Biology subjects

Taylor, J.

Publications and source records attributed to Taylor, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Altered Aperiodic EEG Activity in Adolescents with Neurofibromatosis Type 1

BackgroundThe balance between excitatory and inhibitory neuronal signalling (E/I balance), proposed as a key mechanism controlling neuronal activity, is disrupted in many neurodevelopmental conditions. One such condition is Neurofibromatosis Type 1, a monogenic neurodevelopmental disorder characterised by increased inhibitory tone. While previous research suggests that E/I balance may be altered in infancy, it is unknown whether E/I balance remains altered during adolescence in NF1. Here we investigated this question using the aperiodic exponent of the resting electroencephalogram (EEG) power spectrum, a proposed electrophysiological index of E/I balance. MethodThe aperiodic exponent of the EEG power spectrum ( 1/f) was estimated for 16 adolescents with NF1 diagnosis aged 11-16, and 16 age- and sex-matched neurotypical controls. General linear models (GLM) were fit to estimate effects of NF1 diagnosis, age and their interaction on aperiodic exponent. We also estimated the peak dominant frequency and power in oscillatory activity of the EEG signal and fitted the same structure of GLM models. Cognitive assessments across domains of memory, executive function and attention were also analysed with GLM to examine brain-cognition associations. ResultsThe NF1 group had higher aperiodic exponent compared to neurotypical controls, but the aperiodic exponent was not associated with cognitive performance. After accounting for aperiodic activity, the NF1 group also had lower dominant oscillatory frequency than the control group. There was no significant interaction between NF1 diagnosis and age on PAF. There were no group differences in peak alpha power. ConclusionsWe demonstrate for the first time that the alterations to aperiodic activity in NF1 are consistent with the proposed mechanism of increased inhibitory tone. These findings show the potential of this paradigm for future pharmacological and brain stimulation trials investigating treatment-related changes in cortical function.

neuroscience↗

bioRxiv2026

A Pooled CRISPR Screen Protocol for Comparative Pathway Analysis Across Multiple Stressors

High content CRISPR screens have become a leading method for the identification of new cellular pathways, proteins functions, and drug targets. However, as the complexity of these screens increase, so does the possibility of artifacts. Here, we describe a refined CRISPR screening protocol that can compare acute cellular responses across multiple cellular treatments and timepoints, while reducing false positives by up to 40% compared to conventional screening approaches. This is achieved through the use of a fluorescence-based reporter line responsive to multiple stressors, as well as a fixation step to preserve acute response differences and avoid sorting-related false positives. We recently performed a version of this workflow to compare kinases regulating different types of selective autophagy, including starvation-induced autophagy, ERphagy, and pexophagy. Beyond autophagy research, this screen approach can be implemented for any fluorescence-based screen where preservation of acute cellular responses is important. Here we present a complete workflow of this optimized screening protocol using our selective autophagy screen as a specific example throughout. Implementation of these strategies should allow researchers to increase the number of stressors tested within a single screen without sacrificing cell health, reliability, or statistical power.

genomics↗

bioRxiv2026

An Integrated Preclinical Platform for Lethal Neuroendocrine Prostate Cancer from Rapid Autopsy Bone and Liver Metastases.

