Biology subjects

Moore, I.

Publications and source records attributed to Moore, I..

12 recordsLinked to original sources

bioRxiv2026

Immune determinants of leuprolide-associated cardiovascular risk in prostate cancer

Leuprolide, a widely used androgen-deprivation therapy (ADT) for prostate cancer (PC), has been associated with increased cardiovascular events (CVE), although the underlying mechanisms remain unclear. Through integrated spatial transcriptomic analyses of murine heart and immune-stromal profiling in patient blood, we identified immune programs linked to leuprolide-associated CVE risk. Spatial analyses revealed the distinct organization of lymphoid (T+B cells) aggregates and inflammatory macrophages in the plaque following leuprolide exposure that accompanied by ventricular hypertrophy, relative to normal vasculature. Parallel profiling of circulatory soluble and cellular components in patients demonstrated CD8+T cell enriched pattern in ~44% of patients, including memory and type 1 cytotoxic subsets that linked to treatment-induced CVE, such as ventricular dysfunctions, but no contribution of adipocytokines. These translational findings highlight the stratification of leuprolide-associated CVE risk in PC patients based on circulating T cell profiling and could guide the risk mitigation with alternative ADT agents.

immunology↗

bioRxiv2025

Trans-kingdom coupling of redox signaling to environmental cell stress responses through multiphase partitioning.

Reactive Oxygen Species (ROS) signaling is a conserved biological process with parallel functions in all evolutionary branches of life. Here, we identify Receptor for Activated C Kinase 1 (RACK1) as a conserved redox-regulated hub that integrates ROS signals to coordinate cellular stress responses. Using cysteine reactivity profiling in intestinal epithelial cells, we demonstrate that RACK1 undergoes NOX1-dependent oxidation at multiple residues, with C286 serving as a key regulatory site. Functional studies reveal that RACK1 negatively regulates NF{kappa}B signaling through redox-dependent interactions with upstream signaling complexes. Upon stress stimulation, RACK1 dynamically redistributes into membrane-less condensates that act as redox-privileged microenvironments enriched for hydrogen peroxide. We find that oxidized RACK1 condensates are conserved through evolution with analogous stress response behavior in bacteria and yeast indicating a ubiquitous and ancient stress sensor-effector system. Functionally, redox-dependent RACK1 activity links environmental stress to translational control, with oxidation promoting inhibition of protein synthesis. Furthermore, RACK1 mediates responses to diverse pathogen-associated stimuli, including viral and bacterial infection, highlighting its role in epithelial innate immune responses. Collectively, these findings establish RACK1 as a cellular node for redox signaling, operating within condensate-based microdomains to spatially encode oxidative signals and regulate environmental stress pathways in cells. Significance StatementThis study defines a mechanism by which cells achieve specificity in redox signaling through compartmentalization within condensates. By identifying RACK1 as a redox sensor-effector, we reveal an ancient and broadly conserved system linking environmental stress to innate immune signaling and translational control. The discovery of redox-privileged condensates provides a conceptual framework for understanding how transient ROS signals are stabilized and interpreted in epithelial biology, with implications for inflammatory diseases, host-pathogen interactions, and fundamental cellular stress responses.

cell biology↗

bioRxiv2024

A Rab-Kinesin12-Fused kinase module couples vesicle delivery and phragmoplast remodelling during cytokinesis in Arabidopsis

Cytokinesis is a key process in the development of multicellular organisms, through both formative and proliferative divisions. In land plants, successful cytokinesis requires precise targeting of Golgi-derived vesicles to the future division plane by the phragmoplast, a cytoskeletal structure that undergoes continuous remodelling. Endomembrane trafficking and phragmoplast remodelling are tightly coupled, indicating the existence of active crosstalk. However, although many molecular regulators of membrane trafficking and cytoskeletal organisation are known, it remains poorly understood how these processes are co-ordinated. Here, we describe a regulatory module consisting of the membrane-associated GTPase RAB-A2a, cytoskeleton-associated Class II Kinesin-12s, and the Fused kinase orthologue TIO. We provide evidence that the interaction between these molecules at the midzone is essential for cytokinesis in Arabidopsis through simultaneously targeting vesicles to the midzone and coupling phragmoplast remodelling to vesicle delivery.

plant biology↗

bioRxiv2022

Live-attenuated pediatric parainfluenza vaccine expressing 6P-stabilized SARS-CoV-2 spike protein is protective against SARS-CoV-2 variants in hamsters

