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Insulin is a central autoantigen in the pathogenesis of T1D, and thymic epithelial cell expression of insulin under the control of the Autoimmune Regulator (Aire) is thought to be a key component of maintaining tolerance to insulin. In spite of this general working model, direct detection of this thymic selection on insulin-specific T cells has been somewhat elusive. Here, we used a combination of highly sensitive T cell receptor transgenic models for detecting thymic selection and sorting and sequencing of Insulin-specific CD4+ T cells from Aire-deficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Aire-deficient hosts with high affinity for insulin/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Aire-deficient versus wild-type hosts and found that this model clone could escape thymic negative selection in the absence of thymic Aire. Together, these results suggest that thymic expression of insulin plays a key role in trimming and removing high-affinity insulin-specific T cells from the repertoire to help promote tolerance.

Abstract Deep learning-based image analysis offers great potential in clinical practice. However, it faces mainly two challenges: scarcity of large-scale annotated clinical data for training and susceptibility to adversarial data in inference. As an example, an artificial intelligence (AI) system could check patient positioning, by segmenting and evaluating relative positions of anatomical structures in medical images. Nevertheless, data to train such AI system might be highly imbalanced with mostly well-positioned images being available. Thus, we propose the use of synthetic X-ray images and annotation masks forward projected from 3D photon-counting CT volumes to create realistic non-optimally positioned X-ray images for training. An open-source model (TotalSegmentator) was used to annotate the clavicles in 3D CT volumes. We evaluated model robustness with respect to the internal (simulated) patient rotation $$\alpha$$ α on real-data-trained models and real&synthetic-data-trained models. Our results showed that real&synthetic- data-trained models have Dice score percentage improvements of 3% to 15% across different $$\alpha$$ α groups compared to the real-data-trained model. Therefore, we demonstrated that synthetic data could be supplementary used to train and enrich heavily underrepresented conditions to increase model robustness.

Abstract Climate change and metals independently stress soil microbiomes, but their combined effects remain unresolved. Here we show that future climate affects soil cadmium through altered soil microbiome and nutrient cycles, with soil pH as critical factor. In soils with pH7 soil show no climate impacts on cadmium mobilization, though imprints on microbiome structure were apparent. Subsequent nutrient cycling increased under future climate, stimulating soil respiration and nitrous oxide release. These findings underscore complex interactions between climate change and soil contaminants affecting the soil microbiome and its activity and highlights potential impacts on crop production, groundwater quality, and climate feedback.

Abstract Phosphorus limits primary productivity in many (Sub-)Arctic ecosystems and may constrain biological carbon sequestration. Iron (III) oxides strongly bind phosphate in soils but can dissolve under flooded, reducing conditions induced by permafrost thaw and ground collapse. The ability for iron to regulate phosphate storage and solubility in thawing permafrost landscapes remains unclear. Here, iron-rich sediments containing iron oxides and organic-bound iron were incubated with or without added phosphate in soils along a permafrost thaw gradient to evaluate how iron-phosphate associations respond to thaw-induced redox shifts. Iron oxides partially dissolved and released sorbed phosphate when incubated in soils underlain by degraded permafrost. Iron complexed by organic matter remained stable but provided no phosphate binding capacity. Phosphate addition enhanced iron oxide dissolution and phosphorus concentrations in associated microbial biomass. Our study demonstrates that the capacity for iron oxides to immobilize and retain phosphate in permafrost peatlands decreases with permafrost thaw.

Abstract Electron transfer (ET) is the fundamental redox process of life and element cycling. The ET distance is normally as short as nanometers or micrometers in the subsurface. However, the redox gradient in the subsurface is as long as centimeters or even meters. This gap triggers an intriguing question whether directional long-distance ET from reduced to oxidized zones exists along the redox gradient. By using electron-donating capacity variation as a proxy of ET, we show that ET can last over 10 cm along the redox gradient in sediment columns, through a directional long-distance ET chain from reduced to oxidized zones constituted by a series of short-distance electron hopping reactions. Microbial and chemical processes synergistically mediate the long-distance ET chain, with an estimated flux of 6.73 μmol e−/cm2 per day. This directional long-distance ET represents an overlooked but important “remote” source of electrons for local biogeochemical and environmental processes.

