Biology subjects

Johnson, Z.

Publications and source records attributed to Johnson, Z..

18 recordsLinked to original sources

bioRxiv2026

Metabolites cross the membrane, the transcriptome does not follow: co-localization is required for the cyanobacterial response to a yeast partner

Interactions between phototrophs and heterotrophs are usually explained by cross-feeding, yet whether that exchange alone accounts for the phototroph's response has rarely been tested. We grew the sucrose-secreting cyanobacterium Synechococcus elongatus with the yeast Rhodotorula toruloides as a synthetic community, either in mixed co-culture or in membrane-separated co-culture (0.22 m pore size), each with a matched axenic control. Metabolite exchange occurred in both configurations: sucrose reached the yeast and was consumed, and yeast-derived metabolites reached the cyanobacterium. The yeast reached a higher final density behind the membrane, whereas the cyanobacterium gained about 9% over its axenic control only in mixed co-culture. Yet the cyanobacterial transcriptome responded only with co-localization: expression of 51 genes changed consistently across time points (day-averaged q < 0.05), against one gene behind the membrane, and the number of differentially expressed genes rose from 20 on day 4 to 91 and 127 on days 6 and 8. Nine regulatory programs (iModulons), mainly nitrogen and photosynthesis, responded in mixed co-culture and none behind the membrane. Reactor configuration alone changed 40 genes in axenic culture. These results suggest that co-localization, in addition to metabolite exchange, was required for the heterotrophic partner to trigger a response in the phototroph. Co-culture studies that infer interactions from shared metabolites may miss effects that depend on spatial structure. Importance Partnerships between light-powered microbes and the heterotrophs living alongside them move large amounts of carbon in oceans and soils, and are now built on purpose to turn carbon dioxide into fuels and chemicals. Such partnerships are usually described by the chemicals the partners trade, so we asked whether those chemicals are enough. The cyanobacterium Synechococcus elongatus and the yeast Rhodotorula toruloides were grown together in one vessel, or in two chambers divided by a membrane that molecules cross but cells cannot. The yeast fed on cyanobacterial sugar in both, yet the cyanobacterium changed its gene activity only when the two shared a space. Partners in nature are usually clustered rather than evenly mixed, so closeness may contribute as much as the chemicals themselves. Keeping partners apart in engineered cultures can still deliver carbon to the heterotroph, but may not deliver the benefits of partnership to the phototroph.

microbiology↗

bioRxiv2026

CFTR dysfunction in the intestinal epithelium is sufficient to promote pathogenic expansion of E. coli and enhanced barrier permeability in cystic fibrosis

Changes in the gut microbiome in cystic fibrosis (CF) are well characterized, yet their causes and downstream effects remain largely unknown. Well-documented alterations include reduced overall complexity (i.e. alpha diversity) of the gut microbiota and increased relative abundance of E. coli, which are associated with greater inflammation and shorter stature in infants. Previous results from our laboratory using a germ-free cystic fibrosis transmembrane conductance regulator (Cftr) mutant mouse model (CF mouse) demonstrated that the observed fecal microbiome dysbiosis is driven by mutated Cftr independent of factors such as diet or antibiotic treatment. We expand on these results in this report by using the defined 8-member community Altered Schaedler Flora (ASF) with and without E. coli, to show that E. coli is pathogenic in the context of the CF gut microbiome, resulting in increased intestinal permeability. We also show that Cftr deletion in intestinal epithelial cells alone, using a Villin-Cre targeted model, is sufficient to raise E. coli abundance in the fecal microbiome, increase intestinal permeability, and amplify the number of TH17 cells in the mesenteric lymph nodes. Together, our results demonstrate that the intestinal epithelium plays a dominant role in fecal microbiome alterations in CF and that the resultant dysbiosis contributes to CF pathogenesis.

microbiology↗

bioRxiv2026

Stress-Related Transcriptional Regulators Dominate the Conserved Core GRN for Three Cyanobacteria: Network Topology Maps the Highest-Influence Nodes as Promising Engineering Targets

