bluuebunny/crossref_metadata_2025_split huggingface dataset:
NORTH: a highly accurate and scalable Naive Bayes based ORTHologous gene clustering algorithm
Authors: Ibtehaz Nabil , Ahmed Shafayat , Saha Bishwajit , Rahman M. Sohel , Bayzid Md. Shamsuzzoha 
Published: January 2019

AbstractBackgroundThe principal objective of comparative genomics is inferring attributes of an unknown gene by comparing it with well-studied genes. In this regard, identifying orthologous genes plays a pivotal role as the orthologous genes remain less diverged in the course of evolution. However, identifying orthologous genes is often difficult, slow, and idiosyncratic, especially in the presence of multiplicity of domains in proteins, evolutionary dynamics (gene duplication, transfer, loss, introgression etc.), multiple paralogous genes, incomplete genome data, and for distantly related species where similarity is hard to recognize.MotivationAdvances in identifying orthologs have mostly been constrained to developing databases of genes or methods which involve computationally expensive BLAST search or constructing phylogenetic trees to infer orthologous relationships. These methods do not generally scale well and cannot analyze large amount of data from diverse organisms with high accuracy. Moreover, most of these methods involve manual parameter tuning, and hence are neither fully automated nor free from human bias.ResultsWe present NORTH, a novel, automated, highly accurate and scalable machine learning based orhtologous gene clustering method. We have utilized the biological basis and intuition of orthologous genes and made an effort to incorporate appropriate ideas from machine learning (ML) and natural language processing (NLP). We have discovered that the BLAST search based protocols deeply resemble a “text classification” problem. Thus, we employ the robustbag-of-words modelaccompanied by a Naive Bayes classifier to cluster the orthologous genes. We studied 1,255,877 genes in the largest 250 ortholog clusters from the KEGG database, across 3,880 organisms comprising the six major groups of life, namely, Archaea, Bacteria, Animals, Fungi, Plants and Protists. Despite having more than a million of genes on distantly related species with acute data imbalance, NORTH is able to cluster them with 98.48% Precision, 98.43% Recall and 98.44%F1score, showing that automatic orthologous gene clustering can be both highly accurate and scalable. NORTH is available as a web interface with a server side application, along with cross-platform native applications (available athttps://nibtehaz.github.io/NORTH/) – allowing queries based on individual genes.
Ketamine Affects Prediction Errors about Statistical Regularities: A Computational Single-Trial Analysis of the Mismatch Negativity
Authors: Weber Lilian A. , Diaconescu Andreea O. , Mathys Christoph , Schmidt André , Kometer Michael , Vollenweider Franz , Stephan Klaas E. 
Published: January 2019

AbstractThe auditory mismatch negativity (MMN) is significantly reduced in schizophrenia. Notably, a similar MMN reduction can be achieved with NMDA receptor (NMDAR) antagonists. Both phenomena have been interpreted as reflecting an impairment of predictive coding or, more generally, the “Bayesian brain” notion that the brain continuously updates a hierarchical model to infer the causes of its sensory inputs. Specifically, predictive coding views perceptual inference as an NMDAR-dependent process of minimizing hierarchical precision-weighted prediction errors (PEs). Disturbances of this putative process play a key role in hierarchical Bayesian theories of schizophrenia.Here, we provide empirical evidence for this clinical theory, demonstrating the existence of multiple, hierarchically related PEs in a “roving MMN” paradigm. We applied a computational model, the Hierarchical Gaussian Filter (HGF), to single-trial EEG data from healthy volunteers that received the NMDAR antagonist S-ketamine in a placebo-controlled, double-blind, within-subject fashion. Using an unrestricted analysis of the entire time-sensor space, our computational trial-by-trial analysis indicated that low-level PEs (about stimulus transitions) are expressed early (102-207ms post-stimulus), while high-level PEs (about transition probability) are reflected by later components (152-199ms, 215-277ms) of single-trial responses. Furthermore, we find that ketamine significantly diminished the expression of high-level PE responses, implying that NMDAR antagonism disrupts inference on abstract statistical regularities.Our findings are consistent with long-standing notions that NMDAR dysfunction may cause positive symptoms in schizophrenia by impairing hierarchical Bayesian inference about the world’s statistical structure. Beyond their relevance for schizophrenia, our results illustrate the potential of computational single-trial analyses for assessing potential disease mechanisms.
Genetic Identification of Cell Types Underlying Brain Complex Traits Yields Novel Insights Into the Etiology of Parkinson’s Disease
Authors: Bryois Julien , Skene Nathan G. , Hansen Thomas Folkmann , Kogelman Lisette J.A. , Watson Hunna J. ,   Eating Disorders Working Group of the Psychiatric Genomics Consortium,   International Headache Genetics Consortium,   The 23andMe Research Team, Brueggeman Leo , Breen Gerome , Bulik Cynthia M. , Arenas Ernest , Hjerling-Leffler Jens , Sullivan Patrick F. 
Published: January 2019

