bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting microRNA targeting efficacy in Drosophila
Authors: Agarwal Vikram , Subtelny Alexander O. , Thiru Prathapan , Ulitsky Igor , Bartel David P. 
Published: October 2017

ABSTRACTImportant for understanding the regulatory roles of miRNAs is the ability to predict the mRNA targets most responsive to each miRNA. Here, we acquired datasets needed for the quantitative study of microRNA targeting in Drosophila. Analyses of these data expanded the types of sites known to be effective in flies, expanded the mRNA regions with detectable targeting to include 5′ UTRs, and identified features of site context that correlate with targeting efficacy. Updated evolutionary analyses evaluated the probability of conserved targeting for each predicted site and indicated that more than a third of the Drosophila genes are preferentially conserved targets of miRNAs. Based on these results, a quantitative model was developed to predict targeting efficacy in insects. This model performed better than existing models and will drive the next version of TargetScanFly (v7.0; targetscan.org), thereby providing a valuable resource for placing miRNAs into gene-regulatory networks of this important experimental organism.
Symbiodiniumgenomes reveal adaptive evolution of functions related to symbiosis
Authors: Liu Huanle , Stephens Timothy G. , González-Pech Raúl A. , Beltran Victor H. , Lapeyre Bruno , Bongaerts Pim , Cooke Ira , Bourne David G. , Forêt Sylvain , Miller David J. , van Oppen Madeleine J. H. , Voolstra Christian R. , Ragan Mark A. , Chan Cheong Xin 
Published: October 2017

AbstractSymbiosis between dinoflagellates of the genusSymbiodiniumand reef-building corals forms the trophic foundation of the world’s coral reef ecosystems. Here we present the first draft genome ofSymbiodinium goreaui(Clade C, type C1: 1.03 Gbp), one of the most ubiquitous endosymbionts associated with corals, and an improved draft genome ofSymbiodinium kawagutii(Clade F, strain CS-156: 1.05 Gbp), previously sequenced as strain CCMP2468, to further elucidate genomic signatures of this symbiosis. Comparative analysis of four availableSymbiodiniumgenomes against other dinoflagellate genomes led to the identification of 2460 nuclear gene families that show evidence of positive selection, including genes involved in photosynthesis, transmembrane ion transport, synthesis and modification of amino acids and glycoproteins, and stress response. Further, we identified extensive sets of genes for meiosis and response to light stress. These draft genomes provide a foundational resource for advancing our understandingSymbiodiniumbiology and the coral-algal symbiosis.
Auranofin inhibits virulence inPseudomonas aeruginosa
Authors: Wei Tan Leon Zhen , Hoong Yam Joey Kuok , Hong Ziyan , Santillan Salido May Margarette , Woo Bau Yi , Yau Li Sam Fong , Yang Liang , Givskov Michael , Chng Shu-Sin 
Published: October 2017

AbstractPseudomonas aeruginosais widely attributed as the leading cause of hospital-acquired infections. Due to intrinsic antibiotic resistance mechanisms and the ability to form biofilms,P. aeruginosainfections are challenging to treat.P. aeruginosaemploys multiple virulence mechanisms to establish infections, many of which are controlled by the global virulence regulator Vfr. An attractive strategy to combatP. aeruginosainfections is thus the use of anti-virulence compounds. Here, we report the discovery that FDA-approved drug auranofin attenuates virulence inP. aeruginosa. We demonstrate that auranofin acts by targeting Vfr, which in turn leads to inhibition of quorum sensing (QS) and Type IV pili (TFP). Consistent with inhibition of QS and TFP expression, we show that auranofin attenuates biofilm maturation, and when used in combination with colistin, displays strong synergy in eradicatingP. aeruginosabiofilms. Auranofin may have immediate applications as an anti-virulence drug againstP. aeruginosainfections.
Neural oscillations during conditional associative learning
Authors: Clarke Alex , Roberts Brooke M. , Ranganath Charan 
Published: October 2017

