Chancellery Research - Research Publications
Now showing items 1-12 of 379
The use of microarray technology for the analysis of Streptococcus pneumoniae
(JOHN WILEY & SONS LTD, 2002-08-01)
Streptococcus pneumoniae is an important human pathogen associated with pneumonia, septicaemia, meningitis and otitis media. It is estimated to result in over 3 million child deaths worldwide every year and an even greater number of deaths among the elderly. Prior to the complete sequencing of the genomes of S. pneumoniae TIGR4 (serotype 4) and S. pneumoniae R6 (serotype 2), we designed a custom miniarray consisting of 497 pneumococcal genes. The overall objectives of our microarray investigations were, first, to assess the genetic diversity between different S. pneumoniae serotypes, clinical isolates and also different Streptococcus species; second, we aimed to use microarray technology to examine the mechanisms by which environmental factors influence pneumococcal gene expression, and ultimately to further the understanding of how these changes in gene expression are achieved and how they may alter the virulence of the organism.
A Depth-Dependent Integrated VF Simulation for Analysis and Visualization of Glaucomatous VF Defects
(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2020-02-01)
Purpose: Visual fields (VF) are measured monocularly at a single depth, yet real-life activities require people to interact with objects binocularly at multiple depths. To better characterize visual functioning in clinical vision conditions such as glaucoma, analyzing visual impairment in a depth-dependent fashion is required. We developed a depth-dependent integrated VF (DD-IVF) simulation and demonstrated its usefulness by evaluating DD-IVF defects associated with 12 glaucomatous archetypes of 24-2 VF. Methods: The 12 archetypes included typical variants of superior and inferior nasal steps, arcuate and altitudinal defects, temporal wedge, biarcuate, and intact VFs. DD-IVF simulation maps the monocular 24-2 VF archetypes to binocular ones as a function of depth by incorporating three parameters of fixation, object, and interpupillary distances. At each location and depth plane, sensitivities are linearly interpolated from corresponding locations in monocular VF and returned as the higher value of the two. Results: The simulation produced 144 DD-IVFs for multiple depths from combinations of 12 glaucomatous archetypes. The DD-IVFs are included as a Shiny app in the binovisualfields package. The number of impaired locations in the DD-IVFs varied according to the overlap of VF loss between eyes. Conclusions: Our DD-IVF program revealed binocular functional visual defects associated with glaucomatous archetypes of the 24-2 pattern and is designed to do the same for empirically measured VFs. The comparison of identified visual impairments across depths may be informative for future empirical exploration of functional visual impairments in depth in glaucoma and other conditions leading to bilateral VF loss. Translational Relevance: Our DD-IVF program can reveal depth-dependent functional visual defects for clinical vision conditions where 24-2 test patterns are available.
Short-Term Attractive Tilt Aftereffects Predicted by a Recurrent Network Model of Primary Visual Cortex
(FRONTIERS MEDIA SA, 2019-11-08)
Adaptation is a multi-faceted phenomenon that is of interest in terms of both its function and its potential to reveal underlying neural processing. Many behavioral studies have shown that after exposure to an oriented adapter the perceived orientation of a subsequent test is repulsed away from the orientation of the adapter. This is the well-known Tilt Aftereffect (TAE). Recently, we showed that the dynamics of recurrently connected networks may contribute substantially to the neural changes induced by adaptation, especially on short time scales. Here we extended the network model and made the novel behavioral prediction that the TAE should be attractive, not repulsive, on a time scale of a few 100 ms. Our experiments, using a novel adaptation protocol that specifically targeted adaptation on a short time scale, confirmed this prediction. These results support our hypothesis that recurrent network dynamics may contribute to short-term adaptation. More broadly, they show that understanding the neural processing of visual inputs that change on the time scale of a typical fixation requires a detailed analysis of not only the intrinsic properties of neurons, but also the slow and complex dynamics that emerge from their recurrent connectivity. We argue that this is but one example of how even simple recurrent networks can underlie surprisingly complex information processing, and are involved in rudimentary forms of memory, spatio-temporal integration, and signal amplification.
Murine and related chapparvoviruses are nephro-tropic and produce novel accessory proteins in infected kidneys
(PUBLIC LIBRARY SCIENCE, 2020-01-01)
Mouse kidney parvovirus (MKPV) is a member of the provisional genus Chapparvovirus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four major MKPV transcripts, created by alternative splicing, to a common initiator region, and use mass spectrometry to identify "p10" and "p15" as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and the splicing-dependent putative accessory protein NS2 are conserved in all near-complete amniote chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that many mammal chapparvoviruses are likely to be nephrotropic.
Mucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity
(NATURE PUBLISHING GROUP, 2020-07-24)
Obesity is associated with low-grade chronic inflammation promoting insulin-resistance and diabetes. Gut microbiota dysbiosis is a consequence as well as a driver of obesity and diabetes. Mucosal-associated invariant T cells (MAIT) are innate-like T cells expressing a semi-invariant T cell receptor restricted to the non-classical MHC class I molecule MR1 presenting bacterial ligands. Here we show that during obesity MAIT cells promote inflammation in both adipose tissue and ileum, leading to insulin resistance and impaired glucose and lipid metabolism. MAIT cells act in adipose tissue by inducing M1 macrophage polarization in an MR1-dependent manner and in the gut by inducing microbiota dysbiosis and loss of gut integrity. Both MAIT cell-induced tissue alterations contribute to metabolic dysfunction. Treatment with MAIT cell inhibitory ligand demonstrates its potential as a strategy against inflammation, dysbiosis and metabolic disorders.
IL-17 production by tissue-resident MAIT cells is locally induced in children with pneumonia
(NATURE PUBLISHING GROUP, 2020-02-28)
Community-acquired pneumonia (CAP) contributes substantially to morbidity and mortality in children under the age of 5 years. In examining bronchoalveolar lavages (BALs) of children with CAP, we found that interleukin-17 (IL-17) production was significantly increased in severe CAP. Immune profiling showed that mucosal-associated invariant T (MAIT) cells from the BALs, but not blood, of CAP patients actively produced IL-17 (MAIT17). Single-cell RNA-sequencing revealed that MAIT17 resided in a BAL-resident PLZFhiCD103+ MAIT subset with high expression of hypoxia-inducible factor 1α (HIF-1α), reflecting the hypoxic state of the inflamed tissue. CAP BALs also contained a T-bet+ MAIT1 subset and a novel DDIT3+ (DNA damage-inducible transcript 3-positive) MAIT subset with low expression of HIF1A. Furthermore, MAIT17 differed from T-helper type 17 (Th17) cells in the expression of genes related to tissue location, innateness, and cytotoxicity. Finally, we showed that BAL monocytes were hyper-inflammatory and elicited differentiation of MAIT17. Thus, tissue-resident MAIT17 cells are induced at the infected respiratory mucosa, likely influenced by inflammatory monocytes, and contribute to IL-17-mediated inflammation during CAP.
BIOADI: a machine learning approach to identifying abbreviations and definitions in biological literature
BACKGROUND: To automatically process large quantities of biological literature for knowledge discovery and information curation, text mining tools are becoming essential. Abbreviation recognition is related to NER and can be considered as a pair recognition task of a terminology and its corresponding abbreviation from free text. The successful identification of abbreviation and its corresponding definition is not only a prerequisite to index terms of text databases to produce articles of related interests, but also a building block to improve existing gene mention tagging and gene normalization tools. RESULTS: Our approach to abbreviation recognition (AR) is based on machine-learning, which exploits a novel set of rich features to learn rules from training data. Tested on the AB3P corpus, our system demonstrated a F-score of 89.90% with 95.86% precision at 84.64% recall, higher than the result achieved by the existing best AR performance system. We also annotated a new corpus of 1200 PubMed abstracts which was derived from BioCreative II gene normalization corpus. On our annotated corpus, our system achieved a F-score of 86.20% with 93.52% precision at 79.95% recall, which also outperforms all tested systems. CONCLUSION: By applying our system to extract all short form-long form pairs from all available PubMed abstracts, we have constructed BIOADI. Mining BIOADI reveals many interesting trends of bio-medical research. Besides, we also provide an off-line AR software in the download section on http://bioagent.iis.sinica.edu.tw/BIOADI/.
Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition
(ROCKEFELLER UNIV PRESS, 2009-01-16)
Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell-mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR-HLA-B*4405(EENLLDFVRF) complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.
