ORCID Profile
0000-0001-5270-0605
Current Organisations
University of Melbourne
,
South African Medical Research Council
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Gene Expression (incl. Microarray and other genome-wide approaches) | Biochemistry and Cell Biology | Bioinformatics | Cell Development, Proliferation and Death
Publisher: Cold Spring Harbor Laboratory
Date: 29-06-2023
DOI: 10.1101/2023.06.28.546913
Abstract: Liver sinusoidal endothelial cells (LSECs) play an important role in liver development, regeneration and pathophysiology, but the differentiation process that generates their unique tissue-specific phenotype is poorly understood and difficult to study as primary cells are only available in limited quantities. To address this, we hypothesised that human induced pluripotent stem cell (hiPSC)-derived endothelial cells (iECs) can produce hiPSC-derived LSECs upon transplantation into the livers of Fah −/− /Rag2 −/− /Il2rg −/− mice, and serve as a model to study LSEC specification. Progressive and long-term repopulation of the liver vasculature was observed, as iECs expanded along the sinusoids that run between hepatocytes and increasingly produced human factor VIII, indicating differentiation into LSEC-like cells. To chart the developmental profile associated with LSEC specification, the bulk transcriptome of transplanted cells at time-points between 1 and 12 weeks were compared against primary human adult LSECs, which demonstrated a chronological increase in LSEC markers, LSEC differentiation pathways, and zonation. Bulk transcriptome analysis suggested that the transcription factors NOTCH1 , GATA4 , and FOS play a central role in LSEC specification, interacting with a network of 27 transcription factors. Novel markers associated with this process include EMCN and CLEC14A . Additionally, single cell transcriptomic analysis demonstrated that transplanted iECs at 4 weeks contain zonal subpopulations with a region-specific phenotype. Collectively, this study confirms that hiPSC can adopt LSEC-like features and provides insight into LSEC specification. This humanised xenograft system can be applied to further interrogate LSEC developmental biology and pathophysiology, bypassing current logistical obstacles associated with primary human LSECs.
Publisher: Oxford University Press (OUP)
Date: 05-04-2011
DOI: 10.1093/BIOINFORMATICS/BTR170
Abstract: Motivation: Current sequencing technologies produce a large number of erroneous reads. The sequencing errors present a major challenge in utilizing the data in de novo sequencing projects as assemblers have difficulties in dealing with errors. Results: We present Coral which corrects sequencing errors by forming multiple alignments. Unlike previous tools for error correction, Coral can utilize also bases distant from the error in the correction process because the whole read is present in the alignment. Coral is easily adjustable to reads produced by different sequencing technologies like Illumina Genome Analyzer and Roche/454 Life Sciences sequencing platforms because the sequencing error model can be defined by the user. We show that our method is able to reduce the error rate of reads more than previous methods. Availability: The source code of Coral is freely available at www.cs.helsinki.fi/u/lmsalmel/coral/. Contact: leena.salmela@cs.helsinki.fi
Publisher: Springer Science and Business Media LLC
Date: 20-07-2017
Publisher: Elsevier BV
Date: 03-2017
Publisher: Springer Science and Business Media LLC
Date: 06-05-2014
Publisher: Springer Science and Business Media LLC
Date: 06-03-2017
DOI: 10.1038/NCOMMS14581
Abstract: The Eμ- Myc mouse is an extensively used model of MYC driven malignancy however to date there has only been partial characterization of MYC co-operative mutations leading to spontaneous lymphomagenesis. Here we sequence spontaneously arising Eμ- Myc lymphomas to define transgene architecture, somatic mutations, and structural alterations. We identify frequent disruptive mutations in the PRC1-like component and BCL6-corepressor gene Bcor . Moreover, we find unexpected concomitant multigenic lesions involving Cdkn2a loss and other cancer genes including Nra s, Kras and Bcor . These findings challenge the assumed two-hit model of Eμ- Myc lymphoma and demonstrate a functional in vivo role for Bcor in suppressing tumorigenesis.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-04-2022
