NK cells and missing self recognition : genetic control, mhc class i dependent education and potential use in cancer therapy

NK cells belong to the innate immune system and are important in the defense against virus infections and malignant cells. They mediate their effector functions via release of cytotoxic granules and by cytokine production which can influence the status of other (immune) cells. NK cells are regulated by germline encoded receptors, both activating and inhibitory, recognizing molecules that are induced upon infection or cellular stress and self ligands respectively. Ly49 receptors (Ly49r) make up the largest NK cell receptor family in mice. It contains both activating and inhibitory receptors most of which bind to major histocompatibility complex class I (MHC I) molecules. NK cells patrol tissues and inspect surrounding cells for alterations in activating ligands and MHC I expression, balancing the input for decision of response. If the activation exceeds the inhibition, the target cell is eliminated. This ability to sense loss of self MHC I is referred to as missing self recognition. It can be directed against virus infected cells and tumor cells which often downmodulate MHC I, while they upregulate activating ligands. NK cells are educated via Ly49r-MHC I interactions to ensure self-tolerance and reactivity against aberrant cells. MHC I dependent education influences the NK cell population in at least two ways; modulation of responsiveness of each cell and skewing of the inhibitory receptor repertoire, i e the frequencies of NK cells expressing different combinations of Ly49r. The main aim of this thesis has been to study missing self recognition and MHC I dependent NK cell education and how these phenomena are influenced by different factors. In paper I, we characterized a genetic defect leading to Impaired Missing Self Recognition, in a mouse strain that we have termed IMSR mice. These mice had originally been developed by targeting a non-classical MHC gene, but the defect and the IMSR defect segregated independently. The IMSR mice were found to have a normal number of NK cells, which retained some functions, while missing self rejection and some activation pathways were partly or completely impaired. This defect was found to be NK cell intrinsic; it was not due to total lack of inhibitory receptors function, nor lack of MHC dependent education. In paper II and III we investigated how NK cells respond to altered inhibitory input from the environment in the host. Antibody mediated inhibitory receptor blockade was used as a tool to reduce the inhibitory input, which led to two different effects on the targeted NK cell populations 1) increased in vivo elimination of MHC I+ tumor cells without breaking tolerance towards normal healthy cells (paper II) and 2) induction of hyporesponsiveness i e reduced in vitro responsiveness or reduced capacity to eliminate MHC I- spleen cells. Importantly, elimination of MHC I- tumor cells was maintained. This was also investigated in an adoptive transfer model where the NK cell responsiveness could be either increased or reduced, depending on the MHC I expression in the recipient host (paper III). In conclusion, we found that NK cells can retune their responsiveness upon altered inhibitory input, but that responsiveness levels are adapted to healthy cells, still allowing efficient killing of tumor cells of the same missing self phenotype. In paper IV, we investigated whether skewing of the inhibitory receptor repertoire occurs already during NK cell development, before they reach the blood and the spleen. We found that the process leading to overrepresentation of NK cells expressing only one self MHC receptor is initiated during in the bone marrow already at the first NK cell developmental stage where inhibitory Ly49 receptors are expressed. This is most probably influenced both by selective proliferation and apoptosis

The fossil record of early tetrapods: worker effort and the end-Permian mass extinction

It is important to understand the quality of the fossil record of early tetrapods (Tetrapoda, minus Lissamphibia and Amniota) because of their key role in the transition of vertebrates from water to land, their dominance of terrestrial faunas for over 100 million years of the late Palaeozoic and earlyMesozoic, and their variable fates during the end−Permian mass extinction. The first description of an early tetrapod dates back to 1824, and since then discoveries have occurred at a rather irregular pace, with peaks and troughs corresponding to some of the vicissitudes of human history through the past two centuries. As expected, the record is dominated by the well−sampled sedimentary basins of Europe and North America, but finds from other continents are increasing rapidly. Comparisons of snapshots of knowledge in 1900, 1950, and 2000 show that discovery of new species has changed the shape of the species−level diversification curve, contrary to earlier studies of family−level taxa. There is, however, little evidence that taxon counts relate to research effort (as counted by numbers of publications), and there are no biasing effects associated with differential study of different time intervals through the late Palaeozoic and Mesozoic. In fact, levels of effort are apparently not related to geological time, with no evidence that workers have spent more time on more recent parts of the record. In particular, the end−Permian mass extinction was investigated to determine whether diversity changes through that interval might reflect worker effort: it turns out that most records of early tetrapod taxa (when corrected for duration of geological series) occur in the Lower Triassic

