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  1. Abstract

    Condensation by phase separation has recently emerged as a mechanism underlying many nuclear compartments essential for cellular functions. Nuclear condensates enrich nucleic acids and proteins, localize to specific genomic regions, and often promote gene expression. How diverse properties of nuclear condensates are shaped by gene organization and activity is poorly understood. Here, we develop a physics-based model to interrogate how spatially-varying transcription activity impacts condensate properties and dynamics. Our model predicts that spatial clustering of active genes can enable precise localization and de novo nucleation of condensates. Strong clustering and high activity results in aspherical condensate morphologies. Condensates can flow towards distant gene clusters and competition between multiple clusters lead to stretched morphologies and activity-dependent repositioning. Overall, our model predicts and recapitulates morphological and dynamical features of diverse nuclear condensates and offers a unified mechanistic framework to study the interplay between non-equilibrium processes, spatially-varying transcription, and multicomponent condensates in cell biology.

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  2. Abstract

    The blastoderm is a broadly conserved stage of early animal development, wherein cells form a layer at the embryo’s periphery. The cellular behaviors underlying blastoderm formation are varied and poorly understood. In most insects, the pre-blastoderm embryo is a syncytium: nuclei divide and move throughout the shared cytoplasm, ultimately reaching the cortex. InDrosophila melanogaster, some early nuclear movements result from pulsed cytoplasmic flows that are coupled to synchronous divisions. Here, we show that the cricketGryllus bimaculatushas a different solution to the problem of creating a blastoderm. We quantified nuclear dynamics during blastoderm formation inG. bimaculatusembryos, finding that: (1) cytoplasmic flows are unimportant for nuclear movement, and (2) division cycles, nuclear speeds, and the directions of nuclear movement are not synchronized, instead being heterogeneous in space and time. Moreover, nuclear divisions and movements co-vary with local nuclear density. We show that several previously proposed models for nuclear movements inD. melanogastercannot explain the dynamics ofG. bimaculatusnuclei. We introduce a geometric model based on asymmetric pulling forces on nuclei, which recapitulates the patterns of nuclear speeds and orientations of both unperturbedG. bimaculatusembryos, and of embryos physically manipulated to have atypical nuclear densities.

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  3. Abstract

    As the SARS-CoV-2 pandemic is rapidly progressing, the need for the development of an effective vaccine is critical. A promising approach for vaccine development is to generate, through codon pair deoptimization, an attenuated virus. This approach carries the advantage that it only requires limited knowledge specific to the virus in question, other than its genome sequence. Therefore, it is well suited for emerging viruses, for which we may not have extensive data. We performed comprehensive in silico analyses of several features of SARS-CoV-2 genomic sequence (e.g., codon usage, codon pair usage, dinucleotide/junction dinucleotide usage, RNA structure around the frameshift region) in comparison with other members of the coronaviridae family of viruses, the overall human genome, and the transcriptome of specific human tissues such as lung, which are primarily targeted by the virus. Our analysis identified the spike (S) and nucleocapsid (N) proteins as promising targets for deoptimization and suggests a roadmap for SARS-CoV-2 vaccine development, which can be generalizable to other viruses.

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  4. Abstract

    Droplet‐based single cell sequencing technologies, such as inDrop, Drop‐seq, and 10X Genomics, are catalyzing a revolution in the understanding of biology. Barcoding beads are key components for these technologies. What is limiting today are barcoding beads that are easy to fabricate, can efficiently deliver primers into drops, and thus achieve high detection efficiency. Here, this work reports an approach to fabricate dissolvable polyacrylamide beads, by crosslinking acrylamide with disulfide bridges that can be cleaved with dithiothreitol. The beads can be rapidly dissolved in drops and release DNA barcode primers. The dissolvable beads are easy to synthesize, and the primer cost for the beads is significantly lower than that for the previous barcoding beads. Furthermore, the dissolvable beads can be loaded into drops with >95% loading efficiency of a single bead per drop and the dissolution of beads does not influence reverse transcription or the polymerase chain reaction (PCR) in drops. Based on this approach, the dissolvable beads are used for single cell RNA and protein analysis.

