Biology subjects

Ke, H.

Publications and source records attributed to Ke, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Chemogenetic excitation and play promote functional recovery in juvenile spinal cord injury

Functional recovery after spinal cord injury depends on whether reorganizing descending circuits form adaptive, task-specific relays rather than maladaptive ones. The corticospinal tract undergoes competitive, activity-dependent refinement during a defined juvenile window, so the timing and polarity of cortical activity may dictate whether injured circuits rewire usefully. Whether biasing cortical activity during this window can steer reorganization toward recovery, and whether naturalistic rehabilitation supplies the activity such steering requires, remain unknown. In juvenile rats we delivered excitatory or inhibitory chemogenetic receptors, or a control vector, to the forelimb motor cortex at postnatal day 5, induced a right cervical hemisection at postnatal day 14, and gave oral clozapine-N-oxide during nightly rough-and-tumble play from postnatal day 20 to 50. Play, the rehabilitation common to all groups, did not differ between them, isolating cortical-activity polarity as the manipulated variable. Outcomes spanned forelimb dexterity, reaching kinematics, cortical output by intracortical microstimulation, descending architecture by intersectional viral tracing, and frequency-dependent depression of the Hoffmann reflex. In untreated injured animals, cortical output re-lateralized maladaptively toward the intact forelimb, driving the ipsilateral (intact) limb in 11 of 15 evoked responses and 3 of 5 animals. Excitation preserved selective drive to the impaired forelimb (38 of 39 responses; concordant-site proportion Kruskal-Wallis H = 9.08, exact P = 0.0031), and pure ipsilateral re-lateralization was absent from all nine treated animals (3 of 5 control versus 0 of 9 treated; Fisher's exact P = 0.027). Across behavioural, kinematic, and anatomical measures a consistent excitatory > control > inhibitory gradient emerged. Excitation enhanced wrist elevation and forward extension during reaching, restored frequency-dependent depression of the Hoffmann reflex, and selectively recruited three parallel lesion-bypassing relays: interhemispheric cortico-cortical-spinal, cortico-reticulo-spinal, and cortico-propriospinal (ipsilesional cortical relay neurons F(2,14) = 56.96, P < 0.0001). Inhibition yielded the weakest behavioural recovery and least relay recruitment, and did not restore contralesional cortical drive. Cortical-activity polarity during a juvenile window thus acts as a developmental switch governing whether descending reorganization is adaptive or maladaptive. Guided excitation, paired with behaviourally meaningful activity, reshapes diffuse sprouting into structured, lesion-bypassing relays and corrects the spontaneous re-lateralization that otherwise misdirects recovery. These findings provide a translational rationale for activity-paired neuromodulation in paediatric spinal cord injury.

neuroscience↗

bioRxiv2025

Skull Bone Marrow Drainage and Its Associations with Inflammation, Sleep Quality, and Cognitive Performance

BackgroundRecent studies using human craniotomy samples and murine models have revealed channels that connect the inner skull cortex to the skull marrow cavities. While cerebrospinal fluid (CSF) tracer access to skull bone marrow has been described in CSF circulation disorders, evidence on regional patterns and clinical correlates in broader clinical cohorts is limited. MethodsThree-dimensional imaging was performed at baseline, 4.5, 15, and 39 hours post-gadolinium administration in 87 patients with neurological conditions. Signal changes in skull bone marrow near the superior sagittal sinus, lateral fissure, and cisterna magna were recorded. CSF drainage function was characterized as the percentage changes in the signal unit ratio within the skull bone marrow from baseline to time points post administration of gadolinium. ResultsThe tracer drained from CSF into the skull bone marrow, highlighting the drainage variations nearby different regions. Reduced drainage was associated with female sex, hypertension, diabetes, and elevated neutrophil levels (p < 0.05). Drainage near the superior sagittal sinus was inversely associated with sleep quality and positively associated with cognitive scores, and partially accounted for the association of sleep quality with cognitive function (indirect effect {Delta}{beta} = -0.092; bootstrap 95% CI -0.195 to -0.004; proportion mediated {approx} 38%). ConclusionThese results support the presence of skull bone marrow adjacent routes for CSF tracer movement and suggest that skull bone marrow tracer dynamics relate to systemic inflammation, sleep quality, and cognitive performance in this clinical cohort.

