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The ontogeny of conventional and plasmacytoid dendritic cells (DC) and how these two cell types are related is not fully known. Here the authors identify a pool of bone marrow precursor cells expressing Ly6D Siglec-H and Zbtb46 that can differentiate into either cDC or pDC and show that type I IFN can limit cDC and favor pDC output from these precursors.

Background and Aims: Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. There are strong preclinical data and rationale to support targeting epidermal growth factor receptor (EGFR) for HCC chemoprevention. Small molecule inhibitors of EGFR have been Food and Drug Administration–approved for cancer therapy, which provides an opportunity to repurpose one of these drugs for chemoprevention of HCC. Unfortunately, the frequency of side effects associated with administration of these drugs at oncology doses renders them ineffective for chemoprevention. This clinical trial assesses whether lower doses of one of these inhibitors, erlotinib, still engages EGFR in the liver to block signaling (eg, EGFR phosphorylation). The objective of this clinical trial was determination of a safe and minimum effective dose of erlorinib for which ≥ 50% reduction phospho-EGFR immunohistochemical staining in the liver was observed. Methods: Forty six participants were preregistered and 25 participants were registered in this multicenter trial. By dose de-escalation trial design, cohorts of participants received a 7-day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib. Results: A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants (predetermined threshhold) at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. Favorable modulation of the Prognostic Liver Signature was observed in participants who received erlotinib. Conclusion: These data support the selection of erlotinib doses as low as 25 mg/day of for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug (ClinicalTrials.gov NCT02273362).

Abstract Background Accurate measurement of disease associated with endemic bacterial agents in pig populations is challenging due to their commensal ecology, the lack of disease-specific antemortem diagnostic tests, and the polymicrobial nature of swine diagnostic cases. The main objective of this retrospective study was to estimate temporal patterns of agent detection and disease diagnosis for five endemic bacteria that can cause systemic disease in porcine tissue specimens submitted to the Iowa State University Veterinary Diagnostic Laboratory (ISU VDL) from 2017 to 2022. The study also explored the diagnostic value of specific tissue specimens for disease diagnosis, estimated the frequency of polymicrobial diagnosis, and evaluated the association between phase of pig production and disease diagnosis. Results S. suis and G. parasuis bronchopneumonia increased on average 6 and 4.3%, while S. suis endocarditis increased by 23% per year, respectively. M. hyorhinis and A. suis associated serositis increased yearly by 4.2 and 12.8%, respectively. A significant upward trend in M. hyorhinis arthritis cases was also observed. In contrast, M. hyosynoviae arthritis cases decreased by 33% average/year. Investigation into the diagnostic value of tissues showed that lungs were the most frequently submitted sample, However, the use of lung for systemic disease diagnosis requires caution due to the commensal nature of these agents in the respiratory system, compared to systemic sites that diagnosticians typically target. This study also explored associations between phase of production and specific diseases caused by each agent, showcasing the role of S. suis arthritis in suckling pigs, meningitis in early nursery and endocarditis in growing pigs, and the role of G. parasuis, A. suis, M. hyorhinis and M. hyosynoviae disease mainly in post-weaning phases. Finally, this study highlighted the high frequency of co-detection and -disease diagnosis with other infectious etiologies, such as PRRSV and IAV, demonstrating that to minimize the health impact of these endemic bacterial agents it is imperative to establish effective viral control programs. Conclusions Results from this retrospective study demonstrated significant increases in disease diagnosis for S. suis, G. parasuis, M. hyorhinis, and A. suis, and a significant decrease in detection and disease diagnosis of M. hyosynoviae. High frequencies of interactions between these endemic agents and with viral pathogens was also demonstrated. Consequently, improved control programs are needed to mitigate the adverse effect of these endemic bacterial agents on swine health and wellbeing. This includes improving diagnostic procedures, developing more effective vaccine products, fine-tuning antimicrobial approaches, and managing viral co-infections.

