ORCID Profile
0000-0002-0494-2404
Current Organisations
University of Queensland Institute for Molecular Bioscience
,
University of South Australia
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Cellular Interactions (incl. Adhesion, Matrix, Cell Wall) | Animal Developmental and Reproductive Biology | Other Physical Sciences | Biochemistry and Cell Biology | Nanoscale Characterisation | Biochemistry and Cell Biology not elsewhere classified | Biological Physics | Crop and Pasture Biochemistry and Physiology
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Physical Sciences | Expanding Knowledge in the Agricultural and Veterinary Sciences | Expanding Knowledge in the Medical and Health Sciences |
Publisher: Informa UK Limited
Date: 07-07-2017
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.TCB.2011.05.006
Abstract: Cell-cell contacts are major determinants of tissue organization in both health and disease. Adhesive interactions, especially those mediated by classical cadherin receptors, influence cell-cell recognition and tissue patterning during development. Conversely, cadherin dysfunction promotes tumor progression to invasion and metastasis. Over the past three decades, we have learnt a great deal about the molecular mechanisms responsible for cadherin-based cell-cell interactions. Yet our knowledge remains incomplete. The intersection between cell biology and mechanical forces has long been suspected to be an important missing factor in understanding cadherin biology. However, tangible evidence remained elusive until recently, when several reports began to elucidate the role of cadherins and the cytoskeleton in mechanotransduction. In this review, we examine these advances and discuss their implications.
Publisher: The Company of Biologists
Date: 15-04-2014
DOI: 10.1242/JCS.139014
Abstract: The findings presented here demonstrate the role of α-catenin in cadherin-based adhesion and mechanotransduction in different mechanical contexts. Bead-twisting measurements in conjunction with imaging, and the use of different cell lines and α-catenin mutants reveal that the acute local mechanical manipulation of cadherin bonds triggers vinculin and actin recruitment to cadherin adhesions in an actin- and α-catenin-dependent manner. The modest effect of α-catenin on the two-dimensional binding affinities of cell surface cadherins further suggests that force-activated adhesion strengthening is due to enhanced cadherin–cytoskeletal interactions rather than to α-catenin-dependent affinity modulation. Complementary investigations of cadherin-based rigidity sensing also suggest that, although α-catenin alters traction force generation, it is not the sole regulator of cell contractility on compliant cadherin-coated substrata.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2018
Publisher: Springer Science and Business Media LLC
Date: 03-03-2012
DOI: 10.1007/S11064-012-0741-1
Abstract: The functional link between glycolipid glycosyltransferases (GT) relies on the ability of these proteins to form organized molecular complexes. The organization, stoichiometry and composition of these complexes may impact their sorting properties, sub-Golgi localization, and may determine relative efficiency of GT in different glycolipid biosynthetic pathways. In this work, by using Förster resonance energy transfer microscopy in live CHO-K1 cells, we investigated homo- and hetero-complex formation by different GT as well as their spatial organization and molecular stoichiometry on Golgi membranes. We find that GalNAcT and GalT2 Ntd are able to form hetero-complexes in a 1:2 molar ratio at the trans-Golgi network and that GalT2 but not GalNAcT forms homo-complexes. Also, GalNAcT/GalT2 complexes exhibit a stable behavior reflected by its clustered lateral organization. These results reveals that particular topological organization of GTs may have functional implications in determining the composition of glycolipids in cellular membranes.
Publisher: Public Library of Science (PLoS)
Date: 30-11-2010
Publisher: American Society for Cell Biology (ASCB)
Date: 11-2020
Abstract: Apoptotic cell extrusion is predicted to accumulate local tissue stresses that represent a mechanical cost for the epithelium, but how such costs may be alleviated is poorly understood. Here we identify a Src family kinase-mechanosensitive early immediate response of neighbor cells that relieves mechanical stress and allows extrusion to occur.
Publisher: F1000 Research Ltd
Date: 13-01-2023
DOI: 10.12688/F1000RESEARCH.129089.1
Abstract: Glioblastoma (GBM) is the most aggressive form of primary brain cancer, with 5-year survival rates of less than 5%. Clinical management of GBM has not changed in the last 15 years, and current treatment approaches combine surgical resection, followed by radiotherapy and chemotherapy. Tragically, tumour recurrence is inevitable. Still, very little is known about how tumours evolve in response to therapy and become treatment resistant. In 2019, The Glioma Longitudinal AnalySiS (GLASS) consortium curated extensive, publicly accessible genomic profiling data captured from matched primary and recurrent tumours across 222 patients, along with comprehensive clinical annotations. Recently, this longitudinal genomic data resource was expanded by integrating matching transcriptomic and genomic data from 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma captured at two or more time points (Varn et al. , 2022). This has enabled new insights into the dynamic changes in transcriptional programs, cellular compositions and microenvironment interactions within these brain tumours. In this commentary, we will focus on recurrent high-grade IDHwt and the implications of these findings for targeting tumour-microenvironment interactions that may pave new pathways for developing therapies for this type of brain tumour.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.DEVCEL.2016.03.008
Abstract: In this study we sought to identify how contractility at adherens junctions influences apoptotic cell extrusion. We first found that the generation of effective contractility at steady-state junctions entails a process of architectural reorganization whereby filaments that are initially generated as poorly organized networks of short bundles are then converted into co-aligned perijunctional bundles. Reorganization requires coronin 1B, which is recruited to junctions by E-cadherin adhesion and is necessary to establish contractile tension at the zonula adherens. When cells undergo apoptosis within an epithelial monolayer, coronin 1B is also recruited to the junctional cortex at the apoptotic/neighbor cell interface in an E-cadherin-dependent fashion to support actin architectural reorganization, contractility, and extrusion. We propose that contractile stress transmitted from the apoptotic cell through E-cadherin adhesions elicits a mechanosensitive response in neighbor cells that is necessary for the morphogenetic event of apoptotic extrusion to occur.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2019
DOI: 10.1158/2159-8290.23854361
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.EJCB.2014.09.001
Abstract: The physical properties of cells reflect how the structure and dynamics of the actomyosin cortex are coupled to the plasma membrane. In epithelia, adhesive E-cadherin clusters associate with the cell cortex to assemble the junctional actomyosin that participates in epithelial morphogenesis. E-cadherin is present not only at the apical zonula adherens (ZA), but also distributed throughout the lateral adherens junction (LAJ) below the ZA. However, the organizational dynamics of the actomyosin network at the LAJs remains elusive. To address this, we used quantitative real-time imaging to characterize the dynamics of actomyosin contractility at lateral cadherin contacts. Here, we report that contractility is coordinated into smaller actomyosin rings that link cadherin clusters together within the larger cortical network at the lateral junctions. We conclude that Myosin II activity determines the contractility of actomyosin cables between cadherin clusters to propagate pulsatility across lateral cell-cell contacts.
Publisher: Springer Science and Business Media LLC
Date: 10-03-2017
DOI: 10.1038/NCOMMS14729
Abstract: Remarkably little is known about how intracellular pathogens exit the host cell in order to infect new hosts. Pathogenic chlamydiae egress by first rupturing their replicative niche (the inclusion) before rapidly lysing the host cell. Here we apply a laser ablation strategy to specifically disrupt the chlamydial inclusion, thereby uncoupling inclusion rupture from the subsequent cell lysis and allowing us to dissect the molecular events involved in each step. Pharmacological inhibition of host cell calpains inhibits inclusion rupture, but not subsequent cell lysis. Further, we demonstrate that inclusion rupture triggers a rapid necrotic cell death pathway independent of BAK, BAX, RIP1 and caspases. Both processes work sequentially to efficiently liberate the pathogen from the host cytoplasm, promoting secondary infection. These results reconcile the pathogen's known capacity to promote host cell survival and induce cell death.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2021
DOI: 10.1038/S41416-021-01394-X
Abstract: Glioblastoma is the most aggressive type of brain cancer with high-levels of intra- and inter-tumour heterogeneity that contribute to its rapid growth and invasion within the brain. However, a spatial characterisation of gene signatures and the cell types expressing these in different tumour locations is still lacking. We have used a deep convolutional neural network (DCNN) as a semantic segmentation model to segment seven different tumour regions including leading edge (LE), infiltrating tumour (IT), cellular tumour (CT), cellular tumour microvascular proliferation (CTmvp), cellular tumour pseudopalisading region around necrosis (CTpan), cellular tumour perinecrotic zones (CTpnz) and cellular tumour necrosis (CTne) in digitised glioblastoma histopathological slides from The Cancer Genome Atlas (TCGA). Correlation analysis between segmentation results from tumour images together with matched RNA expression data was performed to identify genetic signatures that are specific to different tumour regions. We found that spatially resolved gene signatures were strongly correlated with survival in patients with defined genetic mutations. Further in silico cell ontology analysis along with single-cell RNA sequencing data from resected glioblastoma tissue s les showed that these tumour regions had different gene signatures, whose expression was driven by different cell types in the regional tumour microenvironment. Our results further pointed to a key role for interactions between microglia ericytes/monocytes and tumour cells that occur in the IT and CTmvp regions, which may contribute to poor patient survival. This work identified key histopathological features that correlate with patient survival and detected spatially associated genetic signatures that contribute to tumour-stroma interactions and which should be investigated as new targets in glioblastoma. The source codes and datasets used are available in GitHub: min20/GBM_WSSM .
