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The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1–4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins—including the lipopolysaccharide receptor complex—from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut–liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.Bacterial products in the gut–liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment. Natural Killer cells regulate foetal growth. Here the authors use a humanized transgenic mouse to demonstrate that specific HLA-C KIR2DL interactions promote changes in maternal and foetal cell transcriptomes, resulting in modifications to placental vasculature, intercellular communications and foetal growth restriction. [ABSTRACT FROM AUTHOR]

It has been hypothesised that romantic partners are more similar than chance in relation to autistic traits. To test this theory, we recruited n = 105 heterosexual couples and examined within-couple correlations for autistic traits [measured using the Autism Spectrum Quotient (AQ)], empathizing [measured using the Empathy Quotient (EQ)], and systemizing [measured using the Systemizing Quotient-Revised (SQ-R)]. For a subsample that attended the lab (n = 58 couples), we also investigated theory of mind via facial expressions using the Reading the Mind in the Eyes Test (RMET) and attention to detail, a component within systemizing, using the Embedded Figures Task (EFT). Variable-centred analyses revealed positive within-couple correlations for all measures except EQ, although these effects were only statistically significant for unmarried couples and not for married/engaged couples. Follow-up analyses indicated that the observed couple similarity effects are likely consistent with people pairing with those more similar than chance (initial assortment) rather than becoming alike over time (convergence), and to seeking out self-resembling partners (active assortment) rather than pairing in this manner via social stratification processes (social homogamy). Additionally, a significant within-couple correlation for autistic traits was observed at the meta-analytic level. However, it should be noted that the meta-analytic effect size estimate was small (r = 0.153) and indicates that only ~ 2% of variance in a person's score on a phenotypic measure of autistic traits can be predicted by that of their partner. [ABSTRACT FROM AUTHOR]

Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4–11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.Seronegative healthcare workers with an innate signature of infection preferentially expand pre-existing T cells targeting the conserved replication transcription complex of SARS-CoV-2 in abortive infection. [ABSTRACT FROM AUTHOR]

Background: A Guide for Healthcare Professionals (HCP Guide) and patient alert card (PAC) for atezolizumab as additional risk minimization measures for physicians were distributed to raise awareness and help in the detection and management of immune-related adverse drug reactions. Objectives: The main objective of this study was to assess the receipt, knowledge, and behaviors of physicians regarding the atezolizumab HCP Guide and PAC. Methods: A multi-country, one-wave, observational, cross-sectional, web-based, self-reported physician survey was conducted to assess the level of knowledge of key messages related to immune-related adverse drug reactions summarized in the atezolizumab HCP Guide and PAC among physicians (oncologists, pulmonologists, and urologists) prescribing atezolizumab in six European countries (Denmark, Germany, Italy, Spain, Sweden, and the UK). Responses regarding the receipt, understanding and use of the materials, and knowledge and behavior related to the HCP Guide and PAC are presented as percentages and continuous scores scaled out of 100 points, with corresponding 95% confidence intervals (CIs). Results: Among 313 physicians (255 oncologists, 30 pulmonologists, and 28 urologists), 77.4% received the HCP Guide and 74.2% the PAC. The HCP Guide was read by 71.3% of the 267 physicians who received the materials, and the mean usage score was 69.5 (95% CI 66.0–72.9), and 57.1% of physicians had scores ≥ 70. The HCP Guide was completely understood by 85.4% of physicians who had read it. Mean knowledge scores were 63.9 (95% CI 62.1–65.7) and 39.4% of physicians had correct knowledge scores ≥ 70. Mean knowledge scores were 66.8 (95% CI 64.9–68.7) for receipt of both the HCP Guide and PAC, 59.4 (95% CI 55.5–63.4) for one of the materials, and 60.8 (95% CI 55.4–66.2) for having received none of the materials. Mean behavior scores were 78.9 (95% CI 76.8–81.0), and 74.8% of physicians had behavior scores ≥ 70. The mean behavior score was 79.0 (95% CI 76.5–81.5) for those who received both the HCP Guide and PAC, 76.9 (95% CI 72.2–81.5) for receipt of one of the materials, and 81.5 (95% CI 75.0–88.0) for those who received none of the materials. Conclusions: The study assessed the effectiveness of the atezolizumab additional risk minimization educational materials among physicians in six European countries, using process indicators. The educational materials reached over 70% of target physicians, 57.1% of whom reported using them. Knowledge and behavior related to immune-related adverse drug reactions for atezolizumab were no better in those who received the additional risk minimization educational materials. The results support the safe use of atezolizumab by these physician groups and contributed to the European Medicines Agency permitting removal of the HCP Guide. [ABSTRACT FROM AUTHOR]

The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression. Jarvis et al demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A)-driven acquisition of CD73 expression, which along with CD39, enables expanded Tregs to convert ATP to immunosuppressive adenosine. Given this, the data suggests that Treg expansion protocols should be optimised for CD39/CD73 co-expression to enhance therapeutic potential. [ABSTRACT FROM AUTHOR]

