899 resultados para Regulatory Authority (RA)
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Agency Performance Plan, Iowa Lottery Authority
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Over the past few years, the therapeutic potential of Treg has been highlighted in the field of autoimmune diseases and after allogeneic transplantation. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non-manipulated individuals, in particular when facing strong immune activation and expanding effector cells, such as in response to an allograft. Here we review current approaches being explored for Treg expansion in the perspective of clinical therapeutic protocols. We describe different Treg subsets that could be suitable for clinical application, as well as discuss factors such as the required dose of Treg, their antigen-specificity and in vivo stability, that have to be considered for optimal Treg-based immunotherapy in transplantation. Since Treg may not be sufficient as stand-alone therapy for solid organ transplantation in humans, we draw attention to possible hurdles and combination therapy with immunomodulatory drugs that could possibly improve the in vivo efficacy of Treg.
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Embryonic cells are expected to possess high growth/differentiation potential, required for organ morphogenesis and expansion during development. However, little is known about the intrinsic properties of embryonic epithelial cells due to difficulties in their isolation and cultivation. We report here that pure keratinocyte populations from E15.5 mouse embryos commit irreversibly to differentiation much earlier than newborn cells. Notch signaling, which promotes keratinocyte differentiation, is upregulated in embryonic keratinocyte and epidermis, and elevated caspase 3 expression, which we identify as a transcriptional Notch1 target, accounts in part for the high commitment of embryonic keratinocytes to terminal differentiation. In vivo, lack of caspase 3 results in increased proliferation and decreased differentiation of interfollicular embryonic keratinocytes, together with decreased activation of PKC-delta, a caspase 3 substrate which functions as a positive regulator of keratinocyte differentiation. Thus, a Notch1-caspase 3 regulatory mechanism underlies the intrinsically high commitment of embryonic keratinocytes to terminal differentiation.
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This thesis examines the interplay between state regulation and the way organisations define performance. Performance is generally understood to be a multidimensional concept, but the extent to which its different facets are shaped by regulation remains an understudied question. This thesis aims to address this question and provide at least a partial answer to it. To do so, it examines whether the level of regulation amplifies or abates the multidimensionality of regulated entities' performance definition, i.e. the way they define the concept of performance. The leading question is whether an organisation's performance definition can be associated with the regulatory intensity its environment confronts it with. Moreover, the study explores whether the type of ownership-public or private-plays a role in regard to how a regulated entity defines performance. In order to undertake this investigation, the thesis focuses on the performance definitions of organisations in six different sport betting and lottery regulations. Qualitative data is gathered from primary and secondary documents as well as through semi-structured interviews with chief executive officers (CEO), members of executive management and gambling experts in each of these countries. The thesis concludes that the performance definitions of the organisations under study are indeed multidimensional, as well as clearly influenced by their respective regulatory environments. However, not all performance dimensions identified in the literature are present, nor can they all be estimated to be part of the performance definition. In addition, the public-private difference in defining performance-as conceptualised in the literature- seems to be abated in a regulated environment. The central role played by regulation in regard to the multidimensionality of the performance definition partially outweighs the effect of the nature of ownership.
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Plants such as Arabidopsis thaliana respond to foliar shade and neighbors who may become competitors for light resources by elongation growth to secure access to unfiltered sunlight. Challenges faced during this shade avoidance response (SAR) are different under a light-absorbing canopy and during neighbor detection where light remains abundant. In both situations, elongation growth depends on auxin and transcription factors of the phytochrome interacting factor (PIF) class. Using a computational modeling approach to study the SAR regulatory network, we identify and experimentally validate a previously unidentified role for long hypocotyl in far red 1, a negative regulator of the PIFs. Moreover, we find that during neighbor detection, growth is promoted primarily by the production of auxin. In contrast, in true shade, the system operates with less auxin but with an increased sensitivity to the hormonal signal. Our data suggest that this latter signal is less robust, which may reflect a cost-to-robustness tradeoff, a system trait long recognized by engineers and forming the basis of information theory.
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This chapter explores the institutional environments in which standards for the service sector are expected to support the rise of a global knowledgebased economy. The analysis relies on global political economy approaches to extend to the area of services standards the assumption that the process of globalisation is not opposing states and markets, but a joint expression of both of them including new patterns and agents of structural change through formal and informal power and regulatory practices. It analyses how services standards gain authority in the institutional environment in Europe and in the United States and the extent to which this authority is recognised at the transnational level. In contrast to conventional views opposing the European and American standardisation systems, the chapter shows that institutional developments of services standards are likely to face trade-offs and compromises across those systems.
