Search

In order to recover from infection, organisms must balance robust immune responses to pathogens with the tolerance of immune-mediated pathology. This balance is particularly critical within the central nervous system, whose complex architecture, essential function, and limited capacity for self-renewal render it susceptible to both pathogen- and immune-mediated pathology. Here, we identify the alarmin IL-33 and its receptor ST2 as critical for host survival to neuroinvasive flavivirus infection. We identify oligodendrocytes as the critical source of IL-33, and microglia as the key cellular responders. Notably, we find that the IL-33/ST2 axis does not impact viral control or adaptive immune responses; rather, it is required to promote the activation and survival of microglia. In the absence of intact IL-33/ST2 signaling in the brain, neuroinvasive flavivirus infection triggered aberrant recruitment of monocyte-derived peripheral immune cells, increased neuronal stress, and neuronal cell death, effects that compromised organismal survival. These findings identify IL-33 as a critical mediator of CNS tolerance to pathogen-initiated immunity and inflammation.

Abstract Epithelial cells control a variety of immune cells by secreting cytokines to maintain tissue homeostasis on mucosal surfaces. Regulatory T (Treg) cells are essential for immune homeostasis and for preventing tissue inflammation; however, the precise molecular mechanisms by which epithelial cell-derived cytokines function on Treg cells in the epithelial tissues are not well understood. Here, we show that peripheral Treg cells preferentially respond to thymic stromal lymphoprotein (TSLP). Although TSLP does not affect thymic Treg differentiation, TSLP receptor-deficient induced Treg cells derived from naïve CD4+ T cells are less activated in an adoptive transfer model of colitis. Mechanistically, TSLP activates induced Treg cells partially through mTORC1 activation and fatty acid uptake. Thus, TSLP modulates the activation status of induced Treg through the enhanced uptake of fatty acids to maintain homeostasis in the large intestine.

Abstract Common alphacoronaviruses and human rhinoviruses (HRV) induce type I and III interferon (IFN) responses important to limiting viral replication in the airway epithelium. In contrast, highly pathogenic betacoronaviruses including SARS-CoV-2 may evade or antagonize RNA-induced IFN I/III responses. In airway epithelial cells (AECs) from children and older adults we compared IFN I/III responses to SARS-CoV-2 and HRV-16, and assessed whether pre-infection with HRV-16, or pretreatment with recombinant IFN-β or IFN-λ, modified SARS-CoV-2 replication. Bronchial AECs from children (ages 6–18 years) and older adults (ages 60–75 years) were differentiated ex vivo to generate organotypic cultures. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 or HRV-16, and RNA and protein was harvested from cell lysates 96 h. following infection and supernatant was collected 48 and 96 h. following infection. In additional experiments cultures were pre-infected with HRV-16, or pre-treated with recombinant IFN-β1 or IFN-λ2 before SARS-CoV-2 infection. In a subset of experiments a range of infectious concentrations of HRV-16, SARS-CoV-2 WA-01, SARS-CoV-2 Delta variant, and SARS-CoV-2 Omicron variant were studied. Despite significant between-donor heterogeneity SARS-CoV-2 replicated 100 times more efficiently than HRV-16. IFNB1, INFL2, and CXCL10 gene expression and protein production following HRV-16 infection was significantly greater than following SARS-CoV-2. IFN gene expression and protein production were inversely correlated with SARS-CoV-2 replication. Treatment of cultures with recombinant IFNβ1 or IFNλ2, or pre-infection of cultures with HRV-16, markedly reduced SARS-CoV-2 replication. In addition to marked between-donor heterogeneity in IFN responses and viral replication, SARS-CoV-2 (WA-01, Delta, and Omicron variants) elicits a less robust IFN response in primary AEC cultures than does rhinovirus, and heterologous rhinovirus infection, or treatment with recombinant IFN-β1 or IFN-λ2, reduces SARS-CoV-2 replication, although to a lesser degree for the Delta and Omicron variants.

