Biology subjects

Cheng, Y.

Publications and source records attributed to Cheng, Y..

At least 181 records · Page 10Linked to original sources

bioRxiv2023

Self-regulatory function of bacterial small heat shock protein IbpA through mRNA binding is conferred by a conserved arginine

Bacterial small heat shock proteins, IbpA and IbpB, co-aggregate with denatured proteins and recruit other chaperones for the processing of aggregates, thereby assisting in their refolding. In addition, as a recently revealed uncommon feature, Escherichia coli IbpA self-represses its own translation through interaction with the 5 untranslated region (UTR) of the ibpA mRNA, enabling IbpA to act as a mediator of negative feedback regulation. Although IbpA also suppresses the expression of IbpB, IbpB does not have the self-repression activity despite the two Ibps being highly homologous. This study demonstrates that the self-repression function of IbpA is conserved in other bacterial IbpAs. Moreover, a cationic residue-rich region in the -crystallin domain (ACD) of IbpA, which is not conserved in IbpB, is critical for the self-suppression activity. Notably, arginine 93 (R93) located within the ACD is an essential residue that cannot be replaced by the other 19 amino acids, including lysine. IbpA-R93 mutants completely lost the interaction with the 5 UTR of the ibpA mRNA but retained almost all of the chaperone activity to sequester denatured proteins. Taken together, the conserved Arg93-mediated translational control of IbpA through RNA binding would be beneficial for a rapid and massive supply of the chaperone on demand.

biochemistry↗

bioRxiv2023

Spatiotemporal transcriptome atlas of human embryos after gastrulation

The spatial and temporal atlas of gene expression in the human embryo at early gestation is critical in understanding embryo development, organogenesis, and disease origins. We obtained the spatiotemporal transcriptome from 90 sagittal sections of 16 whole human embryos from 3 to 8 post-conception weeks by Stereo-seq with high resolution and ultra-large field, establishing the development trajectory/regulatory profiling of 49 organs. We uncovered the organ-specific regulons as potential lineage-determining factors and identified the new regulatory networks during heart and brain development. The atlas refines the key organs/cell types vulnerable to virus infection and genetic disorders, and, reveals the dynamics of allelic gene expression in specific organs at different stages. These results present the first comprehensive delineation of the spatiotemporal transcriptomic dynamics of human organogenesis. One Sentence SummaryThe spatiotemporal transcriptome atlas presents a comprehensive delineation of human embryogenesis after gastrulation.

developmental biology↗

bioRxiv2023

Targeting ABCB4 using mRNA-LNP for the treatment of rare liver diseases

Mutations in the ABCB4 gene lead to a wide-spectrum of rare liver diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3) and low-phospholipid associated cholelithiasis (LPAC) syndrome. PFIC3 patients develop symptoms during late infancy, including severe itching, jaundice, and failure to thrive. The condition may progress to liver failure during childhood or adulthood. This is a highly unmet medical condition where liver transplantation is the only option to correct this disease. Recently, exciting data suggested that restoration of the ABCB4 function via gene replacement could rescue liver phenotypes associated with ABCB4 dysfunction in a preclinical PFIC3 mouse model. Here, we used mRNA LNP platform to determine expression and durability of ABCB4 in the liver of wildtype mice. In addition, we generated Abcb4-/- mice to study the efficacy of systemic delivery of ABCB4 mRNA LNP. We observed a robust and durable expression of hABCB4 up to 72 hours post systemic dosing in the liver of wild-type mice. Systemic administration of hABCB4 mRNA achieved a remarkable restoration of phosphatidylcholine levels in bile, a significant decrease in liver stiffness as measured by shear wave elastography, and amelioration of liver histopathology including fibrosis and ductular reaction. We conclude that administration of hABCB4 mRNA LNPs was sufficient to ameliorate fibrosis markers in the PFIC3 mouse model. Our data suggests that gene replacement using mRNA LNP modality could provide an excellent opportunity for patients with biliary diseases.

