Biology subjects

Davis, K.

Publications and source records attributed to Davis, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte-specific loss of Smyd5 leads to a robust activation of inflammatory signaling and heart failure in mice.

Background: Cardiomyocytes respond to stress by undergoing hypertrophic growth driven by dynamic changes in gene expression. Epigenetic mechanisms, including histone methylation, play critical roles in regulating these transcriptional programs, yet the enzymes controlling these modifications during cardiac disease remain largely unknown. The SMYD family of histone methyltransferases regulates gene expression in multiple biological contexts, but the function of SMYD5 in the mammalian heart has never been investigated. Methods: SMYD5 expression was assessed in human heart failure samples and in a mouse model of cardiac hypertrophy. To define its functional role in vivo, we generated inducible cardiomyocyte-specific Smyd5 knockout mice and characterized their cardiac phenotype using molecular, histological, and functional analyses. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) was performed to examine histone H4 lysine 20 trimethylation (H4K20me3) at the Il-6 promoter. Results: SMYD5 expression was altered in diseased human and mouse hearts. Under basal conditions, cardiomyocyte-specific deletion of Smyd5 resulted in baseline structural cardiac remodeling and transcriptional signatures characteristic of pathological stress. Smyd5-deficient hearts exhibited marked inflammatory activation resembling a cytokine storm with immune cell infiltration and heart failure. Notably, Smyd5 knockout mice displayed a 100-fold increase in Il-6 expression, accompanied by a global reduction in H4K20me3. ChIP-qPCR analysis of the Il-6 promoter, together with loss- and gain-of-function analysis of SMYD5, supports a direct epigenetic role of SMYD5 in regulating Il-6 expression through H4K20me3 in cardiomyocytes. Conclusions: SMYD5 is a previously unrecognized epigenetic regulator of cardiac homeostasis that restrains inflammatory signaling in cardiomyocytes under normal conditions. Loss of Smyd5 disrupts H4K20me3, leading to derepression of Il-6 in cardiomyocytes and a robust inflammatory response characterized by immune cell recruitment and fibrosis, accompanied by rapid progression of cardiac remodeling and heart failure. These findings identify SMYD5 as a critical regulator of intrinsic cardiomyocyte inflammatory signaling and reveal a novel chromatin-based mechanism contributing to inflammatory cardiomyopathies.

molecular biology↗

bioRxiv2026

Rapid neural analysis of linguistic stress and meter in continuous speech

Continuous speech evolves around vowels, the centerpieces of individual syllables. Vowels vary in linguistic and acoustic salience: Linguistically, stressed syllables are more salient than unstressed syllables: Stress patterns convey critical lexico-semantic and prosodic information, and their regularity defines the speech meter. Acoustically, English vowel intensity cues lexical stress but also marks salient syllables irrespective of stress status. Recent evidence demonstrates rapid neural analysis of vowel intensity and identity during perception of continuous speech. Here, we probe how these processes integrate lexical stress and metrical regularity. We recorded EEG while participants (n=26) listened to childrens stories with either an irregular, speech-like meter, or a regular poetic meter. Stress and meter modulated cortical encoding of vowels throughout processing: Preparatory activity preceded vowel onsets in an irregular meter only, and early sensory responses were enhanced for unstressed vowels, suggesting additional resource allocation during processing of uncertain and less discriminable speech sounds. In contrast, later processing (300-500ms) was stronger for stressed syllables and in irregular meters, suggesting a combined effect of uncertainty and informational content. Finally, responses were stronger for small intensity rises within metrically predicted stressed vowels than in all other conditions. In the time-frequency domain, the spectral profile of neural phase-locking corresponded to spectral signatures of individual evoked responses, syllable and stress rates in the stimuli. Overall, our findings reveal rapid neural integration of stress and metrical expectations in neural processing of continuous speech. These dynamics may underlie the perceptual benefits of metrically regular speech, such as poetry and song lyrics.

neuroscience↗

bioRxiv2026

Temperature-dependent performance scales with maximum heat tolerance across ectotherms