On Arctic shelves, where primary production occurs in both the pelagic and sympagic (ice-associated) habitats, sympagic organic material (OM) can constitute a disproportionate fraction of benthic diets due to higher sinking rates and lower grazing pressure than pelagic OM. Less documented is how sympagic OM assimilation across feeding guilds varies seasonally and in relation to sea ice duation. We therefore investigated the relative abundance of sympagic vs pelagic OM in Barents Sea shelf megabenthos in the summer and winter of 2018 and 2019, from 10 stations where sea ice duration ranged from 0 to 245 days per year. We use highly branched isoprenoids, which are lipid biomarkers produced with distinct molecular structures by diatoms in sea ice and the water column, to determine the ratio of sympagic-to-pelagic OM assimilated by benthic organisms. From 114 samples of 25 taxa analysed, we found that the proportion of sympagic OM assimilated ranged from 0.4% to 95.8% and correlated strongly (r2 = 0.754) with the duration of sea ice cover. The effect of sea ice duration was more evident in fauna collected during summer than winter, indicating that sympagic signals are more evident in the summer than in the winter at higher latitudes. Our data show that sympagic production can supply a high fraction of carbon for Barents Sea benthos, although this is highly variable and likely dependent on availability and patchiness of sympagic OM deposition. These results are comparable to similar studies conducted on benthos in the Pacific Arctic and highlight the variable importance of sympagic OM in the seasonal ice zone of Arctic inflow shelves, which are the Arctic regions with highest rates of sea ice loss.

Summary: Foxp3+ regulatory T cells (Tregs) are critical mediators of peripheral tolerance and immune homeostasis and exert tissue-specific functions. In many nonlymphoid tissues, Tregs show enriched expression of the IL-33 receptor ST2. Through comprehensive profiling of murine ST2+ and ST2- Tregs, we found that Treg transcriptomes and phenotypes formed a hierarchical relationship across tissues. Only a small core signature distinguished ST2+ Tregs from ST2- Tregs across all tissues, and differences in transcriptional profiles were predominantly tissue-specific. We also identified unique, highly proliferative, circulating ST2+ Tregs with high migratory potential. In adoptive transfers, both ST2+ and ST2- Tregs seeded various host tissues and demonstrated plasticity in ST2 expression. Furthermore, Tregs from donor lungs were differentially recovered from host nonlymphoid tissues in an IL-33-dependent manner. In summary, our work identified tissue residency rather than ST2 expression as a primary driver of tissue Treg identity and highlights the unique, tissue-specific adaption of ST2+ Tregs.

Prostate cancer is the second most commonly diagnosed cancer in men worldwide. Despite this, current diagnostic tools are still not satisfactory, lacking sensitivity for early-stage or single-cell diagnosis. This study describes the development of small-molecule tracers for the well-known tumor marker prostate-specific membrane antigen (PSMA). These tracers contain a urea motif for PSMA-targeting and iodinated aromatic moieties to allow detection via X-ray fluorescence imaging (XFI). Tracers with a triiodobenzoyl moiety allowed the specific targeting and successful imaging of PSMA+ cell lines with XFI. The XFI-measured uptake of 7.88 × 10 -18 mol iodine (I) per cell is consistent with the uptake of known PSMA tracers measured by other techniques such as inductively coupled plasma mass spectrometry (ICP-MS). This is the first successful application of XFI to tumor cell targeting with a small-molecule tracer. In addition, iodinated tracers were used for the characterization of quantum dots (QDs) conjugated to PSMA-targeting urea motifs. The resulting targeted QD conjugates were shown to selectively bind PSMA+ cell lines via confocal microscopy. The immobilized iodinated targeting vectors allowed the determination of the tracer/QD ratio via XFI and ICP-MS. This ratio is a key property of targeted particles and difficult to measure by other techniques.

The vertebrate sense of taste allows rapid assessment of the nutritional quality and potential presence of harmful substances prior to ingestion. Among the five basic taste qualities, salty, sour, sweet, umami, and bitter, bitterness is associated with the presence of putative toxic substances and elicits rejection behaviors in a wide range of animals including humans. However, not all bitter substances are harmful, some are thought to be health-beneficial and nutritious. Among those compound classes that elicit a bitter taste although being non-toxic and partly even essential for humans are bitter peptides and L-amino acids. Using functional heterologous expression assays, we observed that the 5 dominant human bitter taste receptors responsive to bitter peptides and amino acids are activated by bile acids, which are notorious for their extreme bitterness. We further demonstrate that the cross-reactivity of bitter taste receptors for these two different compound classes is evolutionary conserved and can be traced back to the amphibian lineage. Moreover, we show that the cross-detection by some receptors relies on "structural mimicry" between the very bitter peptide L-Trp-Trp-Trp and bile acids, whereas other receptors exhibit a phylogenetic conservation of this trait. As some bile acid-sensitive bitter taste receptor genes fulfill dual-roles in gustatory and non-gustatory systems, we suggest that the phylogenetic conservation of the rather surprising cross-detection of the two substance classes could rely on a gene-sharing-like mechanism in which the non-gustatory function accounts for the bitter taste response to amino acids and peptides., (© 2024. The Author(s).)

