Inflammation, kinins, and kinin receptors

Evidence is accumulating that the pathogenesis of many diseases is triggered by inappropriate inflammatory responses. These serious complications may occur when the tightly regulated inflammatory network is out of balance and it is now clear that this can eventually cause substantial harm to own cells and tissues. Successful infectious agents have evolved an enormous repertoire of modulatory mechanisms that allow the evasion, re-direction, dampening, over-stimulation, and even the use of inflammatory responses for their own purposes. The contact system, which is studied in the present thesis, is part of this inflammatory network and it has been shown that its systemic activation contributes to an exacerbation in many disease areas. Bradykinin (BK) belongs to the group of vasoactive peptides, so-called kinins, which are potent inflammatory mediators. BK, once released from the human contact system, elicits a transient inflammatory response via activation of the constitutively expressed B2 receptor, which desensitizes and is internalized upon ligand binding. The kininase I metabolite of BK, desArg9BK, on the other hand mediates chronic deleterious inflammatory responses by interacting with the B1 receptor. Although normally absent, B1 receptor expression can be induced under inflammatory conditions. The aim of the present thesis was to explore and analyze modifications in the regulation of kinins and their receptors in different settings of inflammation. It is known that BK is generated in the airways of asthmatic subjects and that disease symptoms are exacerbated during respiratory viral infections. In paper I, we report that BK induces an up-regulation of B2 receptors in human airway epithelial cells, which is in sharp contrast to other investigated cells. Further more, rhinovirus induces up-regulation of functional B1 receptors in the same cell type (paper II). Both mechanisms may render the respiratory tract more responsive to generated kinins and can significantly influence the inflammatory response and thereby symptom severity. In paper III and IV we demonstrate that the important human pathogens S. aureus and S. pyogenes can induce profound inflammatory reactions in the human host by secreting toxins that via stimulation of monocytic cells induce up-regulation of B1 receptors. Concurrently, both bacterial species are able to induce release of BK and its subsequent conversion to desArg9BK, which can evoke an over-amplification and prolongation of the inflammatory response. Taken together, the present thesis demonstrates that kinin receptor regulation and kinin generation is affected during different settings of inflammation and we conclude that this may have a great impact on disease progression

Whistler Waves in the Radiation Belt

The Van Allen Radiation Belt is a region in space populated with high-energy, electrically-charged particles trapped in earth’s magnetic field. These particles constitute a danger to spacecraft in low-earth orbit, including the ISS and its crew. Solar storms and high-altitude nuclear explosions can increase the number of particles in the radiation belt by a factor of 100, rendering many important defense and communications satellites inoperable. It is of national security interest to develop a physical understanding of remediation of energetic particles from space. One possible method to achieve this is to use electromagnetic whistler-mode waves. Using data from the Van Allen Probes, we have conducted a preliminary analysis to validate simulations developed by Dr. Anatoly Streltsov which describe the propagation of whistler waves in space. Over the next year, we plan to further validate the models. This poster will present advances in whistler-wave physics which have important applications to future projects of launching whistlers into the radiation belt

Observations and Simulations of Whistler Waves in the Van Allen Radiation Belts

When the first American satellite, Explorer I, was launched into space in 1958 it inadvertently discovered one the most significant features of our local space environment: the Van Allen Radiation Belts. This region contains highly energetic protons and electrons from the sun which become trapped in the Earth’s magnetic field. These particles are extremely hazardous for spacecraft, causing damage to electronics and endangering astronauts on the International Space Station. Certain natural or artificial events, such as solar coronal mass ejections or high-altitude nuclear explosions, can enhance the radiation belts and decrease satellite lifetimes by orders of magnitude. Therefore, there is a strong motivation to develop a means by which to deplete the radiation and protect our assets in space from this threat. We present one promising remediation mechanism based on the interactions between these particles and very-low-frequency electromagnetic waves known as whistlers. One important property of whistler waves is that they can be guided along narrow inhomogeneities of plasma density called ducts. We have analyzed several events of ducted whistlers observed by the Van Allen Probes satellites and reproduce them with numerical simulations based on whistler theory. We demonstrate quantitative agreement between our simulations and the observations, indicating that our model successfully explains the existing satellite observations and can be used to predict the results from future experiments of launching whistler waves into the radiation belts from ground stations and space-based transmitters

Ducting of Whistler Waves in the Van Allen Radiation Belts

Whistler waves are electromagnetic waves in the very-low-frequency range which propagate in the near-earth space plasma environment, specifically within a region called the Van Allen Radiation Belts. This region contains many highly energetic particles which pose a significant threat to spacecraft in Earth orbit, including the International Space Station. Whistler waves are particularly interesting because they can interact with the energetic particles and precipitate them out of the Van Allen Radiation Belts. One important characteristic of whistlers is that they can become trapped inside enhancements or depletions of the ambient plasma density. We compare wave and particle observations from the Van Allen Probes spacecraft to results from a numerical simulation developed to model the wave propagation physics. By using the observed conditions as inputs to the simulation, we can reproduce the ducted waves with good, quantitative agreement. The results from this study will be important for future experiments of launching whistler waves into the Van Allen Radiation Belts from ground antennae or space vehicles

