Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Gull plumages are, and are not, what they appear to human vision

Clear correlations between human and bird visual assessments of color have been documented, and are often assumed, despite fundamental differences in human and avian visual physiology and morphology. Analyses of plumage colors with avian perceptual models have shown widespread hidden inter-sexual and inter-specific color variation among passerines perceived as monochromatic to humans, highlighting the uncertainty of human vision to predict potentially relevant variation in color. Herein, we use reflectance data from 13 Larus gull species as an exemplar data set to study concordance between human vision and avian visual modeling of feather colors near, or below, the human threshold for discrimination. We found little evidence among gulls for sexual dichromatism hidden from human vision, but did find inter-specific color variation among gulls that is not seen by humans. Neither of these results were predictable a priori, and we reassert that reflectance measurements of actual feather colors, analyzed with avian relevant visual models, represent best practice when studying bird coloration

Combined influence of B-cell receptor rearrangement and somatic hypermutation on B-cell class-switch fate in health and in chronic lymphocytic leukaemia

A diverse B-cell receptor (BCR) repertoire is required to bind a wide range of antigens. BCRs are generated through genetic recombination and can be diversified through somatic hypermutation (SHM) or class-switch recombination (CSR). Patterns of repertoire diversity can vary substantially between different health conditions. We use isotyperesolved BCR sequencing to compare B-cell evolution and class-switch fate in healthy individuals and in patients with chronic lymphocytic leukemia (CLL). We show that the patterns of SHM and CSR in B-cells from healthy individuals are distinct from CLL. We identify distinct properties of clonal expansion that lead to the generation of antibodies of different classes in healthy, malignant, and non-malignant CLL BCR repertoires. We further demonstrate that BCR diversity is affected by relationships between antibody variable and constant regions leading to isotype-specific signatures of variable gene usage. This study provides powerful insights into the mechanisms underlying the evolution of the adaptive immune responses in health and their aberration during disease

Quantifying and classifying coastal change in Scotland using satellite-derived coastal boundaries

Global sea levels and the frequency and severity of coastal storm events are both predicted to rise with anthropogenic climate change. Coastal storms are often accompanied by intense wave energy producing large waves which lead to impact damage, wave overtopping and flooding of coastal infrastructure Erosion of soft coasts can cause instability and infrastructure damage, and exacerbate flood risk with weakening of natural protective features like dunes. To plan effectively for a changing climate and increased coastal risks, coastal managers require continuous, repeatable datasets on past coastal change to anticipate potential future changes and assess adaptation options

Watching the Grass Grow: Delineating Coastal Vegetation Edges from Satellite Imagery

Our coasts are increasingly under threat of climate change related risks such as sea level rise, increased erosion rates, and increased frequency and severity of storms and associated wave action. To identify and adequately support the communities at greatest risk of these impacts, regular and repeatable observations of coastal change are required. Shoreline positions offer a simplistic measure of geomorphic change across the intertidal zone, but they fluctuate significantly in macrotidal areas and are subject to tidal bias. To gain a broader understanding of the interplay of coastal processes, a coupling of change indicators is desirable. A more stable measure of coastal change, and one arguably more relevant to coastal communities and infrastructure, is the vegetation edge. Presented here is a Python toolkit which builds on the shoreline extraction tool CoastSat (https://doi.org/10.1016/j.envsoft.2019.104528), but adapted to automatically identify coastal vegetation edges from satellite imagery. A trained neural network classifies pixels and uses Weighted Peaks to extract sub-pixel contours between vegetation and non-vegetation classes. Sentinel-2 images offer the highest accuracy at the test site of St Andrews (RMSE of 10.4m). By taking advantage of the back catalogue of freely available satellite images, dense vegetation timeseries with an average observation interval of 12 days can be easily built to assess historic trends. Extracted vegetation edges are then compared with other derived coastal characteristics such as the vegetation transition zone, beach width, and dune slope, to infer relationships between these different change indicators and therefore create proxies for predicting different geomorphic regimes

Prognostic value of upper respiratory tract microbes in children presenting to primary care with respiratory infections:a prospective cohort study