molecular biology↗

bioRxiv2023

Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes

Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

genomics↗

bioRxiv2023

Coronavirus endoribonuclease nsp15 induces host cellular protein synthesis shutoff

The endoribonuclease (EndoU) nsp15 of coronaviruses plays an important role in evasion of host innate immune responses by reducing the abundance of viral double-stranded RNA, whereas less is known about potential host cellular targets of nsp15. In this study, we show that cellular protein synthesis is inhibited upon over-expression of nsp15 from four genera of coronaviruses and this is accompanied by nuclear retention of the poly(A) binding protein cytoplasmic 1 (PABPC1). We also show that the EndoU activity of nsp15 is indispensable for both, inhibition of protein synthesis and PABPC1 nuclear relocation. FISH analysis using oligo-dT probes, revealed an overlap between the localization of cellular mRNA and that of overexpressed nsp15 in some cells, suggesting that, when expressed alone, nsp15 may target host mRNA. When investigating the association of nsp15 on protein shut off in the context of a viral infection, we observed that the{gamma} -coronavirus infectious bronchitis virus (IBV), induced host translation shutoff in an p-eIF2-independent manner and mainly retained PABPC1 in the cytoplasm, whereas the nsp15 EndoU-deficient IBV accumulated viral dsRNA and caused p-PKR-p-eIF2-dependent host protein translation shutoff, accompanied with PABPC1 nuclear relocation or stress granule (SG) localization. This phenomenon suggests that during infection with wild type IBV, although the cellular translation is inhibited, initiation of viral mRNA translation leads to PABPC1 binding to viral mRNA, thereby preventing its nuclear entry; during infection with nsp15 EndoU-deficient IBV however, the eIF2-dependent host protein translation shutoff prevents both host and viral mRNA translation initiation, releasing PABPC1 from binding to cytosolic and viral mRNA, thereby relocating it to the nucleus or to SG. Altogether, this study reveals unique yet conserved mechanisms of host protein shutoff that add to our understanding of how coronaviruses regulate host protein expression through a mechanism that involves catalytically active nsp15 EndoU, and describes how nsp15 may target both, viral and host mRNA. Author summaryIt has been reported that coronavirus infection suppresses host protein translation, - and {beta}- coronavirus nsp1 is responsible for inhibition of host gene expression. However, for{gamma} - and{delta} -coronavirus, there is no nsp1 and the underlying mechanisms by which virus regulates host translation are not well characterized. Here, we show that coronavirus endoribonuclease nsp15 is responsible for the inhibition of host translation by targeting to host factors, meanwhile it helps virus bypass the PKR-eIF2 mediated host translation shutoff, which is harmful for virus gene expression, by reducing the accumulation of viral dsRNA. This novel finding gives insight how does nsp15 targets to both host factors and viral RNA, to facilitate virus replication. Moreover, the novel function of nsp15 is found to be conserved among coronaviruses, revealing the essential role of this endoribonuclease in hijacking host translation machinery for virus replication.

microbiology↗

bioRxiv2023

A systematic search for RNA structural switches across the human transcriptome

RNA structural switches are key regulators of gene expression in bacteria, yet their characterization in Metazoa remains limited. Here we present SwitchSeeker, a comprehensive computational and experimental approach for systematic identification of functional RNA structural switches. We applied SwitchSeeker to the human transcriptome and identified 245 putative RNA switches. To validate our approach, we characterized a previously unknown RNA switch in the 3UTR of the RORC transcript. In vivo DMS-MaPseq, coupled with cryogenic electron microscopy, confirmed its existence as two alternative structural conformations. Furthermore, we used genome-scale CRISPR screens to identify trans factors that regulate gene expression through this RNA structural switch. We found that nonsense-mediated mRNA decay acts on this element in a conformation-specific manner. SwitchSeeker provides an unbiased, experimentally-driven method for discovering RNA structural switches that shape the eukaryotic gene expression landscape.

systems biology↗

bioRxiv2023

NDC80 status pinpoints mitotic kinase inhibitors as emerging therapeutic options in clear cell renal cell carcinoma

