bluuebunny/crossref_metadata_2025_split huggingface dataset:
Locally-adapted Mimulus ecotypes differentially impact rhizosphere bacterial and archaeal communities in an environment-dependent manner
Authors: Bowsher Alan W. , Kearns Patrick J. , Popovic Damian , Lowry David B. , Shade Ashley 
Published: May 2019

AbstractPlant root-microbe interactions influence plant productivity, health, and resistance to stress. Although there is evidence that plant species and even genotypes can alter soil microbial community structure, environmental conditions can potentially outweigh plant genetic effects. Here, we used a reciprocal transplant experiment to understand the contributions of the environment and the host plant to rhizosphere microbiome composition in locally-adapted ecotypes of Mimulus guttatus (syn. Erythranthe guttata (Fisch. ex DC.) G.L. Nesom). Two genotypes of a coastal ecotype and two genotypes of an inland ecotype were planted at coastal and inland sites. After three months, we collected rhizosphere and bulk soil and assessed microbial communities by 16S rRNA gene sequencing. We found that local environment (coastal versus inland site) strongly influenced rhizosphere communities, at least in part due to distinct local microbial species pools. Host identity played a smaller role: at each site, the ecotypes exhibited remarkably similar composition of microbial communities at the class level, indicating that divergent M. guttatus ecotypes recruit phylogenetically similar rhizosphere communities, even in environments to which they are maladapted. Nevertheless, the two ecotypes significantly differed in community composition at the inland site due to an exclusive set of rare taxa associated with each ecotype. Although our results indicate that locally-adapted M. guttatus ecotypes are genetically diverged in factors shaping rhizosphere communities, environmental factors can trump genetic factors in shaping the M. guttatus microbiome. Overall, our findings demonstrate that wild plants strongly impact root-associated microbial communities, but hierarchical drivers interact to shape microbial community assembly outcomes.
gapsplit: Efficient random sampling for non-convex constraint-based models
Authors: Keaty Thomas C. , Jensen Paul A. 
Published: May 2019

AbstractSummaryGapsplit generates random samples from convex and non-convex constraint-based models. Gapsplit targets under-sampled regions of the solution space for uniform coverage.Availability and ImplementationPython and Matlab source code are freely available at http://jensenlab.net/tools.Contactpjens@illinois.edu
Making the most of Clumping and Thresholding for polygenic scores
Authors: Privé Florian , Vilhjálmsson Bjarni J. , Aschard Hugues , Blum Michael G.B. 
Published: May 2019

AbstractPolygenic prediction has the potential to contribute to precision medicine. Clumping and Thresh-olding (C+T) is a widely used method to derive polygenic scores. When using C+T, it is common to test several p-value thresholds to maximize predictive ability of the derived polygenic scores. Along with this p-value threshold, we propose to tune three other hyper-parameters for C+T. We implement an efficient way to derive thousands of different C+T polygenic scores corresponding to a grid over four hyper-parameters. For example, it takes a few hours to derive 123,200 different C+T scores for 300K individuals and 1M variants on a single node with 16 cores.We find that optimizing over these four hyper-parameters improves the predictive performance of C+T in both simulations and real data applications as compared to tuning only the p-value threshold. A particularly large increase can be noted when predicting depression status, from an AUC of 0.557 (95% CI: [0.544-0.569]) when tuning only the p-value threshold in C+T to an AUC of 0.592 (95% CI: [0.580-0.604]) when tuning all four hyper-parameters we propose for C+T.We further propose Stacked Clumping and Thresholding (SCT), a polygenic score that results from stacking all derived C+T scores. Instead of choosing one set of hyper-parameters that maximizes prediction in some training set, SCT learns an optimal linear combination of all C+T scores by using an efficient penalized regression. We apply SCT to 8 different case-control diseases in the UK biobank data and find that SCT substantially improves prediction accuracy with an average AUC increase of 0.035 over standard C+T.
Strong Purifying Selection Contributes to Genome Streamlining in Epipelagic Marinimicrobia
Authors: Martinez-Gutierrez Carolina Alejandra , Aylward Frank O. 
Published: May 2019