Projecting species responses to changing temperatures remains a major challenge in ecology. Central to this effort is harnessing our understanding of species thermal physiological traits, which underlie ectotherm fitness. These traits are typically characterized by describing performance across temperatures (thermal performance curve, TPC), and/or tolerance limits, which capture endpoints of biological failure. Despite their importance, we still lack an understanding of the functional relationship between these traits, limiting our ability to integrate them into comprehensive vulnerability assessments. Using a synthesized dataset of >100 ectotherms, we tested how heat tolerance (CTmax) relates to key TPC traits: thermal optima, thermal maxima, and the supra-optimal range of temperatures where performance is positive. Across taxa, TPC traits were positively related to CTmax, demonstrating a link between heat tolerance and temperature-dependent performance at sub-critical temperatures. While acute locomotor performance scaled proportionally with CTmax, metabolic processes and sustained locomotion scaled sub-proportionally, suggesting decoupling of CTmax and performance among high-CTmax species. This suggests that using CTmax as a comparative metric may overestimate thermal safety margins for metabolic processes critical to growth. Our results indicate that while CTmax and TPCs reflect shared underlying constraints--particularly in acute neuro-muscular traits--their relationship is dependent on timescale and the TPC response trait. Our findings connect our understanding of the processes that maintain performance over thermal gradients with those that cause performance to fail, improving our ability to project species persistence in a warming world. SignificanceClimate warming is increasingly reshaping the thermal environments that govern species persistence worldwide. Predicting vulnerability requires integrating multiple aspects of thermal biology, yet relationships among widely used thermal traits remain poorly understood. By synthesizing data from more than 100 ectotherm species, we quantify links between acute heat tolerance and traits describing sustained biological function across temperatures. We show that performance at relatively benign temperatures and performance at thermal extremes are coupled, but this coupling is strongly process and timescale dependent, with close correspondence for short term locomotion but weaker coupling for metabolic processes. Our results link the processes that maintain performance across temperatures with those that cause failure, fundamentally advancing our projections of species performance in a warming world.

ecology↗

bioRxiv2026

Sympathetic neurons control adaptive immunity in response to Streptococcus pneumoniae infection by regulating T cell and B cell effector function

Adaptive immunity in the lung must be rapidly mobilized to control bacterial pathogens, yet the neuroimmune signals that shape local B and T cell responses remain poorly defined. Here we identify a sympathetic-immune axis that regulates lung-resident memory B cells, antigen-specific IgG production, and protection against Streptococcus pneumoniae. Lung-targeted chemical sympathectomy reduced norepinephrine availability, diminished Tbet memory and resident-memory B cell populations, and markedly impaired S. pneumoniae-specific IgG, resulting in increased bacterial burden. Mice lacking Adrb1 & Adrb2-adrenergic receptors phenocopied these defects, and adoptive transfer of Adrb1/Adrb2-/- B cells into Ighm-/- hosts was sufficient to reduce IgG and worsen infection. Combined T cell depletion and B cell-intrinsic adrenergic receptor loss further impaired bacterial control and suppressed IFNgamma, indicating that norepinephrine stimulates T cell IFNgamma release and that norepinephrine and IFNgamma together drive optimal B cell IgG production. In vitro, norepinephrine enhanced T cell IFNgamma secretion, and norepinephrine plus IFNgamma synergistically increased IgG. These findings define norepinephrine as a key regulator of lung-resident humoral immunity and reveal a neuroimmune mechanism that promotes antibody-mediated bacterial clearance at the respiratory mucosa.

immunology↗

bioRxiv2025

Activation of Toll and IMD pathways in the Drosophila brain following local and systemic bacterial infection

Brain infections are often life-threatening and have been linked to the development of neurodegenerative diseases. The fruit fly Drosophila melanogaster is a valuable experimental model to study immunity and the pathophysiology of brain infections. The exact cellular pathways through which brain-specific immune responses are mounted in Drosophila, however, remain poorly characterized. Here, we investigated how brain-specific or systemic infection with Micrococcus luteus and Escherichia coli bacteria activates the Drosophila NF-{kappa}B innate immune pathways Toll and immune deficiency (IMD) in the central nervous system of the fly. We tested the hypothesis that these pathways are acutely activated in the Drosophila brain, and that their activation persists over time, even if bacteria have been cleared. We demonstrate that in control genotypes, brain-specific bacterial infection leads to Drosomycin (Drs, Toll pathway) and Diptericin B (DiptB, IMD pathway) upregulation and that glia appear to be the primary cell type mounting this immune response at both early and later stages of infection, although some activation is observed in neurons as well. We show that the upregulation of Drs and DiptB expression also depends on canonical components of the Toll and IMD pathways, respectively. Interestingly, we found that systemic infection with M. luteus leads to brain-specific Drs activation and that signals from the fat body and hemocytes can activate the Toll pathway in the brain, pointing to an inter-organ communication. Together, these results contribute to our understanding of how non-lethal bacterial infections result in activation of NF-{kappa}B immunity in Drosophila brain that could potentially be targeted to prevent progression of neurodegeneration. HighlightsO_LIBrain immunity is induced following bacterial brain infection and depends on canonical NF-{kappa}B pathway components. C_LIO_LINF-{kappa}B signaling pathways are induced acutely and persist over time after bacterial brain infection. C_LIO_LIHost functional immunity clears bacteria in the brain post-bacterial brain infection. C_LIO_LIGlia are the main brain cell type in which NF-{kappa}B immunity is induced at both early and later stages of bacterial infection. C_LI