Treatment-emergent neuroendocrine prostate cancer (NEPC) is an aggressive, therapy-resistant disease arising in up to 20% of castration resistant prostate cancers, yet robust biologically relevant preclinical models remain scarce. Here, we describe a technical blueprint for establishing an integrated platform of patient-derived models from visceral and bone metastases collected through a prostate cancer rapid autopsy program (PC RAP). We report the establishment and characterization of patient-derived xenograft (PDX) models from liver metastasis tissue, liver and bone metastasis-derived organoid lines (PDOs), and corresponding patient-derived organoid xenograft (PDOX) models. In addition, we established, to our knowledge, the first mesenchymal stem cell (MSC) cultures derived from neuroendocrine prostate cancer (NEPC) bone metastases. The PDOs preserved intratumoral heterogeneity, displaying both CRPC-NE and CRPC-adenocarcinoma features. These organoids retained neuroendocrine identity across multiple passages, with transcriptomic profiles concordant with the original patient tissue and matched PDX models generated at our institution and at the National Cancer Institute (NCI Patient-Derived Models Repository). To model the bone metastatic microenvironment, we generated novel organoid-based New Approach Methodologies (NAMs) by co-culturing PDOs with iPSC-derived bone marrow organoids, establishing a physiologically relevant vascularized organotypic model of PC bone metastasis. To extend our studies in vivo, we established preclinical models using the liver and bone metastasis-derived organoid models. The PDOX models were tumorigenic and developed spontaneous lymph node metastases, providing clinically relevant models for investigating lethal NEPC biology. Together, these complementary patient-derived models provide a robust and versatile platform for investigating NEPC biology, metastatic progression, and evaluating new therapeutic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/740121v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1c641f1org.highwire.dtl.DTLVardef@113696aorg.highwire.dtl.DTLVardef@16dcc72org.highwire.dtl.DTLVardef@1898d9f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINovel preclinical models of visceral and bone metastases established from a prostate cancer rapid autopsy program. C_LIO_LIThis study is the first to establish mesenchymal stem cell cultures from NEPC bone metastases. C_LIO_LIPDOs preserve heterogeneity, showing both CRPC-NE and CRPC-Adeno features, with transcriptomic profiles concordant with originator tissue and PDX models. C_LIO_LIPC RAP-derived organoids are tumorigenic in vivo and generate spontaneous lymph node metastases. C_LI

cancer biology↗

bioRxiv2026

Combinatorial screening of biological degrader modules identifies heterobifunctional molecules that efficiently destroy MYC, leading to rapid tumour cell death in vitro and in vivo

Targeted protein degradation is a potent strategy against intracellular proteins impervious to traditional drugs. We describe a platform reliant on high-throughput cloning and mRNA-based delivery to quickly screen 100s-1000s of modular biological degraders, which we challenge against the high-turnover c-Myc oncoprotein. We uncover critical principles to drive degrader discovery against any target, free from tagging or prior cell line engineering, with direct applications in research and potentially therapy. We demonstrate the feasibility of targeted protein degradation of c-Myc across in vitro cancer models and in vivo xenograft model, uncovering distinct cellular responses between c-Myc degradation and inhibition.

bioengineering↗

bioRxiv2026

Targeting an RNA Editor to Impede H3K27M+ Pediatric Gliomas

Diffuse midline glioma (DMG) is a lethal pediatric brain tumor with no curative therapies. Immune checkpoint blockade (ICB) has shown limited efficacy in DMG, largely due to poor T cell infiltration, low immune checkpoint (IC) expression, and a low tumor mutational burden. Here, we identify adenosine deaminase acting on RNA (ADAR), an RNA-editing enzyme that suppresses endogenous dsRNA sensing, as a key mediator of immune evasion in H3K27M-mutant DMG. ADAR is significantly overexpressed in H3K27M tumors relative to wild-type high-grade gliomas, and its depletion selectively suppresses proliferation in patient-derived DMG cells. The H3K27M mutation was found to synergize with ADAR loss to increase retroelement expression, activate type I interferon signaling, and induce immune checkpoint expression. We further identify all-trans retinoic acid (ATRA) as a pharmacologic inducer of ADAR degradation. At clinically relevant doses, ATRA phenocopies ADAR depletion, enhancing antiviral and interferon responses while increasing tumor immunogenicity. In orthotopic immunocompetent DMG models, ATRA enhances CD8+ T cell infiltration and synergizes with ICB and irradiation to improve survival.

cancer biology↗

bioRxiv2026

Urban soils along the Kern River and Los Gatos Creek are hotspots for Coccidioides in the San Joaquin Valley of California

