bluuebunny/crossref_metadata_2025_split huggingface dataset:
Base-pair Ambiguity and the Kinetics of RNA Folding
Authors: Zhou Guangyao , Loper Jackson , Geman Stuart 
Published: May 2018

AbstractBackgroundA folding RNA molecule encounters multiple opportunities to form non-native yet energetically favorable pairings of nucleotide sequences. Given this forbidding free-energy landscape, mechanisms have evolved that contribute to a directed and efficient folding process, including catalytic proteins and error-detecting chaperones. Among structural RNA molecules we make a distinction between “bound” molecules, which are active as part of ribonucleoprotein (RNP) complexes, and “unbound,” with physiological functions performed without necessarily being bound in RNP complexes. We hypothesized that unbound molecules, lacking the partnering structure of a protein, would be more vulnerable than bound molecules to kinetic traps that compete with native stem structures. We defined an “ambiguity index”—a normalized function of the primary and secondary structure of an individual molecule that measures the number of kinetic traps available to nucleotide sequences that are paired in the native structure, presuming that unbound molecules would have lower indexes. The ambiguity index depends on the purported secondary structure, and was computed under both the comparative (“gold standard”) and an equilibrium-based prediction which approximates the minimum free energy (MFE) structure. Arguing that kinetically accessible metastable structures might be more biologically relevant than thermodynamic equilibrium structures, we also hypothesized that MFE-derived ambiguities would be less effective in separating bound and unbound molecules.ResultsWe have introduced an intuitive and easily computed function of primary and secondary structures that measures the availability of complementary sequences that could disrupt the formation of native stems on a given molecule—an ambiguity index. Using comparative secondary structures, the ambiguity index is systematically smaller among unbound than bound molecules, as expected. Furthermore, the effect is lost when the presumably more accurate comparative structure is replaced instead by the MFE structure.ConclusionsA statistical analysis of the relationship between the primary and secondary structures of non-coding RNA molecules suggests that stem-disrupting kinetic traps are substantially less prevalent in molecules not participating in RNP complexes. In that this distinction is apparent under the comparative but not the MFE secondary structure, the results highlight a possible deficiency in structure predictions when based upon assumptions of thermodynamic equilibrium.
The QNOAEL vs. BMD for Point of Departure
Authors: Dickerson Cynthia , Lodder Robert A. 
Published: May 2018

AbstractQuantile bootstrap (QB) methods can be applied to the problem of estimating the No Observed Adverse Effect Level (NOAEL) of a New Molecular Entity (NME) to anticipate a safe starting dose for beginning clinical trials. An estimate of the NOAEL from the extended QB method (called the QNOAEL) can be calculated using multiple disparate studies in the literature and/or from laboratory experiments. The QNOAEL is similar in some ways to the Benchmark Dose (BMD) and is superior to the BMD in others. The Benchmark Dose method is currently widely used in toxicological research.Results are used in a simulation based on nonparametric cluster analysis methods to calculate confidence levels on the difference between the Effect and the No Effect studies. The QNOAEL simulation generates an intuitive curve that is comparable to the dose-response curve.The QNOAEL of ellagic acid (EA) will be calculated for clinical trials of its use as a component therapeutic agent (in BSN476) for treating Chikungunya infections. This will be the first application of QB to the problem of NOAEL estimation for a drug. The specific aims of the proposed study are to evaluate the accuracy and precision of the QB Simulation and QNOAEL compared to the Benchmark Dose Method, and to calculate the QNOAEL of EA for BSN476 Drug Development.
Netrin G1 promotes pancreatic tumorigenesis through cancer associated fibroblast driven nutritional support and immunosuppression
Authors: Francescone Ralph , Vendramini-Costa Débora Barbosa , Franco-Barraza Janusz , Wagner Jessica , Muir Alexander , Lau Allison N. , Gabitova Linara , Pazina Tatiana , Gupta Sapna , Luong Tiffany , Shah Neelima , Rollins Dustin , Malik Ruchi , Thapa Roshan , Restifo Diana , Zhou Yan , Cai Kathy Q. , Hensley Harvey H. , Tan Yinfei , Kruger Warren D. , Devarajan Karthik , Balachandran Siddharth , Klein-Szanto Andres J. , Wang Huamin , El-Deiry Wafik S. , Vander Heiden Matthew G. , Peri Suraj , Campbell Kerry S. , Astsaturov Igor , Cukierman Edna 
Published: May 2018

AbstractPancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multi-plex data from patient tissue, three-dimensional co-culturingin vitroassays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. NetG1+cancer-associated fibroblasts (CAFs) supported PDAC survival, through a NetG1 mediated effect on glutamate/glutamine metabolism. NetG1+CAFs were intrinsically immunosuppressive and inhibited NK cell mediated killing of tumor cells. These pro-tumor functions were controlled by a signaling circuit downstream to NetG1, which was comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally blocking NetG1 with a neutralizing antibody stuntedin vivotumorigenesis, suggesting NetG1 as potential target in PDAC.SignificancePDAC is a devastating disease lacking effective therapies. A major hallmark of PDAC is desmoplasia, characterized by the expansion of CAFs and their extracellular matrix, creating a unique microenvironment that limits blood-supplied nutrition and is highly immunosuppressive. A better understanding of the role of CAFs in PDAC may lead to the identification of new targets for therapeutic intervention. Here, we uncovered roles for NetG1 in CAFs to promote tumorigenesis. NetG1 was important for two major CAF functions: the metabolic support of PDAC cells and the intrinsic immunosuppressive capacity of CAFs. Our results helped clarify the role that CAFs play in PDAC, by defining CAF phenotypes through NetG1 expression. Moreover, we established a link between CAF driven metabolism and their intrinsic immunosuppressive capacity, and identified a signaling circuit that governs NetG1 functions. Finally, we demonstrated the therapeutic potential of inhibiting NetG1in vivoby limiting tumorigenesis in mice with a neutralizing antibody, illustrating that targeting stromal NetG1 could be an attractive therapeutic approach.
Let-7i-5p regulation of cell morphology and migration through distinct signaling pathways in normal and pathogenic fibroblasts from urethra
Authors: Zhang Kaile , Chen Jun , Zhou Shukui , Yang Ranxin , Wang Ying , Fu Qiang , Chen Rong , Fang Xiaolan 
Published: May 2018

AbstractPelvic fracture urethral distraction defects (PFUDD) is a common disease that could severely affect patients’ life quality, yet little is known about the molecular mechanism associated with pathogenic fibrosis in PFUDD. In this study, we found that let-7i-5p could regulate different cellular events in normal and pathogenic fibroblasts through three distinct signaling pathways. Interestingly, those regulations are compromised during the translation from mRNA to protein, and partially based on pathogenic status of the fibroblasts. By analyzing the molecular mechanism associated with its function, we conclude that let-7i-5p plays an essential role in regulating cell shape and tissue elasticity, cell migration, cell morphology and cytoskeleton, and could serve as a potential target for clinical treatment of urethral stricture patients.
A competence-regulated toxin-antitoxin system in Haemophilus influenzae
Authors: Black Hailey Findlay , Mastromatteo Scott , Sinha Sunita , Ehrlich Rachel L. , Nislow Corey , Mell Joshua Chang , Redfield Rosemary J. 
Published: May 2018

ABSTRACTNatural competence allows bacteria to respond to environmental and nutritional cues by taking up free DNA from their surroundings, thus gaining nutrients and genetic information. In the Gram-negative bacterium Haemophilus influenae, the DNA uptake machinery is induced by the CRP and Sxy transcription factors in response to lack of preferred carbon sources and nucleotide precursors. Here we show that HI0659—which is absolutely required for DNA uptake— encodes the antitoxin of a competence-regulated toxin-antitoxin operon (‘toxTA’), likely acquired by horizontal gene transfer from a Streptococcus species. Deletion of the toxin restores uptake to the antitoxin mutant. In addition to the expected Sxy-and CRP-dependent-competence promoter, transcript analysis using RNA-seq identified an internal antitoxin-repressed promoter whose transcription starts within toxT and will yield nonfunctional protein. We present evidence that the most likely effect of unopposed toxin expression is non-specific cleavage of mRNAs and arrest or death of competent cells in the culture, and we show that the toxin gene has been inactivated by deletion in many H. influenzae strains. We suggest that this competence-regulated toxin-antitoxin system may facilitate downregulation of protein synthesis and recycling of nucleotides under starvation conditions, or alternatively be a simple genetic parasite.
crossword: A data-driven simulation language for the design of genetic-mapping experiments and breeding strategies
Authors: Walid Korani , Vaughn Justin N 
Published: May 2018

