CD4+CD25+ Immunoregulatory T Cells: New Therapeutics for Graft-Versus-Host Disease

CD4+CD25+ immunoregulatory T cells play a pivotal role in preventing organ-specific autoimmune diseases and in tolerance induction to allogeneic organ transplants. We investigated whether these cells could also control graft-versus-host disease (GVHD), the main complication after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we show that the few CD4+CD25+ T cells naturally present in the transplant regulate GVHD because their removal from the graft dramatically accelerates this disease. Furthermore, the addition of freshly isolated CD4+CD25+ T cells at time of grafting significantly delays or even prevents GVHD. Ex vivo–expanded CD4+CD25+ regulatory T cells obtained after stimulation by allogeneic recipient-type antigen-presenting cells can also modulate GVHD. Thus, CD4+CD25+ regulatory T cells represent a new therapeutic tool for controlling GVHD in allogeneic HSCT. More generally, these results outline the tremendous potential of regulatory T cells as therapeutics

Action scales for quantum decoherence and their relation to structures in phase space

A characteristic action $\Delta S$ is defined whose magnitude determines some properties of the expectation value of a general quantum displacement operator. These properties are related to the capability of a given environmental `monitoring' system to induce decoherence in quantum systems coupled to it. We show that the scale for effective decoherence is given by $\Delta S\approx\hbar$. We relate this characteristic action with a complementary quantity, $\Delta Z$, and analyse their connection with the main features of the pattern of structures developed by the environmental state in different phase space representations. The relevance of the $\Delta S$-action scale is illustrated using both a model quantum system solved numerically and a set of model quantum systems for which analytical expressions for the time-averaged expectation value of the displacement operator are obtained explicitly.Comment: 12 pages, 3 figure

Seasonal predictability of wintertime precipitation in Europe using the snow advance index

This study tests the applicability of Eurasian snow cover increase in October, as described by the recently published snow advance index (SAI), for forecasting December–February precipitation totals in Europe. On the basis of a classical correlation analysis, global significance was obtained and locally significant correlation coefficients of up to 0.89 and 20.78 were found for the Iberian Peninsula and southern Norway, respectively. For a more robust assessment of these results, a linear regression approach is followed to hindcast the precipitation sums in a 1-yr-out cross-validation framework, using the SAI as the only predictor variable. With this simple empirical approach, local-scale precipitation could be reproduced with a correlation of up to 0.84 and 0.71 for the Iberian Peninsula and southern Norway, respectively, while catchment aggregations on the Iberian Peninsula could be hindcast with a correlation of up to 0.73. These findings are confirmed when repeating the hindcast approach to a degraded but much longer version of the SAI. With the recommendation to monitor the robustness of these results as the sample size of the SAI increases, the authors encourage its use for the purpose of seasonal forecasting in southern Norway and the Iberian Peninsula, where general circulation models are known to perform poorly for the variable in question.SB, RM, and JMG acknowledge funding from the CICYT Project CGL2010-21869 and from QWeCI (EU Grant 243964) and the CSIC JAE-PREDOC program. JC is supported by the National Science Foundation Grants ARC-0909459 and ARC-0909457, and NOAA Grant NA10OAR4310163. The authors are thankful for the helpful comments of the three anonymous reviewers and acknowledge the E-OBS dataset from the ENSEMBLES project (http://ensembles-eu.metoffice.com/) as well the ECA&D(http:// eca.knmi.nl/) and AEMET station datasets

Systemic IL-2/anti-IL-2Ab complex combined with sublingual immunotherapy suppresses experimental food allergy in mice through induction of mucosal regulatory T cells

Therapeutic tolerance restoration has been proven to modify food allergy in patients and animal models and although sublingual immunotherapy (SLIT) has showed promise, combined therapy may be necessary to achieve a strong and long‐term tolerance. In this work, we combined SLIT with systemic administration of IL‐2 associated with an anti‐IL‐2 monoclonal antibody (IL‐2/anti‐IL‐2Ab complex or IL‐2C) to reverse the IgE‐mediated experimental allergy. Balb/c mice were sensitized with cholera toxin and milk proteins and orally challenged with allergen to elicit hypersensitivity reactions. Then, allergic mice were treated with a sublingual administration of very low amounts of milk proteins combined with intraperitoneal injection of low doses of IL‐2C. The animals were next re‐exposed to allergens and mucosal as well as systemic immunological parameters were assessed in vivo and in vitro. The treatment reduced serum specific IgE, IL‐5 secretion by spleen cells and increased IL‐10 and TGF‐β in the lamina propria of buccal and duodenal mucosa. We found an augmented frequency of IL‐10‐secreting CD4+CD25+Foxp3+ regulatory T cells (Treg) in the submaxilar lymph nodes and buccal lamina propria. Tregs were sorted, characterized and adoptively transferred to naïve mice, which were subsequently sensitized. No allergy was experienced in these mice and we encouragingly discovered a faster and more efficient tolerance induction with the combined therapy compared with SLIT. The combination of two therapeutic strategies rendered Treg‐mediated tolerance more efficient compared to individual treatments and reversed the established IgE‐mediated food allergy. This approach highlights the ability of IL‐2C to expand Tregs, and it may represent a promising disease‐modifying therapy for managing food allergyInstituto de Estudios Inmunológicos y FisiopatológicosConsejo Nacional de Investigaciones Científicas y Técnica

Systemic IL-2/anti-IL-2Ab complex combined with sublingual immunotherapy suppresses experimental food allergy in mice through induction of mucosal regulatory T cells

Therapeutic tolerance restoration has been proven to modify food allergy in patients and animal models and although sublingual immunotherapy (SLIT) has showed promise, combined therapy may be necessary to achieve a strong and long‐term tolerance. In this work, we combined SLIT with systemic administration of IL‐2 associated with an anti‐IL‐2 monoclonal antibody (IL‐2/anti‐IL‐2Ab complex or IL‐2C) to reverse the IgE‐mediated experimental allergy. Balb/c mice were sensitized with cholera toxin and milk proteins and orally challenged with allergen to elicit hypersensitivity reactions. Then, allergic mice were treated with a sublingual administration of very low amounts of milk proteins combined with intraperitoneal injection of low doses of IL‐2C. The animals were next re‐exposed to allergens and mucosal as well as systemic immunological parameters were assessed in vivo and in vitro. The treatment reduced serum specific IgE, IL‐5 secretion by spleen cells and increased IL‐10 and TGF‐β in the lamina propria of buccal and duodenal mucosa. We found an augmented frequency of IL‐10‐secreting CD4+CD25+Foxp3+ regulatory T cells (Treg) in the submaxilar lymph nodes and buccal lamina propria. Tregs were sorted, characterized and adoptively transferred to naïve mice, which were subsequently sensitized. No allergy was experienced in these mice and we encouragingly discovered a faster and more efficient tolerance induction with the combined therapy compared with SLIT. The combination of two therapeutic strategies rendered Treg‐mediated tolerance more efficient compared to individual treatments and reversed the established IgE‐mediated food allergy. This approach highlights the ability of IL‐2C to expand Tregs, and it may represent a promising disease‐modifying therapy for managing food allergyInstituto de Estudios Inmunológicos y FisiopatológicosConsejo Nacional de Investigaciones Científicas y Técnica

Stream metabolism sources a large fraction of carbon dioxide to the atmosphere in two hydrologically contrasting headwater streams

Headwater streams are control points for carbon dioxide (CO$_{2}$) emissions to the atmosphere, with relative contributions to CO$_{2}$ emission fluxes from lateral groundwater inputs widely assumed to overwhelm those from in-stream metabolic processes. We analyzed continuous measurements of stream dissolved CO$_{2}$ and oxygen (CO$_{2}$) concentrations during spring and early summer in two Mediterranean headwater streams from which we evaluated the contribution of in-stream net ecosystem production (NEP) to CO$_{2}$ emission. The two streams exhibited contrasting hydrological regimes: one was non-perennial with relatively small groundwater inflows, while the other was perennial and received significant lateral groundwater inputs. The non-perennial stream exhibited strong inverse coupling between instantaneous and daily CO$_{2}$ and CO$_{2}$ concentrations, and a strong correlation between aerobic ecosystem respiration (ER) and gross primary production (GPP) despite persistent negative NEP. At the perennial stream, the CO$_{2}$–O$_{2}$ relationship varied largely over time, ER and GPP were uncorrelated, and NEP, which was consistently negative, increased with increasing temperature. Mean NEP contribution to CO$_{2}$ emission was 51% and 57% at the non-perennial and perennial stream, respectively. Although these proportions varied with assumptions about metabolic stoichiometry and groundwater CO$_{2}$ concentration, in-stream CO$_{2}$ production consistently and substantially contributed to total atmospheric CO$_{2}$ flux in both streams. We conclude that in-stream metabolism can be more important for driving C cycling in some headwater streams than previously assumed

Cohesin Removal along the Chromosome Arms during the First Meiotic Division Depends on a NEK1-PP1γ-WAPL Axis in the Mouse

SummaryMammalian NIMA-like kinase-1 (NEK1) is a dual-specificity kinase highly expressed in mouse germ cells during prophase I of meiosis. Loss of NEK1 induces retention of cohesin on chromosomes at meiotic prophase I. Timely deposition and removal of cohesin is essential for accurate chromosome segregation. Two processes regulate cohesin removal: a non-proteolytic mechanism involving WAPL, sororin, and PDS5B and direct cleavage by separase. Here, we demonstrate a role for NEK1 in the regulation of WAPL loading during meiotic prophase I, via an interaction between NEK1 and PDS5B. This regulation of WAPL by NEK1-PDS5B is mediated by protein phosphatase 1 gamma (PP1γ), which both interacts with and is a phosphotarget of NEK1. Taken together, our results reveal that NEK1 phosphorylates PP1γ, leading to the dephosphorylation of WAPL, which, in turn, results in its retention on chromosome cores to promote loss of cohesion at the end of prophase I in mammals

Electroweak Baryogenesis in Non-minimal Composite Higgs Models

We address electroweak baryogenesis in the context of composite Higgs models, pointing out that modifications to the Higgs and top quark sectors can play an important role in generating the baryon asymmetry. Our main observation is that composite Higgs models that include a light, gauge singlet scalar in the spectrum [as in the model based on the symmetry breaking pattern SO(6)/SO(5)], provide all necessary ingredients for viable baryogenesis. In particular, the singlet leads to a strongly first-order electroweak phase transition and introduces new sources of CP violation in dimension-five operators involving the top quark. We discuss the amount of baryon asymmetry produced and the experimental constraints on the model.Comment: 15 pages, 7 figure

Magnetic strings in anti-de Sitter General Relativity

We obtain spacetimes generated by static and spinning magnetic string sources in Einstein Relativity with negative cosmological constant. Since the spacetime is asymptotically a cylindrical anti-de Sitter spacetime, we will be able to calculate the mass, momentum, and electric charge of the solutions. We find two families of solutions, one with longitudinal magnetic field and the other with angular magnetic field. The source for the longitudinal magnetic field can be interpreted as composed by a system of two symmetric and superposed electrically charged lines with one of the electrically charged lines being at rest and the other spinning. The angular magnetic field solution can be similarly interpreted as composed by charged lines but now one is at rest and the other has a velocity along the axis. This solution cannot be extended down to the origin.Comment: Latex, 26 page