Coccidioidomycosis (Valley fever) is acquired through inhalation of spores produced by fungi in the genus Coccidioides. Coccidioides is commonly detected in, and cultivated from, the lung tissue of native rodents and the soils within their burrows. Coccidioidomycosis is acquired by exposure to environmentally produced spores and is not spread between hosts. Thus, determining the location of rodent burrows with soils harboring Coccidioides will be critical for understanding coccidioidomycosis incidence and modelling how Coccidioides distributions will be affected by global change. Coccidioides is readily detected in rodent burrows on undisturbed land, has not been detected on agricultural land, and is unstudied on urban land. To test the hypothesis that Coccidioides is in urban soil, we sampled rodent burrow soils from the banks of two water ways, the Kern River and Los Gatos Creek, which transect two cities, Bakersfield and Coalinga, in the San Joaquin Valley of California. To test the hypothesis that Coccidioides would not be detected at higher elevations, we extended our sampling of rodent burrows along waterways into the mountains of California. From 1178 soil and settled dust samples, we find that Coccidioides is found in urban riparian environments in Bakersfield and Coalinga, on riparian land on the floor of the San Joaquin Valley but not at higher elevations and is negatively correlated with modeled soil moisture. Coccidioides shows significant co-occurrence patterns with animal-associated fungal taxa, but no broader relationships with the greater fungal community. Our results warrant caution when excavating urban rodent burrows in the region. Author SummaryCoccidioidomycosis, or Valley fever, is caused by a fungus that primarily infects people when its spores become airborne and are inhaled. Although the fungus is found in the burrows of rodents, its presence in cities has been unclear. We investigated whether urban environments in Californias San Joaquin Valley, an area with high Valley fever incidence, harbor the fungus. By sampling more than a thousand soils and settled dust samples along riparian areas (waterways and adjacent environments) in Bakersfield and Coalinga, we found that the fungus that causes Valley fever, Coccidioides, occurs in urban riparian zones. The fungus was restricted to low elevations and was more likely to be detected in drier soils. We also compared positive and negative soils using DNA-based surveys of fungi. While the broader fungal community showed no strong relationship to Coccidioides, several species tied to animal activity were more common in positive samples, supporting a link to rodent hosts. These findings show that urban waterways can serve as habitat for Coccidioides. Because these areas lie within major population centers, identifying and avoiding disturbance of rodent burrows may reduce exposure risk, and future models of Valley fever should account for riparian corridors and local ecological conditions.

microbiology↗

bioRxiv2026

Rethinking yield stability through phenotypic plasticity and its link to modern statistical methods

In the context of advocacy for yield stability, trade-offs between yield and yield stability, the frequent lack of definitions, and the variation in methods when they are explicit, we connect two perspectives: phenotypic plasticity and factor analytics. Phenotypic plasticity brings over a century of research in developmental biology, ecology and evolution, and is gaining traction in crop science. Factor analytics is an advanced linear mixed model of multi-environment data with factor analytic variance structures for the variety-by-environment interaction effect. We (1) review phenotypic plasticity, define agronomically adaptive plasticity where varieties (or practices) consistently return superior yield (or other traits) across environments with no trade-off, and describe percentile-plasticity plots to assess the agronomic value of plasticity; (2) outline factor analytic models, and (3) link plasticity and factor analytic models mathematically and empirically. We show that phenotypic plasticity of cereal yield correlates positively with overall performance obtained from factor analytic models when plasticity is adaptive and negatively when it is maladaptive. We conclude that phenotypic plasticity contributes biological meaning to opaque analytical approaches, and that biologically grounded statistics are needed to challenge weak agronomic narratives, such as advocacy for stability that might reflect decision biases rather than critical consideration of its benefits. HighlightUncritical advocacy for crop yield stability is common. Here we advance a biological-statistical synthesis of yield stability and test theoretical predictions with actual wheat and oat yield data.

plant biology↗

bioRxiv2025

Diverse haplotypes at a complex Solanum americanum locus confer resistance to Phytophthora infestans and P. capsici

