Context-dependent Effects Research Articles

M6 A RNA methylation: from mechanisms to therapeutic potential.

RNA carries a diverse array of chemical modifications that play important roles in the regulation of gene expression. N6 -methyladenosine (m6 A), installed onto mRNA by the METTL3/METTL14 methyltransferase complex, is the most prevalent mRNA modification. m6 A methylation regulates gene expression by influencing numerous aspects of mRNA metabolism, including pre-mRNA processing, nuclear export, decay, and translation. The importance of m6 A methylation as a mode of post-transcriptional gene expression regulation is evident in the crucial roles m6 A-mediated gene regulation plays in numerous physiological and pathophysiological processes. Here, we review current knowledge on the mechanisms by which m6 A exerts its functions and discuss recent advances that underscore the multifaceted role of m6 A in the regulation of gene expression. We highlight advances in our understanding of the regulation of m6 A deposition on mRNA and its context-dependent effects on mRNA decay and translation, the role of m6 A methylation of non-coding chromosomal-associated RNA species in regulating transcription, and the activities of the RNA demethylase FTO on diverse substrates. We also discuss emerging evidence for the therapeutic potential of targeting m6 A regulators in disease.

The Blockade of TACE-Dependent EGF Receptor Activation by Losartan-Erlotinib Combination Attenuates Renal Fibrosis Formation in 5/6-Nephrectomized Rats Under Vitamin D Deficiency.

Chronic kidney disease (CKD) has been considered a major public health issue. In addition to cardiovascular diseases and infections, hypovitaminosis D has been considered a non-traditional aggravating factor for CKD progression. Interstitial fibrosis is a hallmark of CKD strongly correlated with deterioration of renal function. Transforming growth factor β (TGF-β) is the major regulatory profibrotic cytokine in CKD. Many injurious stimuli converge on the TGF-β pathway, which has context-dependent pleiotropic effects and interacts with several related renal fibrosis formation (RFF) pathways. Epidermal growth factor receptor (EGFR) is critically involved in CKD progression, exerting a pathogenic role in RFF associated with TGF-β-related fibrogenesis. Among others, EGFR pathway can be activated by a disintegrin and a metalloproteinase known as tumor necrosis factor α-converting enzyme (TACE). Currently no effective therapy is available to completely arrest RFF and slow the progression of CKD. Therefore, we investigated the effects of a double treatment with losartan potassium (L), an AT1R antagonist, and the tyrosine kinase inhibitor erlotinib (E) on the alternative pathway of RFF related to TACE-dependent EGFR activation in 5/6-nephrectomized rats under vitamin D deficiency (D). During the 90-day protocol, male Wistar rats under D, were submitted to 5/6 nephrectomy (N) on day 30 and randomized into four groups: N+D, no treatment; N+D+L, received losartan (50 mg/kg/day); N+D+E, received erlotinib (6 mg/kg/day); N+D+L+E received losartan+erlotinib treatment. N+D+L+E data demonstrated that the double treatment with losartan+erlotinib not only blocked the TACE-dependent EGF receptor activation but also prevented the expression of TGF-β, protecting against RFF. This renoprotection by losartan+erlotinib was corroborated by a lower expression of ECM proteins and markers of phenotypic alteration as well as a lesser inflammatory cell infiltrate. Although erlotinib alone has been emerging as a renoprotective drug, its association with losartan should be considered as a potential therapeutic strategy on the modulation of RFF.

Altering preferences for suicide crisis resources using the decoy nudge: Evidence of context-dependent effects in suicide prevention decision making.