A Triple-Transgenic Immunotolerant Mouse Model

ABSTRACTAvoiding unwanted immunogenicity is of key importance in the development of therapeutic drug proteins. Animal models are of less predictive value because most of the drug proteins are recognized as foreign proteins. However, different methods have been developed to obtain immunotolerant animal models. So far, the immunotolerant animal models have been developed to assess one protein at a time and are not suitable for the assessment of combination products. Our aim was to develop an animal model for evaluating the impact of manufacturing and formulation changes on immunogenicity, suitable for both single protein and combination products. We constructed two lines of transgenic mice expressing the three human coagulation factors, II, VII, and X, by inserting a single vector containing the three coagulation factors encoding sequences separated by insulator sequences derived from the chicken beta-globin locus into the mouse genome. Immunization of transgenic mice from the two lines and their wild-type littermates showed that transgenic mice from both lines were immunotolerant to the expressed human coagulation factors. We conclude that transgenic mice immunotolerant to multiple proteins can be obtained, and that these mice are potentially useful as animal models in the assessment of immunogenicity in response to manufacturing changes. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1116-1124, 201

Marine ecosystem assessment for the Southern Ocean: birds and marine mammals in a changing climate

The massive number of seabirds (penguins and procellariiformes) and marine mammals (cetaceans and pinnipeds) – referred to here as top predators – is one of the most iconic components of the Antarctic and Southern Ocean. They play an important role as highly mobile consumers, structuring and connecting pelagic marine food webs and are widely studied relative to other taxa. Many birds and mammals establish dense breeding colonies or use haul-out sites, making them relatively easy to study. Cetaceans, however, spend their lives at sea and thus aspects of their life cycle are more complicated to monitor and study. Nevertheless, they all feed at sea and their reproductive success depends on the food availability in the marine environment, hence they are considered useful indicators of the state of the marine resources. In general, top predators have large body sizes that allow for instrumentation with miniature data-recording or transmitting devices to monitor their activities at sea. Development of scientific techniques to study reproduction and foraging of top predators has led to substantial scientific literature on their population trends, key biological parameters, migratory patterns, foraging and feeding ecology, and linkages with atmospheric or oceanographic dynamics, for a number of species and regions. We briefly summarize the vast literature on Southern Ocean top predators, focusing on the most recent syntheses. We also provide an overview on the key current and emerging pressures faced by these animals as a result of both natural and human causes. We recognize the overarching impact that environmental changes driven by climate change have on the ecology of these species. We also evaluate direct and indirect interactions between marine predators and other factors such as disease, pollution, land disturbance and the increasing pressure from global fisheries in the Southern Ocean. Where possible we consider the data availability for assessing the status and trends for each of these components, their capacity for resilience or recovery, effectiveness of management responses, risk likelihood of key impacts and future outlook

All Citizens are Equal but Some Citizens are More Equal than Others (?) - On The Current Trajectory of Western European Citizenship Regimes and What Human Rights Have Got to Do with It

Citizenship regimes in Western Europe are changing. On the one hand, over the past 30 years, citizenship has been liberalized. On the other, in particular over the past ten years, access to citizenship through naturalization has become restricted in most Western European states. This development has been intertwined with public discourses on ‘integration’ of those Europeans who once migrated to the continent. The same integration concerns have also had an impact on what in this thesis is viewed as forming part of the content of citizenship. Simultaneously with the restricted rules of naturalization, regulations restricting the right to family reunion for Europeans with a migration background have been adopted. In this thesis, the current trajectory of citizenship regimes in Western Europe as briefly described is discussed, through a comparative analysis of the regulation of citizenship in three states; Denmark, Germany and Sweden. Citizenship is in this thesis analysed as composed of three dimensions. Citizenship has a formal dimension, by being the status of ‘full membership’ in the nation-state. It has a substantive dimension, since citizens as ‘full members’ should have ‘a right to equal rights’. But citizenship is also a set of ideals, more or less explicit public and institutionalized ideas about who is the ideal member of a community. Rules of naturalization regulate the access to the status of citizenship, and family reunification is something that all citizens, as full members of a state, should enjoy equally. This thesis comparatively investigates regulations of naturalization and family reunification, which thus pertain to the formal and substantive dimensions of citizenship, in Denmark, Germany and Sweden, with a view to then analyse the regulations in light of the third dimension of citizenship; what ideals are evoked by the regulations? Citizenship as discussed in this thesis has furthermore international dimensions. To what extent are the regulations of naturalization and family reunification compatible with the international human rights norms of the right to a nationality and the right to family life? It is noted in the thesis that, in international law, citizenship resides in the tension between the state prerogative to exclude and human rights obligations to include, and it is argued that the results of this tension in the European human rights system are reflected in the current trajectory of Western European citizenship regimes