ORCID Profile
0000-0002-5253-4747
Current Organisation
University of Sydney
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Applied Statistics | Cellular Interactions (incl. Adhesion, Matrix, Cell Wall) | Statistics | Bioinformatics |
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Mathematical Sciences | Expanding Knowledge in the Medical and Health Sciences
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488953.V1
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Apollo - University of Cambridge Repository
Date: 2022
DOI: 10.17863/CAM.80476
Publisher: Springer Science and Business Media LLC
Date: 13-07-2020
Publisher: Public Library of Science (PLoS)
Date: 19-04-2021
DOI: 10.1371/JOURNAL.PPAT.1009522
Abstract: Although HIV infection inhibits interferon responses in its target cells in vitro , interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, pDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.
Publisher: Springer Science and Business Media LLC
Date: 12-04-2021
DOI: 10.1038/S41467-021-22375-X
Abstract: Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a erse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells CD14 + CD1c + monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).
Publisher: Springer Science and Business Media LLC
Date: 30-03-2021
Publisher: Cold Spring Harbor Laboratory
Date: 20-07-2022
DOI: 10.1101/2022.07.19.500604
Abstract: The spatial architecture of the tumour microenvironment and phenotypic heterogeneity of tumour cells have been shown to be associated with cancer prognosis and clinical outcomes, including survival. Recent advances in highly multiplexed imaging, including imaging mass cytometry (IMC), capture spatially resolved, high-dimensional maps that quantify dozens of disease-relevant biomarkers at single-cell resolution, that contain potential to inform patient-specific prognosis. However, existing automated methods for predicting survival typically do not leverage spatial phenotype information captured at the single-cell level, and current methods tend to focus on a single modality, such as patient variables (PVs). There is no end-to-end method designed to leverage the rich information in whole IMC images and all marker channels, and aggregate this information with PVs in a complementary manner to predict survival with enhanced accuracy. We introduce a deep multimodal graph-based network (DMGN) that integrates entire IMC images and multiple PVs for end-to-end survival prediction of breast cancer. We propose a multimodal graph-based module that considers relationships between spatial phenotype information in all image regions and all PVs, and scales each region–PV pair based on its relevance to survival. We propose another module to automatically generate embeddings specialised for each PV to enhance multimodal aggregation. We show that our modules are consistently effective at improving survival prediction performance using two public datasets, and that DMGN can be applied to an independent validation dataset across the same antigens but different antibody clones. Our DMGN outperformed state-of-the-art methods at survival prediction.
Publisher: Oxford University Press (OUP)
Date: 09-10-2023
Publisher: Rockefeller University Press
Date: 15-03-2023
DOI: 10.1084/JEM.20221392
Abstract: The hallmark of tuberculosis (TB) is the formation of immune cell-enriched aggregates called granulomas. While granulomas are pathologically erse, their tissue-wide heterogeneity has not been spatially resolved at the single-cell level in human tissues. By spatially mapping in idual immune cells in every lesion across entire tissue sections, we report that in addition to necrotizing granulomas, the human TB lung contains abundant non-necrotizing leukocyte aggregates surrounding areas of necrotizing tissue. These cellular lesions were more erse in composition than necrotizing lesions and could be stratified into four general classes based on cellular composition and spatial distribution of B cells and macrophages. The cellular composition of non-necrotizing structures also correlates with their proximity to necrotizing lesions, indicating these are foci of distinct immune reactions adjacent to necrotizing granulomas. Together, we show that during TB, diseased lung tissue develops a histopathological superstructure comprising at least four different types of non-necrotizing cellular aggregates organized as satellites of necrotizing granulomas.
Publisher: BMJ
Date: 10-2023
Publisher: Elsevier BV
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532844.V1
Abstract: AbstractPurpose: The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown. Experimental Design: We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior. Results: Nonprogressing primary HNcSCC were characterized by higher CD8 sup + /sup and CD4 sup + /sup T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell–enriched tumor regions associated with primary nonprogressing tumors. Conclusions: Effective responses from both CD8 sup + /sup and CD4 sup + /sup T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC. /
Publisher: Wiley
Date: 23-10-2021
DOI: 10.1111/ALL.14422
Abstract: Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
Publisher: BMJ
Date: 15-11-2017
Abstract: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.
Publisher: Oxford University Press (OUP)
Date: 09-2019
DOI: 10.1093/GIGASCIENCE/GIZ106
Abstract: Single-cell RNA-seq (scRNA-seq) profiling has revealed remarkable variation in transcription, suggesting that expression of many genes at the single-cell level is intrinsically stochastic and noisy. Yet, on the cell population level, a subset of genes traditionally referred to as housekeeping genes (HKGs) are found to be stably expressed in different cell and tissue types. It is therefore critical to question whether stably expressed genes (SEGs) can be identified on the single-cell level, and if so, how can their expression stability be assessed? We have previously proposed a computational framework for ranking expression stability of genes in single cells for scRNA-seq data normalization and integration. In this study, we perform detailed evaluation and characterization of SEGs derived from this framework. Here, we show that gene expression stability indices derived from the early human and mouse development scRNA-seq datasets and the "Mouse Atlas" dataset are reproducible and conserved across species. We demonstrate that SEGs identified from single cells based on their stability indices are considerably more stable than HKGs defined previously from cell populations across erse biological systems. Our analyses indicate that SEGs are inherently more stable at the single-cell level and their characteristics reminiscent of HKGs, suggesting their potential role in sustaining essential functions in in idual cells. SEGs identified in this study have immediate utility both for understanding variation and stability of single-cell transcriptomes and for practical applications such as scRNA-seq data normalization. Our framework for calculating gene stability index, "scSEGIndex," is incorporated into the scMerge Bioconductor R package (sydneybiox.github.io/scMerge/reference/scSEGIndex.html) and can be used for identifying genes with stable expression in scRNA-seq datasets.
Publisher: Springer Science and Business Media LLC
Date: 14-01-2021
DOI: 10.1038/S41398-020-01175-9
Abstract: Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer’s disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs—modules 113 and 114—relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes ( ACADVL, TRABD , and VASP ) encode proteins that are upregulated in activated microglia in AD.
Publisher: Frontiers Media SA
Date: 05-02-2019
Publisher: Cold Spring Harbor Laboratory
Date: 17-12-2016
DOI: 10.1101/095067
Abstract: Given multiple studies of brain microRNA (miRNA) in relation to Alzheimer’s disease (AD) with few consistent results and the heterogeneity of this disease, the objective of this study was to explore their mechanism by evaluating their relation to different elements of Alzheimer’s disease pathology, confounding factors and mRNA expression data from the same subjects in the same brain region. We report analyses of expression profiling of miRNA (n=700 subjects) and lincRNA (n=540 subjects) from the dorsolateral prefrontal cortex of in iduals participating in two longitudinal cohort studies of aging. Evaluating well-established (miR-132, miR-129), we confirm their association with pathologic AD in our dataset, and then characterize their in disease role in terms of neuritic β-amyloid plaques and neurofibrillary tangle pathology. Additionally, we identify one new miRNA (miR-99) and four lincRNA that are associated with these traits. Many other previously reported associations of microRNA with AD are associated with the confounders quantified in our longitudinal cohort. Finally, by performing analyses integrating both miRNA and RNA sequence data from the same in iduals (525 s les), we characterize the impact of AD associated miRNA on human brain expression: we show that the effects of miR-132 and miR-129-5b converge on certain genes such as EP300 and find a role for miR200 and its target genes in AD using an integrated miRNA/mRNA analysis. Overall, miRNAs play a modest role in human AD, but we observe robust evidence that a small number of miRNAs are responsible for specific alterations in the cortical transcriptome that are associated with AD.