Suicide is the 10th leading cause of death in the United States. There are several important decisions that could confer later risk to a suicide attempt (e.g., how to store lethal means). Therefore, understanding how people make decisions that are relevant for suicide risk is an important area of study for suicidology. Human behavior diverges from perfectly rational economic decision making according to observable patterns based on predictable cognitive processes. Nudges attempt to diminish, leverage, or circumvent these deviations to increase the probability of a desired choice being selected or behavior being performed. One deviation from rationality is that human choice is context dependent. This deviation can be observed by introducing an objectively inferior alternative option (a decoy) into a choice array that alters an individual's preference. Using decoys could be one way to nudge people toward best practices in suicide prevention work. This study examined if decoys could reliably alter participant preferences for suicide prevention resources using a hypothetical scenario in three separate online samples (i.e., general population, participants with recent suicidal thoughts, gun owners). Our results found that introducing a slightly (but objectively) worse version of an existing suicide prevention resource increased the preference toward the slightly better option. These findings indicate that using decoys could be an effective nudge for influencing people's preference toward best practices. Most important, these findings highlight the importance of context effects on choice preference in suicide research and prevention efforts, as well as suggest irrational decision-making processes in suicide-relevant decision making. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Susceptible host availability modulates climate effects on dengue dynamics.

Experiments and models suggest that climate affects mosquito-borne disease transmission. However, disease transmission involves complex nonlinear interactions between climate and population dynamics, which makes detecting climate drivers at the population level challenging. By analysing incidence data, estimated susceptible population size, and climate data with methods based on nonlinear time series analysis (collectively referred to as empirical dynamic modelling), we identified drivers and their interactive effects on dengue dynamics in San Juan, Puerto Rico. Climatic forcing arose only when susceptible availability was high: temperature and rainfall had net positive and negative effects respectively. By capturing mechanistic, nonlinear and context-dependent effects of population susceptibility, temperature and rainfall on dengue transmission empirically, our model improves forecast skill over recent, state-of-the-art models for dengue incidence. Together, these results provide empirical evidence that the interdependence of host population susceptibility and climate drives dengue dynamics in a nonlinear and complex, yet predictable way.

Behavioral and Neural Effects of Familiarization on Object-Background Associations.

Associative memory is the ability to link together components of stimuli. Previous evidence suggests that prior familiarization with study items affects the nature of the association between stimuli. More specifically, novel stimuli are learned in a more context-dependent fashion than stimuli that have been encountered previously without the current context. In the current study, we first acquired behavioral data from 62 human participants to conceptually replicate this effect. Participants were instructed to memorize multiple object-scene pairs (study phase) and were then tested on their recognition memory for the objects (test phase). Importantly, 1 day prior, participants had been familiarized with half of the object stimuli. During the test phase, the objects were either matched to the same scene as during study (intact pair) or swapped with a different object’s scene (rearranged pair). Our results conceptually replicated the context-dependency effect by showing that breaking up a studied object-context pairing is more detrimental to object recognition performance for non-familiarized objects than for familiarized objects. Second, we used functional magnetic resonance imaging (fMRI) to determine whether medial temporal lobe encoding-related activity patterns are reflective of this familiarity-related context effect. Data acquired from 25 human participants indicated a larger effect of familiarization on encoding-related hippocampal activity for objects presented within a scene context compared to objects presented alone. Our results showed that both retrieval-related accuracy patterns and hippocampal activation patterns were in line with a familiarization-mediated context-dependency effect.

Context-dependent memory effects in two immersive virtual reality environments: On Mars and underwater

The context-dependent memory effect, in which memory for an item is better when the retrieval context matches the original learning context, has proved to be difficult to reproduce in a laboratory setting. In an effort to identify a set of features that generate a robust context-dependent memory effect, we developed a paradigm in virtual reality using two semantically distinct virtual contexts: underwater and Mars environments, each with a separate body of knowledge (schema) associated with it. We show that items are better recalled when retrieved in the same context as the study context; we also show that the size of the effect is larger for items deemed context-relevant at encoding, suggesting that context-dependent memory effects may depend on items being integrated into an active schema.

Mir142 loss unlocks IDH2R140-dependent leukemogenesis through antagonistic regulation of HOX genes

AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations.

Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2.