Beside the oral cavity, bitter taste receptors are expressed in several non-gustatory tissues. Whether extra-oral bitter taste receptors function as sensors for endogenous agonists is unknown. To address this question, we devised functional experiments combined with molecular modeling approaches to investigate human and mouse receptors using a variety of bile acids as candidate agonists. We show that five human and six mouse receptors are responsive to an array of bile acids. Moreover, their activation threshold concentrations match published data of bile acid concentrations in human body fluids, suggesting a putative physiological activation of non-gustatory bitter receptors. We conclude that these receptors could serve as sensors for endogenous bile acid levels. These results also indicate that bitter receptor evolution may not be driven solely by foodstuff or xenobiotic stimuli, but also depend on endogenous ligands. The determined bitter receptor activation profiles of bile acids now enable detailed physiological model studies., (© 2023. The Author(s).)

Introduction: Although the physiological role of the C-terminal hydrolase domain of the soluble epoxide hydrolase (sEH-H) is well investigated, the function of its N-terminal phosphatase activity (sEH-P) remains unknown., Objectives: This study aimed to assess in vivo the physiological role of sEH-P., Methods: CRISPR/Cas9 was used to generate a novel knock-in (KI) rat line lacking the sEH-P activity., Results: The sEH-P KI rats has a decreased metabolism of lysophosphatidic acids to monoacyglycerols. KI rats grew almost normally but with less weight and fat mass gain while insulin sensitivity was increased compared to wild-type rats. This lean phenotype was more marked in males than in female KI rats and mainly due to decreased food consumption and enhanced energy expenditure. In fact, sEH-P KI rats had an increased lipolysis allowing to supply fatty acids as fuel to potentiate brown adipose thermogenesis under resting condition and upon cold exposure. The potentiation of thermogenesis was abolished when blocking PPARγ, a nuclear receptor activated by intracellular lysophosphatidic acids, but also when inhibiting simultaneously sEH-H, showing a functional interaction between the two domains. Furthermore, sEH-P KI rats fed a high-fat diet did not gain as much weight as the wild-type rats, did not have increased fat mass and did not develop insulin resistance or hepatic steatosis. In addition, sEH-P KI rats exhibited enhanced basal cardiac mitochondrial activity associated with an enhanced left ventricular contractility and were protected against cardiac ischemia-reperfusion injury., Conclusion: Our study reveals that sEH-P is a key player in energy and fat metabolism and contributes together with sEH-H to the regulation of cardiometabolic homeostasis. The development of pharmacological inhibitors of sEH-P appears of crucial importance to evaluate the interest of this promising therapeutic strategy in the management of obesity and cardiac ischemic complications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Production and hosting by Elsevier B.V.)

