Bi-specific TCR-anti CD3 redirected T-cell targeting of NY-ESO-1- and LAGE-1-positive tumors

NY-ESO-1 and LAGE-1 are cancer testis antigens with an ideal profile for tumor immunotherapy, combining up-regulation in many cancer types with highly restricted expression in normal tissues and sharing a common HLA-A*0201 epitope, 157–165. Here, we present data to describe the specificity and anti-tumor activity of a bifunctional ImmTAC, comprising a soluble, high-affinity T-cell receptor (TCR) specific for NY-ESO-1_157–165 fused to an anti-CD3 scFv. This reagent, ImmTAC-NYE, is shown to kill HLA-A2, antigen-positive tumor cell lines, and freshly isolated HLA-A2- and LAGE-1-positive NSCLC cells. Employing time-domain optical imaging, we demonstrate in vivo targeting of fluorescently labelled high-affinity NYESO-specific TCRs to HLA-A2-, NY-ESO-1_157–165-positive tumors in xenografted mice. In vivo ImmTAC-NYE efficacy was tested in a tumor model in which human lymphocytes were stably co-engrafted into NSG mice harboring tumor xenografts; efficacy was observed in both tumor prevention and established tumor models using a GFP fluorescence readout. Quantitative RT-PCR was used to analyze the expression of both NY-ESO-1 and LAGE-1 antigens in 15 normal tissues, 5 cancer cell lines, 10 NSCLC, and 10 ovarian cancer samples. Overall, LAGE-1 RNA was expressed at a greater frequency and at higher levels than NY-ESO-1 in the tumor samples. These data support the clinical utility of ImmTAC-NYE as an immunotherapeutic agent for a variety of cancers.     

How are nitrogen availability,fine‐root mass,and nitrogen uptake related empirically? Implications for models and theory

Understanding the effects of global change in terrestrial communities requires an understanding of how limiting resources interact with plant traits to affect productivity. Here, we focus on nitrogen and ask whether plant community nitrogen uptake rate is determined (a) by nitrogen availability alone or (b) by the product of nitrogen availability and fine‐root mass. Surprisingly, this is not empirically resolved. We performed controlled microcosm experiments and reanalyzed published pot experiments and field data to determine the relationship between community‐level nitrogen uptake rate, nitrogen availability, and fine‐root mass for 46 unique combinations of species, nitrogen levels, and growing conditions. We found that plant community nitrogen uptake rate was unaffected by fine‐root mass in 63% of cases and saturated with fine‐root mass in 29% of cases (92% in total). In contrast, plant community nitrogen uptake rate was clearly affected by nitrogen availability. The results support the idea that although plants may over‐proliferate fine roots for individual‐level competition, it comes without an increase in community‐level nitrogen uptake. The results have implications for the mechanisms included in coupled carbon‐nitrogen terrestrial biosphere models (CN‐TBMs) and are consistent with CN‐TBMs that operate above the individual scale and omit fine‐root mass in equations of nitrogen uptake rate but inconsistent with the majority of CN‐TBMs, which operate above the individual scale and include fine‐root mass in equations of nitrogen uptake rate. For the much smaller number of CN‐TBMs that explicitly model individual‐based belowground competition for nitrogen, the results suggest that the relative (not absolute) fine‐root mass of competing individuals should be included in the equations that determine individual‐level nitrogen uptake rates. By providing empirical data to support the assumptions used in CN‐TBMs, we put their global climate change predictions on firmer ground.     

Adapting Stand‐Alone Renewable Energy Technologies for the Circular Economy through Eco‐Design and Recycling

Renewable energy (RE) technologies are looked upon favorably to provide for future energy demands and reduce greenhouse gas (GHG) emissions. However, the installation of these technologies requires large quantities of finite material resources. We apply life cycle assessment to 100 years of electricity generation from three stand‐alone RE technologies—solar photovoltaics, run‐of‐river hydro, and wind—to evaluate environmental burden profiles against baseline electricity generation from fossil fuels. We then devised scenarios to incorporate circular economy (CE) improvements targeting hotspots in systems’ life cycle, specifically (1) improved recycling rates for raw materials and (ii) the application of eco‐design. Hydro presented the lowest environmental burdens per kilowatt‐hour of electricity generation compared with other RE technologies, owing to its higher efficiency and longer life spans for main components. Distinct results were observed in the environmental performance of each system based on the consideration of improved recycling rates and eco‐design. CE measures produced similar modest savings in already low GHG emissions burdens for each technology, while eco‐design specifically had the potential to provide significant savings in abiotic resource depletion. Further research to explore the full potential of CE measures for RE technologies will curtail the resource intensity of RE technologies required to mitigate climate change.     

