Allergy for a Lifetime?

ABSTRACTAs the key molecule of type-I-hypersensitivity, IgE provides specificity for the allergen and links it to the allergic effector functions. Antibodies are secreted by plasma cells and their precursors, the plasma blasts. The fate of plasma cells is a subject of controversy, with respect to their lifetime and persistence in the absence of allergen. In general, plasma cells were for a long time considered as short-lived end products of B-cell differentiation, and many of them are short-lived, although already for more than 20 years evidence has been provided that IgE-secreting plasma cells can persist over months. Today long-lived, "memory" plasma cells are considered to represent a distinct cellular entity of immunological memory, with considerable therapeutic relevance. Long-lived plasma cells resist current therapeutic and experimental approaches such as immunosuppression, e.g. cyclophosphamide, steroids, X-ray irradiation, anti-CD20 antibodies and anti-inflammatory drugs, while the chronic generation of short-lived plasma cells is sensitive to conventional immunosuppression. The seasonal variation in pollen-specific IgE can be suppressed by immunotherapy, indicating that component of the IgE response, which is stimulated with pollen allergen is susceptible to suppression. Targeting of the remaining long-lived, allergen-specific plasma cells, providing the stable IgE-titers, represents a therapeutic challenge.Here we discuss recent evidence suggesting, why current protocols for the treatment of IgE-mediated allergies fail: Memory plasma cells generated by inhalation of the allergen become long-lived and are maintained preferentially in the bone marrow. They do not proliferate, and are refractory to conventional therapies. Current concepts target plasma cells for depletion, e.g. the proteasome inhibitor bortezomib, BAFF and APRIL antagonists and autologous hematopoietic stem cell transplantation

Radiation Hardness Studies in a CCD with High-Speed Column Parallel Readout

Charge Coupled Devices (CCDs) have been successfully used in several high energy physics experiments over the past two decades. Their high spatial resolution and thin sensitive layers make them an excellent tool for studying short-lived particles. The Linear Collider Flavour Identification (LCFI) collaboration is developing Column-Parallel CCDs (CPCCDs) for the vertex detector of the International Linear Collider (ILC). The CPCCDs can be read out many times faster than standard CCDs, significantly increasing their operating speed. The results of detailed simulations of the charge transfer inefficiency (CTI) of a prototype CPCCD are reported and studies of the influence of gate voltage on the CTI described. The effects of bulk radiation damage on the CTI of a CPCCD are studied by simulating the effects of two electron trap levels, 0.17 and 0.44 eV, at different concentrations and operating temperatures. The dependence of the CTI on different occupancy levels (percentage of hit pixels) and readout frequencies is also studied. The optimal operating temperature for the CPCCD, where the effects of the charge trapping are at a minimum, is found to be about 230 K for the range of readout speeds proposed for the ILC. The results of the full simulation have been compared with a simple analytic model.Comment: 3 pages, 6 figures; presented at IEEE'07, ALCPG'07, ICATPP'0

Characterisation of the key determinants of Phd antitoxin mediated Doc toxin inactivation in Salmonella

In the search for novel antimicrobial therapeutics, toxin-antitoxin (TA) modules are promising yet underexplored targets for overcoming antibiotic failure. The bacterial toxin Doc has been associated with the persistence of Salmonella in macrophages, enabling its survival upon antibiotic exposure. After developing a novel method to produce the recombinant toxin, we have used antitoxin-mimicking peptides to thoroughly investigate the mechanism by which its cognate antitoxin Phd neutralizes the activity of Doc. We reveal insights into the molecular detail of the Phd–Doc relationship and discriminate antitoxin residues that stabilize the TA complex from those essential for inhibiting the activity of the toxin. Coexpression of Doc and antitoxin peptides in Salmonella was able to counteract the activity of the toxin, confirming our in vitro results with equivalent sequences. Our findings provide key principles for the development of chemical tools to study and therapeutically interrogate this important class of protein–protein interactions

Climate warming, marine protected areas and the ocean-scale integrity of coral reef ecosystems

Coral reefs have emerged as one of the ecosystems most vulnerable to climate variation and change. While the contribution of a warming climate to the loss of live coral cover has been well documented across large spatial and temporal scales, the associated effects on fish have not. Here, we respond to recent and repeated calls to assess the importance of local management in conserving coral reefs in the context of global climate change. Such information is important, as coral reef fish assemblages are the most species dense vertebrate communities on earth, contributing critical ecosystem functions and providing crucial ecosystem services to human societies in tropical countries. Our assessment of the impacts of the 1998 mass bleaching event on coral cover, reef structural complexity, and reef associated fishes spans 7 countries, 66 sites and 26 degrees of latitude in the Indian Ocean. Using Bayesian meta-analysis we show that changes in the size structure, diversity and trophic composition of the reef fish community have followed coral declines. Although the ocean scale integrity of these coral reef ecosystems has been lost, it is positive to see the effects are spatially variable at multiple scales, with impacts and vulnerability affected by geography but not management regime. Existing no-take marine protected areas still support high biomass of fish, however they had no positive affect on the ecosystem response to large-scale disturbance. This suggests a need for future conservation and management efforts to identify and protect regional refugia, which should be integrated into existing management frameworks and combined with policies to improve system-wide resilience to climate variation and change