Cyanobacteria manage photosynthetic and environmental stresses through transcriptional programs controlled by regulators also affecting carbon flux, growth states, and metabolic output that bioproduction seeks to optimize. This regulatory architecture and its most influential nodes remain incompletely characterized. We hypothesized two influential regulator layers: a conserved core responding to common stresses, and species-specific regulators mediating strain-level niche adaptations. Mapping both layers underpins understanding genome[->]regulatory-network[->]phenotype flow, enabling global transcription machinery engineering for reliable bioproduction. To test our hypothesis, we constructed conserved-core and species-specific gene regulatory networks (GRNs) for three cyanobacteria, Synechococcus elongatus PCC 7942, Synechocystis sp. PCC 6803 and Picosynechococcus sp. PCC 7002, integrating a manually curated multi-pipeline regulator inventory with 1,098 harmonized transcriptome states for the 1,362-gene tri-homolog core genome. We quantified each regulator influence using local (degree, k-core), global (betweenness, closeness), and community-aware (eigenvector) centrality measures, and an Integrated Centrality score aggregating influence across complementary topological measures. High-influence regulators are predicted to exert broad metabolic effects when manipulated, making them priority candidates for single-target engineering interventions that modulate multiple genes and reprogram complex phenotypes. Across the three cyanobacteria, the two GRN layers proved topologically distinct: the conserved core concentrated influence in stress-related hubs (11 of its top 15 by Integrated Centrality were stress-related), while species-specific networks spread influence across functionally diverse regulators. Stress-coupled enrichment also held per individual centrality measure: regulators ranking top in both the core and species-specific GRNs by the same measure were mostly stress-related (15 of 19 instances), including the multi-stress regulators RpaB, Rre1, and BolA, the heat-shock HrcA, and the nitrogen NtcA. In species-specific GRNs, stress-related regulators remained the leading category alongside circadian, carbon-metabolism, morphology, and housekeeping regulators, including PlmA, Pex, TetR, and SrrB in PCC 7942; KaiC3, Sycrp1, Rre28, and Bhl in PCC 6803; and Zur, Sycrp1, and NarL in PCC 7002. High-influence putative regulators included the iron-stress AraC-family paralogs IutR1-IutR3, OmpR-family paralogs OmpR1-OmpR2, and chromosome- or plasmid-encoded Xre-family, AraC, and HypP. Stress regulation emerges as a recurring high-influence axis across these networks. The conserved core identifies universal regulatory programs, and species-specific layers reveal strain-level innovations for cross-strain transfer to support engineering of robust bioproduction. ImportanceCyanobacteria are studied as platforms for sustainable, carbon-recycling production of fuels and chemicals from sunlight, water, and atmospheric carbon dioxide. Their reliable deployment in industrial settings is limited by environmental stresses that depress photosynthetic efficiency and product yields. The same regulatory proteins that govern stress responses also control how cells partition carbon, switch growth states, and direct metabolic output, making them natural levers for engineering robust production strains. Yet systematic, cross-species maps of these regulators have been missing. We present the first comparative regulatory map spanning three biotechnologically important model cyanobacteria, Synechococcus elongatus PCC 7942, Synechocystis sp. PCC 6803, and Picosynechococcus sp. PCC 7002, and identify the conserved regulators most influential across all three. The resulting catalog prioritizes candidate targets for experimental validation, and the supporting datasets and analytical framework are released for reuse to support efforts to engineer cyanobacterial strains for reliable industrial bioproduction.

systems biology↗

bioRxiv2026

Adaptive Neural Reorganization Enables Real-Time Finger-Level Robotic Control in BCI-Naïve Stroke Survivors

Restoring hand function remains a major challenge for individuals with motor impairments following stroke. Noninvasive brain-computer interfaces (BCIs) aim to address this problem by translating neural signals into robotic assistance; however, control of individual fingers has not been demonstrated in BCI-naive populations. In this study, we investigated whether individuals with stroke and no prior BCI experience could achieve finger-level robotic control using motor imagery. Nine stroke-affected participants performed real-time BCI tasks to control a robotic hand through imagined finger movements decoded from electroencephalography. On average, participants achieved decoding accuracies of 84% for two-finger tasks and 61% for three-finger tasks, demonstrating reliable control at the level of individual fingers. These results indicate that discriminable neural signals for fine motor control persist after stroke and can be leveraged using data-driven deep learning decoders. Sensor-level and source-level electrophysiological analyses further reveal patterns of stroke-related neural reorganization. Overall, these findings support the potential of noninvasive, finger-level BCIs for post-stroke robotic assistance.

