Effects of Purified Salmonella enteritidis Endotoxin on the Immune Response of Balb/c Mice

Wasting disease was produced in neonatal Balb/c mice with purified Salmonella enteritidis endotoxins. The endotoxins were chemically characterized to provide the study with a potent endotoxin with constant biological activity. Neonatal mice received an initial injection of 35 μg/g body weight of endotoxin and a dose of 75 μg every third day until day 18. The degree of wasting was estimated by the runting (weight loss) index. Mortality was calculated to be 46%, with a mean survival time of approximately 15 days. The hematologic studies conducted at days 10, 20, and 30 showed an absolute neutrophilia and leukocytosis by day 10 which persisted to day 30. Immunologic data indicated that the responsiveness to sheep erythrocytes was depressed to day 20 and continued to persist at day 30. It was postulated that endotoxin either directly or indirectly affects the immune apparatus which allows the normal flora of the animal to establish an infection leading to wasting and death

The total assessment profile, volume 2

Appendices are presented which include discussions of interest formulas, factors in regionalization, parametric modeling of discounted benefit-sacrifice streams, engineering economic calculations, and product innovation. For Volume 1, see

The total assessment profile, volume 1

A methodology is described for the evaluation of societal impacts associated with the implementation of a new technology. Theoretical foundations for the methodology, called the total assessment profile, are established from both the economic and social science perspectives. The procedure provides for accountability of nonquantifiable factors and measures through the use of a comparative value matrix by assessing the impacts of the technology on the value system of the society

Natural products that reduce rotavirus infectivity identified by a cell-based moderate-throughput screening assay

BACKGROUND: There is widespread interest in the use of innate immune modulators as a defense strategy against infectious pathogens. Using rotavirus as a model system, we developed a cell-based, moderate-throughput screening (MTS) assay to identify compounds that reduce rotavirus infectivity in vitro, toward a long-term goal of discovering immunomodulatory agents that enhance innate responses to viral infection. RESULTS: A natural product library consisting of 280 compounds was screened in the assay and 15 compounds that significantly reduced infectivity without cytotoxicity were identified. Time course analysis of four compounds with previously characterized effects on inflammatory gene expression inhibited replication with pre-treatment times as minimal as 2 hours. Two of these four compounds, α-mangostin and 18-β-glycyrrhetinic acid, activated NFκB and induced IL-8 secretion. The assay is adaptable to other virus systems, and amenable to full automation and adaptation to a high-throughput format. CONCLUSION: Identification of several compounds with known effects on inflammatory and antiviral gene expression that confer resistance to rotavirus infection in vitro suggests the assay is an appropriate platform for discovery of compounds with potential to amplify innate antiviral responses

The subconvexity problem for \GL_{2}

Generalizing and unifying prior results, we solve the subconvexity problem for the $L$-functions of \GL_{1} and \GL_{2} automorphic representations over a fixed number field, uniformly in all aspects. A novel feature of the present method is the softness of our arguments; this is largely due to a consistent use of canonically normalized period relations, such as those supplied by the work of Waldspurger and Ichino--Ikeda.Comment: Almost final version to appear in Publ. Math IHES. References updated

Evidence for the classical integrability of the complete AdS(4) x CP(3) superstring

We construct a zero-curvature Lax connection in a sub-sector of the superstring theory on AdS(4) x CP(3) which is not described by the OSp(6|4)/U(3) x SO(1,3) supercoset sigma-model. In this sub-sector worldsheet fermions associated to eight broken supersymmetries of the type IIA background are physical fields. As such, the prescription for the construction of the Lax connection based on the Z_4-automorphism of the isometry superalgebra OSp(6|4) does not do the job. So, to construct the Lax connection we have used an alternative method which nevertheless relies on the isometry of the target superspace and kappa-symmetry of the Green-Schwarz superstring.Comment: 1+26 pages; v2: minor typos corrected, acknowledgements adde