DOI: 10.1126/SCITRANSLMED.AAZ8454
Abstract: Postnatal maturation of the immune system is poorly understood, as is its impact on illnesses afflicting term or preterm infants, such as bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension. These are both cardiopulmonary inflammatory diseases that cause substantial mortality and morbidity with high treatment costs. Here, we characterized blood s les collected from 51 preterm infants longitudinally at five time points, 20 healthy term infants at birth and age 3 to 16 weeks, and 5 healthy adults. We observed strong associations between type 2 immune polarization in circulating CD3 + CD4 + T cells and cardiopulmonary illness, with odds ratios up to 24. Maternal magnesium sulfate therapy, delayed hepatitis B vaccination, and increasing fetal, but not maternal, chorioamnionitis severity were associated with attenuated type 2 polarization. Blocking type 2 mediators such as interleukin-4 (IL-4), IL-5, IL-13, or signal transducer and activator of transcription 6 (STAT6) in murine neonatal cardiopulmonary disease in vivo prevented changes in cell type composition, increases in IL-1β and IL-13, and losses of pulmonary capillaries, but not gains in larger vessels. Thereby, type 2 blockade ameliorated lung inflammation, protected alveolar and vascular integrity, and confirmed the pathological impact of type 2 cytokines and STAT6. In-depth flow cytometry and single-cell transcriptomics of mouse lungs further revealed complex associations between immune polarization and cardiopulmonary disease. Thus, this work advances knowledge on developmental immunology and its impact on early life disease and identifies multiple therapeutic approaches that may relieve inflammation-driven suffering in the youngest patients.
Publisher: BMJ
Date: 24-08-2020
DOI: 10.1136/INJURYPREV-2019-043531
Abstract: While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2020
DOI: 10.1038/S41586-020-2734-6
Abstract: The reprogramming of human somatic cells to primed or naive induced pluripotent stem cells recapitulates the stages of early embryonic development
Publisher: BMJ
Date: 13-03-2020
DOI: 10.1136/INJURYPREV-2019-043495
Abstract: As global rates of mortality decrease, rates of non-fatal injury have increased, particularly in low Socio-demographic Index (SDI) nations. We hypothesised this global pattern of non-fatal injury would be demonstrated in regard to bony hand and wrist trauma over the 27-year study period. The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 was used to estimate prevalence, age-standardised incidence and years lived with disability for hand trauma in 195 countries from 1990 to 2017. In idual injuries included hand and wrist fractures, thumb utations and non-thumb digit utations. The global incidence of hand trauma has only modestly decreased since 1990. In 2017, the age-standardised incidence of hand and wrist fractures was 179 per 100 000 (95% uncertainty interval (UI) 146 to 217), whereas the less common injuries of thumb and non-thumb digit utation were 24 (95% UI 17 to 34) and 56 (95% UI 43 to 74) per 100 000, respectively. Rates of injury vary greatly by region, and improvements have not been equally distributed. The highest burden of hand trauma is currently reported in high SDI countries. However, low-middle and middle SDI countries have increasing rates of hand trauma by as much at 25%. Certain regions are noted to have high rates of hand trauma over the study period. Low-middle and middle SDI countries, however, have demonstrated increasing rates of fracture and utation over the last 27 years. This trend is concerning as access to quality and subspecialised surgical hand care is often limiting in these resource-limited regions.
Publisher: BMJ
Date: 08-01-2020
DOI: 10.1136/INJURYPREV-2019-043296
Abstract: The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm—the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.