neuroscience↗

bioRxiv2026

Extreme genome reduction selectively retains modular regulatory architecture in Prochlorococcus MED4: conserved transcriptional modules reveal core physiological regulatory programs

Prochlorococcus MED4 is a minimal photoautotroph whose extreme genome streamlining extends to its transcriptional regulatory architecture, yet it dominates high-light oligotrophic surface waters and drives marine carbon cycling. Despite ecological significance, MED4 remains genetically intractable, lacking molecular tools to characterize regulatory mechanisms and construct a transcriptome-wide regulatory map. To address this, we assembled an RNA-seq compendium of 253 samples, including 207 new samples capturing transcriptional responses across three classes of experiments: diverse environmental perturbations, a 24-hour circadian cycle, and phage infection. Using independent component analysis (ICA) applied to 247 quality-filtered samples, we identify 32 independently regulated gene set modules in MED4 (iModulons). By comparison, we previously identified 78 iModulons in the model cyanobacterium Synechococcus elongatus PCC 7942, revealing how dramatically genome reduction has simplified MED4s regulatory architecture. Of the 32 iModulons in MED4, 13 are conserved modules that correlate with experimentally validated transcriptional regulons in PCC 7942, identifying regulatory programs that resisted elimination under extreme selective pressure. These conserved modules reveal regulatory programs governing photosynthesis and light responses (RpaB), circadian rhythms (RpaA), and nutrient assimilation (NtcA, PhoB). Known regulator-specific DNA-binding motifs upstream of genes in conserved modules independently support their identification as regulatory targets. Notably, RpaA governs circadian rhythms through three temporally distinct modules in MED4 versus one in PCC 7942, and the RpaB photoprotection module similarly splits into two. This work uncovers the minimal regulatory core governing photosynthesis, circadian rhythms, and C/N/P metabolism in a globally critical but genetically intractable photoautotroph. This approach offers a generalizable framework for regulatory inference beyond model organisms. ImportanceThe minimal photoautotroph Prochlorococcus MED4 possesses only 28 transcriptional regulators, versus 150+ found in most cyanobacteria, reflecting a genome streamlined by billions of years of natural selection. This streamlining minimized metabolic costs, enabling MED4 to dominate nutrient-depleted oceans today. This raises a fundamental question: which regulatory programs did nature choose to keep? The answer matters, but MED4 cannot be studied by conventional genetics, placing its molecular machinery beyond direct experimental reach. Instead, we use large-scale computational methods to define groups of co-regulated genes in MED4. By comparing MED4 with a genetically tractable model cyanobacterium, we can distinguish which regulatory programs nature preserved from those it discarded. This work reveals the minimal regulatory architecture sufficient to sustain the smallest oxygenic photoautotroph on Earth. The principles uncovered here, distinguishing essential from dispensable regulatory programs in a naturally streamlined organism, inform the design of minimal photosynthetic platforms for biotechnology.

systems biology↗

bioRxiv2026

EEG Foundation Model Improves Online Directional Motor Imagery Brain-computer Interface Control

Brain-Computer interfaces (BCIs) offer a link between neural signals and external computation, enabling control of devices for the purposes of restoring function to motor-affected individuals and enhancing capabilities of a wider set of populations. Electroencephalography (EEG) offers a high temporal resolution for dynamic and potential real-time feedback for non-invasive systems. However, its practical efficacy remains limited due to low spatial resolution and poor signal-to-noise ratio, leading to insufficient decoding accuracy and unintuitive control paradigms that hinder reliable user interaction. In this study, we present a framework for an online EEG foundation model by creating a custom foundation model through spectrogram reconstruction of compact temporal windows and online constraints during pretraining. We evaluate the performance of the model in a challenging control paradigm of single-arm, directional motor imagery with dynamic movements for guided and free movement cursor control tasks. Our foundation model approach achieved a final average accuracy of 51.3% during a goal-oriented guided control task. This represents a 15.8% increase over a conventional deep learning framework and a 26.3% increase above chance level, evaluated in a cohort of 11 human participants. During the free movement task, the foundation model invoked a higher rate of completion and lower completion times. Furthermore, the custom EEG foundation model demonstrated superior adaptability from same-session finetuning and indicated an enhanced capability to assist subject learning. These findings highlight the potential of EEG foundation models to support more robust and intuitive non-invasive BCI systems, providing a promising modelling framework for future BCI development.