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Regulatory gene networks contain generic modules, like those involving feedback loops, which are essential for the regulation of many biological functions (Guido et al. in Nature 439:856-860, 2006). We consider a class of self-regulated genes which are the building blocks of many regulatory gene networks, and study the steady-state distribution of the associated Gillespie algorithm by providing efficient numerical algorithms. We also study a regulatory gene network of interest in gene therapy, using mean-field models with time delays. Convergence of the related time-nonhomogeneous Markov chain is established for a class of linear catalytic networks with feedback loops.
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Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is of pivotal importance for self-tolerance, with deficiency or unfavorable polymorphisms leading to autoimmune disease. Tolerance to self-antigens is achieved through thymic deletion of highly autoreactive conventional T (Tconv) cells and generation of FoxP3(+) regulatory T (Treg) cells. The main costimulatory molecule, CD28, augments the negative selection of Tconv cells and promotes the generation of FoxP3(+) Treg cells. The role of its antagonistic homolog CTLA-4, however, remains a topic of debate. To address this topic, we investigated the thymic development of T cells in the presence and absence of CTLA-4 in a T-cell receptor (TCR) transgenic mouse model specific for the myelin basic protein peptide Ac1-9. We reveal that CTLA-4 is expressed in the corticomedullary region of the thymus. Its absence alters the response of CD4(+)CD8(-) thymocytes to self-antigen recognition, which affects the quantity of the Treg cells generated and broadens the repertoire of peripheral Tconv cells. T-cell repertoire alteration after deletion of CTLA-4 results from changes in TCR Vα and Jα segment selection as well as CDR3α composition in Tconv and Treg cells. CTLA-4, therefore, regulates the early development of self-reactive T cells in the thymus and plays a key role in central tolerance.
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Audit report on the Iowa Water Pollution Control Works Financing Program and the Iowa Drinking Water Facilities Financing Program, joint programs of the Iowa Finance Authority and the Iowa Department of Natural Resources for the year ended June 30, 2013
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Antitumor immunity is strongly influenced by the balance of tumor antigen-specific effector and regulatory T cells. However, the impact that vaccine adjuvants have in regulating the balance of antigen-specific T cell populations is not well understood. We found that antigen-specific T regulatory cells (Treg) were induced following subcutaneous vaccination with either OVA or melanoma-derived peptides, with a restricted expansion of effector T cells. Addition of the adjuvants CpG-ODN or Poly(I:C) preferentially amplified effector T cells over Tregs, dramatically increasing the antigen-specific T effector:Treg ratios and inducing polyfunctional effector cells. In contrast, two other adjuvants, imiquimod and Quil A saponin, favored an expansion of antigen-specific Tregs and failed to increase effector T cell:Treg ratios. Following therapeutic vaccination of tumor-bearing mice, high ratios of tumor-specific effector T cells:Tregs in draining lymph nodes were associated with enhanced CD8+ T cell infiltration at the tumor site and a durable rejection of tumors. Vaccine formulations of peptide+CpG-ODN or Poly(I:C) induced selective production of pro-inflammatory Type I cytokines early after vaccination. This environment promoted CD8+ and CD4+ effector T cell expansion over that of antigen-specific Tregs, tipping the effector T cell to Treg balance to favor effector cells. Our findings advance understanding of the influence of different adjuvants on T cell populations, facilitating the rational design of more effective cancer vaccines.
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In Pseudomonas fluorescens CHA0 and other fluorescent pseudomonads, the Gac/Rsm signal transduction pathway is instrumental for secondary metabolism and biocontrol of root pathogens via the expression of regulatory small RNAs (sRNAs). Furthermore, in strain CHA0, an imbalance in the Krebs cycle can affect the strain's ability to produce extracellular secondary metabolites, including biocontrol factors. Here, we report the metabolome of wild-type CHA0, a gacA-negative mutant, which has lost Gac/Rsm activities, and a retS-negative mutant, which shows strongly enhanced Gac/Rsm-dependent activities. Capillary electrophoresis-based metabolomic profiling revealed that the gacA and retS mutations had opposite effects on the intracellular levels of a number of central metabolites, suggesting that the Gac/Rsm pathway regulates not only secondary metabolism but also primary metabolism in strain CHA0. Among the regulated metabolites identified, the alarmone guanosine tetraphosphate (ppGpp) was characterized in detail by the construction of relA (for ppGpp synthase) and spoT (for ppGpp synthase/hydrolase) deletion mutants. In a relA spoT double mutant, ppGpp synthesis was completely abolished, the expression of Rsm sRNAs was attenuated, and physiological functions such as antibiotic production, root colonization, and plant protection were markedly diminished. Thus, ppGpp appears to be essential for sustaining epiphytic fitness and biocontrol activity of strain CHA0.
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Audit report on the Waste Authority of Jackson County for the year ended June 30, 2013
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Audit report on the Great River Regional Waste Authority for the year ended June 30, 2013
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Audit report on the Iowa State Fair Authority for the year ended October 31, 2013
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Report on the Iowa Economic Development Authority for the year ended June 30, 2013