AbstractAssociative learning requires mapping between complex stimuli and behavioural responses. When multiple stimuli are involved, conditional associative learning is a gradual process with learning based on trial and error. It is established that a distributed network of regions track associative learning, however the role of neural oscillations in human learning remains less clear. Here we used scalp EEG to test how neural oscillations change during learning of arbitrary visuo-motor associations. Participants learned to associative 48 different abstract shapes to one of four button responses through trial and error over repetitions of the shapes. To quantify how well the associations were learned for each trial, we used a state-space computational model of learning that provided a probability of each trial being correct given past performance for that stimulus, that we take as a measure of the strength of the association. We used linear modelling to relate single-trial neural oscillations to single-trial measures of association strength. We found frontal midline theta oscillations during the delay period tracked learning, where theta activity was strongest during the early stages of learning and declined as the associations were formed. Further, posterior alpha and low-beta oscillations in the cue period showed strong desynchronised activity early in learning, while stronger alpha activity during the delay period were seen as associations became well learned. Moreover, the magnitude of these effects during early learning, before the associations were learned, related to improvements in memory seen on the next presentation of the stimulus. The current study provides clear evidence that frontal theta and posterior alpha/beta oscillations play a key role during associative memory formation.
Directed functional connectivity using dynamic graphical models
Authors: Schwab Simon , Harbord Ruth , Zerbi Valerio , Elliott Lloyd , Afyouni Soroosh , Smith Jim Q. , Woolrich Mark W. , Smith Stephen M. , Nichols Thomas E. 
Published: October 2017

AbstractThere are a growing number of neuroimaging methods that model spatio-temporal patterns of brain activity to allow more meaningful characterizations of brain networks. This paper proposes dynamic graphical models (DGMs) for dynamic, directed functional connectivity. DGMs are a multivariate graphical model with time-varying coefficients that describe instantaneous directed relationships between nodes. A further benefit of DGMs is that networks may contain loops and that large networks can be estimated. We use network simulations, human resting-state fMRI (N = 500) to investigate the validity and reliability of the estimated networks. We simulate systematic lags of the hemodynamic response at different brain regions to investigate how these lags potentially bias directionality estimates. In the presence of such lag confounds (0.4–0.8 seconds offset between connected nodes), our method has a sensitivity of 72%–77% to detect the true direction. Stronger lag confounds have reduced sensitivity, but do not increase false positives (i.e., directionality estimates of the opposite direction). In human resting-state fMRI, we find the DMN has consistent influence on the cerebellar, the limbic and the auditory/temporal network, as well a consistent reciprocal relationship between the visual medial and visual lateral network. Finally, we apply the method in a small mouse fMRI sample and discover a highly plausible relationship between areas in the hippocampus feeding into the cingulate cortex. We provide a computationally efficient implementation of DGM as a free software package for R.
Control of Cardiac Mitochondrial Fuel Selection by Calcium
Authors: Jones Edith , Kandel Sunil M. , Dasika Santosh K. , Nourabadi Neda , Van den Bergh Françoise , Choi Hyo Sub , Haidar Ali , Dash Ranjan K. , Beard Daniel A. 
Published: October 2017