[~]30% of clear cell renal cell carcinoma (ccRCC) patients present with metastatic disease at the time of diagnosis, causing a dire 5-year survival rate of 13%. Whereas anti-PD-1 immunotherapy has improved survival, a strong need remains for new therapeutic options. Using integrated network analysis, we identified the mitotic regulator NDC80 as a predictor of ccRCC progression. Overexpression of NDC80 fosters the malignant phenotype by promoting cell cycle progression through S phase as well as boosting glycolysis and mitochondrial respiration. Despite high levels of immune infiltration, particularly derived from tumor resident CD8+ T cells with an exhausted phenotype, NDC80 defines a class of ccRCCs that poorly respond to immune checkpoint blockade. Instead, bioinformatics identified NDC80-high ccRCCs as sensitive to inhibitors of mitotic kinases, PLK1 and AURK, therapeutic approaches we validated in cell lines and mouse xenograft studies. Thus, NDC80 status pinpoints mitotic kinase inhibitors as promising therapeutic options in difficult-to-treat ccRCCs.

cancer biology↗

bioRxiv2023

Molecular cascades and cell-type specific signatures in ASD revealed by single cell genomics

Understanding how genetic variation exerts its effects on the human brain in health and disease has been greatly informed by functional genomic characterization. Studies over the last decade have demonstrated robust evidence of convergent transcriptional and epigenetic profiles in post-mortem cerebral cortex from individuals with Autism Spectrum Disorder (ASD). Here, we perform deep single nuclear (sn) RNAseq to elucidate changes in cell composition, cellular transcriptomes and putative candidate drivers associated with ASD, which we corroborate using snATAC-seq and spatial profiling. We find changes in cell state composition representing transitions from homeostatic to reactive profiles in microglia and astrocytes, a pattern extending to oligodendrocytes and blood brain barrier cells. We identify profound changes in differential expression involving thousands of genes across neuronal and glial subtypes, of which a substantial portion can be accounted for by specific transcription factor networks that are significantly enriched in common and rare genetic risk for ASD. These data, which are available as part of the PsychENCODE consortium, provide robust causal anchors and resultant molecular phenotypes for understanding ASD changes in human brain. One-Sentence SummaryWe define the molecular cascades and cells disrupted in post-mortem brain in ASD by performing spatial, single nuclear RNA, and epigenetic profiling, and characterize, at unmatched resolution, the functional regulation of cell-type specific signatures underlying the molecular differences and physiology of ASD. Main TextPsychiatric disorders are defined primarily by behavioral and cognitive characteristics and are classically distinguished from neurological disorders by lacking the associated visible histological or macroscopic pathology observed in neurological conditions. However, a growing body of evidence based on genomic profiling reveals consistent molecular differences in brain tissue from specific neuropsychiatric conditions compared with brain tissue from neurotypical individuals (1-5). In Autism Spectrum Disorder (ASD) robust transcriptomic and epigenetic alterations in the cerebral cortex from patients have been documented over the last decade, delineating a reproducible pattern of molecular pathology (5-13). This robust molecular signature obtained primarily from transcriptomic profiling of bulk cortical tissue has identified convergent biological pathways in ASD brain, which is characterized by an upregulation of immune signaling genes, downregulation of specific neuronal markers, synaptic genes, and an attenuation of the typical patterns of gene expression associated with cortical regional identity (6-8,12-14). These genomic data represent an essential lens through which to understand the cellular and physiological changes occurring in the brains of autistic individuals and to describe potential causal mechanisms via their integration with genetic risk variants (1,4,5). However, small sample sizes in the case of single cell analysis (13), or profiling restricted to bulk tissue have limited biological insights as to the differences in laminar, circuit level, and cell-type specific pathways affected in ASD, as well as their underlying gene regulatory mechanisms. To address these limitations, we leveraged improvement in single cell analyses to profile the largest ASD cohort to date, consisting of 64 cases and controls. This resource, generated as a core component of the PsychENCODE consortium (1,2,4,5,8; http://www.psychencode.org), also enables us to characterize underlying candidate regulatory mechanisms and to connect causal drivers with the observed changes at a cell-type specific level in ASD, providing a deeper and more generalizable understanding of the cell types and biological mechanisms that underlie ASD. These data are available via PsychEncode portals for download (http://psychencode.synapse.org) and on the PsychSCREEN browser (in development, http://psychscreen.beta.wenglab.org).