Salmon is a nutritious and popular food among consumers predominantly in wealthy countries around the world. Since the mid-1990s farmed salmon production has exceeded wild salmon harvest, and is now 80 % of total global salmon supply. The environmental impacts of farmed salmon are frequently discussed and consumers are faced with a multitude of choices even after deciding to have salmon for dinner: species, production method, origin, product form. We present life cycle impacts of fresh and frozen salmon products, originating in purse seine fisheries for pink salmon and gill net fisheries for sockeye salmon in Alaska, when sold on markets in Europe and the United States. Norwegian salmon products are then modelled to the same markets in fresh and frozen form, based on literature data. Impact categories included were greenhouse gas emissions, marine eutrophication, marine ecotoxicity and land use. A fish in, fish out ratio is also calculated and differences in content of nutrients and contaminants described. Frozen products from wild sockeye and pink salmon had the lowest emissions in both markets. For consumers in the U.S. and Europe, wild salmon products have 46-86 % and 12-71 % lower greenhouse gas emissions than farmed Norwegian salmon, respectively, depending on species and product form. Farmed salmon also had higher land use, marine ecotoxic and eutrophying emissions and fish in, fish out ratio. Important differences exist in nutritional and contaminant content between the three types of salmon production. Improvement options as well as an optimized supply chain are modelled showing greenhouse gas reduction opportunities of 40-50 % also for the best performing chains. Results can be used as a baseline for improved data collection and emission reductions. Recommendations for consumers, industry and policymakers who can facilitate and even drive development towards more sustainable salmon products are provided., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RH reports financial support was provided by Bristol Bay Regional Seafood Development Agency. FZ is employed by an institute that does research and contract work in her area of expertise commissioned by governmental and non-governmental organisations or by seafood companies. The institute has received funding for multiple private and publicly funded projects in the space of sustainable seafood production and consumption, including many projects related to farmed salmon. FZ was involved in research funded by the Norwegian Seafood Research Fund, FHF, in 2019, which led to the data for farmed salmon used in this study. FZ is also part of the sustainability advisory board of Nomad Foods. RH receives research funding from many groups that have interests in fisheries outcomes including environmental NGOs, foundations, governments and fishing industry groups., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The composition of menus and the sequence of foodstuffs consumed during a meal underlies elaborate rules. However, the molecular foundations for the observed taste- and pleasure-raising effects of complex menus are obscure. The molecular identification and characterization of taste receptors can help to gain insight into the complex interrelationships of food items and beverages during meals. In our study, we quantified important bitter compounds in chicory and chicory-based surrogate coffee and used them to identify responsive bitter taste receptors. The two receptors, TAS2R43 and TAS2R46, are exquisitely sensitive to lactucin, lactucopicrin, and 11β,13-dihydrolactucin. Sensory testing demonstrated a profound influence of the sequence of consumption of chicory, surrogate coffee, and roasted coffee on the perceived bitterness by human volunteers. These findings pave the way for a molecular understanding of some of the mixture effects underlying empirical meal compositions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lang, Lang, Dunkel, Ziegler and Behrens.)

Purpose: The ability to develop and evaluate approaches to the management of advanced cancer in sub-Saharan Africa is limited by the lack of local, reliable and valid data to ensure that practice is evidence-based, replicable and reflects the needs of the population served., Methods: A secondary qualitative analysis of in-depth interviews with 59 health professionals delivering palliative cancer care in Nigeria, Uganda and Zimbabwe were conducted to determine the use and needs for data and information for patient care and service delivery. Framework analysis was used, informed by a conceptual model for data use in low and middle-income countries., Results: Three meta-themes include: (1) Current practice in data gathering and use; (2) Gaps for capturing, storing information and supporting communication, and; (3) Needs and opportunities for data use. Deficits in current data access and use were identified, alongside targets for improving the quality, accessibility and utility of data to inform the development of palliative cancer care., Conclusions: The availability and use of relevant and reliable data relating to the current provision of palliative cancer care are requisite for the contextually appropriate and effective development of health services. The requirements and constraints articulated by participants can guide future development and optimisation of digital health approaches for palliative cancer care in the participating countries, with relevance to the wider sub-Saharan Africa region.

The effect of pain and analgesics on stress biomarkers is not well studied. We evaluated the effect of acute pain and analgesics on serum cortisol and copeptin in an experimental pain model in healthy volunteers. Healthy volunteers presented at 8 a.m. for an experimental pain stimulation. Cortisol and copeptin levels were measured before, during and after electrophysiological stimulation, first before and then during opioid delivery. Difference in biomarker levels compared to baseline levels was calculated, and potential influencing factors were evaluated by linear regression analysis. Cortisol decreased by 13% during the 10 min of rest at baseline, but copeptin did not change significantly. Cortisol had a median decrease of -24% or -83 nmol/l (-44 to -124 nmol/l, p = 0.0002) during the electrophysiological stimulation training session, while the median difference for copeptin was -22% or -1.01 pmol/l (-2.35 to 0.08 pmol/l, p = 0.0003). After administration of opioids, cortisol did not decrease but increased by 3% (p = 0.043), indicating an increasing opioids effect on cortisol. This effect was not visible for copeptin (median change -0.003 pmol/l (-0.50 to 0.24), p = 0.45). In this experimental pain model performed in the morning, moderate pain did not have a relevant effect on cortisol or copeptin levels, whereas opioids led to a discrete peak of cortisol.Clinicaltrials.gov identifier: NCT01975753 (registered on November 5, 2013, before start of recruitment)., (© 2022. The Author(s).)