immunology↗

bioRxiv2025

General predictions for the effects of warming on competition

Understanding the effects of climate change on ecological communities has been limited by a lack of general theory for how temperature affects competition. To fill this knowledge gap, we integrated Modern Coexistence Theory and the Metabolic Theory of Ecology by incorporating empirically-derived temperature sensitivities into Modern Coexistence Theorys central model. We then simulated warming in consumer-resource systems and found that warming reduced both niche and fitness differences, making species more ecologically similar and competitive interactions more neutral. The greatest shifts in competition occurred when temperature sensitivities among species were highly asymmetrical. Effects of warming on competition via niche differences were comparable to those on fitness differences, suggesting that the emphasis on vital rates in global change research may overlook key biodiversity drivers. This general theory expands the domains of two prominent ecological theories and provides predictions for how warming may alter competition even in benign regions of species thermal niches.

ecology↗

bioRxiv2025

Immunoregulatory effect of metformin in monocytes exposed to SARS-CoV-2 spike protein subunit 1

BackgroundSevere COVID-19 is characterized by a hyperinflammatory state associated with an exacerbated inflammatory activation of monocytes and macrophages in the respiratory tract. Metformin has been identified as a potent monocyte inflammatory suppressor, and it has been demonstrated to attenuate inflammation in COVID-19. The mechanisms underlying metformin anti-inflammatory effects are, however, unclear. We thus sought to investigate metformins main interactions and their respective isolated effects in modulating monocyte inflammatory response to SARS-CoV-2 stimulation. MethodsClassical human monocytes were isolated from healthy 18-40-year-old individuals and stimulated in vitro with recombinant spike protein subunit 1 (rS1) to assess glycolytic and oxidative metabolic responses by Seahorse extracellular flux analysis, and inflammatory gene expression by qPCR. Stimulated monocytes were either pre-treated with metformin, rotenone, S1QEL, or A769662. ResultsMonocytes stimulated in vitro with rS1 showed an increased glycolytic response associated with production of pro-inflammatory cytokines. Metformin pre-treatment reduced glycolytic activation while partially suppressing inflammation. Rotenone-dependent mitochondrial complex I inhibition was not able to replicate the same effect, and neither complex I specific ROS scavenging. Conversely, A769662 induced AMPK activation led to suppressed glycolytic inflammatory response and cytokine expression pattern similar to metformin, thus suggesting AMPK modulation as a possible central component for metformins mode of action upon S1 stimulation. ConclusionsIn summary, further investigation into the interactions underlying AMPK activity on monocytes in the context of SARS-CoV-2 may provide a better elucidation of metformins anti-inflammatory effect.

immunology↗

bioRxiv2025

GT61 β-1,2-xylosyltransferases define a conserved xylan modification in gymnosperm and Arabidopsis primary cell walls

Plant primary and secondary cell walls differ in molecular composition, structure, and mechanical properties. While secondary wall xylan has been extensively characterised, the structure of xylan in primary walls remains less well understood, particularly in gymnosperms. Here, we identify a previously uncharacterised {beta}-1,2-linked xylosyl side chain in conifer and Arabidopsis thaliana xylan. Using enzymatic fingerprinting, NMR, and mass spectrometry, we show that this structure is positioned two xylose residues away from glucuronic acid substitutions, forming an evenly patterned substituted xylan. This spacing pattern is consistent with xylan-cellulose interaction, suggesting a structural role in primary wall architecture. This modification, found in primary wall-rich tissues of diverse conifer species, including needles and pro-embryogenic mass (PEM), is also present in Arabidopsis callus. We demonstrate that conifer Group III GT61 glycosyltransferases introduce this modification with consistent positional specificity. In Arabidopsis, three closely related GT61 enzymes act redundantly to generate the same structure, and their combined loss results in its complete absence. These findings uncover a conserved primary wall xylan modification in seed plants and define the GT61 enzymes responsible for its biosynthesis, opening new avenues to explore how xylan structure contributes to primary wall function. Significance StatementXylan structure is well characterised in secondary walls, but its primary wall counterpart remains poorly understood. We identified a conserved {beta}-1,2-xylosyl modification on xylan in the primary walls of conifers and Arabidopsis. This side chain is positioned at a defined position from a glucuronic acid substitution and is introduced by GT61 glycosyltransferases that cluster in one phylogenetic subclade. Our findings revealed a previously unrecognised xylan structural pattern and the biosynthetic enzymes responsible for its addition. This work expands the current understanding of primary wall architecture across seed plants.