BACKGROUND: The association between upper respiratory tract microbial positivity and illness prognosis in children is unclear. This impedes clinical decision-making and means the utility of upper respiratory tract microbial point-of-care tests remains unknown. We investigated for relationships between pharyngeal microbes and symptom severity in children with suspected respiratory tract infection (RTI). METHODS: Baseline characteristics and pharyngeal swabs were collected from 2,296 children presenting to 58 general practices in Bristol, UK with acute cough and suspected RTI between 2011–2013. Post-consultation, parents recorded the severity of six RTI symptoms on a 0–6 scale daily for ≤28 days. We used multivariable hurdle regression, adjusting for clinical characteristics, antibiotics and other microbes, to investigate associations between respiratory microbes and mean symptom severity on days 2–4 post-presentation. RESULTS: Overall, 1,317 (57%) children with complete baseline, microbiological and symptom data were included. Baseline characteristics were similar in included participants and those lacking microbiological data. At least one virus was detected in 869 (66%) children, and at least one bacterium in 783 (60%). Compared to children with no virus detected (mean symptom severity score 1.52), adjusted mean symptom severity was 0.26 points higher in those testing positive for at least one virus (95% CI 0.15 to 0.38, p<0.001); and was also higher in those with detected Influenza B (0.44, 0.15 to 0.72, p = 0.003); RSV (0.41, 0.20 to 0.60, p<0.001); and Influenza A (0.25, -0.01 to 0.51, p = 0.059). Children positive for Enterovirus had a lower adjusted mean symptom severity (-0.24, -0.43 to -0.05, p = 0.013). Children with detected Bordetella pertussis (0.40, 0.00 to 0.79, p = 0.049) and those with detected Moraxella catarrhalis (-0.76, -1.06 to -0.45, p<0.001) respectively had higher and lower mean symptom severity compared to children without these bacteria. CONCLUSIONS: There is a potential role for upper respiratory tract microbiological point-of-care tests in determining the prognosis of childhood RTIs

Toll-like receptor orchestrates a tumor suppressor response in non-small cell lung cancer

Targeting early-stage lung cancer is vital to improve survival. However, the mechanisms and components of the early tumor suppressor response in lung cancer are not well understood. In this report, we study the role of Toll-like receptor 2 (TLR2), a regulator of oncogene-induced senescence, which is a key tumor suppressor response in premalignancy. Using human lung cancer samples and genetically engineered mouse models, we show that TLR2 is active early in lung tumorigenesis, where it correlates with improved survival and clinical regression. Mechanistically, TLR2 impairs early lung cancer progression via activation of cell intrinsic cell cycle arrest pathways and the proinflammatory senescence-associated secretory phenotype (SASP). The SASP regulates non-cell autonomous anti-tumor responses, such as immune surveillance of premalignant cells, and we observe impaired myeloid cell recruitment to lung tumors after Tlr2 loss. Last, we show that administration of a TLR2 agonist reduces lung tumor growth, highlighting TLR2 as a possible therapeutic target.F.R.M. is funded by a Wellcome Trust clinical research fellowship through the Edinburgh Clinical Academic Track (ECAT) program (203913/Z/16/Z), a Wellcome Trust-ISSF3 award (IS3-R1.07 20/21), and a Wellcome Trust iTPA award (209710/Z/17/Z). J.C.A. core lab funding was received from Cancer Research UK (C47559/A16243, Training and Career Development Board – Career Development Fellowship), the University of Edinburgh (Chancellor’s Fellowship), and the Ministry of Science and Innovation of the Government of Spain (Proyecto PID2020-117860GB-100 financiado por MCIN/AEI/10.13039/501100011033). S.W. is supported by a Cancer Research UK senior fellowship (A29576). J.C. is supported by a Wellcome Trust clinical lectureship through the ECAT program (203913/Z/16/Z). M.M. is supported by a CRUK Edinburgh Centre Award (C157/A25140). S.V. and J.F.P. are funded by National Institute on Aging (NIA) grants (R01AG 68048-1 and UG3CA 268103-1)

Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike

The emergence of SARS-CoV-2 variants has exacerbated the COVID-19 global health crisis. Thus far, all variants carry mutations in the spike glycoprotein, which is a critical determinant of viral transmission being responsible for attachment, receptor engagement and membrane fusion, and an important target of immunity. Variants frequently bear truncations of flexible loops in the N-terminal domain (NTD) of spike; the functional importance of these modifications has remained poorly characterised. We demonstrate that NTD deletions are important for efficient entry by the Alpha and Omicron variants and that this correlates with spike stability. Phylogenetic analysis reveals extensive NTD loop length polymorphisms across the sarbecoviruses, setting an evolutionary precedent for loop remodelling. Guided by these analyses, we demonstrate that variations in NTD loop length, alone, are sufficient to modulate virus entry. We propose that variations in NTD loop length act to fine-tune spike; this may provide a mechanism for SARS-CoV-2 to navigate a complex selection landscape encompassing optimisation of essential functionality, immune-driven antigenic variation and ongoing adaptation to a new host

Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant

Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups: the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants