bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards selective-alignment: Bridging the accuracy gap between alignment-based and alignment-free transcript quantification
Authors: Sarkar Hirak , Zakeri Mohsen , Malik Laraib , Patro Rob 
Published: May 2017

AbstractMotivationWe introduce an algorithm for selectively aligning high-throughput sequencing reads to a transcriptome, with the goal of improving transcript-level quantification. This algorithm attempts to bridge the gap between fast “mapping” algorithms and more traditional alignment procedures.ResultsWe adopt a hybrid approach that is able to increase mapping accuracy while still retaining much of the efficiency of fast mapping algorithms. To achieve this, we introduce a new approach that explores the candidate search space with high sensitivity as well as a collection of carefully-engineered heuristics to efficiently filter these candidates. Additionally, unlike the strategies adopted in most aligners which first align the ends of paired-end reads independently, we introduce a notion of co-mapping. This procedure exploits relevant information between the “hits” from the left and right ends of paired-end reads before full alignments or mappings for each are generated, which improves the efficiency of filtering likely-spurious alignments. Finally, we demonstrate the utility of selective alignment in improving the accuracy of efficient transcript-level quantification from RNA-seq reads. Specifically, we show that selective-alignment is able to resolve certain complex mapping scenarios that can confound existing fast mapping procedures, while simultaneously eliminating spurious alignments that fast mapping approaches can produce.AvailabilitySelective-alignment is implemented in C++11 as a part ofSalmon, and is available as open source software, under GPL v3, at:https://github.com/COMBINE-lab/salmon/tree/selective-alignmentContactrob.patro@cs.stonybrook.edu
The AWSEM-Amylometer: predicting amyloid propensity and fibril topology using an optimized folding landscape model
Authors: Chen Mingchen , Schafer Nicholas P , Zheng Weihua , Wolynes Peter G 
Published: May 2017

AbstractAmyloids are fibrillar protein aggregates with simple repeated structural motifs in their cores, usuallyβ-strands but sometimesα-helices. Identifying the amyloid-prone regions within protein sequences is important both for understanding the mechanisms of amyloid-associated diseases and for understanding functional amyloids. Based on the crystal structures of seven cross-βamyloidogenic peptides with different topologies and one recently solved cross-αfiber structure, we have developed a computational approach for identifying amyloidogenic segments in protein sequences using the Associative memory, Water mediated, Structure and Energy Model. The AWSEM-Amylometer performs favorably in comparison with other predictors in predicting aggregation-prone sequences in multiple datasets. The method also predicts the specific topologies (the relative arrangement ofβ-strands in the core) of the amyloid fibrils well. An important advantage of the AWSEM-Amylometer over other existing methods is its direct connection with an efficient, optimized protein folding simulation model, AWSEM. This connection allows one to combine efficient and accurate search of protein sequences for amyloidogenic segments with the detailed study of the thermodynamic and kinetic roles that these segments play in folding and aggregation in the context of the entire protein sequence. We present new simulation results that highlight the free energy landscapes of peptides that can take on multiple fibril topologies. We also demonstrate how the Amylometer methodology can be straightforwardly extended to the study of functional amyloids that have the recently discovered cross-αfibril architecture.
On the importance of being stable ‒ evolutionarily frozen species can win in fluctuating environment
Authors: Flegr Jaroslav , Ponížil Petr 
Published: May 2017

AbstractThe ability of organisms to adaptively respond to environmental changes (evolvability) is usually considered to be an important advantage in interspecific competition. It has been suggested, however, that evolvability could be a double-edged sword that could present a serious handicap in fluctuating environments. The authors of this counterintuitive idea have published only verbal models to support their claims.Here we present the results of individual-based stochastic modelling of competition between two asexual species differing only by their evolvability. They show that, in changeable environments, less evolvable species could outperform their more evolvable competitors in a broad area of a parameter space, regardless of whether the conditions fluctuated periodically or aperiodically. Highly evolvable species prospered better nearly all the time; however, they sustained a higher probability of extinction during rare events of the rapid transient change of conditions.Our results offer an explanation of why sexually reproducing species, with their reduced capacity to respond adaptively to local or temporal environmental changes, prevail in most eukaryotic taxa in nearly all biotopes on the surface of Earth. These species may suffer several important disadvantages in direct competitive battles with asexual species; however, they might win in changeable environments in the more important sorting-according-to-stability war.
Identifying parameters of host cell vulnerability duringSalmonellainfection by quantitative image analysis and modeling
Authors: Voznica Jakub , Gardella Christophe , Belotserkovsky Ilia , Dufour Alexandre , Enninga Jost , Stévenin Virginie 
Published: May 2017

