Transgenic expression of IL15 improves antiglioma activity of IL13Rα2-CAR T cells but results in antigen loss variants

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CAR) is an attractive approach to improve outcomes. Although CAR T cells targetingGBMantigens, such as IL13 receptor subunit α2 (IL13Rα2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity. Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function. We tested this approach in our IL13Rα2-positive glioma model in which limited IL13Rα2-CAR T-cell persistence results in recurrence of antigenpositive gliomas. T cells were genetically modified with retroviral vectors encoding IL13Rα2-CARs or IL15 (IL13Rα2-CAR.IL15 T cells). IL13Rα2-CAR.IL15 T cells recognized glioma cells in an antigen-dependent fashion, had greater proliferative capacity, and produced more cytokines after repeated stimulations in comparison with IL13Rα2-CAR T cells. No autonomous IL13Rα2-CAR. IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Rα2-CAR T-cell viability in the absence of exogenous cytokines or antigen. In vivo, IL13Rα2-CAR.IL15 T cells persisted longer and had greater antiglioma activity than IL13Rα2-CAR T cells, resulting in a survival advantage. Gliomas recurring after 40 days after T-cell injection had downregulated IL13Rα2 expression, indicating that antigen loss variants occur in the setting of improved T-cell persistence. Thus, CAR T cells for GBM should not only be genetically modified to improve their proliferation and persistence, but also to target multiple antigens. Summary: Glioblastoma responds imperfectly to immunotherapy. Transgenic expression of IL15 in T cells expressing CARs improved their proliferative capacity, persistence, and cytokine production. The emergence of antigen loss variants highlights the need to target multiple tumor antigens. Cancer Immunol Res; 5(7); 571-81

Large body size constrains dispersal assembly of communities even across short distances

International audienc

Consistent phenological shifts in the making of a biodiversity hotspot: the Cape flora

Background The best documented survival responses of organisms to past climate change on short (glacial-interglacial) timescales are distributional shifts. Despite ample evidence on such timescales for local adaptations of populations at specific sites, the long-term impacts of such changes on evolutionary significant units in response to past climatic change have been little documented. Here we use phylogenies to reconstruct changes in distribution and flowering ecology of the Cape flora - South Africa's biodiversity hotspot - through a period of past (Neogene and Quaternary) changes in the seasonality of rainfall over a timescale of several million years. Results Forty-three distributional and phenological shifts consistent with past climatic change occur across the flora, and a comparable number of clades underwent adaptive changes in their flowering phenology (9 clades; half of the clades investigated) as underwent distributional shifts (12 clades; two thirds of the clades investigated). Of extant Cape angiosperm species, 14-41% have been contributed by lineages that show distributional shifts consistent with past climate change, yet a similar proportion (14-55%) arose from lineages that shifted flowering phenology. Conclusions Adaptive changes in ecology at the scale we uncover in the Cape and consistent with past climatic change have not been documented for other floras. Shifts in climate tolerance appear to have been more important in this flora than is currently appreciated, and lineages that underwent such shifts went on to contribute a high proportion of the flora's extant species diversity. That shifts in phenology, on an evolutionary timescale and on such a scale, have not yet been detected for other floras is likely a result of the method used; shifts in flowering phenology cannot be detected in the fossil record

Insect herbivores should follow plants escaping their relatives

Neighboring plants within a local community may be separated by many millions of years of evolutionary history, potentially reducing enemy pressure by insect herbivores. However, it is not known how the evolutionary isolation of a plant affects the fitness of an insect herbivore living on such a plant, especially the herbivore's enemy pressure. Here, we suggest that evolutionary isolation of host plants may operate similarly as spatial isolation and reduce the enemy pressure per insect herbivore. We investigated the effect of the phylogenetic isolation of host trees on the pressure exerted by specialist and generalist enemies (parasitoids and birds) on ectophagous Lepidoptera and galling Hymenoptera. We found that the phylogenetic isolation of host trees decreases pressure by specialist enemies on these insect herbivores. In Lepidoptera, decreasing enemy pressure resulted from the density dependence of enemy attack, a mechanism often observed in herbivores. In contrast, in galling Hymenoptera, enemy pressure declined with the phylogenetic isolation of host trees per se, as well as with the parallel decline in leaf damage by non-galling insects. Our results suggest that plants that leave their phylogenetic ancestral neighborhood can trigger, partly through simple density-dependency, an enemy release and fitness increase of the few insect herbivores that succeed in tracking these plants

The use of phylogeny to interpret cross-cultural patterns in plant use and guide medicinal plant discovery: an example from Pterocarpus (Leguminosae)

