Hypomethylating Agent-Based Combination Therapies to Treat Post-Hematopoietic Stem Cell Transplant Relapse of Acute Myeloid Leukemia

Allogeneic stem cell transplantation still represents the best curative option for most patients with acute myeloid leukemia, but relapse is still dramatically high. Due to their immunologic activity and safety profile, hypomethylating agents (HMAs) represent an interesting backbone for combination therapies. This review reports mechanism of action, safety, and efficacy data on combination strategies based on HMAs in the setting of post-allogeneic stem cell transplant relapse. Several studies highlighted how HMAs and donor lymphocyte infusion (DLI) combination may be advantageous. The combination strategy of HMA with venetoclax, possibly in association with DLI, is showing excellent results in terms of response rate, including molecular responses. Lenalidomide, despite its well-known high rates of severe graft-versus-host disease in post-transplant settings, is showing an acceptable safety profile in association with HMAs with a competitive response rate. Regarding FLT3 internal tandem duplication (ITD) mutant AML, tyrosine kinase inhibitors and particularly sorafenib have promising results as monotherapy and in combination with HMAs. Conversely, combination strategies with gemtuzumab ozogamicin or immune checkpoint inhibitors did not show competitive response rates and seem to be currently less attractive strategies. Associations with histone deacetylase inhibitors and isocitrate dehydrogenase 1 and 2 (IDH1/2) inhibitors represent new possible strategies that need to be better investigated.

The Genomic Architecture of Competitive Response of Arabidopsis thaliana Is Highly Flexible Among Plurispecific Neighborhoods

Plants are daily challenged by multiple abiotic and biotic stresses. A major biotic constraint corresponds to competition with other plant species. Although plants simultaneously interact with multiple neighboring species throughout their life cycle, there is still very limited information about the genetics of the competitive response in the context of plurispecific interactions. Using a local mapping population of Arabidopsis thaliana, we set up a genome wide association study (GWAS) to estimate the extent of genetic variation of competitive response in 12 plant species assemblages, based on three competitor species (Poa annua, Stellaria media, and Veronica arvensis). Based on five phenotypic traits, we detected strong crossing reaction norms not only between the three bispecific neighborhoods but also among the plurispecific neighborhoods. The genetic architecture of competitive response was highly dependent on the identity and the relative abundance of the neighboring species. In addition, most of the enriched biological processes underlying competitive responses largely differ among neighborhoods. While the RNA related processes might confer a broad range response toolkit for multiple traits in diverse neighborhoods, some processes, such as signaling and transport, might play a specific role in particular assemblages. Altogether, our results suggest that plants can integrate and respond to different species assemblages depending on the identity and number of each neighboring species, through a large range of candidate genes associated with diverse and unexpected processes leading to developmental and stress responses.

Combining Genetic Gain and Diversity in Plant Breeding: Heritability of Root Selection in Wheat Populations

To increase the resilience of agroecological farming systems against weeds, pests, and pathogens, evolutionary breeding of diversified crop populations is highly promising. A fundamental challenge in population breeding is to combine effective selection and breeding progress while maintaining intraspecific diversity. A hydroponic system was tested for its suitability to non-destructively select root traits on a population level in order to achieve genetic gain and maintain diversity. Forty wheat progenies were selected for long seminal root length (SRL) and 40 for short SRL from a wheat composite cross population grown in a hydroponic system. Wheat progenies were multiplied, and a subset evaluated again in a hydroponic system. Preliminary tests in soil and competition experiments with a model weed were performed. The hydroponic selection for long SRL led to an increase of SRL by 1.6 cm (11.6%) in a single generation. Heritability for selection of SRL was 0.59. Selecting for short SRL had no effect. The preliminary soil-based test confirmed increased shoot length but not increased SRL. Preliminary competition experiments point to slightly improved competitive response of wheat progenies but no improved competitive effect on mustard. These results indicate a heritable selection effect for SRL on a population level, combining genetic gain and intraspecific diversity.

