Biology subjects

Hicks, C.

Publications and source records attributed to Hicks, C..

11 recordsLinked to original sources

bioRxiv2026

MeCP2 is Necessary in Cerebellar Purkinje Cells for Precise Network Dynamics During Associative Motor Learning

Loss-of-function variants of MECP2 cause Rett syndrome; however, their impact on cerebellar computations for learning remains poorly understood. Here, we show that Mecp2 deletion specifically in Purkinje cells does not broadly disrupt cerebellar-dependent behaviors but selectively compromises those that require precise timing, coordination, and associative updating in the cerebellar cortex. Mecp2 loss altered the emergence of learning-related Purkinje cell activity in vivo and disrupted their intrinsic and synaptic properties that support adaptive cerebellar output. These findings identify MeCP2 as a critical player in Purkinje cell function to regulate cerebellar learning signals and suggest that Rett syndrome-related motor dysfunction reflects impaired adaptive computation rather than a generalized loss of motor capacity.

neuroscience↗

bioRxiv2026

Nutrient content estimation of the world's fishes

Seafood nutrients from global fisheries are of increasing importance for research and policy in food security and nutrition. As the chemical composition of fish is determined by what they eat, their energetic demands, and the environment in which they live, nutrient content reflects aspects of physiology and life history, ecological and environmental traits, as well as evolutionary history. Here we present data from Bayesian model estimates of 12 key nutrients (calcium, iron, phosphorus, magnesium, selenium, zinc, vitamin A, vitamin B9, vitamin B12, vitamin D, omega-3 fatty acids, and protein) in wild fish, using a database of reported nutrient content for freshwater and marine species. We then predict the nutrient content of 5588 fish species with traits available from FishBase. We compare our previous model using traits alone with a new model of both traits and phylogeny, and present the data, code, and predictions for models coded in PyMC. These models and predictions, made freely available through FishBase, can be used to explore the historical, current, and future nutrient content of fisheries catch.

ecology↗

bioRxiv2026

Harnessing within-cultivar variation to identify hidden genetic resistance using single plant-omics

Fusarium graminearum is a fungal pathogen that causes scab or head blight in small grain cereals and threatens global cereal production. Disease progression varies widely among individual plants of the same cultivar, reflecting both genetic and environmental heterogeneity. This complicates the identification of early host responses, because each individual plant in a population is at a slightly different phase of disease progression. Here we apply single plant-transcriptomics to a population of 121 malt-barley exposed to F. graminearum, enabling us to reconstruct a temporal sequence of regulatory processes during early infection. We identified several disease-resistance associated genetic variants that are already endemic in this high-yielding cultivar, suggesting potential as breeding targets. These variants were within proteins involved in ROS-burst production, a lectin-kinase PRR, and enzymes with DON-detoxification activity. Single plant-transcriptomics offers a novel strategy for characterising early plant-pathogen interactions, turning intra-population heterogeneity from an experimental barrier into an asset.

plant biology↗

bioRxiv2024

Location-biased β-arrestin conformations direct GPCR signaling

{beta}-arrestins are multifunctional intracellular proteins that regulate the desensitization, internalization and signaling of over 800 different G protein-coupled receptors (GPCRs) and interact with a diverse array of cellular partners1,2. Beyond the plasma membrane, GPCRs can initiate unique signaling cascades from various subcellular locations, a phenomenon known as "location bias"3,4. Here, we investigate how {beta}-arrestins direct location-biased signaling of the angiotensin II type I receptor (AT1R). Using novel bioluminescence resonance energy transfer (BRET) conformational biosensors and extracellular signal-regulated kinase (ERK) activity reporters, we reveal that in response to the endogenous agonist Angiotensin II and the {beta}-arrestin-biased agonist TRV023, {beta}-arrestin 1 and {beta}-arrestin 2 adopt distinct conformations across different subcellular locations, which are intricately linked to differential ERK activation profiles. We also uncover a population of receptor-free catalytically activated {beta}-arrestins in the plasma membrane that exhibits insensitivity to different agonists and promotes ERK activation on the plasma membrane independent of G proteins. These findings deepen our understanding of GPCR signaling complexity and also highlight the nuanced roles of {beta}-arrestins beyond traditional G protein pathways.

