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Oronasal mucosal melanoma is defined by two transcriptional subtypes in humans and dogs with implications for diagnosis and therapy
No full textMucosal melanoma is a rare melanoma subtype associated with a poor prognosis and limited existing therapeutic interventions, in part due to a lack of actionable targets and translational animal models for preclinical trials. Comprehensive data on this tumour type are scarce, and existing data often overlooks the importance of the anatomical site of origin. We evaluated human and canine oronasal mucosal melanoma (OMM) to determine whether the common canine disease could inform the rare human equivalent. Using a human and canine primary OMM cohort of treatment-naive archival tissue, alongside clinicopathological data, we obtained transcriptomic, immunohistochemical, and microbiome data from both species. We defined the transcriptomic landscape in both species and linked our findings to immunohistochemical, microbiome, and clinical data. Human and dog OMM stratified into two distinctive transcriptional groups, which we defined using a species-independent 41-gene signature. These two subgroups are termed CTLA4-high and MET-high and indicate actionable targets for OMM patients. To guide clinical decision-making, we developed immunohistochemical diagnostic tools that distinguish between transcriptomic subgroups. We found that OMM had conserved transcriptomic subtypes and biological similarity between human and canine OMM, with significant implications for patient classification, treatment, and clinical trial design.</p
Assessing the Impact of Non-Pharmaceutical Interventions During the COVID-19 Pandemic on RSV Seasonality in Europe
No full textBACKGROUND: During the COVID-19 pandemic, atypical respiratory syncytial virus (RSV) circulation patterns emerged, with the occurrence of RSV activity outside the typical winter season. This study investigates the impact of COVID-19 and associated non-pharmaceutical interventions (NPIs) on RSV seasonality.METHODS: The onset, offset and peak of RSV epidemics from 2018 to 2022 across 12 European countries were determined using the 3% positivity threshold method. A multilevel longitudinal logit regression model for proportions assessed the associations between five NPIs (school closures, mask use, workplace measures, public gathering restrictions and closure of public spaces) and RSV, utilising RSV surveillance data, two NPI databases (ECDC-JRC and Oxford) and COVID-19 surveillance data.RESULTS: Before 2020, consistent RSV seasonality patterns were observed, but the seasonal increase of RSV-positive cases in winter remained absent during the COVID-19 pandemic (2020-2022). Analysis revealed inconsistent associations between individual NPIs and RSV. The associations differed depending on the data source used (ECDC-JRC or Oxford), not only in magnitude but also in the direction of the coefficients. Public gathering restrictions and closure of public spaces exhibited significant negative associations with RSV incidence. However, this was only observed when using surveillance data for the entire epidemiological year and not when only examining weeks with increased RSV activity.CONCLUSIONS: This study highlights the need for standardised international data collection and procedures for infectious disease modelling, as varying NPI implementations, NPI registration and RSV surveillance across countries complicate the understanding of RSV dynamics during the pandemic. Caution is recommended when interpreting the effects of NPIs on RSV circulation.</p
New ways to use imaging data in cardiovascular research: survey of opinions on federated learning and synthetic data
No full textThe NE/AAT/CBG axis regulates adipose tissue glucocorticoid exposure
No full textCorticosteroid binding globulin (CBG; SERPINA6) binds >85% of circulating glucocorticoids but its influence on their metabolic actions is unproven. Targeted proteolytic cleavage of CBG by neutrophil elastase (NE; ELANE) significantly reduces CBG binding affinity, potentially increasing ‘free’ glucocorticoid levels at sites of inflammation. NE is inhibited by alpha-1-antitrypsin (AAT; SERPINA1). Using complementary approaches in mice and humans to manipulate NE or AAT, we show high-fat diet (HFD) increases the NE:AAT ratio specifically in murine visceral adipose tissue, an effect only observed in males. Notably, HFD-fed male mice lacking NE have reduced glucocorticoid levels and action specifically in visceral adipose tissue, with improved glucose tolerance and insulin sensitivity, independent of systemic changes in free glucocorticoids. The protective effect of NE deficiency is lost when the adrenals are removed. Moreover, human asymptomatic heterozygous carriers of deleterious mutations in SERPINA1 resulting in lower AAT levels have increased adipose tissue glucocorticoid levels and action. However, in contrast to mice, humans present with systemic increases in free circulating glucocorticoid levels, an effect independent of HPA axis activation. These findings show that NE and AAT regulate local tissue glucocorticoid bioavailability in vivo, providing crucial evidence of a mechanism linking inflammation and metabolism
Action research at the BBC:Interrogating artificial intelligence with journalists to generate actionable insights for the newsroom
Get PDFIn this paper, we provide reflections from an embedded action research project undertaken at the UK’s largest public service broadcaster, the BBC, over a three-year period. It was aimed at eliciting research insights about the role and understanding of AI in news production and also intervening to engender change in the newsroom. We surface the messy realities of conducting this work, including the challenges to funding such long-term and resource-intensive research and the difficulties of measuring impacts. We include practical guidance to demystify the process of action-oriented research that strives for targeted change in news contexts, highlighting the need for researchers to cost in time for translational work and the importance of having ‘critical friends’ to hold them to account. Ultimately, we emphasise the value of action research in journalism studies and particularly at the nexus of news and technology. We argue for approaches that retain a critical perspective whilst closing the gap between theory, critique, and practice