A Thin Skin Calorimeter (TSC) for Quantifying Irradiation During Large-scale Fire Testing

This paper details a novel method for quantifying irradiation (incident radiant heat flux) at the exposed surface of solid elements during large-scale fire testing. Within the scope of the work presented herein, a type of Thin Skin Calorimeter (TSC) was developed intending for a practical, low cost device enabling the cost-effective mass production required for characterising the thermal boundary conditions during multiple large-scale fire tests. The technical description of the TSC design and a formulation of the proposed calibration technique are presented. This methodology allows for the quantification of irradiation by means of an a posteriori analysis based on a temperature measurement from the TSC, a temperature measurement of the gas-phase in the vicinity of the TSC and a correction factor defined during a pre-test calibration process. The proposed calibration methodology is designed to account for uncertainties inherent to the simplicity of the irradiation measurement technique, therefore not requiring precise information regarding material thermal and optical properties. This methodology is designed and presented so as to enable adaption of the technique to meet the specific requirements of other experimental setups. This is conveyed by means of an example detailing the design and calibration of a device designed for a series of large-scale experiments as part of the ‘Real Fires for the Safe Design of Tall Buildings’ project

E.U. paediatric MOG consortium consensus: Part 4 - Outcome of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders

There is increasing knowledge on the role of antibodies against myelin oligodendrocyte glycoprotein (MOG-abs) in acquired demyelinating syndromes and autoimmune encephalitis in children. Better understanding and prediction of outcome is essential to guide treatment protocol decisions. Therefore, this part of the Paediatric European Collaborative Consensus provides an oversight of existing knowledge of clinical outcome assessment in paediatric MOG-ab-associated disorders (MOGAD). The large heterogeneity in disease phenotype, disease course, treatment and follow-up protocols is a major obstacle for reliable prediction of outcome. However, the clinical phenotype of MOGAD appears to be the main determinant of outcome. Patients with a transverse myelitis phenotype in particular are at high risk of accruing neurological disability (motor and autonomic), which is frequently severe. In contrast, having a single episode of optic neuritis any time during disease course is broadly associated with a lower risk of persistent disability. Furthermore, MOG-ab-associated optic neuritis often results in good functional visual recovery, although retinal axonal loss may be severe. The field of cognitive and behavioural outcome and epilepsy following demyelinating episodes has not been extensively explored, but in recent studies acute disseminated encephalomyelitis (-like) phenotype in the young children was associated with cognitive problems and epilepsy in long-term follow-up. In conclusion, main domains of importance in determining clinical outcome in paediatric MOGAD are visual, motor, autonomic and cognitive function. A standardised evaluation of these outcome domains in all children is of importance to allow adequate rehabilitation and follow-up

Cumulative occupational lumbar load and lumbar disc disease – results of a German multi-center case-control study (EPILIFT)

Background The to date evidence for a dose-response relationship between physical workload and the development of lumbar disc diseases is limited. We therefore investigated the possible etiologic relevance of cumulative occupational lumbar load to lumbar disc diseases in a multi-center case-control study. Methods In four study regions in Germany (Frankfurt/Main, Freiburg, Halle/Saale, Regensburg), patients seeking medical care for pain associated with clinically and radiologically verified lumbar disc herniation (286 males, 278 females) or symptomatic lumbar disc narrowing (145 males, 206 females) were prospectively recruited. Population control subjects (453 males and 448 females) were drawn from the regional population registers. Cases and control subjects were between 25 and 70 years of age. In a structured personal interview, a complete occupational history was elicited to identify subjects with certain minimum workloads. On the basis of job task-specific supplementary surveys performed by technical experts, the situational lumbar load represented by the compressive force at the lumbosacral disc was determined via biomechanical model calculations for any working situation with object handling and load-intensive postures during the total working life. For this analysis, all manual handling of objects of about 5 kilograms or more and postures with trunk inclination of 20 degrees or more are included in the calculation of cumulative lumbar load. Confounder selection was based on biologic plausibility and on the change-in-estimate criterion. Odds ratios (OR) and 95% confidence intervals (CI) were calculated separately for men and women using unconditional logistic regression analysis, adjusted for age, region, and unemployment as major life event (in males) or psychosocial strain at work (in females), respectively. To further elucidate the contribution of past physical workload to the development of lumbar disc diseases, we performed lag-time analyses. Results We found a positive dose-response relationship between cumulative occupational lumbar load and lumbar disc herniation as well as lumbar disc narrowing among men and women. Even past lumbar load seems to contribute to the risk of lumbar disc disease. Conclusions According to our study, cumulative physical workload is related to lumbar disc diseases among men and women