bioengineering↗

bioRxiv2026

Spatiotemporal 4D Whole-cell Modeling of a Minimal Autotroph Reveals Central Carbon Metabolism Regulated Locally by Protein Megacomplexes via Post-translational Modifications under Light Disturbance

Photosynthetic microorganisms rely on multiple pathways in central carbon metabolism to adapt to fluctuating light and energy availability across diel cycles. Mechanistic insight into the regulatory dynamics of this adaptation requires integrating processes spanning disparate timescales, from rapid redox-dependent post-translational modifications (PTMs) to slower changes in protein expression and metabolic pathway usage. To address this complexity beyond genome-based inference and traditional modeling, we develop a whole-cell four-dimensional (3D + time) model of the marine cyanobacterium Prochlorococcus marinus MED4 that explicitly represents the spatial organization of enzymatic and molecular processes in central carbon metabolism under light perturbation. We employ a perturbation-based research design to experimentally generate time-series, multi-omics measurements that provide molecular descriptors and cryo-ET images as constraints for this dynamic 4D framework. The integration of experiments and modeling across defined light regimes enables quantitative validation of system-level responses and forecasting under distinct light disturbances. We test the hypothesis that light-dependent redox PTMs regulating the structural assembly of a protein megacomplex, the "dark complex," modulate metabolic flux at a conserved regulatory node of the Calvin-Benson cycle (CBC) in cyanobacteria. Our model shows that subcellular spatial organization buffers rapid light-induced changes in thylakoid reaction rates, which are followed by redox-PTM-mediated sequestration or release of CBC enzymes in the dark complex, ultimately impacting carbon fixation dynamics within carboxysomes. Comparison with an equivalently parameterized well-mixed stochastic model demonstrates that post-translational regulation not only buffers transcriptional noise and diffusion-driven fluctuations but also stabilizes phenotypic outcomes, underscoring the importance of spatial heterogeneity in phenotypic robustness. This ability to probe adaptive, spatiotemporally resolved mechanisms in photosynthetic machinery and central carbon metabolism addresses a critical gap in genotype-to-phenotype inference and expands modeling and design capabilities for understudied or genetically intractable autotrophs such as P. marinus MED4. Significance StatementThis work advances 4D whole-cell modeling by presenting the first spatiotemporal simulation of a photosynthetic autotroph using the Lattice Microbes platform. Using Prochlorococcus marinus MED4, we show that subcellular spatial organization of organelles, diffusion constraints, and redox regulation collectively shape central carbon metabolism across orders of magnitude in space and time. Through a perturbation-based strategy that generates multi-omics data sets over time, we construct and validate a spatially and temporally resolved model of MED4, constrained by high-resolution (10 nm) cryo-electron tomography. Our results highlight the importance of localized biochemical reactions and redox-dependent post-translational modification of enzymes in regulating carbon fixation in a noisy environment under light disturbance. This study establishes a spatiotemporal, whole-cell physiology modeling framework as a transformative tool for uncovering multiscale regulatory responses to environmental gradients.

systems biology↗

bioRxiv2025

Developmental time course of social touch, parvalbumin interneurons, perineuronal nets and Mef2c expression reveals a sensitive period of somatosensory cortex development in prairie voles