This study evaluated the use of endemic enteric coronaviruses polymerase chain reaction (PCR)-negative testing results as an alternative approach to detect the emergence of animal health threats with similar clinical diseases presentation. This retrospective study, conducted in the United States, used PCR-negative testing results from porcine samples tested at six veterinary diagnostic laboratories. As a proof of concept, the database was first searched for transmissible gastroenteritis virus (TGEV) negative submissions between January 1st, 2010, through April 29th, 2013, when the first porcine epidemic diarrhea virus (PEDV) case was diagnosed. Secondly, TGEV- and PEDV-negative submissions were used to detect the porcine delta coronavirus (PDCoV) emergence in 2014. Lastly, encountered best detection algorithms were implemented to prospectively monitor the 2023 enteric coronavirus-negative submissions. Time series (weekly TGEV-negative counts) and Seasonal Autoregressive-Integrated Moving-Average (SARIMA) were used to control for outliers, trends, and seasonality. The SARIMA's fitted and residuals were then subjected to anomaly detection algorithms (EARS, EWMA, CUSUM, Farrington) to identify alarms, defined as weeks of higher TGEV-negativity than what was predicted by models preceding the PEDV emergence. The best-performing detection algorithms had the lowest false alarms (number of alarms detected during the baseline) and highest time to detect (number of weeks between the first alarm and PEDV emergence). The best-performing detection algorithms were CUSUM, EWMA, and Farrington flexible using SARIMA fitted values, having a lower false alarm rate and identified alarms 4 to 17 weeks before PEDV and PDCoV emergences. No alarms were identified in the 2023 enteric negative testing results. The negative-based monitoring system functioned in the case of PEDV propagating epidemic and in the presence of a concurrent propagating epidemic with the PDCoV emergence. It demonstrated its applicability as an additional tool for diagnostic data monitoring of emergent pathogens having similar clinical disease as the monitored endemic pathogens.

Abstract The development of stable barium (Ba) isotope measurements provides a novel tool to investigate the geochemical cycling of Ba in the ocean and its sediments. In sediment pore waters, gradients of dissolved Ba concentrations result from various diagenetic processes. The distribution and fractionation of Ba isotopes in the pore waters are expected to further improve our understanding of these early diagenetic control mechanisms. Here, we present pore water profiles of dissolved stable Ba isotopic signatures (δ138Bapw) from shallow water sediments covering the entire Pearl River Estuary (PRE) in Southern China. We find pronounced depth‐dependent Ba isotope variations generally showing a shift from heavy to light δ138Bapw signatures from the sediment surface down to 15 cm depth. These gradients are well reproduced by a diffusion‐reaction model, which generates an apparent fractionation factor (138ε) of −0.60 ± 0.10‰ pointing to preferential removal of low‐mass Ba isotopes from the pore water during solution‐solid phase interactions. Consequently, the combined diagenetic processes induce the highest δ138Bapw values of +0.5 to +0.7‰ in the pore waters of the topmost sediment layer. Although the detrital fraction dominates the Ba content in the PRE surface sediments, the determined gradients of pore water Ba isotopes, together with concentration variations of Ba and other redox‐sensitive elements such as manganese (Mn), show that non‐detrital excess Ba carriers including Mn oxides and authigenic barite clearly affect the post‐depositional Ba dynamics. Stable Ba isotopes are thus a potentially powerful tracer of Ba geochemistry during early sediment diagenesis in estuarine depositional environments.

Subterranean estuaries are connective zones between inland aquifers and the open sea where terrestrial freshwater and circulating seawater mix and undergo major biogeochemical changes. They are biogeochemical reactors that modify groundwater chemistry prior to discharge into the sea. We propose that subterranean estuaries of high-energy beaches are particularly dynamic environments, where the effect of the dynamic boundary conditions propagates tens of meters into the subsurface, leading to strong spatio-temporal variability of geochemical conditions. We hypothesize that they form a unique habitat with an adapted microbial community unlike other typically more stable subsurface environments. So far, however, studies concerning subterranean estuaries of high-energy beaches have been rare and therefore their functioning, and their importance for coastal ecosystems, as well as for carbon, nutrient and trace element cycling, is little understood. We are addressing this knowledge gap within the interdisciplinary research project DynaDeep by studying the combined effect of surface (hydro- and morphodynamics) on subsurface processes (groundwater flow and transport, biogeochemical reactions, microbiology). A unique subterranean estuary observatory was established on the northern beach of the island of Spiekeroog facing the North Sea, serving as an exemplary high-energy research site and model system. It consists of fixed and permanent infrastructure such as a pole with measuring devices, multi-level groundwater wells and an electrode chain. This forms the base for autonomous measurements, regular repeated sampling, interdisciplinary field campaigns and experimental work, all of which are integrated via mathematical modelling to understand and quantify the functioning of the biogeochemical reactor. First results show that the DynaDeep observatory is collecting the intended spatially and temporally resolved morphological, sedimentological and biogeochemical data. Samples and data are further processed ex-situ and combined with experiments and modelling. Ultimately, DynaDeep aims at elucidating the global relevance of these common but overlooked environments.