AbstractCalcium ion concentration modulates the function of pyruvate dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase. Previous studies have shown that despite its ability to affect the function of these dehydrogenases, [Ca2+] does not substantially alter mitochondrial ATP synthesis in vitro under physiological sub-strate conditions. We hypothesize that, rather than contributing to respiratory control, [Ca2+] governs fuel selection. Specifically, cardiac mitochondria are able to use different primary carbon substrates to synthesize ATP aerobically. To determine if and how [Ca2+] affects the relative use of carbohydrates versus fatty acids we measured oxygen consumption and tricarboxylic acid cycle intermediate concentrations in suspensions of cardiac mitochondria with different combinations of pyruvate and palmitoyl-L-carnitine in the media at various [Ca2+] and ADP infusion rates. Results reveal that when both fatty acid and carbohydrate substrates are available, fuel selection is sensitive to both calcium and ATP synthesis rate. When no Ca2+is added under low ATP-demand conditions, β-oxidation provides roughly half of acetyl-CoA for the citrate synthase reaction with the rest coming from the pyruvate dehydrogenase reaction. Under low demand conditions with increasing [Ca2+], the fuel utilization ratio shifts to increased fractional consumption of pyruvate, with 83±10% of acetyl-CoA derived from pyruvate at the highest [Ca2+] evaluated. With high ATP demand, the majority of acetyl-CoA is derived from pyruvate, regardless of the Ca2+level. Our results suggest that changes in work rate alone are enough to effect a switch to carbohydrate use while in vivo the rate at which this switch happens may depend on mitochondrial calcium.Key PointsDespite its effects on activity of mitochondrial dehydrogenases, Ca2+does not substantially alter mitochondrial ATP synthesis in vitro under physiological substrate conditions. Nor does is appear to play an important role in respiratory control in vivo in the myocardium.We hypothesize that Ca2+plays a role mediating the switch in fuel selection to increasing carbohydrate oxidation and decreasing fatty acid oxidation with increasing work rate.To determine if and how Ca2+affects the relative use of carbohydrates versus fatty acids in vitro we measured oxygen consumption and TCA cycle intermediate concentrations in suspensions of purified rat ventricular mitochondria with carbohydrate, fatty acid, and mixed substrates at various [Ca2+] and ATP demand rates.Our results suggest that changes in work rate alone are enough to effect a switch to carbohydrate use in vitro while in vivo the rate at which this switch happens may depend on mitochondrial calcium.
Immuno-phenotypes of Pancreatic Ductal Adenocarcinoma: Metaanalysis of transcriptional subtypes
Authors: Santiago Ines de , Yau Christopher , Middleton Mark , Dustin Michael , Markowetz Florian , Sivakumar Shivan 
Published: October 2017

AbstractPancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and has one of the highest mortality rates of any cancer type with a 5-year survival rate of < 5% and median overall survival of typically six months from diagnosis. Recent transcriptional studies of PDAC have provided several competing stratifications of the disease. However, the development of therapeutic strategies will depend on a unique and coherent classification of PDAC. Here, we use an integrative meta-analysis of four different PDAC gene expression studies to derive the consensus PDAC classification. Despite the fact that immunotherapies have yet to have an impact in treatment of PDAC, the gene expression signatures that stratify PDAC across studies are immunologic. We define these as “adaptive”, “innate” and “immune-exclusion” immunologic signatures, which are prognostic across independent cohorts. An appreciation of the immune composition of PDAC with prognostic significance is an opportunity to understand distinct immune escape mechanisms in development of the disease and design novel immune-oncology therapeutic strategies to overcome current barriers.
Bayesian multiple logistic regression for case-control GWAS
Authors: Banerjee Saikat , Zeng Lingyao , Schunkert Heribert , Söding Johannes 
Published: October 2017

AbstractGenetic variants in genome-wide association studies (GWAS) are tested for disease association mostly using simple regression, one variant at a time. Standard approaches to improve power in detecting disease-associated SNPs use multiple regression with Bayesian variable selection in which a sparsity-enforcing prior on effect sizes is used to avoid overtraining and all effect sizes are integrated out for posterior inference. For binary traits, thelogisticmodel has not yielded clear improvements over the linear model. For multi-SNP analysis, the logistic model required costly and technically challenging MCMC sampling to perform the integration.Here, we introduce thequasi-Laplaceapproximation to solve the integral and avoid MCMC sampling. We expect the logistic model to perform much better than multiple linear regression except when predicted disease risks are spread closely around 0.5, because only close to its inflection point can the logistic function be well approximated by a linear function. Indeed, in extensive benchmarks with simulated phenotypes and real genotypes, our Bayesian multiple LOgistic REgression method (B-LORE) showed considerable improvements (1) when regressing on many variants in multiple loci at heritabilities ≥ 0.4 and (2) for unbalanced case-control ratios.B-LORE also enables meta-analysis by approximating the likelihood functions of individual studies by multivariate normal distributions, using their means and covariance matrices as summary statistics. Our work should make sparse multiple logistic regression attractive also for other applications with binary target variables. B-LORE is freely available from:https://github.com/soedinglab/b-lore.
“Cell surface associated LapA ofPseudomonas fluorescensis anchored inside its Type-1 Secretion TolC-like Pore”
Authors: Jarrod Smith T. , Sondermann Holger , A. O’Toole George 
Published: October 2017