The pediatric live-attenuated bovine/human parainfluenza virus type 3 (B/HPIV3)-vectored vaccine expressing the prefusion-stabilized SARS-CoV-2 spike (S) protein (B/HPIV3/S-2P) was previously evaluated in vitro and in hamsters. To improve its immunogenicity, we generated B/HPIV3/S-6P, expressing S further stabilized with 6 proline mutations (S-6P). Intranasal immunization of hamsters with B/HPIV3/S-6P reproducibly elicited significantly higher serum anti-S IgA/IgG titers than B/HPIV3/S-2P; hamster sera efficiently neutralized variants of concern (VoCs), including Omicron variants. B/HPIV3/S-2P and B/HPIV3/S-6P immunization protected hamsters against weight loss and lung inflammation following SARS-CoV-2 challenge with the vaccine-matched strain WA1/2020 or VoCs B.1.1.7/Alpha or B.1.351/Beta and induced near-sterilizing immunity. Three weeks post-challenge, B/HPIV3/S-2P- and B/HPIV3/S-6P-immunized hamsters exhibited a robust anamnestic serum antibody response with increased neutralizing potency to VoCs, including Omicron sublineages. B/HPIV3/S-6P primed for stronger anamnestic antibody responses after challenge with WA1/2020 than B/HPIV3/S-2P. B/HPIV3/S-6P will be evaluated as an intranasal vaccine to protect infants against both HPIV3 and SARS-CoV-2. AUTHOR SUMMARYSARS-CoV-2 infects and causes disease in all age groups. While injectable SARS-CoV-2 vaccines are effective against severe COVID-19, they do not fully prevent SARS-CoV-2 replication and transmission. This study describes the preclinical comparison in hamsters of B/HPIV3/S-2P and B/HPIV3/S-6P, live-attenuated pediatric vector vaccine candidates expressing the "2P" prefusion stabilized version of the SARS-CoV-2 spike protein, or the further-stabilized "6P" version. B/HPIV3/S-6P induced significantly stronger anti-S serum IgA and IgG responses than B/HPIV3/S-2P. A single intranasal immunization with B/HPIV3/S-6P elicited broad systemic antibody responses in hamsters that efficiently neutralized the vaccine-matched isolate as well as variants of concern, including Omicron. B/HPIV3/S-6P immunization induced near-complete airway protection against the vaccine-matched SARS-CoV-2 isolate as well as two variants. Furthermore, following SARS-CoV-2 challenge, immunized hamsters exhibited strong anamnestic serum antibody responses. Based on these data, B/HPIV3/S-6P will be further evaluated in a phase I study.

microbiology↗

bioRxiv2022

Characterisation of organised smooth endoplasmic reticulum suggests a route towards synthetic compartmentalisation

Engineering of subcellular compartmentalisation is one of synthetic biologys key challenges. Among different approaches, de novo construction of a synthetic compartment is the most coveted but also most difficult option. Restructuring the endoplasmic reticulum (ER), via the introduction of recombinant oligomerising ER-membrane resident proteins, is an alternative starting point for building a new compartment. The presence of such proteins leads to a massive expansion of the ER and the formation of organised smooth endoplasmic reticulum (OSER), a large membranous compartment. However, OSER is poorly characterised and our understanding of its effect on the underlying biology of the plant is limited. Here we characterise a range of OSER compartments and show how the structure of the inducing polyprotein constructs affect the final compartment morphology, with the cytosolic-facing antiparallel oligomerisation domain demonstrated to be an essential component to trigger OSER formation. We show that while OSER retains a connection to the ER, a diffusional barrier exists to both the ER and the cytosol. Using high-resolution quantitative image analysis, we also show that the presence of this large compartment does not disrupt the rest of the ER network. Moreover, transgenic Arabidopsis constitutively expressing the compartment-forming polyproteins grew and developed normally. These properties collectively suggest that OSER could be developed as a plant synthetic biology tool for compartmentalisation, combining the benefits of several existing strategies. Only a single protein construct is necessary to induce its formation, and the compartment retains a delimiting membrane and a diffusional barrier to the rest of the cell.

plant biology↗

bioRxiv2022

Edge-based growth control in Arabidopsis involves two cell wall-associated Receptor-Like Proteins

Morphogenesis of multicellular organs requires coordination of cellular growth. In plants, 3D growth is driven by undirected turgor pressure, whereas growth directionality is controlled by cell wall mechanical properties at 2D cell faces. Their shared cell wall also fixes cells in their position, and plants thus have to integrate tissue-scale mechanical stresses arising due to growth in a fixed tissue topology. This implies a need to monitor cell wall mechanical and biochemical status and to adapt growth accordingly. Here, we propose that plant cells use their 1D cell edges to monitor cell wall status. We describe two Receptor-Like Proteins, RLP4 and RLP4-L1, which occupy a unique polarity domain at cell edges established through a targeted secretory transport pathway. We show that at cell edges, RLP4s associate with the cell wall via their extracellular domain, and contribute to directional growth control in Arabidopsis.