A mosaic genetic screen for novel mutations affecting Drosophila neuroblast divisions
(BIOMED CENTRAL LTD, 2006-06-02)
BACKGROUND: The asymmetric segregation of determinants during cell division is a fundamental mechanism for generating cell fate diversity during development. In Drosophila, neural precursors (neuroblasts) divide in a stem cell-like manner generating a larger apical neuroblast and a smaller basal ganglion mother cell. The cell fate determinant Prospero and its adapter protein Miranda are asymmetrically localized to the basal cortex of the dividing neuroblast and segregated into the GMC upon cytokinesis. Previous screens to identify components of the asymmetric division machinery have concentrated on embryonic phenotypes. However, such screens are reaching saturation and are limited in that the maternal contribution of many genes can mask the effects of zygotic loss of function, and other approaches will be necessary to identify further genes involved in neuroblast asymmetric division. RESULTS: We have performed a genetic screen in the third instar larval brain using the basal localization of Miranda as a marker for neuroblast asymmetry. In addition to the examination of pupal lethal mutations, we have employed the MARCM (Mosaic Analysis with a Repressible Cell Marker) system to generate postembryonic clones of mutations with an early lethal phase. We have screened a total of 2,300 mutagenized chromosomes and isolated alleles affecting cell fate, the localization of basal determinants or the orientation of the mitotic spindle. We have also identified a number of complementation groups exhibiting defects in cell cycle progression and cytokinesis, including both novel genes and new alleles of known components of these processes. CONCLUSION: We have identified four mutations which affect the process of neuroblast asymmetric division. One of these, mapping to the imaginal discs arrested locus, suggests a novel role for the anaphase promoting complex/cyclosome (APC/C) in the targeting of determinants to the basal cortex. The identification and analysis of the remaining mutations will further advance our understanding of the process of asymmetric cell division. We have also isolated a number of mutations affecting cell division which will complement the functional genomics approaches to this process being employed by other laboratories. Taken together, these results demonstrate the value of mosaic screens in the identification of genes involved in neuroblast division.
Drosophila neuroblast asymmetric divisions: cell cycle regulators, asymmetric protein localization, and tumorigenesis
(ROCKEFELLER UNIV PRESS, 2008-01-28)
Over the past decade, many of the key components of the genetic machinery that regulate the asymmetric division of Drosophila melanogaster neural progenitors, neuroblasts, have been identified and their functions elucidated. Studies over the past two years have shown that many of these identified components act to regulate the self-renewal versus differentiation decision and appear to function as tumor suppressors during larval nervous system development. In this paper, we highlight the growing number of molecules that are normally considered to be key regulators of cell cycle events/progression that have recently been shown to impinge on the neuroblast asymmetric division machinery to control asymmetric protein localization and/or the decision to self-renew or differentiate.
Screening circulating proteins to identify biomarkers of fetal macrosomia.
(BioMed Central, 2019-09-18)
OBJECTIVE: Fetal macrosomia is a major risk factor for shoulder dystocia, which can lead to birth asphyxia, maternal and neonatal traumatic injuries, and perinatal death. If macrosomia is diagnosed in the antenatal period, labour can be induced to decrease shoulder dystocia. But current clinical methods to diagnose fetal macrosomia antenatally perform with poor accuracy. Therefore, improved methods to accurately diagnose fetal macrosomia are required. Blood biomarkers that predict fetal macrosomia could be one such novel diagnostic strategy. We undertook a nested case-control study from a prospective collection of 1000 blood samples collected at 36 weeks' gestation. We analysed plasma samples from 52 women who subsequently delivered a macrosomic (> 95th centile for gestational age) infant and 106 controls. Circulating concentrations of the proteins COBLL1, CSH1, HSD3B1, EGFL6, XAGE3, S100P, PAPPA-1, ERBB2 were assessed for their ability to predict macrosomic infants. RESULTS: We did not identify any significant changes in the plasma concentrations of COBLL1, CSH1, HSD3B1, EGFL6, XAGE3, S100P, PAPPA-1, ERBB2 from women who subsequently delivered macrosomic neonates relative to control samples. Although we have not identified any potential biomarkers of fetal macrosomia, we have ruled out these particular eight protein candidates.
Challenges in Professionalizing Data Stewardship: Professionalising Data Stewardship at the University of Melbourne
Slides for a lightning talk presented as part of the Challenges in Professionalizing Data Stewardship Birds of a Feather (BoF) session. This session was due to be held at the Research Data Alliance (RDA) Plenary 15 in Melbourne, which was cancelled, so was held virtually online instead.