Publisher: American Association for the Advancement of Science (AAAS)
Date: 16-05-2014
Abstract: Signaling from JAK (Janus kinase) protein kinases to STAT (signal transducers and activators of transcription) transcription factors is key to many aspects of biology and medicine, yet the mechanism by which cytokine receptors initiate signaling is enigmatic. We present a complete mechanistic model for activation of receptor-bound JAK2, based on an archetypal cytokine receptor, the growth hormone receptor. For this, we used fluorescence resonance energy transfer to monitor positioning of the JAK2 binding motif in the receptor dimer, substitution of the receptor extracellular domains with Jun zippers to control the position of its transmembrane (TM) helices, atomistic modeling of TM helix movements, and docking of the crystal structures of the JAK2 kinase and its inhibitory pseudokinase domain with an opposing kinase-pseudokinase domain pair. Activation of the receptor dimer induced a separation of its JAK2 binding motifs, driven by a ligand-induced transition from a parallel TM helix pair to a left-handed crossover arrangement. This separation leads to removal of the pseudokinase domain from the kinase domain of the partner JAK2 and pairing of the two kinase domains, facilitating trans-activation. This model may well generalize to other class I cytokine receptors.
Publisher: Springer Science and Business Media LLC
Date: 04-07-2023
DOI: 10.1186/S12859-023-05400-2
Abstract: P4 medicine (predict, prevent, personalize, and participate) is a new approach to diagnosing and predicting diseases on a patient-by-patient basis. For the prevention and treatment of diseases, prediction plays a fundamental role. One of the intelligent strategies is the design of deep learning models that can predict the state of the disease using gene expression data. We create an autoencoder deep learning model called DeeP4med, including a Classifier and a Transferor that predicts cancer's gene expression (mRNA) matrix from its matched normal s le and vice versa. The range of the F1 score of the model, depending on tissue type in the Classifier, is from 0.935 to 0.999 and in Transferor from 0.944 to 0.999. The accuracy of DeeP4med for tissue and disease classification was 0.986 and 0.992, respectively, which performed better compared to seven classic machine learning models (Support Vector Classifier, Logistic Regression, Linear Discriminant Analysis, Naive Bayes, Decision Tree, Random Forest, K Nearest Neighbors). Based on the idea of DeeP4med, by having the gene expression matrix of a normal tissue, we can predict its tumor gene expression matrix and, in this way, find effective genes in transforming a normal tissue into a tumor tissue. Results of Differentially Expressed Genes (DEGs) and enrichment analysis on the predicted matrices for 13 types of cancer showed a good correlation with the literature and biological databases. This led that by using the gene expression matrix, to train the model with features of each person in a normal and cancer state, this model could predict diagnosis based on gene expression data from healthy tissue and be used to identify possible therapeutic interventions for those patients.
Publisher: Wiley
Date: 05-12-2017
DOI: 10.1002/CM.21420
Abstract: Adherens junctions in epithelia are contractile structures, where coupling of adhesion to the actomyosin cytoskeleton generates mechanical tension for morphogenesis and homeostasis. In established monolayers, junctional contractility is supported by the interplay between cell signals and scaffolding proteins. However, less is known about how contractile junctions develop, especially during the establishment of epithelial monolayers. Here, we show that junctional tension increases concomitant with accumulation of actomyosin networks as Caco-2 epithelia become confluent. This is associated with development of a zone of RhoA signaling at junctions. Further, we find that the low levels of RhoA signaling and contractility found in subconfluent cultures reflect a mechanism for their active suppression. Specifically, the RhoA antagonist, SRGAP1, is present at subconfluent junctions to a greater extent than in confluent cultures and SRGAP1 RNAi restores RhoA signaling and contractility in subconfluent cultures to levels seen in confluent cells. Overall, these observations suggest that regulated changes in junctional contractility mediated by modulation of RhoA signaling occur as epithelial monolayers mature.
Publisher: AME Publishing Company
Date: 12-2019
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854361.V1
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: Portland Press Ltd.
Date: 22-03-2019
DOI: 10.1042/BST20180444
Abstract: Glioblastoma is the deadliest form of brain cancer. Aside from inadequate treatment options, one of the main reasons glioblastoma is so lethal is the rapid growth of tumour cells coupled with continuous cell invasion into surrounding healthy brain tissue. Significant intra- and inter-tumour heterogeneity associated with differences in the corresponding tumour microenvironments contributes greatly to glioblastoma progression. Within this tumour microenvironment, the extracellular matrix profoundly influences the way cancer cells become invasive, and changes to extracellular (pH and oxygen levels) and metabolic (glucose and lactate) components support glioblastoma growth. Furthermore, studies on clinical s les have revealed that the tumour microenvironment is highly immunosuppressive which contributes to failure in immunotherapy treatments. Although technically possible, many components of the tumour microenvironment have not yet been the focus of glioblastoma therapies, despite growing evidence of its importance to glioblastoma malignancy. Here, we review recent progress in the characterisation of the glioblastoma tumour microenvironment and the sources of tumour heterogeneity in human clinical material. We also discuss the latest advances in technologies for personalised and in vitro preclinical studies using brain organoid models to better model glioblastoma and its interactions with the surrounding healthy brain tissue, which may play an essential role in developing new and more personalised treatments for this aggressive type of cancer.
Publisher: Informa UK Limited
Date: 11-2016
Publisher: Royal Society of Chemistry (RSC)
Date: 1999
DOI: 10.1039/A809571J
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854346.V1
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: Frontiers Media SA
Date: 06-04-2022
DOI: 10.3389/FIMMU.2022.850226
Abstract: Glioblastoma is the most common and aggressive form of primary brain cancer, with no improvements in the 5-year survival rate of 4.6% over the past three decades. T-cell-based immunotherapies such as immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapy have prolonged the survival of patients with other cancers and have undergone early-phase clinical evaluation in glioblastoma patients. However, a major challenge for T-cell-based immunotherapy of glioblastoma and other solid cancers is T-cell infiltration into tumours. This process is mediated by chemokine-chemokine receptor and integrin-adhesion molecule interactions, yet the specific nature of the molecules that may facilitate T-cell homing into glioblastoma are unknown. Here, we have characterised chemokine receptor and integrin expression profiles of endogenous glioblastoma-infiltrating T cells, and the chemokine expression profile of glioblastoma-associated cells, by single-cell RNA-sequencing. Subsequently, chemokine receptors and integrins were validated at the protein level to reveal enrichment of receptors CCR2, CCR5, CXCR3, CXCR4, CXCR6, CD49a, and CD49d in glioblastoma-infiltrating T-cell populations relative to T cells in matched patient peripheral blood. Complementary chemokine ligand expression was then validated in glioblastoma biopsies and glioblastoma-derived primary cell cultures. Together, enriched expression of homing receptor-ligand pairs identified in this study implicate a potential role in mediating T-cell infiltration into glioblastoma. Importantly, our data characterising the migratory receptors on endogenous tumour-infiltrating T cells could be exploited to enhance the tumour-homing properties of future T-cell immunotherapies for glioblastoma.