neuroscience↗

bioRxiv2025

Comparative chemosensory mechanisms underlying larval foraging and competitive advantage in Aedes albopictus and Aedes aegypti

The invasive Asian tiger mosquito, Aedes albopictus (Skuse), and yellow fever mosquito, Aedes aegypti (L.) are known to compete for resources during the larval stage, often resulting in the ecological displacement of Ae. aegypti by Ae. albopictus. The chemosensory system plays a pivotal role in larval foraging behavior and may contribute to the competitive advantage. Here, we employed comparative transcriptomics and functional characterization of odorant receptors (ORs) to investigate species-specific differences in larval olfaction. Notably, we uncovered functional variation within the conserved olfactory indole receptor clade, indicating distinct ecological adaptations across species and life stages. We also developed a novel approach to functionally characterize the larval sensory cone and mapped its receptor neuron projections to two key brain regions: the antennal lobe and the subesophageal ganglion. This study provides new insights into the molecular and neural basis of chemosensory-driven behavior in mosquito larvae and highlights the potential role of olfaction in shaping interspecies competition and ecological success.

neuroscience↗

bioRxiv2025

Heme-NO dilates arteries via mobilization of NO moieties from a vascular intracellular NO store

Nitrosyl heme (heme-NO) has recently emerged as a surrogate signaling entity for nitric oxide (NO). However, questions remain about how heme-NO signals across the cell membrane. Herein, we test the hypothesis that heme-NO signals as a nitrodilator that vasodilates by mobilizing NO moiety from a nitrodilator-activated intracellular NO store (NANOS) in the vasculature. We identify a novel mechanism for glutathione-catalyzed formation of a model compound, alb-heme-NO, and determine glutathione (GSH) as a ligand in its structure. Heme-NO complexes with plasma proteins in blood and, as such, it is impermeable to red blood cells or the vascular wall. Alb-heme-NO-mediated vasodilation, both in vitro and in vivo, is attenuated by prior depletion of the NANOS and potentiated by NANOS supplementation. Incubation with alb-heme-NO induces efflux of NO moieties from arteries. Additionally, the role of nitrosyl hemoglobin (HbNO) in mediating NO bioactivity export from erythrocytes is challenged. In conclusion, heme-NO functions as an extracellular nitrodilator via activation of the intracellular NANOS.

physiology↗

bioRxiv2025

Inferring non-coding RNA regulatory network from transcriptomic data and curated databases

Non-coding RNAs (ncRNAs) have played an indispensable role in regulating gene expression and cellular processes. However, the complex regulatory circuits between ncRNAs and coding genes remain understudied. Major challenges for inferring ncRNA regulatory network (NRN) on a transcriptome-wide scale include high dimensionality of both ncRNA and coding gene expression data, their context-dependent interaction, and lack of validation. We hereby propose a comprehensive analytical framework, namely Construction and Analysis of non-coding RNA regulatory NETwork (CAR-NET), specifically designed to infer NRN from transcriptomic data and curated databases on experimentally validated ncRNA-gene interactions and disease-related ncRNAs. At its core is a novel computationally efficient Bayesian network structure learning method that leverages the semi-bipartite graph structure of NRN for dimension reduction, edge orientation and global network search. We also developed and applied algorithms to perform differential network, subnetwork and pathway analysis of the inferred network. We showed the strength of CAR-NET in simulations and three case studies, encompassing lncRNA regulation in brain development, miRNA differential regulation in renal cell carcinoma and regulation by different classes of ncRNAs in different cell lines using bulk or single cell RNA-seq data. An R-shiny app (https://github.com/kehongjie/CAR-NET) was developed to implement the method(s) with interactive GUI.

bioinformatics↗

bioRxiv2025

Inheritance of the genome-less apicoplast in the 'apicoplast-minus' Plasmodium falciparum