Social touch facilitates our attachment to others, especially early in life, which may be linked to the maturation of parvalbumin interneurons (PVI) in the somatosensory cortex (S1). These neurons respond to social touch, mature in a sensory experience-dependent manner, and influence both somatosensory processing and social behavior in models of Autism Spectrum Disorder. Prairie voles (Microtus ochrogaster) are an ideal rodent model for studying these concepts since they engage in a species-typical social touch called "huddling". This study first showed that over development from juvenile to adult, same-sex siblings huddled less and explored more. Next, we tracked two markers of plasticity indicative of PVI maturation, extracellular perineuronal nets (PNNs) and nuclear transcription factor Myocyte enhancing factor 2C (Mef2c) - across seven developmental timepoints. We found that, while PV expression in S1 was stable by P21, PNNs and Mef2c continued to shift afterwards, indicating a protracted development. Four unique clusters of PVIs converge during development between P14-P21, suggesting a sensitive period of PVI development. Finally, to determine environmental factors affecting these processes, environmental enrichment between P21-P28 led to accelerated PVI maturation. This developmental mapping provides a particularly salient model to investigate the molecular underpinnings of cortical and social development.

neuroscience↗

bioRxiv2025

Modular cyanobacterial regulatory architecture enables dynamic graded responses to oxidative stress

A fundamental paradox of oxygenic photosynthesis: growth-essential energy machinery generates reactive oxygen species (ROS) threatening survival, yet the systems-level regulatory networks balancing the growth-survival trade-off remain unclear. Through integrative experimental-computational analysis combining steady-state transcriptomics with independent component analysis across 0-78.4% oxygen, we decoded the regulatory architecture driving progressive transitions in Synechococcus elongatus PCC 7942 from ROS sensing through defense to growth shutdown. Integration of 407 transcriptome samples identified 78 regulatory modules (iModulons) explaining 72.3% of expression variance and revealed calibrated responses: low stress triggers metalloregulators (SufR, PerR) for ROS sensing and primary antioxidants; moderate stress activates RpaB operating through four distinct regulatory states redirecting metabolism to defense; severe stress induces growth arrest via stringent response pathway convergence. This quantitative regulatory framework enables precise growth-defense calibration through modular network architecture: RpaB coordinates genome-wide resource reallocation (RpaB[~]P growth-promoting, RpaB ROS defense-activating, RpaABC circadian-integrating, RpaB ycf46 checkpoint activation), offering systematic strategies for engineering stress-tolerant bioplatforms and predictive models for environmental stress responses.

systems biology↗

bioRxiv2025

Epitranscriptome-wide profiling identifies RNA editing events regulated by ADAR1 that are associated with DNA repair mechanisms in human TK6 cells

Adenosine-to-inosine (A-to-I) editing is an endogenous RNA modification in eukaryotes, catalyzed by adenosine deaminases acting on RNA (ADARs). This modification modulates the gene expression by influencing splicing, RNA stability, and coding potential, depending on the site of editing. Although recent studies suggest a crosstalk between A-to-I editing and transcripts involved in DNA repair, the extent and functional significance of this interaction remain unclear. To investigate this, we applied the EpiPlex RNA assay--a method enabling epitranscriptome-wide detection of RNA modifications--in human lymphoblastoid TK6 cells. Across two biological replicates, we identified 869 transcripts bearing A-to-I-modifications. Gene Ontology analysis revealed significant enrichment in genome maintenance pathways, including "chromatin remodeling" and "DNA repair." Notably, 27 transcripts encoding DNA repair proteins--such as ATM, FANCA, BRCA1, POLH, and XPA--contained A-to-I sites within introns or 3' untranslated regions. To assess the isoform-specific contributions of ADAR enzymes--specifically ADAR1 p150 and p110--to RNA editing, we generated p150-deficient (p150 KO) and p150/p110-deficient (p150/p110 KO) TK6 cells. A-to-I editing peaks were reduced by [~]73.4% in p150 KO cells and nearly abolished (99.9%) in p150/p110 KO cells, indicating that most editing sites are p150-dependent, while a notable subset relies on p110. Importantly, a novel splice variant of XPA emerged in ADAR1-deficient cells, suggesting a role for RNA editing in alternative splicing regulation. Our epitranscriptomic analysis of A-to-I RNA editing underscores a multifaceted role for ADAR1-dependent editing in preserving genome integrity through posttranscriptional regulation of DNA repair genes, laying the groundwork for future studies into RNA-based mechanisms of genome maintenance.

