Immunogenetics of drug-induced skin blistering disorders. Part I: Perspective

The overall immunopathogenesis relevant to a large series of disorders caused by a drug or its associated hyperimmune condition is discussed based upon the examination of the genetics of severe drug-induced bullous skin problems (sporadic idiosyncratic adverse events, including Stevens-Johnson syndrome and toxic epidermal necrolysis). An overarching pharmacogenetic schema is proposed. Immune cognition and early-effector processes are focused upon and a challenging synthesis around systems evolution is explained by a variety of projective analogies. Etiology, human leukocyte antigen-B, immune stability, clysiregulation, pharmacomimicry, viruses and an aggressive ethnically differentiated 'karmic' response are discussed.

A singular vector perspective of 4DVAR: The spatial structure and evolution of baroclinic weather systems

The extent to which the four-dimensional variational data assimilation (4DVAR) is able to use information about the time evolution of the atmosphere to infer the vertical spatial structure of baroclinic weather systems is investigated. The singular value decomposition (SVD) of the 4DVAR observability matrix is introduced as a novel technique to examine the spatial structure of analysis increments. Specific results are illustrated using 4DVAR analyses and SVD within an idealized 2D Eady model setting. Three different aspects are investigated. The first aspect considers correcting errors that result in normal-mode growth or decay. The results show that 4DVAR performs well at correcting growing errors but not decaying errors. Although it is possible for 4DVAR to correct decaying errors, the assimilation of observations can be detrimental to a forecast because 4DVAR is likely to add growing errors instead of correcting decaying errors. The second aspect shows that the singular values of the observability matrix are a useful tool to identify the optimal spatial and temporal locations for the observations. The results show that the ability to extract the time-evolution information can be maximized by placing the observations far apart in time. The third aspect considers correcting errors that result in nonmodal rapid growth. 4DVAR is able to use the model dynamics to infer some of the vertical structure. However, the specification of the case-dependent background error variances plays a crucial role.

Evaluation of the model representation of the evolution of convective systems using satellite observations of outgoing longwave radiation

We introduce a technique for assessing the diurnal development of convective storm systems based on outgoing longwave radiation fields. Using the size distribution of the storms measured from a series of images, we generate an array in the lengthscale-time domain based on the standard score statistic. It demonstrates succinctly the size evolution of storms as well as the dissipation kinematics. It also provides evidence related to the temperature evolution of the cloud tops. We apply this approach to a test case comparing observations made by the Geostationary Earth Radiation Budget instrument to output from the Met Office Unified Model run at two resolutions. The 12km resolution model produces peak convective activity on all lengthscales significantly earlier in the day than shown by the observations and no evidence for storms growing in size. The 4km resolution model shows realistic timing and growth evolution although the dissipation mechanism still differs from the observed data.

Evolution in software systems: foundations of the SPE classification scheme

The SPE taxonomy of evolving software systems, first proposed by Lehman in 1980, is re-examined in this work. The primary concepts of software evolution are related to generic theories of evolution, particularly Dawkins' concept of a replicator, to the hermeneutic tradition in philosophy and to Kuhn's concept of paradigm. These concepts provide the foundations that are needed for understanding the phenomenon of software evolution and for refining the definitions of the SPE categories. In particular, this work argues that a software system should be defined as of type P if its controlling stakeholders have made a strategic decision that the system must comply with a single paradigm in its representation of domain knowledge. The proposed refinement of SPE is expected to provide a more productive basis for developing testable hypotheses and models about possible differences in the evolution of E- and P-type systems than is provided by the original scheme. Copyright (C) 2005 John Wiley & Sons, Ltd.

Evolution of immune systems: specificity and autoreactivity

Multicellularity evolved well before 600 million years ago, and all multicellular animals have evolved since then with the need to protect against pathogens. There is no reason to expect their immune systems to be any less sophisticated than ours. The vertebrate system, based on rearranging immunoglobulin-superfamily domains, appears to have evolved partly as a result of chance insertion of RAG genes by horizontal transfer. Remarkably sophisticated systems for expansion of immunological repertoire have evolved in parallel in many groups of organisms. Vaccination of invertebrates against commercially important pathogens has been empirically successful, and suggests that the definition of an adaptive and innate immune system should no longer depend on the presence of memory and specificity, since these terms are hard to define in themselves. The evolution of randomly-created immunological repertoire also carries with it the potential for generating autoreactive specificities and consequent autoimmune damage.While invertebrates may use systems analogous to ours to control autoreactive specificities, they may have evolved alternative mechanisms which operate either at the level of individuals-within-populations rather than cells-within-individuals, by linking self-reactive specificities to regulatory pathways and non-self-reactive to effector pathways.

Divergent evolution of the activity and regulation of the glutamate decarboxylase systems in Listeria monocytogenes EGD-e and 10403S : roles in virulence and acid tolerance

