CD3+CD4+LAP+Foxp3-regulatory cells of the colonic lamina propria limit disease extension in ulcerative colitis

Background and Aims: In ulcerative colitis (UC), inflammation begins in the rectum and can extend proximally throughout the entire colon. The extension of inflammation is an important determinant of disease course, and may be limited by the action of regulatory T cells (Tregs). In this cross-sectional study, we evaluated the relationship between UC extension and the proportions of CD3+CD4+Foxp3+ and CD3+CD4+LAP+Foxp3- Tregs in the colonic lamina propria (LP) of 79 UC patients and 29 controls. The role of these cells in UC extension was also investigated in the murine oxazolone-induced colitis model. Methods: Patients: Disease extension was classified according to the Montreal classification. Where possible, endoscopic biopsies of involved and uninvolved tissue were obtained from UC patients. Mouse model: Colitis was induced by intrarectal oxazolone administration. Lamina propria mononuclear cells were isolated from patient biopsies and mouse colon tissue using enzymatic method and the percentage of CD3+CD4+Foxp3+ and CD3+CD4+LAP+Foxp3-cells evaluated by immunofluorescence. Confocal microscopy was applied for the visualization and quantification of CD4+LAP+ cells on tissue histological sections. Results: In UC patients with distal colitis the proportion of LP CD3+CD4+Foxp3+ Tregs was significantly higher in inflamed tissue than uninvolved tissue. As opposite, the proportion of LP CD3+CD4+LAP+ Tregs was significantly higher in uninvolved tissue than involved tissue. Both LP CD3+CD4+Foxp3+ and LP CD3+CD4+LAP+ Tregs proportion in involved tissue was significantly higher than in controls irrespective of the extension of inflammation. In mice with oxazolone-induced distal colitis, treatment with LAP-depleting antibody was associated with the development of extensive colitis. Conclusions: Our findings suggest that CD3+CD4+LAP+Foxp3-Tregs limit the extension of inflammatory lesions in UC patients

Mixing the spacers in azacryptands: effects on halide recognition

Replacement of just one spacer in dicopper cryptates drastically alters the cavity's shape, thus affecting halide recognition

Chloride-binding in organic–water mixtures: the powerful synergy of C–H donor groups within a bowl-shaped cavity

2,3,4,5-Tetrafluorobenzyl and imidazolium groups within an open-chain receptor allow for the effective binding of chloride in organic–water solution

Non-linear dark energy clustering

We consider a dark energy fluid with arbitrary sound speed and equation of state and discuss the effect of its clustering on the cold dark matter distribution at the non-linear level. We write the continuity, Euler and Poisson equations for the system in the Newtonian approximation. Then, using the time renormalization group method to resum perturbative corrections at all orders, we compute the total clustering power spectrum and matter power spectrum. At the linear level, a sound speed of dark energy different from that of light modifies the power spectrum on observationally interesting scales, such as those relevant for baryonic acoustic oscillations. We show that the effect of varying the sound speed of dark energy on the non-linear corrections to the matter power spectrum is below the per cent level, and therefore these corrections can be well modelled by their counterpart in cosmological scenarios with smooth dark energy. We also show that the non-linear effects on the matter growth index can be as large as 10-15 per cent for small scales.Comment: 33 pages, 7 figures. Improved presentation. References added. Matches published version in JCA

Digital interaction: where are we going?

In the framework of the AVI 2018 Conference, the interuniversity center ECONA has organized a thematic workshop on "Digital Interaction: where are we going?". Six contributions from the ECONA members investigate different perspectives around this thematic

Brane Worlds and the Cosmic Coincidence Problem

Brane world models with `large' extra dimensions with radii in the r_l ~ 0.01- 0.1 mm range and smaller ones at r_s < (1 TeV)^(-1) have the potential to solve the cosmic coincidence problem, i.e. the apparently fortuitous equality between dark matter and dark energy components today. The main ingredient is the assumption of a stabilization mechanism fixing the total volume of the compact submanifold, but allowing for shape deformations. The latter are associated with phenomenologically safe ultra-light scalar fields. Bulk fields Casimir energy naturally plays the role of dark energy, which decreases in time because of expanding r_l. Stable Kaluza Klein states may play the role of dark matter with increasing, O(1/r_s), mass. The cosmological equations exhibit attractor solutions in which the global equation of state is negative, the ratio between dark energy and dark matter is constant and the observed value of the ratio is obtained for two large extra dimensions. Experimental searches of large extra dimensions should take into account that, due to the strong coupling between dark matter and radii dynamics, the size of the large extra dimensions inside the galactic halo may be smaller than the average value.Comment: 6 pages, enlarged discussion on the compact volume stabilization mechanism. Version to appear on Phys. Rev.