Most apicomplexan parasites contain a plastid-derived organelle called the apicoplast, which originated through secondary endosymbiosis. As a result of this evolutionary trajectory, the non-photosynthetic apicoplast is surrounded by four membranes and contains many bacterial-like, druggable targets. It is widely accepted that asexual malaria parasites (Plasmodium falciparum) can thrive under antibiotic treatment if supplemented with high concentrations of isopentenyl pyrophosphate (IPP, 200 {micro}M) and these IPP-rescued parasites are thought to lack the apicoplast and its 35 kb genome but possess many vesicles. However, our findings challenge this apicoplast-minus concept. In late-stage schizonts, we observed that the apicoplast-derived vesicles nearly colocalize with mitochondria and are properly distributed into merozoites during schizogony, suggesting that they are inherited rather than newly synthesized in each asexual cycle. Further, immuno-electron microscopy (immuno-EM) revealed that the "apicoplast-minus" parasites possess structures surrounded by four membranes, in addition to single-membrane-surrounded entities. The presence of four-membrane-bound structures suggests that the apicoplast has not truly disappeared in the "apicoplast-minus" P. falciparum but remains in a distinct, diminished form. We termed this genome-less apicoplast derivative the apicosome, drawing an analogy to the genome-less mitochondrial derivative known as the mitosome. We propose that apicosomes retain essential biochemical and/or structural functions, which act as barriers to the complete loss of apicoplast when the parasites face antibiotic stress and IPP rescue.

microbiology↗

bioRxiv2025

Maintenance of pyrophosphate homeostasis in multiple subcellular compartmentsis essential in Plasmodium falciparum

Pyrophosphate is a byproduct of numerous cellular reactions that use ATP or other nucleoside triphosphates to synthesize DNA, RNA, protein, and other molecules. Its degradation into monophosphate is thus crucial for the survival and proliferation of all life forms. The human malaria parasite Plasmodium falciparum encodes two classes of pyrophosphatases to hydrolyze pyrophosphate. The first consists of P. falciparum proton pumping vacuolar pyrophosphatases (PfVP1 and PfVP2), which localize to the parasites subcellular membranes and work as proton pumps. The second includes P. falciparum soluble pyrophosphatases (PfsPPases), which have not been well characterized. Interestingly, the gene locus of PfsPPase encodes two isoforms, PfsPPase1 (PF3D7_0316300.1) and PfsPPase2 (PF3D7_0316300.2). PfsPPase2 contains a 51- amino acid organellar localization peptide that is absent in PfsPPase1. Here, we combine reverse genetics and biochemical approaches to identify the localization of PfsPPase1 and PfsPPase2 and elucidate their individual functions. We show that PfsPPases are essential for the asexual blood stage. While PfsPPase1 solely localizes to the cytoplasm, PfsPPase2 exhibits multiple localizations including the mitochondrion, the apicoplast, and, to a lesser extent, the cytoplasm. Our data suggest that P. falciparum has taken a unique evolutionary trajectory in pyrophosphate metabolism by utilizing a leader sequence to direct sPPases to the mitochondrion and apicoplast. This differs from model eukaryotes as they generally encode multiple sPPases at distinct genetic loci to facilitate pyrophosphate degradation in cytosolic and organellar compartments. Our study highlights PfsPPases as promising targets for the development of novel antimalarial drugs.

microbiology↗

bioRxiv2024

The dynamin-related protein Dyn2 is essential for both apicoplast and mitochondrial fission in Plasmodium falciparum