AbstractThe simulation of genetic systems can save time and resources by optimizing the logistics of an experiment. Current tools are difficult to use by those unfamiliar with programming, and these tools rarely address the actual genetic structure of the population under study. Here, we introduce crossword, which utilizes the widely available results of re-sequencing and genomics data to create more realistic simulations and to simplify user input. The software was written in R, making installation and implementation straightforward. Because crossword is a domain-specific language, it allows complex and unique simulations to be performed, but the language is supported by a graphical interface that guides users through functions and options. We first show crossword’s utility in QTL-seq design, where its output accurately reflects empirical data. By introducing the concept of levels to reflect family relatedness, crossword is suitable to a broad range of breeding programs and crops. Using levels, we further illustrate crossword’s capabilities by examining the effect of family size and number of selfing generations on phenotyping accuracy and genomic selection. Additionally, we explore the ramifications of effect polarity among parents in a mapping cross, a scenario that is common in crop genetics but often difficult to simulate. Given the ease of use and apparent realism, we anticipate crossword will quickly become a “bicycle for the [geneticist’s] mind”.
Revealing subthreshold motor contributions to perceptual confidence
Authors: Gajdos Thibault , Fleming Stephen M. , Garcia Marta Saez , Weindel Gabriel , Davranche Karen 
Published: May 2018

AbstractEstablished models of perceptual metacognition, the ability to evaluate our perceptual judgments, posit that perceptual confidence depends on the strength or quality of feedforward sensory evidence. However, alternative theoretical accounts suggest the entire perception-action cycle, and not only variation in sensory evidence, is monitored when evaluating confidence in one’s percepts. Such models lead to the counterintuitive prediction that perceptual confidence should be directly modulated by features of motor output. To evaluate this proposal here we recorded electromyographic (EMG) activity of motor effectors while subjects performed a near-threshold perceptual discrimination task and reported their confidence in each response. A subset of trials exhibited sub-threshold EMG activity in response effectors before a decision was made. Strikingly, trial-by-trial analysis showed that confidence, but not accuracy, was significantly higher on trials with subthreshold motor activation. These findings support a hypothesis that preparatory motor activity impacts upon confidence over and above performance, consistent with models in which perceptual metacognition integrates information across the perception-action cycle.
Multi-Tissue Transcriptome-Wide Association Study Identifies 26 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer
Authors: Gusev Alexander , Lawrenson Kate , Segato Felipe , Fonseca Marcos A.S. , Kar Siddhartha , Vavra Kevin C. , Lee Janet M , Pejovic Tanya ,   Ovarian Cancer Association Consortium, Karlan Beth Y. , Freedman Matthew L. , Noushmehr Houtan , Pharoah Paul D.P. , Pasaniuc Bogdan , Gayther Simon A. 
Published: May 2018

ABSTRACTGenome-wide association studies (GWASs) have identified about 30 different susceptibility loci associated with high grade serous ovarian cancer (HGSOC) risk. We sought to identify potential susceptibility genes by integrating the risk variants at these regions with genetic variants impacting gene expression and splicing of nearby genes. We compiled gene expression and genotyping data from 2,169 samples for 6 different HGSOC-relevant tissue types. We integrated these data with GWAS data from 13,037 HGSOC cases and 40,941 controls, and performed a transcriptome-wide association study (TWAS) across >70,000 significantly heritable gene/exon features. We identified 24 transcriptome-wide significant associations for 14 unique genes, plus 90 significant exon-level associations in 20 unique genes. We implicated multiple novel genes at risk loci, e.g.LRRC46at 19q21.32 (TWASP=1×10−9) and aPRC1splicing event (TWASP=9×10−8) which was splice-variant specific and exhibited no eQTL signal. Functional analyses in HGSOC cell lines found evidence of essentiality forGOSR2, INTS1, KANSL1andPRC1; with the latter gene showing levels of essentiality comparable to that ofMYC. Overall, gene expression and splicing events explained 41% of SNP-heritability for HGSOC (s.e. 11%,P=2.5×10−4), implicated at least one target gene for 6/13 distinct genome-wide significant regions and revealed 2 known and 26 novel candidate susceptibility genes for HGSOC.STATEMENT OF SIGNIFICANCEFor many ovarian cancer risk regions, the target genes regulated by germline genetic variants are unknown. Using expression data from >2,100 individuals, this study identified novel associations of genes and splicing variants with ovarian cancer risk; with transcriptional variation now explaining over one-third of the SNP-heritability for this disease.
Individual behavioral type captured by a Bayesian model comparison of cap making by sponge crabs
Authors: Harada Keita , Hayashi Naoki , Kagaya Katsushi 
Published: May 2018

