25 research outputs found
A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells
Human exposure to carcinogens occurs via a plethora of environmental sources, with 70–90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-testing paradigm in human cancer risk assessment fail to accurately represent and predict whether a chemical causes human carcinogenesis. The study aimed to establish whether the integrated analysis of multiple cellular endpoints related to the Hallmarks of Cancer could advance in vitro carcinogenicity assessment. Human lymphoblastoid cells (TK6, MCL-5) were treated for either 4 or 23 h with 8 known in vivo carcinogens, with doses up to 50% Relative Population Doubling (maximum 66.6 mM). The adverse effects of carcinogens on wide-ranging aspects of cellular health were quantified using several approaches; these included chromosome damage, cell signalling, cell morphology, cell-cycle dynamics and bioenergetic perturbations. Cell morphology and gene expression alterations proved particularly sensitive for environmental carcinogen identification. Composite scores for the carcinogens’ adverse effects revealed that this approach could identify both DNA-reactive and non-DNA reactive carcinogens in vitro. The richer datasets generated proved that the holistic evaluation of integrated phenotypic alterations is valuable for effective in vitro risk assessment, while also supporting animal test replacement. Crucially, the study offers valuable insights into the mechanisms of human carcinogenesis resulting from exposure to chemicals that humans are likely to encounter in their environment. Such an understanding of cancer induction via environmental agents is essential for cancer prevention
The Role of Schools in Early Adolescents’ Mental Health: Findings from the MYRIAD Study
This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordData Sharing:
The corresponding study protocol can be found at
https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-017-1917-4.
R code is available from the Open Science Framework
(https://osf.io/s63fm/?view_only=5ae58f6c053c4a16b5ddfccd0e6e1ece).
The baseline data and codebook from the MYRIAD trial is available from Prof. Kuyken
([email protected]) upon request (release of data is subject to an approved
proposal and a signed data access agreement).Objective: Recent studies suggest deteriorating youth mental health. The current UK policy
emphasises the role of schools for mental health promotion and prevention, but little data
exist on what aspects of schools explain pupils’ mental health. We explored school-level
influences on the mental health of young people in a large school-based sample from the UK.
Methods: We analysed baseline data from a large cluster randomized controlled trial
(ISRCTN 86619085) collected between 2016‒2018 from mainstream UK secondary schools
selected to be representative in relation to their quality rating, size, deprivation, mixed or
single-sex pupil population and country. Participants were pupils in their first or second year
of secondary school. We assessed whether school-level factors were associated with pupil
mental health.
Results: 26,885 pupils (response rate=90%), aged 11‒14 years, 55% female, attending 85 UK
schools, were included. Schools accounted for 2.4% (95% CI=2.0‒2.8; p<0.0001) of the
variation in psychopathology, 1.6% (95% CI=1.2‒2.1; p<0.0001) of depression and 1.4%
(95% CI=1.0‒1.7; p<0.0001) of well-being. Schools in urban locations, with a higher
percentage of free school meals and of White British, were associated with poorer pupil
mental health. A more positive school climate was associated with better mental health.