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  5. Two robust rules have been discovered about animal hybrids: Heterogametic hybrids are more unfit (Haldane’s rule), and sex chromosomes are disproportionately involved in hybrid incompatibility (the large-X/Z effect). The exact mechanisms causing these rules in female heterogametic taxa such as butterflies are unknown but are suggested by theory to involve dominance on the sex chromosome. We investigate hybrid incompatibilities adhering to both rules inPapilioandHeliconiusbutterflies and show that dominance theory cannot explain our data. Instead, many defects coincide with unbalanced multilocus introgression between the Z chromosome and all autosomes. Our polygenic explanation predicts both rules because the imbalance is likely greater in heterogametic females, and the proportion of introgressed ancestry is more variable on the Z chromosome. We also show that mapping traits polygenic on a single chromosome in backcrosses can generate spurious large-effect QTLs. This mirage is caused by statistical linkage among polygenes that inflates estimated effect sizes. By controlling for statistical linkage, most incompatibility QTLs in our hybrid crosses are consistent with a polygenic basis. Since the two genera are very distantly related, polygenic hybrid incompatibilities are likely common in butterflies.

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    Free, publicly-accessible full text available October 31, 2024
  6. Free, publicly-accessible full text available August 1, 2024
  7. Free, publicly-accessible full text available July 1, 2024
  8. Problem-solving and reasoning involve mental exploration and navigation in sparse relational spaces. A physical analogue is spatial navigation in structured environments such as a network of burrows. Recent experiments with mice navigating a labyrinth show a sharp discontinuity during learning, corresponding to a distinct moment of “sudden insight” when mice figure out long, direct paths to the goal. This discontinuity is seemingly at odds with reinforcement learning (RL), which involves a gradual build-up of a value signal during learning. Here, we show that biologically plausible RL rules combined with persistent exploration generically exhibit discontinuous learning. In tree-like structured environments, positive feedback from learning on behavior generates a “reinforcement wave” with a steep profile. The discontinuity occurs when the wave reaches the starting point. By examining the nonlinear dynamics of reinforcement propagation, we establish a quantitative relationship between the learning rule, the agent’s exploration biases, and learning speed. Predictions explain existing data and motivate specific experiments to isolate the phenomenon. Additionally, we characterize the exact learning dynamics of various RL rules for a complex sequential task.

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  9. Foraging mammals exhibit a familiar yet poorly characterized phenomenon, ‘alternation’, a pause to sniff in the air preceded by the animal rearing on its hind legs or raising its head. Rodents spontaneously alternate in the presence of airflow, suggesting that alternation serves an important role during plume-tracking. To test this hypothesis, we combine fully resolved simulations of turbulent odor transport and Bellman optimization methods for decision-making under partial observability. We show that an agent trained to minimize search time in a realistic odor plume exhibits extensive alternation together with the characteristic cast-and-surge behavior observed in insects. Alternation is linked with casting and occurs more frequently far downwind of the source, where the likelihood of detecting airborne cues is higher relative to ground cues. Casting and alternation emerge as complementary tools for effective exploration with sparse cues. A model based on marginal value theory captures the interplay between casting, surging, and alternation.

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  10. Passive acoustic monitoring is emerging as a low-cost, non-invasive methodology for automated species-level population surveys. However, systems for automating the detection and classification of vocalizations in complex soundscapes are significantly hindered by the overlap of calls and environmental noise. We propose addressing this challenge by utilizing an acoustic vector sensor to separate contributions from different sound sources. More specifically, we describe and implement an analytical pipeline consisting of (1) calculating direction-of-arrival, (2) decomposing the azimuth estimates into angular distributions for individual sources, and (3) numerically reconstructing source signals. Using both simulation and experimental recordings, we evaluate the accuracy of direction-of-arrival estimation through the active intensity method (AIM) against the baselines of white noise gain constraint beamforming (WNC) and multiple signal classification (MUSIC). Additionally, we demonstrate and compare source signal reconstruction with simple angular thresholding and a wrapped Gaussian mixture model. Overall, we show that AIM achieves higher performance than WNC and MUSIC, with a mean angular error of about 5°, robustness to environmental noise, flexible representation of multiple sources, and high fidelity in source signal reconstructions.

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