AbstractGenome-wide association studies (GWAS) have discovered hundreds of loci associated with complex brain disorders, and provide the best current insights into the etiology of these idiopathic traits. However, it remains unclear in which cell types these variants may be active, which is essential for understanding disease etiology and for disease modelling. Here we integrate GWAS results with single-cell transcriptomic data from the entire nervous system to systematically identify cell types underlying psychiatric disorders, neurological conditions, and other brain complex traits. We show that psychiatric disorders are predominantly associated with excitatory neurons from the cortex/hippocampus, medium spiny neurons from the striatum, diverse sets of midbrain neurons, and inhibitory neurons from the cortex/hippocampus. Cognitive traits were generally associated with similar cell types but their associations were driven by different genes. Neurological disorders were associated with different cell types, consistent with other lines of evidence. Notably, we found that Parkinson’s disease is not only genetically associated with dopaminergic neurons but also with serotonergic neurons and cells from the oligodendrocyte lineage. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Altogether, our study provides a solid framework for understanding the cellular basis of complex brain disorders and reveals a new unexpected role of oligodendrocytes in Parkinson’s disease.
Characterization of Spontaneously Arising Chlorhexidine-Tolerant Variants inStreptococcus mutans
Authors: Kaspar Justin R. , Godwin Matthew J. , Velsko Irina M. , Richards Vincent P. , Burne Robert A. 
Published: January 2019

ABSTRACTBroad spectrum antimicrobials, both in dental products and within the clinic, have been used in the suppression of cariogenic bacteria such asStreptococcus mutansfor over 40 years. One such antimicrobial is chlorhexidine (CHX), and serves as a standard in dental research against which other antimicrobial therapies are compared against for their efficacy. However, very little is known about the mode of action for CHX against Streptococci and whether tolerance can be developed from repeated exposures. Here, we begin to answer such questions by passagingS. mutanswith increasing concentrations of CHX and isolating spontaneously-arising tolerant variants (CTVs) from separate lineages. We find that these CTVs display a higher minimal inhibitory concentration (MIC) against CHX than the wild-type strain and have altered virulence properties such as acid tolerance and biofilm formation. We record higher MICs for the variants against both daptomycin and bacitracin, but find increased sensitivity to triclosan and sodium fluoride. Measurements of antagonistic capabilities against other health-associated oral streptococci show decreased bacteriocin production compared to wild-type and increased sensitivity to hydrogen peroxide. Finally whole genome sequencing of the CTVs show common single nucleotide polymorphisms (SNPs) within a diacylglycerol kinase homolog and a glycolipid synthesis enzyme, altering LTA accumulation and potentially lipid profile of the cell wall. Together, these findings confirm that streptococci may develop tolerance to antimicrobial agents such as CHX but in the case ofS. mutans,increased tolerance may come at a fitness cost for survival within oral biofilms that keeps variants suppressed within the population.
Cortical and subcortical neurons discriminate sounds in noise on the sole basis of acoustic amplitude modulations
Authors: Souffi S. , Lorenzi C. , Huetz C. , Edeline J-M 
Published: January 2019