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatin-binding protein involved in neuronal development and maturation. Loss-of-function mutations in MeCP2 result in Rett syndrome (RTT), a neurodevelopmental disorder that is the main cause of mental retardation in females. MeCP2 is an intrinsically disordered protein (IDP) constituted by six domains. Two domains are the main responsible elements for DNA binding (methyl-CpG binding domain, MBD) and recruitment of gene transcription/silencing machinery (transcription repressor domain, TRD). These two domains concentrate most of the RTT-associated mutations. R106W and R133C are associated with severe and mild RTT phenotype, respectively. We have performed a comprehensive characterization of the structural and functional impact of these substitutions at molecular level. Because we have previously shown that the MBD-flanking disordered domains (N-terminal domain, NTD, and intervening domain, ID) exert a considerable influence on the structural and functional features of the MBD (Claveria-Gimeno, R. et al. Sci Rep. 2017, 7, 41635), here we report the biophysical study of the influence of the protein scaffold on the structural and functional effect induced by these two RTT-associated mutations. These results represent an example of how a given mutation may show different effects (sometimes opposing effects) depending on the molecular context.

Effects of lifelong testosterone exposure on health and disease using Mendelian randomization.

Testosterone products are prescribed to males for a variety of possible health benefits, but causal effects are unclear. Evidence from randomized trials are difficult to obtain, particularly regarding effects on long-term or rare outcomes. Mendelian randomization analyses were performed to infer phenome-wide effects of free testosterone on 461 outcomes in 161,268 males from the UK Biobank study. Lifelong increased free testosterone had beneficial effects on increased bone mineral density, and decreased body fat; adverse effects on decreased HDL, and increased risks of prostate cancer, androgenic alopecia, spinal stenosis, and hypertension; and context-dependent effects on increased hematocrit and decreased C-reactive protein. No benefit was observed for type 2 diabetes, cardiovascular or cognitive outcomes. Mendelian randomization suggests benefits of long-term increased testosterone should be considered against adverse effects, notably increased prostate cancer and hypertension. Well-powered randomized trials are needed to conclusively address risks and benefits of testosterone treatment on these outcomes.

Individual species provide multifaceted contributions to the stability of ecosystems.

Exploration of the relationship between species diversity and ecological stability has occupied a prominent place in ecological research for decades. Yet, a key component of this puzzle-the contributions of individual species to the overall stability of ecosystems-remains largely unknown. Here, we show that individual species simultaneously stabilize and destabilize ecosystems along different dimensions of stability, and also that their contributions to functional (biomass) and compositional stability are largely independent. By simulating experimentally the extinction of three consumer species (the limpet Patella, the periwinkle Littorina and the topshell Gibbula) from a coastal rocky shore, we found that the capacity to predict the combined contribution of species to stability from the sum of their individual contributions varied among stability dimensions. This implies that the nature of the diversity-stability relationship depends upon the dimension of stability under consideration, and may be additive, synergistic or antagonistic. We conclude that, although the profoundly multifaceted and context-dependent consequences of species loss pose a significant challenge, the predictability of cumulative species contributions to some dimensions of stability provide a way forward for ecologists trying to conserve ecosystems and manage their stability under global change.

Autophagy displays divergent roles during intermittent amino acid starvation and toxic stress-induced senescence in cultured skeletal muscle cells.

Due to the ever-expanding functions attributed to autophagy, there is widespread interest in understanding its contribution to human physiology; however, its specific cellular role as a stress-response mechanism is still poorly defined. To investigate autophagy's role in this regard, we repeatedly subjected cultured mouse myoblasts to two stresses with diverse impacts on autophagic flux: amino acid and serum withdrawal (Hank's balanced salt solution [HBSS]), which robustly induces autophagy, or low-level toxic stress (staurosporine, STS). We found that intermittent STS (int-STS) administration caused cell cycle arrest, development of enlarged and misshapen cells/nuclei, increased senescence-associated heterochromatic foci and senescence-associated β-galactosidase activity, and prevented myogenic differentiation. These features were not observed in cells intermittently incubated in HBSS (int-HB). While int-STS cells displayed less DNA damage (phosphorylated H2A histone family, member X content) and caspase activity when administered cisplatin, int-HB cells were protected from STS-induced cell death. Interestingly, STS-induced senescence was attenuated in autophagy related 7-deficient cells. Therefore, while repeated nutrient withdrawal did not cause senescence, autophagy was required for senescence caused by toxic stress. These results illustrate the context-dependent effects of different stressors, potentially highlighting autophagy as a distinguishing factor.

