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Metabolic dysfunction associated steatotic liver disease (MASLD) presents a growing global health problem. Disease progression is promoted not only by hepatic leukocyte accumulation but also by inflammatory signals from adipose tissue and an altered gut microbiome. To determine the contribution of intercellular adhesion molecule-1 (ICAM-1) to MASLD pathogenesis, male mice with an ICAM-1 mutation (Icam1 tmBay ) and wild type (WT) mice were compared in 12 and 24-week feeding experiments with a Western-style diet (WD) containing 40 kcal% fat, 20 kcal% fructose, and 2% cholesterol. WD-induced MASLD was accompanied by increased ICAM-1 expression in liver, epididymal white adipose tissue (EWAT), and intestine in WT mice. WD-fed Icam1 tmBay mice exhibited increased circulating neutrophils, higher frequencies of inflammatory leukocytes in EWAT, and a worsened glucose tolerance when compared to WT mice. In contrast, the mutation resulted in reduced WD-induced liver disease activity and less accumulation of intrahepatic leukocytes. WD-feeding caused substantial changes in fecal microbiota with decreased microbial diversity that differed between the mouse strains. In conclusion, ICAM-1 positively regulates adipose tissue homeostasis and protects from insulin resistance but promotes liver damage in diet-induced obesity. This points to organ-specific roles for ICAM-1 and the potential of liver-specific targeting of ICAM-1 for treatment of MASLD.

This work explores the use of Kuhn verdazyl radicals as building blocks in multifunctional molecular materials in an exemplary study, focusing on the magnetic and the electron transfer (ET) characteristics, but also addressing the question whether chemical modification by cross-coupling is possible. The ET in solution is studied spectroscopically, whereas solid state measurements afford information about the magnetic susceptibility or the conductivity of the given samples. The observed results are rationalized based on the chemical structures of the molecules, which have been obtained by X-ray crystallography. The crystallographically observed molecular structures as well as the interpretation based on the spectroscopic and physical measurements are backed up by DFT calculations. The measurements indicate that only weak, antiferromagnetic (AF) coupling is observed in Kuhn verdazyls owed to the low tendency to form face-to-face stacks, but also that steric reasons alone are not sufficient to explain this behavior. Furthermore, it is also demonstrated that ET reactions proceed rapidly in verdazyl/verdazylium redox couples and that Kuhn verdazyls are suited as donor molecules in ET reactions.

An analytical model is proposed to investigate properties of composite electrodes that utilize more than one active material. We demonstrate how the equations can be applied to aid in the design of electrodes by comparing silicon-graphite and tin-graphite composite negative electrodes as examples with practical relevance. Based on simple assumptions, the results show how volume expansion tolerance and initial porosity are important factors for the achievable gravimetric and volumetric capacities as well as volumetric energy density. A Si-alloy/graphite composite electrode is used as an experimental system to corroborate the formulated analysis. Kinetic limitations are also addressed based on a novel heuristic approach.

The rate of SARS-CoV-2 infections in children remains unclear due to many asymptomatic cases. We present a study of cross-sectional seroprevalence surveys of anti-SARS-CoV-2 IgG in 10,358 children recruited in paediatric hospitals across Germany from June 2020 to May 2021. Seropositivity increased from 2.0% (95% CI 1.6, 2.5) to 10.8% (95% CI 8.7, 12.9) in March 2021 with little change up to May 2021. Rates increased by migrant background (2.8%, 4.4% and 7.8% for no, one and two parents born outside Germany). Children under three were initially 3.6 (95% CI 2.3, 5.7) times more likely to be seropositive with levels equalising later. The ratio of seropositive cases per recalled infection decreased from 8.6 to 2.8. Since seropositivity exceeds the rate of recalled infections considerably, serologic testing may provide a more valid estimate of infections, which is required to assess both the spread and the risk for severe outcomes of SARS-CoV-2 infections. Children are less likely to be infected with SARS-CoV-2 and develop less severe disease than adults, which makes estimation of infection rates challenging. Here, the authors conduct seroprevalence surveys of children in Germany, describe changes in prevalence over time, and identify risk factors for infection.

Introduction The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß 2 -sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß 2 -sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological T H 2-phenotype in asthma, acting—at least partially—through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease. Methods After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM- knockout ), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß 2 -adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function. Results Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1 −/− ) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol. Conclusion Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the T H 2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.

Arising in inflammatory conditions, myeloid-derived suppressor cells (MDSCs) are constantly confronted with intracellular and extracellular reactive oxygen species molecules and oxidative stress. Generating mice with a constitutive activation of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) we show a pivotal role of the antioxidant stress defense for development of these immune-modulatory cells. These mice are characterized by a massive increase of splenic CD11b Gr-1 cells, which exhibit typical suppressive characteristics of MDSCs. Whole transcriptome analysis revealed Nrf2-dependent activation of cell cycle and metabolic pathways, which resemble pathways in CD11b Gr-1 MDSCs expanded by LPS exposure. Constitutive Nrf2 activation thereby regulates activation and balance between glycolysis and mitochondrial metabolism and hence expansion of highly suppressive MDSCs, which mediate protection in LPS-induced sepsis. Our study establishes Nrf2 as key regulator of MDSCs and acquired tolerance against LPS-induced sepsis.