Publisher: Oxford University Press (OUP)
Date: 15-09-2021
DOI: 10.1093/BIOINFORMATICS/BTAA780
Abstract: Autofluorescence is a long-standing problem that has hindered the analysis of images of tissues acquired by fluorescence microscopy. Current approaches to mitigate autofluorescence in tissue are lab-based and involve either chemical treatment of sections or specialized instrumentation and software to ‘unmix’ autofluorescent signals. Importantly, these approaches are pre-emptive and there are currently no methods to deal with autofluorescence in acquired fluorescence microscopy images. To address this, we developed Autofluorescence Identifier (AFid). AFid identifies autofluorescent pixels as discrete objects in multi-channel images post-acquisition. These objects can then be tagged for exclusion from downstream analysis. We validated AFid using images of FFPE human colorectal tissue stained for common immune markers. Further, we demonstrate its utility for image analysis where its implementation allows the accurate measurement of HIV–Dendritic cell interactions in a colorectal explant model of HIV transmission. Therefore, AFid represents a major leap forward in the extraction of useful data from images plagued by autofluorescence by offering an approach that is easily incorporated into existing workflows and that can be used with various s les, staining panels and image acquisition methods. We have implemented AFid in ImageJ, Matlab and R to accommodate the erse image analysis community. AFid software is available at ellispatrick.github.io/AFid. Supplementary data are available at Bioinformatics online.
Publisher: Cold Spring Harbor Laboratory
Date: 22-01-2022
DOI: 10.1101/2022.01.20.476845
Abstract: Recent advances in single-cell technologies enable scientists to measure molecular data at high-resolutions and hold the promise to substantially improve clinical outcomes through personalised medicine. However, due to a lack of tools specifically designed to represent each s le (e.g. patient) from the collection of cells sequenced, disease outcome prediction on the s le level remains a challenging task. Here, we present scFeatures, a tool that creates interpretable molecular representation of single-cell and spatial data using 17 types of features motivated by current literature. The feature types span across six distinct categories including cell type proportions, cell type specific gene expressions, cell type specific pathway scores, cell type specific cell–cell interaction scores, overall aggregated gene expressions and spatial metrics. By generating molecular representation using scFeatures for single-cell RNA-seq, spatial proteomic and spatial transcriptomic data, we demonstrate that different types of features are important for predicting different disease outcomes in different datasets and the downstream analysis of features uncover novel biological discoveries.
Publisher: Cold Spring Harbor Laboratory
Date: 09-12-2020
DOI: 10.1101/2020.12.09.415927
Abstract: There is no consensus methodology that can account for the variation in omics signatures when they are acquired across different platforms and times. This poses a significant barrier to the implementation of valuable biomarkers into clinical practice. We present a novel procedure (Cross-Platform Omics Prediction) that accounts for these variations and demonstrate its utility in three risk models for different diseases that is suitable for prospective and multi-centre clinical implementation.
Publisher: Cold Spring Harbor Laboratory
Date: 07-06-2021
DOI: 10.1101/2021.06.07.447307
Abstract: High parameter histological techniques have allowed for the identification of a variety of distinct cell types within an image, providing a comprehensive overview of the tissue environment. This allows the complex cellular architecture and environment of diseased tissue to be explored. While spatial analysis techniques have revealed how cell-cell interactions are important within the disease pathology, there remains a gap in exploring changes in these interactions within the disease process. Specifically, there are currently no established methods for performing inference on cell localisation changes across images, hindering an understanding of how cellular environments change with a disease pathology. We have developed the spicyR R package to perform inference on changes in the spatial localisation of cell types across groups of images. Application to simulated data demonstrates a high sensitivity and specificity. We demonstrate the utility of spicyR by applying it to a type 1 diabetes imaging mass cytometry dataset, revealing changes in cellular associations that were relevant to the disease progression. Ultimately, spicyR allows changes in cellular environments to be explored under different pathologies or disease states. R package freely available at ackages/release/bioc/html/spicyR.html and shiny app implementation at shiny.maths.usyd.edu.au/spicyR/ ellis.patrick@sydney.edu.au Code for reproducing key figures available at ickcee/spicyRPaper .
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488956.V1
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Public Library of Science (PLoS)
Date: 22-05-2019
Publisher: Cold Spring Harbor Laboratory
Date: 17-08-2021
DOI: 10.1101/2021.08.16.456469
Abstract: Highly multiplexed in situ imaging cytometry assays have made it possible to study the spatial organisation of numerous cell types simultaneously. We have addressed the challenge of quantifying complex multi-cellular relationships by proposing a statistical method which clusters local indicators of spatial association. Our approach successfully identifies distinct tissue architectures in datasets generated from three state-of-the-art high-parameter assays demonstrating its value in summarising the information-rich data generated from these technologies.
Publisher: Elsevier BV
Date: 05-2023
Publisher: Springer Science and Business Media LLC
Date: 04-09-2017
DOI: 10.1038/NN.4632
Publisher: Cold Spring Harbor Laboratory
Date: 19-04-2022
DOI: 10.1101/2022.04.19.488697
Abstract: The tumour immune microenvironment impacts the biological behaviour of the tumour but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown. We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasised using multi-parameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumour behaviour. Non-progressing primary HNcSCC were characterised by higher CD8+ and CD4+ T cell responses, including numerically increased Regulatory T cells. By contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterised by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with non-progressing primary tumours that were distinct in primary tumours of disease progressing patients. Cellular regional analysis of the tumour microenvironment also shows squamous cell-enriched tumour regions associated with primary non-progressing tumours. Effective responses from both CD8+ and CD4+ T cells in the tumour microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumours dictate progression and disease outcomes in HNcSCC. The ability to predict metastatic tumour progression at the time of initial diagnosis of primary HNcSCC could tailor personalised medical care including disease surveillance strategies and identifying patients who will benefit most from adjuvant therapy. The immune landscape of high-risk cutaneous squamous cell carcinoma differs in tumours that never progress compared to those that progress to metastasis.
Publisher: F1000 Research Ltd
Date: 10-03-2023
DOI: 10.12688/F1000RESEARCH.130623.1
Abstract: Background : Globally, scientists now have the ability to generate a vast amount of high throughput biomedical data that carry critical information for important clinical and public health applications. This data revolution in biology is now creating a plethora of new single-cell datasets. Concurrently, there have been significant methodological advances in single-cell research. Integrating these two resources, creating tailor-made, efficient, and purpose-specific data analysis approaches can assist in accelerating scientific discovery. Methods: We developed a series of living workshops for building data stories, using Single-cell data integrative analysis (scdney). scdney is a wrapper package with a collection of single-cell analysis R packages incorporating data integration, cell type annotation, higher order testing and more. Results: Here, we illustrate two specific workshops. The first workshop examines how to characterise the identity and/or state of cells and the relationship between them, known as phenotyping. The second workshop focuses on extracting higher-order features from cells to predict disease progression. Conclusions: Through these workshops, we not only showcase current solutions, but also highlight critical thinking points. In particular, we highlight the Thinking Process Template that provides a structured framework for the decision-making process behind such single-cell analyses. Furthermore, our workshop will incorporate dynamic contributions from the community in a collaborative learning approach, thus the term ‘living’.
