bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fitness barriers limit reversion of a proofreading-deficient coronavirus
Authors: Graepel Kevin W. , Agostini Maria L. , Lu Xiaotao , Sexton Nicole R. , Denison Mark R. 
Published: April 2019

ABSTRACTThe 3′-to-5′ exoribonuclease in coronavirus (CoV) nonstructural protein 14 (nsp14-ExoN) mediates RNA proofreading during genome replication. ExoN catalytic residues are arranged in three motifs: I (DE), II (E), III (D). Alanine substitution of the motif I residues (AA-E-D, four nucleotide substitutions) in murine hepatitis virus (MHV) and SARS-CoV yields viable mutants with impaired replication and fitness, increased mutation rates, and attenuated virulencein vivo. Despite these impairments, MHV- and SARS-CoV ExoN motif I AA mutants (ExoN-AA) have not reverted at motif I in diversein vitroandin vivoenvironments, suggesting that profound fitness barriers prevent motif I reversion. To test this hypothesis, we engineered MHV-ExoN-AA with 1, 2 or 3 nucleotide mutations along genetic pathways to AA-to-DE reversion. We show that engineered intermediate revertants were viable but had no increased replication or competitive fitness compared to MHV-ExoN-AA. In contrast, a low passage (P10) MHV-ExoN-AA showed increased replication and competitive fitness without reversion of ExoN-AA. Finally, engineered reversion of ExoN-AA to ExoN-DE in the presence of ExoN-AA passage-adaptive mutations resulted in significant fitness loss. These results demonstrate that while reversion is possible, at least one alternative adaptive pathway is more rapidly advantageous than intermediate revertants and may alter the genetic background to render reversion detrimental to fitness. Our results provide an evolutionary rationale for lack of ExoN-AA reversion, illuminate potential multi-protein replicase interactions and coevolution, and support future studies aimed at stabilizing attenuated CoV ExoN-AA mutants.IMPORTANCECoronaviruses encode an exoribonuclease (ExoN) that is important for viral replication, fitness, and virulence, yet coronaviruses with a defective ExoN (ExoN-AA) have not reverted under diverse experimental conditions. In this study, we identify multiple impediments to MHV-ExoN-AA reversion. We show that ExoN-AA reversion is possible but evolutionarily unfavorable. Instead, compensatory mutations outside of ExoN-AA motif I are more accessible and beneficial than partial reversion. We also show that coevolution between replicase proteins over long-term passage partially compensates for ExoN-AA motif I but renders the virus inhospitable to a reverted ExoN. Our results reveal the evolutionary basis for the genetic stability of ExoN-inactivating mutations, illuminate complex functional and evolutionary relationships between coronavirus replicase proteins, and identify potential mechanisms for stabilization of ExoN-AA coronavirus mutants.
Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts ultimate human lifespan limit
Authors: Pyrkov Timothy V. , Avchaciov Konstantin , Tarkhov Andrei E. , Menshikov Leonid I. , Gudkov Andrei V. , Fedichev Peter O. 
Published: April 2019

ABSTRACTWe investigated the dynamic properties of the organism state fluctuations along individual aging trajectories in a large longitudinal database of CBC measurements from a consumer diagnostics laboratory. To simplify the analysis, we used a log-linear mortality estimate from the CBC variables as a single quantitative measure of aging process, henceforth referred to as dynamic organism state index (DOSI). We observed, that the age-dependent population DOSI distribution broadening could be explained by a progressive loss of physiological resilience measured by the DOSI auto-correlation time. Extrapolation of this trend suggested that DOSI recovery time and variance would simultaneously diverge at a critical point of 120 − 150 years of age corresponding to a complete loss of resilience. The observation was immediately confirmed by the independent analysis of correlation properties of intraday physical activity levels fluctuations collected by wearable devices. We conclude that the criticality resulting in the end of life is an intrinsic biological property of an organism that is independent of stress factors and signifies a fundamental or absolute limit of human lifespan.
A Framework for Integrating Directed and Undirected Annotations to Build Explanatory Models of cis-eQTL Data
Authors: Lamparter David , Bhatnagar Rajat , Hebestreit Katja , Belgard T. Grant , Hanson-Smith Victor 
Published: April 2019