Impacts of Extreme Weather Events on Bacterial Community Composition of a Temperate Humic Lake

Extreme weather events are projected to increase in frequency and intensity as climate change continues. Heterotrophic bacteria play a critical role in lake ecosystems, yet little research has been done to determine how they are affected by such extremes. The purpose of this study was to use high-throughput sequencing to explore the bacterial community composition of a humic oligotrophic lake on the North Atlantic Irish coast and to assess the impacts on composition dynamics related to extreme weather events. Samples for sequencing were collected from Lough Feeagh on a fortnightly basis from April to November 2018. Filtration was used to separate free-living and particle-associated bacterial communities and amplicon sequencing was performed for the 16S rRNA V4 region. Two named storms, six high discharge events, and one drought period occurred during the sampling period. These events had variable, context-dependent effects on bacterial communities in Lough Feeagh. The particle-associated community was found to be more likely to respond to physical changes, such as mixing, while the free-living population responded to changes in nutrient and carbon concentrations. Generally, however, the high stability of the bacterial community observed in Lough Feeagh suggests that the bacterial community is relatively resilient to extreme weather events.

The effect of virtual reality environments on auditory memory

Auditory recall is stronger in the environment in which a memory was originally encoded, an effect of context-dependent memory (CM) [Godden and Baddeley, Brit. J. Psychol.66(3), 325–331 (1975)]. Innovations in virtual reality (VR) have resulted in the adoption of VR as a communication platform in professional, medical, and educational contexts. The present study reports an experiment testing how CM impacts auditory memory across differing VR environments. An experiment will be described in which participants in one of two distinct virtual environments (e.g., beach and forest) within the VR-communication platform AltSpace hear three iterations of a pre-recorded list of 16 words controlled for frequency and syllable count. Participants are tested for recall of the word-list in either the same or the differing virtual environment. Improved accuracy when tested in the same environment would suggest that CM can be observed for auditory memory between virtual environments. Preliminary results indicate a potential context-dependent effect between virtual environments. Results will be discussed, with implications for professional, medical, and pedagogical applications in virtual settings.

CD8 T cells drive anorexia, dysbiosis, and blooms of a commensal with immunosuppressive potential after viral infection

Infections elicit immune adaptations to enable pathogen resistance and/or tolerance and are associated with compositional shifts of the intestinal microbiome. However, a comprehensive understanding of how infections with pathogens that exhibit distinct capability to spread and/or persist differentially change the microbiome, the underlying mechanisms, and the relative contribution of individual commensal species to immune cell adaptations is still lacking. Here, we discovered that mouse infection with a fast-spreading and persistent (but not a slow-spreading acute) isolate of lymphocytic choriomeningitis virus induced large-scale microbiome shifts characterized by increased Verrucomicrobia and reduced Firmicute/Bacteroidetes ratio. Remarkably, the most profound microbiome changes occurred transiently after infection with the fast-spreading persistent isolate, were uncoupled from sustained viral loads, and were instead largely caused by CD8 T cell responses and/or CD8 T cell-induced anorexia. Among the taxa enriched by infection with the fast-spreading virus, Akkermansia muciniphila, broadly regarded as a beneficial commensal, bloomed upon starvation and in a CD8 T cell-dependent manner. Strikingly, oral administration of A. muciniphila suppressed selected effector features of CD8 T cells in the context of both infections. Our findings define unique microbiome differences after chronic versus acute viral infections and identify CD8 T cell responses and downstream anorexia as driver mechanisms of microbial dysbiosis after infection with a fast-spreading virus. Our data also highlight potential context-dependent effects of probiotics and suggest a model in which changes in host behavior and downstream microbiome dysbiosis may constitute a previously unrecognized negative feedback loop that contributes to CD8 T cell adaptations after infections with fast-spreading and/or persistent pathogens.