Publisher: Public Library of Science (PLoS)
Date: 31-08-2015
Publisher: Oxford University Press (OUP)
Date: 29-11-2013
DOI: 10.1093/BIOINFORMATICS/BTS690
Abstract: Motivation: The imperfect sequence data produced by next-generation sequencing technologies have motivated the development of a number of short-read error correctors in recent years. The majority of methods focus on the correction of substitution errors, which are the dominant error source in data produced by Illumina sequencing technology. Existing tools either score high in terms of recall or precision but not consistently high in terms of both measures. Results: In this article, we present Musket, an efficient multistage k-mer-based corrector for Illumina short-read data. We use the k-mer spectrum approach and introduce three correction techniques in a multistage workflow: two-sided conservative correction, one-sided aggressive correction and voting-based refinement. Our performance evaluation results, in terms of correction quality and de novo genome assembly measures, reveal that Musket is consistently one of the top performing correctors. In addition, Musket is multi-threaded using a master–slave model and demonstrates superior parallel scalability compared with all other evaluated correctors as well as a highly competitive overall execution time. Availability: Musket is available at musket.sourceforge.net. Contact: liuy@uni-mainz.de or bertil.schmidt@uni-mainz.de Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: BMJ
Date: 24-04-2020
DOI: 10.1136/INJURYPREV-2019-043494
Abstract: Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 09-2022
DOI: 10.1038/S41556-022-00986-W
Abstract: Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. However, the sequences of events that orchestrate these intermingled modifications have never been comparatively dissected. Here, we deconvolute the cellular trajectories of reprogramming (via Oct4/Sox2/Klf4/c-Myc) and transformation (via Ras/c-Myc) at the single-cell resolution and reveal how the two processes intersect before they bifurcate. This approach led us to identify the transcription factor Bcl11b as a broad-range regulator of cell fate changes, as well as a pertinent marker to capture early cellular intermediates that emerge simultaneously during reprogramming and transformation. Multiomics characterization of these intermediates unveiled a c-Myc/Atoh8/Sfrp1 regulatory axis that constrains reprogramming, transformation and transdifferentiation. Mechanistically, we found that Atoh8 restrains cellular plasticity, independent of cellular identity, by binding a specific enhancer network. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.
Publisher: Public Library of Science (PLoS)
Date: 03-09-2015
Publisher: Wiley
Date: 14-05-2022
DOI: 10.1002/BTM2.10329
Abstract: Transcranial scanning ultrasound combined with intravenously injected microbubbles (SUS +MB ) has been shown to transiently open the blood–brain barrier and reduce the amyloid‐β (Aβ) pathology in the APP23 mouse model of Alzheimer's disease (AD). This has been accomplished through the activation of microglial cells however, their response to the SUS treatment is incompletely understood. Here, wild‐type (WT) and APP23 mice were subjected to SUS +MB , using nonsonicated mice as sham controls. After 48 h, the APP23 mice were injected with methoxy‐XO4 to label Aβ aggregates, followed by microglial isolation into XO4 + and XO4 − populations using flow cytometry. Both XO4 + and XO4 − cells were subjected to RNA sequencing and transcriptome profiling. The analysis of the microglial cells revealed a clear segregation depending on genotype (AD model vs. WT mice) and Aβ internalization (XO4 + vs. XO4 − microglia), but interestingly, no differences were found between SUS +MB and sham in WT mice. Differential gene expression analysis in APP23 mice detected 278 genes that were significantly changed by SUS +MB in the XO4 + cells (248 up/30 down) and 242 in XO − cells (225 up/17 down). Pathway analysis highlighted differential expression of genes related to the phagosome pathway and marked upregulation of cell cycle‐related transcripts in XO4 + and XO4‐ microglia isolated from SUS +MB ‐treated APP23 mice. Together, this highlights the complexity of the microglial response to transcranial ultrasound, with potential applications for the treatment of AD.
Publisher: Springer Science and Business Media LLC
Date: 16-01-2018
DOI: 10.1038/S41598-017-19025-Y
Abstract: Gastric cancer is a leading cause of cancer death worldwide, with advanced stage being correlated to the level of tumour invasion and metastasis. Current research is heavily focused on the identification and development of efficacious therapeutics targeting these fundamental hallmarks of cancer, however there are currently no animal models that mimic the invasive phenotypes observed in humans. To address this we have developed an orthotopic mouse model whereby gastric cancer cell lines are tagged with luciferase and injected into the subserosal layer of the stomach. This allows for the monitoring of primary tumour growth and metastasis in real-time as well as quantitation of the degree of tumour invasion through the stomach wall by immunohistochemistry. We have three models based on the degree of invasion and metastasis that are cell line specific: The AGS cells develop into invasive tumours by 4-weeks with no evidence of metastases, MKN45 cells are moderately metastatic with minimal invasion till week 2 and MKN28 cells are highly metastatic and fully invasive by week 1. These models have utility as a tool for testing the efficacy of anti-tumour, anti-invasive and anti-metastatic therapies in the setting of gastric cancer, which currently has poor treatment options.