1AbstractA longstanding goal of regulatory genetics is to understand how variants in genome sequences lead to changes in gene expression. Here we present a method named Bayesian Annotation Guided eQTL Analysis (BAGEA), a variational Bayes framework to model cis-eQTLs using directed and undirected genomic annotations. In a use case, we integrated directed genomic annotations with eQTL summary statistics from tissues of various origins. This analysis revealed epigenetic marks that are relevant for gene expression in different tissues and cell types. We estimated the predictive power of the models that were fitted based on directed genomic annotations. This analysis showed that, depending on the underlying eQTL data used, the directed genomic annotations could predict up to 1.5% of the variance observed in the expression of genes with top nominal eQTL association p-values < 10−7. For genes with estimated effect sizes in the top 25% quantile, up to 5% of the expression variance could be predicted. Based on our results, we recommend the use of BAGEA for the analysis of cis-eQTL data to reveal annotations relevant to expression biology.
Selective Influence and Sequential Operations: A Research Strategy for Visual Search
Authors: Lowe Kaleb A. , Reppert Thomas R. , Schall Jeffrey D 
Published: April 2019

ABSTRACTWe introduce conceptually and empirically a powerful but underutilized experimental approach to dissect the cognitive processes supporting performance of a visual search task with factorial manipulations of singleton-distractor identifiability and stimulus-response cue discriminability. We show that systems factorial technology can distinguish processing architectures from the performance of macaque monkeys. This demonstration offers new opportunities to distinguish neural mechanisms through selective manipulation of visual encoding, search selection, rule encoding, and stimulus-response mapping.
Irrational risk aversion in ants is driven by perceptual mechanisms
Authors: De Agrò Massimo , Grimwade Daniel , Czaczkes Tomer J. 
Published: April 2019

AbstractAnimals must often decide between exploiting safe options or risky options with a chance for large gains. While traditional optimal foraging theories assume rational energy maximisation, they fail to fully describe animal behaviour. A logarithmic rather than linear perception of stimuli may shape preference, causing animals to make suboptimal choices. Budget-based rules have also been used to explain risk-preference, and the relative importance of these theories is debated. Eusocial insects represent a special case of risk sensitivity, as they must often make collective decisions based on resource evaluations from many individuals. Previously, colonies of the antLasius nigerwere found to be risk-neutral, but the risk preference of individual foragers was unknown. Here, we tested individualL. nigerin a risk sensitivity paradigm. Ants were trained to associate a scent with 0.55M sucrose solution and another scent with an equal chance of either 0.1 and 1.0M sucrose. Preference was tested in a Y-maze. Ants were extremely risk averse, with 91% choosing the safe option. Even when the risky option offered on average more sucrose (0.8M) than the fixed option, 75% preferred the latter. Based on the psychophysical Weber-Fechner law, we predicted that logarithmically balanced alternatives (0.3M vs 0.1M/0.9M) would be perceived as having equal value. Our prediction was supported, with ants having no preference for either feeder (53% chose the fixed option). Our results thus strongly support perceptual mechanisms driving risk-aversion in ants, and demonstrate that the behaviour of individual foragers can be a very poor predictor of colony-level behaviour.
The Drosophila metallopeptidase superdeath decouples apoptosis from the activation of the ER stress response
Authors: Palu Rebecca A.S. , Chow Clement Y. 
Published: April 2019

