SignificanceAll animals have associated microbial communities called microbiomes that influence the physiology and fitness of their host. It is unclear to what extent individual microbial species versus interactions between them influence the host. Here, we mapped all possible interactions between individual species of bacteria against Drosophila melanogaster fruit fly fitness traits. Our approach revealed that the same bacterial interactions that shape microbiome abundances also shape host fitness traits. The fitness traits of lifespan and fecundity showed a life history tradeoff, where equal total fitness can be gotten by either high fecundity over a short life or low fecundity over a long life. The microbiome interactions are as important as the individual species in shaping these fundamental aspects of fly physiology.

SUMMARY Species compositions of gut microbiomes impact host health [1–3], but the processes determining these compositions are largely unknown. An unexplained observation is that gut species composition varies widely between individuals but is largely stable over time within individuals [4, 5]. Stochastic factors during establishment may drive these alternative stable states (colonized versus non-colonized) [6, 7], which can influence susceptibility to pathogens such as Clostridium difficile. Here we sought to quantify and model the dose-response, dynamics, and stability of bacterial colonization in the fruit fly (Drosophila melanogaster) gut. Our precise, high-throughput technique revealed stable between-host variation in colonization when individual germ-free flies were fed their own natural commensals (including the probiotic Lactobacillus plantarum). Some flies were colonized while others remained germ-free even at extremely high bacterial doses. Thus, alternative stable states of colonization exist even in this low complexity model of host-microbe interactions. These alternative states are driven by a fundamental asymmetry between the inoculum population and the stably colonized population that is mediated by spatial localization and a population bottleneck, which makes stochastic effects important by lowering the effective population size. Prior colonization with other bacteria reduced the chances of subsequent colonization, thus increasing the stability of higher diversity guts. Therefore, stable gut diversity may be driven by inherently stochastic processes, which has important implications for combatting infectious diseases and for stably establishing probiotics in the gut.

Recent results from clinical trials with the BRAF inhibitors GSK2118436 (dabrafenib) and PLX4032 (vemurafenib) have shown encouraging response rates; however, the duration of response has been limited. To identify determinants of acquired resistance to GSK2118436 and strategies to overcome the resistance, we isolated GSK2118436 drug-resistant clones from the A375 BRAF V600E and the YUSIT1 BRAF V600K melanoma cell lines. These clones also showed reduced sensitivity to the allosteric mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor GSK1120212 (trametinib).

The objective of this study was to further establish and confirm the relationship of adipose mitochondrial biogenesis in diabetes/obesity and the effects of rosiglitazone (RSG), a peroxisome proliferator-activated receptor (PPAR) ␥ agonist, by systematically analyzing mitochondrial gene expression and function in two mouse models of obesity and type 2 diabetes. Using microarray technology, adipose mitochondrial gene transcription was studied in db/db, high-fat diet-fed C57BL/6 (HFD) and respective control mice with or without RSG treatment. The findings were extended using mitochondrial staining, DNA quantification, and measurements of citrate synthase activity. In db/db and HFD mice, gene transcripts associated with mitochondrial ATP production, energy uncoupling, mitochondrial ribosomal proteins, outer and inner membrane translocases, and mitochondrial heat-shock proteins were decreased in abundance, compared with db/؉ and standardfat diet-fed control mice, respectively. RSG dose-dependently increased these transcripts in both db/db and HFD mice and induced transcription of mitochondrial structural proteins and cellular antioxidant enzymes responsible for removal of reactive oxygen species generated by increased mitochondrial activity. Transcription factors, including PPAR coactivator (PGC)-1␤, PGC-1␣, estrogen-related receptor ␣, and PPAR␣, were suppressed in both models and induced by RSG. The effects of RSG on adipose mitochondrial genes were confirmed by quantitative RT-PCR and further supported by mitochondrial staining, mitochondrial DNA quantification, and citrate synthase activity. Adipose mitochondrial biogenesis was overwhelmingly suppressed in both mouse models of diabetes/obesity and globally induced by RSG. These findings suggest an important role of adipose mitochondria in diabetes/obesity and the potential for new treatment approaches targeting adipose mitochondria. Diabetes 56:1751-1760, 2007 P eroxisome proliferator-activated receptor (PPAR) ␥ agonists, including rosiglitazone (RSG), are effective drugs for the treatment of type 2 diabetes. It is well established that RSG induces adipogenesis and causes body-wide lipid repartitioning by increasing adipose triglyceride content, thereby lowering free fatty acids, glycerol, triglycerides, and glucose in the circulation, which is associated with increased insulin sensitivity of the liver, muscle, and other organs. Critical to this process, adipose tissue, which highly expresses PPAR␥, serves not only as a lipid storage depot but also as an endocrine organ producing adipokines that regulate the activity of other tissues (rev. in 1,2).There has been growing interest in exploring the involvement of adipose mitochondria in the regulation of whole-body energy homeostasis (3-9). Recent studies suggest that diabetes/obesity is accompanied by a decrease in the expression of adipose mitochondrial genes in ob/ob mice (8) and impaired adipose mitochondria in db/db mice (9) and that the compromised mitochondrial conditions in ob/ob and db/db mice were reversi...

