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Background There is growing evidence for a negative impact of traffic-related air pollution on risk of dementia. However, the contribution of noise exposure to this association has been rarely examined. Objective We aimed to investigate the individual and combined effect of noise and air pollution on risk of dementia. Methods Data on dementia incidence over a 15 year period was obtained from the Betula project, a longitudinal study on health and ageing. Estimates of annual mean levels of nitrogen oxides (NO x ) at the participants’ residential address were obtained using a land-use regression model. Modelled data provided road traffic noise levels (Leq. 24 h) at the participants’ residential address at baseline. Cox proportional hazard regression was used to calculate hazard ratios (HR). Results Of 1721 participants at baseline, 302 developed dementia during the follow up period. Exposure to noise levels (Leq. 24 h) > 55 dB had no significant effect on dementia risk (HR 0.95; CI: 0.57, 1.57). Residing in the two highest quartiles of NO x exposure was associated with an increased risk of dementia. The risk associated with NO x was not modified by adjusting for noise. Moreover, we found no significant interaction effects between NO x and road traffic noise on dementia risk. Conclusion We found no evidence that exposure to road traffic noise, either independently or in combination with traffic air pollution, was associated with risk of dementia in our study area. Our results suggest that pollution should be considered the main component in the association between traffic related exposures and dementia. [ABSTRACT FROM AUTHOR]

In this paper we discuss the obstacle problem for the p -Laplace operator. We prove optimal growth results for the solution. Of particular interest is the point-wise regularity of the solution at free boundary points. The most surprising result we prove is the one for the p -obstacle problem: Find the smallest u such that div ( | ∇ u | p − 2 ∇ u ) ≤ 0 , u ≥ ϕ , in B 1 , with ϕ ∈ C 1 , 1 ( B 1 ) and given boundary datum on ∂ B 1 . We prove that the solution is uniformly C 1 , 1 at free boundary points. Similar results are obtained in the case of an inhomogeneity belonging to L ∞ . When applied to the corresponding parabolic problem, these results imply that any solution which is Lipschitz in time is C 1 , 1 p − 1 in the spatial variables. [ABSTRACT FROM AUTHOR]

In this paper we initiate the study of maps minimising the energy ∫ D ( | ∇ u | 2 + 2 | u | ) d x , which, due to Lipschitz character of the integrand, gives rise to the singular Euler equations Δ u = u | u | χ { | u | > 0 } , u = ( u 1 , ⋯ , u m ) . Our primary goal in this paper is to set up a road map for future developments of the theory related to such energy minimising maps. Our results here concern regularity of the solution as well as that of the free boundary. They are achieved by using monotonicity formulas and epiperimetric inequalities, in combination with geometric analysis. [ABSTRACT FROM AUTHOR]

Abstract: Atherosclerosis involves the formation of inflammatory arterial lesions and is one of the most common causes of death globally. It has been evident for more than 20 years that adaptive immunity and T cells in particular regulate the magnitude of the atherogenic pro-inflammatory response. T cells also influence the stability of the atherosclerotic lesion and thus the propensity for thrombus formation and the clinical outcome of disease. This review summarizes our current understanding of T cells in atherogenesis, including which antigens they recognize, the role of T cell costimulation/coinhibition, and their secretion of pro- and anti-inflammatory mediators. Furthermore, we outline future areas of research and potential clinical intervention strategies. [Copyright &y& Elsevier]

Abstract: We investigate the regularity of a free boundary near contact points with a fixed boundary, with boundary data, for an obstacle-like free boundary problem. We will show that under certain assumptions on the solution, and the boundary function, the free boundary is uniformly up to the fixed boundary. We will also construct some examples of irregular free boundaries. [Copyright &y& Elsevier]

Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS) and is often assessed through biological samples. Due to the easier access, peripheral blood is more commonly phenotyped instead of cerebrospinal fluid (CSF) or affected tissues in ALS. Here, using flow cytometry, we compared the composition of T cell subsets in blood and CSF in ALS patients. We found consistent but weak correlations between blood and CSF for all T cell subsets examined. This finding implies that blood and CSF offer complementary information when characterizing T cell immunity in ALS and blood may not be used as a surrogate for CSF. • Weak longitudinal correlations of T cells between blood and CSF in ALS. • Blood's predictive power limited for CSF T cell repertoire at the time of ALS diagnosis. • Statistical considerations are crucial for longitudinal correlation analysis. [ABSTRACT FROM AUTHOR]

