wild-type and daf-2 mutants, revealing expression differences between L4 larval and adult neurons in chemoreceptors, synaptic genes, and learning/memory genes.

Integrative Computational Framework, , Links Mutated Driver Genes to Expression Dysregulation Across 19 Cancer Types.

Though somatic mutations play a critical role in driving cancer initiation and progression, the systems-level functional impacts of these mutations-particularly, how they alter expression across the genome and give rise to cancer hallmarks-are not yet well-understood, even for well-studied cancer driver genes. To address this, we designed an integrative machine learning model, Dyscovr, that leverages mutation, gene expression, copy number alteration (CNA), methylation, and clinical data to uncover putative relationships between nonsynonymous mutations in key cancer driver genes and transcriptional changes across the genome. We applied Dyscovr pan-cancer and within 19 individual cancer types, finding both broadly relevant and cancer type-specific links between driver genes and putative targets, including a subset we further identify as exhibiting negative genetic relationships.