ABSTRACTEndoplasmic reticulum (ER) stress-induced apoptosis is a primary cause and modifier of degeneration in a number of genetic disorders. Understanding how genetic variation between individuals influences the ER stress response and subsequent activation of apoptosis could improve individualized therapies and predictions of outcomes for patients. In this study, we find that the uncharacterized, membrane-bound metallopeptidase CG14516 in Drosophila melanogaster, which we rename as SUPpressor of ER stress-induced DEATH (superdeath), plays a role in modifying ER stress-induced apoptosis. We demonstrate that loss of superdeath reduces apoptosis and degeneration in the Rh1G69D model of ER stress through the JNK signaling cascade. This effect on apoptosis occurs without altering the activation of the unfolded protein response (IRE1 and PERK), suggesting that the beneficial pro-survival effects of this response are intact. Furthermore, we show that superdeath functions epistatically upstream of CDK5, a known JNK-activated pro-apoptotic factor in this model of ER stress. We demonstrate that superdeath is not only a modifier of this particular model, but functions as a general modifier of ER stress-induced apoptosis across different tissues and ER stresses. Finally, we present evidence of Superdeath localization to the endoplasmic reticulum membrane. While similar in sequence to a number of human metallopeptidases found in the plasma membrane and ER membrane, its localization suggests that superdeath is orthologous to ERAP1/2 in humans. Together, this study provides evidence that superdeath is a link between stress in the ER and activation of cytosolic apoptotic pathways.SIGNIFICANCE STATEMENTGenetic diseases display a great deal of variability in presentation, progression, and overall outcomes. Much of this variability is caused by differences in genetic background among patients. One process that commonly modifies degenerative disease is the endoplasmic reticulum (ER) stress response. Understanding the genetic sources of variation in the ER stress response could improve individual diagnosis and treatment decisions. In this study, we characterized one such modifier in Drosophila melanogaster, the membrane-bound metallopeptidase CG14516 (superdeath). Loss of this enzyme suppresses a model of ER stress-induced degeneration by reducing cell death without altering the beneficial activation of the unfolded protein response. Our findings make superdeath and its orthologues attractive therapeutic targets in degenerative disease.
Deconvolute individual genomes from metagenome sequences through read clustering
Authors: Li Kexue , Wang Lili , Shi Lizhen , Deng Li , Wang Zhong 
Published: April 2019

ABSTRACTMotivationMetagenome assembly from short next-generation sequencing data is a challenging process due to its large scale and computational complexity. Clustering short reads before assembly offers a unique opportunity for parallel downstream assembly of genomes with individualized optimization. However, current read clustering methods suffer either false negative (under-clustering) or false positive (over-clustering) problems.ResultsBased on a previously developed scalable read clustering method on Apache Spark, SpaRC, that has very low false positives, here we extended its capability by adding a new method to further cluster small clusters. This method exploits statistics derived from multiple samples in a dataset to reduce the under-clustering problem. Using a synthetic dataset from mouse gut microbiomes we show that this method has the potential to cluster almost all of the reads from genomes with sufficient sequencing coverage. We also explored several clustering parameters that deferentially affect genomes with various sequencing coverage.Availabilityhttps://bitbucket.org/berkeleylab/jgi-sparc/.Contactzhongwang@lbl.gov
Neuronal avalanches in input and associative layers of auditory cortex
Authors: Bowen Zac , Winkowski Daniel E. , Seshadri Saurav , Plenz Dietmar , Kanold Patrick O. 
Published: April 2019

AbstractThe primary auditory cortex processes acoustic sequences for the perception of behaviorally meaningful sounds such as speech. Sound information arrives at its input layer 4 from where activity propagates to associative layer 2/3. It is currently not known whether there is a particular organization of neuronal population activity that is stable across layers and sound levels during sound processing. We used in vivo 2-photon imaging of pyramidal neurons in cortical layers L4 and L2/3 of mouse A1 to characterize the populations of neurons that were active spontaneously, i.e. in the absence of a sound stimulus, and those recruited by single-frequency tonal stimuli at different sound levels. Single-frequency sounds recruited neurons of widely ranging frequency selectivity in both layers. We defined neural ensembles as neurons being active within or during successive temporal windows at the temporal resolution of our imaging. For both layers, neuronal ensembles were highly variable in size during spontaneous activity as well as during sound presentation. Ensemble sizes distributed according to power laws, the hallmark of neuronal avalanches, and were similar across sound levels. Avalanches activated by sound were composed of neurons with diverse tuning preference, yet with selectivity independent of avalanche size. Thus, spontaneous and evoked activity in both L4 and L2/3 of A1 are composed of neuronal avalanches with similar power law relationships. Our results demonstrate network principles linked to maximal dynamic range, optimal information transfer and matching complexity between L4 and L2/3 to shape population activity in auditory cortex.
Bacteriophage can promote the emergence of physiologically sub-optimal host phenotypes
Authors: Schenk Hanna , Sieber Michael 
Published: April 2019

