Conflict within mutually beneficial associations is predicted to destabilize relationships, and theoretical and empirical work exploring this has provided significant insight into the dynamics of cooperative interactions. Within mutualistic associations, the expression and regulation of conflict is likely more complex than in intraspecific cooperative relationship, because of the potential presence of: i) multiple genotypes of microbial species associated with individual hosts, ii) multiple species of symbiotic lineages forming cooperative partner pairings, and iii) additional symbiont lineages. Here we explore complexity of conflict expression within the ancient and coevolved mutualistic association between attine ants, their fungal cultivar, and actinomycetous bacteria (Pseudonocardia). Specifically, we examine conflict between the ants and their Pseudonocardia symbionts maintained to derive antibiotics against parasitic microfungi (Escovopsis) infecting the ants' fungus garden. Symbiont assays pairing isolates of Pseudonocardia spp. associated with fungus-growing ants spanning the phylogenetic diversity of the mutualism revealed that antagonism between strains is common. In contrast, antagonism was substantially less common between more closely related bacteria associated with Acromyrmex leaf-cutting ants. In both experiments, the observed variation in antagonism across pairings was primarily due to the inhibitory capabilities and susceptibility of individual strains, but also the phylogenetic relationships between the ant host of the symbionts, as well as the pair-wise genetic distances between strains. The presence of antagonism throughout the phylogenetic diversity of Pseudonocardia symbionts indicates that these reactions likely have shaped the symbiosis from its origin. Antagonism is expected to prevent novel strains from invading colonies, enforcing single-strain rearing within individual ant colonies. While this may align ant-actinomycete interests in the bipartite association, the presence of single strains of Pseudonocardia within colonies may not be in the best interest of the ants, because increasing the diversity of bacteria, and thereby antibiotic diversity, would help the ant-fungus mutualism deal with the specialized parasites.

Summary Host–parasite associations are potentially shaped by evolutionary reciprocal selection dynamics, in which parasites evolve to overcome host defences and hosts are selected to counteract these through the evolution of new defences. This is expected to result in variation in parasite-defence interactions, and the evolution of resistant parasites causing increased virulence. Fungus-growing ants maintain antibiotic-producing Pseudonocardia (Actinobacteria) that aid in protection against specialized parasites of the ants’ fungal gardens, and current evidence indicates that both symbionts have been associated with the ants for millions of years. Here we examine the extent of variation in the defensive capabilities of the ant–actinobacterial association against Escovopsis (parasite-defence interactions), and evaluate how variation impacts colonies of fungus-growing ants. We focus on five species of Acromyrmex leaf-cutting ants, crossing 12 strains of Pseudonocardia with 12 strains of Escovopsis in a Petri plate bioassay experiment, and subsequently conduct subcolony infection experiments using resistant and non-resistant parasite strains. Diversity in parasite-defence interactions, including pairings where the parasites are resistant, suggests that chemical variation in the antibiotics produced by different actinobacterial strains are responsible for the observed variation in parasite susceptibility. By evaluating the role this variation plays during infection, we show that infection of ant subcolonies with resistant parasite strains results in significantly higher parasite-induced morbidity with respect to garden biomass loss. Our findings thus further establish the role of Pseudonocardia-derived antibiotics in helping defend the ants’ fungus garden from the parasite Escovopsis, and provide evidence that small molecules can play important roles as antibiotics in a natural system.

Lavine JA, Kibbe CR, Baan M, Sirinvaravong S, Umhoefer HM, Engler KA, Meske LM, Sacotte KA, Erhardt DP, Davis DB. Cholecystokinin expression in the ␤-cell leads to increased ␤-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis. Am J Physiol Endocrinol Metab 309: E819 -E828, 2015. First published September 22, 2015; doi:10.1152/ajpendo.00159.2015.-Cholecystokinin (CCK) is a peptide hormone produced in the gut and brain with beneficial effects on digestion, satiety, and insulin secretion. CCK is also expressed in pancreatic ␤-cells, but only in models of obesity and insulin resistance. Whole body deletion of CCK in obese mice leads to reduced ␤-cell mass expansion and increased apoptosis. We hypothesized that islet-derived CCK is important in protection from ␤-cell apoptosis. To determine the specific role of ␤-cell-derived CCK in ␤-cell mass dynamics, we generated a transgenic mouse that expresses CCK in the ␤-cell in the lean state (MIP-CCK). Although this transgene contains the human growth hormone minigene, we saw no expression of human growth hormone protein in transgenic islets. We examined the ability of MIP-CCK mice to maintain ␤-cell mass when subjected to apoptotic stress, with advanced age, and after streptozotocin treatment. Aged MIP-CCK mice have increased ␤-cell area. MIP-CCK mice are resistant to streptozotocin-induced diabetes and exhibit reduced ␤-cell apoptosis. Directed CCK overexpression in cultured ␤-cells also protects from cytokineinduced apoptosis. We have identified an important new paracrine/ autocrine effect of CCK in protection of ␤-cells from apoptotic stress. Understanding the role of ␤-cell CCK adds to the emerging knowledge of classic gut peptides in intraislet signaling. CCK receptor agonists are being investigated as therapeutics for obesity and diabetes. While these agonists clearly have beneficial effects on body weight and insulin sensitivity in peripheral tissues, they may also directly protect ␤-cells from apoptosis.cholecystokinin; islet; ␤-cell; apoptosis; aging; streptozotocin TYPE 1 AND TYPE 2 DIABETES MELLITUS are both diseases of reduced ␤-cell mass. In type 1 diabetes, autoimmune destruction of ␤-cells results in an absolute ␤-cell mass deficit. In type 2 diabetes, obesity increases insulin resistance, resulting in a relative insulin deficiency. In patients with type 2 diabetes, ␤-cell mass is lost via increased ␤-cell apoptosis (7, 16). Therefore, there has been wide interest in the development of diabetes therapeutics that preserve ␤-cell mass and prevent ␤-cell apoptosis.Cholecystokinin (CCK) is a gastrointestinal peptide produced by duodenal I cells and secreted in response to fat and protein (31). CCK signals through two G protein-coupled receptors, the CCK1(A) receptor [CCK1(A)R] and the CCK2(B) receptor [CCK2(B)R]. In healthy and diabetic patients, CCK infusion increases insulin secretion and decreases glucose excursion after a meal, suggesting that CCK is a potential diabetes therapeutic (1, 2). CCK also increases satiety by ...

Differences in persistence and adherence between the MTX-TNFi and triple therapy groups appear to be primarily related to ADE that were most often attributed to SSZ. This article is protected by copyright. All rights reserved.