ABSTRACTSalmonellatarget and enter epithelial cells at permissive entry sites: some cells are more likely to be infected than others. However the parameters that lead to host cell heterogeneity are not known. Here, we quantitatively characterized host cell “vulnerability” towardsSalmonellainfection based on imaged parameters. We performed successive infections of the same host cell population followed by automated high-throuput microscopy and observed that infected cells have higher probability of being re-infected. Establishing a predictive model we identified two combined origins of host cell vulnerability: the pathogen-induced cellular vulnerability emerging fromSalmonellauptake and persisting at later stage of the infection, and the host cell-inherent vulnerability. We linked the host cell inherent vulnerability with its morphological attributes such as the local cell crowding, and with host cell cholesterol content. This showed that the probability ofSalmonellainfection success can be forecast from morphological or molecular host cell parameters.
Isolation and characterization of key genes that promote flavonoid accumulation in purple-leaf tea (Camellia sinensisL.)
Authors: He Xiujuan , Zhao Xuecheng , Gao Liping , Shi Xingxing , Dai Xinlong , Liu Yajun , Xia Tao , Wang Yunsheng 
Published: May 2017

AbstractThere were several high concentrations of flavonoid components in tea leaves that present health benefits. A novel purple-leaf tea variety, ‘Mooma1’, was obtained from the natural hybrid population of Longjing 43 variety. The buds and young leaves of ‘Mooma1’ were displayed in bright red. HPLC and LC-MS analysis showed that anthocyanins and O-Glycosylated flavonols were remarkably accumulated in the leaves of ‘Mooma1’, while the total amount of catechins in purple-leaf leaves was slightly decreased compared with the control. A R2R3-MYB transcription factor (CsMYB6A) and a novel UGT gene (CsUGT72AM1), that were highly expressed in purple leaf were isolated and identified by transcriptome sequencing. The over-expression of transgenic tobacco confirmed thatCsMYB6Acan activate the expression of flavonoid-related structural genes, especiallyCHS and 3GT,controlling the accumulation of anthocyanins in the leaf of transgenic tobacco. Enzymatic assaysin vitroconfirmed that CsUGT72AM1 has catalytic activity as a flavonol 3-O-glucosyltransferase, and displayed broad substrate specificity. The results were useful for further elucidating the molecular mechanisms of the flavonoid metabolic fluxes in the tea plant.
Interdependence, Reflexivity, Fidelity, Impedance Matching, and the Evolution of Genetic Coding
Authors: Carter Charles W. , Wills Peter 
Published: May 2017

ABSTRACTGenetic coding is generally thought to have required ribozymes whose functions were taken over by polypeptide aminoacyl-tRNA synthetases (aaRS). Two discoveries about aaRS and their tRNA substrates now furnish a unifying rationale for the opposite conclusion: that the key processes of the Central Dogma of molecular biology emerged simultaneously and naturally from simple origins in a peptide•RNA partnership, eliminating the epistemological need for a prior RNA world. First, the two aaRS classes likely arose from opposite strands of the same ancestral gene, implying a simple genetic alphabet. Inversion symmetries in aaRS structural biology arising from genetic complementarity would have stabilized the initial and subsequent differentiation of coding specificities and hence rapidly promoted diversity in the proteome. Second, amino acid physical chemistry maps onto tRNA identity elements, establishing reflexivity in protein aaRS. Bootstrapping of increasingly detailed coding is thus intrinsic to polypeptide aaRS, but impossible in an RNA world. These notions underline the following concepts that contradict gradual replacement of ribozymal aaRS by polypeptide aaRS: (i) any set of aaRS must be interdependent; (ii) reflexivity intrinsic to polypeptide aaRS production dynamics promotes bootstrapping; (iii) takeover of RNA-catalyzed aminoacylation by enzymes will necessarily degrade specificity; (iv) the Central Dogma’s emergence is most probable when replication and translation error rates remain comparable. These characteristics are necessary and sufficient for the essentiallyde novoemergence of a coupled gene-replicase-translatase system of genetic coding that would have continuously preserved the functional meaning of genetically encoded protein genes whose phylogenetic relationships match those observed today.
Improved estimation of SNP heritability using Bayesian multiple-phenotype models
Authors: Elhezzani Najla Saad 
Published: May 2017