AbstractReproduction of bacteria-specific viruses, or bacteriophage, requires the replication and translation machinery of the host cell. As a consequence, phage fitness depends intimately on the physiological state, i.e. growth rate, of the host. We include this dependence of critical phage traits on host growth rate in a mathematical model of a bacteria-phage interaction. This leads to a feedback loop between phage success, host population size, nutrient availability and host growth rate. We find that this feedback allows slow growing bacteria to have a competitive advantage in the presence of phage. Under certain conditions a slow growing host mutant can even drive the phage to extinction. Since in a phage-free environment slow growth is deleterious, the mutant subsequentely dies out as well, constituting a kind of altruistic scenario similar to abortive infections.
Consistent trade-offs in ecosystem services between land covers with different production intensities
Authors: Gómez-Creutzberg Carla , Lagisz Malgorzata , Nakagawa Shinichi , Brockerhoff Eckehard G. , Tylianakis Jason M. 
Published: April 2019

ABSTRACTSustaining multiple ecosystem services across a landscape requires an understanding of how consistently services are shaped by different categories of land uses. Yet, this understanding is generally constrained by the availability of fine-resolution data for multiple services across large areas and the spatial variability of land-use effects on services. We systematically surveyed published literature for New Zealand (1970 – 2015) to quantify the supply of 17 services across 25 land covers (as a proxy for land use). We found a consistent trade-off in the services supplied by anthropogenic land covers with a high production intensity (e.g., cropping) versus those with extensive or no production. In contrast, forest cover was not associated with any distinct patterns of service supply. By drawing on existing research findings we reveal complementarity and redundancy (potentially influencing resilience) in service supply from different land covers. This can guide practitioners in shaping land systems that sustainably support human well-being.
Intron-targeted mutagenesis reveals roles forDscam1RNA pairing-mediated splicing bias in neuronal wiring
Authors: Hong Weiling , Dong Haiyang , Zhang Jian , Zhou Fengyan , Wu Yandan , Shi Yang , Chen Shuo , Xu Bingbing , You Wendong , Shi Feng , Yang Xiaofeng , Gong Zhefeng , Huang Jianhua , Jin Yongfeng 
Published: April 2019

AbstractDrosophila melanogasterDown syndrome cell adhesion molecule (Dscam1) can potentially generate 38,016 different isoforms through stochastic, yet highly biased, alternative splicing. Genetic studies demonstrated that stochastic expression of multiple Dscam1 isoforms provides each neuron with a unique identity for self/non-self-discrimination. However, due to technical obstacles, the functional significance of the highly specific bias in isoform expression remains entirely unknown. Here, we provide conclusive evidence thatDscam1splicing bias is required for precise mushroom body (MB) axonal wiring in flies in a variable exon-specific manner. We showed that targeted deletion of the intronic docking site perturbed base pairing-mediated regulation of inclusion of variable exons. Unexpectedly, we generated mutant flies with normal overall Dscam1 protein levels and an identical number but global changes in exon 4 and exon 9 isoform bias (DscamΔ4D−/−and DscamΔ9D−/−), respectively. DscamΔ9D−/−mutant exhibited remarkable mushroom body defects, which were correlated with the extent of the disrupted isoform bias. By contrast, the DscamΔ4D−/−animals exhibited a much less severe defective phenotype than DscamΔ9D−/−animals, suggestive of a variable domain-specific requirement for isoform bias. Importantly, mosaic analysis revealed that changes in isoform bias caused axonal defects but did not influence the self-avoidance of axonal branches. We concluded that, in contrast to the Dscam1 isoform number that provides the molecular basis for neurite self-avoidance, isoform bias may play a non-repulsive role in mushroom body axonal wiring.
Myelination of major white matter tracts continues beyond childhood—combining tractography and myelin water imaging
Authors: Meissner Tobias W. , Genç Erhan , Mädler Burkhard , Weigelt Sarah 
Published: April 2019

AbstractAxonal myelination is a key white matter maturation process as it increases conduction velocity, synchrony, and reliability. While diffusion tensor imaging (DTI) is sensitive to myelination, it is also sensitive to unrelated microstructural properties, thus hindering straightforward interpretations. Myelin water imaging (MWI) provides a more reliable and direct in vivo measure of myelination. Although early histological studies show protracted myelination from childhood to adulthood, reliable tract-specific in vivo evidence from MWI is still lacking. Here, we combine MWI and DTI tractography to investigate myelination in middle childhood, late childhood, and adulthood in 18 major white matter tracts. In the vast majority of major white matter tracts, myelin water fraction continued to increase beyond late childhood. Our study provides first in vivo evidence for protracted myelination beyond late childhood.
Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome
Authors: Abildgaard Amanda B. , Stein Amelie , Nielsen Sofie V. , Schultz-Knudsen Katrine , Papaleo Elena , Shrikhande Amruta , Hoffmann Eva R. , Bernstein Inge , Gerdes Anne-Marie , Takahashi Masanobu , Ishioka Chikashi , Lindorff-Larsen Kresten , Hartmann-Petersen Rasmus 
Published: April 2019