plant biology↗

bioRxiv2021

An intranasally administrated SARS-CoV-2 beta variant subunit booster vaccine prevents beta variant viral replication in rhesus macaques

Emerging of SARS-CoV-2 variants and waning of vaccine/infection-induced immunity poses threats to curbing the COVID-19 pandemic. An effective, safe, and convenient booster vaccine will be needed. We hypothesized that a variant-modified mucosal booster vaccine might induce local immunity to prevent SARS-CoV-2 infection at the port of entry. The beta-variant is hardest to cross-neutralize. Herein we assessed the protective efficacy of an intranasal booster composed of beta variant-spike protein S1 with IL-15 and TLR agonists in previously immunized macaques. The macaques were first vaccinated with Wuhan strain S1 with the same adjuvant. One year later, negligibly detectable SARS-CoV-2-specific antibody remained. Nevertheless, the booster induced vigorous humoral immunity including serum- and bronchoalveolar lavage (BAL)-IgG, secretory nasal- and BAL-IgA, and neutralizing antibody against the original strain and/or beta variant. Beta-variant S1-specifc CD4+ and CD8+ T cell responses were also elicited in PBMC and BAL. Following SARS-CoV-2 beta variant challenge, the vaccinated group demonstrated significant protection against viral replication in the upper and lower respiratory tracts, with almost full protection in the nasal cavity. The fact that one intranasal beta-variant booster administrated one year after the first vaccination provoked protective immunity against beta variant infections may inform future SARS-CoV-2 booster design and administration timing.

immunology↗

bioRxiv2021

A NET4-RabG3 couple mediate the link between actin and the tonoplast and is essential for normal actin cytoskeletal remodelling in stomatal closure to flg22

Members of the NETWORKED (NET) family are involved in actin-membrane interactions. They tether the cells plasma membrane (PM) to the actin network. Moreover, in a similar manner, they are also involved in the tethering of membrane bound organelles to the actin cytoskeleton; the endoplasmic reticulum (ER) and the ER to the PM. This raises the question as to whether NET proteins are involved in actin cytoskeletal remodelling. Here we show that two members of the NET family, NET4A and NET4B, are essential for normal guard cell actin reorganization, which is a process critical for stomatal closure in plant immunity. NET4 proteins interact with F-actin and with members of the Rab7 GTPase RABG3 family through two distinct domains, allowing for simultaneous localization to actin filaments and the tonoplast. NET4 proteins interact with GTP-bound, active RABG3 members, suggesting their function as downstream effectors. We also show that RABG3b is critical for stomatal closure induced by microbial patterns. Taken together, we conclude that the actin cytoskeletal remodelling during stomatal closure depends on a molecular link between actin filaments and the tonoplast, which is mediated by the NET4-RABG3b interaction. We propose that stomatal closure to microbial patterns involves the coordinated action of immune signalling events and proper actin cytoskeletal remodelling.

plant biology↗

bioRxiv2021

Evaluation of mRNA-1273 against SARS-CoV-2 B.1.351 Infection in Nonhuman Primates

BackgroundVaccine efficacy against the B.1.351 variant following mRNA-1273 vaccination in humans has not been determined. Nonhuman primates (NHP) are a useful model for demonstrating whether mRNA-1273 mediates protection against B.1.351. MethodsNonhuman primates received 30 or 100 {micro}g of mRNA-1273 as a prime-boost vaccine at 0 and 4 weeks, a single immunization of 30 {micro}g at week 0, or no vaccine. Antibody and T cell responses were assessed in blood, bronchioalveolar lavages (BAL), and nasal washes. Viral replication in BAL and nasal swabs were determined by qRT-PCR for sgRNA, and histopathology and viral antigen quantification were performed on lung tissue post-challenge. ResultsEight weeks post-boost, 100 {micro}g x2 of mRNA-1273 induced reciprocal ID50 neutralizing geometric mean titers against live SARS-CoV-2 D614G and B.1.351 of 3300 and 240, respectively, and 430 and 84 for the 30 {micro}g x2 group. There were no detectable neutralizing antibodies against B.1351 after the single immunization of 30 {micro}g. On day 2 following B.1.351 challenge, sgRNA in BAL was undetectable in 6 of 8 NHP that received 100 {micro}g x2 of mRNA-1273, and there was a [~]2-log reduction in sgRNA in NHP that received two doses of 30 {micro}g compared to controls. In nasal swabs, there was a 1-log10 reduction observed in the 100 {micro}g x2 group. There was limited inflammation or viral antigen in lungs of vaccinated NHP post-challenge. ConclusionsImmunization with two doses of mRNA-1273 achieves effective immunity that rapidly controls lower and upper airway viral replication against the B.1.351 variant in NHP.

