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Mucosal immunity develops in the human fetal intestine by 11–14 weeks of gestation, yet whether viable microbes exist in utero and interact with the intestinal immune system is unknown. Bacteria-like morphology was identified in pockets of human fetal meconium at mid-gestation by scanning electron microscopy ( n  = 4), and a sparse bacterial signal was detected by 16S rRNA sequencing ( n  = 40 of 50) compared to environmental controls ( n  = 87). Eighteen taxa were enriched in fetal meconium, with Micrococcaceae ( n  = 9) and Lactobacillus ( n  = 6) the most abundant. Fetal intestines dominated by Micrococcaceae exhibited distinct patterns of T cell composition and epithelial transcription. Fetal Micrococcus luteus , isolated only in the presence of monocytes, grew on placental hormones, remained viable within antigen presenting cells, limited inflammation ex vivo and possessed genomic features linked with survival in the fetus. Thus, viable bacteria are highly limited in the fetal intestine at mid-gestation, although strains with immunomodulatory capacity are detected in subsets of specimens. Microscopy and 16S rRNA sequencing suggest that there is a limited bacterial presence in the human fetal intestine, with one enriched Micrococcus species exhibiting immunomodulatory activity ex vivo.

IgA + B cells expressing programmed death ligand 1 (PD-L1) and interleukin 10 accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease where they promote the progression to hepatocellular carcinoma by limiting the local activation of PD-1-expressing CD8 + T cells. The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA + ) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8 + T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8 + T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA + cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8 + T-lymphocyte activation as a tumour-promoting mechanism. Increased cancer risk in fatty livers Cancer progression beyond the early stages is thought to be caused in some cases by adaptive immunity, but its role remains controversial. In this study, Michael Karin and colleagues show that PD-L1-expressing IgA + B cells accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease. The inflammation-induced IgA + cells promote the progression to hepatocellular carcinoma by suppressing liver cytotoxic CD8 + T cells that prevent the emergence of this aggressive tumour.

The thymus’ key function in the immune system is to provide the necessary environment for the development of diverse and self-tolerant T lymphocytes. While recent evidence suggests that the thymic stroma is comprised of more functionally distinct subpopulations than previously appreciated, the extent of this cellular heterogeneity in the human thymus is not well understood. Here we use single-cell RNA sequencing to comprehensively profile the human thymic stroma across multiple stages of life. Mesenchyme, pericytes and endothelial cells are identified as potential key regulators of thymic epithelial cell differentiation and thymocyte migration. In-depth analyses of epithelial cells reveal the presence of ionocytes as a medullary population, while the expression of tissue-specific antigens is mapped to different subsets of epithelial cells. This work thus provides important insight on how the diversity of thymic cells is established, and how this heterogeneity contributes to the induction of immune tolerance in humans. The thymus supports T cell immunity by providing the environment for thymocyte differentiation. Here the authors profile human thymic stroma at the single cell level, identifying ionocytes as a new medullary population and defining tissue specific antigen expression in multiple stromal cell types.

Infants are capable of mounting adaptive immune responses, but their ability to develop long-lasting immunity is limited. Understanding the particularities of the neonatal adaptive immune system is therefore critical to guide the design of immune-based interventions, including vaccines, in early life. In this review, we present a thorough summary of T cell, B cell, and humoral immunity in early life and discuss infant adaptive immune responses to pathogens and vaccines. We focus on the differences between T and B cell responses in early life and adulthood, which hinder the generation of long-lasting adaptive immune responses in infancy. We discuss how knowledge of early life adaptive immunity can be applied when developing vaccine strategies for this unique period of immune development. In particular, we emphasize the use of novel vaccine adjuvants and optimization of infant vaccine schedules. We also propose integrating maternal and infant immunization strategies to ensure optimal neonatal protection through passive maternal antibody transfer while avoiding hindering infant vaccine responses. Our review highlights that the infant adaptive immune system is functionally distinct and uniquely regulated compared to later life and that these particularities should be considered when designing interventions to promote pediatric health.