AbstractLinear mixed models (LMM) are widely used to estimate narrow sense heritability explained by tagged single-nucleotide polymorphisms (SNPs). However, those estimates are valid only if large sample sizes are used. We propose a Bayesian matrix-variate model that takes into account the genetic correlation among phenotypes and genetic correlation among individuals. The use of multivariate Bayesian methods allows us to circumvent some issues related to small sample sizes, mainly overfitting and boundary estimates. Using gene expression pathways, we demonstrate a significant improvement in SNP-based heritability estimates over univariate and likelihood-based methods, thus explaining why recent progress in eQTL identification has been limited.
A non-parametric Bayesian prior for causal inference of auditory streaming
Authors: Yates Tim , Larigaldie Nathanael , Beierholm Ulrik R. 
Published: May 2017

AbstractHuman perceptual grouping of sequential auditory cues has traditionally been modeled using a mechanistic approach. The problem however is essentially one of source inference – a problem that has recently been tackled using statistical Bayesian models in visual and auditory-visual modalities. Usually the models are restricted to performing inference over just one or two possible sources, but human perceptual systems have to deal with much more complex scenarios. To characterize human perception we have developed a Bayesian inference model that allows an unlimited number of signal sources to be considered: it is general enough to allow any discrete sequential cues, from any modality. The model uses a non-parametric prior, hence increased complexity of the signal does not necessitate more parameters. The model not only determines the most likely number of sources, but also specifies the source that each signal is associated with. The model gives an excellent fit to data from an auditory stream segregation experiment in which the pitch and presentation rate of pure tones determined the perceived number of sources.
De novomutations implicate novel genes with burden of rare variants in Systemic Lupus Erythematosus
Authors: Pullabhatla Venu , Roberts Amy L. , Lewis Myles J. , Mauro Daniele , Morris David L. , Odhams Christopher A. , Tombleson Philip , Liljedahl Ulrika , Vyse Simon , Simpson Michael A. , Sauer Sascha , Rinaldis Emanuele de , Syvänen Ann-Christine , Vyse Timothy J. 
Published: May 2017

AbstractThe omnigenic model of complex diseases stipulates that the majority of the heritability will be explained by the effects of common variation on genes in the periphery of core disease pathways. Rare variant associations, expected to explain far less of the heritability, may be enriched in core disease genes and thus will be instrumental in the understanding of complex disease pathogenesis and their potential therapeutic targets. Here, using complementary whole-exome sequencing (WES), high-density imputation, andin vitrocellular assays, we identify three candidate core genes in the pathogenesis of Systemic Lupus Erythematosus (SLE). Using extreme-phenotype sampling, we sequenced the exomes of 30 SLE parent-affected-offspring trios and identified 14 genes with missensede novomutations (DNM), none of which are within the >80 SLE susceptibility loci implicated through genome-wide association studies (GWAS). In a follow-up cohort of 10,995 individuals of matched European ancestry, we imputed genotype data to the density of the combined UK10K-1000 genomes Phase III reference panel across the 14 candidate genes. We identify a burden of rare variants acrossPRKCDassociated with SLE risk (P=0.0028), and acrossDNMT3Aassociated with two severe disease prognosis sub-phenotypes (P=0.0005 andP=0.0033). Both genes are functional candidates and significantly constrained against missense mutations in gene-level analyses, along withC1QTNF4. We further characterise the TNF-dependent functions of candidate geneC1QTNF4on NF-κB activation and apoptosis, which are inhibited by the p.His198Gln DNM. Our results support extreme-phenotype sampling and DNM gene discovery to aid the search for core disease genes implicated through rare variation.Significance StatementRare variants, present in <1% in population, are expected to explain little of the heritability of complex diseases, such as Systemic Lupus Erythematosus (SLE), yet are likely to identify core genes crucial to disease mechanisms. Their rarity, however, limits the power to show their statistical association with disease. Through sequencing the exomes of SLE patients and their parents, we identified non-inheritedde novomutations in 14 genes and hypothesised that these are prime candidates for harbouring additional disease-associated rare variants. We demonstrate that two of these genes also carry a significant excess of rare variants in an independent, large cohort of SLE patients. Our findings will influence future study designs in the search for the ‘missing heritability’ of complex diseases.
Health Status by Gender, Hair Color, and Eye Color: Red-Haired Women are the Most Divergent with the Lowest Viability and the Highest Fertility
Authors: Frost P. , Kleisner K. , Flegr J. 
Published: May 2017