Background: The diagnosis of hypercortisolism requires multiple biochemical investigations, due to variations in cortisol production during the 24-hour circadian cycle. Midnight serum cortisol is difficult to interpret since the threshold value is dependent on the analytical method used and is often not provided by the manufacturer. Second-generation assays are more specific than first-generation assays and may have lower threshold values., Objectives: The aim of this study was to determine a novel threshold value of midnight serum cortisol for the biochemical diagnosis of hypercortisolism, using the Roche Cobas Cortisol® second-generation assay., Methods: This study was performed in adult patients hospitalized in the endocrinology unit of a university hospital. Patients had a complete assessment of their 24-hour cortisol cycle, i.e., a serum cortisol test every four hours and at least two first-line tests: late night salivary cortisol, dexamethasone suppression test and/or 24-hour urinary free cortisol. First-line tests were used to identify patients with hypercortisolism. Serum samples were analyzed by second-generation electrochemiluminescence immunoassays (ECLIA) from Roche Cobas Cortisol®., Results: Midnight serum cortisol samples were obtained from 175 hospitalized patients. The novel threshold value obtained was 157 nmol/L with a sensitivity of 82.9% (68.6 to 94.3%) and a specificity of 90.0% (85.0 to 95.0%)., Conclusion: Our study confirms that the threshold value of midnight serum cortisol is not comparable between first- and second-generation Roche Cobas Cortisol® assays and that the threshold value is lower with the second-generation assay., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Covalent organic frameworks (COFs) offer vast structural and chemical diversity enabling a wide and growing range of applications. While COFs are well-established as heterogeneous catalysts, so far, their high and ordered porosity has scarcely been utilized to its full potential when it comes to spatially confined reactions in COF pores to alter the outcome of reactions. Here, we present a highly porous and crystalline, large-pore COF as catalytic support in α,ω-diene ring-closing metathesis reactions, leading to increased macrocyclization selectivity. COF pore-wall modification by immobilization of a Grubbs-Hoveyda-type catalyst via a mild silylation reaction provides a molecularly precise heterogeneous olefin metathesis catalyst. An increased macro(mono)cyclization (MMC) selectivity over oligomerization (O) for the heterogeneous COF-catalyst (MMC:O=1.35) of up to 51 % compared to the homogeneous catalyst (MMC:O=0.90) was observed along with a substrate-size dependency in selectivity, pointing to diffusion limitations induced by the pore confinement., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Rh(I) NHC and Rh(III) Cp* NHC complexes (Cp*=pentamethylcyclopentadienyl, NHC=N-heterocyclic carbene=pyrid-2-ylimidazol-2-ylidene (Py-Im), thiophen-2-ylimidazol-2-ylidene) are presented. Selected catalysts were selectively immobilized inside the mesopores of SBA-15 with average pore diameters of 5.0 and 6.2 nm. Together with their homogenous progenitors, the immobilized catalysts were used in the hydrosilylation of terminal alkynes. For aromatic alkynes, both the neutral and cationic Rh(I) complexes showed excellent reactivity with exclusive formation of the β(E)-isomer. For aliphatic alkynes, however, selectivity of the Rh(I) complexes was low. By contrast, the neutral and cationic Rh(III) Cp* NHC complexes proved to be highly regio- and stereoselective catalysts, allowing for the formation of the thermodynamically less stable β-(Z)-vinylsilane isomers at room temperature. Notably, the SBA-15 immobilized Rh(I) catalysts, in which the pore walls provide an additional confinement, showed excellent β-(Z)-selectivity in the hydrosilylation of aliphatic alkynes, too. Also, in the case of 4-aminophenylacetylene, selective formation of the β(Z)-isomer was observed with a neutral SBA-15 supported Rh(III) Cp* NHC complex but not with its homogenous counterpart. These are the first examples of high β(Z)-selectivity in the hydrosilylation of alkynes by confinement generated upon immobilization inside mesoporous silica., (© 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)