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.BIOMATERIALS.2013.11.023
Abstract: Cell behaviours within tissues are influenced by a broad array of physical and biochemical microenvironmental factors. Whilst 'stiffness' is a recognised physical property of substrates and tissue microenvironments that influences many cellular behaviours, tissues and their extracellular matrices are not purely rigid but 'viscoelastic' materials, composed of both rigid-like (elastic) and dissipative (viscous) elements. This viscoelasticity results in materials displaying increased deformation with time under the imposition of a defined force or stress, a phenomenon referred to as time-dependent deformation or 'creep'. Previously, we compared the behaviour of human mesenchymal stem cells (hMSCs) on hydrogels tailored to have a constant stiffness, but to display varying levels of creep in response to an applied force. Using polyacrylamide as a model material, we showed that on high-creep hydrogels (HCHs), hMSCs displayed increased proliferation, spread area and differentiation towards multiple lineages, compared to their purely stiff analogue, with a particular propensity for differentiation towards a smooth muscle cell (SMC) lineage. In this present study, we investigate the mechanisms behind this phenomenon and show that hMSCs adhered to HCHs have increased expression of SMC induction factors, including soluble factors, ECM proteins and the cell-cell adhesion molecule, N-Cadherin. Further, we identify a key role for Rac1 signalling in mediating this increased N-Cadherin expression. Using a real-time Rac1-FRET biosensor, we confirm increased Rac1 activation on HCHs, an observation that is further supported functionally by observed increases in motility and lamellipodial protrusion rates of hMSCs. Increased Rac1 activity in hMSCs on HCHs provides underlying mechanisms for enhanced commitment towards a SMC lineage and the compensatory increase in spread area (isotonic tension) after a creep-induced loss of cytoskeletal tension on viscoelastic substrates, in contrast to previous studies that have consistently demonstrated up-regulation of RhoA activity with increasing substrate stiffness. Tuning substrate viscoelasticity to introduce varying levels of creep thus equips the biomaterial scientist or engineer with a new tool with which to tune and direct stem cell outcomes.
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.CUB.2021.01.003
Abstract: Epithelia must eliminate apoptotic cells to preserve tissue barriers and prevent inflammation.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709852
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/5194239
Abstract: Use of antioxidants to mitigate oxidative stress during ocular inflammatory diseases has shown therapeutic potential. This work examines a nanoscale therapeutic modality for the eye on the base of antioxidant enzyme, superoxide dismutase 1 (SOD1), termed “nanozyme.” The nanozyme is produced by electrostatic coupling of the SOD1 with a cationic block copolymer, poly(L-lysine)-poly(ethyleneglycol), followed by covalent cross-linking of the complexes with 3,3′-dithiobis(sulfosuccinimidylpropionate) sodium salt. The ability of SOD1 nanozyme as well as the native SOD1 to reduce inflammatory processes in the eye was examined in vivo in rabbits with immunogenic uveitis. Results suggested that topical instillations of both enzyme forms demonstrated anti-inflammatory activity however, the nanozyme was much more effective compared to the free enzyme in decreasing uveitis manifestations. In particular, we noted statistically significant differences in such inflammatory signs in the eye as the intensities of corneal and iris edema, hyperemia of conjunctiva, lens opacity, fibrin clots, and the protein content in aqueous humor. Clinical findings were confirmed by histological data. Thus, SOD1-containing nanozyme is potentially useful therapeutic agent for the treatment of ocular inflammatory disorders.
Publisher: American Society for Cell Biology (ASCB)
Date: 04-2015
Abstract: Cell–cell adhesion couples the contractile cortices of epithelial cells together, generating tension to support a range of morphogenetic processes. E-cadherin adhesion plays an active role in generating junctional tension by promoting actin assembly and cortical signaling pathways that regulate myosin II. Multiple myosin II paralogues accumulate at mammalian epithelial cell–cell junctions. Earlier, we found that myosin IIA responds to Rho-ROCK signaling to support junctional tension in MCF-7 cells. Although myosin IIB is also found at the zonula adherens (ZA) in these cells, its role in junctional contractility and its mode of regulation are less well understood. We now demonstrate that myosin IIB contributes to tension at the epithelial ZA. Further, we identify a receptor type-protein tyrosine phosphatase alpha–Src family kinase–Rap1 pathway as responsible for recruiting myosin IIB to the ZA and supporting contractile tension. Overall these findings reinforce the concept that orthogonal E-cadherin–based signaling pathways recruit distinct myosin II paralogues to generate the contractile apparatus at apical epithelial junctions.
Publisher: MDPI AG
Date: 12-11-2020
DOI: 10.3390/JPM10040224
Abstract: In recent years, improved deep learning techniques have been applied to biomedical image processing for the classification and segmentation of different tumors based on magnetic resonance imaging (MRI) and histopathological imaging (H& E) clinical information. Deep Convolutional Neural Networks (DCNNs) architectures include tens to hundreds of processing layers that can extract multiple levels of features in image-based data, which would be otherwise very difficult and time-consuming to be recognized and extracted by experts for classification of tumors into different tumor types, as well as segmentation of tumor images. This article summarizes the latest studies of deep learning techniques applied to three different kinds of brain cancer medical images (histology, magnetic resonance, and computed tomography) and highlights current challenges in the field for the broader applicability of DCNN in personalized brain cancer care by focusing on two main applications of DCNNs: classification and segmentation of brain cancer tumors images.
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.DEVCEL.2018.09.016
Abstract: Adherens junctions are tensile structures that couple epithelial cells together. Junctional tension can arise from cell-intrinsic application of contractility or from the cell-extrinsic forces of tissue movement. Here, we report a mechanosensitive signaling pathway that activates RhoA at adherens junctions to preserve epithelial integrity in response to acute tensile stress. We identify Myosin VI as the force sensor, whose association with E-cadherin is enhanced when junctional tension is increased by mechanical monolayer stress. Myosin VI promotes recruitment of the heterotrimeric Gα12 protein to E-cadherin, where it signals for p114 RhoGEF to activate RhoA. Despite its potential to stimulate junctional actomyosin and further increase contractility, tension-activated RhoA signaling is necessary to preserve epithelial integrity. This is explained by an increase in tensile strength, especially at the multicellular vertices of junctions, that is due to mDia1-mediated actin assembly.
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/2159-8290.CD-22-1396
Abstract: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. This article is highlighted in the In This Issue feature, p. 1749
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854355.V1
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2018
DOI: 10.1038/S41467-017-02486-0
Abstract: Mechanotransduction is a strong driver of mesenchymal stem cell (MSC) fate. In vitro, variations in matrix mechanics invoke changes in MSC proliferation, migration and differentiation. However, when incorporating MSCs within injectable, inherently soft hydrogels, this dominance over MSC response substantially limits our ability to couple the ease of application of hydrogels with efficiently directed MSC differentiation, especially in the case of bone generation. Here, we identify differential miRNA expression in response to varying hydrogel stiffness and RhoA activity. We show that modulation of miR-100-5p and miR-143-3p can be used to bias MSC fate and provide mechanistic insight by demonstrating convergence on mTOR signalling. By modulating these mechanosensitive miRNAs, we can enhance osteogenesis in a soft 3D hydrogel. The outcomes of this study provide new understanding of the mechanisms regulating MSC mechanotransduction and differentiation, but also a novel strategy with which to drive MSC fate and significantly impact MSC-based tissue-engineering applications.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.BBRC.2015.10.148
Abstract: The protein farnesyltransferase (FTase) mediates posttranslational modification of proteins with isoprenoid lipids. FTase is a heterodimer and although the β subunit harbors the active site, it requires the α subunit for its activity. Here we explore the other functions of the FTase α subunit in addition to its established role in protein prenylation. We found that in the absence of the β subunit, the α subunit of FTase forms a stable autonomous dimeric structure in solution. We identify interactors of FTase α using mass spectrometry, followed by rapid in vitro analysis using the Leishmania tarentolae cell - free system. Vps4A was validated for direct binding to the FTase α subunit both in vitro and in vivo. Analysis of the interaction with Vps4A in Hek 293 cells demonstrated that FTase α controls trafficking of transferrin receptor upstream of this protein. These results point to the existence of previously undetected biological functions of the FTase α subunit that includes control of intracellular membrane trafficking.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709858
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709855
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: Informa UK Limited
Date: 02-2015
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709873.V1
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: Springer Science and Business Media LLC
Date: 04-2021
DOI: 10.1186/S42490-021-00049-5
Abstract: Organoids are a reliable model used in the study of human brain development and under pathological conditions. However, current methods for brain organoid culture generate tissues that range from 0.5 to 2 mm of size, which need to be constantly agitated to allow proper oxygenation. The culture conditions are, therefore, not suitable for whole-brain organoid live imaging, required to study developmental processes and disease progression within physiologically relevant time frames (i.e. days, weeks, months). Here we designed 3D-printed microplate inserts adaptable to standard 24 multi-well plates, which allow the growth of multiple organoids in pre-defined and fixed XYZ coordinates. This innovation facilitates high-resolution imaging of whole-cerebral organoids, allowing precise assessment of organoid growth and morphology, as well as cell tracking within the organoids, over long periods. We applied this technology to track neocortex development through neuronal progenitors in brain organoids, as well as the movement of patient-derived glioblastoma stem cells within healthy brain organoids. This new bioengineering platform constitutes a significant advance that permits long term detailed analysis of whole-brain organoids using multimodal inverted fluorescence microscopy.
