Biology subjects

Carr, M.

Publications and source records attributed to Carr, M..

13 recordsLinked to original sources

bioRxiv2026

An Aurora Kinase-Dependent Role for Vif in Regulating HIV-1-Induced Cell-Cell Fusion

Viral infectivity factor (Vif) is an HIV-1 accessory protein best known for its counteraction of APOBEC3 enzymes, interferon-inducible host defenses against viral infection, as well as PPP2R5A-E, which are regulatory subunits of the PP2A cellular phosphatase holoenzyme, resulting in striking Vif-dependent phosphoproteome remodeling. One reported consequence of this remodeling is hyperphosphorylation of several Aurora kinase substrates in HIV-1 infected cells, which is reversed when Vif-deficient virus is used. We previously showed that infection of T cells with Vif-deficient HIV-1 results in significantly accelerated formation of syncytia compared to wild-type HIV-1 infection. More recently, others have shown that application of Aurora kinase B inhibitors during HIV-1 infection in T cells also results in a similar hyperfusogenic phenotype. Both effects were specific to Env-driven cell-cell fusion, and did not influence virus infectivity. We thus hypothesized that Vifs influence on the rate of HIV-1-induced cell-cell fusion was mediated by Aurora kinase activity. To start testing this hypothesis, we have evaluated the effects of a small panel of Aurora kinase inhibitors on HIV-1-induced cell-cell fusion in the presence or absence of Vif. Our results replicate the previously documented increase in cell-cell fusion in the absence of Vif, as well as the increase in cell-cell fusion observed upon inhibition of Aurora kinase B in the presence of Vif. Critically, we now present evidence that Vif deletion significantly blunts the impact of Aurora kinase inhibition on cell-cell fusion, supporting our hypothesis that Vif-mediated regulation of cell-cell fusion depends on Aurora kinase signaling dysregulation, likely because of PPP2R5A-E degradation. Further, we document that the cell-cell fusion regulator downstream of Aurora kinase signaling is likely Ezrin, which we have previously shown to prevent excess HIV-1-induced syncytium formation when in its phosphorylated (activated) state. Taken together, these findings establish a Vif, Aurora kinase, and Ezrin-dependent mechanistic framework for the regulation of HIV-1-induced cell-cell fusion in infected T cells which likely helps preserve optimal cell-to-cell virus transmission.

Cell Biology↗

bioRxiv2026

Tradeoffs in planning marine protected areas for kelp forest resilience: protecting climate refugia is not always the best solution

Marine protected areas (MPAs) are increasingly promoted as climate mitigation tools, yet guidance on their placement to maximize resilience against climate stressors like marine heatwaves remains limited. Here, we develop MPA placement guidelines that explicitly consider a mechanistic pathway through which MPAs could enhance kelp forest resilience to heatwaves: protecting fishery-targeted urchin predators to prevent kelp overgrazing. Using a spatially explicit, tri-trophic model of California kelp forests, we evaluate alternative MPA configurations across a hypothetical coastline where half the habitat experiences an increased probability of experiencing heatwaves. We found that effective MPA placement depends on whether MPAs are being newly established or reconfigured within an existing network, and that among-patch connectivity and spillover played vital roles in the relative effectiveness of different MPA configurations. Changes in resilience occurred primarily at the patch scale, with trade-offs between increased within-MPA resilience and decreased resilience in some fished areas, resulting in minimal coastwide population effects. For example, for new MPAs, large single MPAs within heatwave-prone areas maximized within-MPA resilience gains, while multiple small MPAs in heatwave refugia best supported whole-coast resilience. When reconfiguring established networks, expanding existing MPAs in refugia areas was most effective. We also demonstrate the importance of considering MPA recovery timescales: for example, relocating old MPAs to heatwave refugia yielded minimal short-term benefits due to the loss of rebuilt, previously fished, predator biomass. Our findings demonstrate that climate-adaptive marine planning should explicitly consider the spatiotemporal implications of trophic cascades, connectivity, and transient population dynamics to support ecosystem resilience.