neuroscience↗

bioRxiv2023

Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome

Major depressive disorder (MDD) is the most burdensome psychiatric disorder characterized by remarkably heterogeneous clinical phenotypes. It remains challenging to delineate the heterogeneity of neurobiological abnormalities underlying the clinical variance and, on this basis, to identify neurophysiological subtypes of MDD patients. Here, using a large multisite resting-state functional MRI data from 1,148 MDD patients and 1,079 healthy controls, we generated lifespan normative models of functional connectivity strengths, mapped the heterogeneity of patients individual deviations, and identified neurobiological MDD subtypes. MDD patients showed positive deviations mainly in the default mode and subcortical areas, and negative deviations widely distributed over the cortex. However, there was a great inter-subject heterogeneity as indicated by that no more than 3.14% of patients deviated from the normative range for any brain region. Two neurophysiological MDD subtypes were identified. Subtype 1 showed severe deviations with positive deviations in the default mode, limbic, and subcortical areas, and negative deviations in the sensorimotor, dorsal and ventral attention areas, while subtype 2 showed a moderate but conversed deviation pattern. The severe-deviation subtype had older age, higher medicated proportion, and higher Suicide item score, while the moderate-deviation subtype showed higher Work and Activities and Depressed Mood item scores. Moreover, the baseline deviations in the severe-deviation subtype were predictive of 6-month antidepressant treatment effects in a subsample. To our knowledge, the current study is the largest multisite analysis of neurophysiological MDD subtyping to date and the findings shed light on our understanding of the biological mechanisms underlying the intersubject heterogeneity of clinical phenotypes, which are informative for the development of personalized treatments for this disorder.

neuroscience↗

bioRxiv2023

Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks

Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3 receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 by in situ hybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modelling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.

neuroscience↗

bioRxiv2023

High-content image-based CRISPR screening reveals regulators of 3D genome architectures

Three-dimensional (3D) genome organization becomes altered during development, aging, and disease1-23, but the factors regulating chromatin topology are incompletely understood and currently no technology can efficiently screen for new regulators of multiscale chromatin organization. Here, we developed an image-based high-content screening platform (Perturb-tracing) that combines pooled CRISPR screen, a new cellular barcode readout method (BARC-FISH), and chromatin tracing. We performed a loss-of-function screen in human cells, and visualized alterations to their genome organization from 13,000 imaging target-perturbation combinations, alongside perturbation-paired barcode readout in the same single cells. Using 1.4 million 3D positions along chromosome traces, we discovered tens of new regulators of chromatin folding at different length scales, ranging from chromatin domains and compartments to chromosome territory. A subset of the regulators exhibited 3D genome effects associated with loop-extrusion and A-B compartmentalization mechanisms, while others were largely unrelated to these known 3D genome mechanisms. We found that the ATP-dependent helicase CHD7, the loss of which causes the congenital neural crest syndrome CHARGE24 and a chromatin remodeler previously shown to promote local chromatin openness25-27, counter-intuitively compacts chromatin over long range in different genomic contexts and cell backgrounds including neural crest cells, and globally represses gene expression. The DNA compaction effect of CHD7 is independent of its chromatin remodeling activity and does not require other protein partners. Finally, we identified new regulators of nuclear architectures and found a functional link between chromatin compaction and nuclear shape. Altogether, our method enables scalable, high-content identification of chromatin and nuclear topology regulators that will stimulate new insights into the 3D genome functions, such as global gene and nuclear regulation, in health and disease.

genetics↗

bioRxiv2023

Biallelic Variants in MAD2L1BP (p31comet) Cause Female Infertility Characterized by Oocyte Maturation Arrest