plant biology↗

bioRxiv2025

CellFuse Enables Multi-modal Integration of Single-cell and Spatial Proteomics Data

Single-cell and spatial proteomic technologies capture complementary biological information, yet no single platform can measure all modalities within the same cell. Most existing integration methods are optimized for transcriptomic data and rely on a large set of shared, strongly linked features, an assumption that often fails for low-dimensional proteomic modalities. We present CellFuse, a deep learning-based, modality-agnostic integration framework designed specifically for settings with limited feature overlap. CellFuse leverages supervised contrastive learning to learn a shared embedding space, enabling accurate cell type prediction and seamless integration across modalities and experimental conditions. Across a range of datasets including healthy PBMCs, bone marrow, CAR-T-treated lymphoma, and healthy and tumor tissues--CellFuse consistently outperforms existing methods in both integration quality and runtime efficiency. It maintains high accuracy even in the presence of missing markers and rare cell types, and performs robustly in cross-dataset comparisons, making it a powerful tool for scalable and high-fidelity single-cell data integration in basic and translational research.

bioinformatics↗

bioRxiv2025

Efficient packaging of HIV-1 genomes via recognition of its adenosine-rich content by a heterologous RNA-binding domain

The HIV-1 genome (gRNA) has an unusually biased nucleotide content and is rich in adenosines. Selective packaging of the gRNA is thought to be driven by specific binding of the nucleocapsid (NC) domain of the viral Gag protein to the packaging signal ({Psi}) in the host cell cytosol. However, deletion of regions within {Psi} reduces--but does not completely abolish--genome packaging. To probe whether another feature of the gRNA may contribute to the selective gRNA packaging process, we replaced NC with heterologous RNA-binding domains (RBDs) with distinct RNA-binding properties. Surprisingly, despite disparate RNA binding specificities, all Gag-RBD chimeras successfully recruited the gRNA to the plasma membrane, suggesting that the initial gRNA recognition in the cytosol is not rate limiting. Notwithstanding, many chimeras exhibiting G/C binding specificity were arrested at the assembly stage. Only the Gag-SRSF5 chimera, which multimerized efficiently on adenosine-rich sequences on the gRNA, assembled efficiently and packaged gRNA at near wild-type levels. Importantly, rationally designed mutations that altered the A/G-rich binding specificity of Gag-SRSF5 decreased genome encapsidation efficiency. Furthermore, many Gag chimeras displayed potent dominant negative activities, highlighting NC functions as a targetable step in virus replication. Together, our findings reveal an unexpected aspect of the HIV-1 gRNA, its biased nucleotide content, as a key driver of selective genome packaging. SIGNIFICANCEHow HIV-1 selectively packages its genome (gRNA) into virions is poorly understood. To probe this, we replaced the viral nucleocapsid (NC) protein with heterologous RNA-binding domains (RBDs) from cellular hnRNP and SR protein families. Remarkably, despite their distinct RNA-binding specificities, all Gag-RBD chimeras successfully recruited the gRNA to the plasma membrane, suggesting that the initial gRNA recognition is not rate limiting. Only the Gag-SRSF5 chimera packaged gRNA efficiently which correlated with its capacity to multimerize on adenosine-rich sequences on the gRNA. Notably, several Gag chimeras exhibited strong dominant negative effects, underscoring NC functions as a targetable step in virus replication. Together, these findings uncover that the biased nucleotide content of the HIV-1 gRNA facilitates its selective packaging into virus particles.

microbiology↗

bioRxiv2025

An experimental test of the influence of microbial manipulation on sugar kelp (Saccharina latissima) supports the the core influences host function hypothesis