Publisher: Impact Journals, LLC
Date: 11-08-2016
Publisher: Springer Science and Business Media LLC
Date: 07-02-2018
DOI: 10.1038/S41467-018-02926-5
Abstract: With a rapidly aging global human population, finding a cure for late onset neurodegenerative diseases has become an urgent enterprise. However, these efforts are hindered by the lack of understanding of what constitutes the phenotype of aged human microglia—the cell type that has been strongly implicated by genetic studies in the pathogenesis of age-related neurodegenerative disease. Here, we establish the set of genes that is preferentially expressed by microglia in the aged human brain. This HuMi_Aged gene set captures a unique phenotype, which we confirm at the protein level. Furthermore, we find this gene set to be enriched in susceptibility genes for Alzheimer’s disease and multiple sclerosis, to be increased with advancing age, and to be reduced by the protective APOEε2 haplotype . APOEε4 has no effect. These findings confirm the existence of an aging-related microglial phenotype in the aged human brain and its involvement in the pathological processes associated with brain aging.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488956
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Oxford University Press (OUP)
Date: 30-08-2022
DOI: 10.1093/BIOINFORMATICS/BTAC590
Abstract: With the recent surge of large-cohort scale single cell research, it is of critical importance that analytical methods can fully utilize the comprehensive characterization of cellular systems that single cell technologies produce to provide insights into s les from in iduals. Currently, there is little consensus on the best ways to compress information from the complex data structures of these technologies to summary statistics that represent each s le (e.g. in iduals). Here, we present scFeatures, an approach that creates interpretable cellular and molecular representations of single-cell and spatial data at the s le level. We demonstrate that summarizing a broad collection of features at the s le level is both important for understanding underlying disease mechanisms in different experimental studies and for accurately classifying disease status of in iduals. scFeatures is publicly available as an R package at github.com/SydneyBioX/scFeatures. All data used in this study are publicly available with accession ID reported in the Section 2. Supplementary data are available at Bioinformatics online.
Publisher: Springer Science and Business Media LLC
Date: 03-2021
DOI: 10.1038/S41598-021-83872-Z
Abstract: Tau pathology in Alzheimer’s disease (AD) spreads in a predictable pattern that corresponds with disease symptoms and severity. At post-mortem there are cortical regions that range from mildly to severely affected by tau pathology and neuronal loss. A comparison of the molecular signatures of these differentially affected areas within cases and between cases and controls may allow the temporal modelling of disease progression. Here we used RNA sequencing to explore differential gene expression in the mildly affected primary visual cortex and moderately affected precuneus of ten age-, gender- and RNA quality-matched post-mortem brains from AD patients and healthy controls. The two regions in AD cases had similar transcriptomic signatures but there were broader abnormalities in the precuneus consistent with the greater tau load. Both regions were characterised by upregulation of immune-related genes such as those encoding triggering receptor expressed on myeloid cells 2 and membrane spanning 4-domains A6A and milder changes in insulin/IGF1 signalling. The precuneus in AD was also characterised by changes in vesicle secretion and downregulation of the interneuronal subtype marker, somatostatin. The ‘early’ AD transcriptome is characterised by perturbations in synaptic vesicle secretion on a background of neuroimmune dysfunction. In particular, the synaptic deficits that characterise AD may begin with the somatostatin ision of inhibitory neurotransmission.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2019
DOI: 10.1038/S41467-019-10697-W
Abstract: Langerhans cells (LC) are thought to be the only mononuclear phagocyte population in the epidermis where they detect pathogens. Here, we show that CD11c + dendritic cells (DCs) are also present. These cells are transcriptionally similar to dermal cDC2 but are more efficient antigen-presenting cells. Compared to LCs, epidermal CD11c + DCs are enriched in anogenital tissues where they preferentially interact with HIV, express the higher levels of HIV entry receptor CCR5, support the higher levels of HIV uptake and replication and are more efficient at transmitting the virus to CD4 T cells. Importantly, these findings are observed using both a lab-adapted and transmitted/founder strain of HIV. We also describe a CD33 low cell population, which is transcriptionally similar to LCs but does not appear to function as antigen-presenting cells or acts as HIV target cells. Our findings reveal that epidermal DCs in anogenital tissues potentially play a key role in sexual transmission of HIV.
Publisher: Springer Science and Business Media LLC
Date: 29-01-2013
Abstract: RNA-Seq has the potential to answer many erse and interesting questions about the inner workings of cells. Estimating changes in the overall transcription of a gene is not straightforward. Changes in overall gene transcription can easily be confounded with changes in exon usage which alter the lengths of transcripts produced by a gene. Measuring the expression of constitutive exons— exons which are consistently conserved after splicing— offers an unbiased estimation of the overall transcription of a gene. We propose a clustering-based method, exClust, for estimating the exons that are consistently conserved after splicing in a given data set. These are considered as the exons which are “constitutive” in this data. The method utilises information from both annotation and the dataset of interest. The method is implemented in an openly available R function package, sydSeq. When used on two real datasets exClust includes more than three times as many reads as the standard UI method, and improves concordance with qRT-PCR data. When compared to other methods, our method is shown to produce robust estimates of overall gene transcription.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488959
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 16-01-2014
DOI: 10.1038/GENE.2013.66
Abstract: The IFNL3 genotype predicts the clearance of hepatitis C virus (HCV), spontaneously and with interferon (IFN)-based therapy. The responder genotype is associated with lower expression of interferon stimulated genes (ISGs) in liver biopsies from chronic hepatitis C patients. However, ISGs represent many interacting molecular pathways, and we hypothesised that the IFNL3 genotype may produce a characteristic pattern of ISG expression explaining the effect of genotype on viral clearance. For the first time, we identified an association between a cluster of ISGs, the metallothioneins (MTs) and IFNL3 genotype. Importantly, MTs were significantly upregulated (in contrast to most other ISGs) in HCV-infected liver biopsies of rs8099917 responders. An association between lower fibrosis scores and higher MT levels was demonstrated underlying clinical relevance of this association. As expected, overall ISGs were significantly downregulated in biopsies from subjects with the IFNL3 rs8099917 responder genotype (P=2.38 × 10(-7)). Peripheral blood analysis revealed paradoxical and not previously described findings with upregulation of ISGs seen in the responder genotype (P=1.00 × 10(-4)). The higher MT expression in responders may contribute to their improved viral clearance and MT-inducing agents may be useful adjuncts to therapy for HCV. Upregulation of immune cell ISGs in responders may also contribute to the IFNL3 genotype effect.