biochemistry↗

bioRxiv2024

ACKR3 Proximity Labeling Identifies Novel G protein- and β-arrestin-independent GPCR Interacting Proteins

The canonical paradigm of GPCR signaling recognizes G proteins and {beta}-arrestins as the two primary transducers that promote GPCR signaling. Recent evidence suggests the atypical chemokine receptor 3 (ACKR3) does not couple to G proteins, and {beta}-arrestins are dispensable for some of its functions. Here, we employed proximity labeling to identify proteins that interact with ACKR3 in cells devoid of {beta}-arrestin. We identified proteins involved in the endocytic machinery and evaluated a subset of proteins conserved across several GPCR-based proximity labeling experiments. We discovered that the bone morphogenic protein 2-inducible kinase (BMP2K) interacts with many different GPCRs with varying dependency on {beta}-arrestin. Together, our work highlights the existence of modulators that can act independently of G proteins and {beta}-arrestins to regulate GPCR signaling and provides important evidence for other targets that may regulate GPCR signaling. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/577545v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@56a61org.highwire.dtl.DTLVardef@18b17baorg.highwire.dtl.DTLVardef@c2bd55org.highwire.dtl.DTLVardef@11c39b0_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2023

Mechanism of histone H2B monoubiquitination by Bre1

Monoubiquitination of histone H2BK120/123 plays multiple roles in regulating transcription, DNA replication and the DNA damage response. The structure of a nucleosome in complex with the dimeric RING E3 ligase, Bre1, reveals that one RING domain binds to the nucleosome acidic patch, where it can position the Rad6 E2, while the other RING domain contacts the DNA. Comparisons with H2A-specific E3 ligases suggests a general mechanism of tuning histone specificity via the non-E2-binding RING domain.

biophysics↗

bioRxiv2022

Subcellular localization of GPCR kinases differentially modulate biased signaling at CXCR3

Some G protein-coupled receptors (GPCRs) demonstrate biased signaling, where ligands of the same receptor differentially activate specific downstream signaling pathways over others. Ligand-specific receptor phosphorylation by GPCR kinases (GRKs) is one mechanism underlying this phenomenon. Recent evidence demonstrates that GPCRs traffic to and signal from subcellular compartments beyond the plasma membrane, a paradigm termed location bias. Here, we show that GRKs translocate to endosomes following stimulation of the chemokine receptor CXCR3 and other GPCRs. The GRK recruitment patterns at the plasma membrane and endosome are distinct and depend on the identity of the ligand used to activate the receptor. Using cells deficient of GRKs, we demonstrate that biased ligands have unique signaling profiles upon rescue of location-specific GRK isoforms. Our work highlights a role of the GRKs in location-biased GPCR signaling and demonstrates the complex interactions between ligand, GRK isoform and cellular location that contribute to biased signaling.

biochemistry↗

bioRxiv2022

Location bias contributes to functionally selective responses of biased CXCR3 agonists

Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" which preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the chemokine GPCR CXCR3. The signaling profile of CXCR3 changed as it trafficked from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling was critical for biased activation of G proteins, {beta}-arrestins, and ERK1/2. In CD8+ T cells, the chemokines promoted unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, {beta}-arrestin-biased CXCR3-mediated inflammation was dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs.

biochemistry↗

bioRxiv2021

HolistiC: Leveraging Hi-C and Whole Genome Shotgun Sequencing for Double Minute Chromosome Discovery

