Prolyl-4-hydroxylase Α subunit 2 (P4HA2) expression is a predictor of poor outcome in breast ductal carcinoma in situ (DCIS)

© 2018, Cancer Research UK. Background: Extracellular matrix (ECM) plays a crucial role in tumour behaviour. Prolyl-4-hydroxlase-A2 (P4HA2) is a key enzyme in ECM remodelling. This study aims to evaluate the prognostic significance of P4HA2 in breast ductal carcinoma in situ (DCIS). Methods: P4HA2 expression was assessed immunohistochemically in malignant cells and surrounding stroma of a large DCIS cohort comprising 481 pure DCIS and 196 mixed DCIS and invasive carcinomas. Outcome analysis was evaluated using local recurrence free interval (LRFI). Results: High P4HA2 expression was detected in malignant cells of half of pure DCIS whereas its expression in stroma was seen in 25% of cases. Higher P4HA2 expression was observed in mixed DCIS cases compared to pure DCIS both in tumour cells and in stroma. High P4HA2 was associated with features of high risk DCIS including younger age, higher grade, comedo necrosis, triple negative and HER2-positive phenotypes. Interaction between P4HA2 and radiotherapy was also observed regarding the outcome. High P4HA2 expression was an independent prognostic factor in predicting shorter LRFI. Conclusion: P4HA2 plays a role in DCIS progression and can potentially be used to predict DCIS outcome. Incorporation of P4HA2 with other clinicopathological parameters could refine DCIS risk stratification that can potentially guide management decisions

Формирование эмоциональной культуры как компонента инновационной культуры студентов

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Trees tell tales : UBC's changing landscapes

An expert on the native plant life of British Columbia, Shona Ellis has restructured UBC’s Biology program, the largest undergraduate science program offered at UBC, by shifting instructional strategies to improve teaching and student advising, as well as integrating sustainability into the curriculum so students become informed global citizens.Science, Faculty ofBotany, Department ofUnreviewedFacult

Thiarubrine production in roots and root cultures of Ambrosia chamissonis

Ambrosia chamissonis (Asteraceae) provides antibiotic sulphur heterocyclic polyynes known as thiarubrines and thiophenes. They occur in all parts of the plant, especially in the roots and can be visualized in hand sections. Methods were developed for their isolation, purification and quantification. Plants were collected from various locations in B.C. and found to have different thiarubrine profiles. A new thiarubrine (3-(1-propyny1)-6-(6-hydroxyhex-3-yn-1yny1)-1,2-dithiacyclohexadiene) and thiophene (2-(1-propyny1)-6-(6-hydroxyhex-3-yn-1yny1)-thiophene) were identified from roots and root cultures. Transgenic and non-transgenic root cultures were generated and shown to produce the same compounds as occur in natural roots. Quantitative chemical profiles of the cultured roots matched those of roots which had little secondary growth. Elicitation, with fungal preparations, did not enhance the over-all thiarubrine concentration, but the content of a more fungicidal thiarubrine was enhanced at the expense of a less active, but predominant thiarubrine. Administration of biosynthetic precursors did not have any effect on thiarubrine production. Antibiotic testing indicated that the thiarubrines are toxic against a number of fungi and, to a lesser degree, bacteria.Science, Faculty ofBotany, Department ofGraduat

Lipid abundance in zebrafish embryos is regulated by complementary actions of the endocannabinoid system and retinoic acid pathway

The endocannabinoid system (ECS) and retinoic acid (RA) signaling have been associated with influencing lipid metabolism. We hypothesized that modulation of these pathways could modify lipid abundance in developing vertebrates and that these pathways could have a combinatorial effect on lipid levels. Zebrafish embryos were exposed to chemical treatments altering the activity of the ECS and RA pathway. Embryos were stained with the neutral lipid dye Oil-Red-O (ORO) and underwent whole-mount in situ hybridization. Mouse 3T3-L1 fibroblasts were differentiated under exposure to RA modulating chemicals and subsequently stained with ORO and analyzed for gene expression by qRT-PCR. ECS activation and RA exposure increased lipid abundance and the expression of lipoprotein lipase. Additionally, RA treatment increased expression of CCAAT/enhancer binding protein alpha. Both ECS receptors and RA receptor subtypes were separately involved in modulating lipid abundance. Finally, increased ECS or RA activity ameliorated the reduced lipid abundance caused by peroxisome proliferator-activated receptor gamma (PPAR&gamma;) inhibition. Therefore, the ECS and RA pathway influence lipid abundance in zebrafish embryos and have an additive effect when treated simultaneously. Furthermore, we demonstrated that these pathways act downstream or independently of PPAR&gamma; to influence lipid levels. Our study shows for the first time that the RA and ECS pathways have additive function in lipid abundance during vertebrate development