Publisher: Oxford University Press (OUP)
Date: 24-10-2014
DOI: 10.1093/BIOINFORMATICS/BTT616
Abstract: Motivation: With the advancement of high-throughput techniques, large-scale profiling of biological systems with multiple experimental perturbations is becoming more prevalent. Pathway analysis incorporates prior biological knowledge to analyze genes roteins in groups in a biological context. However, the hypotheses under investigation are often confined to a 1D space (i.e. up, down, either or mixed regulation). Here, we develop direction pathway analysis (DPA), which can be applied to test hypothesis in a high-dimensional space for identifying pathways that display distinct responses across multiple perturbations. Results: Our DPA approach allows for the identification of pathways that display distinct responses across multiple perturbations. To demonstrate the utility and effectiveness, we evaluated DPA under various simulated scenarios and applied it to study insulin action in adipocytes. A major action of insulin in adipocytes is to regulate the movement of proteins from the interior to the cell surface membrane. Quantitative mass spectrometry-based proteomics was used to study this process on a large-scale. The combined dataset comprises four separate treatments. By applying DPA, we identified that several insulin responsive pathways in the plasma membrane trafficking are only partially dependent on the insulin-regulated kinase Akt. We subsequently validated our findings through targeted analysis of key proteins from these pathways using immunoblotting and live cell microscopy. Our results demonstrate that DPA can be applied to dissect pathway networks testing erse hypotheses and integrating multiple experimental perturbations. Availability and implementation: The R package ‘directPA’ is distributed from CRAN under GNU General Public License (GPL)-3 and can be downloaded from: eb ackages/directPA/index.html Contact: jean.yang@sydney.edu.au Supplementary Information: Supplementary data are available at Bioinformatics online.
Publisher: SAGE Publications
Date: 23-12-2014
Abstract: Models of connected speech production in Mandarin Chinese must specify how lexical tone, speech segments, and phrase-level prosody are integrated in speech production. This study used tongue twisters to test predictions of the two different models of word form encoding. Tongue twisters were constructed from 5 sets of characters that rotated pairs of initial segments or pairs of tones, or both, across format (ABAB, ABBA), and across position of the characters in four-character tongue twister strings. Fifty two native Mandarin Chinese speakers read aloud 120 tongue twisters, repeating each one six times in a row. They made a total of 3503 (2.34%) segment errors and 1372 (.92%) tone errors. Segment errors occurred on the onsets of the first and third characters in the ABBA but not ABAB segment-alternating tongue twisters, and on the onsets of the second and fourth characters of the tone-alternating tongue twisters. Tone errors were highest on the third and fourth characters in the tone-alternating tongue twisters. The pattern of tone errors is consistent with the claim that tone is associated to a metrical frame prior to segment encoding, while the format by position interaction found for the segment-alternating tongue twisters suggest articulatory gestures oscillate in segment production as proposed by gestural phonology.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532844
Abstract: AbstractPurpose: The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown. Experimental Design: We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior. Results: Nonprogressing primary HNcSCC were characterized by higher CD8 sup + /sup and CD4 sup + /sup T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell–enriched tumor regions associated with primary nonprogressing tumors. Conclusions: Effective responses from both CD8 sup + /sup and CD4 sup + /sup T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC. /
Publisher: Springer Science and Business Media LLC
Date: 17-07-2023
DOI: 10.1038/S41467-023-39923-2
Abstract: The recent emergence of multi-s le multi-condition single-cell multi-cohort studies allows researchers to investigate different cell states. The effective integration of multiple large-cohort studies promises biological insights into cells under different conditions that in idual studies cannot provide. Here, we present scMerge2, a scalable algorithm that allows data integration of atlas-scale multi-s le multi-condition single-cell studies. We have generalized scMerge2 to enable the merging of millions of cells from single-cell studies generated by various single-cell technologies. Using a large COVID-19 data collection with over five million cells from 1000+ in iduals, we demonstrate that scMerge2 enables multi-s le multi-condition scRNA-seq data integration from multiple cohorts and reveals signatures derived from cell-type expression that are more accurate in discriminating disease progression. Further, we demonstrate that scMerge2 can remove dataset variability in CyTOF, imaging mass cytometry and CITE-seq experiments, demonstrating its applicability to a broad spectrum of single-cell profiling technologies.
Publisher: Elsevier BV
Date: 09-2019
Publisher: Elsevier BV
Date: 03-2023
Publisher: Informa UK Limited
Date: 24-07-2020
Publisher: Springer Science and Business Media LLC
Date: 25-05-2018
Publisher: MDPI AG
Date: 06-05-2020
Abstract: Pharmacists have a valuable role in the management of allergic rhinitis (AR) at the community pharmacy level. This role has been reported extensively in numerous papers. However, a systematic review of the available literature and a comprehensive analysis of the outcomes has not been published. This systematic review aimed to evaluate the impact of interventions developed by pharmacists on clinical AR outcomes. A thorough search was performed in three electronic databases, including studies published between January 2000 and June 2019. After the selection process, only three articles met the inclusion criteria and were further analysed. Despite the scarcity of the available studies, in all of them was clear that the pharmacist plays a pivotal role in the management of AR, significantly improving the patients’ quality of life and symptom control. This systematic review also stresses the utmost importance to investigate and report practices and interventions developed by pharmacists using measurable outcomes.
Publisher: American Society of Hematology
Date: 26-08-2022
DOI: 10.1182/BLOODADVANCES.2022007103
Abstract: Virus-specific T-cells (VSTs) from third-party donors mediate short- and long-term antiviral effects in allogeneic hematopoietic stem cell transplant (HSCT) recipients with relapsed or refractory viral infections. We investigated early administration of third-party VSTs, together with antiviral therapy in patients requiring treatment for first cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection. Thirty HSCT patients were treated with 1 to 4 VST infusions (2 × 107 cells/m2 CMV n=27, EBV n=3) at a median of 4 days after initiation of antiviral treatment. The overall viral response rate was 100%, with a complete response (CR) rate of 94%. Of the 28 patients who achieved a CR, 23 remained virus PCR negative (n=9) or below quantitation limit (n=14) for the duration of follow-up. Four patients had brief episodes of quantifiable reactivation not requiring additional therapy, and one required a second infusion after initial CR, remaining PCR negative thereafter. All 3 patients treated for EBV post-transplant lymphoproliferative disorder achieved sustained CR. Rates of aGVHD and cGVHD after infusion were 13% and 23%, respectively. There were no serious infusion-related adverse events. VST infusion was associated with rapid recovery of CD8+CD45RA−CD62L− and a slower recovery of CD4+CD45RA−CD62L− effector memory T-cells CMV-specific T-cells comprised up to 13% of CD8+ cells. At 1 year post-transplant, non-relapse mortality was 10%, cumulative incidence of relapse was 7%, overall survival was 88% and 25 of 27 patients had ECOG status of 0 or 1. Early administration of third-party VSTs in conjunction with antiviral treatment appears safe and leads to excellent viral control and clinical outcomes. Registered on Australian New Zealand Clinical Trials Registry as #ACTRN12618000343202.