genetics↗

bioRxiv2024

Mapping multiple RNA modifications simultaneously by proximity barcode sequencing

RNA is subject to a multitude of different chemical modifications that collectively represent the epitranscriptome. Individual RNA modifications including N6-methyladenosine (m6A) on mRNA play essential roles in the posttranscriptional control of gene expression. Recent technological advances have enabled the transcriptome-wide mapping of certain RNA modifications, to reveal their broad relevance and characteristic distribution patterns. However, convenient methods that enable the simultaneous mapping of multiple different RNA marks within the same sample are generally lacking. Here we present EpiPlex RNA modification profiling, a bead-based proximity barcoding assay with sequencing readout that expands the scope of molecular recognition-based RNA modification detection to multiple targets, while providing relative quantification and enabling low RNA input. Measuring signal intensity against spike-in controls provides relative quantification, indicative of the RNA mod abundance at each locus. We report on changes in the modification status of HEK293T cells upon treatment with pharmacological inhibitors separately targeting METTL3, the dominant m6A writer enzyme, and the EIF4A3 component of the exon junction complex (EJC). The treatments resulted in decreased or increased m6A levels, respectively, without effect on inosine levels. Inhibiting the helicase activity of EIF4A3 and EIF4A3 knockdown both cause a significant increase of m6A sites near exon junctions, consistent with the previously reported role of EIF4A3 in shaping the m6A landscape. Thus, EpiPlex offers a reliable and convenient method for simultaneous mapping of multiple RNA modifications to facilitate epitranscriptome studies.

genomics↗

bioRxiv2023

A Gulf Stream cold-core eddy harbors a distinct microbiome compared to environmentally-similar adjacent waters

AbstractMesoscale oceanographic features, including eddies, have the potential to alter productivity and other biogeochemical rates in the ocean. Here, we examine the microbiome of a cyclonic, Gulf Stream frontal eddy, with a distinct origin and environmental parameters compared to surrounding waters, in order to better understand the processes dominating microbial community assembly in the dynamic coastal ocean. Our microbiome-based approach identified the eddy as distinct from the surround Gulf Stream waters. The eddy-associated microbial community occupied a larger area than identified by temperature and salinity alone, increasing the predicted extent of eddy-associated biogeochemical processes. While the eddy formed on the continental shelf, after two weeks both environmental parameters and microbiome composition of the eddy were most similar to the Gulf Stream, suggesting the effect of environmental filtering on community assembly or physical mixing with adjacent Gulf Stream waters. In spite of the potential for eddy-driven upwelling to introduce nutrients and stimulate primary production, eddy surface waters exhibit lower chlorophyll a along with a distinct and less even microbial community, compared to the Gulf Stream. At the population level, the eddy microbiome exhibited differences among the cyanobacteria (e.g. lower Trichodesmium and higher Prochlorococcus) and in the heterotrophic alpha Proteobacteria (e.g. lower relative abundances of specific SAR11 clades) versus the Gulf Stream. However, better delineation of the relative roles of processes driving eddy community assembly will likely require following the eddy and surrounding waters since inception; additionally, sampling throughout the water column could better clarify the contribution of these mesoscale features to primary production and carbon export in the oceans.

ecology↗

bioRxiv2023

Investigating a Gulf Stream Frontal Eddy North of Cape Hatteras: Questioning Overall Impacts on Ecology