Barium (Ba) isotopes are a promising new tracer for riverine freshwater input to the ocean and marine biogeochemical cycling. However, many processes that affect Ba cycling at continental margins have not yet been investigated with respect to Ba isotope fractionation. Here, we present a comprehensive data set of Ba concentration and isotope data for water column, pore water and sediment samples from Kiel Bight, a seasonally stratified and hypoxic fjord in the southwestern Baltic Sea. The surface water Ba concentration and Ba isotope inventory of the water column can generally be explained by mixing of riverine freshwater and Atlantic seawater. However, the deep-water below the seasonal pycnocline (10 - 15 m water depth) is characterized by a pronounced positive Ba concentration anomaly (up to 915 nM) that is accompanied by a δ138Ba of ~+0.25 ‰, which is lighter than expected from the seawater-freshwater mixing line (Ba: 77 nM, δ138Ba: +0.32 ‰ at a salinity of 18). Pore water profiles indicate a Ba flux across the sediment-water interface, which contributes to the enrichment in isotopically light Ba in the deep-water. Pore waters of surface sediments and deep-waters are oversaturated with respect to barite. Therefore, barite dissolution is unlikely to account for the benthic Ba flux. Water column Ba concentrations closely correlate with those of the nutrients phosphate and silica, which are removed from surface waters by biological processes and recycled from the sediment by diffusion across the sediment-water interface. As nutrient-to-Ba ratios differ among sites and from those observed in open-marine systems, we propose that Ba is removed from surface waters by adsorption onto biogenic particles (rather than assimilation) and regenerated within surface sediments upon organic matter degradation. Pore water data for subsurface sediments in Kiel Bight indicate preferential transfer of isotopically heavy Ba into an authigenic phase during early diagenesis. Quantifying the burial flux associated with this authigenic Ba phase along continental margins could potentially help to settle the isotopic imbalance between known Ba source and sink fluxes in the ocean.

Physical activity (PA) might influence the risk or progression of chronic pain through pain tolerance. Hence, we aimed to assess whether habitual leisure-time PA level and PA change affects pain tolerance longitudinally in the population. Our sample (n = 10,732; 51% women) was gathered from the sixth (Tromsø6, 2007-08) and seventh (Tromsø7, 2015-16) waves of the prospective population-based Tromsø Study, Norway. Level of leisure-time PA (sedentary, light, moderate, or vigorous) was derived from questionnaires; experimental pain tolerance was measured by the cold-pressor test (CPT). We used ordinary, and multiple-adjusted mixed, Tobit regression to assess 1) the effect of longitudinal PA change on CPT tolerance at follow-up, and 2) whether a change in pain tolerance over time varied with level of LTPA. We found that participants with high consistent PA levels over the two surveys (Tromsø6 and Tromsø7) had significantly higher tolerance than those staying sedentary (20.4 s. (95% CI: 13.7, 27.1)). Repeated measurements show that light (6.7 s. (CI 3.4, 10.0)), moderate (CI 14.1 s. (9.9, 18.3)), and vigorous (16.3 s. (CI 6.0, 26.5)) PA groups had higher pain tolerance than sedentary, with non-significant interaction showed slightly falling effects of PA over time. In conclusion, being physically active at either of two time points measured 7-8 years apart was associated with higher pain tolerance compared to being sedentary at both time-points. Pain tolerance increased with higher total activity levels, and more for those who increased their activity level during follow-up. This indicates that not only total PA amount matters but also the direction of change. PA did not significantly moderate pain tolerance change over time, though estimates suggested a slightly falling effect possibly due to ageing. These results support increased PA levels as a possible non-pharmacological pathway towards reducing or preventing chronic pain.

As the world becomes increasingly complex, students must learn how to critically evaluate media messages and facts. Young people often obtain information from social media. Due to the ease with which information can be spread through such media, science misinformation is more prevalent. Learning how to critically evaluate information is expected to develop students’ abilities to critically evaluate science and media content. Group discussions were conducted with 33 secondary school students in northern Germany to examine (1) their experiences with social media in the (science) classroom, (2) their strategies for dealing with science-based information in the media, and (3) their perception of the role of social media in the science classroom. Qualitative coding revealed that students frequently use social media for information purposes, both in school and privately, and perceive social media as relevant to science education. In social media, they are successful at applying general media literacy and IT strategies, but struggle with science-related strategies. This study suggests that more opportunities should be provided for students to critique science information, and a greater focus should be placed on educating students about evaluation skills and scientific reasoning.

Abstract In the last decade, autoimmune pancreatitis has become recognised as part of a wider spectrum of IgG4-related disease, typically associated with elevated serum IgG4 levels and demonstrating a response to corticosteroid therapy. Radiologically, there is imaging overlap with other benign and neoplastic conditions. This pictorial review discusses the intra-abdominal manifestations of this disease on cross-sectional imaging before and after steroid treatment and the main radiological features which help to distinguish it from other key differentials. Teaching Points • Autoimmune pancreatitis is part of a spectrum of IgG4-related disease. • Diagnosis is based on raised serum IgG4, clinical, radiological and histopathological findings. • Cross-sectional imaging can demonstrate the typical findings of abdominal IgG4-related disease. • Cross-sectional imaging can be used to monitor response to corticosteroid treatment.