Regulatory B cells shape the development of Th2 immune responses in BALB/c mice infected with Leishmania major through IL-10 production.

Recent evidence indicates that B cells are required for susceptibility to infection with Leishmania major in BALB/c mice. In this study, we analyzed the role of the IL-10 produced by B cells in this process. We showed that B cells purified from the spleen of BALB/c mice produced IL-10 in response to stimulation with L. major in vitro. In vivo, early IL-10 mRNA expression is detected after L. major infection in B cells from draining lymph nodes of susceptible BALB/c, but not of resistant C57BL/6 mice. Although adoptive transfer of naive wild-type B cells prior to infection in B cell-deficient BALB/c mice restored Th2 cell development and susceptibility to infection with L. major of these otherwise resistant mice, adoptive transfer of IL-10(-/-) B cells mice did not. B cells stimulated by L. major, following in vitro or in vivo encounter, express the CD1d and CD5 molecules and the IL-10 produced by these cells downregulate IL-12 production by L. major-stimulated dendritic cells. These observations indicate that IL-10 secreting B cells are phenotypically and functionally regulatory B cells. Altogether these results demonstrate that the IL-10 produced by regulatory CD1d+ CD5+ B cells in response to L. major is critical for Th2 cell development in BALB/c mice.

A user's guide to the encyclopedia of DNA elements (ENCODE).

The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome.

Regulação do sector farmacêutico em Cabo Verde: o desafio da criação de uma agência de regulação

O medicamento é uma tecnologia cuja importância é indiscutível seja para a saúde, como enquanto factor económico de crescimento e desenvolvimento. A sua regulação está fundamentada acrescidos os factores da sua essencialidade, da assimetria de informação, da cadeia de intermediários, dos interesses financeiros, dos requisitos para a demonstração de eficácia e segurança e as normas para promover a sua utilização eficiente. O Estado tem diversas abordagens possíveis para a regulação farmacêutica que implica sempre a existência de uma estrutura orgânica que assuma as atribuições de forma eficaz e eficiente. Este trabalho discute o modelo de regulação farmacêutica para as condições específicas de Cabo Verde usando como linhas de pesquisa (1) o enquadramento geral da prática de regulação a nível internacional, as recomendações da OMS e os países de referência no âmbito da Comunidade dos Países de Língua Oficial Portuguesa para procurar caracterizar esse processo, identificar as diferenças entre a regulação implementada em países mais desenvolvidos e os países em desenvolvimento e decidir se as agências de regulação podem ser vistas como uma transferência de tecnologia de gestão; (2) o modelo de institucionalização da regulação farmacêutica previsto para Cabo Verde e aquele que foi na prática implementado, com ênfase nas competências, estratégia de intervenção e constrangimentos, para por fim (3) proceder-se à elaboração de uma apreciação crítica, sob o pano de fundo da harmonização técnica e normativa, retomando as recomendações da OMS, a prática internacional neste contexto, corporizada pelos casos da experiência no Brasil e em Portugal e o modelo conceptualizado, relacionando as disparidades com os constrangimentos identificados. Feita a apreciação crítica propõe-se um novo modelo de regulação fazendo referência à revisão dos estatutos da autoridade reguladora e a alterações do figurino institucional.

Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3(+) T-regulatory cells.

Epithelial ovarian cancer (EOC) is the fifth most common cause of cancer death among women. Despite its immunogenicity, effective antitumor responses are limited, due, in part, to the presence of forkhead box protein 3-positive (Foxp3(+)) T regulatory (Treg) cells in the tumor microenvironment. However, the mechanisms that regulate the accumulation and the suppressive function of these Foxp3(+) Treg cells are poorly understood. Here, we found that the majority of Foxp3(+) Treg cells accumulating in the tumor microenvironment of EOCs belong to the subset of Foxp3(+) Treg cells expressing inducible costimulator (ICOS). The expansion and the suppressive function of these cells were strictly dependent on ICOS-L costimulation provided by tumor plasmacytoid dendritic cells (pDC). Accordingly, ICOS(+) Foxp3(+) Treg cells were found to localize in close vicinity of tumor pDCs, and their number directly correlated with the numbers of pDCs in the tumors. Furthermore, pDCs and ICOS(+) Foxp3(+) Treg cells were found to be strong predictors for disease progression in patients with ovarian cancer, with ICOS(+) Treg cell subset being a stronger predictor than total Foxp3(+) Treg cells. These findings suggest an essential role for pDCs and ICOS-L in immunosuppression mediated by ICOS(+) Foxp3(+) Treg cells, leading to tumor progression in ovarian cancer.