ecology↗

bioRxiv2025

Sea urchin consumption of kelp controlled by the density of drift algae

Rocky reef kelp forests can exhibit abrupt shifts between forested and barren states where unchecked sea urchin grazing inhibits kelp recovery. Forefront to urchin barren formation is a behavioral switch where sedentary urchins become active and graze upon attached kelp. This is hypothesized to occur when the availability of drift (i.e., detached kelp on the surface of the reef), which urchins are believed to prefer over intact and attached kelp, declines. Although observed repeatedly, the density-dependent nature of this apparent resource preference has not been characterized quantitatively. We used a series of subtidal functional response experiments in central California, USA, to quantify how consumption rates by Strongylocentrotus purpuratus (purple urchins) on Macrocystis pyrifera (giant kelp) and drift varied with their relative availability and over time as urchins became satiated. Our experiments indicate that the preference for drift over kelp is strong when drift and kelp are at equal abundance, that the abundance of drift has a strong effect on kelp consumption but not vice versa, and that the preferences for drift is indeed density dependent with the qualitative switch to a greater preference for kelp occurring when the availability of drift declines below approximately 1 g of drift for every 60 g of kelp. Our analyses suggest further that maintaining at least equal amounts of drift and kelp is sufficient to all but preclude urchins from grazing on live kelp. We recommend drift be used as an indicator of reef health, and that our thresholds be considered to guide drift subsidies to preserve and restore kelp forests.

ecology↗

bioRxiv2025

Commensal-derived Trehalose Monocorynomycolate Triggers γδ T Cell-driven Protective Ocular Barrier Immunity

Commensals shape host physiology through molecular crosstalk with host receptors. Identifying specific microbial factors that causally influence host immunity is key to understanding homeostasis at the host-microbe interface and advancing microbial-based therapeutics. Here, we identify trehalose monocorynomycolate (TMCM) from Corynebacterium mastitidis (C. mast) as a potent stimulator of IL-17 production by {gamma}{delta} T cells at the ocular surface. Mechanistically, TMCM-driven IL-17 responses require both IL-1 signals and {gamma}{delta} TCR signaling, which also supports endogenous {gamma}{delta} T cell IL-1R1 expression. Notably, synthetic TMCM alone is sufficient to mimic the effect of C. mast in inducing {gamma}{delta} T cell immunity and protect against pathogenic corneal infection. Our findings establish TMCM as a key mediator of commensal-driven immune defense, highlighting its potential as a {gamma}{delta} T cell adjuvant and a microbiome-informed therapeutic to enhance IL-17-driven protection at barrier sites such as the ocular surface. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/643820v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@63139forg.highwire.dtl.DTLVardef@9d6978org.highwire.dtl.DTLVardef@775e37org.highwire.dtl.DTLVardef@ca84b6_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LICorynomycolates enable ocular C. mast colonization and protective IL-17 immunity C_LIO_LITMCM drives IL-17 from {gamma}{delta} T cells through TCR and IL-1R signaling C_LIO_LI{gamma}{delta} TCR signaling maintains the expression of endogenous IL-1R1 C_LIO_LISynthetic TMCM mimics the ability of C. mast to induce {gamma}{delta} T cell immunity in the eye C_LIO_LITMCM protects against P. aeruginosa keratitis, highlighting its therapeutic potential C_LI

immunology↗

bioRxiv2024

ARTIC RSV amplicon sequencing reveals global RSV genotype dynamics.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections (LTRIs) in young children and adults over 65, contributing significantly to global healthcare burdens. With the recent approval of multiple pharmacological interventions for RSV, there is an increased demand for efficient, high-throughput sequencing methods to monitor RSV genetic diversity and any potential impact these interventions may have. Here we introduce two novel amplicon-based sequencing schemes designed for RSV A and B, optimised for integration with widespread existing ARTIC sequencing workflows. We demonstrate that these primer schemes can produce high quality genomes from RSV samples across the globe, with eight laboratories in five countries generating complete genomes on both Nanopore and Illumina sequencing platforms. The ability to effectively multiplex these RSV A and B primer schemes, enables streamlined, high-throughput sequencing without prior subtyping. Furthermore, these results provide a snapshot of the circulating diversity of RSV. Phylogenetic analysis of the 882 samples sequenced for this study suggests only minimal geographic clustering of RSV sequences, underscoring the global nature of RSV spread. It also highlights the distinct lineage dynamics seen between RSV A and B. This study represents an advancement in RSV genomics, providing robust tools for global sequencing efforts aimed at tracking RSV evolution and assessing the efficacy of new therapeutic interventions both rapidly and at scale.