Publisher: Public Library of Science (PLoS)
Date: 22-09-2010
Publisher: Springer Science and Business Media LLC
Date: 03-06-2021
DOI: 10.1038/S41562-021-01108-6
Abstract: Exclusive breastfeeding (EBF)—giving infants only breast-milk for the first 6 months of life—is a component of optimal breastfeeding practices effective in preventing child morbidity and mortality. EBF practices are known to vary by population and comparable subnational estimates of prevalence and progress across low- and middle-income countries (LMICs) are required for planning policy and interventions. Here we present a geospatial analysis of EBF prevalence estimates from 2000 to 2018 across 94 LMICs mapped to policy-relevant administrative units (for ex le, districts), quantify subnational inequalities and their changes over time, and estimate probabilities of meeting the World Health Organization’s Global Nutrition Target (WHO GNT) of ≥70% EBF prevalence by 2030. While six LMICs are projected to meet the WHO GNT of ≥70% EBF prevalence at a national scale, only three are predicted to meet the target in all their district-level units by 2030.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Elsevier BV
Date: 07-2023
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 10-2020
Publisher: Springer Science and Business Media LLC
Date: 17-03-2021
Publisher: Oxford University Press (OUP)
Date: 25-11-2017
DOI: 10.1093/BIOINFORMATICS/BTW685
Abstract: The application of a genomics assay to s les from a cohort is a frequently applied experimental design in cancer genomics studies. The collection and analysis of cancer sequencing data in the clinical setting is an elaborate process that may involve consenting patients, obtaining possibly-multiple DNA s les, sequencing and analysis. Many of these steps are manual. At any stage mistakes can occur that cause a DNA s le to be labelled incorrectly. However, there is a paucity of methods in the literature to identify such swaps specifically in cancer studies. Here, we introduce a simple method, HYSYS, to estimate the relatedness of s les and test for s le swaps and contamination. The test uses the concordance of homozygous SNPs between s les. The method is motivated by the observation that homozygous germline population variants rarely change in the disease and are not affected by loss of heterozygosity. Our tools include visualization and a testing framework to flag possible s le swaps. We demonstrate the utility of this approach on a small cohort. github.com/PapenfussLab/HaveYouSwappedYourS les Supplementary data are available at Bioinformatics online.