AbstractThe type-1 secretion system (T1SS) of gram-negative bacteria enables a one-step translocation strategy known to move functionally diverse proteins from the cytoplasm into the extracellular environment without a periplasmic intermediate. LapA ofPseudomonas fluorescensPf0-1 is a giant type-1 secreted (T1S) adhesin that facilitates biofilm formation only when displayed at the cell surface. A LapA-targeting periplasmic protease, LapG, connects intracellular cyclic diguanylate (c-di-GMP) levels with cell surface-associated LapA by cleaving and absolving LapA from the cell surface under conditions unsuitable for biofilm formation. Here, we demonstrate that LapA contains a novel N-terminal element, called the retention module (RM), which prohibits classical one-step T1S of LapA. We provide evidence that the RM of LapA tethers LapA at the cell surface through its outer membrane TolC-like pore, LapE, where LapA is accessible to the periplasmic protease LapG. We also demonstrate that this unusual retention strategy is likely conserved among LapA-like proteins and represents a new subclass of T1SS ABC transporters exclusively involved in transporting LapA-like adhesins.Significance StatementBacteria have evolved multiple secretion strategies to interact with their environment. For many bacteria, the secretion of cell surface associated adhesins is often key for initiating contact with a preferred substrate to facilitate biofilm formation. Our work demonstrates thatP. fluorescensuses a previously unrecognized secretion strategy to retain the giant adhesin LapA at its cell surface. Further, we identify likely LapA-like adhesins in various pathogenic and commensal Proteobacteria and provide phylogenetic evidence these adhesins are secreted by a new subclass of T1SS ABC transporters.
Testing the role of the Red Queen and Court Jester as drivers of the macroevolution of Apollo butterflies
Authors: Condamine Fabien L. , Rolland Jonathan , Höhna Sebastian , Sperling Felix A. H. , Sanmartín Isabel 
Published: October 2017

AbstractIn macroevolution, the Red Queen (RQ) model posits that biodiversity dynamics depend mainly on species-intrinsic biotic factors such as interactions among species or life-history traits, while the Court Jester (CJ) model states that extrinsic environmental abiotic factors have a stronger role. Until recently, a lack of relevant methodological approaches has prevented the unraveling of contributions from these two types of factors to the evolutionary history of a lineage. Here we take advantage of the rapid development of new macroevolution models that tie diversification rates to changes in paleoenvironmental (extrinsic) and/or biotic (intrinsic) factors. We inferred a robust and fully-sampled species-level phylogeny, as well as divergence times and ancestral geographic ranges, and related these to the radiation of Apollo butterflies (Parnassiinae) using both extant (molecular) and extinct (fossil/morphological) evidence. We tested whether their diversification dynamics are better explained by a RQ or CJ hypothesis, by assessing whether speciation and extinction were mediated by diversity-dependence (niche filling) and clade-dependent host-plant association (RQ) or by large-scale continuous changes in extrinsic factors such as climate or geology (CJ). For the RQ hypothesis, we found significant differences in speciation rates associated with different host-plants but detected no sign of diversity-dependence. For CJ, the role of Himalayan-Tibetan building was substantial for biogeography but not a driver of high speciation, while positive dependence between warm climate and speciation/extinction was supported by continuously varying maximum-likelihood models. We find that rather than a single factor, the joint effect of multiple factors (biogeography, species traits, environmental drivers, and mass extinction) is responsible for current diversity patterns, and that the same factor might act differently across clades, emphasizing the notion of opportunity. This study confirms the importance of the confluence of several factors rather than single explanations in modeling diversification within lineages.
Spatial Control of Draper Receptor Signaling Initiates Apoptotic Cell Engulfment
Authors: Williamson Adam P. , Vale Ronald D. 
Published: October 2017