A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here we collected assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing data under resting and stimulated conditions for up to 32 immune cell populations. Stimulation caused widespread chromatin remodeling, including response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the importance of these cell states in autoimmunity. Allele-specific read mapping identified variants that alter chromatin accessibility in particular conditions, allowing us to observe evidence of function for a candidate causal variant that is undetected by existing large-scale studies in resting cells. Our results provide a resource of chromatin dynamics and highlight the need to characterize the effects of genetic variation in stimulated cells. Analysis of gene expression and open chromatin regions in up to 32 immune cell populations under resting and stimulated conditions identifies widespread chromatin remodeling and shared response elements between stimulated B and T cells.

BackgroundAccurate evaluation of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) is important to identify patients who may develop complications. The aim of this study was to compare the diagnostic performance of simple non-invasive tests in identifying advanced fibrosis among patients with biopsy-proven NAFLD.MethodsConsecutive patients with biopsy proven NAFLD were recruited from the Newcastle Hospitals Fatty Liver Clinic from 2003 to 2009. The AST/ALT ratio, AST to platelet ratio index, BARD (weighted sum of BMI>28=1 point, AST/ALT ratio>0.8=2 points, diabetes=1 point), FIB-4 (age×AST (IU/l)/platelet count (×109/litre)×√ALT (IU/l)) and NAFLD fibrosis scores were calculated from blood tests taken at time of biopsy.Results145 patients (82 male (61%), mean age 51±12 years) were included. The mean body mass index was 35±5 kg/m2. 73 subjects (50%) had diabetes. 93 patients (64%) had non-alcoholic steatohepatitis. 27 (19%) had advanced fibrosis (Kleiner stage 3–4). The FIB-4 score had the best diagnostic accuracy for advanced fibrosis (area under receiver operator characteristic curve (AUROC) 0.86), followed by AST/ALT ratio (AUROC 0.83), NAFLD fibrosis score (AUROC 0.81), BARD (AUROC 0.77) and AST to platelet ratio index (AUROC 0.67). The AST/ALT ratio, BARD score, FIB-4 and NAFLD fibrosis scores had negative predictive values greater than 90% (93%, 95%, 95% and 92% respectively). Positive predictive values were modest. In order to exclude advanced fibrosis liver biopsy could potentially be avoided in 69% with AST/ALT ratio, 62% with FIB-4, 52% with NAFLD fibrosis score and 38% with BARD.ConclusionsThe ALT/AST ratio, FIB-4 and NAFLD fibrosis scores can reliably exclude advanced fibrosis in a high proportion of patients with NAFLD, allowing liver biopsy to be used in a more directed manner.

The annual photoperiod cycle provides the critical environmental cue synchronizing rhythms of life in seasonal habitats. In 1936, Bünning proposed a circadian-based coincidence timer for photoperiodic synchronization in plants. Formal studies support the universality of this so-called coincidence timer, but we lack understanding of the mechanisms involved. Here we show in mammals that long photoperiods induce the circadian transcription factor BMAL2, in the pars tuberalis of the pituitary, and triggers summer biology through the eyes absent/thyrotrophin (EYA3/TSH) pathway. Conversely, long-duration melatonin signals on short photoperiods induce circadian repressors including DEC1, suppressing BMAL2 and the EYA3/TSH pathway, triggering winter biology. These actions are associated with progressive genome-wide changes in chromatin state, elaborating the effect of the circadian coincidence timer. Hence, circadian clock-pituitary epigenetic pathway interactions form the basis of the mammalian coincidence timer mechanism. Our results constitute a blueprint for circadian-based seasonal timekeeping in vertebrates.