Abstract Assimilatory nitrate reduction and methane (CH4) oxidation by bacteria play important roles in carbon (C) and nitrogen (N) biogeochemical cycles. Here, an investigation of enzymatic assimilatory nitrate reduction and CH4 oxidation by Methylobacter sp. YHQ from the wetlands is presented, specifically concentrating on N and oxygen (O) isotope fractionation with various initial nitrate and oxygen concentrations. The N enrichment factors (15 ε assimilation) increased from 4.2 ± 0.7‰ to 6.9 ±1.3‰ and the O isotope enrichment factors (18 ε assimilation) increased from 2.7 ± 0.9‰ to 4.7 ± 0.8‰ during nitrate assimilation when initial nitrate concentrations increased from 0.9 mM to 2 mM. Similar 18 ε and 15 ε values were observed at different oxygen concentrations. The values of 18 ε and 15 ε provided vital parameters for the assessment of assimilatory nitrate reduction via the Rayleigh equation approach. The ratios of O and N isotope enrichment factors (18 ε:15 ε)assimilation ranged from 0.64 ± 0.15 to 0.74 ± 0.18 during nitrate assimilation by Methylobacter sp. YHQ with Nas, which were different from (18 ε:15 ε)assimilation for assimilatory eukaryotic nitrate reductase (eukNR) from literature data. Thus, N and O isotope fractionation could be useful tools to distinguish eukNR from Nas during nitrate assimilation. Additionally, the rates of CH4 oxidation and nitrate reduction were evaluated with a reaction-based kinetic model, and it quantitatively described the enzymatic reactions of nitrate assimilation. Combining dual N-O isotope analysis with kinetic modeling provides new insights into the microbially driven C-N interactions. Graphical Abstract

Summary: Background: The phase 2 ASUNCTIS study assessed the efficacy and safety of asunercept, a fully human CD95 (Fas) ligand-binding protein, in hospitalised patients with moderate-to-severe coronavirus disease (COVID-19) to assess the clinical benefit of CD95 ligand inhibition in this viral disease. Methods: In this open-label, multicentre, randomised, controlled, phase 2 trial, patients with COVID-19–induced pneumonia and respiratory deterioration were randomly assigned (1:1:1:1) in 12 Russian and Spanish hospitals using an interactive web-response system to receive standard of care (SOC) or SOC plus weekly asunercept 25 mg, 100 mg, or 400 mg, administered intravenously for up to 4 weeks, or until hospital discharge or death. The randomisation was stratified according to the respiratory support methods at the time of enrolment, corresponding to categories 4–6 of a clinical severity assessment scale comprising 9 levels that was recommended by the World Health Organization (WHO) at the time of the study. The main inclusion criterion was laboratory confirmed infection with SARS-CoV-2 OR typical radiological signs of SARS-CoV-2 infection. The primary endpoint was time from randomisation to clinical improvement on two consecutive days of at least one category on a WHO clinical severity assessment scale in the modified intent-to-treat population. All patients were subjected to regular safety analyses. This trial is registered with EudraCT (2020-001887-27) and ClinicalTrials.gov (NCT04535674). Findings: Between October 9, 2020, and September 24, 2021, 438 patients were randomly assigned to SOC (n = 110) or SOC plus asunercept 25 mg (n = 109), 100 mg (n = 109), or 400 mg (n = 110). The primary endpoint, time to sustained clinical improvement of one WHO category on two consecutive days from randomization, was in median [95% confidence interval]: 9 [6–12], 8 [7–12], 8 [7–11] and 13 [9–20] days for the 400 mg, 100 mg, 25 mg asunercept and SOC groups, respectively. The standard deviations for the 400 mg, 100 mg, 25 mg asunercept and SOC groups were 5.3, 4.9, 4.7 and 5 days, respectively. The observed differences between groups failed to reach statistical significance (one-sided p-value = 0.041). In total, 290 adverse events (AE) were registered in 145 patients who received at least one dose of the study treatment: 77 AEs in 37 (33.6%) patients in the SOC group, 80 AEs in 38 (34.9%) patients in the 25 mg group, 61 AEs in 35 (32.7%) patients in the 100 mg group and 72 AEs in 35 (32.1%) patients in the 400 mg group. There was no treatment-related death reported. In summary, asunercept was well tolerated at all doses tested and no specific safety signals were detected. Interpretation: The primary endpoint of time to sustained clinical improvement for distinct asunercept arms compared to SOC failed to meet statistical significance. The compound was safe and well tolerated. Funding: Apogenix GmbH, Heidelberg, Germany.