AbstractHumans and animals maintain accurate sound discrimination in the presence of loud sources of background noise. It is commonly assumed that this ability relies on the robustness of auditory cortex responses. However, no attempt has been made to characterize neural discrimination of sounds masked by noise at each stage of the auditory system and disentangle the sub-effects of noise, namely the distortion of temporal cues conveyed by modulations in instantaneous amplitude and frequency, and the introduction of randomness (stochastic fluctuations in amplitude). Here, we measured neural discrimination between communication sounds masked by steady noise in the cochlear nucleus, inferior colliculus, auditory thalamus, primary and secondary auditory cortex at several signal-to-noise ratios. Sound discrimination by neuronal populations markedly decreased in each auditory structure, but collicular and thalamic populations showed better performance than cortical populations at each signal-to-noise ratio. Comparison with neural responses to tone-vocoded sounds revealed that the reduction in neural discrimination caused by noise was mainly driven by the attenuation of slow amplitude modulation cues, with the exception of the cochlear nucleus that showed a dramatic drop in discrimination caused by the randomness of noise. These results shed new light on the specific contributions of subcortical structures to robust sound encoding, and demonstrate that neural discrimination in the presence of background noise is mainly determined by the distortion of the slow temporal cues conveyed by communication sounds.
Tempo of gene regulation in wild and cultivatedVitisspecies shows coordination between cold deacclimation and budbreak
Authors: Kovaleski Alisson P. , Londo Jason P. 
Published: January 2019

HighlightFaster deacclimation and budbreak phenology is related to a faster regulon rather than higher expression of specific genes. ABA is a master regulator of deacclimation.AbstractDormancy release, loss of cold hardiness and budbreak are critical aspects of the annual cycle of deciduous perennial plants. Molecular control of these processes is not fully understood, and genotypic variation may be important for climate adaptation. Single-node cuttings from wild (Vitis amurensis, V. riparia) and cultivatedVitisgenotypes (V. vinifera‘Cabernet Sauvignon’, ‘Riesling’) were collected from the field during winter and placed under forcing conditions. Cold hardiness was measured daily, and buds were collected for RNA-Seq until budbreak. Field-collected single-node cuttings of ‘Riesling’ were treated with abscisic acid (ABA), and cold hardiness and budbreak at 7 °C were tracked. WildVitisgenotypes had faster deacclimation and budbreak thanV. vinifera. Temperature-sensing related genes were quickly and synchronously differentially expressed in all genotypes. ABA synthesis was down-regulated in all genotypes, and exogenous ABA prevented deacclimation. Ethylene- and oxidative stress-related genes were transiently up-regulated. Growth-related genes were up-regulated and showed staggering similar to deacclimation and budbreak of the four genotypes. The gene expression cascade that occurs during deacclimation and budburst phenology of fast (wild) and slow (cultivated) grapevines appears coordinated and temporally conserved. This may extend to other temperate woody species and suggest constraints on identification of process-specific keystone genes.
A High-Throughput Screen of a Library of Therapeutics Identifies Substrates of P-glycoprotein
Authors: Lee Tobie D. , Lee Olivia W. , Brimacombe Kyle R. , Chen Lu , Guha Rajarshi , Lusvarghi Sabrina , Tebase Bethilehem G. , Klumpp-Thomas Carleen , Robey Robert W. , Ambudkar Suresh V. , Shen Min , Gottesman Michael M. , Hall Matthew D. 
Published: January 2019