Dynamins, or dynamin-related proteins (DRPs), are large mechano-sensitive GTPases mediating membrane dynamics or organellar fission/fusion events. Plasmodium falciparum encodes three dynamin-like proteins whose functions are poorly understood. Here, we demonstrate that PfDyn2 mediates both apicoplast and mitochondrial fission. Using super-resolution and ultrastructure expansion microscopy, we show that PfDyn2 is expressed in the schizont stage and localizes to both the apicoplast and mitochondria. Super-resolution long-term live cell microscopy shows that PfDyn2-deficient parasites cannot complete cytokinesis because the apicoplast and mitochondria do not undergo fission. Further, the basal complex or cytokinetic ring in Plasmodium cannot fully contract upon PfDyn2 depletion, a phenotype secondary to physical blockage of undivided organelles in the middle of the ring. Our data suggest that organellar fission defects result in aberrant schizogony, generating unsuccessful merozoites. The unique biology of PfDyn2, mediating both apicoplast and mitochondrial fission, has not been observed in other organisms possessing two endosymbiotic organelles. HighlightsO_LIPfDyn2 is essential for schizont-stage development. C_LIO_LIPfDyn2 mediates both apicoplast and mitochondrial fission. C_LIO_LIDeficiency of PfDyn2 leads to organellar fission failures and blockage of basal complex contraction. C_LIO_LIAddition of apicoplast-derived metabolite IPP does not rescue the growth defects. C_LI

microbiology↗

bioRxiv2023

The dual coding of a single sex pheromone receptor in regulating the mating behavior of Asian Honeybee Apis cerana

In honeybee society, a virgin queen usually mates only once with several drones before founding a colony. For the rest of her prolific life, she will not engage in subsequent mating events. In the Asian honeybee Apis cerana, the mechanisms controlling this reproductive strategy involves the queen-released mandibular pheromone (QMP). This pheromone blend regulates the physiology and reproductive behavior of workers and drones. Its main component, 9-oxo-(E)-2-decenoic acid (9-ODA), acts as a sex pheromone and attracts drones. However, how the QMP prevents additional mating later in the queens life remains elusive. Using behavioral and chemical analysis, we show that the QMP component methyl p-hydroxybenzoate (HOB) released by mated queens inhibits male attraction to 9-ODA. Furthermore, in vivo electroantennogram and single sensillum recording data indicated that HOB alone significantly reduces the spontaneous spike activity of 9-ODA-sensitive olfactory receptor neurons (ORNs). To explore the molecular mechanism underlying this inverse effect, we conducted qPCR and in situ hybridization assays. The results indicated that AcerOr11 is specifically expressed in sensilla placodea from the drones antennae, which are the sensilla that narrowly respond to both 9-ODA and HOB. We then cloned and expressed AcerOr11 in a Xenopus oocyte expression system, where AcerOr11 induced robust inward (regular) currents in response to 9-ODA. Intriguingly, HOB induced inverse currents in a dose-dependent manner. This suggests that HOB may act as an inverse agonist against AcerOr11, providing additional odor-coding information. Based on these findings, we propose a model in which AcerOr11 function as a dual modulators in regulating the mating behavior of A. cerana. The inverse agonist, HOB, can help manage the population dynamics of honeybees in apiculture.

molecular biology↗

bioRxiv2023

In situ cryoET reveals inhibitor-induced perturbations in Pf80S GTPase interactions

Malaria parasites rely heavily on rapid, high fidelity protein synthesis to infect and replicate in human erythrocytes, making translation an attractive target for new antimalarials. Here, we have determined in situ structures of Pf80S ribosomes in thirteen conformational and compositional states from cryoFIB-milled Plasmodium falciparum-infected human erythrocytes across the stages of asexual intraerythrocytic parasite replication. We observe eight active translation intermediates, enabling us to define the native malarial translation elongation cycle, which surprisingly features a bifurcation at the decoding stage of the cycle that has not previously been described. Examination of perturbations in the distribution of ribosomes among these states in the presence of a malaria-specific translation inhibitor suggests that the inhibitor impedes PfeEF2 and PfeEF1 interactions with the ribosome. We integrated our in situ cryoET data with proteomic and ultrastructural data to arrive at a deeper understanding of malarial translation, which will inform development of new therapies.