Publisher: Elsevier BV
Date: 07-2022
Publisher: Public Library of Science (PLoS)
Date: 27-10-2015
Publisher: Oxford University Press (OUP)
Date: 19-06-2009
DOI: 10.1093/BIOINFORMATICS/BTP379
Abstract: Motivation: Second-generation sequencing technologies produce a massive amount of short reads in a single experiment. However, sequencing errors can cause major problems when using this approach for de novo sequencing applications. Moreover, existing error correction methods have been designed and optimized for shotgun sequencing. Therefore, there is an urgent need for the design of fast and accurate computational methods and tools for error correction of large amounts of short read data. Results: We present SHREC, a new algorithm for correcting errors in short-read data that uses a generalized suffix trie on the read data as the underlying data structure. Our results show that the method can identify erroneous reads with sensitivity and specificity of over 99% and 96% for simulated data with error rates of up to 3% as well as for real data. Furthermore, it achieves an error correction accuracy of over 80% for simulated data and over 88% for real data. These results are clearly superior to previously published approaches. SHREC is available as an efficient open-source Java implementation that allows processing of 10 million of short reads on a standard workstation. Availability: SHREC source code in JAVA is freely available at www.informatik.uni-kiel.de/∼jasc/Shrec/ Contact: jasc@informatik.uni-kiel.de
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-020-14351-8
Abstract: We present SVclone, a computational method for inferring the cancer cell fraction of structural variant (SV) breakpoints from whole-genome sequencing data. SVclone accurately determines the variant allele frequencies of both SV breakends, then simultaneously estimates the cancer cell fraction and SV copy number. We assess performance using in silico mixtures of real s les, at known proportions, created from two clonal metastases from the same patient. We find that SVclone’s performance is comparable to single-nucleotide variant-based methods, despite having an order of magnitude fewer data points. As part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we use SVclone to reveal a subset of liver, ovarian and pancreatic cancers with subclonally enriched copy-number neutral rearrangements that show decreased overall survival. SVclone enables improved characterisation of SV intra-tumour heterogeneity.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2023
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.CCELL.2014.09.010
Abstract: We isolated and analyzed, at single-nucleotide resolution, cancer-associated neochromosomes from well- and/or dedifferentiated liposarcomas. Neochromosomes, which can exceed 600 Mb in size, initially arise as circular structures following chromothripsis involving chromosome 12. The core of the neochromosome is lified, rearranged, and corroded through hundreds of breakage-fusion-bridge cycles. Under selective pressure, lified oncogenes are overexpressed, while co lified passenger genes may be silenced epigenetically. New material may be captured during punctuated chromothriptic events. Centromeric corrosion leads to crisis, which is resolved through neocentromere formation or native centromere capture. Finally, lification terminates, and the neochromosome core is stabilized in linear form by telomere capture. This study investigates the dynamic mutational processes underlying the life history of a special form of cancer mutation.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2020
DOI: 10.1038/S41586-020-03043-4
Abstract: The safe, highly effective measles vaccine has been recommended globally since 1974, yet in 2017 there were more than 17 million cases of measles and 83,400 deaths in children under 5 years old, and more than 99% of both occurred in low- and middle-income countries (LMICs) 1–4 . Globally comparable, annual, local estimates of routine first-dose measles-containing vaccine (MCV1) coverage are critical for understanding geographically precise immunity patterns, progress towards the targets of the Global Vaccine Action Plan (GVAP), and high-risk areas amid disruptions to vaccination programmes caused by coronavirus disease 2019 (COVID-19) 5–8 . Here we generated annual estimates of routine childhood MCV1 coverage at 5 × 5-km 2 pixel and second administrative levels from 2000 to 2019 in 101 LMICs, quantified geographical inequality and assessed vaccination status by geographical remoteness. After widespread MCV1 gains from 2000 to 2010, coverage regressed in more than half of the districts between 2010 and 2019, leaving many LMICs far from the GVAP goal of 80% coverage in all districts by 2019. MCV1 coverage was lower in rural than in urban locations, although a larger proportion of unvaccinated children overall lived in urban locations strategies to provide essential vaccination services should address both geographical contexts. These results provide a tool for decision-makers to strengthen routine MCV1 immunization programmes and provide equitable disease protection for all children.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2020
DOI: 10.1038/S41591-020-0807-6
Abstract: A double burden of malnutrition occurs when in iduals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of % in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic.