Global patterns in fine root decomposition: climate,chemistry, mycorrhizal association and woodiness

Fine root decomposition constitutes a critical yet poorly understood flux of carbon and nutrients in terrestrial ecosystems. Here, we present the first large‐scale synthesis of species trait effects on the early stages of fine root decomposition at both global and local scales. Based on decomposition rates for 279 plant species across 105 studies and 176 sites, we found that mycorrhizal association and woodiness are the best categorical traits for predicting rates of fine root decomposition. Consistent positive effects of nitrogen and phosphorus concentrations and negative effects of lignin concentration emerged on decomposition rates within sites. Similar relationships were present across sites, along with positive effects of temperature and moisture. Calcium was not consistently related to decomposition rate at either scale. While the chemical drivers of fine root decomposition parallel those of leaf decomposition, our results indicate that the best plant functional groups for predicting fine root decomposition differ from those predicting leaf decomposition.     

Multi-patch deterministic and stochastic models for wildlife diseases

Spatial heterogeneity and host demography have a direct impact on the persistence or extinction of a disease. Natural or human-made landscape features such as forests, rivers, roads, and crops are important to the persistence of wildlife diseases. Rabies, hantaviruses, and plague are just a few examples of wildlife diseases where spatial patterns of infection have been observed. We formulate multi-patch deterministic and stochastic epidemic models and use these models to investigate problems related to disease persistence and extinction. We show in some special cases that a unique disease-free equilibrium exists. In these cases, a basic reproduction number ?(0) can be computed and shown to be bounded below and above by the minimum and maximum patch reproduction numbers ?(j), j=1, …, n. The basic reproduction number has a simple form when there is no movement or when all patches are identical or when the movement rate approaches infinity. Numerical examples of the deterministic and stochastic models illustrate the disease dynamics for different movement rates between three patches.     

Soil biota,carbon cycling and crop plant biomass responses to biochar in a temperate mesocosm experiment

Plant and Soil - Shifts of plant community composition with enhanced atmospheric nitrogen (N) deposition in grasslands have occurred globally. Despite extensive studies on the effects of enhanced N...     

CURRICULUM GUIDE FOR RESEARCH ETHICS WORKSHOPS FOR COUNTRIES IN THE MIDDLE EAST

To help ensure the ethical conduct of research, many have recommended educational efforts in research ethics to investigators and members of research ethics committees (RECs). One type of education activity involves multi‐day workshops in research ethics. To be effective, such workshops should contain the appropriate content and teaching techniques geared towards the learning styles of the targeted audiences. To ensure consistency in content and quality, we describe the development of a curriculum guide, core competencies and associated learning objectives and activities to help educators organize research ethics workshops in their respective institutions. The curriculum guide is divided into modular units to enable planners to develop workshops of different lengths and choose content materials that match the needs, abilities, and prior experiences of the target audiences. The content material in the curriculum guide is relevant for audiences in the Middle East, because individuals from the Middle East who participated in a Certificate Program in research ethics selected and developed the training materials (e.g., articles, powerpoint slides, case studies, protocols). Also, many of the activities incorporate active‐learning methods, consisting of group work activities analyzing case studies and reviewing protocols. The development of such a workshop training curriculum guide represents a sustainable educational resource to enhance research ethics capacity in the Middle East.     

Relative contribution of hemopoietic and pulmonary parenchymal cells to lung inducible nitric oxide synthase (inos) activity in murine endotoxemia

Acute lung injury is an important feature of sepsis and increased iNOS expression and NO production contribute to the pathogenesis of this syndrome. We generated bone marrow-transplanted chimeric mice with iNOS expression limited to either inflammatory or pulmonary parenchymal cells, and assessed pulmonary iNOS activity and systemic levels of NO metabolites in an endotoxemic model of sepsis. We found that while both pulmonary parenchymal cells and inflammatory cells contribute to the increased lung iNOS activity in endotoxemia, pulmonary parenchymal cells contribute to a significantly greater degree. Using measurement of plasma NO(-)(x), whole body NO production was assessed in this model. We found that the main source of NO(-)(x) was again, parenchymal cells and not inflammatory cells. This is the first study to demonstrate that most of the increased NO production in this model of endotoxemic sepsis derives from parenchymal cells rather than inflammatory cells.