Delving into defence: identifying the Pseudomonas protegens Pf-5 gene suite involved in defence against secreted products of fungal, oomycete and bacterial rhizosphere competitors

Competitive behaviours of plant growth promoting rhizobacteria (PGPR) are integral to their ability to colonize and persist on plant roots and outcompete phytopathogenic fungi, oomycetes and bacteria. PGPR engage in a range of antagonistic behaviours that have been studied in detail, such as the production and secretion of compounds inhibitory to other microbes. In contrast, their defensive activities that enable them to tolerate exposure to inhibitory compounds produced by their neighbours are less well understood. In this study, the genes involved in the Pseudomonas protegens Pf-5 response to metabolites from eight diverse rhizosphere competitor organisms, Fusarium oxysporum, Rhizoctonia solani, Gaeumannomyces graminis var. tritici, Pythium spinosum, Bacillus subtilis QST713, Pseudomonas sp. Q2-87, Streptomyces griseus and Streptomyces bikiniensis subspecies bikiniensi, were examined. Proximity induced excreted metabolite responses were confirmed for Pf-5 with all partner organisms through HPLC before culturing a dense Pf-5 transposon mutant library adjacent to each of these microbes. This was followed by transposon-directed insertion site sequencing (TraDIS), which identified genes that influence Pf-5 fitness during these competitive interactions. A set of 148 genes was identified that were associated with increased fitness during competition, including cell surface modification, electron transport, nucleotide metabolism, as well as regulatory genes. In addition, 51 genes were identified for which loss of function resulted in fitness gains during competition. These included genes involved in flagella biosynthesis and cell division. Considerable overlap was observed in the set of genes observed to provide a fitness benefit during competition with all eight test organisms, indicating commonalities in the competitive response to phylogenetically diverse micro-organisms and providing new insight into competitive processes likely to take place in the rhizosphere.

The effect of interference time in a predator–prey–nonprey system

In this paper, we propose a three-species model consisting of two competing (prey and nonprey) species and a predator species. Here, nonprey species are not included in the predator’s food choice. The competition process follows Holling type II competitive response to interference time. Basic results include the stability of the system. First, it is established that an increasing number of interference time stabilizes the system. Second, it is shown that the interference time has an impact on the predator equilibrium density. Third, we develop the criterion of persistence of all the species. It is also shown that the system may not be persistent when multiple steady states appear. We examine the global stability of the coexistence equilibrium point. Numerical experiments are carried out to understand the analytical outcomes.

Seasonality of Food Use and Caching in New Zealand Robins (Petroica Australis)

<p>Foraging behaviour in birds is strongly determined by temporal factors such as season and time of day. Most birds show a limited number of food use methods such as consuming, feeding to conspecifics, or discarding. A relatively small number of birds also cache food for later use. The expression of caching in birds has been attributed to numerous factors. However, noting the environmental instability experienced by most caching species, researchers tend to cite survival of future food scarcity as the predominant advantage. Recording the food use behaviour of wild birds is typically difficult and time consuming, and many studies of north-temperate food-caching birds are limited by long caching distances, protracted caching durations, and a lack of year-round data. Additionally, food-caching in Australasian passerines has received limited quantification. The naïveté of the New Zealand robin (Petroica australis) makes it ideal for behavioural observations in the wild. Robins express a wide range of food use behaviours within close proximity of observers, and cached food is retrieved within a few days. Food use can be observed year-round in a temperate environment that is relatively stable. Thus, food use decisions in robins can be assessed in a wider context. In this study, behavioural data were collected from robins inhabiting the Karori Wildlife Sanctuary in Wellington. Robin behaviour was quantified by presenting monogamous, paired birds an ephemeral food resource and observing their responses. Seasonal variation in food use differed with sex and season. Birds mediated their food use in response to the presence of conspecifics. Males dominated food use year-round. During the breeding season, males cached little, mostly feeding familial conspecifics. However, non-breeding males selfishly cached food. Conversely, female caching propensity was mediated by courtship feeding during the breeding season, and the threat of male pilferage outside of it. Birds did not appear to anticipate future food scarcity. Instead, food was cached in the season in which retrieval would be least necessary. In robins, food is opportunistically cached, mainly as a competitive response to excess food.</p>

Seasonality of Food Use and Caching in New Zealand Robins (Petroica Australis)