Conclusion: School-level variables, primarily related to contextual factors, characteristics of
their pupil population, and school climate explain a small but significant amount of variability
in young people’s mental health. This might be used to identify schools that are in need of
more resources to support young people’s mental health.Wellcome TrustNational Institute for Health Research (NIHR)Medical Research Council (MRC
The Pneumococcal Iron Uptake Protein a (PiuA) Specifically Recognizes Tetradentate FeIIIbis- and Mono-Catechol Complexes
Streptococcus pneumoniae (Spn) is an important Gram-positive human pathogen that causes millions of infections worldwide with an increasing occurrence of antibiotic resistance. Fe acquisition is a crucial virulence determinant in Spn; further, Spn relies on exogenous FeIII-siderophore scavenging to meet nutritional Fe needs. Recent studies suggest that the human catecholamine stress hormone, norepinephrine (NE), facilitates Fe acquisition in Spn under conditions of transferrin-mediated Fe starvation. Here we show that the solute binding lipoprotein PiuA from the piu Fe acquisition ABC transporter PiuBCDA, previously described as an Fe-hemin binding protein, binds tetradentate catechol FeIII complexes, including NE and the hydrolysis products of enterobactin. Two protein-derived ligands (H238, Y300) create a coordinately-saturated FeIII complex, which parallel recent studies in the Gram-negative intestinal pathogen Campylobacter jejuni. Our in vitro studies using NMR spectroscopy and 54Fe LC-ICP-MS confirm the FeIII can move from transferrin to apo-PiuA in a NE-dependent manner. Structural analysis of PiuA FeIII-bis-catechol and GaIII-bis-catechol and GaIII-(NE)2 complexes by NMR spectroscopy reveals only localized structural perturbations in PiuA upon ligand binding, largely consistent with recent descriptions of other solute binding proteins of type II ABC transporters. We speculate that tetradentate FeIII complexes formed by mono- and bis-catechol species are important Fe sources in Gram-positive human pathogens, since PiuA functions in the same way as SstD from Staphylococcus aureus
Recommended from our members
Luciano Floridi and contemporary art practice
This article examines how the thinking of Luciano Floridi, especially his emphasis on information, could affect the way we approach art practice. It aims to situate art practice in relation to contemporary informational theories and suggests that the way we view contemporary art practice needs to move beyond existing theories. Key components to Floridi’s philosophy are introduced with relevance to art practice, followed by an analysis of these concepts with examples from the history of art. It is hoped that, by clarifying some of the more complex terms and concepts, readers will form a better understanding of the connections and potential synergy between art practice and the sciences of information, through the philosophy of Floridi
The Seventeenth Data Release of the Sloan Digital Sky Surveys: Complete Release of MaNGA, MaStar and APOGEE-2 Data
This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library (MaStar) accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) survey which publicly releases infra-red spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the sub-survey Time Domain Spectroscopic Survey (TDSS) data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey (SPIDERS) sub-survey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated Value Added Catalogs (VACs). This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper (MWM), Local Volume Mapper (LVM) and Black Hole Mapper (BHM) surveys
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio
Recommended from our members
Update to the effectiveness and cost-effectiveness of a mindfulness training programme in schools compared with normal school provision (MYRIAD): study protocol for a randomised controlled trial
Abstract: Background: MYRIAD (My Resilience in Adolescence) is a superiority, parallel group, cluster randomised controlled trial designed to examine the effectiveness and cost-effectiveness of a mindfulness training (MT) programme, compared with normal social and emotional learning (SEL) school provision to enhance mental health, social-emotional-behavioural functioning and well-being in adolescence. The original trial protocol was published in Trials (accessible at https://doi.org/10.1186/s13063-017-1917-4). This included recruitment in two cohorts, enabling the learning from the smaller first cohort to be incorporated in the second cohort. Here we describe final amendments to the study protocol and discuss their underlying rationale. Methods: Four major changes were introduced into the study protocol: (1) there were changes in eligibility criteria, including a clearer operational definition to assess the degree of SEL implementation in schools, and also new criteria to avoid experimental contamination; (2) the number of schools and pupils that had to be recruited was increased based on what we learned in the first cohort; (3) some changes were made to the secondary outcome measures to improve their validity and ability to measure constructs of interest and to reduce the burden on school staff; and (4) the current Coronavirus Disease 2019 (SARS-CoV-2 or COVID-19) pandemic both influences and makes it difficult to interpret the 2-year follow-up primary endpoint results, so we changed our primary endpoint to 1-year follow-up. Discussion: These changes to the study protocol were approved by the Trial Management Group, Trial Steering Committee and Data and Ethics Monitoring Committees and improved the enrolment of participants and quality of measures. Furthermore, the change in the primary endpoint will give a more reliable answer to our primary question because it was collected prior to the COVID-19 pandemic in both cohort 1 and cohort 2. Nevertheless, the longer 2-year follow-up data will still be acquired, although this time-point will be now framed as a second major investigation to answer some new important questions presented by the combination of the pandemic and our study design. Trial registration: International Standard Randomised Controlled Trials ISRCTN86619085. Registered on 3 June 2016
Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity
A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC50 >3× EC50) towards human coronavirus (HCoV)-NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC50 100μM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses.publisher: Elsevier
articletitle: Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity
journaltitle: Bioorganic & Medicinal Chemistry Letters
articlelink: http://dx.doi.org/10.1016/j.bmcl.2015.05.039
content_type: article
copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.status: publishe