A Role for Caenorhabditis elegans COMPASS in Germline Chromatin Organization.

Deposition of histone H3 lysine 4 (H3K4) methylation at promoters is catalyzed by the SET1/COMPASS complex and is associated with context-dependent effects on gene expression and local changes in chromatin organization. The role of SET1/COMPASS in shaping chromosome architecture has not been investigated. Here we used Caenorhabditis elegans to address this question through a live imaging approach and genetic analysis. Using quantitative FRET (Förster resonance energy transfer)-based fluorescence lifetime imaging microscopy (FLIM) on germ cells expressing histones eGFP-H2B and mCherry-H2B, we find that SET1/COMPASS influences meiotic chromosome organization, with marked effects on the close proximity between nucleosomes. We further show that inactivation of set-2, encoding the C. elegans SET1 homologue, or CFP-1, encoding the chromatin targeting subunit of COMPASS, enhances germline chromosome organization defects and sterility of condensin-II depleted animals. set-2 loss also aggravates germline defects resulting from conditional inactivation of topoisomerase II, another structural component of chromosomes. Expression profiling of set-2 mutant germlines revealed only minor transcriptional changes, suggesting that the observed effects are at least partly independent of transcription. Altogether, our results are consistent with a role for SET1/COMPASS in shaping meiotic chromosomes in C. elegans, together with the non-histone proteins condensin-II and topoisomerase. Given the high degree of conservation, our findings expand the range of functions attributed to COMPASS and suggest a broader role in genome organization in different species.

Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia

Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT myeloid neoplasia (MN), clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.

Context-dependent effects of a reintroduced ungulate on soil properties are driven by soil texture, moisture, and herbivore activity.

Although there is considerable evidence that large mammalian herbivores influence ecosystem‐level processes, studies have reported such widely varying results that generalizations have remained elusive. Here, we use an 18‐year‐old exclosure experiment—stratified across a landscape heterogeneous with respect to soil texture, moisture and herbivore activity—to understand the variable effects of tule elk (Cervus canadensis nannodes), a native reintroduced herbivore, on soil properties along the coast of northern California. Elk significantly increased soil bulk density and created a compacted layer at shallow soil depth, while decreasing infiltration rate and pH. The effects of elk on bulk density, penetration resistance, and pH varied with soil type, being least pronounced in coarse, sandy loams, and greatest in loose sand. The effects of elk on nutrient availability varied along gradients of soil texture and moisture. In coarser soils, elk decreased ammonium availability, but increased it in finer soils. Elk also decreased soil moisture content, in part through their positive effect on bulk density, and this effect was most pronounced in coarser soils. Through decreasing soil moisture content, elk also decreased nitrate availability in coarser soils. At greater levels of elk activity (as measured by dung deposition), the elk effect on bulk density was amplified, and this had a corresponding negative effect on nitrate and phosphate availability. Our study has demonstrated that a better understanding of spatial variation in the effects of herbivores on ecosystems can emerge by evaluating their influences across gradients of soil texture, soil moisture, and herbivore activity. These data enabled us to evaluate several frameworks that have been developed to understand the variable effects of herbivores on ecosystems, which is a significant step in reconciling the many competing ideas put forth to explain the context‐dependent effects of large herbivores on grazed ecosystems.