genomics↗

bioRxiv2024

A site selection decision framework for effective kelp restoration

HighlightsO_LISite selection is one of the most important factors for ecosystem restoration success C_LIO_LIA spatial prioritization framework for application to kelp restoration in California C_LIO_LIThe framework merges kelp metrics derived from in-situ surveys and satellite imagery C_LIO_LISite prioritization classification for every kelp forest site in California C_LIO_LIThis framework can be applied to other species and regions with similar datasets C_LI We present a decision support framework in the form of a spatially explicit site classification scheme to prioritize locations for conducting kelp restoration. The framework was created for the entire coast of California, where kelp has been lost and restoration projects are increasingly proposed, but the framework is broadly applicable to other coastal habitats or species that are being considered for restoration. We first created spatial distribution models using almost two decades of in situ kelp forest monitoring data and a comprehensive suite of environmental and biological variables, and used the outputs to evaluate the historical stability of kelp forests prior to a marine heatwave (MHW). We then used kelp canopy abundance data derived from satellite imagery to measure the impact of the MHW (i.e. extent of forest loss) and the recent state of kelp forests, including the trend of increase or decrease following the MHW. Finally, we integrated these site-specific kelp metrics to construct a classification tree for prioritizing restoration sites. Outputs of site prioritization are mapped across the study region, readily usable for managers and restoration practitioners with site-specific recommendations for restoration approaches. The framework can be updated due to knowledge of the important predictors of kelp and with new satellite imagery. Further, the framework can be adapted to other species and regions with similar data sets. This regional site selection framework is intended to be used in addition to socio-ecological, socio-economic, and administrative considerations.

ecology↗

bioRxiv2024

Highly effective verified lucid dream induction using combined cognitive-sensory training and wearable EEG: a multi-centre study

Lucid dreaming occurs when one is aware of dreaming while asleep. While lucid dreaming can occur spontaneously, it remains rare. This multi-center study (Netherlands, Italy, Canada) tested a combined induction approach integrating senses-initiated lucid dreaming (SSILD) with targeted lucidity reactivation in a large sample of participants with varying lucid dreaming experience. Sixty participants (33 F; 26.5 {+/-}6.2 years old) completed two morning naps in the sleep laboratory. Participants received pre-sleep SSILD training paired with visual, auditory, and tactile cues that were then reintroduced in REM sleep, with stimulation and sham conditions counterbalanced. Lucidity and cue perception were verified using intentional eye movements from within the dream (signal-verified lucid dream, SVLD). SVLDs occurred in 31 participants (51.7%) across both naps. Subjective lucidity occurred in 63 naps (52.5%), including 40 SVLDs (33.3%) with no difference between stimulation (38.3%) and sham (28.3%) conditions. However, SVLD duration and number of predefined eye movements were higher with sensory cueing. Cues were perceived within sleep in most cued REM periods (71.1%), sometimes acting as lucidity signals (39.1% of stim SVLDs) and occasionally disrupting sleep (23.7% of cued periods). Overall, our combined cognitive-sensory induction method produced relatively high lucid dreaming rates, even in participants who rarely experience them. While cues were sometimes perceived as lucidity signals and may help prolong lucid episodes, our results do not show clear benefits of REM cueing over SSILD training alone. Further refinement of these methods may support clinical applications and deepen insight into consciousness and sensory processing during sleep.

neuroscience↗

bioRxiv2024

Drivers of spatio-temporal variability in a marine foundation species

Marine foundation species are critical for the structure and functioning of ecosystems and constitute the pillar of trophic chains while also providing a variety of ecosystem services. In recent decades many foundation species have declined in abundance, sometimes threatening their current geographical distribution. Kelps (Laminariales) are the primary foundation species in temperate coastal systems worldwide. Kelp ecosystems are notoriously variable and identifying the key factors that control the dynamics of kelp abundance is key to predicting the fate of kelp ecosystems under climatic change and informing management and conservation decisions such as forest restoration. Here, we used in situ data from long-term monitoring programs across 1,350 km of coast spanning multiple biogeographic regions in the state of California (USA) to identify the major regional drivers of density of two dominant canopy-forming kelp species and to elucidate the spatial and temporal scales over which they operate. We used generalized additive models to identify the key drivers of density of two dominant kelp species (Nereocystis luetkeana and Macrocystis pyrifera) across four ecological regions of the state of California (north, central, south-west and south-east) and for the past two decades (2004-2021). Our study identified that the dominant drivers of kelp density varied between regions and species but always included some combination of nitrate availability, wave energy and exposure, density of purple sea urchins, and temperature as the most important predictors explaining 63% of the variability of bull kelp in the north and central regions, and 45% and 51.4% of the variability in giant kelp for the central/south-west and south-east regions, respectively. These large-scale analyses infer that a combination of lower nutrient availability, changes in wave energy and exposure, and increases in temperature and purple sea urchin counts have contributed to the decline of kelp observed in the last decade. Understanding the drivers of kelp dynamics can be used to identify regions and periods of significant change and historical stability, ultimately informing resource management and conservation decisions such as site selection for kelp protection and restoration. Open research statementData (Giraldo-Ospina et al. 2023) are available in DataOne at doi:10.25494/P6/When_where_and_how_kelp_restoration_guidebook_2.