AbstractDefective mismatch repair leads to increased mutation rates, and germline loss-of-function variants in the repair component MLH1 cause the hereditary cancer predisposition disorder known as Lynch syndrome. Early diagnosis is important, but complicated by many variants being of unknown significance. Here we show that a majority of the disease-linked MLH1 variants we studied are present at reduced cellular levels. We show that destabilized MLH1 variants are targeted for chaperone-assisted proteasomal degradation, resulting also in degradation of co-factors PMS1 and PMS2.In silicosaturation mutagenesis and computational predictions of thermodynamic stability of MLH1 missense variants revealed a correlation between structural destabilization, reduced steady-state levels and loss-of-function. Thus, we suggest that loss of stability and cellular degradation is an important mechanism underlying manyMLH1variants in Lynch syndrome. Combined with analyses of conservation, the thermodynamic stability predictions separate disease-linked from benignMLH1variants, and therefore hold potential for Lynch syndrome diagnostics.
Identifying Novel Candidates for Re-Purposing as Potential Therapeutic Agents for Alzheimer’s disease
Authors: Ballard C , Creese B , Gatt A , Doherty P , Francis PT , Whitfield D , Corbett A , Corcoran J , Hanger D , Thuret S , Killick R , Williams G 
Published: April 2019

AbstractThe current paper describes the identification of novel candidate compounds for repositioning as treatments for Alzheimer’s disease (AD) from the CMAP library. Candidate compounds were identified based on inverse correlation with transcriptome signatures developed from meta-analyses of Alzheimer RNA expression studies using the SPIED platform. The 78 compounds with a significant inverse correlation were taken forward into an in vitro programme using 6 well validated screening assays relevant to potential treatment targets in AD. Nineteen pf the compounds were hits in at least 2 of these assays. A description of each of these compounds is presented.
Chlamydia trachomatisoutbreak: when the virulence-associated genome backbone imports a prevalence-associated major antigen signature
Authors: Borges Vítor , Cordeiro Dora , Salas Ana Isabel , Lodhia Zohra , Correia Cristina , Isidro Joana , Fernandes Cândida , Rodrigues Ana Maria , Azevedo Jacinta , Alves João , Roxo João , Rocha Miguel , Côrte-Real Rita , Vieira Luís , Borrego Maria José , Gomes João Paulo 
Published: April 2019

AbstractChlamydia trachomatisis the most prevalent sexually transmitted bacteria worldwide and the causative agent of blinding trachoma. Strains are classified based onompAgenotypes, which are strongly linked with differential tissue tropism and disease outcomes. A lymphogranuloma venereum (LGV) epidemics, characterized by ulcerative proctitis, has emerged in the last two decades (mainly L2b genotype), raising high concern especially due to its circulation among men who have sex with men (MSM). Here, we report an ongoing outbreak (mostly affecting HIV-positive MSM engaging in high-risk practices) caused by an L2b strain with a rather unique genome makeup that precluded the laboratory notification of this outbreak as LGV due to its non-LGVompAsignature. Homologous recombination mediated the transfer of a ~4.5Kbp fragment enrollingCT681/ompAand neighboring genes (CT677/rrf, CT678/pyrH, CT679/tsf, CT680/rpsB) from a serovar D/Da strain likely possessing the typical T1 clade genome backbone associated with most prevalent genotypes (E and F). The hybrid L2b/D-Da strain presents the adhesin and immunodominant antigen MOMP (coded byompA) with an epitope repertoire typical of non-invasive genital strains, while keeping the genome-dispersed virulence fingerprint of a classical LGV (L2b) strain. As previously reported for inter-cladeompAexchange among non-LGV clades, this unprecedentedC. trachomatisgenomic mosaic involving a contemporary epidemiologically and clinically relevant LGV strain may have implications on its transmission, tissue tropism and pathogenic capabilities. The emergence of such variants with epidemic and pathogenic potential highlights the need of more oriented surveillance strategies focused on capturing the C.trachomatisevolution in action.