Kelp are valued for a wide range of commercial products and for their role in kelp forest ecosystems, making kelp cultivation a rapidly expanding economic sector. Microbes associated with kelp and other macroalgae play a critical role in processes such as nutrient exchange, chemical signaling, and defense against pathogens. Thus, manipulating the microbiome to enhance macroalgal growth and resilience is a promising yet underexplored approach for sustainable kelp cultivation. The core microbiome hypothesis suggests that the bacteria that are consistently found on a host (the core microbes) are likely to have a disproportionate impact on host biology, making them an attractive target for microbiome manipulation. In this study, we surveyed wild Saccharina latissima and their surrounding environment to identify core bacterial taxa, compared them to cultivated kelp, and experimentally tested how cultured bacterial isolates affect kelp development. We found that core bacteria are nearly absent in cultivated juvenile sporophytes in nurseries but eventually colonized them after outplanting to ocean farm sites. Bacterial inoculants had both positive and negative effects on kelp development. Notably, the strength of association of a bacterial genus with kelp in the wild positively correlated with its impact on gametophyte settlement and sporophyte development in kelp co-culture experiments, aligning with predictions from the core microbiome influences host function hypothesis. These findings affirm the feasibility of using microbial manipulations to improve current kelp aquaculture practices and provide a framework for developing these techniques. IMPORTANCEMicroorganisms consistently associated with hosts are widely thought to be more likely to impact host biology and health. However, this intuitive concept has not been experimentally evaluated. This study formalizes this concept as the Core microbiome Influences Host Function hypothesis and experimentally tests this hypothesis in sugar kelp (Saccharina). The distribution of bacteria on wild kelp and core microbes were first identified by compiling a broad dataset of the kelp microbiome sampled across space and time. Bacterial cultures were isolated from the surface of sugar kelp and individually grown in laboratory co-culture with sugar kelp spores to assess the ability of bacterial isolates to influence kelp growth and development. In support of the core influences host function hypothesis, isolates belonging to bacterial genera that are more strongly associated with wild sugar kelp are more likely to influence development in laboratory experiments.

ecology↗

bioRxiv2024

Modulatory Effects of Mdivi-1 on OxLDL-Induced Metabolic Alterations, Inflammatory Responses, and Foam Cell Formation in Human Monocytes

Atherosclerosis, a major contributor to cardiovascular disease, involves lipid accumulation and inflammatory processes in arterial walls, with oxidized low-density lipoprotein (OxLDL) playing a central role. OxLDL is increased during aging and stimulates monocyte transformation into foam cells and induces metabolic reprogramming and pro-inflammatory responses, accelerating atherosclerosis progression and contributing to other age-related diseases. This study investigated the effects of Mdivi-1, a mitochondrial fission inhibitor, and S1QEL, a selective complex I-associated reactive oxygen species (ROS) inhibitor, on OxLDL-induced responses in monocytes. Healthy monocytes isolated from participants were treated with OxLDL, with or without Mdivi-1 or S1QEL, and assessed for metabolic shifts, inflammatory cytokine expression, foam cell formation, and ROS production. OxLDL treatment elevated glycolytic activity (ECAR) and expression of pro-inflammatory cytokines IL1B and CXCL8, promoting foam cell formation and mitochondrial ROS (mtROS) production. Mdivi-1 and S1QEL effectively reduced OxLDL-induced glycolytic reprogramming, inflammatory cytokine levels, and foam cell formation while limiting mtROS. These findings suggest that both Mdivi-1 and S1QEL modulate key monocyte responses to OxLDL, providing insights into potential therapeutic approaches for age-related diseases.

immunology↗

bioRxiv2024

Mining for microbial metabolites associated with disease progression in an age-dependent model of experimental autoimmune encephalomyelitis