Global Diversity Hotspots and Conservation Priorities for Sharks

Sharks are one of the most threatened groups of marine animals, as high exploitation rates coupled with low resilience to fishing pressure have resulted in population declines worldwide. Designing conservation strategies for this group depends on basic knowledge of the geographic distribution and diversity of known species. So far, this information has been fragmented and incomplete. Here, we have synthesized the first global shark diversity pattern from a new database of published sources, including all 507 species described at present, and have identified hotspots of shark species richness, functional diversity and endemicity from these data. We have evaluated the congruence of these diversity measures and demonstrate their potential use in setting priority areas for shark conservation. Our results show that shark diversity across all species peaks on the continental shelves and at mid-latitudes (30–40 degrees N and S). Global hotspots of species richness, functional diversity and endemicity were found off Japan, Taiwan, the East and West coasts of Australia, Southeast Africa, Southeast Brazil and Southeast USA. Moreover, some areas with low to moderate species richness such as Southern Australia, Angola, North Chile and Western Continental Europe stood out as places of high functional diversity. Finally, species affected by shark finning showed different patterns of diversity, with peaks closer to the Equator and a more oceanic distribution overall. Our results show that the global pattern of shark diversity is uniquely different from land, and other well-studied marine taxa, and may provide guidance for spatial approaches to shark conservation. However, similar to terrestrial ecosystems, protected areas based on hotspots of diversity and endemism alone would provide insufficient means for safeguarding the diverse functional roles that sharks play in marine ecosystems

Predicting consumer biomass, size-structure, production, catch potential, responses to fishing and associated uncertainties in the world's marine ecosystems

Existing estimates of fish and consumer biomass in the world’s oceans are disparate. This creates uncertainty about the roles of fish and other consumers in biogeochemical cycles and ecosystem processes, the extent of human and environmental impacts and fishery potential. We develop and use a size-based macroecological model to assess the effects of parameter uncertainty on predicted consumer biomass, production and distribution. Resulting uncertainty is large (e.g. median global biomass 4.9 billion tonnes for consumers weighing 1 g to 1000 kg; 50% uncertainty intervals of 2 to 10.4 billion tonnes; 90% uncertainty intervals of 0.3 to 26.1 billion tonnes) and driven primarily by uncertainty in trophic transfer efficiency and its relationship with predator-prey body mass ratios. Even the upper uncertainty intervals for global predictions of consumer biomass demonstrate the remarkable scarcity of marine consumers, with less than one part in 30 million by volume of the global oceans comprising tissue of macroscopic animals. Thus the apparently high densities of marine life seen in surface and coastal waters and frequently visited abundance hotspots will likely give many in society a false impression of the abundance of marine animals. Unexploited baseline biomass predictions from the simple macroecological model were used to calibrate a more complex size- and trait-based model to estimate fisheries yield and impacts. Yields are highly dependent on baseline biomass and fisheries selectivity. Predicted global sustainable fisheries yield increases ≈4 fold when smaller individuals (< 20 cm from species of maximum mass < 1kg) are targeted in all oceans, but the predicted yields would rarely be accessible in practice and this fishing strategy leads to the collapse of larger species if fishing mortality rates on different size classes cannot be decoupled. Our analyses show that models with minimal parameter demands that are based on a few established ecological principles can support equitable analysis and comparison of diverse ecosystems. The analyses provide insights into the effects of parameter uncertainty on global biomass and production estimates, which have yet to be achieved with complex models, and will therefore help to highlight priorities for future research and data collection. However, the focus on simple model structures and global processes means that non-phytoplankton primary production and several groups, structures and processes of ecological and conservation interest are not represented. Consequently, our simple models become increasingly less useful than more complex alternatives when addressing questions about food web structure and function, biodiversity, resilience and human impacts at smaller scales and for areas closer to coasts

Operational experience, improvements, and performance of the CDF Run II silicon vertex detector

The Collider Detector at Fermilab (CDF) pursues a broad physics program at Fermilab's Tevatron collider. Between Run II commissioning in early 2001 and the end of operations in September 2011, the Tevatron delivered 12 fb-1 of integrated luminosity of p-pbar collisions at sqrt(s)=1.96 TeV. Many physics analyses undertaken by CDF require heavy flavor tagging with large charged particle tracking acceptance. To realize these goals, in 2001 CDF installed eight layers of silicon microstrip detectors around its interaction region. These detectors were designed for 2--5 years of operation, radiation doses up to 2 Mrad (0.02 Gy), and were expected to be replaced in 2004. The sensors were not replaced, and the Tevatron run was extended for several years beyond its design, exposing the sensors and electronics to much higher radiation doses than anticipated. In this paper we describe the operational challenges encountered over the past 10 years of running the CDF silicon detectors, the preventive measures undertaken, and the improvements made along the way to ensure their optimal performance for collecting high quality physics data. In addition, we describe the quantities and methods used to monitor radiation damage in the sensors for optimal performance and summarize the detector performance quantities important to CDF's physics program, including vertex resolution, heavy flavor tagging, and silicon vertex trigger performance.Comment: Preprint accepted for publication in Nuclear Instruments and Methods A (07/31/2013

An excess of niche differences maximizes ecosystem functioning

Ecologists have long argued that higher functioning in diverse communities arises from the niche differences stabilizing species coexistence and from the fitness differences driving competitive dominance. However, rigorous tests are lacking. We couple field-parameterized models of competition between 10 annual plant species with a biodiversity-functioning experiment under two contrasting environmental conditions, to study how coexistence determinants link to biodiversity effects (selection and complementarity). We find that complementarity effects positively correlate with niche differences and selection effects differences correlate with fitness differences. However, niche differences also contribute to selection effects and fitness differences to complementarity effects. Despite this complexity, communities with an excess of niche differences (where niche differences exceeded those needed for coexistence) produce more biomass and have faster decomposition rates under drought, but do not take up nutrients more rapidly. We provide empirical evidence that the mechanisms determining coexistence correlate with those maximizing ecosystem functioning. It is unclear how biodiversity-ecosystem functioning and species coexistence mechanisms are linked. Here, Godoy and colleagues combine field-parameterised competition models with a BEF experiment to show that mechanisms leading to more stable species coexistence lead to greater productivity, but not necessarily to enhanced functions other than primary production