AbstractBackgroundRed hair is associated with pain sensitivity, and more so in women than in men. Hair redness may thus interact with a female-specific factor. We tested this hypothesis on a large sample of Czech and Slovak respondents. They were asked about the natural redness and darkness of their hair, their natural eye color, their physical and mental health (24 categories), and other personal attributes (height, weight, number of children, lifelong number of sexual partners, frequency of smoking).ResultsWe found that red-haired women did worse than other women in ten health categories and better in only three. In particular, they were more prone to colorectal, cervical, uterine, and ovarian cancer. Cancer risk increased steadily with increasing hair redness except for the reddest shade. Red-haired men showed a balanced pattern of health effects, doing better than other men in three categories and worse in three. Number of children was the only category where both male and female redheads did better than other respondents. We also confirmed earlier findings that red hair is naturally more frequent in women than in men.ConclusionRed-haired women had higher fecundity and sexual attractiveness, but this selective advantage seems offset by worse health outcomes and therefore lower viability. The resulting equilibrium between these two counterbalancing forces might explain why red hair has remained less common than other hair and eye colors. Of the ‘new’ hair and eye colors, red hair diverges the most from the ancestral state of black hair and brown eyes. It is the most sexually dimorphic variant, not only in population frequency but also in health outcomes. This sexual dimorphism seems to have resulted from a selection pressure that acted primarily on early European women and which led to a general and apparently rapid diversification of hair and eye colors.
Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia
Authors: Pavel Ana B. , Korolev Kirill S. 
Published: May 2017

AbstractGenetic alterations initiate tumors and enable the evolution of drug resistance. The pro-cancer view of mutations is however incomplete, and several studies show that mutational load can reduce tumor fitness. Given its negative effect, genetic load should make tumors more sensitive to anticancer drugs. Here, we test this hypothesis across all major types of cancer from the Cancer Cell Line Encyclopedia, that provides genetic and expression data of 496 cell lines together with their response to 24 common anticancer drugs. We found that the efficacy of 9 out of 24 drugs showed significant association with genetic load in a pan-cancer analysis. The associations for some tissue-drug combinations were remarkably strong with genetic load explaining up to 83% of the variance in the drug response. Overall, the role of genetic load depended on both the drug and the tissue type with 10 tissues being particularly vulnerable to genetic load. We also identified changes in gene expression associated with increased genetic load, which included cell-cycle checkpoints, DNA damage and apoptosis. Our results show that genetic load is an important component of tumor fitness and can predict drug sensitivity. Beyond being a biomarker, genetic load might be a new, unexplored vulnerability of cancer.
Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-onset Epilepsy
Authors: Demos Michelle , Guella Ilaria , McKenzie Marna B. , Buerki Sarah E. , Evans Daniel M. , Toyota Eric B. , Boelman Cyrus , Huh Linda L. , Datta Anita , Michoulas Aspasia , Selby Kathryn , Bjornson Bruce H. , Horvath Gabriella , Lopez-Rangel Elena , van Karnebeek Clara DM , Salvarinova Ramona , Slade Erin , Eydoux Patrice , Adam Shelin , Van Allen Margot. I. , Nelson Tanya N. , Bolbocean Corneliu , Connolly Mary B. , Farrer Matthew J. 
Published: May 2017