"Stockpile" of slight transcriptomic changes determines the indirect genotoxicity of low-dose BPA in thyroid cells

Epidemiological and experimental data highlighted the thyroid-disrupting activity of bisphenol A (BPA). Although pivotal to identify the mechanisms of toxicity, direct low-dose BPA effects on thyrocytes have not been assessed. Here, we report the results of microarray experiments revealing that the transcriptome reacts dynamically to low-dose BPA exposure, adapting the changes in gene expression to the exposure duration. The response involves many genes, enriching specific pathways and biological functions mainly cell death/proliferation or DNA repair. Their expression is only slightly altered but, since they enrich specific pathways, this results in major effects as shown here for transcripts involved in the DNA repair pathway. Indeed, even though no phenotypic changes are induced by the treatment, we show that the exposure to BPA impairs the cell response to further stressors. We experimentally verify that prolonged exposure to low doses of BPA results in a delayed response to UV-C-induced DNA damage, due to impairment of p21-Tp53 axis, with the BPA-treated cells more prone to cell death and DNA damage accumulation. The present findings shed light on a possible mechanism by which BPA, not able to directly cause genetic damage at environmental dose, may exert an indirect genotoxic activity

NFE2-Related transcription factor 2 coordinates antioxidant defense with thyroglobulin production and iodination in the thyroid gland

Background: The thyroid gland has a special relationship with oxidative stress. While generation of oxidative substances is part of normal iodide metabolism during thyroid hormone synthesis, the gland must also defend itself against excessive oxidation in order to maintain normal function. Antioxidant and detoxification enzymes aid thyroid cells to maintain homeostasis by ameliorating oxidative insults, including during exposure to excess iodide, but the factors that coordinate their expression with the cellular redox status are not known. The antioxidant response system comprising the ubiquitously expressed NFE2-related transcription factor 2 (Nrf2) and its redox-sensitive cytoplasmic inhibitor Kelch-like ECH-associated protein 1 (Keap1) defends tissues against oxidative stress, thereby protecting against pathologies that relate to DNA, protein, and/or lipid oxidative damage. Thus, it was hypothesized that Nrf2 should also have important roles in maintaining thyroid homeostasis. Methods: Ubiquitous and thyroid-specific male C57BL6J Nrf2 knockout (Nrf2-KO) mice were studied. Plasma and thyroids were harvested for evaluation of thyroid function tests by radioimmunoassays and of gene and protein expression by real-time polymerase chain reaction and immunoblotting, respectively. Nrf2-KO and Keap1-KO clones of the PCCL3 rat thyroid follicular cell line were generated using CRISPR/Cas9 technology and were used for gene and protein expression studies. Software-predicted Nrf2 binding sites on the thyroglobulin enhancer were validated by site-directed in vitro mutagenesis and chromatin immunoprecipitation. Results: The study shows that Nrf2 mediates antioxidant transcriptional responses in thyroid cells and protects the thyroid from oxidation induced by iodide overload. Surprisingly, it was also found that Nrf2 has a dramatic impact on both the basal abundance and the thyrotropin-inducible intrathyroidal abundance of thyroglobulin (Tg), the precursor protein of thyroid hormones. This effect is mediated by cell-autonomous regulation of Tg gene expression by Nrf2 via its direct binding to two evolutionarily conserved antioxidant response elements in an upstream enhancer. Yet, despite upregulating Tg levels, Nrf2 limits Tg iodination both under basal conditions and in response to excess iodide. Conclusions: Nrf2 exerts pleiotropic roles in the thyroid gland to couple cell stress defense mechanisms to iodide metabolism and the thyroid hormone synthesis machinery, both under basal conditions and in response to excess iodide.Fil: Ziros, Panos G. Lausanne University; SuizaFil: Habeos, Ioannis. Patras University; GreciaFil: Chartoumpekis, Dionysios V. University of Pittsburgh; Estados UnidosFil: Ntalampyra, Eleni. Universite de Lausanne; SuizaFil: Somm, Emmanuel. Universite de Lausanne; SuizaFil: Renaud, Cédric O.. Universite de Lausanne; SuizaFil: Bongiovanni, Massimo. Institute Of Pathology Locarno; SuizaFil: Trougakos, Ioannis P. Universidad Nacional y Kapodistríaca de Atenas; GreciaFil: Yamamoto, Masayuki. University Of Tohoku; JapónFil: Kensler, Thomas W.. University of Pittsburgh at Johnstown; Estados UnidosFil: Santisteban, Pilar. Universidad Autónoma de Madrid; EspañaFil: Carrasco, Nancy. University of Yale. School of Medicine; Estados UnidosFil: Ris Stalpers, Carrie. Academic Medical Center; Países BajosFil: Amendola, Elena. Universidad de Nápoles; ItaliaFil: Liao, Xiao-Hui. University of Chicago; Estados UnidosFil: Rossich, Luciano Esteban. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Thomasz, Lisa. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Juvenal, Guillermo Juan. Comisión Nacional de Energía Atómica de Argentina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Refetoff, Samuel. University of Chicago; Estados UnidosFil: Sykiotis, Gerasimos P.. Universite de Lausanne; Suiz

Clinical characterization and whole genome sequence-based typing of two cases of endophthalmitis due to Listeria monocytogenes

Endophthalmitis due to Listeria monocytogenes is an exceedingly rare cause of listeriosis. Here, we report two cases which occurred in patients with different medical history, a 46-years-old immunocompetent woman and an elderly man with several comorbidities. There was no history of trauma or surgery in either patient suggesting an endogenous origin. Despite antibiotic treatment, both patients showed poor visual acuity outcomes. Subtyping clinical isolates using whole genome sequencing could allow to identified Listeria monocytogenes strains involved in rare clinical manifestation, such as in unusual anatomical sites, even in immunocompetent patients, and could be helpful in the redefinition of the hypervirulent strains