Testing for context-dependent effects of prenatal thyroid hormones on offspring survival and physiology: an experimental temperature manipulation

Maternal effects via hormonal transfer from the mother to the offspring provide a tool to translate environmental cues to the offspring. Experimental manipulations of maternally transferred hormones have yielded increasingly contradictory results, which may be explained by differential effects of hormones under different environmental contexts. Yet context-dependent effects have rarely been experimentally tested. We therefore studied whether maternally transferred thyroid hormones (THs) exert context-dependent effects on offspring survival and physiology by manipulating both egg TH levels and post-hatching nest temperature in wild pied flycatchers (Ficedula hypoleuca) using a full factorial design. We found no clear evidence for context-dependent effects of prenatal THs related to postnatal temperature on growth, survival and potential underlying physiological responses (plasma TH levels, oxidative stress and mitochondrial density). We conclude that future studies should test for other key environmental conditions, such as food availability, to understand potential context-dependent effects of maternally transmitted hormones on offspring, and their role in adapting to changing environments.

Malignant cell-specific CXCL14 promotes tumor lymphocyte infiltration in oral cavity squamous cell carcinoma.

ObjectivesTo explore lymphocyte infiltration as a potential mechanism behind CXCL14-mediated tumor growth suppression in oral cavity squamous cell carcinoma (OSCC).MethodsWe analyzed single cell RNA-sequencing (scRNA-seq) data from OSCC to identify expression changes among malignant cells in lymph nodes (LN) versus primary tumors. CXCL14 expression in murine OSCC cell lines was quantified using qRT-PCR. Short hairpin RNA knockdown of CXCL14 was performed in mouse oral cavity (MOC)1 cells, and CXCL14 overexpression was performed in MOC2 cells. Cells in each condition were injected into C57BL/6 mice with and without T cell depletion, and tumor volume was measured. At 30 days, tumors were dissociated and analyzed by flow cytometry for CD45+CD3+ T cells. CXCL14 expression was correlated with gene expression signatures of tumor infiltrating lymphocytes (TIL) in scRNA-seq data, as well as TCGA tumors.ResultsscRNA-seq revealed CXCL14 as the most significantly downregulated gene among malignant cells in LNs relative to primary tumor, supporting a role in preventing invasion and/or metastasis. In a murine immunocompetent model, CXCL14 expression was higher in indolent MOC1 cells than in more aggressive MOC2 cells. Tumor growth in vivo was significantly increased by CXCL14 knockdown in MOC1 cells relative to control, with a corresponding decrease in TIL. In MOC2 cells, tumor growth was significantly reduced by CXCL14 overexpression relative to control and TIL were increased. Both effects were lost with T cell depletion. In a human tumor scRNA-seq cohort, we found that only malignant cell CXCL14, but not non-malignant cell or fibroblast CXCL14, was associated with TIL. Bulk CXCL14 from the TCGA cohort had no association with TIL.ConclusionsHigher CXCL14 expression by tumor cells is associated with reduced tumor growth and increased TIL, supporting immune-mediated suppression of tumor growth in OSCC. Given that CXCL14 is downregulated in LN metastases compared with primary tumors, our data raise the possibility that CXCL14-mediated immune infiltration may discourage invasion and metastasis. In human scRNA-seq data, only malignant cell-specific CXCL14 was associated with TIL, suggesting a critical context-dependent effect of CXCL14 expression.

Environmental specificity in Drosophila-bacteria symbiosis affects host developmental plasticity

Environmentally acquired microbial symbionts could contribute to host adaptation to local conditions like vertically transmitted symbionts do. This scenario necessitates symbionts to have different effects in different environments. We investigated this idea in Drosophila melanogaster, a species which communities of bacterial symbionts vary greatly among environments. We isolated four bacterial strains isolated from the feces of a D. melanogaster laboratory strain and tested their effects in two conditions: the ancestral environment (i.e. the laboratory medium) and a new environment (i.e. fresh fruit with live yeast). All bacterial effects on larval and adult traits differed among environments, ranging from very beneficial to marginally deleterious. The joint analysis of larval development speed and adult size further shows bacteria affected developmental plasticity more than resource acquisition. This effect was largely driven by the contrasted effects of the bacteria in each environment. Our study illustrates that understanding D. melanogaster symbiotic interactions in the wild will necessitate working in ecologically realistic conditions. Besides, context-dependent effects of symbionts, and their influence on host developmental plasticity, shed light on how environmentally acquired symbionts may contribute to host evolution.