AbstractBackgroundTo examine the impact on diagnosis, treatment and cost with early use of targeted whole-exome sequencing (WES) in early-onset epilepsy.MethodsWES was performed on 50 patients with early-onset epilepsy (≤ 5 years) of unknown cause. Patients were classified as retrospective (epilepsy diagnosis > 6 months) or prospective (epilepsy diagnosis < 6 months). WES was performed on an Ion ProtonTM and variant reporting was restricted to the sequences of 565 known epilepsy genes. Diagnostic yield and time to diagnosis were calculated. An analysis of cost and impact on treatment was also performed.ResultsA likely/definite diagnosis was made in 17/50 patients (34%) with immediate treatment implications in 8/17 (47%). A possible diagnosis was identified in 9 additional patients (18%) for whom supporting evidence is pending. Time from epilepsy onset to genetic diagnosis was faster when WES was performed early in the diagnostic process (mean: 143 days prospective versus 2,172 days retrospective). Costs of prior negative tests averaged $8,344 in the retrospective group, suggesting savings of up to $5,110 per patient.InterpretationThese results support the clinical utility and potential cost-effectiveness of using targeted WES early in the diagnostic workup of patients with unexplained early-onset epilepsy. The costs and clinical benefits are likely to continue to improve. Advances in precision medicine and further studies regarding impact on long-term clinical outcome will be important.
Research Advance: Extending chemical perturbations of the Ubiquitin fitness landscape in a classroom setting
Authors: Mavor David , Barlow Kyle A. , Asarnow Daniel , Birman Yuliya , Britain Derek , Chen Weilin , Green Evan M. , Kenner Lillian R. , Mensa Bruk , Morinishi Leanna S. , Nelson Charlotte , Poss Erin M. , Suresh Pooja , Tian Ruilin , Arhar Taylor , Ary Beatrice , Bauer David , Bergman Ian , Brunetti Rachel , Chio Cynthia , Dai Shizhong , Dickinson Miles , Elledge Susanna , Helsell Cole , Hendel Nathan , Kang Emily , Kern Nadja , Khoroshkin Matvei , Kirkemo Lisa , Lewis Greyson , Lou Kevin , Marin Wesley , Maxwell Alison , McTigue Peter , Myers-Turnbull Douglas , Nagy Tamas , Natale Andrew , Oltion Keely , Pourmal Sergei , Reder Gabriel , Rettko Nicholas , Rohweder Peter , Schwarz Daniel , Tan Sophia , Thomas Paul , Tibble Ryan , Town Jason , Tsai Kaitlyn , Ugur Fatima , Wassarmann Douglas R. , Wolff Alexander , Wu Taia , Bogdanoff Derrick , Li Jennifer , Thorn Kurt S. , O’Conchúir Shane , Swaney Danielle L. , Chow Eric D. , Madhani Hiten , Redding Sy , Bolon Daniel N. , Kortemme Tanja , DeRisi Joseph L. , Kampmann Martin , Fraser James S. 
Published: May 2017

AbstractAlthough the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it is highly tolerant to mutation during selection experiments performed in the laboratory. We have proposed that this discrepancy results from the difference between fitness under laboratory culture conditions and the selective pressures in changing environments over evolutionary time scales. Building on our previous work (Mavor et al 2016), we used deep mutational scanning to determine how twelve new chemicals (3-Amino-1,2,4-triazole, 5-fluorocytosine, Amphotericin B, CaCl2, Cerulenin, Cobalt Acetate, Menadione, Nickel Chloride, p-fluorophenylalanine, Rapamycin, Tamoxifen, and Tunicamycin) reveal novel mutational sensitivities of ubiquitin residues. We found sensitization of Lys63 in eight new conditions. In total, our experiments have uncovered a sensitizing condition for every position in Ub except Ser57 and Gln62. By determining the Ubiquitin fitness landscape under different chemical constraints, our work helps to resolve the inconsistencies between deep mutational scanning experiments and sequence conservation over evolutionary timescales.Builds onMavor D, Barlow KA, Thompson S, Barad BA, Bonny AR, Cario CL, Gaskins G, Liu Z, Deming L, Axen SD, Caceres E, Chen W, Cuesta A, Gate R, Green EM, Hulce KR, Ji W, Kenner LR, Mensa B, Morinishi LS, Moss SM, Mravic M, Muir RK, Niekamp S, Nnadi CI, Palovcak E, Poss EM, Ross TD, Salcedo E, See S, Subramaniam M, Wong AW, Li J, Thorn KS, Conchúir SÓ, Roscoe BP, Chow ED, DeRisi JL, Kortemme T, Bolon DN, Fraser JS. Determination of Ubiquitin Fitness Landscapes Under Different Chemical Stresses in a Classroom Setting.eLife. 2016.Impact StatementWe organized a project-based course that used deep mutational scanning in multiple chemical conditions to resolve the inconsistencies between tolerance to mutations in laboratory conditions and sequence conservation over evolutionary timescales.