biophysics↗

bioRxiv2023

ZmPILS6 is an auxin efflux carrier required for maize root morphogenesis

Plant root systems play a pivotal role in plant physiology and exhibit diverse phenotypic traits. Understanding the genetic mechanisms governing root growth and development in model plants like maize is crucial for enhancing crop resilience to drought and nutrient limitations. This study focused on identifying and characterizing ZmPILS6, an annotated auxin efflux carrier, as a key regulator of various crown root traits in maize. ZmPILS6-modified roots displayed reduced network area and suppressed lateral root formation, desirable traits during drought and low phosphate conditions. The research revealed that ZmPILS6 localizes to the endoplasmic reticulum and plays a vital role in controlling the spatial distribution of indole-3-acetic acid (IAA or "auxin") in primary roots. The study also demonstrated that ZmPILS6 can actively efflux IAA when expressed in yeast. Furthermore, the loss of ZmPILS6 resulted in significant proteome remodeling in maize roots, particularly affecting hormone signaling pathways. To identify potential interacting partners of ZmPILS6, a weighted gene co-expression analysis (WGNA) was performed. Altogether, this research contributes to the growing knowledge of essential genetic determinants governing maize root morphogenesis, which is crucial for guiding agricultural improvement strategies. Significance StatementCrop yield and stress resilience are significantly influenced by crown root architecture. A reverse genetic screen aimed at identifying novel regulators of maize root morphogenesis led to the discovery of ZmPILS6, an auxin efflux carrier. The loss of ZmPILS6 negatively impacts numerous root traits that are linked to plant physiology and function. Proteomic characterization of pils6-1 roots revealed that this evolutionarily conserved transporter is required for the proper expression of numerous phytohormone pathways, including abscisic acid, gibberellins, and jasmonic acid. Notably, ZmPILS6 appears to have a contrasting role in regulating root morphogenesis compared to its Arabidopsis ortholog, PILS6. This finding emphasizes the need for functional characterization of candidate genes directly within key crops of interest, which cannot always be correctly inferred from other model plants.

plant biology↗

bioRxiv2023

Multifunctionality of V-type ATPase during asexual growth and development of Plasmodium falciparum

V-type ATPases are highly conserved hetero-multi-subunit proton pumping machineries found in all eukaryotic organisms. They use ATP hydrolysis to pump protons, acidifying intracellular or extracellular compartments, and are thus crucial for various biological processes. Despite being evolutionarily conserved in malaria parasites, this proton pump remains understudied. To understand the localization and biological function of V-type ATPase in the deadliest human malaria parasite Plasmodium falciparum, we utilized CRISPR/Cas9 to endogenously tag the subunit A of the V1 domain at the C-terminus. V1A (PF3D7_1311900) was tagged with a triple hemagglutinin (3HA) epitope and TetR-DOZI-aptamers for conditional expression under the regulation of anhydrotetracycline. Through immunofluorescence assays, we identified that V-type ATPase was expressed throughout the intraerythrocytic developmental cycle and was mainly localized on the digestive vacuole and plasma membrane. Immuno-electron microscopy further revealed that V-type ATPase was also localized on secretory organelles, such as rhoptries in merozoites. Knockdown of V1A led to cytosolic pH imbalance and blockage of hemoglobin digestion in the digestive vacuole, resulting in an arrest of parasite development in the trophozoite stage and, ultimately, parasite demise. Using BN-PAGE/Western blot, we detected a large molecular weight complex ([~] 1.0 MDa) corresponding to the total molecular weights of V1 and Vo domains. The complex was readily disrupted by the V-type ATPase specific inhibitor Bafilomycin A1, but not by low glucose conditions or treatment with chloroquine. Together, our data suggest that V-type ATPase is localized on several subcellular compartments in P. falciparum and plays critical roles to support malaria parasites to grow and replicate inside red blood cells.

microbiology↗

bioRxiv2023

Apical annuli are specialised sites of post-invasion secretion of dense granules in Toxoplasma

