82 research outputs found
The response of the lymphatic endothelium to inflammation and infection in in vitro and in vivo systems
No full textThe lymphatic endothelium is involved in the drainage of interstitial fluid and in the migration of immune cells like dendritic cells (DCs) from the periphery to draining lymph nodes (LNs). Tuberculosis has been declared a pandemic infectious disease accounting for more than 2 million deaths annually and is caused by the intracellular bacteria, Mycobacterium tuberculosis. The chronic inflammatory response to M. tuberculosis infection is characterized by the formation of granulomatous structures in the pulmonary compartments of infected individuals. These structures contain excess interstitial fluid and are enriched with immune cells including DCs. Therefore, the lymphatic vessels might play important roles in regulating drainage of fluid and migration of immune cells from granulomas to the draining LNs. My hypothesis was that there is an increased concentration of lymphatic vessels in these granulomatous structures and that the inflammatory environment including mycobacterial components present in granulomas and at other sites of infection elicit an inflammatory response from these lymphatic vessels which contribute to the overall immune response to M. tuberculosis infection. To address this hypothesis I have examined the distribution of lymphatic vessels in granulomatous and LN tissues obtained from nonhuman primates infected with M. tuberculosis and analyzed their expression of multiple chemokines and lymphatic markers. In addition, I evaluated the response of LECs to inflammatory mediators that included multiple TLR ligands, M. tuberculosis components and cytokines. I observed an association of lymphatic vessels with granulomas, and found that there was heterogeneity in the expression of chemokines and lymphatic markers by LECs in tissues. I also found that primary human LECs expressed multiple TLR molecules and responded to TLR ligands, cytokines and M. tuberculosis components by increasing expression of inflammatory chemokines, cytokines and adhesion molecules. These LECs also demonstrated phenotypic similarities with DCs. Overall my findings support the involvement of the lymphatic endothelium in the inflammatory immune response to pathogens like M. tuberculosis. From the perspective of public health relevance, these studies provide direction in the development of new therapeutic targets against M. tuberculosis infections and aid in the development of better adjuvants for vaccines for infectious diseases and cancers
Longevity: Trends, uncertainty and the implications for pension systems
No full textThis paper presents historical trends in life expectancy in the United Kingdom and other countries and discusses how these trends might evolve over the coming decades. The paper argues that the expected increases in longevity are likely to have significant implications for the structure of pension systems in the future. Individuals, businesses and governments have already responded to these expected increases – for example by working longer, closing defined-benefit pension schemes or introducing parametric reforms to the state pension system – and are likely to change their behaviours further in the future. The issue is complicated by the fact that future longevity trends are uncertain. This makes it more difficult to allocate longevity risk efficiently and fairly across the different economic agents, while making it also more difficult to guarantee the sustainability of the system overall. The paper shows though that innovative solutions to this challenge are being developed, from businesses moving towards hybrid defined-benefit/defined-contribution pension schemes, to governments introducing mechanisms which automatically split the financial burden arising from future increases in life expectancy between state and individual, to businesses taking advantage of new products being developed to transfer any risk to the capital markets. --Pensions,Uncertainty,Financial markets,Longevity,Pension liabilities
Back to the drawing board: The economic crisis and its implications for pension provision in the United Kingdom
No full textThis paper focuses on an issue, which so far has received relatively little attention by policy makers and the media, namely that the economic crisis has highlighted inherent weaknesses in existing pension systems in many countries. Using the example of the UK, the paper argues that the economic crisis will usher in further changes to the future provision of pensions, with the role of the private and public sectors likely to evolve in the years ahead. To support this argument, the paper first presents the pension landscape in the UK prior to the crisis, which was dominated by the closure of defined benefit pension schemes in the private sector and the government’s reform efforts. The paper then describes the impact of the economic crisis from both a macroeconomic and financial perspective on all aspects of the pension system, from the government’s deteriorating public finances to the collapsing funding position of occupational defined-benefit and defined-contribution schemes. The paper concludes by suggesting that the crisis has left the British pension system in a weakened state and that it is unlikely that it will return to its “pre-crisis” status once the economy recovers from the crisis. --Economic crisis,Pension finances,Pension systems,Defined benefit pensions,Pension liabilities,Government policy,Financial markets
Curating Experiences: Rethinking the Estate Landscape for Sensorial Affordances