There are few validated contextual measures predicting adoption of evidence-based programs. Variation in context at clinical sites can hamper dissemination. We examined organizational characteristics of Veterans Affairs hospitals implementing STRIDE, a hospital walking program, and characteristics’ influences on program adoption. Using a parallel mixed-method design, we describe context and organizational characteristics by program adoption. Organizational characteristics included: organizational resilience, implementation climate, organizational readiness to implement change, highest complexity sites versus others, material support, adjusted length of stay (LOS) above versus below national median, and improvement experience. We collected intake forms at hospital launch and qualitative interviews with staff members at 4 hospitals that met the initial adoption benchmark, defined as completing supervised walks with 5+ unique hospitalized Veterans during months 5 to 6 after launch with low touch implementation support. We identified that 31% (n = 11 of 35) of hospitals met adoption benchmarks. Seven percent of highest complexity hospitals adopted compared to 48% with lower complexity. Forty-three percent that received resources adopted compared to 29% without resources. Thirty-six percent of hospitals with above-median LOS adopted compared to 23% with below-median. Thirty-five percent with at least some implementation experience adopted compared to 0% with very little to no experience. Adopters reported higher organizational resilience than non-adopters (mean = 23.5 [SD = 2.6] vs 22.7 [SD = 2.6]). Adopting hospitals reported greater organizational readiness to change than those that did not (mean = 4.2 [SD = 0.5] vs 3.8 [SD = 0.6]). Qualitatively, all sites reported that staff were committed to implementing STRIDE. Participants reported additional barriers to adoption including challenges with staffing and delays associated with hiring staff. Adopters reported that having adequate staff facilitated implementation. Implementation climate did not have an association with meeting STRIDE program adoption benchmarks in this study. Contextual factors which may be simple to assess, such as resource availability, may influence adoption of new programs without intensive implementation support.

Abstract Biogenic magnetite is a potential biosignature for microbial iron cycling in hydrothermal sulfide systems, critical environments for unraveling the emergence and early evolution of life. However, the preservation potential of biogenic magnetite under hydrothermal conditions is poorly understood. Here, we show that the hydrothermal sulfidation of abiogenic and biogenic magnetite (sulfide/iron = 4, 80 °C) yields pyrite with various distinct morphologies, including framboid-like spheroids. We demonstrate that the variability in pyrite morphologies resulted from the modulation of pyritization rates by interrelated effects between organic matter and elemental sulfur (crystalline or colloidal). Notably, framboid-like pyrite, commonly considered a potential fingerprint of microbial sulfur cycling, was exclusively produced from the hydrothermal sulfidation of biogenic (i.e., organic matter-associated) magnetite produced by iron-cycling microorganisms. Thus, framboid-like pyrite can additionally be a taphonomic fingerprint of microbial iron cycling, enabling a better understanding of the evolution of Earth’s biosphere in deep time.