Publisher: Public Library of Science (PLoS)
Date: 08-04-2014
Publisher: Wiley
Date: 12-2014
DOI: 10.1002/CM.21202
Abstract: Epithelial cells generate contractile forces at their cell-cell contacts. These are concentrated at the specialized apical junction of the zonula adherens (ZA), where a ring of stabilized E-cadherin lies adjacent to prominent actomyosin bundles. Coupling of adhesion and actomyosin contractility yields tension in the junction. The biogenesis of junctional contractility requires actin assembly at the ZA as well as the recruitment of nonmuscle myosin II, but the molecular regulators of these processes are not yet fully understood. We now report a role for tropomyosins 5NM1 (Tm5NM1) and 5NM2 (Tm5NM2) in their generation. Both these tropomyosin isoforms were found at the ZA and their depletion by RNAi or pharmacological inhibition reduced both F-actin and myosin II content at the junction. Photoactivation analysis revealed that the loss of F-actin was attributable to a decrease in filament stability. These changes were accompanied by a decrease in E-cadherin content at junctions. Ultimately, both long-term depletion of Tm5NM1/2 and acute inhibition with drugs caused junctional tension to be reduced. Thus these tropomyosin isoforms are novel contributors to junctional contractility and integrity.
Publisher: Oxford University Press (OUP)
Date: 2015
DOI: 10.1039/C5IB00053J
Abstract: We use a two-dimensional cellular Potts model to represent the behavior of an epithelial cell layer and describe its dynamics in response to a microscopic wound.
Publisher: MDPI AG
Date: 21-04-2021
DOI: 10.3390/IJMS22094322
Abstract: Glioblastoma is one of the most common and lethal types of primary brain tumor. Despite aggressive treatment with chemotherapy and radiotherapy, tumor recurrence within 6–9 months is common. To overcome this, more effective therapies targeting cancer cell stemness, invasion, metabolism, cell death resistance and the interactions of tumor cells with their surrounding microenvironment are required. In this study, we performed a systematic review of the molecular mechanisms that drive glioblastoma progression, which led to the identification of 65 drugs/inhibitors that we screened for their efficacy to kill patient-derived glioma stem cells in two dimensional (2D) cultures and patient-derived three dimensional (3D) glioblastoma explant organoids (GBOs). From the screening, we found a group of drugs that presented different selectivity on different patient-derived in vitro models. Moreover, we found that Costunolide, a TERT inhibitor, was effective in reducing the cell viability in vitro of both primary tumor models as well as tumor models pre-treated with chemotherapy and radiotherapy. These results present a novel workflow for screening a relatively large groups of drugs, whose results could lead to the identification of more personalized and effective treatment for recurrent glioblastoma.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854352.V1
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: Elsevier BV
Date: 12-2014
Publisher: Springer Science and Business Media LLC
Date: 10-11-2017
DOI: 10.1038/S41467-017-01325-6
Abstract: Forces play erse roles in vascular development, homeostasis and disease. VE-cadherin at endothelial cell-cell junctions links the contractile acto-myosin cytoskeletons of adjacent cells, serving as a tension-transducer. To explore tensile changes across VE-cadherin in live zebrafish, we tailored an optical biosensor approach, originally established in vitro. We validate localization and function of a VE-cadherin tension sensor (TS) in vivo. Changes in tension across VE-cadherin observed using ratio-metric or lifetime FRET measurements reflect acto-myosin contractility within endothelial cells. Furthermore, we apply the TS to reveal biologically relevant changes in VE-cadherin tension that occur as the dorsal aorta matures and upon genetic and chemical perturbations during embryonic development.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709849
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.DEVCEL.2019.04.031
Abstract: RhoA stimulates cell contractility by recruiting downstream effectors to the cortical plasma membrane. We now show that direct binding by anillin is required for effective signaling: this antagonizes the otherwise labile membrane association of GTP-RhoA to promote effector recruitment. However, since its binding to RhoA blocks access by other effectors, we demonstrate that anillin must also concentrate membrane phosphoinositide-4,5-P
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2023
DOI: 10.1161/HYPERTENSIONAHA.123.21119
Abstract: Glioblastoma invasion is the primary mechanism responsible for its dismal prognosis and is the direct result of interactions between glioblastoma cells and the tumor vasculature. The dysregulated microvasculature in glioblastoma tumors and vessels co-opted from surrounding brain tissue support rapid tumor growth and are utilized as pathways for invasive cancer cells. Attempts to target the glioblastoma vasculature with antiangiogenic agents (eg, bevacizumab) have nonetheless shown limited and inconsistent efficacy, and the underlying causes of such heterogeneous responses remain unknown. Several studies have identified that patients with glioblastoma who develop hypertension following treatment with bevacizumab show significant improvement in overall survival compared with normotensive nonresponders. Here we review these findings and discuss the potential of hypertension as a biomarker for glioblastoma treatment response in in idual patients and the role of hypertension as a modulator of interactions between tumor cells and cells in the perivascular niche. We suggest that a better understanding of the actions of bevacizumab and hypertension at the cellular level will contribute to developing more effective personalized therapies that address glioblastoma tumor cell invasion.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2014
DOI: 10.1038/NCB2900
Abstract: E-cadherin cell-cell junctions couple the contractile cortices of epithelial cells together, generating tension within junctions that influences tissue organization. Although junctional tension is commonly studied at the apical zonula adherens, we now report that E-cadherin adhesions induce the contractile actomyosin cortex throughout the apical-lateral axis of junctions. However, cells establish distinct regions of contractile activity even within in idual contacts, producing high tension at the zonula adherens but substantially lower tension elsewhere. We demonstrate that N-WASP (also known as WASL) enhances apical junctional tension by stabilizing local F-actin networks, which otherwise undergo stress-induced turnover. Further, we find that cells are extruded from monolayers when this pattern of intra-junctional contractility is disturbed, either when N-WASP redistributes into lateral junctions in H-Ras(V12)-expressing cells or on mosaic redistribution of active N-WASP itself. We propose that local control of actin filament stability regulates the landscape of intra-junctional contractility to determine whether or not cells integrate into epithelial populations.
Publisher: Elsevier BV
Date: 08-2014
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854334
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709849.V1
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: Frontiers Media SA
Date: 30-09-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854331
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.CUB.2017.05.067
Abstract: The embryonic notochord is a flexible structure present during development that serves as scaffold for formation of the vertebrate spine. This rod-like organ is thought to have evolved in non-vertebrate chordates to facilitate locomotion by providing a rigid but flexible midline structure against which the axial muscles can contract. This hydrostatic "skeleton" is exposed to a variety of mechanical forces during oscillation of the body. There is evidence that caveolae, submicroscopic cup-shaped plasma membrane pits, can buffer tension in cells that undergo high levels of mechanical stress. Indeed, caveolae are particularly abundant in the embryonic notochord. In this study, we used the CRISPR/Cas9 system to generate a mutant zebrafish line lacking Cavin1b, a coat protein required for caveola formation. Our cavin1b
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854325.V1
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709855.V1
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709870.V1
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: Public Library of Science (PLoS)
Date: 22-07-2011
Publisher: Springer Science and Business Media LLC
Date: 02-03-2020
DOI: 10.1007/S11517-020-02147-3
Abstract: Histopathological whole slide images of haematoxylin and eosin (H& E)-stained biopsies contain valuable information with relation to cancer disease and its clinical outcomes. Still, there are no highly accurate automated methods to correlate histolopathological images with brain cancer patients’ survival, which can help in scheduling patients therapeutic treatment and allocate time for preclinical studies to guide personalized treatments. We now propose a new classifier, namely, DeepSurvNet powered by deep convolutional neural networks, to accurately classify in 4 classes brain cancer patients’ survival rate based on histopathological images (class I, 0–6 months class II, 6–12 months class III, 12–24 months and class IV, months survival after diagnosis). After training and testing of DeepSurvNet model on a public brain cancer dataset, The Cancer Genome Atlas, we have generalized it using independent testing on unseen s les. Using DeepSurvNet, we obtained precisions of 0.99 and 0.8 in the testing phases on the mentioned datasets, respectively, which shows DeepSurvNet is a reliable classifier for brain cancer patients’ survival rate classification based on histopathological images. Finally, analysis of the frequency of mutations revealed differences in terms of frequency and type of genes associated to each class, supporting the idea of a different genetic fingerprint associated to patient survival. We conclude that DeepSurvNet constitutes a new artificial intelligence tool to assess the survival rate in brain cancer.