The glutamate decarboxylase (GAD) system has been shown to be important for the survival of Listeria monocytogenes in low pH environments. The bacterium can use this faculty to maintain pH homeostasis under acidic conditions. The accepted model for the GAD system proposes that the antiport of glutamate into the bacterial cell in exchange for γ-aminobutyric acid (GABA) is coupled to an intracellular decarboxylation reaction of glutamate into GABA that consumes protons and therefore facilitates pH homeostasis. Most strains of L. monocytogenes possess three decarboxylase genes (gadD1, D2 & D3) and two antiporter genes (gadT1 & gadT2). Here, we confirm that the gadD3 encodes a glutamate decarboxylase dedicated to the intracellular GAD system (GADi), which produces GABA from cytoplasmic glutamate in the absence of antiport activity. We also compare the functionality of the GAD system between two commonly studied reference strains, EGD-e and 10403S with differences in terms of acid resistance. Through functional genomics we show that EGD-e is unable to export GABA and relies exclusively in the GADi system, which is driven primarily by GadD3 in this strain. In contrast 10403S relies upon GadD2 to maintain both an intracellular and extracellular GAD system (GADi/GADe). Through experiments with a murinised variant of EGD-e (EGDm) in mice, we found that the GAD system plays a significant role in the overall virulence of this strain. Double mutants lacking either gadD1D3 or gadD2D3 of the GAD system displayed reduced acid tolerance and were significantly affected in their ability to cause infection following oral inoculation. Since EGDm exploits GADi but not GADe the results indicate that the GADi system makes a contribution to virulence within the mouse. Furthermore, we also provide evidence that there might be a separate line of evolution in the GAD system between two commonly used reference strains.

Sensitivity of large-scale atmospheric analyses to humidity observations and its impact on the global water cycle and tropical and extratropical weather systems in ERA40

Reanalysis data obtained from data assimilation are increasingly used for diagnostic studies of the general circulation of the atmosphere, for the validation of modelling experiments and for estimating energy and water fluxes between the Earth surface and the atmosphere. Because fluxes are not specifically observed, but determined by the data assimilation system, they are not only influenced by the utilized observations but also by model physics and dynamics and by the assimilation method. In order to better understand the relative importance of humidity observations for the determination of the hydrological cycle, in this paper we describe an assimilation experiment using the ERA40 reanalysis system where all humidity data have been excluded from the observational data base. The surprising result is that the model, driven by the time evolution of wind, temperature and surface pressure, is able to almost completely reconstitute the large-scale hydrological cycle of the control assimilation without the use of any humidity data. In addition, analysis of the individual weather systems in the extratropics and tropics using an objective feature tracking analysis indicates that the humidity data have very little impact on these systems. We include a discussion of these results and possible consequences for the way moisture information is assimilated, as well as the potential consequences for the design of observing systems for climate monitoring. It is further suggested, with support from a simple assimilation study with another model, that model physics and dynamics play a decisive role for the hydrological cycle, stressing the need to better understand these aspects of model parametrization. .

Deep Convective System Evolution over Africa and the Tropical Atlantic

In the tropical African and neighboring Atlantic region there is a strong contrast in the properties of deep convection between land and ocean. Here, satellite radar observations are used to produce a composite picture of the life cycle of convection in these two regions. Estimates of the broadband thermal flux from the geostationary Meteosat-8 satellite are used to identify and track organized convective systems over their life cycle. The evolution of the system size and vertical extent are used to define five life cycle stages (warm and cold developing, mature, cold and warm dissipating), providing the basis for the composite analysis of the system evolution. The tracked systems are matched to overpasses of the Tropical Rainfall Measuring Mission satellite, and a composite picture of the evolution of various radar and lightning characteristics is built up. The results suggest a fundamental difference in the convective life cycle between land and ocean. African storms evolve from convectively active systems with frequent lightning in their developing stages to more stratiform conditions as they dissipate. Over the Atlantic, the convective fraction remains essentially constant into the dissipating stages, and lightning occurrence peaks late in the life cycle. This behavior is consistent with differences in convective sustainability in land and ocean regions as proposed in previous studies. The area expansion rate during the developing stages of convection is used to provide an estimate of the intensity of convection. Reasonable correlations are found between this index and the convective system lifetime, size, and depth.

Ethnobiology and the evolution of the human mind

An evolutionary perspective on human thought and behaviour indicates that we should expect to find universal systems of perception, classification, and decision-making regarding the natural world. It is the interaction between these evolved aspects of the human mind, the biodiversity of the natural world, and unique historical, social, and economic contexts within which individuals develop and act that gives rise to cultural diversity. The palaeoanthropological record also indicates that language is a recently evolved phenomenon. This suggests that linguistic approaches in ethnobiology are likely to provide only a partial understanding of how humans perceive, classify, and engage with the natural world.

Later Pleistocene evolution of the Exe valley: a chronostratigraphic model of terrace formation and its implications for Palaeolithic archaeology

This paper presents the first systematic chronostratigraphic study of the river terraces of the Exe catchment in South West England and a new conceptual model for terrace formation in unglaciated basins with applicability to terrace staircase sequences elsewhere. The Exe catchment lay beyond the maximum extent of Pleistocene ice sheets and the drainage pattern evolved from the Tertiary to the Middle Pleistocene, by which time the major valley systems were in place and downcutting began to create a staircase of strath terraces. The higher terraces (8-6) typically exhibit altitudinal overlap or appear to be draped over the landscape, whilst the middle terraces show greater altitudinal separation and the lowest terraces are of a cut and fill form. The terrace deposits investigated in this study were deposited in cold phases of the glacial-interglacial Milankovitch climatic cycles with the lowest four being deposited in the Devensian Marine Isotope Stages (MIS) 4-2. A new cascade process-response model is proposed of basin terrace evolution in the Exe valley, which emphasises the role of lateral erosion in the creation of strath terraces and the reworking of inherited resistant lithological components down through the staircase. The resultant emergent valley topography and the reworking of artefacts along with gravel clasts, have important implications for the dating of hominin presence and the local landscapes they inhabited. Whilst the terrace chronology suggested here is still not as detailed as that for the Thames or the Solent System it does indicate a Middle Palaeolithic hominin presence in the region, probably prior to the late Wolstonian Complex or MIS 6. This supports existing data from cave sites in South West England.