AbstractThe ATP-binding cassette transporter P-glycoprotein (P-gp) is known to limit brain penetration of many chemotherapy drugs. Although Food and Drug Administration guidelines require that potential interactions of investigational drugs with P-gp be explored, often this information does not enter into the literature. As such, we developed a high-throughput screen (HTS) to identify substrates of P-gp from a series of chemical libraries, testing a total of 10,804 compounds, most of which have known mechanisms of action. We used the CellTiter-Glo viability assay to test library compounds against parental KB-3-1 human cervical adenocarcinoma cells and the colchicine-selected sub-line KB-8-5-11 that over-expresses P-gp. KB-8-5-11 cells were also tested in the presence of a P-gp inhibitor (tariquidar) to assess reversability of transporter-mediated resistance. Of the tested compounds, a total of 90 P-gp substrates were identified including 55 newly identified P-gp substrates. Substrates were confirmed using an orthogonal killing assay against HEK-293 cells transfected with P-gp. We confirmed that AT7159 (cyclin-dependent kinase inhibitor); AT9283, (Janus kinase 2/3 inhibitor); ispinesib (kinesin spindle protein inhibitor); gedatolisib (PKI-587, phosphoinositide 3-kinase/mammalian target of rampamycin inhibitor); GSK-690693 (AKT inhibitor); and KW-2478 (heat shock protein 90 inhibitor) were substrates, and direct ATPase stimulation was assessed. ABCG2 was also found to confer high levels of resistance to AT9283, GSK-690693 and gedatolisib, while ispinesib, AT7519 and KW-2478 were weaker substrates. Combinations of P-gp substrates and inhibitors were assessed to demonstrate on-target synergistic cell killing. This data will be of use in determining understanding how chemotherapeutic agents will cross the blood-brain barrier.
Social hierarchy position in female mice is associated with plasma corticosterone levels and hypothalamic gene expression
Authors: Williamson Cait M. , Lee Won , Decasien Alexandra R. , Lanham Alesi , Romeo Russell D. , Curley James P. 
Published: January 2019

AbstractSocial hierarchies emerge when animals compete for access to resources such as food, mates or physical space. Wild and laboratory male mice have been shown to develop linear hierarchies, however, less is known regarding whether female mice have sufficient intrasexual competition to establish significant social dominance relationships. In this study, we examined whether groups of outbred CD-1 virgin female mice housed in a large vivaria formed social hierarchies. We show that females use fighting, chasing and mounting behaviors to rapidly establish highly directionally consistent social relationships. Notably, these female hierarchies are less linear, steep and despotic compared to male hierarchies. Female estrus state was not found to have a significant effect on aggressive behavior, though dominant females had elongated estrus cycles (due to increased time in estrus) compared to subordinate females. Plasma estradiol levels were equivalent between dominant and subordinate females. Subordinate females had significantly lower levels of basal corticosterone compared to dominant females. Analyses of gene expression in the ventromedial hypothalamus indicated that subordinate females have elevated ERα, ERβ and OTR mRNA compared to dominant females. This study provides a methodological framework for the study of the neuroendocrine basis of female social aggression and dominance in laboratory mice.
Leveraging functional annotation to identify genes associated with complex diseases
Authors: Liu Wei , Li Mo , Zhang Wenfeng , Zhou Geyu , Wu Xing , Wang Jiawei , Lu Qiongshi , Zhao Hongyu 
Published: January 2019

AbstractTo increase statistical power to identify genes associated with complex traits, a number of transcriptome-wide association study (TWAS) methods have been proposed using gene expression as a mediating trait linking genetic variations and diseases. These methods first predict expression levels based on inferred expression quantitative trait loci (eQTLs) and then identify expression-mediated genetic effects on diseases by associating phenotypes with predicted expression levels. The success of these methods critically depends on the identification of eQTLs, which may not be functional in the corresponding tissue, due to linkage disequilibrium (LD) and the correlation of gene expression between tissues. Here, we introduce a new method called T-GEN (Transcriptome-mediated identification of disease-associatedGens withEpigenetic aNnotation) to identify disease-associated genes leveraging epigenetic information. Through prioritizing SNPs with tissue-specific epigenetic annotation, T-GEN can better identify SNPs that are both statistically predictive and biologically functional. We found that a significantly higher percentage (an increase of 18.7% to 47.2%) of eQTLs identified by T-GEN are inferred to be functional by ChromHMM and more are deleterious based on their Combined Annotation Dependent Depletion (CADD) scores. Applying T-GEN to 207 complex traits, we were able to identify more trait-associated genes (ranging from 7.7 % to 102%) than those from existing methods. Among the identified genes associated with these traits, T-GEN can better identify genes with high (>0.99) pLI scores compared to other methods. When T-GEN was applied to late-onset Alzheimer’s disease, we identified 96 genes located at 15 loci, including two novel loci not implicated in previous GWAS. We further replicated 50 genes in an independent GWAS, including one of the two novel loci.Author summaryTWAS-like methods have been widely applied to understand disease etiology using eQTL data and GWAS results. However, it is still challenging to discriminate the true disease-associated genes from those in strong LD with true genes, which is largely due to the misidentification of eQTLs. Here we introduce a novel statistical method named T-GEN to identify disease-associated genes considering epigenetic information. Compared to current TWAS methods, T-GEN can not only identify eQTLs with higher CADD scores and function potentials in gene-expression imputation models, but also identify more disease-associated genes across 207 traits and more genes with high (>0.99) pLI scores. Applying T-GEN in late-onset Alzheimer’s disease identified 96 genes at 15 loci with two novel loci. Among 96 identified genes, 50 genes were further replicated in an independent GWAS.
The complete mitochondrial genome of the Golden Birdwing butterflyTroides aeacus: insights into phylogeny and divergence times of the superfamily Papilionoidea
Authors: Dong Si-Yu , Jiang Guo-Fang , Liu Gang , Hong Fang , Hsu Yu-Feng 
Published: January 2019