Publisher: Cold Spring Harbor Laboratory
Date: 09-07-2021
DOI: 10.1101/2021.07.08.451609
Abstract: High-throughput single cell technologies hold the promise of discovering novel cellular relationships with disease. However, analytical workflows constructed for these technologies to associate cell proportions with disease often employ unsupervised clustering techniques that overlook the valuable hierarchical structures that have been used to define cell types. We present treekoR, a framework that empirically recapitulates these structures, facilitating multiple quantifications and comparisons of cell type proportions. Our results from twelve case studies reinforce the importance of quantifying proportions relative to parent populations in the analyses of cytometry data — as failing to do so can lead to missing important biological insights.
Publisher: Wiley
Date: 09-09-2023
DOI: 10.1111/EXD.14921
Publisher: Cold Spring Harbor Laboratory
Date: 08-2022
DOI: 10.1101/2022.07.31.502240
Abstract: The histopathological hallmark of tuberculosis (TB) is the formation of immune cell enriched aggregates called granulomas, but the scope of granuloma heterogeneity in human TB is unknown. By spatially mapping in idual immune cells across large regions of TB lung tissue, we report that in addition to necrotizing granulomas, the human TB lung contains abundant non-necrotizing leukocyte aggregates surrounding areas of necrotizing tissue. These cellular lesions were more erse in composition than necrotizing lesions and could be stratified into four general classes based on cellular composition and spatial distribution of B cells and macrophages, indicating there are foci of distinct immune reactions adjacent to necrotizing granulomas. We further show that the specific cellular composition of non-necrotizing structures correlates with their proximity to necrotizing lesions. Together, our study shows that during tuberculosis diseased lung tissue develops a histopathological superstructure comprising at least four different types of non-necrotizing cellular aggregates organized as satellites of necrotizing granulomas.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488959.V1
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488950
Abstract: Supplementary Table from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2017
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488953
Abstract: Supplementary Figure from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Wiley
Date: 23-03-2023
DOI: 10.1002/CYTO.A.24729
Abstract: Highly multiplexed in situ imaging cytometry assays have made it possible to study the spatial organization of numerous cell types simultaneously. We have addressed the challenge of quantifying complex multi‐cellular relationships by proposing a statistical method which clusters local indicators of spatial association. Our approach successfully identifies distinct tissue architectures in datasets generated from three state‐of‐the‐art high‐parameter assays demonstrating its value in summarizing the information‐rich data generated from these technologies.
Publisher: MDPI AG
Date: 16-05-2020
Abstract: The paradigm of how we manage allergic rhinitis is shifting with a growing understanding that it is a complex process, requiring a coordinated effort from healthcare providers and patients. Pharmacists are key members of these integrated care pathways resolving medication-related problems, optimizing regimens, improving adherence and recommending therapies while establishing liaisons between patients and physicians. Community pharmacists are the most accessible healthcare professionals to the public and allergic rhinitis is one of the most common diseases managed by pharmacists. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines developed over the past 20 years have improved the care of allergic rhinitis patients through an evidence-based, integrated care approach. In this paper, we propose an integrated approach to allergic rhinitis management in community pharmacy following the 2019 ARIA in the pharmacy guidelines.
Publisher: Oxford University Press (OUP)
Date: 09-2023
Publisher: Cold Spring Harbor Laboratory
Date: 14-06-2023
DOI: 10.1101/2023.06.13.544733
Abstract: Recent advances in subcellular imaging transcriptomics platforms have enabled high-resolution spatial mapping of gene expression, while also introducing significant analytical challenges in accurately identifying cells and assigning transcripts. Existing methods grapple with cell segmentation, frequently leading to fragmented cells or oversized cells that capture contaminated expression. To this end, we present BIDCell, a self-supervised deep learning-based framework with biologically-informed loss functions that learn relationships between spatially resolved gene expression and cell morphology. BIDCell incorporates cell-type data, including single-cell transcriptomics data from public repositories, with cell morphology information. Using a comprehensive evaluation framework consisting of metrics in five complementary categories for cell segmentation performance, we demonstrate that BIDCell outperforms other state-of-the-art methods according to many metrics across a variety of tissue types and technology platforms. Our findings underscore the potential of BIDCell to significantly enhance single-cell spatial expression analyses, including cell-cell interactions, enabling great potential in biological discovery.
Publisher: Springer Science and Business Media LLC
Date: 24-07-2018
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488947
Abstract: Supplementary Table from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Springer Science and Business Media LLC
Date: 03-09-2019
Publisher: Springer Science and Business Media LLC
Date: 29-11-2021
DOI: 10.1186/S13059-021-02526-5
Abstract: High-throughput single-cell technologies hold the promise of discovering novel cellular relationships with disease. However, analytical workflows constructed for these technologies to associate cell proportions with disease often employ unsupervised clustering techniques that overlook the valuable hierarchical structures that have been used to define cell types. We present treekoR, a framework that empirically recapitulates these structures, facilitating multiple quantifications and comparisons of cell type proportions. Our results from twelve case studies reinforce the importance of quantifying proportions relative to parent populations in the analyses of cytometry data — as failing to do so can lead to missing important biological insights.
Publisher: Springer Science and Business Media LLC
Date: 03-04-2020
DOI: 10.1186/S12860-020-00256-3
Abstract: Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms. We demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects. Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with increased PI3K/AKT activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/AKT activation. Mutation of Y180F strongly attenuated subcutaneous xenograft tumor growth in NOD-SCID gamma mice. Elsewhere we demonstrate altered metabolism, mutation incidence, and epigenetic status in these cells. Altogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology.
Publisher: Oxford University Press (OUP)
Date: 19-04-2022
DOI: 10.1093/BIOINFORMATICS/BTAC268
Abstract: High parameter histological techniques have allowed for the identification of a variety of distinct cell types within an image, providing a comprehensive overview of the tissue environment. This allows the complex cellular architecture and environment of diseased tissue to be explored. While spatial analysis techniques have revealed how cell–cell interactions are important within the disease pathology, there remains a gap in exploring changes in these interactions within the disease process. Specifically, there are currently few established methods for performing inference on cell-type co-localization changes across images, hindering an understanding of how cellular environments change with a disease pathology. We have developed the spicyR R package to perform inference on changes in the spatial co-localization of types across groups of images. Application to simulated data demonstrates a high sensitivity and specificity. We the utility of spicyR by applying it to a type 1 diabetes imaging mass cytometry dataset, revealing changes in cellular associations that were relevant to the disease progression. Ultimately, spicyR allows changes in cellular environments to be explored under different pathologies or disease states. R package is freely available at ackages/release/bioc/html/spicyR.html and shiny app implementation at shiny.maths.usyd.edu.au/spicyR/. Supplementary data are available at Bioinformatics online.