immunology↗

bioRxiv2020

Mapping cellular nanoscale viscoelasticity and relaxation times relevant to growth of living Arabidopsis thaliana plants using multifrequency AFM

The shapes of living organisms are formed and maintained by precise control in time and space of growth, which is achieved by dynamically fine-tuning the mechanical (viscous and elastic) properties of their hierarchically built structures from the nanometer up. Most organisms on Earth including plants grow by yield (under pressure) of cell walls (bio-polymeric matrices equivalent to extracellular matrix in animal tissues) whose underlying nanoscale viscoelastic properties remain unknown. Multifrequency atomic force microscopy (AFM) techniques exist that are able to map properties to a small subgroup of linear viscoelastic materials (those obeying the Kelvin-Voigt model), but are not applicable to growing materials, and hence are of limited interest to most biological situations. Here, we extend existing dynamic AFM methods to image linear viscoelastic behavior in general, and relaxation times of cells of multicellular organisms in vivo with nanoscale resolution, featuring a simple method to test the validity of the mechanical model used to interpret the data. We use this technique to image cells at the surface of living Arabidopsis thaliana hypocotyls to obtain topographical maps of storage E’ = 120 − 200 MPa and loss E’’= 46 − 111 MPa moduli as well as relaxation times τ = 2.2 − 2.7 µs of their cell walls. Our results demonstrate that cell walls, despite their complex molecular composition, display a striking continuity of simple, linear, viscoelastic behavior across scales–following almost perfectly the standard linear solid model–with characteristic nanometer scale patterns of relaxation times, elasticity and viscosity, whose values correlate linearly with the speed of macroscopic growth. We show that the time-scales probed by dynamic AFM experiments (milliseconds) are key to understand macroscopic scale dynamics (e.g. growth) as predicted by physics of polymer dynamics.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biophysics↗

bioRxiv2019

Proteomic studies of the Arabidopsis TRAPP complexes reveal conserved organization and a novel plant-specific component with a role in plant development

How the membrane trafficking system spatially organizes intracellular activities and intercellular signaling networks is not well understood in plants. The Transport Protein Particle (TRAPP) complexes are known to play key roles in selective delivery of membrane vesicles to various subcellular compartments in yeast and animals, but remain to be fully characterized in plants. Here we interrogate the TRAPP complexes in Arabidopsis using quantitative proteomic approaches. TRS33 is a component shared by all TRAPP complexes in yeast and animals, and the Arabidopsis AtTRS33 is essential for the subcellular dynamics of other TRAPP components. Affinity purification of AtTRS33 followed by quantitative mass spectrometry identified fourteen interacting proteins; these include not only thirteen homologs of all known TRAPP components in yeast and mammals but also a novel protein we named TRAPP-interacting plant protein (TRIPP), which is conserved in multi-cellular photosynthetic organisms. Proteomic and molecular analyses showed that TRIPP specifically associates with the TRAPPII complex in vivo and directly interacts with the TRAPPII-specific subunits but not the subunits shared with TRAPPIII. TRIPP co-localizes with a subset of TRS33 compartments, and its localization is disrupted in the trs33 mutant. Loss-of-function tripp mutation caused growth and reproductive development defects, including partial photomorphogenesis in the dark. Our study demonstrates that plants possess at least two distinct TRAPP complexes similar to metazoan, and identifies TRIPP as a novel plant-specific component of the TRAPPII complex with important functions in plant growth and development.

plant biology↗

bioRxiv2018

A Mathematical Modeling Approach to The Cort-Fitness Hypothesis

The Cort-Fitness hypothesis has generated much interest from investigators integrating field endocrinology with evolutionary biology, ecology, and conservation. The hypothesis was developed on the assumption that if glucocorticoid levels increase with environmental challenges and fitness decreases with environmental challenges, then there should be a negative relationship between glucocorticoid levels and fitness. However, studies across diverse taxa have found that the relationship between glucocorticoid levels and fitness is not consistent: some studies show a positive relationship, others negative, and some show no correlation. Hence, support for the hypothesis is not consistent and thus a deeper understanding of the mechanisms underlying the relationship between glucocorticoid levels, environmental pressures, and fitness is needed. We propose a mathematical model representing the links between glucocorticoid levels, environmental challenges, and fitness. Our model explores how variation in the predictability and intensity of environmental challenges, reproductive strategies, and fitness metrics can all contribute to the variability observed in empirical tests of the Cort-Fitness hypothesis. We provide qualitative results showing the Cort-Fitness relationship for different environmental scenarios and discuss how the model can be used to inform future Cort-Fitness studies.

animal behavior and cognition↗