Double minute chromosomes are acentric extrachromosomal DNA artifacts that are frequently observed in the cells of numerous cancers. They are highly amplified and contain oncogenes and drug resistance genes, making their presence a challenge for effective cancer treatment. Algorithmic discovery of double minutes (DM) can potentially improve bench-derived therapies for cancer treatment. A hindrance to this task is that DMs evolve, yielding circular chromatin that shares segments from progenitor double minutes. This creates double minutes with overlapping amplicon coordinates. Existing DM discovery algorithms use whole genome shotgun sequencing in isolation, which can potentially incorrectly classify DMs that share overlapping coordinates. In this study, we describe an algorithm called " HolistIC" that can predict double minutes in tumor genomes by integrating whole genome shotgun sequencing (WGS) and Hi-C sequencing data. The consolidation of these sources of information resolves ambiguity in double minute amplicon prediction that exists in DM prediction with WGS data used in isolation. We implemented and tested our algorithm on the tandem Hi-C and WGS datasets of three cancer datasets and a simulated dataset. Results on the cancer datasets demonstrated HolistICs ability to predict DMs from Hi-C and WGS data in tandem. The results on the simulated data showed the HolistIC can accurately distinguish double minutes that have overlapping amplicon coordinates, an advance over methods that predict extrachromosomal amplification using WGS data in isolation. AvailabilityOur software is available at http://www.github.com/mhayes20/HolistIC.

bioinformatics↗

bioRxiv2018

The mechanism of cross-talk between histone H2B ubiquitination and H3 methylation by Dot1L

Methylation of histone H3, lysine 79 (H3K79), by Dot1L is a hallmark of actively transcribed genes that depends on monoubiquitination of H2B at lysine 120 (H2B-Ub), and is a well-characterized example of histone modification cross-talk that is conserved from yeast to humans. The mechanism by which H2B-Ub stimulates Dot1L to methylate the relatively inaccessible histone core H3K79 residue is unknown. The 3.0 [A] resolution cryo-EM structure of Dot1L bound to ubiquitinated nucleosome reveals that Dot1L contains binding sites for both ubiquitin and the histone H4 tail, which establish two regions of contact that stabilize a catalytically competent state and positions the Dot1L active site over H3K79. We unexpectedly find that contacts mediated by both Dot1L and the H4 tail induce a conformational change in the globular core of histone H3 that reorients K79 from an inaccessible position, thus enabling this side chain to project deep into the active site in a position primed for catalysis. Our study provides a comprehensive mechanism of cross-talk between histone ubiquitination and methylation and reveals an unexpected structural plasticity in histones that makes it possible for histone-modifying enzymes to access residues within the nucleosome core.

biochemistry↗

bioRxiv2018

Exposure to unpredictable trips and slips while walking can improve balance recovery responses with minimum predictive gait alterations

INTRODUCTIONThis study aimed to determine if repeated exposure to unpredictable trips and slips while walking can improve balance recovery responses when predictive gait alterations (e.g. slowing down) are minimised.\n\nMETHODSTen young adults walked on a 10-m walkway that induced slips and trips in fixed and random locations. Participants were exposed to a total of 12 slips, 12 trips and 6 non-perturbed walks in three conditions: 1) right leg fixed location, 2) left leg fixed location and 3) random leg and location. Kinematics during non-perturbed walks and previous and recovery steps were analysed.\n\nRESULTSThroughout the three conditions, participants walked with similar gait speed, step length and cadence(p>0.05). Participants extrapolated centre of mass (XCoM) was anteriorly shifted immediately before slips at the fixed location (p<0.01), but this predictive gait alteration did not transfer to random perturbation locations. Improved balance recovery from trips in the random location was indicated by increased margin of stability and step length during recovery steps (p<0.05). Changes in balance recovery from slips in the random location was shown by reduced backward XCoM displacement and reduced slip speed during recovery steps (p<0.05).\n\nCONCLUSIONSEven in the absence of most predictive gait alterations, balance recovery responses to trips and slips were improved through exposure to repeated unpredictable perturbations. A common predictive gait alteration to lean forward immediately before a slip was not useful when the perturbation location was unpredictable. Training balance recovery with unpredictable perturbations may be beneficial to fall avoidance in everyday life.

physiology↗