Publisher: Springer Science and Business Media LLC
Date: 24-01-2013
DOI: 10.1007/S00125-012-2811-Y
Abstract: Muscle insulin resistance, one of the earliest defects associated with type 2 diabetes, involves changes in the phosphoinositide 3-kinase/Akt network. The relative contribution of obesity vs insulin resistance to perturbations in this pathway is poorly understood. We used phosphospecific antibodies against targets in the Akt signalling network to study insulin action in muscle from lean, overweight/obese and type 2 diabetic in iduals before and during a hyperinsulinaemic-euglycaemic cl . Insulin-stimulated Akt phosphorylation at Thr309 and Ser474 was highly correlated with whole-body insulin sensitivity. In contrast, impaired phosphorylation of Akt substrate of 160 kDa (AS160 also known as TBC1D4) was associated with adiposity, but not insulin sensitivity. Neither insulin sensitivity nor obesity was associated with defective insulin-dependent phosphorylation of forkhead box O (FOXO) transcription factor. In view of the resultant basal hyperinsulinaemia, we predicted that this selective response within the Akt pathway might lead to hyperactivation of those processes that were spared. Indeed, the expression of genes targeted by FOXO was downregulated in insulin-resistant in iduals. These results highlight non-linearity in Akt signalling and suggest that: (1) the pathway from Akt to glucose transport is complex and (2) pathways, particularly FOXO, that are not insulin-resistant, are likely to be hyperactivated in response to hyperinsulinaemia. This facet of Akt signalling may contribute to multiple features of the metabolic syndrome.
Publisher: Cold Spring Harbor Laboratory
Date: 08-12-2022
DOI: 10.1101/2022.12.08.519588
Abstract: The recent emergence of multi-s le multi-condition single-cell multi-cohort studies allow researchers to investigate different cell states. The effective integration of multiple large-cohort studies promises biological insights into cells under different conditions that in idual studies cannot provide. Here, we present scMerge2, a scalable algorithm that allows data integration of atlas-scale multi-s le multi-condition single-cell studies. We have generalised scMerge2 to enable the merging of millions of cells from single-cell studies generated by various single-cell technologies. Using a large COVID-19 data collection with over five million cells from 1000+ in iduals, we demonstrate that scMerge2 enables multi-s le multi-condition scRNA-seq data integration from multiple cohorts and reveals signatures derived from cell-type expression that are more accurate in discriminating disease progression. Further, we demonstrate that scMerge2 can remove dataset variability in CyTOF, imaging mass cytometry and CITE-seq experiments, demonstrating its applicability to a broad spectrum of single-cell profiling technologies.
Publisher: Oxford University Press (OUP)
Date: 09-08-2018
DOI: 10.1093/BIOINFORMATICS/BTY698
Abstract: Genes act as a system and not in isolation. Thus, it is important to consider coordinated changes of gene expression rather than single genes when investigating biological phenomena such as the aetiology of cancer. We have developed an approach for quantifying how changes in the association between pairs of genes may inform the outcome of interest called Differential Correlation across Ranked S les (DCARS). Modelling gene correlation across a continuous s le ranking does not require the dichotomisation of s les into two distinct classes and can identify differences in gene correlation across early, mid or late stages of the outcome of interest. When we evaluated DCARS against the typical Fisher Z-transformation test for differential correlation, as well as a typical approach testing for interaction within a linear model, on real TCGA data, DCARS significantly ranked gene pairs containing known cancer genes more highly across several cancers. Similar results are found with our simulation study. DCARS was applied to 13 cancers datasets in TCGA, revealing several distinct relationships for which survival ranking was found to be associated with a change in correlation between genes. Furthermore, we demonstrated that DCARS can be used in conjunction with network analysis techniques to extract biological meaning from multi-layered and complex data. DCARS R package and s le data are available at hazanfar/DCARS. Publicly available data from The Cancer Genome Atlas (TCGA) was used using the TCGABiolinks R package. Supplementary Files and DCARS R package is available at hazanfar/DCARS. Supplementary data are available at Bioinformatics online.
Publisher: Springer Science and Business Media LLC
Date: 07-2017
Publisher: Cold Spring Harbor Laboratory
Date: 14-11-2019
DOI: 10.1101/841593
Abstract: Single-cell RNA-sequencing has transformed our ability to examine cell fate choice. For ex le, in the context of development and differentiation, computational ordering of cells along ‘pseudotime’ enables the expression profiles of in idual genes, including key transcription factors, to be examined at fine scale temporal resolution. However, while cell fate decisions are typically marked by profound changes in expression, many such changes are observed in genes downstream of the initial cell fate decision. By contrast, the genes directly involved in the cell fate decision process are likely to interact in subtle ways, potentially resulting in observed changes in patterns of correlation and variation rather than mean expression prior to cell fate commitment. Herein, we describe a novel approach, scHOT – single cell Higher Order Testing - which provides a flexible and statistically robust framework for identifying changes in higher order interactions among genes. scHOT is general and modular in nature, can be run in multiple data contexts such as along a continuous trajectory, between discrete groups, and over spatial orientations as well as accommodate any higher order measurement such as variability or correlation. We demonstrate the utility of scHOT by studying embryonic development of the liver, where we find coordinated changes in higher order interactions of programs related to differentiation and liver function. We also demonstrate its ability to find subtle changes in gene-gene correlation patterns across space using spatially-resolved expression data from the mouse olfactory bulb. scHOT meaningfully adds to first order effect testing, such as differential expression, and provides a framework for interrogating higher order interactions from single cell data.
Publisher: Public Library of Science (PLoS)
Date: 27-07-2018
Publisher: Wiley
Date: 21-04-2023
DOI: 10.1111/EXD.14814
Abstract: Despite recent developments in managing metastatic melanomas, patients' overall survival remains low. Therefore, the current study aims to understand better the proteome‐wide changes associated with melanoma metastasis that will assist with identifying targeted therapies. The latest development in mass spectrometry‐based proteomics, together with extensive bioinformatics analysis, was used to investigate the molecular changes in 60 formalin‐fixed and paraffin‐embedded s les of primary and lymph nodes (LN) and distant organ metastatic melanomas. A total of 4631 proteins were identified, of which 72 and 453 were significantly changed between the LN and distant organ metastatic melanomas compared to the primary lesions (adj. p ‐value .05). An increase in proteins such as SLC9A3R1, CD20 and GRB2 and a decrease in CST6, SERPINB5 and ARG1 were associated with regional LN metastasis. By contrast, increased metastatic activities in distant organ metastatic melanomas were related to higher levels of CEACAM1, MC1R, AKT1 and MMP3‐9 and decreased levels of CDKN2A, SDC1 and SDC4 proteins. Furthermore, machine learning analysis classified the lesions with up to 92% accuracy based on their metastatic status. The findings from this study provide up to date proteome‐level information about the progression of melanomas to regional LN and distant organs, leading to the identification of protein signatures with potential for clinical translation.
Publisher: Wiley
Date: 05-01-2015
DOI: 10.1111/PCMR.12343
Abstract: The role of microRNAs (miRNAs) in melanoma is unclear. We examined global miRNA expression profiles in fresh-frozen metastatic melanomas in relation to clinical outcome and BRAF mutation, with validation in independent cohorts of tumours and sera. We integrated miRNA and mRNA information from the same s les and elucidated networks associated with outcome and mutation. Associations with prognosis were replicated for miR-150-5p, miR-142-3p and miR-142-5p. Co-analysis of miRNA and mRNA uncovered a network associated with poor prognosis (PP) that paradoxically favoured expression of miRNAs opposing tumorigenesis. These miRNAs are likely part of an autoregulatory response to oncogenic drivers, rather than drivers themselves. Robust association of miR-150-5p and the miR-142 duplex with good prognosis and earlier stage metastatic melanoma supports their potential as biomarkers. miRNAs overexpressed in association with PP in an autoregulatory fashion will not be suitable therapeutic targets.