Human oocyte maturation arrest represents one of the severe conditions for female patients with primary infertility. However, the genetic factors underlying this human disease remain largely unknown. The spindle assembly checkpoint (SAC) is an intricate surveillance mechanism that ensures accurate segregation of chromosomes throughout cell cycles. Once the kinetochores of chromosomes are correctly attached to bipolar spindles and the SAC is satisfied, the MAD2L1BP, best known as p31comet, binds MAD2 and recruits the AAA+-ATPase TRIP13 to disassemble the mitotic checkpoint complex (MCC), leading to the cell cycle progression. In this study, by whole-exome sequencing (WES), we identified homozygous and compound heterozygous MAD2L1BP variants in three families with female patients diagnosed with primary infertility owing to oocyte metaphase I (MI) arrest. Functional studies revealed that the protein variants resulting from the C-terminal truncation of MAD2L1BP lost their binding ability to MAD2. cRNA microinjection of full-length or truncated MAD2L1BP uncovered their discordant roles in driving the extrusion of polar body 1 (PB1) in mouse oocytes. Furthermore, the patients oocytes carrying the mutated MAD2L1BP variants resumed polar body extrusion (PBE) when rescued by microinjection of full-length MAD2L1BP cRNAs. Together, our studies identified and characterized novel biallelic variants in MAD2L1BP responsible for human oocyte maturation arrest at MI, and thus prompted new therapeutic avenues for curing female primary infertility.

developmental biology↗

bioRxiv2023

Modelling drug responses and evolutionary dynamics using triple negative breast cancer patient-derived xenografts

Triple negative breast cancers (TNBC) exhibit inter- and intra-tumour heterogeneity, which is reflected in diverse drug responses and interplays with tumour evolution. Here, we use TNBC patient-derived tumour xenografts (PDTX) as a platform for co-clinical trials to test their predictive value and explore the molecular features of drug response and resistance. Patients and their matched PDTX exhibited mirrored drug responses to neoadjuvant therapy in a clinical trial. In parallel, additional clinically-relevant treatments were tested in PDTXs in vivo to identify alternative effective therapies for each PDTX model. This framework establishes the foundation for anticipatory personalised therapies for those patients with resistant or relapsed tumours. The PDTXs were further explored to model PDTX- and treatment-specific behaviours. The dynamics of drug response were characterised at single-cell resolution revealing a novel mechanism of response to olaparib. Upon olaparib treatment PDTXs showed phenotypic plasticity, including transient activation of the immediate-early response and irreversible sequential phenotypic switches: from epithelial to epithelial-mesenchymal-hybrid states, and then to mesenchymal states. This molecular mechanism was exploited ex vivo by combining olaparib and salinomycin (an inhibitor of mesenchymal-transduced cells) to reveal synergistic effects. In summary, TNBC PDTXs have the potential to help design individualised treatment strategies derived from model-specific evolutionary insights.

cancer biology↗

bioRxiv2023

Harnessing antimicrobial peptide genes to expedite disease-resistant enhancement in aquaculture: Transgenesis and genome editing

Numerous studies have demonstrated that genome editing and transgenesis by integrating vector-engineered antimicrobial peptide genes (AMGs) is effective to modulate the fishs innate immune system. To generalize the knowledge of AMG application in aquaculture, here we recruited 540 data entries from a pool of empirical studies, which included 18 peer-reviewed publications and spanning 12 diseases. We systematically re-processed and re-analyzed these data by harnessing a cross-disease meta-analysis. On aggregate, AMG-genetic engineering aimed at enhancing disease resistance was shown to decrease the number of colony-forming units of bacteria, improve lysozyme activity, increase the post-infection survival rates, and alter the expression of AMGs and immune-related genes in aquatic animals. Furthermore, the AMG-pathogen combating activity was triggered within two hours after infection and lasted 48 hours, and the overexpression of AMGs was dominant in the spleen and skin, followed by the kidney and liver during this period. Typically, regardless of the type of AMGs, the synergistic expression of AMGs with IL, IK{beta}, TGF{beta}, C3b and TLR in AMG-integrated fish contributed to activating inflammatory/immune responses against pathogens. In addition, innovative CRISPR/Cas9-mediated systems enabling the site-directed knock-in of foreign genes at multiple loci were presented and prospected for disease-resistant enhancement in combination with other favorable fish-producing traits, including fast-growing, sterility, and enriched fatty acid. Altogether, our findings indicated that AMGs as transgenes have substantial potential to modulate the fishs innate immune system and accelerate disease-resistant enhancement combined with genetic engineering.