ecology↗

bioRxiv2022

The Main Themes and Experiences Shared with the Hashtag #BlackintheIvory: A Qualitative Analysis

BackgroundThe movement #BlackintheIvory gave Black academics an opportunity to connect through a social media platform allowing them to share common experiences in the pursuit of higher education. Through the analysis of Twitter posts, using the hashtag #BlackintheIvory, this study investigates the main themes identified among Black scholars in academia and their shared experiences with teaching, mentoring, collegiality, identity, service, and racism. MethodsUsing the Twitter API, we isolated all publicly available tweets, which can include text, images, and links to websites, posted with the hashtag #BlackintheIvory on the Twitter website (www.twitter.com) from the inception of the hashtag in June 2020 to the end of December 2020. To evaluate the tweets, we categorized the tweets inductively. Based on the content of the posts, we identified 6 themes: Teaching, Mentoring, Collegiality, Identity, Service, and Racism. ResultsOur search yielded a total of 12,538 original posts, including tweets between inception in June 2020 to December 2020 from profiles made public (excluding modified tweets and duplicate tweets). We selected and analyzed the top retweeted 2500 tweets, which is 20% (2500/12538) of the total number of downloaded tweets. The greatest percentage of posts were about Teaching (881; 35%), followed by Service (441; 18%) and Racism (414; 17%). The remaining tweets were categorized as Collegiality (388; 15%), Identity (210; 8%), and Mentoring (166; 7%) of the total number of tweets from June-December 2020. ConclusionThe experiences, perspectives, and narratives among the Black diaspora within #BlackintheIvory are not uniform. The commonality exists within the structural systemic racism which impacts Black academics within the ivory tower, this study is a resounding wake-up call for action. FundingThis study was not subject to any funding

scientific communication and education↗

bioRxiv2021

Impact of increased membrane realism on conformational sampling of proteins

The realism and accuracy of lipid bilayer simulations through molecular dynamics (MD) is heavily dependent on the lipid composition. While the field is pushing towards implementing more heterogeneous and realistic membrane compositions, a lack of high-resolution lipidomic data prevents some membrane protein systems from being modeled with the highest level of realism. Given the additional diversity of real-world cellular membranes and protein-lipid interactions, it is still not fully understood how altering membrane complexity affects modeled membrane protein function or if it matters over long timescale simulations. This is especially true for organisms whose membrane environments have little to no computational study, such as the plant plasma membrane. Tackling these issues in tandem, a generalized, realistic, and asymmetric plant plasma with more than 10 different lipid species membrane is constructed herein. Classical MD simulations of pure membrane constructs were performed to evaluate how altering the compositional complexity of the membrane impacted the plant membrane properties. The apo form of a plant sugar transporter, OsSWEET2b, was inserted into membrane models where lipid diversity was calculated in either a size-dependent or -independent manner. An adaptive sampling simulation regime validated by Markov-state models was performed to capture the gating dynamics of OsSWEET2b in each of these membrane constructs. In comparison to previous OsSWEET2b simulations performed in a pure POPC bilayer, we confirm that simulations performed within a native-like membrane composition alter the stabilization of apo OsSWEET2b conformational states by ~1 kcal/mol. The free energy barriers of intermediate conformational states decrease when realistic membrane complexity is simplified, albeit roughly within sampling error, suggesting that protein-specific responses to membranes differ due to altered packing caused by compositional fluctuations. This work serves as a case study where a more realistic bilayer composition makes unbiased conformational sampling easier to achieve than with simplified bilayers.

biophysics↗

bioRxiv2021

Txikispora philomaios n. sp., n. g., a Micro-Eukaryotic Pathogen of Amphipods, Reveals Parasitism and Hidden Diversity in Class Filasterea