Publisher: BMJ
Date: 06-2020
DOI: 10.1136/BMJOPEN-2018-028476
Abstract: Despite the unparalleled success of immunisation in the control of vaccine preventable diseases, immunisation coverage in South Africa remains suboptimal. While many evidence-based interventions have successfully improved vaccination coverage in other countries, they are not necessarily appropriate to the immunisation needs, barriers and facilitators of South Africa. The aim of this research is to investigate barriers and facilitators to optimal vaccination uptake, and develop contextualised strategies and implementation plans to increase childhood and adolescent vaccination coverage in South Africa. The study will employ a mixed-methods research design. It will be conducted over three iterative phases and use the Adopt, Contextualise or Adapt (ACA) model as an overarching conceptual framework. Phase 1 will identify, and develop a s ling frame of, immunisation stakeholders involved in the design, planning and implementation of childhood and human papillomavirus immunisation programmes in South Africa. Phase 2 will identify the main barriers and facilitators to, and solutions for, increasing vaccination coverage. This phase will comprise exploratory qualitative research with stakeholders and a review of existing systematic reviews on interventions for improving vaccination coverage. Using the findings from Phase 2 and the ACA model, Phase 3 will develop a set of proposed interventions and implementation action plans for improving immunisation coverage in South Africa. These plans will be discussed, revised and finalised through a series of participatory stakeholder workshops and an online questionnaire, conducted as part of Phase 3. Ethical approval was obtained from the South African Medical Research Council (EC018-11/2018). No risks to participants are expected. Various steps will be taken to ensure the anonymity and confidentiality of participants. The study findings will be shared at stakeholder workshops, the website of Cochrane South Africa and academic publications and conferences.
Publisher: Elsevier BV
Date: 10-2020
Publisher: Elsevier BV
Date: 06-2020
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2015
DOI: 10.1158/0008-5472.CAN-15-1877
Abstract: Merkel cell carcinoma (MCC) is an uncommon, but highly malignant, cutaneous tumor. Merkel cell polyoma virus (MCV) has been implicated in a majority of MCC tumors however, viral-negative tumors have been reported to be more prevalent in some geographic regions subject to high sun exposure. While the impact of MCV and viral T-antigens on MCC development has been extensively investigated, little is known about the etiology of viral-negative tumors. We performed targeted capture and massively parallel DNA sequencing of 619 cancer genes to compare the gene mutations and copy number alterations in MCV-positive (n = 13) and -negative (n = 21) MCC tumors and cell lines. We found that MCV-positive tumors displayed very low mutation rates, but MCV-negative tumors exhibited a high mutation burden associated with a UV-induced DNA damage signature. All viral-negative tumors harbored mutations in RB1, TP53, and a high frequency of mutations in NOTCH1 and FAT1. Additional mutated or lified cancer genes of potential clinical importance included PI3K (PIK3CA, AKT1, PIK3CG) and MAPK (HRAS, NF1) pathway members and the receptor tyrosine kinase FGFR2. Furthermore, looking ahead to potential therapeutic strategies encompassing immune checkpoint inhibitors such as anti-PD-L1, we also assessed the status of T-cell–infiltrating lymphocytes (TIL) and PD-L1 in MCC tumors. A subset of viral-negative tumors exhibited high TILs and PD-L1 expression, corresponding with the higher mutation load within these cancers. Taken together, this study provides new insights into the underlying biology of viral-negative MCC and paves the road for further investigation into new treatment opportunities. Cancer Res 75(24) 5228–34. ©2015 AACR.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2021
DOI: 10.1038/S41598-020-80165-9
Abstract: Remodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation. Activation of T cells, which triggers extensive changes in transcriptional programs, serves as an instructive model to elucidate how changes in chromatin architecture orchestrate gene expression in response to cell perturbation. To characterize coordinate changes at different levels of chromatin architecture, we analyzed chromatin accessibility, chromosome conformation and gene expression in activated human T cells. T cell activation was characterized by widespread changes in chromatin accessibility and interactions that were shared between activated CD4 + and CD8 + T cells, and with the formation of active regulatory regions associated with transcription factors relevant to T cell biology. Chromatin interactions that increased and decreased were coupled, respectively, with up- and down-regulation of corresponding target genes. Furthermore, activation was associated with disruption of long-range chromatin interactions and with partitioning of topologically associating domains (TADs) and remodelling of their TAD boundaries. Newly formed/strengthened TAD boundaries were associated with higher nucleosome occupancy and lower accessibility, linking changes in lower and higher order chromatin architecture. T cell activation exemplifies coordinate multi-level remodelling of chromatin underlying gene transcription.