Plants encounter diverse pathogens and have evolved a two-layered innate immune system to detect pathogen molecules and activate defense mechanisms that restrict infection. Most cloned plant Resistance (R) genes encode NLR immune receptors. NLR genes are often found in clusters of paralogs with sequence and copy number variation; whether these NLR clusters evolve in response to single or multiple pathogens has been unclear. We report here the isolation of a Phytophthora capsici resistance gene, Rpc2, along with a novel P. infestans resistance gene, Rpi-amr5, from two Solanum americanum accessions. These orthologous genes reside in the Rpi-amr1 cluster, which has previously been associated with resistance to P. infestans. By screening RXLR effector libraries of P. infestans and P. capsici, we identified multiple effectors recognized by both NLRs. Our findings highlight the complexity of NLR clusters and evolution driven by interactions with multiple pathogens. This work will underpin efforts to elevate resistance against Phytophthora pathogens and enhances our understanding of NLR evolution.

plant biology↗

bioRxiv2025

The assembly of stress granule-like foci during foot-and-mouth disease virus infection is uncoupled from activation of cellular intrinsic antiviral signalling

Foot-and-mouth disease virus (FMDV) is highly contagious among cloven-hoofed animals and poses a major threat to the livestock industry worldwide. A fundamental gap in knowledge for high consequence viruses such as FMDV is understanding how the virus evolved to evade cellular antiviral responses. FMDV belongs to the Picornaviridae, a family of positive-sense single-stranded RNA viruses. The detection of viral double-stranded viral RNA intermediates during infection can trigger both the assembly of cytoplasmic stress granules (SGs) and the activation of the RIG-I-like receptors (RLR)-mediated innate immune response (IIR). FMDV has been proposed to antagonize these mechanisms, suggesting that both can limit viral replication. In this study, we investigate the dynamic and importance of SG assembly for IIR activation upon dsRNA stimulation or FMDV replication in porcine epithelial kidney cells. First, we show that the formation of SG following a challenge with poly(I:C), a viral dsRNA mimic, does not modulate the activation of IIR. Our data further reveal transient assembly of SG during FMDV infection followed by virus-induced cleavage of G3BP1, a core SG protein. While SG assembly does not impact viral replication or antiviral response activation, we demonstrate that preventing their disassembly negatively impacts FMDV replication. Overall, our data suggests that while SGs assembly is uncoupled from IIR activation, manipulating their disassembly limits replication and might serve as a potential therapeutic target to prevent FMDV infection. ImportanceBiomolecular condensates, including stress granules, are key regulatory compartments that control fundamental cellular processes. By condensing RNAs and proteins, these structures enable cells to rapidly adapt to stress, such as viral infection. Different biomolecular condensates with specific dynamics or compositions have been described during infection, and many viruses are known to disrupt or highjack their components. Moreover, the cell-autonomous innate immune response is proposed to be regulated by biomolecular condensates. However, the molecular mechanisms underpinning these functions remain unclear and controversial. Here we investigated the interplay between stress granules and the innate response upon the stimulation with a viral dsRNA mimic or foot-and-mouth disease virus infection. We demonstrate that infection triggers the formation of stress granules independently from activation of innate signalling pathways. We also show that stress granules persistence attenuates viral replication posing them as part of the cells response that viruses must overcome or subvert to replicate.