Background Enhanced expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) on high endothelial venules facilitates lymphocyte migration to sites of intestinal inflammation in inflammatory bowel disease (IBD). This process may be accompanied by increased shedding of soluble MAdCAM-1 (sMAdCAM-1) from endothelial cells. Hence, circulating sMAdCAM-1 may serve as a biomarker of intestinal inflammation in IBD. Results This single-center study enrolled pediatric ( n  = 32) and adult ( n  = 73) patients with IBD, as well as healthy controls ( n  = 56). Serum samples were collected from all participants, and sMAdCAM-1 concentrations were quantified using an ELISA assay. In healthy individuals, sMAdCAM-1 levels were highest in early childhood, declined during adolescence, and were lowest in adulthood. Concentrations of sMAdCAM-1 did not correlate with gut inflammation in pediatric or adult patients with Crohn’s disease (CD). In contrast, significantly increased sMAdCAM-1 levels were observed in adults with severe ulcerative colitis (UC). Moreover, sMAdCAM-1 levels distinguished healthy children from pediatric UC patients. Conclusions These findings provide new insights into sMAdCAM-1 as a marker of gut homeostasis and inflammation. Shedding of sMAdCAM-1 decreases during adolescence, and circulating sMAdCAM-1 levels could serve as a biomarker for ulcerative colitis in both pediatric and adult patients, particularly in severe disease.

We aim to assess sedentary behavior (SB) and its determinants, as well as potential strategies to reduce SB among employees in a tertiary hospital in Singapore, using a mixed-methods approach grounded in the socioecological framework. All employees with email and security guards of a tertiary hospital in Singapore were invited to complete a questionnaire that captured sociodemographics and self-reported domain-specific SB. Environmental influences of occupational SB were assessed using an adapted version of the Checklist for Health Promotion Environments at the Worksite (CHEW). Focus group discussion (FGD) addressed perceptions, barriers, and strategies toward reducing workplace SB. Analyses were performed separately and integrated using an inductive comparative approach. The median occupational sitting time (n = 938) was 300 minutes/day, and highest among administrative staff (administrative, 421 minutes/day; allied health, 300 minutes/day; ancillary, 300 minutes/day; nursing, 120 minutes/day; medical/dental/others, 240 minutes/day; p value: <.001). The CHEW assessment identified poor physical and information environment contributing to occupational SB. FGDs confirmed an unsupportive environment and elicited barriers such as low SB awareness, nature of work, and workplace norms. Besides environmental approaches, participants suggested having face-to-face communication and social modelling to promote more breaks from sitting. This mixed-methods study among diverse professional groups of a tertiary hospital indicated a large amount of occupational SB, particularly among administrative staff. Raising awareness of the health risks of SB and building a supportive organizational culture, information, and physical environment emerged as significant factors. To reduce occupational SB, multicomponent interventions addressing these diverse factors are warranted.

IntroductionRegulatory T-cells (Tregs) are characterized by the expression of Foxp3, a master regulator involved in the development and function of Tregs. Foxp3 expression is dependent on activity of the Treg specific demethylated site (TSDR), which contains a CREB binding site. We aimed to find out how Foxp3 specific CREB deletion affects Treg expression and function.MethodsTregs from Foxp3creCREBfl/fl mice and wild type ( CREBfl/fl ) mice were analyzed by flow cytometry. Cytokine analysis was performed by flow cytometry, ELISA and RT-qPCR. Gene expression analysis was performed using Affymetrix HTA2 assays, ATAC-sequencing, and Methylation-assays. For functional relevance, a CD4 T cell mediated transfer colitis was performed.Results and discussionFoxp3creCREBfl/fl mice showed increased frequencies of Tregs (CD25+/Foxp3+) in thymus, spleen and peripheral lymph nodes and in nonlymphoid organs including lung and colon, but decreased Foxp3 expression at the single cell level. Despite decreased Foxp3 expression, enhanced expression of the IL- 33 receptor (ST-2), IL-10, IL-13, and CREM was observed. CREB deficient Tregs were highly suppressive in vitro and prevented disease activity in a CD4 T cell mediated transfer colitis in an IL-10 dependent way. Mechanistically CREB fulfils dual roles in Tregs: (1) it promotes Foxp3 expression under Steady state conditions and (2) in cooperation with CREM, CREB restricts chromatin accessibility at the ST2 locus, thereby modulating IL-33 driven immune responses. This dual regulation balances FoxP3-dependent Treg stability with IL-10 mediated suppression of inflammation.