bioengineering↗

bioRxiv2022

Structural Basis of Prostaglandin Efflux by MRP4

MRP4 is unique among the C family of ATP-binding cassette transporters for its role in translocating prostanoids, an important group of signaling molecules derived from unsaturated fatty acids. Using a reconstituted system, we report that a pair of prostaglandins (PGs) and the sulfonated-sterol DHEA-S preferentially enhance the ATPase activity of MRP4 over other previously proposed physiological substrates such as cyclic nucleotides or leukotrienes. We determined the cryo-EM structures of nanodisc embedded bovine MRP4 in (i) a nucleotide- and substrate-free state, (ii) in complex with PGE1, (iii) PGE2, and (iv) DHEA-S, and (v) a catalytically dead mutant E1202Q bound to ATP-Mg2+. The substrate-bound structures suggest unique features of the MRP4 binding site that distinguish its specificity for prostanoids from that of the related leukotriene transporter MRP1. The ATP-bound structure is in an outward-occluded conformation, revealing a novel state in the proposed alternate-access mechanism of MRP transport. Our study provides insights into the endogenous function of this versatile efflux transporter.

biochemistry↗

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

Sharing Massive Biomedical Data at Magnitudes Lower Bandwidth Using Implicit Neural Function

Efficient storage and sharing of massive biomedical data would open up their wide accessibility to different institutions and disciplines. However, compressors tailored for natural photos/videos are rapidly limited for biomedical data, while emerging deep learning based methods demand huge training data and are difficult to generalize. Here we propose to conduct Biomedical data compRession with Implicit nEural Function (BRIEF) by representing the original data with compact neural networks, which are data specific and thus have no generalization issues. Benefiting from the strong representation capability of implicit neural function, BRIEF achieves 2 [~] 3 orders of magnitude compression on diverse biomedical data at significantly higher fidelity than existing techniques. Besides, BRIEF is of consistent performance across the whole data volume, supports customized spatially-varying fidelity. BRIEFs multi-fold advantageous features also serve reliable downstream tasks at low bandwidth. Our approach will facilitate low-bandwidth data sharing, and promote collaboration and progress in the biomedical field.

bioinformatics↗

bioRxiv2022

A compound PCP scheme underlies sequential rosettes-based cell intercalation

Sequential rosettes are a type of collective cell behavior recently discovered in the C. elegans embryo to mediate directional cell migration through sequential formation and resolution of multicellular rosettes involving the migrating cell and its neighboring cells along the way. Here we show that a Planar Cell Polarity (PCP)-related polarity scheme regulates sequential rosettes, which is distinct from the known mode of how PCP regulates multicellular rosettes in the process of convergent extension. Specifically, non-muscle myosin (NMY) localization and edge contraction are perpendicular to that of Van Gogh as opposed to colocalizing with Van Gogh. Further analyses suggest a two-component polarity scheme: one being the canonical PCP pathway with MIG-1/Frizzled and VANG-1/Van Gogh localized to the vertical edges, the other being MIG-1/Frizzled and NMY-2 localized to the midline/contracting edges. Both MIG-1/Frizzled and VANG-1/Van Gogh are required for NMY-2 localization and contraction of the midline edges, but in redundancy with LAT-1/Latrophilin, an adhesion GPCR which has not been shown to regulate multicellular rosettes. Our results establish a distinct mode of PCP-mediated cell intercalation and shed light on the versatile nature of PCP pathway.

developmental biology↗