Biology subjects

Davis, T.

Publications and source records attributed to Davis, T..

28 records · Page 2Linked to original sources

bioRxiv2019

Targeting the resolvin E1 - eicosapentaenoic acid axis improves hyperinsulinemia and hyperglycemia in a host genetic dependent manner

ObjectiveEicosapentaenoic acid (EPA) has recently garnered strong attention given the success of the REDUCE-IT trial, which overturned previous conclusions on EPA and led to its FDA approval for lowering cardiovascular disease risk. Therefore, there is a need to study EPA for cardiometabolic risk factors. Here we focused on EPAs preventative role on hyperglycemia and hyperinsulinemia. MethodsC57BL/6J male mice were fed a high fat diet in the absence or presence of pure EPA. Mass spectrometry was used to identify how EPA prevents hyperinsulinemia and hyperglycemia that drove subsequent experiments with resolvin E1 (RvE1) across inbred and outbred models. ResultsAdministration of EPA to C57BL/6J mice prevented obesity-induced glucose intolerance, hyperinsulinemia, and hyperglycemia. Supporting analyses of National Health and Nutrition Examination Survey data showed fasting glucose levels of obese adults were inversely related to EPA intake in a sex-specific manner. We next investigated how EPA improved murine hyperinsulinemia and hyperglycemia. Mass spectrometry revealed EPA overturned the obesity-driven decrement in the concentration of 18-hydroxyeicosapentaenoic acid (18-HEPE) in white adipose tissue and liver. Treatment of obese mice with RvE1, the immunoresolvant metabolite of 18-HEPE, reversed hyperinsulinemia and hyperglycemia through the G-protein coupled receptor ERV1/ChemR23. RvE1s effects were not mediated by macrophage enrichment in white adipose tissue. Finally, we determined if the metabolic effects of RvE1 were dependent on host genetics. RvE1s effects on hyperinsulinemia and hyperglycemia were divergent in diversity outbred mice that model human genetic variation. Secondary SNP analyses further revealed extensive genetic variation in human RvE1- and EPA- metabolizing genes. ConclusionsThe data suggest EPA prevents hyperinsulinemia and hyperglycemia through the endogenous bioactive metabolite RvE1 that activates ERV1/ChemR23. Importantly, the studies reveal host genetics are an overlooked but critical factor in the metabolic response to RvE1. These results underscore the need for personalized administration of EPA-derived RvE1 based on genetic/metabolic enzyme profiles.

biochemistry↗

bioRxiv2019

Gating Mechanism of β-Ketoacyl-ACP Synthases

Formation of carbon-carbon bonds via {beta}-ketoacyl-acyl carrier protein (ACP) synthases (KS), are key reactions during de novo fatty acid and polyketide biosynthesis. KSs recognize multiple ACPs and choreograph ping-pong mechanisms often in an iterative fashion. Therefore, KSs must limit non-productive protein-protein interactions (PPIs) to achieve high degrees of reaction fidelity. To better understand the stereochemical features governing substrate discrimination during ACP*KS PPIs, we determined x-ray crystal structures complemented by molecular dynamic simulations of E. coli AcpP in complex with the elongating KSs, FabF and FabB. Covalently trapped substrate analogs were used to interrogate critical catalytic events accompanying carbon-carbon bond formation revealing a previously unknown gating mechanism during the binding and delivery of acyl-AcpPs. Two active site loops undergo large conformational excursions during this dynamic gating mechanism and are likely evolutionarily conserved features generally in elongating KSs.

biochemistry↗

bioRxiv2019

Neural Correlates of Attitudes and Risk Perception for Food Technology Topics

Food technologies provide numerous benefits to society and are extensively vetted for safety. However, many technological innovations still face high levels of skepticism from consumers. To promote development and use of food technologies, it is critical to understand the psychological and neurobiological processes associated with consumer acceptability concerns. The current study uses a neuroscience-based approach to understand consumer attitudes and perceptions of risk associated with food technologies and investigate how such attitudes impact consumers processing of information related to food technologies. We used functional magnetic resonance imaging (fMRI) to measure brain activation while participants processed infographics related to food technology topics. For technology topics perceived as riskier (antibiotics and hormones), activation was higher in areas of the lateral prefrontal cortex that are associated with decisional uncertainty. In contrast, technology topics that were viewed more favorably (sustainability and animal welfare) tended to activate the ventromedial prefrontal cortex, a region that processes positive affect and subjective value. Moreover, for information about hormones, the lateral PFC activation was associated with individual differences in resistance to change in risk perception. These results reveal how attitudes and risk perception relate to how the brain processes information about food technologies and how people respond to information about such technologies.

