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Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator – POU2AF2
No full textBackground:Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, exerting local expression quantitative trait locus (cis-eQTL) effects on POU2AF2, COLCA1 and POU2AF3 genes. However, complex linkage disequilibrium and correlated expression has hindered elucidation of the mechanisms by which genetic variants impart underlying CRC risk. ObjectiveUndertake an interdisciplinary approach to understand how variation at 11q23.1 locus imparts CRC risk.Design:We employ analysis of RNAseq, scRNAseq, ChIPseq and scATACseq data to identify, prioritise and characterise the genes which impart CRC risk. We further validate these findings using mouse models and demonstrate parallel effects in human colonic mucosa.Results:We establish rs3087967 as a prime eQTL variant at 11q23.1, co-localising with CRC risk. Furthermore, rs3087967 influences expression of 21 distant genes, thereby acting as a trans-eQTL hub for a gene-set highly enriched for tuft cell markers. Epigenomic analysis implicates POU2AF2 as controlling the tuft cell specific trans-genes, through POU2F3-correlated genomic regulation. Immunofluorescence confirms rs3087967 risk genotype (T) to be associated with a tuft cell deficit in the human colon. CRISPR-mediated deletion of the 11q23.1 risk locus genes in the mouse germline exacerbated the ApcMin/+ mouse phenotype upon abrogation of Pou2af2 expression specifically. Conclusion:We demonstrate that genotype at rs3087967 controls a portfolio of genes through mis-regulation of POU2AF2. POU2AF2 is the primary transcriptional activator of tuft cells with a tumour suppressive role in mouse models. We therefore implicate tuft cells as having a key tumour-protective role in the large bowel epithelium.<br/
Impact of out-of-home nutrition labelling on people with eating disorders:A systematic review and meta-synthesis
No full textObjectives: Mandatory nutrition labels for out-of-home food consumption have been introduced in several countries to curb rising obesity levels. However, concerns have been raised about the potentia lnegative impacts of such policies on individuals with eating disorders. This review aimed to summarise the literature on the impact of out-of-home nutrition labels on individuals with eating disorders or disordered eating. Design: A systematic search across eight databases was conducted up to 11th of October 2023. Data sources: MEDLINE, EMBASE, APA PsycINFO, Web of Science, ProQuest Dissertations and Theses Global, Scopus and CINAHL. Unpublished studies were searched for on Google Scholar andPsyArXiv. Eligibility criteria: Studies were included if they assessed the impact of out-of-home nutrition labelling policies on individuals with eating disorders or disordered eating. Data extraction and synthesis: 538 studies were screened, of which 16 studies met inclusion criteria. Results: The reviewed studies included 5 experimental/quasi-experimental studies, 5 cross-sectional studies, and 6 qualitative/mixed methods studies. Across studies, eating disorder pathology was associated with noticing labels more frequently, paying more attention to caloric intake, and more frequent behaviour changes due to caloric values. The meta-synthesis identified 5 themes based on the qualitative findings, being drawn to calories, facilitating the eating disorder, reassurance, social eating, and frustration. Conclusions: The current review summarised the existing literature on the impact of out-of-home nutrition label policies on individuals with eating disorders. The evidence suggests that there is cause for concern regarding negative impacts, particularly for those with restrictive eating disorders, which should be explored further by research and considered by policy makers when making decisions on public health policies
<i>Shazam</i>, parodies, and the three-step test
Get PDFThis article focuses on the application of the parody and pastiche exceptions in Shazam v Only Fools. The article contends that the court’s assessment should have focused solely on whether the defendants’ actions could be regarded as fair dealing for purposes of parody or pastiche. It explains why it was unnecessary for the court to apply the three-step test
Corneal Graft Rejection: Is it Reflected in Peripheral Immune Cells? Results of a Prospective Multicenter Study (VISICORT)