microbiology↗

bioRxiv2025

Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged AML

Acute myeloid leukemia (AML) harboring MLL (MLL1, KMT2A) rearrangement (MLL-r) remains a lethal subtype with limited durable responses to single-agent menin inhibition. To define rational combination strategies, we performed a high-throughput screen of >900 epigenetic modulators in combination with menin inhibition in MLL-r AML models. This uncovered consistent synergy between menin and lysine-specific demethylase 1 (LSD1) inhibition, including with the clinical agent iadademstat. Mechanistically, LSD1 was found to interact with LEDGF/p75 (PSIP1), a chromatin-anchoring cofactor of the menin-MLL complex at H3K36me3 marked euchromatin. Chromatin profiling revealed extensive co-occupancy of LSD1 and menin-MLL components at leukemogenic loci in MLL-r AML cells. Dual inhibition of menin and LSD1 dismantled this chromatin complex, evicted H3K36me3 from LEDGF-bound sites, and reprogrammed transcription toward myeloid differentiation. Combined menin and LSD1 blockade repressed canonical MLL targets, including HOXA9, MYC, FLT3, PBX3, and CDK6, while restoring H3K36me3 and H3K4me3 and activating differentiation-associated genes. In vivo, the combination produced potent antileukemic effects in both MOLM-13 and MLL-r patient-derived xenografts, markedly reducing leukemic burden and extending survival without overt toxicity. These findings identify LSD1 as a critical cofactor of the menin-MLL-LEDGF axis and establish concurrent menin and LSD1 inhibition as a mechanistically informed combinatorial therapeutic approach in MLL-r AML.

cancer biology↗

bioRxiv2025

The GLP-1R Agonist Semaglutide Reduces Motivated Running and Alters Dopamine Dynamics in the Nucleus Accumbens

Glucagon-like peptide-1 receptor (GLP-1R) agonists have recently emerged as powerful tools for the treatment of obesity through their ability to suppress food intake. However, their effects on non-ingestive motivated behaviors remain incompletely understood. Here, we show that the long-acting GLP-1R agonist semaglutide (SG) suppresses voluntary wheel running in both lean and diet-induced obese mice. Importantly, this suppression of activity was not caused by hypophagia and was accompanied by decreased motivation, with SG-treated mice displaying reduced effort for wheel access in a progressive ratio task. Real-time measurements of dopamine via fiber photometry revealed specific dopamine changes in the nucleus accumbens at both the beginning and end of running bouts, with SG-treated animals showing amplified dopamine dynamics at these key behavioral timepoints. Collectively, these data reveal important non-ingestive behavioral effects of GLP-1R agonism and suggest a role for dopamine circuits in mediating reductions of volitional activity following SG treatment.

neuroscience↗

bioRxiv2025

Lonafarnib Partially Reverses Cardiac Senescence in Human and Mouse Progeria Models via Autophagy Activation

Hutchinson-Gilford Progeria Syndrome (HGPS), characterised by accelerated ageing, causes cardiovascular defects resembling aspects of cardiovascular ageing. We used human left ventricle cardiomyocytes (CMs) derived from HGPS-induced pluripotent stem cells (iPSCs), and their isogenic-corrected controls, to investigate HGPS-CM dysfunction and identify potential therapies. Our results revealed that HGPS-iPSC-CMs exhibit greater maturity and associated elevated oxidative stress compared to controls, which they could not contend with, leading to cellular senescence. Increased senescence was also observed in cardiac tissue from mouse and human physiologically-aged and HGPS individuals. Functionally, HGPS-iPSC-CMs showed dysregulated mitochondrial respiration and calcium handling. Amongst the six drugs tested, rapamycin and lonafarnib were the most effective against HGPS-cardiac phenotypes. Although lonafarnib raised safety concerns, it partially reverted the cardiac senescent phenotype by inducing cellular autophagy and decreasing progerin expression in progeroid mice. Our study supports the use of HGPS-iPSC-CMs to identify novel biomarkers and therapies for HGPS, and potentially cardiac physiological-ageing.

cell biology↗

bioRxiv2025

A Python Toolbox for Representational Similarity Analysis

Representational similarity analysis (RSA) is a method to characterize neural representations and evaluate computational models based on neural representational geometries. Here we present a wave of recent methodological advances, including improved measures of representational distances, evaluators for representational models, and statistical inference methods, which are available to the community in a new open-source toolbox in Python. The rsatoolbox enables neuroscientists to explore neural representational geometries and to evaluate neural network models, connecting theory to experiment in the new era of big models and big data.