Publisher: Wiley
Date: 31-03-2006
DOI: 10.1111/J.1742-4658.2006.05194.X
Abstract: Gangliosides are sialic acid-containing glycosphingolipids present on mammalian plasma membranes, where they participate in cell-surface events such as modulation of growth factor receptors and cell-to-cell and cell-to-matrix interactions. Antibodies to gangliosides have been associated with a wide range of clinically identifiable acute and chronic neuropathy syndromes. In addition, antibodies to tumor-associated gangliosides are being used as therapeutic agents. Their binding to and release from cell membranes and intracellular destinations have not so far been extensively examined. In this study, we characterized in both GD3 ganglioside-expressing Chinese hamster ovary (CHO)-K1 and SK-Mel 28 melanoma cells the intracellular trafficking and subcellular localization of the mouse monoclonal antibody to GD3, R24. By biochemical techniques and detailed confocal microscopic analysis, we demonstrate that the GD3-R24 antibody complex is rapidly and specifically internalized by a dynamin 2-independent pathway and then accumulates in the endocytic recycling compartment. In addition, we show that the R24 antibody exits the recycling compartment en route to the plasma membrane by a dynamin 2-dependent pathway sensitive to brefeldin A and monensin. Taken together, our results indicate that the GD3-R24 complex is endocytosed in GD3-expressing cells, accumulates in the recycling endosome, and is transported back to the plasma membrane via a route that involves clathrin-coated vesicles.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709873
Abstract: IL3Rα/βc transcript and protein expression ratio in AML patient s les.
Publisher: Springer Science and Business Media LLC
Date: 07-2012
DOI: 10.1038/NCB2532
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709870
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2017
DOI: 10.1038/S41467-017-00797-W
Abstract: Contractile adherens junctions support cell−cell adhesion, epithelial integrity, and morphogenesis. Much effort has been devoted to understanding how contractility is established however, less is known about whether contractility can be actively downregulated at junctions nor what function this might serve. We now identify such an inhibitory pathway that is mediated by the cytoskeletal scaffold, cortactin. Mutations of cortactin that prevent its tyrosine phosphorylation downregulate RhoA signaling and compromise the ability of epithelial cells to generate a contractile zonula adherens. This is mediated by the RhoA antagonist, SRGAP1. We further demonstrate that this mechanism is co-opted by hepatocyte growth factor to promote junctional relaxation and motility in epithelial collectives. Together, our findings identify a novel function of cortactin as a regulator of RhoA signaling that can be utilized by morphogenetic regulators for the active downregulation of junctional contractility.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709858.V1
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854334.V1
Abstract: Increasing IL3Rα/βc ratios lead to hexameric receptor assembly and augmented quiescence.
Publisher: American Association for Cancer Research (AACR)
Date: 20-08-0006
DOI: 10.1158/2159-8290.23854328.V1
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709861.V1
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: eLife Sciences Publications, Ltd
Date: 18-06-2021
DOI: 10.7554/ELIFE.61407
Abstract: Caveolae-associated protein 3 (cavin3) is inactivated in most cancers. We characterized how cavin3 affects the cellular proteome using genome-edited cells together with label-free quantitative proteomics. These studies revealed a prominent role for cavin3 in DNA repair, with BRCA1 and BRCA1 A-complex components being downregulated on cavin3 deletion. Cellular and cell-free expression assays revealed a direct interaction between BRCA1 and cavin3 that occurs when cavin3 is released from caveolae that are disassembled in response to UV and mechanical stress. Overexpression and RNAi-depletion revealed that cavin3 sensitized various cancer cells to UV-induced apoptosis. Supporting a role in DNA repair, cavin3-deficient cells were sensitive to PARP inhibition, where concomitant depletion of 53BP1 restored BRCA1-dependent sensitivity to PARP inhibition. We conclude that cavin3 functions together with BRCA1 in multiple cancer-related pathways. The loss of cavin3 function may provide tumor cell survival by attenuating apoptotic sensitivity and hindering DNA repair under chronic stress conditions.
Publisher: Elsevier BV
Date: 06-2023
DOI: 10.1016/J.ACTBIO.2022.01.020
Abstract: The dynamics of cell mechanics and epigenetic signatures direct cell behaviour and fate, thus influencing regenerative outcomes. In recent years, the utilisation of 2D geometric (i.e. square, circle, hexagon, triangle or round-shaped) substrates for investigating cell mechanics in response to the extracellular microenvironment have gained increasing interest in regenerative medicine due to their tunable physicochemical properties. In contrast, there is relatively limited knowledge of cell mechanobiology and epigenetics in the context of 3D biomaterial matrices, i.e., hydrogels and scaffolds. Scaffold geometry provides biophysical signals that trigger a nucleus response (regulation of gene expression) and modulates cell behaviour and function. In this review, we explore the potential of additive manufacturing to incorporate multi length-scale geometry features on a scaffold. Then, we discuss how scaffold geometry direct cell and nuclear mechanosensing. We further discuss how cell epigenetics, particularly DNA/histone methylation and histone acetylation, are modulated by scaffold features that lead to specific gene expression and ultimately influence the outcome of tissue regeneration. Overall, we highlight that geometry of different magnitude scales can facilitate the assembly of cells and multicellular tissues into desired functional architectures through the mechanotransduction pathway. Moving forward, the challenge confronting biomedical engineers is the distillation of the vast knowledge to incorporate multiscaled geometrical features that would collectively elicit a favourable tissue regeneration response by harnessing the design flexibility of additive manufacturing. STATEMENT OF SIGNIFICANCE: It is well-established that cells sense and respond to their 2D geometric microenvironment by transmitting extracellular physiochemical forces through the cytoskeleton and biochemical signalling to the nucleus, facilitating epigenetic changes such as DNA methylation, histone acetylation, and microRNA expression. In this context, the current review presents a unique perspective and highlights the importance of 3D architectures (dimensionality and geometries) on cell and nuclear mechanics and epigenetics. Insight into current challenges around the study of mechanobiology and epigenetics utilising additively manufactured 3D scaffold geometries will progress biomaterials research in this space.
Publisher: American Society for Microbiology
Date: 03-2011
DOI: 10.1128/JVI.01875-10
Abstract: Tacaribe virus (TCRV) belongs to the Arenaviridae family. Its bisegmented negative-stranded RNA genome encodes the nucleoprotein (N), the precursor of the envelope glycoproteins, the polymerase (L), and a RING finger matrix (Z) protein. The 570-amino-acid N protein binds to viral RNA, forming nucleocapsids, which are the template for transcription and replication by the viral polymerase. We have previously shown that the interaction between N and Z is required for assembly of infectious virus-like particles (VLPs) (J. C. Casabona et al., J. Virol. 83:7029-7039, 2009). Here, we examine the functional organization of TCRV N protein. A series of deletions and point mutations were introduced into the N-coding sequence, and the ability of the mutants to sustain heterotypic (N-Z) or homotypic (N-N) interactions was analyzed. We found that N protein displays two functional domains. By using coimmunoprecipitation studies, VLP incorporation assays, and double immunofluorescence staining, the carboxy-terminal region of N was found to be required for N-Z interaction and also necessary for incorporation of N protein into VLPs. Moreover, further analysis of this region showed that the integrity of a putative zinc-finger motif, as well as its amino-flanking sequence (residues 461 to 489), are critical for Z binding and N incorporation into VLPs. In addition, we provide evidence of an essential role of the amino-terminal region of N protein for N-N interaction. In this regard, using reciprocal coimmunoprecipitation analysis, we identified a 28-residue region predicted to form a coiled-coil domain (residues 92 to 119) as a newly recognized molecular determinant of N homotypic interactions.