Apicomplexans are ubiquitous intracellular parasites of animals. These parasites use a programmed sequence of secretory events to find, invade, and then reengineer their host cells to enable parasite growth and proliferation. The secretory organelles micronemes and rhoptries mediate the first steps of invasion. Both secrete their contents through the apical complex which provides an apical opening in the parasites elaborate inner membrane complex (IMC) -- an extensive subpellicular system of flattened membrane cisternae and proteinaceous meshwork that otherwise limits access of the cytoplasm to the plasma membrane for material exchange with the cell exterior. After invasion, a second secretion programme drives host cell remodelling and occurs from dense granules. The site(s) of dense granule exocytosis, however, has been unknown. In Toxoplasma gondii, small subapical annular structures that are embedded in the IMC have been observed, but the role or significance of these apical annuli to plasma membrane function has also been unknown. Here, we determined that integral membrane proteins of the plasma membrane occur specifically at these apical annular sites, that these proteins include SNARE proteins, and that the apical annuli are sites of vesicle fusion and exocytosis. Specifically, we show that dense granules require these structures for the secretion of their cargo proteins. When secretion is perturbed at the apical annuli, parasite growth is strongly impaired. The apical annuli, therefore, represent a second type of IMC-embedded structure to the apical complex that is specialised for protein secretion, and reveal that in Toxoplasma there is a physical separation of the processes of pre- and post-invasion secretion that mediate host-parasite interactions.

cell biology↗

bioRxiv2023

The conformational landscape of a serpin N-terminal subdomain facilitates folding and in-cell quality control

Many multi-domain proteins including the serpin family of serine protease inhibitors contain non-sequential domains composed of regions that are far apart in sequence. Because proteins are translated vectorially from N-to C-terminus, such domains pose a particular challenge: how to balance the conformational lability necessary to form productive interactions between early and late translated regions while avoiding aggregation. This balance is mediated by the protein sequence properties and the interactions of the folding protein with the cellular quality control machinery. For serpins, particularly 1-antitrypsin (AAT), mutations often lead to polymer accumulation in cells and consequent disease suggesting that the lability/aggregation balance is especially precarious. Therefore, we investigated the properties of progressively longer AAT N-terminal fragments in solution and in cells. The N-terminal subdomain, residues 1-190 (AAT190), is monomeric in solution and efficiently degraded in cells. More y-rich fragments, 1-290 and 1-323, form small oligomers in solution, but are still efficiently degraded, and even the polymerization promoting Siiyama (S53F) mutation did not significantly affect fragment degradation. In vitro, the AAT190 region is among the last regions incorporated into the final structure. Hydrogen-deuterium exchange mass spectrometry and enhanced sampling molecular dynamics simulations show that AAT190 has a broad, dynamic conformational ensemble that helps protect one particularly aggregation prone y-strand from solvent. These AAT190 dynamics result in transient exposure of sequences that are buried in folded, full-length AAT, which may provide important recognition sites for the cellular quality control machinery and facilitate degradation and, under favorable conditions, reduce the likelihood of polymerization.

biophysics↗

bioRxiv2023

Insights into the function of the chloroplastic ribosome-associated GTPase HflX in Arabidopsis thaliana.

Ribosome-associated GTPases are conserved enzymes that participate in ribosome biogenesis and ribosome function. In bacteria, recent studies have identified HflX as a ribosome-associated GTPase that is involved in both ribosome biogenesis and recycling under stress conditions. Plants possess a chloroplastic HflX homolog, but its function remains unknown. Here, we characterised the role of HflX in the plant Arabidopsis thaliana. Our findings demonstrate that HflX does not have a detectable role in plant growth and development, nor does it play a distinct role in acclimation to several different stresses, including heat, manganese, cold, and salt stress. However, we found that HflX is required for plant resistance to chloroplast translational stress mediated by the antibiotic lincomycin. Our results suggest that HflX is a chloroplast ribosome-associated protein that may play a role in the surveillance of translation. These findings provide new insight into the function of HflX as a ribosome-associated GTPase in plants and highlight the importance of investigating conserved proteins in different organisms to gain a comprehensive understanding of their biological roles.

plant biology↗

bioRxiv2023

Benchmark and optimization of AlphaFold structures based virtual screening strategy

