Eigenvalue asymptotics for weighted Laplace equations on rough Riemannian manifolds with boundary

Our topological setting is a smooth compact manifold of dimension two or higher with smooth boundary. Although this underlying topological structure is smooth, the Riemannian metric tensor is only assumed to be bounded and measurable. This is known as a rough Riemannian manifold. For a large class of boundary conditions we demonstrate a Weyl law for the asymptotics of the eigenvalues of the Laplacian associated to a rough metric. Moreover, we obtain eigenvalue asymptotics for weighted Laplace equations associated to a rough metric. Of particular novelty is that the weight function is not assumed to be of fixed sign, and thus the eigenvalues may be both positive and negative. Key ingredients in the proofs were demonstrated by Birman and Solomjak nearly fifty years ago in their seminal work on eigenvalue asymptotics. In addition to determining the eigenvalue asymptotics in the rough Riemannian manifold setting for weighted Laplace equations, we also wish to promote their achievements which may have further applications to modern problems

Thymic stromal lymphopoietin as a novel mediator amplifying immunopathology in rheumatic disease

Thymic stromal lymphopoietin (TSLP) is an IL-7-related cytokine that has been studied extensively in atopic diseases and more recently in various rheumatic disorders. It is involved in T cell development in the thymus and promotes homeostatic T cell expansion by classical dendritic cells. However, deregulated TSLP expression in various rheumatic diseases has implicated this cytokine as a strong mediator in immunopathology. Overexpressed TSLP induces strong T cell activation and production of pro-inflammatory cytokines in human cells and animal models for RA, SSc and LN, underscoring the therapeutic potential of targeting the TSLP-TSLP receptor axis

Comparison of five in vitro digestion models to study the bio-accessibilty of soil contanminants

Soil ingestion can be a major exposure route for humans to many immobile soil contaminants. Exposure to soil contaminants can be overestimated if oral bioavailability is not taken into account. Several in vitro digestion models simulating the human gastrointestinal tract have been developed to assess mobilization of contaminants from soil during digestion, i.e., bioaccessibility. Bioaccessibility is a crucial step in controlling the oral bioavailability for soil contaminants. To what extent in vitro determination of bioaccessibility is method dependent has, until now, not been studied. This paper describes a multi-laboratory comparison and evaluation of five in vitro digestion models. Their experimental design and the results of a round robin evaluation of three soils, each contaminated with arsenic, cadmium, and lead, are presented and discussed. A wide range of bioaccessibility values were found for the three soils: for As 6−95%, 1−19%, and 10−59%; for Cd 7−92%, 5−92%, and 6−99%; and for Pb 4−91%, 1−56%, and 3−90%. Bioaccessibility in many cases is less than 50%, indicating that a reduction of bioavailability can have implications for health risk assessment. Although the experimental designs of the different digestion systems are distinct, the main differences in test results of bioaccessibility can be explained on the basis of the applied gastric pH. High values are typically observed for a simple gastric method, which measures bioaccessibility in the gastric compartment at low pHs of 1.5. Other methods that also apply a low gastric pH, and include intestinal conditions, produce lower bioaccessibility values. The lowest bioaccessibility values are observed for a gastrointestinal method which employs a high gastric pH of 4.0

The additive inflammatory in vivo and in vitro effects of IL-7 and TSLP in arthritis underscore the therapeutic rationale for dual blockade

Introduction: The cytokines interleukin (IL)-7 and thymic stromal lymphopoietin (TSLP) signal through the IL-7R subunit and play proinflammatory roles in experimental arthritis and rheumatoid arthritis (RA). We evaluated the effect of inhibition of IL-7R- and TSLPR-signalling as well as simultaneous inhibition of IL-7R- and TSLPR-signalling in murine experimental arthritis. In addition, the effects of IL-7 and TSLP in human RA dendritic cell (DC)/T-cell co-cultures were studied. Methods: Arthritis was induced with proteoglycan in wildtype mice (WT) and in mice deficient for the TSLP receptor subunit (TSLPR-/-). Both mice genotypes were treated with anti-IL-7R or phosphate buffered saline. Arthritis severity was assessed and local and circulating cytokines were measured. Autologous CD1c-positive DCs and CD4 T-cells were isolated from peripheral blood of RA patients and were co-cultured in the presence of IL-7, TSLP or both and proliferation and cytokine production were assessed. Results: Arthritis severity and immunopathology were decreased in WT mice treated with anti-IL-7R, in TSLPR-/- mice, and the most robustly in TSLPR-/- mice treated with anti-IL-7R. This was associated with strongly decreased levels of IL-17, IL-6 and CD40L. In human DC/T-cell co-cultures, TSLP and IL-7 additively increased T-cell proliferation and production of Th17-associated cytokines, chemokines and tissue destruction factors. Conclusion: TSLP and IL-7 have an additive effect on the production of Th17-cytokines in a human in vitro model, and enhance arthritis in mice linked with enhanced inflammation and immunopathology. As both cytokines signal via the IL-7R, these data urge for IL-7R-targeting to prevent the activity of both cytokines in RA