No full textBackground. Allogeneic graft rejection is the leading cause of graft failure in corneal transplantation (CT) despite the immune privilege of the anterior chamber and corneal bed. The ability to identify patients at higher risk of acute rejection before or after CT could have a major impact on the clinical management of these patients. Methods. To address this important issue, a multicenter European cohort of low-risk (n = 142) and high-risk (n = 102) CT recipients was established, and the immune system was evaluated in detail in peripheral blood mononuclear cells and plasma before and 6 and 12 mo posttransplantation. Eleven patients in the low-risk group and 11 in the high-risk group experienced acute rejection. Results. Mass spectrometry analysis of plasma showed a high similarity in composition between patients with and without acute rejection, regardless of their preexisting clinical risk. Pretransplant and longitudinal immune cell analysis of peripheral blood mononuclear cells using deconvolution of transcriptomic profiling and high-dimensional flow cytometry revealed a lack of immune-related biomarkers associated with acute rejection. Conclusions. Our results indicate that the immune response leading to acute rejection of CT is unlikely to be detected in the peripheral blood and suggest that analysis of compartments in close proximity to the cornea is more likely to yield clinically applicable predictive biomarkers.</p
Possible glendonite mineral pseudomorphs in the aftermath of the end-Permian extinction
Get PDFGlendonites (from the precursor of ikaite, CaCO 3.6H 2O) preferentially precipitate within sediments in cold waters (− 2 to 7°C) via either organotrophic or methanogenic sulphate reduction. Here, we report the first occurrence of possible glendonites associated with the end Permian mass extinction in the earliest Triassic (ca. 252 Million years ago, Ma) subtropical marine carbonates on the Arabian Plateau, Oman. The authigenic carbonate crystals are small (< 2 mm) and precipitated either on bedding planes or reworked within micro cross-laminations, erosional scours, or lags at the base of calcisiltite turbidites, supporting a syn-depositional origin. The observed shape and macrostructure bear resemblance to that of glendonites. SEM and cathodoluminescent imaging reveals unzoned internal structures with three mineral phases: irregular, pseudo-hexagonal and spherical low-Mg calcite crystals (Type 1), low-Mg calcite cement (Type 2), and a later void-filling silica cement (Type 3). The pseudomorphs show δ 13C values from − 0.14‰ to − 0.85‰ (mean − 0.43‰; n = 5) that are more positive than the associated micritic matrix, where values range from − 0.92‰ to − 2.39‰ (mean − 1.64‰; n = 7), indicating that oceanic dissolved inorganic carbon (DIC) was the primary carbon source rather than either methane or organic matter. These δ 13C values significantly differ from typical δ 13C signatures of authentic glendonites, except for Ordovician examples. If these are glendonites, we infer that they could have precipitated due to the unusually elevated alkalinity and pH (> 9) oceanic conditions present in the aftermath of the end-Permian extinction associated with highly disrupted carbon cycle dynamics, possibly accompanied with the upwelling of cold, anoxic oceanic water.</p
Complementary effects of beneficial and non-beneficial mycorrhizal fungi on root phosphatase activity: A mycorrhizal “White Album” effect
Get PDFAbstract Mycorrhizal fungi are diverse, with strains differing in the magnitude and types of benefits provided to their hosts. In mixture, mycorrhizal strains that have complementary functions could provide their hosts with greater benefits than any constituent strain in isolation. Conversely, mycorrhizal strains could also interfere with one another, competing for host resources, providing less benefits than the most beneficial strain. The actual, realized effects are likely a composite of these complementary and competitive effects. Spatial structure in the root system may allow plants to benefit from complementary benefits while reducing competition among mycorrhizal strains. I tested the role of spatial structure using a species of plant from the family Podocarpaceae, which host arbuscular mycorrhizal fungi inside both finely separated nodules and longer, contiguous sections of fine root. In root nodules, co-inoculation with both growth-promoting and non-growth-promoting arbuscular mycorrhizal fungi resulted in complementary increases in aggregate root/fungal phosphatase activity. This complementary effect was not present in longer, contiguous sections of fine root or in either root type with P-fertilization. I dub this interaction a ?White Album effect?, a reference to the Beatles' best-selling album, where complementary effects of single artists were only revealed when individual conflicts were avoided by separating band members and synthesizing their contributions in post-production. Read the free Plain Language Summary for this article on the Journal blog