Publisher: Oxford University Press (OUP)
Date: 02-01-2014
DOI: 10.1093/BIOINFORMATICS/BTT767
Abstract: Motivation: Methods for detecting somatic genome rearrangements in tumours using next-generation sequencing are vital in cancer genomics. Available algorithms use one or more sources of evidence, such as read depth, paired-end reads or split reads to predict structural variants. However, the problem remains challenging due to the significant computational burden and high false-positive or false-negative rates. Results: In this article, we present Socrates (SOft Clip re-alignment To idEntify Structural variants), a highly efficient and effective method for detecting genomic rearrangements in tumours that uses only split-read data. Socrates has single-nucleotide resolution, identifies micro-homologies and untemplated sequence at break points, has high sensitivity and high specificity and takes advantage of parallelism for efficient use of resources. We demonstrate using simulated and real data that Socrates performs well compared with a number of existing structural variant detection tools. Availability and implementation: Socrates is released as open source and available from bioinf.wehi.edu.au/socrates. Contact: papenfuss@wehi.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2021
DOI: 10.1038/S41467-021-22863-0
Abstract: With age, hematopoietic stem cells (HSC) undergo changes in function, including reduced regenerative potential and loss of quiescence, which is accompanied by a significant expansion of the stem cell pool that can lead to haematological disorders. Elevated metabolic activity has been implicated in driving the HSC ageing phenotype. Here we show that nicotinamide riboside (NR), a form of vitamin B3, restores youthful metabolic capacity by modifying mitochondrial function in multiple ways including reduced expression of nuclear encoded metabolic pathway genes, d ing of mitochondrial stress and a decrease in mitochondrial mass and network-size. Metabolic restoration is dependent on continuous NR supplementation and accompanied by a shift of the aged transcriptome towards the young HSC state, more youthful bone marrow cellular composition and an improved regenerative capacity in a transplant setting. Consequently, NR administration could support healthy ageing by re-establishing a more youthful hematopoietic system.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 06-2020
Publisher: Cold Spring Harbor Laboratory
Date: 02-11-2017
Abstract: The identification of genomic rearrangements with high sensitivity and specificity using massively parallel sequencing remains a major challenge, particularly in precision medicine and cancer research. Here, we describe a new method for detecting rearrangements, GRIDSS (Genome Rearrangement IDentification Software Suite). GRIDSS is a multithreaded structural variant (SV) caller that performs efficient genome-wide break-end assembly prior to variant calling using a novel positional de Bruijn graph-based assembler. By combining assembly, split read, and read pair evidence using a probabilistic scoring, GRIDSS achieves high sensitivity and specificity on simulated, cell line, and patient tumor data, recently winning SV subchallenge #5 of the ICGC-TCGA DREAM8.5 Somatic Mutation Calling Challenge. On human cell line data, GRIDSS halves the false discovery rate compared to other recent methods while matching or exceeding their sensitivity. GRIDSS identifies nontemplate sequence insertions, microhomologies, and large imperfect homologies, estimates a quality score for each breakpoint, stratifies calls into high or low confidence, and supports multis le analysis.