AbstractBackgroundThe Lepidoptera is one of the largest insect orders. Previous studies on the evolution of Lepidoptera did not confidently place butterflies, and many relationships among superfamilies in the megadiverse clade Ditrysia remain largely uncertain. Here, we generated a molecular dataset with 78 species of lepidopterian insects, including a new complete mitochondrial genome (mitogenome) sequences of the Golden Birdwing Butterfly,Troides aeacus,which was listed in appendix II of CITES.MethodsBased on the concatenated nucleotide sequences of 13 protein-coding genes, we constructed phylogenetic trees with Bayesian Inference (BI) and Maximum Likelihood (ML) methods, and calculated the divergence times of Lepidoptera.ResultsMonophyly of the Papilionoidea including skippers (Hesperiidae) is strongly supported by a high bootstrap value. Butterflies were placed sister to the remaining obtectomeran Lepidoptera, and the latter was grouped with high bootstrap supports. Additionally, Papilionidae probably diverged from the group (Hesperiidae + (Nymphalidae + Pieridae)) at 102.65 Mya, the Early Cretaceous.T. aeacusand the Golden kaiserihindTeinopalpus aureusdiverged in the Cretaceous of 85.32 Mya. The age of Papilionoidea indicates that the primary break up of Gondwana may have an effect on the current distributions of butterflies.
Resting state fMRI reveals differential effects of glucose administration on central appetite signalling in young and old adults
Authors: Peters Riccarda , White David J , Scholey Andrew 
Published: January 2019

AbstractBackgroundHealthy aging has been associated with reduced appetite and energy intake, which can lead to loss of bodyweight and undernutrition and related health problems. The causes for the decline in caloric intake are multifactorial involving physiological and non-physiological processes.AimsHere we examined age-related, physiological changes in brain responses associated with macronutrient intake.MethodsUsing a randomized, double blind, balanced cross-over design, younger (n=16, aged 21-30) and older adults (n=16, aged 55-78) received a drink containing glucose and a taste-matched placebo after an overnight fast. Blood glucose and hunger were assessed at baseline and 20 minutes post-ingestion, after which participants underwent resting state functional magnetic resonance imaging (rsfMRI).ResultsFrequency dependent changes in slow-5 (0.01-0.027Hz) and slow-4 (0.027-0.073Hz) amplitude of low frequency fluctuations (ALFF) and fractional ALFF (fALFF) of the blood oxygen level-dependent (BOLD) signal were contrasted between sessions and age groups. We observed a significant treatment x age-group interaction in slow-5 ALFF and fALFF in the left insula. Younger participants showed a decrease in BOLD amplitude, whereas older participants showed an increase. We further observed a treatment x age-group interaction in slow-4 ALFF in the occipital and lingual gyrus and precuneus with older participants showing an increase in magnitude of slow-4 ALFF and younger participants showing a decrease in the same measure.ConclusionThese age-related, frequency-dependent changes in the magnitude of the BOLD signal in a key region related to energy homeostasis following feeding may contribute to behavioral changes in energy intake during senescence.