AbstractMarine microorganisms inhabiting nutrient-depleted waters play critical roles in global biogeochemical cycles due to their abundance and broad distribution. Many of these microbes share similar genomic features including small genome size, low % G+C content, short intergenic regions, and low nitrogen content in encoded amino acids, but the evolutionary drivers of these characteristics are unclear. Here we compared the strength of purifying selection across the Marinimicrobia, a candidate phylum which encompasses a broad range of phylogenetic groups with disparate genomic features, by estimating the ratio of non-synonymous and synonymous substitutions (dN/dS) in conserved marker genes. Our analysis shows significantly lower dN/dS values in epipelagic Marinimicrobia that exhibit features consistent with genome streamlining when compared to their mesopelagic counterparts. We found a significant positive correlation between median dN/dS values and genomic traits associated to streamlined organisms, including % G+C content, genome size, and intergenic region length. Our findings are consistent with genome streamlining theory, which postulates that small, compact genomes with low G+C contents are adaptive and the product of strong purifying selection. Our results are also in agreement with previous findings that genome streamlining is common in epipelagic waters, suggesting that genomes inhabiting this region of the ocean have been shaped by strong selection together with prevalent nutritional constraints characteristic of this environment.
Cochlear activity in silent cue-target intervals shows a theta-rhythmic pattern and is correlated to attentional alpha modulations
Authors: Albrecht Köhler Moritz Herbert , Demarchi Gianpaolo , Weisz Nathan 
Published: May 2019

AbstractA long-standing debate concerns where in the processing hierarchy of the central nervous system (CNS) selective attention takes effect. In the auditory system cochlear processes can be influenced via direct and mediated (by the inferior colliculus) projections from the auditory cortex to the superior olivary complex (SOC). Studies illustrating attentional modulations of cochlear responses have so far been limited to sound-evoked responses. The aim of the present study is to investigate intermodal (audiovisual) selective attention in humans simultaneously at the cortical and cochlear level during a stimulus-free cue-target period. We found that cochlear activity in the silent cue-target periods was modulated by a theta-rhythmic pattern (∼6 Hz). While this pattern was present independently of attentional focus, cochlear theta activity was clearly enhanced when attending to the upcoming auditory input. On a cortical level, classical posterior alpha and beta power enhancements were found during auditory selective attention. Interestingly, participants with a stronger release of inhibition in auditory brain regions show a stronger attentional modulation of cochlear theta activity. These results hint at a putative theta-rhythmic sampling of auditory input at the cochlear level. Furthermore, our results point to an interindividual variable engagement of efferent pathways in an attentional context that are linked to processes within and beyond processes in auditory cortical regions.
Reward-predictive representations generalize across tasks in reinforcement learning
Authors: Lehnert Lucas , Littman Michael L. , Frank Michael J. 
Published: May 2019