Publisher: Elsevier BV
Date: 10-2005
Publisher: American Chemical Society (ACS)
Date: 03-10-2019
Abstract: The ability of mesenchymal stem cells to sense nanoscale variations in extracellular matrix (ECM) compositions in their local microenvironment is crucial to their survival and their fate however, the underlying molecular mechanisms defining how such fates are temporally modulated remain poorly understood. In this work, we have utilized self-assembled block copolymer surfaces to present nanodomains of an adhesive peptide found in many ECM proteins at different lateral spacings (from 30 to 60 nm) and studied the temporal response (2 h to 14 days) of human mesenchymal stem cells (hMSCs) using a panel of real-time localization and activity biosensors. Our findings revealed that within the first 4 to 24 h postadhesion and spreading, hMSCs on smaller nanodomain spacings recruit more activated FAK and Src proteins to produce larger, longer-lived, and increased numbers of focal adhesions (FAs). The adhesions formed on smaller nanospacings rapidly recruit higher amounts of nonmuscle myosin IIA and vinculin and experience tension forces (by >5 pN/FA) significantly higher than those observed on larger nanodomain spacings. The transmission of higher levels of tension into the cytoskeleton at short times was accompanied by higher Rac1, cytosolic β-catenin, and nuclear localization of YAP/TAZ and RUNX2, which together biased the commitment of hMSCs to an osteogenic fate. This investigation provides mechanistic insights to confirm that smaller lateral spacings of adhesive nanodomains alter hMSC mechanosensing and biases mechanotransduction at short times
Publisher: IWA Publishing
Date: 31-10-2014
Abstract: Scour around bridge piers is one of the main causes of bridge failures and is of great importance for hydraulic engineers and scientists. Prediction of the scour depth around piers is complicated, and accurate results are rarely achieved by the existing models. Recently, data mining approaches such as artificial neural networks and fuzzy inference systems have been applied successfully to predict scour depth around hydraulic structures. In this study, an alternative robust data mining approach was used for the predictions of the scour depth around piers, and the results were compared with those of three empirical approaches. Performances of developed models were tested by experimental data sets collected in laboratory experiments and field measurements, together with existing empirical approaches. Statistical measures indicate that the proposed M5′ model provides a better prediction of scour depth than the empirical approaches.
Publisher: American Society for Cell Biology (ASCB)
Date: 2017
Abstract: Rho kinases (ROCK1 and ROCK2) function downstream of the small GTPase RhoA to drive actomyosin cytoskeletal remodeling. It has often been believed that ROCK1 and ROCK2 may be functionally redundant, as they share a highly conserved kinase domain. However, in this study, we report differential functional effects for these ROCKs at the epithelial zonula adherens (ZA). Using specific siRNA, we found that ROCK1 depletion disrupted cadherin organization at the ZA, accompanied by loss of F-actin and NMIIA, whereas ROCK2 knockdown had no significant effect. Further, ROCK1, but not ROCK2, was necessary to stabilize GTP-RhoA at the ZA, thereby sustaining junctional tension and inhibiting intraepithelial cell movement. We also found that nonmuscle myosin IIA is a major determinant of ROCK1 cortical stability. Thus, despite sharing the catalytic domain with ROCK2, ROCK1 appears to be the dominant kinase essential for junctional integrity and contractile tension at epithelial ZA.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709867.V1
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: The Company of Biologists
Date: 09-2021
DOI: 10.1242/JCS.258767
Abstract: Epithelia migrate as physically coherent populations of cells. Previous studies have revealed that mechanical stress accumulates in these cellular layers as they move. These stresses are characteristically tensile in nature and have often been inferred to arise when moving cells pull upon the cell–cell adhesions that hold them together. We now report that epithelial tension at adherens junctions between migrating cells also increases due to an increase in RhoA-mediated junctional contractility. We found that active RhoA levels were stimulated by p114 RhoGEF (also known as ARHGEF18) at the junctions between migrating MCF-7 monolayers, and this was accompanied by increased levels of actomyosin and mechanical tension. Applying a strategy to restore active RhoA specifically at adherens junctions by manipulating its scaffold, anillin, we found that this junctional RhoA signal was necessary to stabilize junctional E-cadherin (CDH1) during epithelial migration and promoted orderly collective movement. We suggest that stabilization of E-cadherin by RhoA serves to increase cell–cell adhesion to protect against the mechanical stresses of migration. This article has an associated First Person interview with the first author of the paper.
Publisher: ACM
Date: 23-09-2020
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709864
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709861
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: Elsevier BV
Date: 07-2020
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709864.V1
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854340.V1
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854328
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709867
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: American Vacuum Society
Date: 11-2022
DOI: 10.1116/6.0002034
Abstract: The ability to create complex three-dimensional cellular models that can effectively replicate the structure and function of human organs and tissues in vitro has the potential to revolutionize medicine. Such models could facilitate the interrogation of developmental and disease processes underpinning fundamental discovery science, vastly accelerate drug development and screening, or even be used to create tissues for implantation into the body. Realization of this potential, however, requires the recreation of complex biochemical, biophysical, and cellular patterns of 3D tissues and remains a key challenge in the field. Recent advances are being driven by improved knowledge of tissue morphogenesis and architecture and technological developments in bioengineering and materials science that can create the multidimensional and dynamic systems required to produce complex tissue microenvironments. In this article, we discuss challenges for in vitro models of tissues and organs and summarize the current state-of-the art in biomaterials and bioengineered systems that aim to address these challenges. This includes both top-down technologies, such as 3D photopatterning, magnetism, acoustic forces, and cell origami, as well as bottom-up patterning using 3D bioprinting, microfluidics, cell sheet technology, or composite scaffolds. We illustrate the varying ways that these can be applied to suit the needs of different tissues and applications by focussing on specific ex les of patterning the bone-tendon interface, kidney organoids, and brain cancer models. Finally, we discuss the challenges and future prospects in applying materials science and bioengineering to develop high-quality 3D tissue structures for in vitro studies.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854325
Abstract: Summary of the key interactions in the IL-3R ternary complex in the IL-3R ternary complex crystal structure.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.C.6749895.V2
Abstract: Abstract Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the in idual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. Significance: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-8-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1749 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.C.6749895.V1
Abstract: Abstract Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the in idual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. Significance: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854355
Abstract: Key interactions between distinct residues in the IL-3R ternary complex crystal structure.
Publisher: American Society for Cell Biology (ASCB)
Date: 12-2012
Abstract: The epithelial zonula adherens (ZA) is a specialized adhesive junction where actin dynamics and myosin-driven contractility coincide. The junctional cytoskeleton is enriched in myosin II, which generates contractile force to support junctional tension. It is also enriched in dynamic actin filaments, which are replenished by ongoing actin assembly. In this study we sought to pursue the relationship between actin assembly and junctional contractility. We demonstrate that WAVE2–Arp2/3 is a major nucleator of actin assembly at the ZA and likely acts in response to junctional Rac signaling. Furthermore, WAVE2–Arp2/3 is necessary for junctional integrity and contractile tension at the ZA. Maneuvers that disrupt the function of either WAVE2 or Arp2/3 reduced junctional tension and compromised the ability of cells to buffer side-to-side forces acting on the ZA. WAVE2–Arp2/3 disruption depleted junctions of both myosin IIA and IIB, suggesting that dynamic actin assembly may support junctional tension by facilitating the local recruitment of myosin.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854352
Abstract: IL3Rα P248 at the IL-3R assembly interface is critical for cell differentiation.
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1191
Publisher: Massachusetts Medical Society
Date: 27-07-2000
Publisher: American Society for Cell Biology (ASCB)
Date: 04-2016
Abstract: We used a computational approach to analyze the biomechanics of epithelial cell aggregates—islands, stripes, or entire monolayers—that combines both vertex and contact-inhibition-of-locomotion models to include cell–cell and cell–substrate adhesion. Examination of the distribution of cell protrusions (adhesion to the substrate) in the model predicted high-order profiles of cell organization that agree with those previously seen experimentally. Cells acquired an asymmetric distribution of basal protrusions, traction forces, and apical aspect ratios that decreased when moving from the edge to the island center. Our in silico analysis also showed that tension on cell–cell junctions and apical stress is not homogeneous across the island. Instead, these parameters are higher at the island center and scale up with island size, which we confirmed experimentally using laser ablation assays and immunofluorescence. Without formally being a three-dimensional model, our approach has the minimal elements necessary to reproduce the distribution of cellular forces and mechanical cross-talk, as well as the distribution of principal stress in cells within epithelial cell aggregates. By making experimentally testable predictions, our approach can aid in mechanical analysis of epithelial tissues, especially when local changes in cell–cell and/or cell–substrate adhesion drive collective cell behavior.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.C.6749895
Abstract: Abstract Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the in idual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance. Significance: Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-8-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1749 /a /i /
Publisher: Springer Science and Business Media LLC
Date: 24-02-2015
DOI: 10.1038/NCOMMS7297
Abstract: In neurosecretory cells, secretory vesicles (SVs) undergo Ca(2+)-dependent fusion with the plasma membrane to release neurotransmitters. How SVs cross the dense mesh of the cortical actin network to reach the plasma membrane remains unclear. Here we reveal that, in bovine chromaffin cells, SVs embedded in the cortical actin network undergo a highly synchronized transition towards the plasma membrane and Munc18-1-dependent docking in response to secretagogues. This movement coincides with a translocation of the cortical actin network in the same direction. Both effects are abolished by the knockdown or the pharmacological inhibition of myosin II, suggesting changes in actomyosin-generated forces across the cell cortex. Indeed, we report a reduction in cortical actin network tension elicited on secretagogue stimulation that is sensitive to myosin II inhibition. We reveal that the cortical actin network acts as a 'casting net' that undergoes activity-dependent relaxation, thereby driving tethered SVs towards the plasma membrane where they undergo Munc18-1-dependent docking.