Publisher: Oxford University Press (OUP)
Date: 24-04-2015
DOI: 10.1093/BIOINFORMATICS/BTV220
Abstract: Motivation: In practice, identifying and interpreting the functional impacts of the regulatory relationships between micro-RNA and messenger-RNA is non-trivial. The sheer scale of possible micro-RNA and messenger-RNA interactions can make the interpretation of results difficult. Results: We propose a supervised framework, pMim, built upon concepts of significance combination, for jointly ranking regulatory micro-RNA and their potential functional impacts with respect to a condition of interest. Here, pMim directly tests if a micro-RNA is differentially expressed and if its predicted targets, which lie in a common biological pathway, have changed in the opposite direction. We leverage the information within existing micro-RNA target and pathway databases to stabilize the estimation and annotation of micro-RNA regulation making our approach suitable for datasets with small s le sizes. In addition to outputting meaningful and interpretable results, we demonstrate in a variety of datasets that the micro-RNA identified by pMim, in comparison to simpler existing approaches, are also more concordant with what is described in the literature. Availability and implementation: This framework is implemented as an R function, pMim, in the package sydSeq available from -packages. Contact: jean.yang@sydney.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488950.V1
Abstract: Supplementary Table from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Cold Spring Harbor Laboratory
Date: 18-05-2023
DOI: 10.1101/2023.05.16.541040
Abstract: Imaging-based spatial transcriptomics technologies have achieved subcellular resolution, enabling detection of in idual molecules in their native tissue context. Data associated with these technologies promises unprecedented opportunity towards understanding cellular and subcellular biology. However, in R/Bioconductor there is a scarcity of existing computational infrastructure to represent such data, and particularly to summarise and transform it for existing widely adopted computational tools in single cell transcriptomics analysis, including SingleCellExperiment and SpatialExperiment classes. With the emergence of several commercial offerings of imaging-based spatial transcriptomics, there is a pressing need to develop consistent data structure standards for these technologies at the in idual molecule level. To this end, we have developed MoleculeExperiment, an R/Bioconductor package, which i) stores molecule and cell segmentation boundary information at the molecule-level, ii) standardises this molecule-level information across different imaging-based ST technologies, including 10x Genomics’ Xenium, and iii) streamlines transition from a MoleculeExperiment object to a SpatialExperiment object. Overall, MoleculeExperiment is generally applicable as a data infrastructure class for consistent analysis of imaging-based spatial transcriptomics data.
Publisher: Public Library of Science (PLoS)
Date: 17-08-2020
Publisher: Springer Science and Business Media LLC
Date: 16-08-2021
DOI: 10.1038/S41380-021-01248-1
Abstract: Amyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-β peptide (Aβ) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology. In vitro studies showed that an interaction between APP and the iron-bound form of Lf secreted from activated microglia erted neuronal APP endocytosis from the canonical clathrin-dependent pathway to one requiring ADP ribosylation factor 6 trafficking. By rerouting APP recycling to the Rab11-positive compartment for amyloidogenic processing, Lf dramatically increased neuronal Aβ production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between Aβ production, neuroinflammation and iron dysregulation.
Publisher: Cold Spring Harbor Laboratory
Date: 29-05-2020
DOI: 10.1101/2020.05.26.117408
Abstract: Tissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. They are the first cells of the immune system to encounter HIV and play a key role in transmission as they deliver the virus to CD4 T cells, which are the primary HIV target cell in which the virus undergoes replication. Most studies have investigated the role that epithelial MNPs play in HIV transmission but, as mucosal trauma and inflammation are strongly associated with HIV transmission, it is also important to examine the role that sub-epithelial MNPs play. Sub-epithelial MNPs are present in a erse array of subsets which differ in their function and the pathogens they detect. Understanding how specific subsets interact with HIV and deliver the virus to CD4 T cells is therefore of key importance to vaccine and microbicide development. In this study we have shown that, after topical application, HIV can penetrate to interact with sub-epithelial resident myeloid cells in anogenital explants and defined the full array of MNP subsets that are present in all the human anogenital and colorectal sub-epithelial tissues that HIV may encounter during sexual transmission. In doing so we have identified two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells CD14 + CD1c + CD11c + monocyte-derived dendritic cells and langerin-expressing dendritic cells 2 (DC2).
Publisher: Springer Science and Business Media LLC
Date: 24-08-2018
DOI: 10.1007/S00787-018-1212-2
Abstract: There is accumulating evidence that patients with functional neurological symptom disorder (FND) show activation of multiple components of the stress system-the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and brain regions involved in arousal- and emotion-processing. This study aims to examine whether the immune-inflammatory component of the stress system is also activated. C-reactive protein (CRP) blood titre levels were measured in 79 children and adolescents with FND. CRP values ≥ 2 mg/L suggest low-grade inflammation. CRP values > 10 mg/L suggest a disease process. Sixty-six percent of subjects (n = 52) had CRP titres ≥ 2 mg/L. The upward shift in the distribution of CRP levels suggested low-grade inflammation (median CRP concentration was 4.60 mg/L, with 75th and 90th percentiles of 6.1 and 10.3 mg/L, respectively). Elevated CRP titres were not explained by sex, pubertal status, BMI, or medical factors. Confounder analyses suggested that history of maltreatment (χ
Publisher: Frontiers Media SA
Date: 20-10-2021
DOI: 10.3389/FIMMU.2021.733231
Abstract: Dendritic cells (DC) are central to regulating innate and adaptive immune responses. Strategies that modify DC function provide new therapeutic opportunities in autoimmune diseases and transplantation. Current pharmacological approaches can alter DC phenotype to induce tolerogenic DC (tolDC), a maturation-resistant DC subset capable of directing a regulatory immune response that are being explored in current clinical trials. The classical phenotypic characterization of tolDC is limited to cell-surface marker expression and anti-inflammatory cytokine production, although these are not specific. TolDC may be better defined using gene signatures, but there is no consensus definition regarding genotypic markers. We address this shortcoming by analyzing available transcriptomic data to yield an independent set of differentially expressed genes that characterize human tolDC. We validate this transcriptomic signature and also explore gene differences according to the method of tolDC generation. As well as establishing a novel characterization of tolDC, we interrogated its translational utility in vivo , demonstrating this geneset was enriched in the liver, a known tolerogenic organ. Our gene signature will potentially provide greater understanding regarding transcriptional regulators of tolerance and allow researchers to standardize identification of tolDC used for cellular therapy in clinical trials.