neuroscience↗

bioRxiv2025

Resolving the evolutionary history of bighorn sheep to inform future management

Although translocations can be effective for augmenting and restoring wild populations, they can disrupt native patterns of genetic structure, diversity, and local adaptation, thereby hampering conservation efforts. Managers must weigh potential costs and benefits of choosing well-differentiated donor individuals that could confer a boost to genetic diversity while avoiding outbreeding depression or ecological mismatch. This decision is more daunting when taxonomy is unclear or debated. For example, bighorn sheep (Ovis canadensis) populations in the United States that have been managed as the "California" lineage (part of the formerly recognized subspecies O. c. californiana) originate from serial translocations sourced from populations in British Columbia, resulting in reduced genetic diversity and elevated risk of inbreeding. After research on skull shape and RFLP analysis of mtDNA failed to find support for that subspecies, some jurisdictions treated the California lineage as part of the Rocky Mountain subspecies (O. c. canadensis) and mixed individuals in subsequent translocations, in part to increase genetic diversity of bottlenecked populations. Yet detailed genetic data addressing validity of those putative lineages were lacking. We reconstructed the genetic history of bighorn sheep by sampling the major putative subspecies or lineages, focusing on native (remnant) genetic variation, and generating high-throughput DNA sequencing data ([~]15,000-25,000 SNPs). Complementary phylogenetic and population genetic analyses supported the distinctiveness of four bighorn lineages at levels corresponding to subspecies. Our results confirm the genetic identity of the no longer putative California bighorn lineage, answering a question that puzzled geneticists and managers for decades. Moving forward, we recommend that managers 1) maintain the natural variation held in native populations by protecting them from intentional translocations or unintentional mixing with nearby populations; 2) prioritize withinlineage translocations for population augmentation or repatriation to previously occupied regions; and 3) cautiously consider any translocations that would lead to mixing of distinct evolutionary lineages.

evolutionary biology↗

bioRxiv2025

IL-6 underlies microenvironment immunosuppression and resistance to therapy in glioblastoma

The glioblastoma tumor immune microenvironment (TIME) is an immunosuppressive barrier to therapy that encumbers glioblastoma responses to immune checkpoint inhibition (ICI). Immunosuppressive cytokines, pro-tumor myeloid cells, and exhausted T-cells are hallmarks of the glioblastoma TIME. Here we integrate spatial and single-cell analyses of patient-matched human glioblastoma samples before and after ICI with genetic, immunologic, single-cell, and pharmacologic studies in preclinical models to reveal that interleukin-6 (IL-6) inhibition reprograms the glioblastoma TIME to sensitize mouse glioblastoma to ICI and radiotherapy. Rare human glioblastoma patients who achieve clinical responses to ICI have lower pre-treatment IL-6 levels compared to glioblastomas who do not respond to ICI. Immune stimulatory gene therapy suppresses IL-6 tumor levels in preclinical murine models of glioblastoma. Furthermore, survival was longer in Il-6 knockout mice with orthotopic SB28 glioblastoma relative to wild-type mice. IL-6 blockade with a neutralizing antibody transiently sensitizes mouse glioblastoma to anti-PD-1 by increasing MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells, and decreasing immunosuppressive Tregs. To translate these findings to a combination treatment strategy for recurrent glioblastoma patients, we show that IL-6 blockade plus ICI durably sensitizes mouse glioblastoma to high-dose radiotherapy.

cancer biology↗

bioRxiv2025

CD8+ T cells mediate vaccination-induced lymphatic containment of latent Mycobacterium tuberculosis infection following immunosuppression, while B cells are dispensable