Publisher: Rockefeller University Press
Date: 06-02-2018
DOI: 10.1084/JEM.20172222
Abstract: Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular caspase-1 activity are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate caspase-1 dimerization and autoprocessing. Previous studies with recombinant protein identified a caspase-1 tetramer composed of two p20 and two p10 subunits (p20 10) as an active species. In this study, we report that in the cell, the dominant species of active caspase-1 dimers elicited by inflammasomes are in fact full-length p46 and a transient species, p33 10. Further p33 10 autoprocessing occurs with kinetics specified by inflammasome size and cell type, and this releases p20 10 from the inflammasome, whereupon the tetramer becomes unstable in cells and protease activity is terminated. The inflammasome–caspase-1 complex thus functions as a holoenzyme that directs the location of caspase-1 activity but also incorporates an intrinsic self-limiting mechanism that ensures timely caspase-1 deactivation. This intrinsic mechanism of inflammasome signal shutdown offers a molecular basis for the transient nature, and coordinated timing, of inflammasome-dependent inflammatory responses.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854346
Abstract: The IL-3R dodecamer activates STAT1 to induce cell differentiation.
Publisher: American Society for Cell Biology (ASCB)
Date: 04-2017
Abstract: S-acylation/deacylation cycles and vesicular transport are critical for an adequate subcellular distribution of S-acylated Ras proteins. H-Ras is dually acylated on cysteines 181 and 184, but it is unknown how these residues in idually contribute to H-Ras trafficking. In this study, we characterized the acylation and deacylation rates and membrane trafficking of monoacylated H-Ras mutants to analyze their contributions to H-Ras plasma membrane and endomembrane distribution. We demonstrated that dually acylated H-Ras interacts with acyl-protein thioesterases (APTs) 1 and 2 at the plasma membrane. Moreover, single-acylation mutants of H-Ras differed not only in their subcellular distribution, where both proteins localized to different extents at both the Golgi complex and plasma membrane, but also in their deacylation rates, which we showed to be due to different sensitivities to APT1 and APT2. Fluorescence photobleaching and photoactivation experiments also revealed that 1) although S-acylated, single-acylation mutants are incorporated with different efficiencies into Golgi complex to plasma membrane vesicular carriers, and 2) the different deacylation rates of single-acylated H-Ras influence differentially its overall exchange between different compartments by nonvesicular transport. Taken together, our results show that in idual S-acylation sites provide singular information about H-Ras subcellular distribution that is required for GTPase signaling.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854340
Abstract: Enrichment of the IL-3R hexamer versus dodecamer gene signature in primitive normal and leukemic stem cells.
Publisher: American Association for Cancer Research (AACR)
Date: 19-07-2023
DOI: 10.1158/2159-8290.23709852.V1
Abstract: Data collection and refinement statistics for the IL-3R ternary complex crystal structure.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.CELREP.2017.02.078
Abstract: Formins are a erse class of actin regulators that influence filament dynamics and organization. Several formins have been identified at epithelial adherens junctions, but their functional impact remains incompletely understood. Here, we tested the hypothesis that formins might affect epithelial interactions through junctional contractility. We focused on mDia1, which was recruited to the zonula adherens (ZA) of established Caco-2 monolayers in response to E-cadherin and RhoA. mDia1 was necessary for contractility at the ZA, measured by assays that include a FRET-based sensor that reports molecular-level tension across αE-catenin. This reflected a role in reorganizing F-actin networks to form stable bundles that resisted myosin-induced stress. Finally, we found that the impact of mDia1 ramified beyond adherens junctions to stabilize tight junctions and maintain the epithelial permeability barrier. Therefore, control of tissue barrier function constitutes a pathway for cadherin-based contractility to contribute to the physiology of established epithelia.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.DIFF.2013.01.002
Abstract: In simple polarized epithelial cells, the Rho GTPase commonly localizes to E-cadherin-based cell-cell junctions, such as the zonula adherens (ZA), where it regulates the actomyosin cytoskeleton to support junctional integrity and tension. An important question is how E-cadherin contributes to Rho signaling, notably whether junctional Rho may depend on cadherin adhesion. We sought to investigate this by assessing Rho localization and activity in epithelial monolayers depleted of E-cadherin by RNAi. We report that E-cadherin depletion reduced both Rho and Rho-GTP at the ZA, an effect that was rescued by expressing a RNAi-resistant full-length E-cadherin transgene. This impact on Rho signaling was accompanied by reduced junctional localization of the Rho GEF ECT2 and the centralspindlin complex that recruits ECT2. Further, the Rho signaling pathway contributes to the selective stabilization of E-cadherin molecules in the apical zone of the cells compared with E-cadherin at the lateral surface, thereby creating a more defined and restricted pool of E-cadherin that forms the ZA. Thus, E-cadherin and Rho signaling cooperate to ensure proper ZA architecture and function.
Publisher: American Society for Microbiology
Date: 15-07-2009
DOI: 10.1128/JVI.00329-09
Abstract: Arenaviruses, such as Tacaribe virus (TacV) and its closely related pathogenic Junin virus (JunV), are enveloped viruses with a bipartite negative-sense RNA genome that encodes the nucleocapsid protein (N), the precursor of the envelope glycoprotein complex (GP), the polymerase (L), and a RING finger protein (Z), which is the driving force of arenavirus budding. We have established a plasmid-based system which allowed the successful packaging of TacV-like nucleocapsids along with Z and GP of JunV into infectious virus-like particles (VLPs). By coexpressing different combinations of the system components, followed by biochemical analysis of the VLPs, the requirements for the assembly of both N and GP into particles were defined. We found that coexpression of N with Z protein in the absence of minigenome and other viral proteins was sufficient to recruit N within lipid-enveloped Z-containing VLPs. In addition, whereas GP was not required for the incorporation of N, coexpression of N substantially enhanced the ratio of GP to Z into VLPs. Disruption of the RING structure or mutation of residue L79 to alanine within Z protein, although it had no effect on Z self-budding, severely impaired VLP infectivity. These mutations drastically altered intracellular Z-N interactions and the incorporation of both N and GP into VLPs. Our results support the conclusion that the interaction between Z and N is required for assembly of both the nucleocapsids and the glycoproteins into infectious arenavirus budding particles.
Publisher: Portland Press Ltd.
Date: 15-07-2009
DOI: 10.1042/BJ20090484
Abstract: GAP-43 (growth-associated protein-43) is a dually palmitoylated protein, at cysteine residues at positions 3 and 4, that mostly localizes in plasma membrane both in neural and non-neural cells. In the present study, we have examined membrane association, subcellular distribution and intracellular trafficking of GAP-43 in CHO (Chinese hamster ovary)-K1 cells. Using biochemical assays and confocal and video microscopy in living cells we demonstrated that GAP-43, at steady state, localizes at the recycling endosome in addition to the cytoplasmic leaflet of the plasma membrane and TGN (trans-Golgi network). Pharmacological inhibition of newly synthesized GAP-43 acylation or double mutation of Cys3 and Cys4 of GAP-43 completely disrupts TGN, plasma membrane and recycling endosome association. A combination of selective photobleaching techniques and time-lapse fluorescence microscopy reveals a dynamic association of GAP-43 with recycling endosomes in equilibrium with the plasma membrane pool. Newly synthesized GAP-43 is found mainly associated with the TGN, but not with the pericentriolar recycling endosome, and traffics to the plasma membrane by a brefeldin A-insensitive pathway. Impairment of plasma membrane fusion and internalization by treatment with tannic acid does affect the trafficking of GAP-43 from plasma membrane to recycling endosomes which reveals a vesicle-mediated retrograde trafficking of GAP-43. Here, we also show that internalization of GAP-43 is regulated by Arf (ADP-ribosylation factor) 6. Taken together, these results demonstrate that dual acylation is required for sorting of peripheral membrane-associated GAP-43 to recycling endosome via an Arf6-associated endocytic vesicular pathway.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.DEVCEL.2015.09.012
Abstract: This Perspective considers how classical cadherin cell-cell adhesion receptors are organized at the nanoscale to generate lateral clusters. Recent advances in optical microscopy reveal that clustering constitutes a general feature of cadherin organization, but one that takes erse forms. Here we consider the molecular mechanisms responsible for cadherin clustering and their functional implications. We frame our discussion in light of what is known about how nanoscale organization is conferred upon the plasma membrane, through protein-protein interactions, regulation of the cortical actin cytoskeleton, and the lipid environment of the membrane.