AbstractIn computer science, reinforcement learning is a powerful framework with which artificial agents can learn to maximize their performance for any given Markov decision process (MDP). Advances over the last decade, in combination with deep neural networks, have enjoyed performance advantages over humans in many difficult task settings. However, such frameworks perform far less favorably when evaluated in their ability to generalize or transfer representations across different tasks. Existing algorithms that facilitate transfer typically are limited to cases in which the transition function or the optimal policy is portable to new contexts, but achieving “deep transfer” characteristic of human behavior has been elusive. Such transfer typically requires discovery of abstractions that permit analogical reuse of previously learned representations to superficially distinct tasks. Here, we demonstrate that abstractions that minimize error in predictions of reward outcomes generalize across tasks with different transition and reward functions. Such reward-predictive representations compress the state space of a task into a lower dimensional representation by combining states that are equivalent in terms of both the transition and reward functions. Because only state equivalences are considered, the resulting state representation is not tied to the transition and reward functions themselves and thus generalizes across tasks with different reward and transition functions. These results contrast with those using abstractions that myopically maximize reward in any given MDP and motivate further experiments in humans and animals to investigate if neural and cognitive systems involved in state representation perform abstractions that facilitate such equivalence relations.Author summaryHumans are capable of transferring abstract knowledge from one task to another. For example, in a right-hand-drive country, a driver has to use the right arm to operate the shifter. A driver who learned how to drive in a right-hand-drive country can adapt to operating a left-hand-drive car and use the other arm for shifting instead of re-learning how to drive. Despite the fact that both tasks require different coordination of motor skills, both tasks are the same in an abstract sense: In both tasks, a car is operated and there is the same progression from 1st to 2nd gear and so on. We study distinct algorithms by which a reinforcement learning agent can discover state representations that encode knowledge about a particular task, and evaluate how well they can generalize. Through a sequence of simulation results, we show that state abstractions that minimize errors in prediction about future reward outcomes generalize across tasks, even those that superficially differ in both the goals (rewards) and the transitions from one state to the next. This work motivates biological studies to determine if distinct circuits are adapted to maximize reward vs. to discover useful state representations.
Mechanisms of convergent egg-provisioning in poison frogs
Authors: Fischer Eva K. , Roland Alexandre B. , Moskowitz Nora A. , Vidoudez Charles , Ranaivorazo Ndimbintsoa , Tapia Elicio E. , Trauger Sunia A. , Vences Miguel , Coloma Luis A. , O’Connell Lauren A. 
Published: May 2019

AbstractParental provisioning of offspring with physiological products occurs in many animals. Within amphibians, maternal provisioning has evolved multiple times, including in South American dendrobatid and Malagasy mantellid poison frogs. In some of these species, mothers feed unfertilized eggs to their developing tadpoles for several months until tadpoles complete metamorphosis. We conducted field studies in Ecuador and Madagascar to ask whether convergence at the behavioral level provides similar benefits to offspring and whether nursing behavior relies on shared neural mechanisms across frogs and vertebrates more broadly. At an ecological level, we found that nursing allows poison frog mothers to provide chemical defenses to their tadpoles in both species. At the level of brain regions, nursing behavior was associated with increased neural activity in the lateral septum and preoptic area in both species, demonstrating recruitment of shared brain regions in the convergent evolution of maternal care within frogs and across vertebrates. In contrast at a molecular level, only mantellids showed increased oxytocin neuron activity akin to that in nursing mammals. Taken together, our findings demonstrate that convergently evolved maternal provisioning behavior provides similar benefits to offspring and relies on similar brain regions. However, the molecular mechanisms underlying the convergence in nursing behavior may be different, suggesting evolutionary versatility in the mechanisms promoting maternal behavior.
Not a one-way road – severity, progression and prevention of firework fears in dogs
Authors: Riemer Stefanie 
Published: May 2019

AbstractNoise fears represent a highly prevalent welfare problem in dogs. An online survey was performed to explore severity and progression of firework fears in dogs, and relationships with demographics, health, behaviour problems, and owners’ training efforts to prevent or alleviate firework fears. 1225 responses were analysed. Fifty-two percent of dogs were at least partially affected by firework fears, and the great majority developed a fear of fireworks in the first year of life, with a decreasing frequency of new occurrences up until seven years, and only few newly affected dogs beyond this age. While almost three quarters of fearful dogs had recovered by the next morning, recovery took up to one day in 10%, up to one week in 12%, and several weeks or even months in >3%. Univariate analyses indicated a significant effect of breed group, age, sex, neuter status, origin and age at acquisition on severity of firework fears in dogs. However, binomial models including multiple predictors of presence/ absence of firework fears identified only age, breed group (mixed breeds being most affected), health problems, and an interaction between health problems and age as significant predictors. This discrepancy might be explained by collinearities of predictors and underlying differences between mixed-breed dogs and purebreds, such as mixed breeds being acquired from shelters more often, being adopted at higher ages, and being neutered more often. Firework fears are highly correlated with fears of gunshots and thunder, and to a low extent with fears of other noises, but not with any other behavioural problems. Both improvement and deterioration of firework fears were frequently reported. While an early age of onset and breed differences point to a strong genetic contribution to firework fears, training puppies or non-fearful adults to associate the noise with positive stimuli is highly effective in preventing later development of firework fears.
Evaluation and Optimization of Chemically-Cleavable Linkers for Quantitative Mapping of Small Molecule-Protein Interactomes
Authors: Rabalski Adam J. , Bogdan Andrew R. , Baranczak Aleksandra 
Published: May 2019