Publisher: Springer Science and Business Media LLC
Date: 16-06-2022
DOI: 10.1038/S41536-022-00226-7
Abstract: The impact of aging on intestinal stem cells (ISCs) has not been fully elucidated. In this study, we identified widespread epigenetic and transcriptional alterations in old ISCs. Using a reprogramming algorithm, we identified a set of key transcription factors ( Egr1, Irf1, FosB ) that drives molecular and functional differences between old and young states. Overall, by dissecting the molecular signature of aged ISCs, our study identified transcription factors that enhance the regenerative capacity of ISCs.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2020
DOI: 10.1038/S41586-019-1878-8
Abstract: Childhood malnutrition is associated with high morbidity and mortality globally 1 . Undernourished children are more likely to experience cognitive, physical, and metabolic developmental impairments that can lead to later cardiovascular disease, reduced intellectual ability and school attainment, and reduced economic productivity in adulthood 2 . Child growth failure (CGF), expressed as stunting, wasting, and underweight in children under five years of age (0–59 months), is a specific subset of undernutrition characterized by insufficient height or weight against age-specific growth reference standards 3–5 . The prevalence of stunting, wasting, or underweight in children under five is the proportion of children with a height-for-age, weight-for-height, or weight-for-age z -score, respectively, that is more than two standard deviations below the World Health Organization’s median growth reference standards for a healthy population 6 . Subnational estimates of CGF report substantial heterogeneity within countries, but are available primarily at the first administrative level (for ex le, states or provinces) 7 the uneven geographical distribution of CGF has motivated further calls for assessments that can match the local scale of many public health programmes 8 . Building from our previous work mapping CGF in Africa 9 , here we provide the first, to our knowledge, mapped high-spatial-resolution estimates of CGF indicators from 2000 to 2017 across 105 low- and middle-income countries (LMICs), where 99% of affected children live 1 , aggregated to policy-relevant first and second (for ex le, districts or counties) administrative-level units and national levels. Despite remarkable declines over the study period, many LMICs remain far from the ambitious World Health Organization Global Nutrition Targets to reduce stunting by 40% and wasting to less than 5% by 2025. Large disparities in prevalence and progress exist across and within countries our maps identify high-prevalence areas even within nations otherwise succeeding in reducing overall CGF prevalence. By highlighting where the highest-need populations reside, these geospatial estimates can support policy-makers in planning interventions that are adapted locally and in efficiently directing resources towards reducing CGF and its health implications.
Publisher: Springer Science and Business Media LLC
Date: 15-12-2022
DOI: 10.1038/S41467-022-35303-4
Abstract: The vertebrate main-body axis is laid down during embryonic stages in an anterior-to-posterior (head-to-tail) direction, driven and supplied by posteriorly located progenitors. Whilst posterior expansion and segmentation appears broadly uniform along the axis, there is developmental and evolutionary support for at least two discrete modules controlling processes within different axial regions: a trunk and a tail module. Here, we identify Nuclear receptor subfamily 6 group A member 1 (Nr6a1) as a master regulator of trunk development in the mouse. Specifically, Nr6a1 was found to control vertebral number and segmentation of the trunk region, autonomously from other axial regions. Moreover, Nr6a1 was essential for the timely progression of Hox signatures, and neural versus mesodermal cell fate choice, within axial progenitors. Collectively, Nr6a1 has an axially-restricted role in all major cellular and tissue-level events required for vertebral column formation, supporting the view that changes in Nr6a1 levels may underlie evolutionary changes in axial formulae.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Elsevier BV
Date: 06-2020
Publisher: Springer Berlin Heidelberg
Date: 2009
Publisher: Springer Science and Business Media LLC
Date: 25-12-2019
DOI: 10.1038/S41586-019-1872-1
Abstract: Educational attainment is an important social determinant of maternal, newborn, and child health 1–3 . As a tool for promoting gender equity, it has gained increasing traction in popular media, international aid strategies, and global agenda-setting 4–6 . The global health agenda is increasingly focused on evidence of precision public health, which illustrates the subnational distribution of disease and illness 7,8 however, an agenda focused on future equity must integrate comparable evidence on the distribution of social determinants of health 9–11 . Here we expand on the available precision SDG evidence by estimating the subnational distribution of educational attainment, including the proportions of in iduals who have completed key levels of schooling, across all low- and middle-income countries from 2000 to 2017. Previous analyses have focused on geographical disparities in average attainment across Africa or for specific countries, but—to our knowledge—no analysis has examined the subnational proportions of in iduals who completed specific levels of education across all low- and middle-income countries 12–14 . By geolocating subnational data for more than 184 million person-years across 528 data sources, we precisely identify inequalities across geography as well as within populations.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2019
DOI: 10.1038/S41586-019-1545-0
Abstract: Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2020
DOI: 10.1038/S41591-020-0972-7
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Start Date: 06-2019
End Date: 06-2022
Amount: $455,000.00
Funder: Australian Research Council
View Funded Activity