AbstractThe engulfment of apoptotic cells is essential for tissue homeostasis and responding to damage. Engulfment is mediated by receptors that recognize ligands exposed on apoptotic cells, such as phosphatidylserine (PS). Here, we convert Drosophila S2 cells into proficient phagocytes by transfecting the Draper engulfment receptor and replacing apoptotic cells with PS-coated beads. We show that PS-ligated Draper forms microclusters that exclude a bulky transmembrane phosphatase and recruit phosphotyrosine binding proteins, revealing a triggering mechanism similar to the T cell receptor (TCR). Analogous to the TCR, Draper’s extracellular domain and PS can be replaced with FRB and FKBP respectively, resulting in a rapamycin-inducible engulfment system. However, in contrast to the TCR, we show that localized signaling at Draper microclusters results in time-dependent depolymerization of actin filaments. Collectively, our results reveal mechanistic similarities and differences between the receptors involved in apoptotic corpse clearance and mammalian immunity and demonstrate that engulfment can be reprogrammed towards non-native targets.Condensed titleSpatial Control of Engulfment Signaling
Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma
Authors: Kfoury Najla , Qi Zongtai , Prager Briana C , Wilkinson Michael N , Broestl Lauren , Berrett Kristopher C , Moudgil Arnav , Sankararaman Sumithra , Chen Xuhua , Gertz Jay , Rich Jeremy Naftali , Mitra Robi D , Rubin Joshua B 
Published: October 2017

Sex can be an important determinant of cancer phenotype, and exploring sex-biased tumor biology holds promise for identifying novel therapeutic targets and new approaches to cancer treatment. In an established isogenic murine model of glioblastoma, we discovered correlated transcriptome-wide sex differences in gene expression, H3K27ac marks, large Brd4-bound enhancer usage, and Brd4 localization to Myc and p53 genomic binding sites. These sex-biased gene expression patterns were also evident in human glioblastoma stem cells (GSCs). These observations led us to hypothesize that Brd4-bound enhancers might underlie sex differences in stem cell function and tumorigenicity in GBM. We found that male and female GBM cells exhibited opposing responses to pharmacological or genetic inhibition of Brd4. Brd4 knockdown or pharmacologic inhibition decreased male GBM cell clonogenicity andin vivotumorigenesis, while increasing both in female GBM cells. These results were validated in male and female patient-derived GBM cell lines. Furthermore, analysis of the Cancer Therapeutic Response Portal of human GBM samples segregated by sex revealed that male GBM cells are significantly more sensitive to BET inhibitors than are female cells. Thus, for the first time, Brd4 activity is revealed to drive a sex differences in stem cell and tumorigenic phenotype, resulting in diametrically opposite responses to BET inhibition in male and female GBM cells. This has important implications for the clinical evaluation and use of BET inhibitors.SignificanceConsistent sex differences in incidence and outcome have been reported in numerous cancers including brain tumors. GBM, the most common and aggressive primary brain tumor, occurs with higher incidence and shorter survival in males compared to females. Brd4 is essential for regulating transcriptome-wide gene expression and specifying cell identity, including that of GBM. We report that sex-biased Brd4 activity drive sex differences in GBM and render male and female tumor cells differentially sensitive to BET inhibitors. The observed sex differences in BETi treatment strongly indicate that sex differences in disease biology translate into sex differences in therapeutic responses. This has critical implications for clinical use of BET inhibitors further affirming the importance of inclusion of sex as a biological variable.