Ocean physics and biology can interact in myriad and complex ways. Eddies, features found at many scales in the ocean, can drive substantial changes in physical and biogeochemical fields with major implications for marine ecosystems. Mesoscale eddies are challenging to model and difficult to observe synoptically at sea due to their fine-scale variability yet broad extent. In this work we observed a frontal eddy just north of Cape Hatteras via an intensive hydrographic, biogeochemical, and optical sampling campaign. Frontal eddies occur in western boundary currents around the globe and there are major gaps in our understanding of their ecosystem impacts. In the Gulf Stream, frontal eddies have been studied in the South Atlantic Bight, where they are generally assumed to shear apart passing Cape Hatteras. However, we found that the observed frontal eddy had different physical properties and phytoplankton community composition from adjacent water masses, in addition to continued cyclonic rotation. In this work we first synthesize the overall ecological impacts of frontal eddies in a simple conceptual model. This conceptual model led to the hypothesis that frontal eddies could be well timed to supply zooplankton to secondary consumers off Cape Hatteras where there is a notably high concentration and diversity of top predators. Towards testing this hypothesis and our conceptual model we report on the biogeochemical state of this particular eddy connecting physical and biological dynamics, analyze how it differs from Gulf Stream and shelf waters even in "death", and refine our initial model with this new data. Key PointsO_LIIn-depth investigation of a frontal eddy in the Gulf Stream off Cape Hatteras, North Carolina C_LIO_LIContinued physical and biogeochemical differences are observed between the eddy and adjacent water masses even as it begins to shear apart C_LIO_LIWe share a conceptual model of the ecological impact of frontal eddies with a hypothesis that they supply zooplankton to secondary consumers C_LI Plain Language SummaryFrontal eddies are spinning masses of water (~30km in diameter) that move along western boundary currents like the Gulf Stream. When they form they carry productive coastal water into the Gulf Stream and drive upwelling within their cores. Together this leads to an increase in the amount of phytoplankton within them - much higher compared to surrounding nutrient-limited Gulf Stream water. On the east coast of the United States one common area of frontal eddy formation is just off Charleston, SC. Eddies then travel up the coast and dissipate near Cape Hatteras, NC. In this work we measured a wide range of physical and biological properties of a frontal eddy just north of Cape Hatteras. We compared these properties within the eddy to the coastal water on one side and the Gulf Stream water on the other, finding clear differences in phytoplankton community composition and other physical and chemical properties. Using the results of these observations together with previous studies we share a simple model for how frontal eddies may impact phytoplankton, zooplankton, and fish - hypothesizing that they may contribute to the high diversity and density of top predators off Cape Hatteras.

ecology↗

bioRxiv2021

The SCFMet30 ubiquitin ligase senses cellular redox state to regulate the transcription of sulfur metabolism genes

In yeast, control of sulfur amino acid metabolism relies upon Met4, a transcription factor which activates the expression of a network of enzymes responsible for the biosynthesis of cysteine and methionine. In times of sulfur abundance, the activity of Met4 is repressed via ubiquitination by the SCFMet30 E3 ubiquitin ligase, but the mechanism by which the F-box protein Met30 senses sulfur status to tune its E3 ligase activity remains unresolved. Herein, we show that Met30 responds to flux through the transsulfuration pathway to regulate the MET gene transcriptional program. In particular, Met30 is responsive to the biological gas hydrogen sulfide, which is sufficient to induce ubiquitination of Met4 in vivo. Additionally, we identify important cysteine residues in Met30s WD-40 repeat region that sense the availability of sulfur in the cell. Our findings reveal how SCFMet30 dynamically senses the flow of sulfur metabolites through the transsulfuration pathway to regulate synthesis of these special amino acids.

biochemistry↗

bioRxiv2020

Genome-enabled inference of functional genetic variants in the face, brain and behavior

Lake Malawi cichlid fishes exhibit extensive divergence in form and function among closely related species separated by a relatively small number of genetic changes. During the past million years, hundreds of species have diversified along an ecological axis in rock vs. sand habitats. We compared the genomes of rock- and sand-dwelling species and asked which genetic variants in which genes differed among the groups. We found that 96% of differentiated variants reside in non-coding sequence but these non-coding diverged variants are evolutionarily conserved. The majority of divergent coding variants are missense and/or loss of function. Regions near differentiated variants are enriched for craniofacial, neural and behavioral functional categories. To follow up experimentally, we used rock- vs. sand-species and their hybrids to (i) clarify the push-pull roles of BMP signaling and irx1b in the specification of forebrain territories during gastrulation and (ii) reveal striking context-dependent brain gene expression during adult social behavior. Our results suggest compelling ties between early brain development and adult behavior and highlight the promise of evolutionary reverse genetics - the identification of functional variants from genome sequencing in natural populations.

evolutionary biology↗

bioRxiv2020

Primate innate immune responses to bacterial and viral pathogens reveals an evolutionary trade-off between strength and specificity