neuroscience↗

bioRxiv2018

A Stu2-mediated intrinsic tension-sensing pathway promotes chromosome biorientation in vivo

Accurate segregation of chromosomes to daughter cells is a critical aspect of cell division. It requires the kinetochores on duplicated chromosomes to biorient, attaching to microtubules from opposite poles of the cell. Bioriented attachments come under tension, while incorrect attachments lack tension and must be destabilized. A well-studied error correction pathway is mediated by the Aurora B kinase, which destabilizes low tension-bearing attachments. We recently discovered that in vitro, kinetochores display an additional intrinsic tension-sensing pathway that utilizes Stu2. This pathways contribution to error correction in cells, however, was unknown. Here, we identify a Stu2 mutant that abolishes its kinetochore function and show that it causes error correction defects in vivo. We also show that this intrinsic tension-sensing pathway functions in concert with the Aurora B-mediated pathway. Together, our work indicates that cells employ at least two pathways to ensure biorientation and the accuracy of chromosome segregation.

cell biology↗

bioRxiv2018

Understanding RNP remodelling uncovers RBPs functionally required for viral replication

The compendium of RNA-binding proteins (RBPome) has been greatly expanded by the development of RNA-interactome capture (RNA-IC). However, it remains unknown how responsive is the RBPome and whether these responses are biologically relevant. To answer these questions, we created comparative RNA-IC to analyse cells challenged with an RNA virus, called sindbis (SINV). Strikingly, the virus altered the activity of 245 RBPs, many of which were newly discovered by RNA-IC. Mechanistically, alterations in RNA binding upon SINV infection are caused by changes in the subcellular localisation of RBPs and RNA availability. Moreover, RBPome responses are crucial, as perturbation of dynamic RBPs modulates the capacity of the virus to infect the cell. For example, ablation of XRN1 causes cells to be refractory to infection, while GEMIN5 moonlights as a novel antiviral factor. Therefore, RBPome remodelling provides a mechanism by which cells can extensively rewire gene expression in response to physiological cues.\n\nHIGHLIGHTSO_LIA quarter of the RBPome remodels upon SINV infection.\nC_LIO_LIThe remodelling is caused by changes in protein localisation and RNA availability.\nC_LIO_LIRewiring of the RBPome is crucial for viral infection efficacy.\nC_LIO_LIWe discover RBPs with previously unknown anti- or pro-viral activity.\nC_LI

molecular biology↗

bioRxiv2018

Agricultural fungicides inadvertently influence the fitness of Colorado potato beetles, Leptinotarsa decemlineata, and their susceptibility to insecticides

The Colorado potato beetle (CPB), Leptinotarsa decemlineata (Say), is an agricultural pest of solanaceous crops which has developed insecticide resistance at an alarming rate. Up to this point, little consideration has been given to unintended, or inadvertent effects that non-insecticide xenobiotics may have on insecticide susceptibility in L. decemlineata. Fungicides, such as chlorothalonil and boscalid, are often used to control fungal pathogens in potato fields and are applied at regular intervals when L. decemlineata populations are present in the crop. In order to determine whether fungicide use may be associated with elevated levels of insecticide resistance in L. decemlineata, we examined phenotypic responses in L. decemlineata to the fungicides chlorothalonil and boscalid. Using enzymatic and transcript abundance investigations we also examined modes of molecular detoxification in response to both insecticide (imidacloprid) and fungicide (boscalid and chlorothalonil) application to more specifically determine if fungicides and insecticides induce similar metabolic detoxification mechanisms. Both chlorothalonil and boscalid exposure induced a phenotypic, enzymatic and transcript response in L. decemlineata which correlates with known mechanisms of insecticide resistance.\n\nKey MessagesO_LIPrior-exposure to a fungicidal application changes the phenotypic response of Leptinotarsa decemlineata to the insecticide imidacloprid\nC_LIO_LIBoth a fungicide and insecticide application activates similar molecular mechanisms of detoxification in Leptinotarsa decemlineata\nC_LIO_LIFungicidal xenobiotics may contribute to insecticide resistance in Leptinotarsa decemlineata\nC_LI\n\nAuthor Contribution StatementJC, SS, CB, AH, and RG conceived and designed research. JC, AC, DA, TD, and BS conducted experiments. JC and AC analyzed data. JC and RG wrote the manuscript. All authors read and approved the manuscript.

ecology↗

bioRxiv2017

Rule Activation and Ventromedial Prefrontal Engagement Support Accurate Stopping in Self-Paced Learning