Moving beyond the formal: developing significant networks and conversations in higher education: reflections from an interdisciplinary European project team

Conversations and networks are essential for transforming academics’ teaching practices as learning experiences (Palmer 1993). Yet, there has been little research reporting academics’ informal conversations about teaching (Thomson and Trigwell 2018). Teachers will generally access small significant networks (Becher and Trowler 2001) for nuanced and personal issues relating to teaching and learning. Collaborative transnational projects provide fertile ground for unique conversations about Higher Education (HE) teaching (Thomson 2015), with the added value of cross-national perspectives. This study examines the conditions that help to create significant networks and conversations, based on collective autoethnographic reflections of the member of an Erasmus+ project, including five partner universities from four different countries. The results provide insights into how the project have afforded the generation and continuation of cross-national and interdisciplinary significant networks and how unique conversations have allowed for trust, relationships and common goals to develop, which add value beyond the individual level

Organellomic data sets confirm a cryptic consensus on (unrooted) land‐plant relationships and provide new insights into bryophyte molecular evolution

Premise Phylogenetic trees of bryophytes provide important evolutionary context for land plants. However, published inferences of overall embryophyte relationships vary considerably. We performed phylogenomic analyses of bryophytes and relatives using both mitochondrial and plastid gene sets, and investigated bryophyte plastome evolution. Methods We employed diverse likelihood‐based analyses to infer large‐scale bryophyte phylogeny for mitochondrial and plastid data sets. We tested for changes in purifying selection in plastid genes of a mycoheterotrophic liverwort (Aneura mirabilis) and a putatively mycoheterotrophic moss (Buxbaumia), and compared 15 bryophyte plastomes for major structural rearrangements. Results Overall land‐plant relationships conflict across analyses, generally weakly. However, an underlying (unrooted) four‐taxon tree is consistent across most analyses and published studies. Despite gene coverage patchiness, relationships within mosses, liverworts, and hornworts are largely congruent with previous studies, with plastid results generally better supported. Exclusion of RNA edit sites restores cases of unexpected non‐monophyly to monophyly for Takakia and two hornwort genera. Relaxed purifying selection affects multiple plastid genes in mycoheterotrophic Aneura but not Buxbaumia. Plastid genome structure is nearly invariant across bryophytes, but the tufA locus, presumed lost in embryophytes, is unexpectedly retained in several mosses. Conclusions A common unrooted tree underlies embryophyte phylogeny, [(liverworts, mosses), (hornworts, vascular plants)]; rooting inconsistency across studies likely reflects substantial distance to algal outgroups. Analyses combining genomic and transcriptomic data may be misled locally for heavily RNA‐edited taxa. The Buxbaumia plastome lacks hallmarks of relaxed selection found in mycoheterotrophic Aneura. Autotrophic bryophyte plastomes, including Buxbaumia, hardly vary in overall structure

Mapping and characterisation of key biotic and physical attributes of the Torres Strait ecosystem: CRC-TS task number: T2.1 final report