Despite their close genetic relatedness, apes and African and Asian monkeys (AAMs), strongly differ in their susceptibility to severe bacterial and viral infections that are important causes of human disease. Such differences between humans and other primates are thought to be a result, at least in part, of inter-species differences in immune response to infection. However, due to the lack of comparative functional data across species, it remains unclear in what ways the immune systems of humans and other primates differ. Here, we report the whole genome transcriptomic responses of ape species (human, common chimpanzee) and AAMs (rhesus macaque and olive baboon) to bacterial and viral stimulation. We find stark differences in the responsiveness of these groups, with apes mounting a markedly stronger early transcriptional response to both viral and bacterial stimulation, altering the transcription of [~]40% more genes than AAMs. Additionally, we find that genes involved in the regulation of inflammatory and interferon responses show the most divergent early transcriptional responses across primates and that this divergence is attenuated over time. Finally, we find that relative to AAMs, apes engage a much less specific immune response to different classes of pathogens during the early hours of infection, upregulating genes typical of anti-viral and anti-bacterial responses regardless of the nature of the stimulus. Overall, these findings suggest apes exhibit increased sensitivity to bacterial and viral immune stimulation, activating a broader array of defense molecules that may be beneficial for early pathogen killing at the potential cost of increased energy expenditure and tissue damage.

evolutionary biology↗

bioRxiv2020

Secreted autotaxin through LPA suppresses chemotaxis and tumor infiltration of CD8+ T Cells

Autotaxin (ATX) is secreted by diverse cell types to produce lysophosphatidic acid (LPA) that regulates multiple biological functions via G protein-coupled receptors LPAR1-6. ATX/LPA promotes tumor cell migration and metastasis mainly via LPAR1; however, its actions in the tumor immune microenvironment remain unclear. Here, we show that ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes and circulating CD8+ T cells ex vivo, with ATX functioning as an LPA-producing chaperone. Mechanistically, T-cell repulsion predominantly involves G12/13-coupled LPAR6. Upon anti-cancer vaccination of tumor-bearing mice, ATX does not affect the induction of systemic T-cell responses but suppresses tumor infiltration of cytotoxic CD8+ T cells and thereby impairs tumor regression. Moreover, single-cell data from patient samples are consistent with intra-tumor ATX acting as a T-cell repellent. These studies highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8+ T-cell infiltration to impede anti-tumor immunity, suggesting new therapeutic opportunities.

cancer biology↗

bioRxiv2019

Heritability and relationship of oxytocin receptor gene variants with social behavior and central oxytocin in colony-reared adult female rhesus macaques

The genetic contributions to sociality are an important research focus for understanding individual variation in social function and risk of social deficits in neurodevelopmental disorders (e.g. autism). The neuropeptide oxytocin (OXT) and its receptor, OXTR, influence social behavior across species. In humans and animals, common variants within the OXTR gene (OXTR) have been associated with varying socio-behavioral traits. However, the reported magnitude of influence of individual variants on complex behavior has been inconsistent. Compared to human studies, non-human primate (NHP) studies in controlled environments have the potential to result in robust effects detectable in relatively small samples. Here we estimate heritability of social behavior and central OXT concentrations in 214 socially-housed adult female rhesus macaques, a species sharing high similarity with humans in genetics, physiology, brain and social complexity. We present a bioinformatically-informed approach for identifying single nucleotide polymorphisms (SNPs) with likely biological relevance. We tested 13 common SNPs in regulatory and coding regions of OXTR for associations with behavior (pro-social, anxiety-like, and aggressive) and OXT concentration in cerebrospinal fluid (CSF). We found moderate rates of heritability for both social behavior and CSF OXT concentrations. No tested SNPs showed significant associations with behaviors or CSF in this sample. Associations between OXT CSF and social behavior were not significant either. SNP effect sizes were generally comparable to those reported in human studies of complex traits. While environmental control and a socio-biological similarity with humans is an advantage of rhesus models for detecting smaller genetic effects, it is insufficient to obviate large sample sizes necessary for appropriate statistical power.

neuroscience↗