AbstractNumerous reagents have been developed to enable chemical proteomic analysis of small molecule-protein interactomes. However, the performance of these reagents has not been systematically evaluated and compared. Herein, we report our efforts to conduct a parallel assessment of two widely-used chemically-cleavable linkers equipped with dialkoxydiphenylsilane (DADPS linker) and azobenzene (AZO linker) moieties. Profiling a cellular cysteinome using iodoacetamide alkyne probe demonstrated a significant discrepancy between the experimental results obtained through the application of each of the reagents. To better understand the source of observed discrepancy, a mass tolerant database search strategy using MSFragger software was performed. This resulted in identifying a previously unreported artifactual modification on the residual mass of the azobenzene linker. Furthermore, we conducted a comparative analysis of enrichment modes using both cleavable linkers. This effort determined that enrichment of proteolytic digests yielded a far greater number of identified cysteine residues than the enrichment conducted prior to protein digest. Inspired by recent studies where multiplexed quantitative labeling strategies were applied to cleavable biotin linkers, we combined this further optimized protocol using the DADPS cleavable linker with tandem mass tag (TMT) labeling to profile the FDA-approved covalent EGFR kinase inhibitor dacomitinib against the cysteinome of an epidermoid cancer cell line. Our analysis resulted in the detection and quantification of over 10,000 unique cysteine residues, a nearly 3-fold increase over previous studies that used cleavable biotin linkers for enrichment. Critically, cysteine residues corresponding to proteins directly as well as indirectly modulated by dacomitinib treatment were identified. Overall, our study suggests that the dialkoxydiphenylsilane linker could be broadly applied wherever chemically cleavable linkers are required for chemical proteomic characterization of cellular proteomes.
Scribble and Discs-large direct adherens junction positioning and supermolecular assembly to establish apical-basal polarity
Authors: Bonello Teresa T. , Peifer Mark 
Published: May 2019

AbstractApical-basal polarity is a fundamental property of animal tissues. TheDrosophilaembryo provides an outstanding model for defining mechanisms that initiate and maintain polarity. Polarity is initiated during cellularization, when cell-cell adherens junctions are positioned at the future boundary of apical and basolateral domains. Polarity maintenance then involves complementary and antagonistic interplay between apical and basal polarity complexes. The Scribble/Dlg module is well-known for promoting basolateral identity during polarity maintenance. Here we report a surprising role for the Scribble/Dlg module in polarity initiation, placing it at the top of the network that positions adherens junctions. Scribble and Dlg are enriched in nascent adherens junctions and are essential for adherens junction positioning and supermolecular assembly. They also play a role in basal junction assembly. We test hypotheses for the underlying mechanisms. Our data suggest that the Scribble/Dlg module plays multiple roles in polarity initiation, via Par-1-dependent and independent mechanisms. Different domains of Scribble contribute to these distinct roles. Together these data reveal novel roles for Scribble/Dlg as master scaffolds regulating the assembly of distinct junctional complexes at different times and places.
Allosteric regulation of glycogen phosphorylase solution phase structural dynamics at high spatial resolution
Authors: Kish Monika , Smith Victoria , Subramanian Sivaraman , Vollmer Frank , Lethbridge Natasha , Cole Lindsay , Bond Nicholas. J. , Phillips Jonathan J. 
Published: May 2019