Mechanochemical control of epidermal stem cell divisions by B-plexins

The precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. However, the molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we identify a critical requirement of B-plexin transmembrane receptors in the response to crowding-induced mechanical forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail to sense mechanical compression, resulting in disinhibition of the transcriptional coactivator YAP, hyperproliferation, and tissue overgrowth. Mechanistically, we show that B-plexins mediate mechanoresponses to crowding through stabilization of adhesive cell junctions and lowering of cortical stiffness. Finally, we provide evidence that the B-plexin-dependent mechanochemical feedback is also pathophysiologically relevant to limit tumor growth in basal cell carcinoma, the most common type of skin cancer. Our data define a central role of B-plexins in mechanosensation to couple cell density and cell division in development and disease.Peer reviewe

Model prediction vs. reality--testing the predictions of a European eel (Anguilla anguilla) stock dynamics model against the in situ observation of silver eel escapement in compliance with the European eel regulation

A direct monitoring of European silver eel (Anguilla anguilla, L) escapement from rivers and estuaries has been proven to be challenging, and a Europe-wide documentation of escaping silver eel numbers therefore hardly seems realistic. To reinforce management decisions, policy-makers are thus widely reliant on the accuracy of escapement models. A 3-year programme of silver eel escapement monitoring was undertaken to compile model input data and revise an eel population model (German Eel Model II; GEM II) already used in the decision-making process of management authorities. By compiling necessary input data and analysing vital system-specific population characteristics, it was possible to compare the documented silver eel escapement with the modelled potential silver eel escapement. Resulting model predictions were close to actually monitored escapement numbers, which were distinctly lower than reference escapement values for the same freshwater system given in the implementation report of the German Eel Management Plans. Applying different commercial and recreational catch scenarios revealed the sensitivity of the model. The results show the potential of the GEM II and highlight the importance of high-quality input data to use model predictions as the basis for management measures

Fire design method for concrete filled tubular columns based on equivalent concrete core cross-section

In this work, a method for a realistic cross-sectional temperature prediction and a simplified fire design method for circular concrete filled tubular columns under axial load are presented. The generalized lack of simple proposals for computing the cross-sectional temperature field of CFT columns when their fire resistance is evaluated is evident. Even Eurocode 4 Part 1-2, which provides one of the most used fire design methods for composite columns, does not give any indications to the designers for computing the cross-sectional temperatures. Given the clear necessity of having an available method for that purpose, in this paper a set of equations for computing the temperature distribution of circular CFT columns filled with normal strength concrete is provided. First, a finite differences thermal model is presented and satisfactorily validated against experimental results for any type of concrete infill. This model consideres the gap at steel-concrete interface, the moisture content in concrete and the temperature dependent properties of both materials. Using this model, a thermal parametric analysis is executed and from the corresponding statistical analysis of the data generated, the practical expressions are derived. The second part of the paper deals with the development of a fire design method for axially loaded CFT columns based on the general rules stablished in EN 1994-1-1 and employing the concept of room temperature equivalent concrete core cross-section. In order to propose simple equations, a multiple nonlinear regression analysis is made with the numerical results generated through a thermo-mechanical parametric analysis. Once more, predicted results are compared to experimental values giving a reasonable accuracy and slightly safe results.The authors would like to express their sincere gratitude to the Spanish Ministry of Economy and Competitivity for the help provided through the project BIA2012-33144, and to the European Community for the FEDER funds.Ibáñez Usach, C.; Aguado, JV.; Romero, ML.; Espinós Capilla, A.; Hospitaler Pérez, A. (2015). Fire design method for concrete filled tubular columns based on equivalent concrete core cross-section. Fire Safety Journal. 78:10-23. https://doi.org/10.1016/j.firesaf.2015.07.009S10237