Accurate air temperatures underpin environmental research. Most professional meteorological air temperature measurements still expose thermometers within traditional, naturally ventilated screens. Their representation of true air temperature depends on screen airflow, and therefore local winds. Accuracies of daily maximum (Tmax) and minimum (Tmin) air temperatures are assessed by comparison between a naturally ventilated large conventional screen and a co‐located aspirated reference screen. In over 1200 days' data, the naturally ventilated Tmin and Tmax both showed small (median < 0.06°C) cold bias, but, in 1% of cases, warm Tmax bias and cold Tmin bias >|1°C|. The Tmin cold bias is associated with calm clear nights, and the Tmax warm bias events with calm winter days at low sun angles, allowing solar heating of the screen. The prevalence of poor natural ventilation, potentially affecting Tmin and Tmax, is estimated across European sites. Poor ventilation occurred at Tmin for 12% of values, and at Tmax for 4%. Climatological averaging will reduce these effects, but, without corroborating wind data, statistical changes in Tmin or Tmax, including identifying “Tropical Nights” (Tmin > 20°C) or occurrences of winter extremes, may have limited value. Wider adoption of aspirated thermometer screens, with an initial overlap period, will largely eliminate these effects. Naturally ventilated thermometers in Stevenson screens or similar shelters provide the mainstay of surface air temperature data. These work well, except, occasionally, at low wind speeds. This can affect the daily minimum and, rarely, maximum temperatures, which are important in meteorology and climatology. Comparisons with a fan‐aspirated thermometer show underestimations of some air temperature minima, and overestimation of some daily maxima temperatures in winter at low solar elevation.

Non-alcoholic fatty liver disease (NAFLD) is a common liver disease worldwide. Experimental and small clinical trials have demonstrated that angiotensin II blockers (ARB) may be anti-fibrotic in the liver. The aim of this randomised controlled trial was to assess whether treatment with Losartan for 96 weeks slowed, halted or reversed the progression of fibrosis in patients with non-alcoholic steatohepatitis (NASH). Double-blind randomised-controlled trial of Losartan 50 mg once a day versus placebo for 96 weeks in patients with histological evidence of NASH. The primary outcome for the study was change in histological fibrosis stage from pre-treatment to end-of-treatment. The study planned to recruit 214 patients. However, recruitment was slower than expected, and after 45 patients were randomised (median age 55; 56% male; 60% diabetic; median fibrosis stage 2), enrolment was suspended. Thirty-two patients (15 losartan and 17 placebo) completed follow up period: one patient (6.7%) treated with losartan and 4 patients (23.5%) in the placebo group were \"responders\" (lower fibrosis stage at follow up compared with baseline). The major reason for slow recruitment was that 39% of potentially eligible patients were already taking an ARB or angiotensin converting enzyme inhibitor (ACEI), and 15% were taking other prohibited medications. Due to the widespread use of ACEI and ARB in patients with NASH this trial failed to recruit sufficient patients to determine whether losartan has anti-fibrotic effects in the liver. ISRCTN 57849521.

A twice‐daily record of barometric pressure exists for Durham Observatory (54.768 °N, 1.584 °W, barometer cistern 107.3 m above mean sea level, MSL) from 23 July 1843 to 31 December 1960 and is published here for the first time. The Durham record, which is 98.7% complete, is by far the longest digital barometric pressure series in northern England and fills a very large temporal and spatial gap in the International Surface Pressure Database (ISPD: Cram et al, [2015] Geoscience Data Journal, 2, 31–46). In what is believed to be the first study of its kind, the record has been independently quality‐controlled against the NOAA–CIRES–DOE Twentieth Century Reanalysis version 3 (20CRv3; Slivinski et al., [2019] Quarterly Journal of the Royal Meteorological Society, 145, 2876; Slivinski et al., [2021] Journal of Climate, 34, 1417–1438), which did not include the Durham records in its assimilation set. This paper describes the instruments used and their exposure, the sources of the record, digitization work undertaken to generate the digital time series (including quality control assessments using 20CRv3) and reduction to mean sea level pressure from station level observations, and examines consistency over the period of record against 20CRv3, concluding with a summary of monthly and annual means and extremes over the 117 year series and the details of the new dataset. Graphical The contents of this page will be used as part of the graphical of html only. It will not be published as part of main article.A twice‐daily record of barometric pressure exists for Durham Observatory (54.768 °N, 1.584 °W, barometer cistern 107.3 m above mean sea level, MSL) from 23 July 1843 to 31 December 1960, and is published here for the first time. The Durham record, which is 98.7% complete, is by far the longest digital barometric pressure series in northern England, and fills a very large temporal and spatial gap in the International Surface Pressure Database (ISPD). In what is believed to be the first study of its kind, the record has been independently quality‐controlled against the NOAA–CIRES–DOE Twentieth Century Reanalysis version 3 (20CRv3), which did not include the Durham records in its assimilation set.