Sweet diversity: Colonial goods and the rise of European living standards after 1492

When did overseas trade start to matter for living standards? Traditional real-wage indices suggest that living standards in Europe stagnated before 1800. In this paper, we argue thatwelfare rose substantially, but surreptitiously, because of an influx of new goods as a result ofoverseas trade. Colonial luxuries such as tea, coffee, and sugar transformed European diets afterthe discovery of America and the rounding of the Cape of Good Hope. These goods became household items in many countries by the end of the 18th century. We use three different methodsto calculate welfare gains based on price data and the rate of adoption of these new colonialgoods. Our results suggest that by 1800, the average Englishman would have been willing to forego 10% or more of his income in order to maintain access to sugar and tea alone. These findings are robust to a wide range of alternative assumptions, data series, and valuation methods.

Setting standards: Information accumulation in development

We propose a model in which economic relations and institutions in advancedand less developed economies differ as these societies have access to different amounts of information. This lack of information makes it hard to give the right incentives to managers and entrepreneurs. We argue that differences in the amount of information arise because of the differences in the scale of activities in rich and poor economies; namely, there is too little repetition of similar activities in pooreconomies, thus insufficient information to set the appropriate standards for firm performance. Our model predicts a number of institutional and structural transformations as the economy accumulates capital and information.

Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells.

A comprehensive understanding of the complex, autologous cellular interactions and regulatory mechanisms that occur during normal dendritic cell (DC)-stimulated immune responses is critical to optimizing DC-based immunotherapy. We have found that mature, immunogenic human monocyte-derived DCs (moDCs) up-regulate the immune-inhibitory enzyme, indoleamine 2,3-dioxygenase (IDO). Under stringent autologous culture conditions without exogenous cytokines, mature moDCs expand regulatory T cells (Tregs) by an IDO-dependent mechanism. The priming of resting T cells with autologous, IDO-expressing, mature moDCs results in up to 10-fold expansion of CD4(+)CD25(bright)Foxp3(+)CD127(neg) Tregs. Treg expansion requires moDC contact, CD80/CD86 ligation, and endogenous interleukin-2. Cytofluorographically sorted CD4(+) CD25(bright)Foxp3(+) Tregs inhibit as much as 80% to 90% of DC-stimulated autologous and allogeneic T-cell proliferation, in a dose-dependent manner at Treg:T-cell ratios of 1:1, 1:5, and as low as 1:25. CD4(+)CD25(bright)Foxp3(+) Tregs also suppress the generation of cytotoxic T lymphocytes specific for the Wilms tumor antigen 1, resulting in more than an 80% decrease in specific target cell lysis. Suppression by Tregs is both contact-dependent and transforming growth factor-beta-mediated. Although mature moDCs can generate Tregs by this IDO-dependent mechanism to limit otherwise unrestrained immune responses, inhibition of this counter-regulatory pathway should also prove useful in sustaining responses stimulated by DC-based immunotherapy.

Biodiesel Facility Regulatory Assistance Guide, 2008

This guide is a general outline for bio diesel facilities on potential regulatory requirements and regulatory agency approval times. Much of the information is related to environmental permitting by the Iowa Department of Natural Resources (IDNR). Your facility’s permit requirements may differ depending upon the specific operations planned. Information is also provided about regulatory requirements administered by the Iowa Workforce Development, Labor Services Division and the Iowa Department of Public Safety, Fire Marshal Division. Requirements established by local units of government may also apply. Be sure to contact the city in which the facility will be located or the county if the facility is not located in a city, to identify these requirements.

Ethanol Facility Regulatory Assistance Guide, May 19, 2008

This guide is a general outline for ethanol facilities on potential regulatory requirements and regulatory agency approval times. Much of the information is related to environmental permitting by the Iowa Department of Natural Resources (IDNR). Your facility’s permit requirements may differ depending upon the specific operations planned. Information is also provided about regulatory requirements administered by the Iowa Workforce Development, Labor Services Division and the Iowa Department of Public Safety, Fire Marshal Division. Requirements established by local units of government may also apply. Be sure to contact the city in which the facility will be located or the county if the facility is not located in a city, to identify these requirements.