Chlorinated polyfluorinated ether sulfonate (F–53B), a substitute of perfluorooctane sulfonic acid (PFOS), has attracted significant attention for its link to hepatotoxicity and enterotoxicity. Nevertheless, the underlying mechanisms of F–53B-induced enterohepatic toxicity remain incompletely understood. This study aimed to explore the role of F–53B exposure on enterohepatic injury based on the gut microbiota, pathological and molecular analysis in mice. Here, we exposed C57BL/6 mice to F–53B (0, 4, 40, and 400 μg/L) for 28 days. Our findings revealed a significant accumulation of F–53B in the liver, followed by small intestines, and feces. In addition, F–53B induced pathological collagen fiber deposition and lipoid degeneration, up-regulated the expression of fatty acid β-oxidation-related genes (PPARα and PPARγ , etc), while simultaneously down-regulating pro-inflammatory genes (Nlrp3 , IL-1β , and Mcp1) in the liver. Meanwhile, F–53B induced ileal mucosal barrier damage, and an up-regulation of pro-inflammatory genes and mucosal barrier-related genes (Muc1 , Muc2 , Claudin1 , Occludin , Mct1 , and ZO-1) in the ileum. Importantly, F–53B distinctly altered gut microbiota compositions by increasing the abundance of Akkermansia and decreasing the abundance of Prevotellaceae_NK3B31_group in the feces. F–53B-altered microbiota compositions were significantly associated with genes related to fatty acid β-oxidation, inflammation, and mucosal barrier. In summary, our results demonstrate that F–53B is capable of inducing hepatic injury, ileitis, and gut microbiota dysbiosis in mice, and the gut microbiota dysbiosis may play an important role in the F–53B-induced enterohepatic toxicity. [Display omitted] • F–53B that simulated human exposure levels is accumulated in the liver, intestines, and feces of mice. • F–53B led to hepatic deposition of collagen fibers, ileitis, and gut microbiota dysbiosis in mice. • F–53B-altered microbiota was associated with genes related to hepatic fatty acid β-oxidation and ileal mucosal barrier in mice. [ABSTRACT FROM AUTHOR]

Abstract CTLA-4 is required for CD4+Foxp3+ regulatory T (Treg) cell function, but its mode of action remains incompletely defined. Herein we generated Ctla-4 ex2fl/fl Foxp3-Cre mice with Treg cells exclusively expressing a naturally occurring, ligand-independent isoform of CTLA-4 (liCTLA-4) that cannot interact with the costimulatory molecules CD80 and CD86. The mice did not exhibit any signs of effector T cell activation early in life, however, at 6 months of age they exhibited excessive T cell activation and inflammation in lungs. In contrast, mice with Treg cells completely lacking CTLA-4 developed lymphoproliferative disease characterized by multi-organ inflammation early in life. In vitro , Treg cells exclusively expressing liCTLA-4 inhibited CD80 and CD86 expression on dendritic cells (DC). Conversely, Treg cells required the extra-cellular part of CTLA-4 to up-regulate expression of the co-inhibitory molecule PD-L2 on DCs. Transcriptomic analysis of suppressed DCs revealed that Treg cells induced a specific immunosuppressive program in DCs. Highlights • The cell-extrinsic functions of CTLA-4 are dispensable for regulating CD80/86 expression on DCs. • Regulatory T cells use CTLA-4 to induce the co-inhibitory molecule PD-L2 on dendritic cells. • Regulatory T cells induce a specific genetic program in suppressed dendritic cells. • CTLA-4 is required to restrict the size of the regulatory T cell pool. [ABSTRACT FROM AUTHOR]

The forkhead/winged-helix transcription factor FOXP3 confers suppressive ability to CD4 + FOXP3 + regulatory T (Treg) cells. Human Treg cells express several different isoforms of FOXP3 that differ in function. However, the regulation and functional consequences of FOXP3 isoform expression remains poorly understood. In order to study the function of the FOXP3Δ2Δ7 isoform in vivo we generated mice that exclusively expressed a Foxp3 isoform lacking exon 2 and 7. These mice exhibited multi-organ inflammation, increased cytokine production, global T cell activation, activation of antigen-presenting cells and B cell developmental defects, all features that are shared with mice completely deficient in FOXP3. Our results demonstrate that the mouse counterpart of human FOXP3Δ2Δ7 is unable to confer suppressive ability to Treg cells. [ABSTRACT FROM AUTHOR]

The transcription factor FOXP3 is essential for CD4+FOXP3+ regulatory T (Treg) cell development and function. Human FOXP3 exists in distinct isoforms and alterations in isoform expression is associated with inflammatory disease progression, however, the exact functions of FOXP3 isoforms remain poorly understood. Herein we used flow cytometry and RNA-sequencing to analyze subsets of Treg cells from two IPEX patients, and a healthy carrier, of a recently described FOXP3 mutation (c.305delT). This mutation is located in exon 2 and results in the loss of the full-length FOXP3 isoform. Treg cells lacking full-length FOXP3 are found at lower-than-expected frequencies. This loss cannot be explained solely by altered thymic output, changes in proliferation, peripheral induction of Treg cells, or apoptosis. Instead, fulllength FOXP3 control a distinct genetic program, involving the previously identified FOXP3 regulators ID3, BCL6 and eIF4E, that upholds Treg cell lineage stability, while it appears nonessential for Treg cell activation. • The full-length FOXP3 isoform upholds regulatory T cell lineage stability. • FOXP3fl controls expression of ID3, Bcl6 and eIF4E. • The full-length FOXP3 isoform is non-essential for regulatory T cell activation. [ABSTRACT FROM AUTHOR]