Publisher: Informa UK Limited
Date: 09-06-2014
Publisher: Cold Spring Harbor Laboratory
Date: 05-2022
DOI: 10.1101/2022.04.30.490175
Abstract: The initial immune response to HIV is critical in determining transmission. However, due to technical limitations we still do not have a comparative map of early mucosal transmission events. We combined RNAscope, cyclic-immunofluorescence and novel image analysis tools to quantify HIV transmission dynamics in intact human colorectal tissue. We mapped HIV enrichment to mucosal dendritic cells (DC) and submucosal macrophages, but not CD4+ T-cells, the primary targets of downstream infection. DCs appeared to funnel virus to lymphoid aggregates which acted as early sanctuaries of high viral titres whilst facilitating HIV passage to the submucosa. Finally, HIV entry induced rapid recruitment and clustering of target cells, facilitating DC and macrophage mediated HIV transfer and enhanced infection of CD4+ T-cells. These data demonstrate a rapid response to HIV structured to maximise the likelihood of mucosal infection, and provide a framework for in situ studies of host pathogen interactions and immune mediated pathologies. - in situ quantification of host cellular microenvironment response to pathogen invasion in human colorectal tissue. - HIV first localises to mucosal DCs and submucosal macrophages, but not CD4+ T cells. - Viral enrichment first occurs in lymphoid aggregates which is associated with passage into the submucosa. - Early localisation of HIV to CD4+ T cells is associated with interactions with DCs and macrophages.
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1149
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/1471-2164-14-S1-S9
Abstract: The cost of RNA-Seq has been decreasing over the last few years. Despite this, experiments with four or less biological replicates are still quite common. Estimating the variances of gene expression estimates becomes both a challenging and interesting problem in these situations of low replication. However, with the wealth of microarray and other publicly available gene expression data readily accessible on public repositories, these sources of information can be leveraged to make improvements in variance estimation. We have proposed a novel approach called Tshrink+ for inferring differential gene expression through improved modelling of the gene-wise variances. Existing methods share information between genes of similar average expression by shrinking, or moderating, the gene-wise variances to a fitted common variance. We have been able to achieve improved estimation of the common variance by using gene-wise s le variances from external experiments, as well as gene length. Using biological data we show that utilising additional external information can improve the modelling of the common variance and hence the calling of differentially expressed genes. These sources of additional information include gene length and gene-wise s le variances from other RNA-Seq and microarray datasets, of both related and seemingly unrelated tissue types. The results of this are promising, with our differential expression test, Tshrink+, performing favourably when compared to existing methods such as DESeq and edgeR when considering both gene ranking and sensitivity. These improved variance models could easily be implemented in both DESeq and edgeR and highlight the need for a database that offers a profile of gene variances over a range of tissue types and organisms.
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2022
DOI: 10.1158/1078-0432.CCR-22-1332
Abstract: The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown. We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior. Nonprogressing primary HNcSCC were characterized by higher CD8+ and CD4+ T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell–enriched tumor regions associated with primary nonprogressing tumors. Effective responses from both CD8+ and CD4+ T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-10-2019
Publisher: Wiley
Date: 06-2021
DOI: 10.1002/CLT2.12014
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488947.V1
Abstract: Supplementary Table from High-Dimensional and Spatial Analysis Reveals Immune Landscape–Dependent Progression in Cutaneous Squamous Cell Carcinoma
Publisher: Cold Spring Harbor Laboratory
Date: 24-08-2019
DOI: 10.1101/737718
Abstract: Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms. Here, we demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects. Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with increased PI3K/Akt activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/Akt activation. Mutation of Y180F strongly attenuated mouse xenograft tumor growth. An accompanying paper demonstrates altered metabolism, mutation incidence, and epigenetic status in these cells, indicating that PGRMC1 phosphorylation strongly influences cancer biology.
Publisher: Cold Spring Harbor Laboratory
Date: 20-01-2023
DOI: 10.1101/2023.01.18.524659
Abstract: Highly multiplexed in situ imaging cytometry assays have enabled researchers to scru-tinize cellular systems at an unprecedented level. With the capability of these assays to simultaneously profile the spatial distribution and molecular features of many cells, unsuper-vised machine learning, and in particular clustering algorithms, have become indispensable for identifying cell types and subsets based on these molecular features. However, the most widely used clustering approaches applied to these novel technologies were developed for cell suspension technologies and may not be optimal for in situ imaging assays. In this work, we systematically evaluated the performance of various similarity metrics used to quan-tify the similarity between cells when clustering. Our results demonstrate that performance in cell clustering varies significantly when different similarity metrics were used. Lastly, we propose FuseSOM, an ensemble clustering algorithm employing hierarchical multi-view learning of similarity metrics and self-organizing maps (SOM). Using a stratified subsam-pling analysis framework, FuseSOM exhibits superior clustering performance compared to the current best-practice clustering approaches for in situ imaging cytometry data analysis.
Publisher: Public Library of Science (PLoS)
Date: 27-04-2021
DOI: 10.1371/JOURNAL.PPAT.1009536
Abstract: Skin mononuclear phagocytes (MNPs) provide the first interactions of invading viruses with the immune system. In addition to Langerhans cells (LCs), we recently described a second epidermal MNP population, Epi-cDC2s, in human anogenital epidermis that is closely related to dermal conventional dendritic cells type 2 (cDC2) and can be preferentially infected by HIV. Here we show that in epidermal explants topically infected with herpes simplex virus (HSV-1), both LCs and Epi-cDC2s interact with HSV-1 particles and infected keratinocytes. Isolated Epi-cDC2s support higher levels of infection than LCs in vitro , inhibited by acyclovir, but both MNP subtypes express similar levels of the HSV entry receptors nectin-1 and HVEM, and show similar levels of initial uptake. Using inhibitors of endosomal acidification, actin and cholesterol, we found that HSV-1 utilises different entry pathways in each cell type. HSV-1 predominantly infects LCs, and monocyte-derived MNPs, via a pH-dependent pathway. In contrast, Epi-cDC2s are mainly infected via a pH-independent pathway which may contribute to the enhanced infection of Epi-cDC2s. Both cells underwent apoptosis suggesting that Epi-cDC2s may follow the same dermal migration and uptake by dermal MNPs that we have previously shown for LCs. Thus, we hypothesize that the uptake of HSV and infection of Epi-cDC2s will stimulate immune responses via a different pathway to LCs, which in future may help guide HSV vaccine development and adjuvant targeting.
Publisher: Frontiers Media SA
Date: 14-11-2019
Publisher: Wiley
Date: 30-09-2021
DOI: 10.1111/ALL.14838
Abstract: Older adults, especially men and/or those with diabetes, hypertension, and/or obesity, are prone to severe COVID‐19. In some countries, older adults, particularly those residing in nursing homes, have been prioritized to receive COVID‐19 vaccines due to high risk of death. In very rare instances, the COVID‐19 vaccines can induce anaphylaxis, and the management of anaphylaxis in older people should be considered carefully. An ARIA‐EAACI‐EuGMS (Allergic Rhinitis and its Impact on Asthma, European Academy of Allergy and Clinical Immunology, and European Geriatric Medicine Society) Working Group has proposed some recommendations for older adults receiving the COVID‐19 vaccines. Anaphylaxis to COVID‐19 vaccines is extremely rare (from 1 per 100,000 to 5 per million injections). Symptoms are similar in younger and older adults but they tend to be more severe in the older patients. Adrenaline is the mainstay treatment and should be readily available. A flowchart is proposed to manage anaphylaxis in the older patients.
Start Date: 01-2020
End Date: 12-2023
Amount: $427,068.00
Funder: Australian Research Council
View Funded Activity