Age is a risk factor for the neurological decline and physical disability that characterize progressive multiple sclerosis (MS). The intestinal microbiota and the bioactive compounds it produces can influence aging, immunity, and the central nervous system (CNS). Here, we use an experimental autoimmune encephalomyelitis (EAE) model that mimics features of progressive MS in aged, but not young, mice to address the intersection of age and the microbiota on EAE outcomes. Although the microbiota of SJL/J mice aged under controlled laboratory conditions does not promote an aged non-remitting EAE phenotype, young mice harboring heterochronic human fecal microbiota transplants (hFMT) developed a range of EAE phenotypes. Metabolomic profiling of mice colonized with an aged hFMT that promoted non-remitting EAE indicated a severe reduction in circulating levels of the microbiota-derived tryptophan metabolite indole 3-propionic acid (IPA). IPA-supplementation enforced remission in mice colonized with the non-remitting hFMT, demonstrating the utility of this in vivo pipeline for discovering metabolites associated with progressive MS-like disease. SummaryThe microbiota is a critical determinant of disease susceptibility in mouse models of MS. Here, Pu & Fettig et al. demonstrate that disease outcomes (remitting or non-remitting) are microbiota-responsive, and describe an in vivo pipeline that can be mined for microbial metabolites with therapeutic potential for progressive MS.

immunology↗

bioRxiv2024

A video-rate hyperspectral camera for monitoring plant health and biodiversity

Hyperspectral cameras are a key enabling technology in precision agriculture, biodiversity monitoring, and ecological research. Consequently, these applications are fuelling a growing demand for devices that are suited to widespread deployment in such environments. Current hyperspectral cameras, however, require significant investment in post-processing, and rarely allow for live-capture assessments. Here, we introduce a novel hyperspectral camera that combines live spectral data and high-resolution imagery. This camera is suitable for integration with robotics and automated monitoring systems. We explore the utility of this camera for applications including chlorophyll detection and live display of spectral indices relating to plant health. We discuss the performance of this novel technology and associated hyperspectral analysis methods to support an ecological study of grassland habitats at Wytham Woods, UK.

ecology↗

bioRxiv2023

Exploring the impact of microbial manipulation on the early development of kelp (Saccharina latissima) using an ecological core microbiome framework.

Kelp cultivation is a rapidly expanding economic sector, as kelp are valued for a wide range of commercial products and for restoration of kelp forest ecosystems. Microbes associated with kelp and other macroalgae play a critical role in processes such as nutrient exchange, chemical signaling, and defense against pathogens. Thus, manipulating the microbiome to enhance macroalgal growth and resilience is a promising, but largely untested, tool in sustainable kelp cultivation. The core microbiome hypothesis suggests that bacteria that are consistently found on a host (the core microbes) are likely to have a disproportionate impact on host biology, making them an attractive target for microbiome manipulation. Here, we surveyed wild Saccharina latissima and their surrounding environment to identify core bacterial taxa, compared to cultivated kelp, and experimentally tested the effect of cultured bacterial isolates on kelp development. We find that core bacteria are nearly absent in cultivated juvenile sporophytes in nurseries but eventually colonized after outplanting kelp to ocean farm sites. We find that bacterial inoculants can have both positive and negative effects on kelp development. In line with predictions from the core microbiome hypothesis, we find a positive correlation between the frequency of the bacterial genus in the wild and the bacterial effect on the number of sporophytes in kelp co-culture experiments. IMPORTANCEThe core microbiome hypothesis suggests that symbiotic microorganisms consistently associated with hosts have functional effects on host biology and health. However, there is a lack of evidence to either support or refute this idea. This study surveys the distribution of bacteria on wild and cultivated kelp to identify the core microbiome and tests the ability of bacterial isolates cultured from the surface of wild kelp to influence kelp growth and development in laboratory microbial manipulation experiments. The frequency of bacterial genera on wild kelp was positively correlated with influence on kelp development in laboratory experiments, providing support for the core microbiome hypothesis.

ecology↗

bioRxiv2022

G Protein-Coupled Receptor Kinase-2 (GRK-2) regulates exploration through neuropeptide signaling in Caenorhabditis elegans