AbstractGlycogen phosphorylase (GlyP) was the first allosteric enzyme to be described. Yet, the precise dynamic changes in solution phase structure and stability that underpin functional regulation have remained elusive. We have developed a new fully-automated and highly flexible implementation of hydrogen/deuterium-exchange mass spectrometry, operating in the millisecond regime. This enabled measurements of the solution phase local structural dynamics involved in allosteric regulation of GlyP. Here, we quantify GlyP structural dynamics in solution, describing correlated changes in structure in the activated (pSer14) and inhibited (glucose-6-phosphate bound) forms of the enzyme. The sensitivity of these measurements discerned that the 250s’ loop is natively disordered in the apo T-state, adopting a more ordered conformation in the active state. The quantitative change in stability of the 280s loop is identified, providing the first direct evidence of the entropic switch that sterically regulates substrate access to the active site.Significance StatementWe have developed a new fully-automated and highly flexible implementation of hydrogen/deuterium-exchange mass spectrometry, operating in the millisecond regime. Measurements of glycogen phosphorylase quantify the solution phase stability of local structure at near-amino acid structural resolution and with no appreciable lower limit of stability. This uncovered the highly-resolved local alterations in stability which provides direct evidence of the entropic mechanism by which access to the active site is gated by the 280s loop.FootnotesAuthor contributions: M.K., V.S., S.S., N.L., F.V., N.B., L.C. and J.J.P. designed research; M.K., V.S., S.S., L.C. and J.J.P. performed research; M.K., V.S., S.S., L.C. and J.J.P. analyzed data; and M.K. and J.J.P. wrote the manuscript.
Molecular Determinants of μ-Conotoxin KIIIA Interaction with the Human Voltage-Gated Sodium Channel NaV1.7
Authors: Kimball Ian H. , Nguyen Phuong T. , Olivera Baldomero M. , Sack Jon T. , Yarov-Yarovoy Vladimir 
Published: May 2019

AbstractThe voltage-gated sodium (NaV) channel subtype NaV1.7 plays a critical role in pain signaling, making it an important drug target. Here we studied the molecular interactions between μ-conotoxin KIIIA (KIIIA) and the human NaV1.7 channel (hNaV1.7). We developed a structural model of hNaV1.7 using Rosetta computational modeling and performed in silico docking of KIIIA using RosettaDock to predict residues forming specific pairwise contacts between KIIIA and hNaV1.7. We experimentally validated these contacts using mutant cycle analysis. Comparison between our KIIIA-hNaV1.7 model and the cryo-EM structure of KIIIA-hNaV1.2 revealed key similarities and differences between NaVchannel subtypes with potential implications for the molecular mechanism of toxin block. The accuracy of our integrative approach, combining structural data with computational modeling, experimental validation, and molecular dynamics simulations, suggests that Rosetta structural predictions will be useful for rational design of novel biologics targeting specific NaVchannels.
USP1 deubiquitinates protein kinase Akt to inhibit PI3K-Akt-FoxO signaling
Authors: Goldbraikh Dana , Neufeld Danielle , Mutlak-Eid Yara , Lasry Inbal , Parnis Anna , Cohen Shenhav 
Published: May 2019

ABSTRACTPI3K-Akt-FoxO-mTOR signaling is the central pathway controlling growth and metabolism in all cells. Activation of this pathway requires ubiquitination of Akt prior to its activation by phosphorylation. Here, we found that the deubiquitinating (DUB) enzyme USP1 removes K63-linked polyubiquitin chains on Akt to sustain PI3K-Akt-FoxO signaling low during prolonged starvation. DUB screening platform identified USP1 as a direct DUB for Akt, and USP1 depletion in atrophying muscle increased Akt ubiquitination, PI3K-Akt-FoxO signaling, and glucose uptake during fasting. Co-immunoprecipitation and mass spectrometry identified Disabled-2 (Dab2) and the tuberous sclerosis complex TSC1/TSC2 as USP1 bound proteins. During starvation, Dab2 was essential for Akt recruitment to USP1/UAF1 complex, and for PI3K-Akt-FoxO inhibition. Additionally, to maintain its own protein levels high, USP1 limits TSC1 levels to sustain mTOR-mediated basal protein synthesis rates. This USP1-mediated suppression of PI3K-Akt-FoxO signaling probably contributes to insulin resistance in catabolic diseases and perhaps to malignancies seen with USP1 mutations.