It is never an easy task for China to feed 1.4 billion people with only 7% of the world’s arable land. With nearly 30% of the world’s nitrogen (N) fertilizer applied, China achieves high crop yields while facing N pollution resulting from excessive N input. Here, we calculate the farmland N budget on the national and regional scales. The N use efficiency (NUE) in China increased by 28.0% during 2005–2018. This improvement is due to the reduction in fertilization and the improvement of crop management. The fragmented farmland is changing to large-scale farmland with the increase in cultivated land area per rural population and the development of agricultural mechanization. This opportunity brings more possibilities for precision farmland management, thus further improving NUE. The goal of an NUE of 0.6 may be achieved in the 2040s based on the current development trend. This striking N use shift in China has important implications for other developing countries.

Nitrogen (N) fertilization in paddy soils decreases arsenic mobility and methane emissions. However, it is unknown how quantity and frequency of N fertilization affects the interlinked redox reactions of iron(II)-driven denitrification, iron mineral (trans-)formation with subsequent arsenic (im-)mobilization, methane and nitrous oxide emissions, and how this links to microbiome composition. Thus, we incubated paddy soil from Vercelli, Italy, over 129 days and applied nitrate fertilizer at different concentrations (control: 0, low: ∼35, medium: ∼100, high: ∼200 mg N kg−1 soil−1) once at the beginning and after 49 days. In the high N treatment, nitrate reduction was coupled to oxidation of dissolved and solid-phase iron(II), while naturally occurring arsenic was retained on iron minerals due to suppression of reductive iron(III) mineral dissolution. In the low N treatment, 40 μg L−1 of arsenic was mobilized into solution after nitrate depletion, with 69 % being immobilized after a second nitrate application. In the non-fertilized control, concentrations of dissolved arsenic were as high as 76 μg L−1, driven by mobilization of 36 % of the initial mineral-bound arsenic. Generally, N fertilization led to 1.5-fold higher total GHG emissions (sum of CO2, CH4 and N2O as CO2 equivalents), 158-fold higher N2O, and 7.5-fold lower CH4 emissions compared to non-fertilization. On day 37, Gallionellaceae, Comamonadaceae and Rhodospirillales were more abundant in the high N treatment compared to the non-fertilized control, indicating their potential role as key players in nitrate reduction coupled to iron(II) oxidation. The findings underscore the dual effect of N fertilization, immobilizing arsenic in the short-term (low/medium N) or long-term (high N), while simultaneously increasing N2O and lowering CH4 emissions. This highlights the significance of both the quantity and frequency of N fertilizer application in paddy soils.

BackgroundC-reactive protein (CRP) is an established serum biomarker for different pathologies such as tissue injury and inflammatory events. One rising area of interest is the incorporation of low concentrations of CRP, so called high-sensitive (hs-) CRP, in the risk assessment and treatment monitoring of cardiovascular diseases (CVDs). Many research projects and the resulting meta-analyses have reported controversial results for the use of hs-CRP, especially in the risk assessment of CVDs. However, since these analyses used different assays to detect hs-CRP, it is important to assess the current level of assay harmonization.MethodsThis paper analyzes data from 17 external quality assessment (EQA) surveys for hs-CRP conducted worldwide between 2018 and 2023. Each EQA survey consisted of two blinded samples. In 2020 the sample material changed from pooled serum to single-donor samples. The aim was to assess the current status of assay harmonization by a manufacturer-based approach, taking into consideration the clinical decision limits for hs-CRP risk-stratification of CVDs as well as the scatter of results.ResultsOur analyses show that harmonization has increased in recent years from median differences of up to 50% to below 20%, with one exception that showed an increasing bias throughout the observed period. After changing sample materials from pools to single-donor samples, the coefficient of variation decreased to below 10% with one exception. Nevertheless, even these differences in the clinical setting could lead to disparate classification of patients depending on the assay used.ConclusionWhile there was a positive trend towards harmonization, meta-analysis of different risk-score publications should stratify their analysis by assay to account for the manufacturer-specific differences observed in this paper. Furthermore, assays are currently traceable to different international standard preparations, which might have a negative impact on future harmonization.