Animals alter their behavior in manners that depend on environmental conditions as well as their developmental and metabolic states. For example, C. elegans is quiescent during larval molts or during conditions of satiety. By contrast, worms enter an exploration state when removed from food. Sensory perception influences movement quiescence (defined as a lack of body movement), as well as the expression of additional locomotor states in C. elegans that are associated with increased or reduced locomotion activity, such as roaming (exploration behavior) and dwelling (local search). Here we find that movement quiescence is enhanced, and exploration behavior is reduced in G protein-coupled receptor kinase grk-2 mutant animals. grk-2 was previously shown to act in chemosensation, locomotion, and egg-laying behaviors. Using neuron-specific rescuing experiments, we show that GRK-2 acts in multiple ciliated chemosensory neurons to control exploration behavior. grk-2 acts in opposite ways from the cGMP-dependent protein kinase gene egl-4 to control movement quiescence and exploration behavior. Analysis of mutants with defects in ciliated sensory neurons indicates that grk-2 and the cilium-structure mutants act in the same pathway to control exploration behavior. We find that GRK-2 controls exploration behavior in an opposite manner from the neuropeptide receptor NPR-1 and the neuropeptides FLP-1 and FLP-18. Finally, we show that secretion of the FLP-1 neuropeptide is negatively regulated by GRK-2 and that overexpression of FLP-1 reduces exploration behavior. These results define neurons and molecular pathways that modulate movement quiescence and exploration behavior. Author summaryMany modulatory neurotransmitters affect behavior by binding to G protein-coupled receptors (GPCRs) and initiating signals that modify neuronal activity. GPCRs are regulated by G protein-coupled receptor kinases (GRKs). GRKs phosphorylate and promote the inactivation of GPCRs. Here we identify GRK-2 as a regulator of distinct locomotor states in C. elegans. We find that GRK-2 acts in olfactory sensory neurons to promote exploration and suppress movement quiescence. Additionally, we show that GRK-2 acts in opposition to a neuropeptide signaling pathway that acts in interneurons. Thus, this study demonstrates critical roles for GRK-2 in regulating neuromodulatory signaling and locomotor behavior.

genetics↗

bioRxiv2022

Miro GTPase domains regulate assembly of the mitochondrial motor-adaptor complex

Mitochondrial transport relies on a motor-adaptor complex containing Miro1, a mitochondrial outer membrane protein with two GTPase domains, as well as TRAK1/2, kinesin-1, and dynein. Using a peroxisome-directed Miro1, we quantified the ability of GTPase mutations to influence peroxisomal recruitment of complex components. Miro1 whose N-GTPase is locked in the GDP-state doesnt recruit TRAK1/2, kinesin or P135 to peroxisomes whereas the GTP-state does. Miro1 C-GTPase mutations have little influence on complex recruitment. Though Miro2 is thought to support mitochondrial motility, peroxisome-directed Miro2 did not recruit the other complex components regardless of the state of its GTPase domains. Neurons expressing peroxisomal Miro1 with the GTP-state form of the N-GTPase had markedly increased peroxisomal transport to growth cones while the GDP-state caused their retention in the soma. Thus, the N-GTPase of Miro1 is critical for regulating Miro1s interaction with the other components of the motor-adaptor complex and thereby for regulating mitochondrial motility. SummaryA Miro-containing complex mediates mitochondrial motility. Relocalizing Miro1 and 2 to peroxisomes and systematically manipulating each GTPase domain of Miro revealed the importance of the N-terminal GTPase domain of Miro1 for governing interaction with TRAK proteins, motors, and transport.

cell biology↗

bioRxiv2022

Histone H4K20 Trimethylation is Decreased in Murine Models of Heart Disease

Heart disease is the leading cause of death in the developed world, and its comorbidities such as hypertension, diabetes, and heart failure are accompanied by major transcriptomic changes in the heart. During cardiac dysfunction, which leads to heart failure, there are global epigenetic alterations to chromatin that occur concomitantly with morphological changes in the heart in response to acute and chronic stress. These epigenetic alterations include the reversible methylation of lysine residues on histone proteins. Lysine methylation on histone H3K4 and H3K9 were among the first methylated lysine residues identified and have been linked to gene activation and silencing, respectively. However, much less is known regarding other methylated histone residues, including histone H4K20. Trimethylation of histone H4K20 has been shown to repressive gene expression, however this mark has never been examined in the heart. Here we utilized immunoblotting and mass spectrometry to quantify histone H4K20 trimethylation in three models of cardiac dysfunction. Our results show that lysine methylation at this site is regulated in a biphasic manner leading to increased H4K20 trimethylation during acute hypertrophic stress and decreased H4K20 trimethylation during sustained ischemic injury and cardiac dysfunction. In addition, we examined publicly available datasets to analyze enzymes that regulate H4K20 methylation and identified one demethylase (KDM7C) and two methyltransferases (KMT5A and SMYD5) which were all upregulated in heart failure patients. This is the first study to examine histone H4K20 trimethylation in the heart and to determine how this post-translational modification is differentially regulated in multiple models of cardiac disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/479885v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@169abeorg.highwire.dtl.DTLVardef@94bb0org.highwire.dtl.DTLVardef@4812e8org.highwire.dtl.DTLVardef@1d16478_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