<p>Foraging behaviour in birds is strongly determined by temporal factors such as season and time of day. Most birds show a limited number of food use methods such as consuming, feeding to conspecifics, or discarding. A relatively small number of birds also cache food for later use. The expression of caching in birds has been attributed to numerous factors. However, noting the environmental instability experienced by most caching species, researchers tend to cite survival of future food scarcity as the predominant advantage. Recording the food use behaviour of wild birds is typically difficult and time consuming, and many studies of north-temperate food-caching birds are limited by long caching distances, protracted caching durations, and a lack of year-round data. Additionally, food-caching in Australasian passerines has received limited quantification. The naïveté of the New Zealand robin (Petroica australis) makes it ideal for behavioural observations in the wild. Robins express a wide range of food use behaviours within close proximity of observers, and cached food is retrieved within a few days. Food use can be observed year-round in a temperate environment that is relatively stable. Thus, food use decisions in robins can be assessed in a wider context. In this study, behavioural data were collected from robins inhabiting the Karori Wildlife Sanctuary in Wellington. Robin behaviour was quantified by presenting monogamous, paired birds an ephemeral food resource and observing their responses. Seasonal variation in food use differed with sex and season. Birds mediated their food use in response to the presence of conspecifics. Males dominated food use year-round. During the breeding season, males cached little, mostly feeding familial conspecifics. However, non-breeding males selfishly cached food. Conversely, female caching propensity was mediated by courtship feeding during the breeding season, and the threat of male pilferage outside of it. Birds did not appear to anticipate future food scarcity. Instead, food was cached in the season in which retrieval would be least necessary. In robins, food is opportunistically cached, mainly as a competitive response to excess food.</p>

Fitness Cost Associated With Enhanced EPSPS Gene Copy Number and Glyphosate Resistance in an Amaranthus tuberculatus Population

The evolution of resistance to pesticides in agricultural systems provides an opportunity to study the fitness costs and benefits of novel adaptive traits. Here, we studied a population of Amaranthus tuberculatus (common waterhemp), which has evolved resistance to glyphosate. The growth and fitness of seed families with contrasting levels of glyphosate resistance was assessed in the absence of glyphosate to determine their ability to compete for resources under intra- and interspecific competition. We identified a positive correlation between the level of glyphosate resistance and gene copy number for the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) glyphosate target, thus identifying gene amplification as the mechanism of resistance within the population. Resistant A. tuberculatus plants were found to have a lower competitive response when compared to the susceptible phenotypes with 2.76 glyphosate resistant plants being required to have an equal competitive effect as a single susceptible plant. A growth trade-off was associated with the gene amplification mechanism under intra-phenotypic competition where 20 extra gene copies were associated with a 26.5 % reduction in dry biomass. Interestingly, this growth trade-off was mitigated when assessed under interspecific competition from maize.

Competitive ability of native and alien plants: effects of residence time and invasion status

Competition is commonly thought to underlie the impact of plant invasions. However, competitive effects of aliens and competitive response of natives may also change over time. Indeed, as with time, the novelty of an invader decreases, the accumulated eco-evolutionary experience of resident species may eventually limit invasion success. We aimed to gain insights on whether directional changes in biotic interactions over time or more general differences between natives and aliens, for instance, resulting from an introduction bias, are relevant in determining competitive ability. We conducted a pairwise competition experiment in a target-neighbour design, using 47 Asteraceae species with residence times between 8 years-12,000 years in Germany. We first tested whether there are differences in performance in intraspecific competition amongst invasion status groups, that is casual and established neophytes, archaeophytes or native species. We then evaluated whether competitive response and effects depend on residence time or invasion status. Lastly, we assessed whether competitive effects influence range sizes. We found only limited evidence that native target species tolerate neighbours with longer potential co-existence times better, whereas differences in competitive ability were mostly better explained by invasion status than residence time. Although casual neophytes produced most biomass in intraspecific competition, they had the weakest per-capita competitive effects on natives. Notably, we did not find differences between established neophytes and natives, both of which ranked highest in interspecific competitive ability. This lack of differences might be explained by a biased selection of highly invasive or rare native species in previous studies or because invasion success may result from mechanisms other than interspecific competitive superiority. Accordingly, interspecific per-capita competitive effects did not influence range sizes. Further studies across a broader range of environmental conditions, involving other biotic interactions that indirectly influence plant-plant interactions, may clarify when eco-evolutionary adaptations to new invaders are a relevant mechanism.