Return of a racehorse to racing after iatrogenic lipoid pneumonia
Get PDFThere is a paucity of literature describing equine lipoid pneumonia (LP) caused by inadvertent intrapulmonary administration of liquid paraffin (mineral oil). This case report improves our understanding of LP by describing; (1) the first reported return of a horse to racing after LP, (2) the likely benefits of prolonged dexamethasone administration, (3) the detailed short- and long-term pulmonary and systemic responses to intrapulmonary liquid paraffin and (4) the prolonged pulmonary retention of liquid paraffin
Deterministic patterns in single-cell transcriptomic data
Get PDFWe report the existence of deterministic patterns in statistical plots of single-cell transcriptomic data. We develop a theory showing that the patterns are neither artifacts introduced by the measurement process nor due to underlying biological mechanisms. Rather they naturally emerge from finite sample size effects. The theory precisely predicts the patterns in data from multiplexed error-robust fluorescence in situ hybridization and five different types of single-cell sequencing platforms.</p
Board and executive gender diversity as a driver of airline efficiency:A network-DEA analysis
Get PDFThis paper investigates the influence of gender diversity on the efficiency of airlines. Despite global progress towards gender equality, the airline industry continues to exhibit a considerable gender gap, especially in leadership positions. Our study utilises a Network Data Envelopment Analysis (DEA) to assess the performance of airlines concerning gender diversity in board and executive roles. By analysing a dataset of airlines of different continents and covering the period before and after the COVID-19 crisis, gender diversity’s impact on airline efficiency (defined as the ratio of the sum of its weighted outputs to the sum of its weighted inputs) is examined during times of significant operational stress. A second-stage estimation further enriches the analysis to assess the influence of external variables. Our findings reveal that airlines with higher gender diversity on their boards and executive teams exhibit better efficiency before and after COVID-19 crisis. The study contributes to the broader discourse on gender diversity in traditionally male-dominated sectors, offering insights into the strategic benefits of inclusive leadership practices
Sex-associated differences in incentive salience and drinking behaviour in a rodent model of alcohol relapse
Get PDFThe ability of environmental cues to trigger alcohol-seeking behaviours is thought to facilitate problematic alcohol use. Individuals' tendency to attribute incentive salience to cues may increase the risk of addiction. We sought to study the relationship between incentive salience and alcohol addiction using non-preferring rats to model the heterogeneity of human alcohol consumption, investigating both males and females. Adult rats were subjected to the alcohol deprivation effect (ADE) paradigm, where they were given voluntary access to different alcohol solutions with repeated interruptions by deprivation and reintroduction phases over a protracted period (five Alcohol Deprivation Cycles). Before each Alcohol Deprivation Cycle, rats were tested in the Pavlovian Conditioned Approach (PCA) paradigm, which quantifies the individual salience toward a conditional cue and the reward, thus allowing us to trace the process of attributing incentive salience to reward cues. During the final Alcohol Deprivation Cycle (ADE5), animals were tested for compulsive-like behaviour using quinine taste adulteration. We investigated sex differences in drinking behaviour and PCA performance. We observed thatb females drank significantly more alcohol than males and displayed more sign-tracking (ST) behaviour in the PCA, whereas males showed goal-tracking (GT) behaviour. Furthermore, we found that high drinkers exhibited more ST behaviour. The initial PCA phenotype was correlated with later alcohol consumption. Our findings indicate a complex relationship between incentive salience and alcohol addiction and emphasize the importance of considering both sexes in preclinical research.</p
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