The rise of policy coherence for development: a multi-causal approach

In recent years policy coherence for development (PCD) has become a key principle in international development debates, and it is likely to become even more relevant in the discussions on the post-2015 sustainable development goals. This article addresses the rise of PCD on the Western donors’ aid agenda. While the concept already appeared in the work of Organisation for Economic Co-operation and Development (OECD) in the early 1990s, it took until 2007 before PCD became one of the Organisation’s key priorities. We adopt a complexity-sensitive perspective, involving a process-tracing analysis and a multi-causal explanatory framework. We argue that the rise of PCD is not as contingent as it looks. While actors such as the EU, the DAC and OECD Secretariat were the ‘active causes’ of the rise of PCD, it is equally important to look at the underlying ‘constitutive causes’ which enabled policy coherence to thrive well

Murine and Bovine γδ T Cells Enhance Innate Immunity against Brucella abortus Infections

γδ T cells have been postulated to act as a first line of defense against infectious agents, particularly intracellular pathogens, representing an important link between the innate and adaptive immune responses. Human γδ T cells expand in the blood of brucellosis patients and are active against Brucella in vitro. However, the role of γδ T cells in vivo during experimental brucellosis has not been studied. Here we report TCRδ−/− mice are more susceptible to B. abortus infection than C57BL/6 mice at one week post-infection as measured by splenic colonization and splenomegaly. An increase in TCRγδ cells was observed in the spleens of B. abortus-infected C57BL/6 mice, which peaked at two weeks post-infection and occurred concomitantly with diminished brucellae. γδ T cells were the major source of IL-17 following infection and also produced IFN-γ. Depletion of γδ T cells from C57BL/6, IL-17Rα−/−, and GMCSF−/− mice enhanced susceptibility to B. abortus infection although this susceptibility was unaltered in the mutant mice; however, when γδ T cells were depleted from IFN-γ−/− mice, enhanced susceptibility was observed. Neutralization of γδ T cells in the absence of TNF-α did not further impair immunity. In the absence of TNF-α or γδ T cells, B. abortus-infected mice showed enhanced IFN-γ, suggesting that they augmented production to compensate for the loss of γδ T cells and/or TNF-α. While the protective role of γδ T cells was TNF-α-dependent, γδ T cells were not the major source of TNF-α and activation of γδ T cells following B. abortus infection was TNF-α-independent. Additionally, bovine TCRγδ cells were found to respond rapidly to B. abortus infection upon co-culture with autologous macrophages and could impair the intramacrophage replication of B. abortus via IFN-γ. Collectively, these results demonstrate γδ T cells are important for early protection to B. abortus infections

Nasal Acai Polysaccharides Potentiate Innate Immunity to Protect against Pulmonary Francisella tularensis and Burkholderia pseudomallei Infections

Pulmonary Francisella tularensis and Burkholderia pseudomallei infections are highly lethal in untreated patients, and current antibiotic regimens are not always effective. Activating the innate immune system provides an alternative means of treating infection and can also complement antibiotic therapies. Several natural agonists were screened for their ability to enhance host resistance to infection, and polysaccharides derived from the Acai berry (Acai PS) were found to have potent abilities as an immunotherapeutic to treat F. tularensis and B. pseudomallei infections. In vitro, Acai PS impaired replication of Francisella in primary human macrophages co-cultured with autologous NK cells via augmentation of NK cell IFN-γ. Furthermore, Acai PS administered nasally before or after infection protected mice against type A F. tularensis aerosol challenge with survival rates up to 80%, and protection was still observed, albeit reduced, when mice were treated two days post-infection. Nasal Acai PS administration augmented intracellular expression of IFN-γ by NK cells in the lungs of F. tularensis-infected mice, and neutralization of IFN-γ ablated the protective effect of Acai PS. Likewise, nasal Acai PS treatment conferred protection against pulmonary infection with B. pseudomallei strain 1026b. Acai PS dramatically reduced the replication of B. pseudomallei in the lung and blocked bacterial dissemination to the spleen and liver. Nasal administration of Acai PS enhanced IFN-γ responses by NK and γδ T cells in the lungs, while neutralization of IFN-γ totally abrogated the protective effect of Acai PS against pulmonary B. pseudomallei infection. Collectively, these results demonstrate Acai PS is a potent innate immune agonist that can resolve F. tularensis and B. pseudomallei infections, suggesting this innate immune agonist has broad-spectrum activity against virulent intracellular pathogens