Recent advancements in artificial intelligence such as AlphaFold, have enabled more accurate prediction of protein three-dimensional structure from amino acid sequences. This has attracted significant attention, especially for the application of AlphaFold in drug discovery. However, how to take full advantage of AlphaFold to assist with virtual screening remains elusive. We evaluate the AlphaFold structures of 51 selected targets from the DUD-E database in virtual screening. Our analyses show that the virtual screening performance of about 35% of the AlphaFold structures is equivalent to that of DUD-E structures, and about 25% of the AlphaFold structures yield better results than the DUD-E structures. Remarkably, AlphaFold structures produce slightly better results than the Apo structures. Moreover, we develop a new consensus scoring method based on Z-score standardization and exponential function, which shows improved screening performance compared to traditional scoring methods. By implementing a multi-stage virtual screening process and the new consensus scoring method, we are able to improve the speed of virtual screening by about nine times without compromising the enrichment factor. Overall, our results provide insights into the potential use of AlphaFold in drug discovery and highlight the value of consensus scoring and multi-stage virtual screening.

bioinformatics↗

bioRxiv2022

Leptospermum extract (QV0) suppresses pleural mesothelioma tumour growth in vitro and in vivo by mitochondrial dysfunction associated apoptosis

Pleural mesothelioma (PM) is a highly aggressive, fast-growing asbestos-induced cancer with limited effective treatments. There has been an interest in using naturally occurring anticancer agents derived from plant materials for the treatment of PM. However, it is unclear if aqueous extract from the Leptospermum polygalifolium (QV0) has activity against PM. Here we investigated the anti-cancer property of QV0 in vitro and in vivo. Animals treated with Defender(R) (QV0 dietary supply) exhibited a reduced tumour size over 30 days, which was associated with an average extended of seven days mouse life. There was no liver toxicity, nor increased blood glucose post-treatment in animals treated with Defender(R). Moreover, QV0 suppressed the growth of 13 cancer cell lines in a dose-dependent manner, effective at concentrations as low as 0.02% w/v. This response was found to be associated with inhibited cell migration, proliferation, and colony formation, but without evident cell cycle alteration. We observed mitochondrial dysfunction post QV0 treatment, as evidenced by significantly decreased basal and maximal oxygen consumption rates. Significantly enhanced tumour apoptosis was observed in the Defender(R)-treated animals, correlating with mitochondrial dysfunction. To the best of our knowledge, this study constitutes the first demonstration of an improved host survival (without adverse effects) response in a QV0-treated PM mouse model, associated with an evident inhibition of PM cell growth and mitochondrial dysfunction-related enhancement of tumour apoptosis. ImportanceA major problem with cancer chemotherapy or immunotherapy is the severe adverse effects associated with normal tissue damage. PM is known to be treatment resistant and has poor a prognosis, therefore new therapeutic treatment options are urgently needed. In the present study, we explored the potential utility of a Leptospermum extract (QV0) as a treatment option for mesothelioma. We demonstrated for the first time that QV0 exhibits an anti-tumour response in mesothelioma, without any associated adverse effects observed in the PM mouse model. These findings provide a rationale for early-stage clinical trials. We anticipate that prospective translational research will lead to the clinical implementation of a novel QV0-based treatment strategy that will ultimately benefit PM patients.

cancer biology↗

bioRxiv2022

Dosage differences in 12-OXOPHYTODIENOATE REDUCTASE genes modulate wheat primary root growth

Wheat is an essential crop for global food security and is well adapted to a wide variety of soils1. However, the gene networks regulating different root architectures remain poorly understood. We report here the identification of a cluster of a monocot-specific 12-OXOPHYTODIENOATE REDUCTASE genes from subfamily III (OPRIII) that modulate key differences in wheat root architecture associated with grain yield under water-limited conditions. Wheat plants with a loss-of-function mutation in OPRIII showed longer seminal roots, whereas plants with increased OPRIII dosage or transgenic over-expression showed reduced seminal root growth, precocious development of lateral roots and increased jasmonic acid (JA). A JA-biosynthesis inhibitor eliminated the root differences, confirming a JA-mediated mechanism. Multiple transcriptome analysis of transgenic and wild-type lines revealed significant enriched JA-biosynthetic and reactive oxygen species (ROS) pathways that paralleled changes in ROS distribution. The OPRIII genes provide a useful entry point to engineer root architecture in wheat and other cereals.

plant biology↗