It is estimated that two billion people are latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Latent Mtb infection (LTBI) can occur in multiple organs, including the lymphatics. The risk of LTBI reactivation increases in immunocompromised conditions, such as coinfection with human immunodeficiency virus (HIV), and during treatment of autoimmune diseases and organ transplantation. The immunological correlates of protection against TB, including against reactivation of LTBI, remain largely elusive. Here, we used a mouse model of latent lymphatic Mtb infection to dissect the immunological mechanisms underlying LTBI containment versus reactivation. We show that immunosuppression-mediated reactivation of lymphatic LTBI and the subsequent spread to non-lymphatic organs can be prevented by vaccination with multiple recombinant BCG (rBCG) strains despite the deficiency of CD4+ T cells. Using spatial transcriptomics, multi-parameter imaging, network analysis and bioinformatic integration of histopathological images, we reveal that immunosuppression is associated with a distinct repositioning of non-CD4 immune cells at the edge of TB lesions within the infection-draining cervical lymph nodes. While B cells increased in numbers, they are dispensable for the containment of LTBI. Lymphatic Mtb infection in different immune cell-deficient mouse strains, antibody-mediated cell depletion and adoptive transfer experiments into highly susceptible mice unequivocally show that vaccination-mediated prevention of LTBI reactivation is critically dependent on CD8+ T cells. These findings have profound implications for our understanding of immunity to TB and the management of LTBI. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/634479v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@151fdd6org.highwire.dtl.DTLVardef@1efed47org.highwire.dtl.DTLVardef@c2e7e0org.highwire.dtl.DTLVardef@555c7_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Protein phosphatase 4 is required for centrosome asymmetry in fly neural stem cells

Asymmetric cell division is used by stem cells to create diverse cell types while self-renewing the stem cell population. Biased segregation of molecularly distinct centrosomes could provide a mechanism to maintain stem cell fate, induce cell differentiation or both. However, the molecular mechanisms generating molecular and functional asymmetric centrosomes remain incompletely understood. Here, we show that in asymmetrically dividing fly neural stem cells, Protein phosphatase 4 (Pp4) is necessary for correct centrosome asymmetry establishment during mitosis, and microtubule organizing center (MTOC) maintenance in interphase. Using in-vivo live cell imaging we show that while wild type neural stem cells always maintain one active MTOC, Pp4 mutant neuroblasts contain two inactive centrioles in interphase. Furthermore, centrosomes of Pp4 mutant neural stem cells mature in mitosis but fail to correctly transfer the centriolar protein Centrobin (Cnb) from the mother to the daughter centriole. Using superresolution imaging, we find that phosphomimetic Centrobin fails to accurately relocalize in mitosis. We propose that Pp4 regulates the timely relocalization of Cnb in mitosis to establish two molecularly distinct centrosomes. In addition, Pp4 is also necessary to maintain MTOC activity in interphase, ensuring biased centrosome segregation. Mechanistically, Pp4 could regulate centrosome asymmetry by dephosphorylating both Cnb and gamma-Tubulin. SIGNIFICANCE STATEMENTO_LIAsymmetric centrosome segregation occurs in stem cells and has been linked with cell fate decisions. C_LIO_LIProtein phosphatase 4 (Pp4), a conserved Serine/Threonine phosphatase, regulates centrosome asymmetry in Drosophila neural stem cells by acting upon gamma tubulin and Centrobin. C_LIO_LIPp4 regulates centrosome asymmetry establishment in mitosis and interphase, necessary for biased centrosome segregation. C_LI

cell biology↗

bioRxiv2024

Putative neofunctionalization of a Poales-specific EXO70 clade

EXO70s are uniquely expanded in land plants compared to all other eukaryotic lineages. The functional implications of this expansion and diversification on the conserved role of EXO70 as a subunit of the octameric exocyst complex have remained unresolved. We previously demonstrated barley (Hordeum vulgare) EXO70FX12, a member of the monocot-specific EXO70FX clade, is required for resistance to wheat stripe rust in conjunction with the leucine-rich repeat receptor kinase (LRR-RK) HvPUR1. Through phylogenetic analysis, we identified unique features of the EXO70FX clade, leading us to hypothesize that this clade experienced neofunctionalization. Using structural predictions and protein-protein interaction assays, we demonstrate that HvEXO70FX12 lost the ability to serve as a subunit within the exocyst complex. We predict that the EXO70FX clade has largely lost exocyst association and represents a novel acquisition that emerged during Poales diversification for immunity.

plant biology↗