The Torres Strait Protected Zone (TSPZ) is a unique area of ecological and cultural significance, shared under an international treaty with Papua New Guinea. As a joint management area, activities such as commercial fishing and traditional hunting occur with primary natural resource conservation goals. Managers need information on habitats and biodiversity distribution and risks to ensure these activities are conducted sustainably. However, while broad seabed habitat information was available for much of the TSPZ from past projects, there were significant gaps and very limited species level data. From 2003 to 2006, the Torres Strait Mapping and Characterisation Project has mapped habitats and their associated biodiversity across the length and breadth of the Protected Zone to provide information that will help managers with regional planning and to ensure that fisheries are ecologically sustainable, as required by environmental protection legislation.\ud \ud Comprehensive information on the biodiversity of the seabed was acquired by visiting almost 200 sites, representing a wide range of known environments, during two 1-month-long voyages on two vessels and deploying several types of devices such as: towed video and digital cameras, an epibenthic sled and a research trawl to collect samples for more detailed data about plants, invertebrates and fishes on the seabed. Data were collected and processed from ~100 km of towed video and >10,000 photos, and from sorting and identification of ~2,000 benthic samples, ~1,200 seabed fish samples, and ~200 sediment samples. The project has analysed this information and produced all of the outputs as originally proposed; these included:\ud \ud • Images and videos of seabed habitat types and fishes, including more than 120 substratum and biological habitat component types. An inventory of more than 3,600 species of benthos, bycatch and fishes, with catalogued museum voucher specimens, many of which were new species, and a database of almost 25,000 records of species distribution and abundance on the seabed.\ud \ud • Identification of the key environmental variables likely to be important in structuring seabed distributions, and predictive models of bio-physical relationships between seabed species, their assemblages and the physical environment.\ud \ud • Maps of the distribution and abundance of ~250 seabed species throughout the TSPZ region.\ud \ud • Estimates of the likely extent of past effects of trawling on benthos and bycatch over the entire TSPZ region, which indicated that trawl effort had a significant effect on the biomass of 8.2% of ~250 species mapped; with negative change of -3% to -18% for 3.5% of species and positive change of +3% to +63% for 4.7% of species.\ud \ud • Estimates of exposure to trawl effort showed that about 80% of the ~250 species mapped had low or very low exposure, and at the other extreme about 21 species had moderate-high to very-high exposure - of these species, after taking relative catch rates into account, six had moderate-high to very high estimates of proportion caught annually and 13 had moderate-low. The remainder (237) had low or very low estimates of proportion caught annually.\ud \ud • Indicators based on qualitative recovery ranks showed that about 9 species stood out as being at higher relative risk. Another, additional, quantitative absolute sustainability indicator showed that one species exceeded a limit reference point while three others exceeded one or two conservative reference points. Another 10 species were also listed due to uncertainty in parameters though they were below the sustainability reference points. Further research is recommended to address key uncertainties in estimates of these indicators.\ud \ud A key output from the project is the identification, by means of the trawl exposure and sustainability indicators, of species at risk or potentially at risk from trawling. Different species were highlighted by different indicators, though there was some overlap. One indicator was both quantitative and directly related to sustainability, with biologically based reference points - while one species appeared to be at risk and another three species exceeded conservative reference points, there is uncertainty that requires a more precautionary response. Hence, the top ranked species for all indicators were listed and recommended to be considered for stakeholder consultation regarding future action; options may include clarification of the identified uncertainties, monitoring of species at risk, and management interventions that reduce risk or combinations of these actions.\ud \ud It is also recommended that long-term monitoring of trends in ecological condition of identified key seabed habitats and constituent species be implemented to assess responses to regional pressures, including climate change. Candidate habitats should include those that have been demonstrated to be particularly biodiverse such as vegetated areas and epibenthic gardens. The seabed may well be vulnerable to climate change as there is an expectation that the thermocline may deepen and upwellings may become weaker and less frequent, with potential consequences for productive habitat dependent on nutrients from such sources.\ud \ud Further work is needed to address the uncertainties in the risk assessments that arise from uncertainties in estimates of catchability and natural mortality rates. Currently, the uncertainty is such that several additional species could exceed the reference points and many species with unknown mortality might be of concern. It is also possible that clarification of these uncertainties may show that species currently thought to be at risk or potentially at risk may be demonstrated to be of no sustainability concern. Thus, it is recommended that further studies of catchabilities and natural mortality rates be conducted to address this key uncertainty for affected species. Such results are likely to have wide application in risk assessments being conducted in multiple jurisdictions.\ud \ud Many fisheries in Australia are conducting qualitative approaches to Ecological Risk Assessments. However, the results of the more quantitative sustainability indicators applied here raise concerns about the reliability of the qualitative approaches, which have not been benchmarked because of the lack of a suitable test bed. Such a test bed is now available with this Torres Strait seabed mapping and characterisation dataset and an assessment of the performance of the qualitative methods is warranted. This seabed mapping dataset also provides an opportunity to develop condition and trend and vulnerability indicators for seabed communities and ecosystems that are needed to meet the increasing requirement for ecosystem-based management approaches.\ud \ud A follow on project supported by the Marine and Tropical Science Research Facility is quantifying visible species from the available towed camera video to fill significant gaps in areas that were too rough for sampling and are currently lacking species information.\ud \ud Another project supported by the Commonwealth Environment Research Fund National Marine Biodiversity Hub will use the Torres Strait seabed mapping dataset in comparisons with other datasets to test the inter-regional utility of physical variables and cross-taxonomic patterns as surrogates for application in marine planning at a national scale.\ud \ud Other further opportunities include: sorting and identification of remaining samples that could not be completed within the scope of the project, and taxonomic work to properly identify the more difficult specimens. These activities would provide full utilization of the samples and deliver additional value, with expected benefits for greater understanding of the seabed ecosystem, fishery sustainability, and ongoing regional marine planning