The α-globin super-enhancer acts in an orientation-dependent manner
Get PDFIndividual enhancers are defined as short genomic regulatory elements, bound by transcription factors, and able to activate cell-specific gene expression at a distance, in an orientation-independent manner. Within mammalian genomes, enhancer-like elements may be found individually or within clusters referred to as locus control regions or super-enhancers (SEs). While these behave similarly to individual enhancers with respect to cell specificity, distribution and distance, their orientation-dependence has not been formally tested. Here, using the α-globin locus as a model, we show that while an individual enhancer works in an orientation-independent manner, the direction of activity of a SE changes with its orientation. When the SE is inverted within its normal chromosomal context, expression of its normal targets, the α-globin genes, is severely reduced and the normally silent genes lying upstream of the α-globin locus are upregulated. These findings add to our understanding of enhancer-promoter specificity that precisely activate transcription.</p
Anti-phenolic glycolipid antibodies in Mycobacterium bovis infected cattle
Get PDFMycobacterium bovis, the causative agent of bovine tuberculosis (bTB), causes significant financial losses in the agricultural industry. Additionally, M. bovis transmission from animals to humans can result in zoonotic TB, especially in low- and middle-income countries (LMICs), highlighting the need to enhance One Health surveillance to mitigate this threat.Antibodies directed against a major mycobacterial cell wall component of M. leprae, phenolic glycolipid-I (PGL-I), have shown excellent performance in identifying M. leprae infection in humans and animals. In this study, we therefore investigated whether antibodies against M. bovis PGL similarly represent a useful biomarker for M. bovis infection in cattle.Comparing sera from naturally M. bovis-infected and the single intradermal comparative cervical tuberculin test (SICCT)-negative cattle, we assessed the potential of M. bovis PGL antibodies to identify this mycobacterial infection. Our results show that serum levels of anti-M. bovis PGL IgG and -IgM in M. bovis-infected cattle were significantly higher than in the SICCT-negative cattle. The sensitivity for anti-M. bovis PGL IgM in infected animals was, however, moderate (44.9 %) and the false-positive rate was 6.3 % in SICCT-negative cattle. Notably, vaccination with BCG- or heat-killed M. bovis did not affect serum levels of anti-M. bovis PGL IgM in cattle. Moreover, none of the 57 anti-M. bovis PGL-seropositive cattle tested positive in the anti-M. leprae PGL-I assay. This study shows for the first time that anti M. bovis PGL antibodies can be detected in infected cattle: anti-M. bovis PGL IgM is a highly specific, but moderately sensitive biomarker for M. bovis infection in cattle, showing potential for differentiate infected from vaccinated animals (DIVA). It could be a valuable component in a multi-biomarker approach for diagnosing bTB
Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant
Get PDFPIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β, or p110δ. Constitutional PIK3R1 mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function PIK3R1 phenotypes
Red deer resequencing reveals the importance of sex chromosomes for reconstructing Late Quaternary events
Get PDFSex chromosomes differ in their inheritance properties from autosomes and hence may encode complementary information about past demographic events. We compiled and analyzed a range-wide resequencing data set of the red deer (Cervus elaphus), one of the few Eurasian herbivores of the Late Pleistocene megafauna still found throughout much of its historic range. Our analyses of 144 whole genomes reveal striking discrepancies between the population clusters suggested by autosomal and X-chromosomal data. We postulate that the genetic legacy of Late Glacial population structure is better captured and preserved by the X chromosome than by autosomes, for two reasons. First, X chromosomes have a lower Ne and hence lose genetic variation faster during isolation in glacial refugia, causing increased population differentiation. Second, following postglacial recolonization and secondary contact, immigrant males pass on their X chromosomes to female offspring only, which effectively halves the migration rate when gene flow is male mediated. Our study illustrates how a comparison between autosomal and sex chromosomal phylogeographic signals unravels past demographic processes that otherwise would remain hidden.</p
Associations between IL-6 and trajectories of depressive symptoms across the life course:Evidence from ALSPAC and UK Biobank cohorts
Get PDFBACKGROUND: Peripheral inflammatory markers, including serum interleukin 6 (IL-6), are associated with depression, but less is known about how these markers associate with depression at different stages of the life course.METHODS: We examined the associations between serum IL-6 levels at baseline and subsequent depression symptom trajectories in two longitudinal cohorts: ALSPAC (age 10-28 years; N = 4,835) and UK Biobank (39-86 years; N = 39,613) using multilevel growth curve modeling. Models were adjusted for sex, BMI, and socioeconomic factors. Depressive symptoms were measured using the Short Moods and Feelings Questionnaire in ALSPAC (max time points = 11) and the Patient Health Questionnaire-2 in UK Biobank (max time points = 8). RESULTS: Higher baseline IL-6 was associated with worse depression symptom trajectories in both cohorts (largest effect size: 0.046 [ALSPAC, age 16 years]). These associations were stronger in the younger ALSPAC cohort, where additionally higher IL-6 levels at age 9 years was associated with worse depression symptoms trajectories in females compared to males. Weaker sex differences were observed in the older cohort, UK Biobank. However, statistically significant associations (pFDR <0.05) were of smaller effect sizes, typical of large cohort studies.CONCLUSIONS: These findings suggest that systemic inflammation may influence the severity and course of depressive symptoms across the life course, which is apparent regardless of age and differences in measures and number of time points between these large, population-based cohorts.</p
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