When weighing evidence for a decision, individuals are continually faced with the choice of whether to gather more information or act on what has already been learned. The present experiment employed a self-paced category learning task and fMRI to examine the neural mechanisms underlying stopping of information search and how they contribute to choice accuracy. Participants learned to classify triads of face, object, and scene cues into one of two categories using a rule based on one of the stimulus dimensions. After each trial, participants were given the option to explicitly solve the rule or continue learning. Representational similarity analysis (RSA) was used to examine activation of rule-relevant information on trials leading up to a decision to solve the rule. We found that activation of rule-relevant information increased leading up to participants stopping decisions. Stopping was associated with widespread activation that included medial prefrontal cortex and visual association areas. Engagement of ventromedial prefrontal cortex (vmPFC) was associated with accurate stopping, and activation in this region was functionally coupled with signal in dorsolateral prefrontal cortex (dlPFC). Results suggest that activating rule information when deciding whether to stop an information search increases choice accuracy, and that the response profile of vmPFC during such decisions may provide an index of effective learning.

neuroscience↗

bioRxiv2017

Expecting the Unexpected: Base-rate Neglect is Driven by Neural Activation of Common Cues

Extensive evidence suggests that people use base rate information inconsistently in decision making. A classic example is the inverse base rate effect (IBRE), whereby participants classify ambiguous stimuli sharing features of both common and rare categories as members of the rare category. Computational models of the IBRE have either posited that it arises from associative similarity-based mechanisms or dissimilarity-based processes that may depend upon higher-level inference. Here we develop a hybrid model, which posits that similarity- and dissimilarity-based evidence both contribute to the IBRE, and test it using functional magnetic resonance imaging data collected from human subjects completing an IBRE task. Consistent with our model, multivoxel pattern analysis reveals that activation patterns on ambiguous test trials contain information consistent with dissimilarity-based processing. Further, trial-by-trial activation in left rostrolateral prefrontal cortex tracks model-based predictions for dissimilarity-based processing, consistent with theories positing a role for higher-level symbolic processing in the IBRE.

neuroscience↗

bioRxiv2017

The Integrative Role of Frontopolar Cortex in Rule-Based Category Learning

Category learning is a critical neurobiological function that allows organisms to simplify a complex world. Rostrolateral prefrontal cortex (rlPFC) is often active in neurobiological studies of category learning; however, the specific role this region serves in category learning remains uncertain. Previous category learning studies have hypothesized that the rlPFC is involved in switching between rules, whereas others have emphasized rule abstraction and evaluation. We aimed to clarify the role of rlPFC in category learning and dissociate switching and evaluation accounts using two common types of category learning tasks: matching and classification. The matching task involved matching a reference stimulus to one of four target stimuli. In the classification task, participants were shown a single stimulus and learned to classify it into one of two categories. Matching and classification are similar but place different demands on switching and evaluation. In matching, a rule can be known with certainty after a single correct answer. In classification, participants may need to evaluate evidence for a rule even after an initial correct response. This critical difference allows isolation of evaluative functions from switching functions. If the rlPFC is primarily involved in switching between representations, it should cease to be active once participants settle on a given rule in both tasks. If the rlPFC is involved in rule evaluation, its activation should persist in the classification task, but not matching. The results revealed that rlPFC activation persisted into correct trials in classification, but not matching, suggesting that it continues to be involved in the evaluations of evidence for a rule even after participants have arrived at the correct rule.\n\nHighlightsO_LIDifferences between rule-based matching and classification tasks were highlighted.\nC_LIO_LIRostrolateral prefrontal cortex is involved in evaluation of evidence for a rule in rule-based category learning tasks.\nC_LI

neuroscience↗

bioRxiv2016

Can you catch Ebola from a stork bite? Inductive reasoning influences on zoonosis risk perception

Emerging zoonoses are a prominent global health threat. Human beliefs are central to drivers of emerging zoonoses, yet little is known about the factors that influence perceived risks of animal contact. We present an inductive account of zoonosis risk perception, suggesting that beliefs about the range of animals that are able to transmit diseases to each other influence zoonosis risk perception. Consistent with our account, in Study 1, we find that participants who endorse higher likelihoods of cross-species disease transmission have stronger intention to report animal bites. In Study 2, using real world descriptions of Ebola virus from the WHO and CDC, we find that communications conveying a broader range of animals as susceptible increase intentions to report animal bites and decrease perceived safety of wild game meat. These results suggest that cognitive factors may be harnessed to modulate zoonosis risk perception and combat emerging infectious diseases.

epidemiology↗