The study of traditional knowledge of medicinal plants has led to discoveries that have helped combat diseases and improve healthcare. However, the development of quantitative measures that can assist our quest for new medicinal plants has not greatly advanced in recent years. Phylogenetic tools have entered many scientific fields in the last two decades to provide explanatory power, but have been overlooked in ethnomedicinal studies. Several studies show that medicinal properties are not randomly distributed in plant phylogenies, suggesting that phylogeny shapes ethnobotanical use. Nevertheless, empirical studies that explicitly combine ethnobotanical and phylogenetic information are scarce.In this study, we borrowed tools from community ecology phylogenetics to quantify significance of phylogenetic signal in medicinal properties in plants and identify nodes on phylogenies with high bioscreening potential. To do this, we produced an ethnomedicinal review from extensive literature research and a multi-locus phylogenetic hypothesis for the pantropical genus Pterocarpus (Leguminosae: Papilionoideae). We demonstrate that species used to treat a certain conditions, such as malaria, are significantly phylogenetically clumped and we highlight nodes in the phylogeny that are significantly overabundant in species used to treat certain conditions. These cross-cultural patterns in ethnomedicinal usage in Pterocarpus are interpreted in the light of phylogenetic relationships.This study provides techniques that enable the application of phylogenies in bioscreening, but also sheds light on the processes that shape cross-cultural ethnomedicinal patterns. This community phylogenetic approach demonstrates that similar ethnobotanical uses can arise in parallel in different areas where related plants are available. With a vast amount of ethnomedicinal and phylogenetic information available, we predict that this field, after further refinement of the techniques, will expand into similar research areas, such as pest management or the search for bioactive plant-based compounds

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Trends and Regional Differences in Breastfeeding in Germany From 1871 To 1937

This article describes trends and regional differences in breastfeeding within Germany from 1870 to 1937. Sharp regional differences in both the in cidence and duration of breastfeeding are present around 1910. There is a com plex pattern of trends in infant-feeding practices. Breastfeeding declined in urban areas between the late nineteenth century and the first World War. A strong nationwide resurgence in the incidence of breastfeeding occurred between the two world wars, accompanied by a decline in the average duration of breastfeeding. By 1937, the formerly great regional differences in breastfeeding had nearly dis appeared. The article also discusses social, economic, cultural, and historical variables affecting infant-feeding practices, including local breastfeeding customs, a national infant welfare campaign, and allowances to nursing mothers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67272/2/10.1177_036319908501000203.pd

Evolution of Fruit Traits in Ficus Subgenus Sycomorus (Moraceae): To What Extent Do Frugivores Determine Seed Dispersal Mode?

Fig trees are a ubiquitous component of tropical rain forests and exhibit an enormous diversity of ecologies. Focusing on Ficus subgenus Sycomorus, a phenotypically diverse and ecologically important Old World lineage, we examined the evolution of fruit traits using a molecular phylogeny constructed using 5 kilobases of DNA sequence data from 63 species (50% of global diversity). In particular, we ask whether patterns of trait correlations are consistent with dispersal agents as the primary selective force shaping morphological diversity or if other ecological factors may provide a better explanation? Fig colour, size and placement (axial, cauliflorous, or geocarpic) were all highly evolutionarily liable, and the same fruit traits have evolved in different biogeographic regions with substantially different dispersal agents. After controlling for phylogenetic autocorrelation, we found that fig colour and size were significantly associated with fig placement and plant-life history traits (maximum plant height and leaf area, respectively). However, contrary to prevailing assumptions, fig placement correlated poorly with known dispersal agents and appears more likely determined by other factors, such as flowering phenology, nutrient economy, and habitat preference. Thus, plant life-history, both directly and through its influence on fig placement, appears to have played a prominent role in determining fruit traits in these figs

Density and community structure of soil- and bark-dwelling microarthropods along an altitudinal gradient in a tropical montane rainforest

Microarthropod communities in the soil and on the bark of trees were investigated along an elevation gradient (1,850, 2,000, 2,150, 2,300 m) in a tropical montane rain forest in southern Ecuador. We hypothesised that the density of microarthropods declines with depth in soil and increases with increasing altitude mainly due to the availability of resources, i.e. organic matter. In addition, we expected bark and soil communities to differ strongly, since the bark of trees is more exposed to harsher factors. In contrast to our hypothesis, the density of major microarthropod groups (Collembola, Oribatida, Gamasina, Uropodina) was generally low and decreased with altitude. However, as we predicted the density of each of the groups decreased with soil depth. Density of microarthropods on tree bark was lower than in soil. Overall, 43 species of oribatid mites were found, with the most abundant higher taxa being Poronota, pycnonotic Apheredermata, Mixonomata and Eupheredermata. The oribatid mite community on bark did not differ significantly from that in soil. The number of oribatid mite species declined with altitude (24, 23, 17 and 13 species at 1,850, 2,000, 2,150 and 2,300 m, respectively). Rarefaction curves indicate that overall about 50 oribatid mite species are to be expected along the studied altitudinal gradient. Results of this study indicate (1) that microarthropods may be limited by the quality of resources at high altitudes and by the amount of resources at deeper soil layers, and (2) that the bark of trees and the soil are habitats of similar quality for oribatid mites

Oribatid communities and heavy metal bioaccumulation in selected species associated with lichens in a heavily contaminated habitat

The study examines oribatid communities and heavy metal bioaccumulation in selected species associated with different microhabitats of a post-smelting dump, i.e. three lichen species of Cladonia with various growth forms and the slag substrate. The abundance of oribatids collected from the substrate was significantly lower than observed in lichen thalli. The morphology and chemical properties of lichens, and to some extent varying concentrations of heavy metals in thalli, are probably responsible for significant differences in oribatid communities inhabiting different Cladonia species. Some oribatids demonstrate the ability to accumulate zinc and cadmium with unusual efficiency, whereas lead is the most effectively regulated element by all species. A positive correlation was found between Zn content in all studied oribatids and their microhabitats. Oribatids exploring different food resources, i.e. fungivorous and non-fungivorous grazers, show considerable differences in bioconcentrations of certain elements