Propane Regulatory Assistance Guilty,

This fact sheets summarizes, in brief form, the compliance requirements for transportation, storage, handling and use of propane. It is not intended to provide comprehensive guidance on regulatory compliance for those dealing with propane, but to highlight those requirements and to assist those who may be affected by the various requirements to obtain detailed information when needed. Information about requirements which apply to the use of propane as a motor fuel is not included.

Regulatory Assistance, March 12, 2009

The Iowa Business and Regulatory Assistance Network ensures access and responsiveness to inquiries and requests for assistance from citizens, small business, industry and local governments. Facilitated by the Iowa Department of Economic Development (IDED), Business Assistance Coordinators in agencies across state government coordinate regulatory response and service. You may contact IDED or any of the agency contacts listed in this publication for assistance.

Standards and specifications to manage accessibility issues in e-learning

Standards and specifícations to manage accessibility issues in e-learning

Design of new promoters and of a dual-bioreporter based on cross-activation by the two regulatory proteins XylR and HbpR.

The HbpR protein is the sigma54-dependent transcription activator for 2-hydroxybiphenyl degradation in Pseudomonas azelaica. The ability of HbpR and XylR, which share 35% amino acid sequence identity, to cross-activate the PhbpC and Pu promoters was investigated by determining HbpR- or XylR-mediated luciferase expression and by DNA binding assays. XylR measurably activated the PhbpC promoter in the presence of the effector m-xylene, both in Escherichia coli and Pseudomonas putida. HbpR weakly stimulated the Pu promoter in E. coli but not in P. azelaica. Poor HbpR-dependent activation from Pu was caused by a weak binding to the operator region. To create promoters efficiently activated by both regulators, the HbpR binding sites on PhbpC were gradually changed into the XylR binding sites of Pu by site-directed mutagenesis. Inducible luciferase expression from mutated promoters was tested in E. coli on a two plasmid system, and from mono copy gene fusions in P. azelaica and P. putida. Some mutants were efficiently activated by both HbpR and XylR, showing that promoters can be created which are permissive for both regulators. Others achieved a higher XylR-dependent transcription than from Pu itself. Mutants were also obtained which displayed a tenfold lower uninduced expression level by HbpR than the wild-type PhbpC, while keeping the same maximal induction level. On the basis of these results, a dual-responsive bioreporter strain of P. azelaica was created, containing both XylR and HbpR, and activating luciferase expression from the same single promoter independently with m-xylene and 2-hydroxybiphenyl.

Th2 lymphoproliferative disorder of LatY136F mutant mice unfolds independently of TCR-MHC engagement and is insensitive to the action of Foxp3+ regulatory T cells.

Mutant mice where tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (Lat(Y136F) mice) develop a fast-onset lymphoproliferative disorder involving polyclonal CD4 T cells that produce massive amounts of Th2 cytokines and trigger severe inflammation and autoantibodies. We analyzed whether the Lat(Y136F) pathology constitutes a bona fide autoimmune disorder dependent on TCR specificity. Using adoptive transfer experiments, we demonstrated that the expansion and uncontrolled Th2-effector function of Lat(Y136F) CD4 cells are not triggered by an MHC class II-driven, autoreactive process. Using Foxp3EGFP reporter mice, we further showed that nonfunctional Foxp3(+) regulatory T cells are present in Lat(Y136F) mice and that pathogenic Lat(Y136F) CD4 T cells were capable of escaping the control of infused wild-type Foxp3(+) regulatory T cells. These results argue against a scenario where the Lat(Y136F) pathology is primarily due to a lack of functional Foxp3(+) regulatory T cells and suggest that a defect intrinsic to Lat(Y136F) CD4 T cells leads to a state of TCR-independent hyperactivity. This abnormal status confers Lat(Y136F) CD4 T cells with the ability to trigger the production of Abs and of autoantibodies in a TCR-independent, quasi-mitogenic fashion. Therefore, despite the presence of autoantibodies causative of severe systemic disease, the pathological conditions observed in Lat(Y136F) mice unfold in an Ag-independent manner and thus do not qualify as a genuine autoimmune disorder.