Purpose: Soils are important regulators of Critical Zone processes that influence the development of geochemical signals used for sediment fingerprinting. In this study, pedological knowledge of tropical soils was incorporated into sediment source stratification and tracer selection in a large Brazilian catchment. Materials and methods: In the Ingaí River basin (~ 1200 km2), Brazil, three source end-members were defined according to the interpretation of soil and geological maps: the upper, mid, and lower catchment. A tributary sampling design was employed, and sediment geochemistry of three different size fractions was analyzed (2–0.2 mm; 0.2–0.062 mm, and < 0.062 mm). A commonly used statistical methodology to element selection was compared to a knowledge-based approach. The mass balance un-mixing models were solved by a Monte Carlo simulation. Modeled source contributions were evaluated against a set of artificial mixtures with known source proportions. Results and discussion: For the coarse fraction (2–0.2 mm), both approaches to element selection yielded high errors compared to the artificial mixtures (23.8% and 17.8% for the statistical and the knowledge-based approach, respectively). The knowledge-based approach provided the lowest errors for the intermediate (0.2–0.062 mm) (10.9%) and fine (< 0.062 mm) (11.8%) fractions. Model predictions for catchment outlet target samples were highly uncertain for the coarse and intermediate fractions. This is likely the result of the spatial scale of the source stratification not being able to represent sediment dynamics for these fractions. Both approaches to element selection show that most of the fine sediments (median > 90%) reaching the catchment outlet were derived from Ustorthents in the lower catchment. Conclusions: The different element selection methods and the artificial mixtures provide multiple lines of evidence for evaluating the fingerprint approaches. Our findings highlight the importance of considering pedogenetic processes in source stratification, and demonstrate that different sampling strategies might be necessary to model specific sediment fractions. [ABSTRACT FROM AUTHOR]

Plant growth in nitrogen (N)-limited, unfertilised terrestrial ecosystems should respond to additional N inputs from atmospheric deposition (Ndep). We investigated this for sites in Great Britain (GB) by compiling 796 estimates of net primary productivity (NPP) from measured biomass production over the period 1932–2014, although the great majority were for 1990 onwards. The sites were largely vegetated with shrubs, grass and bracken, and had a wide range of Ndep (0.5–3.3 gN m−2 a−1 in 2000). The measured NPP estimates were compared with calculated values from the biogeochemical ecosystem model N14CP, which predicts that NPP depends strongly upon Ndep. The measured and modelled average total NPP values (gC m−2 a−1) from all data were 387 (standard deviation, SD = 193) and 377 (SD = 72) respectively. Measured and modelled averages for vegetation classes followed the sequence: broadleaved trees ~ needle-leaved trees > herbs (rough grassland + bracken) ~ shrubs. After averaging measured values for sites in individual model grid cells (5 km × 5 km) with 10 or more replicates, the measured and modelled NPP values were correlated (n = 26, r2 = 0.22, p = 0.011), with a slope close to unity. Significant linear relationships were found between measured ln NPP and cumulative Ndep for both herbs (n = 298, p = 0.021) and shrubs (n = 473, p = 0.006), with slopes comparable to those predicted with the model. The results suggest that semi-natural NPP in GB depends positively upon Ndep, in a manner that agrees quantitatively with N14CP predictions. Calculations with the model, using modelled temporal variation in Ndep, indicate that fertilisation by Ndep caused average increases in semi-natural NPP over the period 1800 to 2010 of 30% for shrubs, 71% for herbs, and 91% for broadleaved trees. Combined with previous published results for forests, our findings suggest a general and widespread vegetation response to fertilisation by Ndep. [ABSTRACT FROM AUTHOR]

The high redundancy actuator (HRA) concept is a novel approach to fault tolerant actuation that uses a high number of small actuation elements, assembled in series and parallel in order to form a single actuator which has intrinsic fault tolerance. Whilst this structure affords resilience under passive control methods alone, active control approaches are likely to provide higher levels of performance. A multiple-model control scheme for an HRA applied through the framework of multi-agent control is presented here. The application of this approach to a 10×10 HRA is discussed and consideration of reconfiguration delays and fault detection errors are made. The example shows that multi-agent control can provide tangible performance improvements and increase fault tolerance in comparison to a passive fault tolerant approach. Reconfiguration delays are shown to be tolerable, and a strategy for handling false fault detections is detailed. [ABSTRACT FROM AUTHOR]

When model-checking reports that a property holds on a model, vacuity detection increases user confidence in this result by checking that the property is satisfied in the intended way. While vacuity detection is effective, it is a relatively expensive technique requiring many additional model-checking runs. We address the problem of efficient vacuity detection for Bounded Model Checking (BMC) of linear temporal logic properties, presenting three partial vacuity detection methods based on the efficient analysis of the resolution proof produced by a successful BMC run. In particular, we define a characteristic of resolution proofs— peripherality—and prove that if a variable is a source of vacuity, then there exists a resolution proof in which this variable is peripheral. Our vacuity detection tool, VaqTree, uses these methods to detect vacuous variables, decreasing the total number of model-checking runs required to detect all sources of vacuity. [ABSTRACT FROM AUTHOR]