Publisher: IOP Publishing
Date: 25-01-2018
Abstract: Epithelial tissues form physically integrated barriers against the external environment protecting organs from infection and invasion. Within each tissue, epithelial cells respond to different challenges that can potentially compromise tissue integrity. In particular, cells collectively respond to injuries by reorganizing their cell-cell junctions and migrating directionally towards the sites of damage. Notwithstanding, the mechanisms that drive collective responses in epithelial aggregates remain poorly understood. In this work, we develop a minimal mechanistic model that is able to capture the essential features of epithelial collective responses to injuries. We show that a model that integrates the mechanics of cells at the cell-cell and cell-substrate interfaces as well as contact inhibition of locomotion (CIL) correctly predicts two key properties of epithelial response to injury as: (1) local relaxation of the tissue and (2) collective reorganization involving the extension of cryptic lamellipodia that extend, on average, up to 3 cell diameters from the site of injury and morphometric changes in the basal regions. Our model also suggests that active responses (like the actomyosin purse string and softening of cell-cell junctions) are needed to drive morphometric changes in the apical region. Therefore, our results highlight the importance of the crosstalk between junctional biomechanics, cell substrate adhesion, and CIL, as well as active responses, in guiding the collective rearrangements that are required to preserve the epithelial barrier in response to injury.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.JENVMAN.2016.06.021
Abstract: Nesting cavities are often a limited resource that multiple species use. There is an ongoing discussion on whether invasive cavity nesting birds restrict the availability of this key limited resource. While the answer to this question has important conservation implications, little experimental work has been done to examine it. Here, we aimed to experimentally test whether alien cavity nesting birds affect the occupancy of cavities and the resulting breeding success of native cavity breeders in a large urban park located in Tel Aviv, Israel. Over three breeding seasons, we manipulated the entry size of nest boxes and compared the occupancy and breeding success of birds in nest boxes of two treatments. These included nest boxes with large-entrance and small-entrance holes. The large-entrance holes allowed access for both the native and invasive birds (the two main aliens in the park are the common mynas and rose-ringed parakeets). The smaller-entrance boxes, on the other hand, allowed only the smaller sized native cavity breeders (great tits and house sparrows) to enter the boxes but prevented the alien species from entering. We found that the large-entrance nest boxes were occupied by five different bird species, comprising three natives (great tit, house sparrow, Scops owl) and two invasive species (common myna, rose-ringed parakeet) while the small-entrance boxes were only occupied by the two native species. The alien common mynas and rose-ringed parakeets occupied 77.5% of the large-entrance nest boxes whereas native species, mainly great tits, occupied less than 9% of the large-entrance boxes and 36.5% of the small-entrance boxes. When examining the occupancy of those cavities that were not occupied by the aliens, natives occupied both the small and large-entrance nest boxes equally. Three quarters (78%) of the great tits breeding in the large-entrance boxes were usurped by common mynas during the breeding season and as a result breeding success was significantly lower for great tits breeding in the large-entrance boxes compared with the small-entrance boxes. The results of this study suggests that the invasive alien species can reduce the breeding potential of native cavity breeders both by exploiting the limited breeding resource (nest cavities) and by directly usurping cavities already occupied by the native species. Since the majority of large-entrance nest boxes were occupied by the larger alien birds, less native species bred in the limited number of unoccupied large-entrance nest boxes because of exploitation competition. We propose that for management purposes, nest-box programs that alter the entrance size of available natural cavities may be a practical approach, reducing the competition between native cavity breeders and alien invasive birds, and especially benefiting the smaller native cavity breeders.
Publisher: Public Library of Science (PLoS)
Date: 08-03-2017
Publisher: Wiley
Date: 05-04-2007
DOI: 10.1111/J.1742-4658.2007.05758.X
Abstract: K-Ras is a small G-protein, localized mainly at the inner leaflet of the plasma membrane. The membrane targeting signal of this protein consists of a polybasic C-terminal sequence of six contiguous lysines and a farnesylated cysteine. Results from biophysical studies in model systems suggest that hydrophobic and electrostatic interactions are responsible for the membrane binding properties of K-Ras. To test this hypothesis in a cellular system, we first evaluated in vitro the effect of electrolytes on K-Ras membrane binding properties. Results demonstrated the electrical and reversible nature of K-Ras binding to anionic lipids in membranes. We next investigated membrane binding and subcellular distribution of K-Ras after disruption of the electrical properties of the outer and inner leaflets of plasma membrane and ionic gradients through it. Removal of sialic acid from the outer plasma membrane caused a redistribution of K-Ras to recycling endosomes. Inhibition of polyphosphoinositide synthesis at the plasma membrane, by depletion of cellular ATP, resulted in a similar subcellular redistribution of K-Ras. Treatment of cells with ionophores that modify transmembrane potential caused a redistribution of K-Ras to cytoplasm and endomembranes. Ca2+ ionophores, compared to K+ ionophores, caused a much broader redistribution of K-Ras to endomembranes. Taken together, these results reveal the dynamic nature of interactions between K-Ras and cellular membranes, and indicate that subcellular distribution of K-Ras is driven by electrostatic interaction of the polybasic region of the protein with negatively charged membranes.
Publisher: American Association for Cancer Research (AACR)
Date: 04-08-2023
DOI: 10.1158/2159-8290.23854331.V1
Abstract: Increasing IL3Rα/βc ratios and enforced hexamer signaling lead to reduced differentiation in in vivo engraftments.
Publisher: Bio-Protocol, LLC
Date: 2021
Publisher: Bio-Protocol, LLC
Date: 2016
Publisher: Elsevier BV
Date: 03-2014
Publisher: AIP Publishing
Date: 15-11-2018
DOI: 10.1063/1.5045124
Abstract: Stem cell-derived brain organoids provide a powerful platform for systematic studies of tissue functional architecture and the development of personalized therapies. Here, we review key advances at the interface of soft matter and stem cell biology on synthetic alternatives to extracellular matrices. We emphasize recent biomaterial-based strategies that have been proven advantageous towards optimizing organoid growth and controlling the geometrical, biomechanical, and biochemical properties of the organoid's three-dimensional environment. We highlight systems that have the potential to increase the translational value of region-specific brain organoid models suitable for different types of manipulations and high-throughput applications.
Publisher: Springer Science and Business Media LLC
Date: 14-09-2015
DOI: 10.1038/NCB3239
Abstract: Actomyosin at the epithelial zonula adherens (ZA) generates junctional tension for tissue integrity and morphogenesis. This requires the RhoA GTPase, which establishes a strikingly stable active zone at the ZA. Mechanisms must then exist to confer robustness on junctional RhoA signalling at the population level. We now identify a feedback network that generates a stable mesoscopic RhoA zone out of dynamic elements. The key is scaffolding of ROCK1 to the ZA by myosin II. ROCK1 protects junctional RhoA by phosphorylating Rnd3 to prevent the cortical recruitment of the Rho suppressor, p190B RhoGAP. Combining predictive modelling and experimentation, we show that this network constitutes a bistable dynamical system that is realized at the population level of the ZA. Thus, stability of the RhoA zone is an emergent consequence of the network of interactions that allow myosin II to feedback to RhoA.
Location: Australia
Location: Argentina
Start Date: 2019
End Date: 2019
Funder: University of South Australia
View Funded ActivityStart Date: 2018
End Date: 2018
Funder: Cancer Council South Australia
View Funded ActivityStart Date: 2017
End Date: 12-2020
Amount: $680,524.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2021
End Date: 06-2022
Amount: $909,079.00
Funder: Australian Research Council
View Funded Activity