No full textPeople continually shape the landscape. The landscape being a palimpset of their socio-economic and cultural ethos. Few landscapes become valued as heritage and a marker for regional identity. However, often times, landscapes deemed as heritage might not strike upan attachment with the lives of the people around and within it. A heritage landscape for a few might mean very little to many others. Additionally, when elements composition the heritage landscape begin to fall apart, the landscape is pushed further into a state of disassociations.The estate landscape of the Baakse Beek narrates quite a similar tale. It is an estate landscape losing prominence and attachment from the rural lives. This broken relationship is further aggravated by the brook decaying functionally, ecologically and sensorially. Curating experiences offers a revitalisation of the heritage estates to become a setting for formation of experiential narratives and appreciation of the brook, which vitalises the aesthetic and ecological diversity within these estates. In doing so, the research entails the use of narratives as a method for documenting the uniqueness that lies in the basic unitof the landscape’s composition i.e the enclosures, mapping the experiences in these enclosures and alongthe brook, and constructing the plethora of socio-cultural engagements and perceptions in and with the landscape. Enriched by the theories of Sensorial Landscape, Seasonality of Landscape and Aesthetic Engagement, the research led to the curation of a tapestry of sensorially stimulating and engaging spaces. The project delivers a way of seeing the brook as integral to the experience of the landscape . It hopes to inspire the different stakeholders of the landscape to envision a more whole some outlook of looking at the sustainability of these heritage landscapes not only in functional terms, but also in terms of socio-cultural connections that sustain the value of this landscape.Architecture, Urbanism and Building Sciences | Landscape Architectur
Afferent and Efferent Interfaces of Lymph Nodes Are Distinguished by Expression of Lymphatic Endothelial Markers and Chemokines
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Eliminating antibody polyreactivity through addition of N-linked glycosylation
No full textAntibody polyreactivity can be an obstacle to translating a candidate antibody into a clinical product. Standard tests such as antibody binding to cardiolipin, HEp-2 cells, or nuclear antigens provide measures of polyreactivity, but its causes and the means to resolve are often unclear. Here we present a method for eliminating antibody polyreactivity through the computational design and genetic addition of N-linked glycosylation near known sites of polyreactivity. We used the HIV-1-neutralizing antibody, VRC07, as a test case, since efforts to increase VRC07 potency at three spatially distinct sites resulted in enhanced polyreactivity. The addition of N-linked glycans proximal to the polyreactivity-enhancing mutations at each of the spatially distinct sites resulted in reduced antibody polyreactivity as measured by (i) anti-cardiolipin ELISA, (ii) Luminex AtheNA Multi-Lyte ANA binding, and (iii) HEp-2 cell staining. The reduced polyreactivity trended with increased antibody concentration over time in mice, but not with improved overall protein stability as measured by differential scanning calorimetry. Moreover, glycan proximity to the site of polyreactivity appeared to be a critical factor. The results provide evidence that antibody polyreactivity can result from local, rather than global, features of an antibody and that addition of N-linked glycosylation can be an effective approach to reducing antibody polyreactivity.</p
Early short-term treatment with neutralizing human monoclonal antibodies halts SHIV infection in infant macaques
No full textPrevention of mother-to-child transmission (MTCT) of HIV remains a major objective where antenatal care is not readily accessible. We tested HIV-1–specific human neutralizing monoclonal antibodies (NmAbs) as a post-exposure therapy in an infant macaque model for intrapartum MTCT. One-month-old rhesus macaques were inoculated orally with the simian-human immunodeficiency virus SHIVSF162P3. On days 1, 4, 7 and 10 after virus exposure, we injected animals subcutaneously with NmAbs and quantified systemic distribution of NmAbs in multiple tissues within 24 h after antibody administration. Replicating virus was found in multiple tissues by day 1 in animals that were not treated. All NmAb-treated macaques were free of virus in blood and tissues at 6 months after exposure. We detected no anti-SHIV T cell responses in blood or tissues at necropsy, and no virus emerged after CD8+ T cell depletion. These results suggest that early passive immunotherapy can eliminate early viral foci and thereby prevent the establishment of viral reservoirs.Fil: Hessell, Ann J.. Oregon Health and Science University; Estados UnidosFil: Jaworski, Juan Pablo. Oregon Health and Science University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Epson, Erin. Oregon Health and Science University; Estados UnidosFil: Matsuda, Kenta. National Institutes of Health; Estados UnidosFil: Pandey, Shilpi. Oregon Health and Science University; Estados UnidosFil: Kahl, Christoph. Oregon Health and Science University; Estados UnidosFil: Reed, Jason. Oregon Health and Science University; Estados UnidosFil: Sutton, William F.. Oregon Health and Science University; Estados UnidosFil: Hammond, Katherine B.. Oregon Health and Science University; Estados UnidosFil: Cheever, Tracy A.. Oregon Health and Science University; Estados UnidosFil: Barnette, Philip T.. Oregon Health and Science University; Estados UnidosFil: Legasse, Alfred W.. Oregon Health and Science University; Estados UnidosFil: Planer, Shannon. Oregon Health and Science University; Estados UnidosFil: Stanton, Jeffrey J.. Oregon Health and Science University; Estados UnidosFil: Pegu, Amarendra. National Institutes of Health; Estados UnidosFil: Chen, Xuejun. National Institutes of Health; Estados UnidosFil: Wang, Keyun. National Institutes of Health; Estados UnidosFil: Siess, Don. Oregon Health and Science University; Estados UnidosFil: Burke, David. Oregon Health and Science University; Estados UnidosFil: Park, Byung S.. Oregon Health and Science University; Estados UnidosFil: Axthelm, Michael K. Oregon Health and Science University; Estados UnidosFil: Lewis, Anne. Oregon Health and Science University; Estados UnidosFil: Hirsch, Vanessa M.. National Institutes of Health; Estados UnidosFil: Graham, Barney S.. National Institutes of Health; Estados UnidosFil: Mascola, John R.. National Institutes of Health; Estados UnidosFil: Sacha, Jonah B.. Oregon Health and Science University; Estados UnidosFil: Haigwood, Nancy L.. Oregon Health and Science University; Estados Unido
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