Starved animals often exhibit elevated locomotion, which has been speculated to partly resemble foraging behavior and facilitate food acquisition and energy intake. Despite its importance, the neural mechanism underlying this behavior remains unknown in any species. In this study we confirmed and extended previous findings that starvation induced locomotor activity in adult fruit flies Drosophila melanogaster. We also showed that starvationinduced hyperactivity was directed toward the localization and acquisition of food sources, because it could be suppressed upon the detection of food cues via both central nutrient-sensing and peripheral sweet-sensing mechanisms, via induction of food ingestion. We further found that octopamine, the insect counterpart of vertebrate norepinephrine, as well as the neurons expressing octopamine, were both necessary and sufficient for starvationinduced hyperactivity. Octopamine was not required for starvation-induced changes in feeding behaviors, suggesting independent regulations of energy intake behaviors upon starvation. Taken together, our results establish a quantitative behavioral paradigm to investigate the regulation of energy homeostasis by the CNS and identify a conserved neural substrate that links organismal metabolic state to a specific behavioral output.T he CNS plays an essential role in energy homeostasis (1). It actively monitors changes in the internal energy state and modulates an array of physiological and behavioral responses to enable energy homeostasis. Foraging behavior is critical for the localization and acquisition of food supply and hence energy homeostasis. It has been extensively documented both in ethological settings (2, 3) and under well-controlled laboratory conditions (4). Laboratory rodents with limited food access exhibit stereotypic food anticipatory activity (FAA) several hours before the mealtime, which is characterized by a steady increase in locomotion and other appetitive behaviors (5). The neural substrate that drives FAA still remains elusive (5, 6). Notably, the regulation of FAA seems to be dissociable from that of feeding behavior (7,8). These results hint at the presence of an independent and somewhat discrete regulatory mechanism of foraging behavior.Foraging behavior has also been extensively studied in invertebrate species such as the roundworm Caenorhabditis elegans (9) and fruit flies Drosophila melanogaster (10). Roundworm populations exhibit two naturally emerged foraging patterns: "solitary" worms disperse across the bacterial lawn, and "social" worms aggregate along the food edge and form clumps (9). This behavioral dimorphism is controlled by natural variations of the npr-1 (neuropeptide receptor resemblance) gene that encodes a receptor homologous to the receptor family of orexigenic neuropeptide Y in mammals (9). A comparable scenario has also been identified in larval fruit flies (10), with two distinct forms of foraging present in nature: "rover" and "sitter." On food sources, sitter but not rover reduces moving speed ...

Starvation induces sustained increase in locomotion, which facilitates food localization and acquisition and hence composes an important aspect of food-seeking behavior. We investigated how nutritional states modulated starvation-induced hyperactivity in adult Drosophila. The receptor of the adipokinetic hormone (AKHR), the insect analog of glucagon, was required for starvation-induced hyperactivity. AKHR was expressed in a small group of octopaminergic neurons in the brain. Silencing AKHR+ neurons and blocking octopamine signaling in these neurons eliminated starvation-induced hyperactivity, whereas activation of these neurons accelerated the onset of hyperactivity upon starvation. Neither AKHR nor AKHR+ neurons were involved in increased food consumption upon starvation, suggesting that starvation-induced hyperactivity and food consumption are independently regulated. Single cell analysis of AKHR+ neurons identified the co-expression of Drosophila insulin-like receptor (dInR), which imposed suppressive effect on starvation-induced hyperactivity. Therefore, insulin and glucagon signaling exert opposite effects on starvation-induced hyperactivity via a common neural target in Drosophila.DOI: http://dx.doi.org/10.7554/eLife.15693.001

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We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.