Decreased expression of thymic stromal lymphopoietin in salivary glands of patients with primary Sjögren’s syndrome is associated with increased disease activity

Objectives: Thymic Stromal Lymphopoietin (TSLP) is a potent immunomodulatory cytokine involved in Th2- and Th17-mediated immune responses in different autoimmune diseases. TSLP expression in relation to disease activity was studied in salivary glands of primary Sjögren’s syndrome (pSS) patients as compared to non-SS sicca (nSS) controls. Methods: Tissue sections of minor salivary glands from pSS and nSS patients were stained with monoclonal antibodies against human TSLP, CD3, CD19 and cytokeratin high molecular weight (CK HMW) or stained for Alcian blue to detect mucus production. The number of TSLP-expressing cells was quantified and expression was correlated to local and systemic disease parameters. Results: The number of TSLP-expressing cells was significantly lower in pSS patients than in nSS controls and correlated with a range of disease markers. In pSS patients, TSLP was expressed outside of lymphocytic infiltrates at sections that also encompassed high numbers of intact acinar cells. This difference was independent of tissue destruction. Conclusions: Reduced TSLP expression in pSS patients is associated with increased local and systemic inflammatory markers. Loss of TSLP expression may contribute to Th1/Th17-associated immunopathology in pSS, in line with previous studies demonstrating that TSLP promotes a protective Th2 milieu at mucosal sites

TSLP and IL-7 additively induce T-cell proliferation and Th17-activity in a human cDC/T-cell co-culture.

<p>Paired CD1c-expressing classical dendritic cells (cDCs) and CD4⁺ T-cells were isolated from rheumatoid arthritis patients. CD4 T-cells were co-cultured with cDCs for 6 days in the presence of thymic stromal lymphopoietin (TSLP), IL-7 or both cytokines. TSLP and IL-7 additively induce T-cell proliferation as measured with tritium thymidine incorporation (A). TSLP and IL-7 show additive induction of Th17-associated cytokines (B). Additive effects were also found on expression of other proinflammatory cytokines and T-cell attracting chemokines (C). * and ** indicate statistical differences of p<0.05 and p<0.01 respectively.</p

TSLPR-deficiency and IL-7R blockade alter numbers of thymocytes and splenocytes.

<p>Total numbers of thymocytes were modestly increased in anti-IL-7R treated TSLPR-/- mice as compared to PBS treated WT mice (A), associated with an increase in CD4+ CD8+ double positive (DP) thymocytes (B). Total numbers of splenocytes were decreased in anti-IL-7R treated TSLPR-/- mice compared to PBS treated WT mice (C), associated with a decrease in CD4+ and CD8+ T-cells in the anti-IL-7R treated TSLPR-/- mice (D). The number of CD4+ T-cells with characteristics of naive (Naive; CD44-CD62L+), central memory (CM; CD44+CD62L+) and effector memory (EM; CD44+CD62L-) T-cells were significantly decreased in anti-IL-7R TSLPR-/- mice as compared to PBS WT mice. Values are mean ± SEM of 16 mice per group. * and *** indicate statistical differences of p<0.05 and p<0.005 respectively.</p

Arthritis severity is inhibited in TSLPR deficient mice and upon blockade of the IL-7R.

<p>WT or TSLPR-/- mice were treated with PBS or anti IL-7Rα antibodies (anti IL-7R, 100 μg ip. on day 21, 24, 27, 30, and 33) and arthritis severity was graded by visual examination of the paws. IL-7R blockade, TSLPR deficiency or a combination of both significantly decreased arthritis severity compared to PBS WT mice (A). The same was true for radiological joint damage (B, C), histology (D) and osteoclast formation as measured by the number of TRAP+ cells (E). Anti-IL-7R TSLPR-/- mice showed almost complete inhibition of joint damage. Values are mean ± SEM of 16 mice per group. *, **, and *** indicate statistical differences of p<0.05, p<0.01, or p<0.005 respectively.</p

IL-7R blockade and TSLPR-deficiency additively reduce production of pro-inflammatory cytokines, chemokines and mediators involved in tissue destruction and angiogenesis.

<p>Cytokine concentrations in paw protein lysates (A) and serum (B) were measured by multicytokine analysis. Cytokines associated with T-cell and monocyte/macrophage activation, chemotaxis, angiogenesis and tissue destruction were reduced by IL-7R blockade and TSLPR deficiency. Values are mean ± SEM of 10 mice per group with representative arthritis scores. *, **, and *** indicate statistical differences of p<0.05, p<0.01, or p<0.005 respectively.</p