This study provides a morphological, ultrastructural, and phylogenetic characterization of a novel micro-eukaryotic parasite (2.3-2.6 {micro}m) infecting genera Echinogammarus and Orchestia. Longitudinal studies across two years revealed that infection prevalence peaked in late April and May, reaching 64% in Echinogammarus sp. and 15% in Orchestia sp., but was seldom detected during the rest of the year. The parasite infected predominantly haemolymph, connective tissue, tegument, and gonad, although hepatopancreas and nervous tissue were affected in heavier infections, eliciting melanization and granuloma formation. Cell division occurred inside walled parasitic cysts, often within host haemocytes, resulting in haemolymph congestion. Small subunit (18S) rRNA gene phylogenies including related environmental sequences placed the novel parasite as a highly divergent lineage within Class Filasterea, which together with Choanoflagellatea represent the closest protistan relatives of Metazoa. We describe the new parasite as Txikispora philomaios n. sp. n. g., the first confirmed parasitic filasterean lineage, which otherwise comprises four free-living flagellates and a rarely observed endosymbiont of snails. Lineage-specific PCR probing of other hosts and surrounding environments only detected T. philomaios in the platyhelminth Procerodes sp. We expand the known diversity of Filasterea by targeted searches of metagenomic datasets, resulting in 13 previously unknown lineages from environmental samples.

pathology↗

bioRxiv2020

Crystal structure and molecular dynamics of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability

Polymerase {delta}-interacting protein 2 (POLDIP2, PDIP38) is a multifaceted, moonlighting protein, involved in binding protein partners from many different cellular processes, including mitochondrial metabolism, DNA replication and repair, and reactive oxygen species generation. POLDIP2 is found in multiple cellular compartments, potentially shuttled depending on its role. How POLDIP2 binds to and coordinates many different proteins is currently unknown. Towards this goal, we present the crystal structure of the mitochondrial fragment of POLDIP2 to 2.8 [A]. POLDIP2 exhibited a compact two-domain {beta}-strand-rich globular structure, confirmed by circular dichroism and small angle X-ray scattering approaches. POLDIP2 comprised canonical DUF525 (ApaG) and YccV-like domains, but with the conserved domain linker packed tightly, resulting in an extended YccV module. A central channel through POLDIP2 was observed which we hypothesise could influence structural changes potentially mediated by redox conditions, following observation of a modified cysteine residue in the channel. Unstructured regions were rebuilt by ab initio modelling to generate a model of full length POLDIP2. Molecular dynamics simulations revealed a highly dynamic N-terminal region tethered to the YccV-domain by an extended linker, potentially facilitating interactions with distal binding partners. Finally we build models of POLDIP2 interacting in complex with two of its partners in genome stability, PrimPol and PCNA. These indicate that dynamic flexibility of the POLDIP2 N-terminal and loop regions are critical to mediate protein-protein interactions.

biochemistry↗

bioRxiv2019

Cross-validation of technologies for genotyping CYP2D6 and CYP2C19

BackgroundCYP2D6 and CYP2C19 are cytochrome P450 enzymes involved in the metabolism of many medications from multiple therapeutic classes. Associations between patterns of variants (known as haplotypes) in the genes encoding them (CYP2D6 and CYP2C19) and enzyme activities are well described. The genes in fact comprise 21% of biomarkers in drug labels. Despite this, genotyping is not common, partly attributable to its challenging nature (CYP2D6 having >100 haplotypes, including those with sequence from an adjacent pseudogene, and gene duplications). We cross-validated different methodologies for identifying haplotypes in these genes against each other. MethodsNinety-two samples with a variety of CYP2D6 and CYP2C19 genotypes according to prior AmpliChip CYP450 and TaqMan CYP2C19*17 data were selected from the Genome-based therapeutic drugs for depression (GENDEP) study. Genotyping was performed with TaqMan copy number variant (CNV) and single nucleotide variant (SNV) analysis, the next generation sequencing-based Ion S5 AmpliSeq Pharmacogenomics Panel, PharmacoScan, long-range polymerase chain reaction (L-PCR) followed by amplicon analysis, and Agena for CYP2C19. Variant pattern to haplotype translation was automated. ResultsThe inter-platform concordance for CYP2C19 was high (up to 100% for available data). For CYP2D6, the IonS5-PharmacoScan concordance was 94% for a range of variants tested apart from those with at least one extra copy of a CYP2D6 gene (occurring at a frequency of 3.8%, 33/853), or those with substantial sequence derived from pseudogene, known as hybrids (3%, 26/853). ConclusionsInter-platform concordance for CYP2C19 was high, and, moreover, the Ion S5 and PharmacoScan data were 100% concordant with that from a TaqMan CYP2C19*2 assay. We have also demonstrated feasibility of using an NGS platform for genotyping CYP2D6 and CYP2C19, with automated data interpretation methodology. This points the way to a method of making CYP2D6 and CYP2C19 genotyping more readily accessible.

genetics↗