ABSTRACT‘Animal personality’ is considered to be developed through complex interactions of an individual with its surrounding environment. How can we quantify the ‘personality’ of an individual? Quantifying intra- and inter-individual variability of behavior, or individual behavioral type, appears to be a prerequisite in the study of animal personality. We propose a statistical method from a predictive point of view to measure the appropriateness of our assumption of ‘individual’ behavior in repeatedly measured behavioral data from several individuals. For a model case, we studied the sponge crab Lauridromia dehaani known to make and carry a ‘cap’ from a natural sponge for camouflage. Because a cap is most likely to be rebuilt and replaced repeatedly, we hypothesized that each individual crab would grow a unique behavioral type and it would be observed under an experimentally controlled environmental condition. To test the hypothesis, we conducted behavioral experiments and employed a new Bayesian model-based comparison method to examine whether crabs have individual behavioral types in the cap making behavior. Crabs were given behavioral choices by using artificial sponges of three different sizes. We modeled the choice of sponges, size of the trimmed part of a cap, size of the cavity of a cap, and the latency to produce a cap, as random variables in 26 models, including hierarchical models specifying the behavioral types. In addition, we calculated the marginal-level widely applicable information criterion (mWAIC) values for hierarchical models to evaluate and compared them with the non-hierarchical models from the predictive point of view. As a result, the crabs of less than about 9 cm in size were found to make caps from the sponges. The body size explained the behavioral variables namely, choice, trimmed cap characteristics, and cavity size, but not latency. Furthermore, we captured the behavioral type as a probabilistic distribution structure of the behavioral data by comparing WAIC. Our statistical approach is not limited to behavioral data but is also applicable to physiological or morphological data when examining whether some group structure exists behind fluctuating empirical data.
Thermal plasticity of the circadian clock is under nuclear and cytoplasmic control in wild barley
Authors: Bdolach Eyal , Prusty Manas Ranjan , Faigenboim-Doron Adi , Filichkin Tanya , Helgerson Laura , Schmid Karl J , Greiner Stephan , Fridman Eyal 
Published: May 2018

AbstractTemperature compensation, expressed as the ability to maintain clock characteristics (mainly period) in face of temperature changes, is considered a key feature of circadian clock systems. In this study, we explore the genetic basis for circadian clock plasticity under high temperatures by utilizing a new doubled haploid (DH) population derived from two reciprocalHordeum vulgaresps.spontaneumhybrids genotypes (crosses between B1K-50-04 and B1K-09-07). Genotyping by sequencing of DH lines indicated a rich recombination landscape, with minor fixation (less than 8%), for one of the parental alleles, yet with prevalent and varied segregation distortion across seven barley chromosomes. Phenotyping was conducted with a high-throughput platform under optimal and high temperature environments. Genetic analysis, which included QxE and binary-threshold models, identified a significant influence of the maternal organelle genome (the plasmotype), as well as several nuclear quantitative trait loci (QTL), on clock phenotypes (free-running period and amplitude). Moreover, it showed the differential contribution of cytoplasmic genome clock rhythm buffering against high temperature. Resequencing of the parental chloroplast indicated the presence of several candidate genes underlying these significant effects. This first reported plasmotype-driven clock plasticity paves the way for identifying an hitherto unknown impact of nuclear and plasmotype variations on clock robustness and on plant adaptation to changing environments.HighlightCircadian clock robustness to high temperature is controlled by nuclear and plasmotype quantitative trait loci in a wild barley(Hordeum vulgaressp.spontaneum)reciprocal doubled haploid population.
Genetic determinants of resistance and virulence among carbapenemase-producing Klebsiella pneumoniae from Sri Lanka
Authors: Zhu Chendi , Liyanapathirana Veranja , Li Carmen , Pinto V. , Hui Mamie , Lo Norman , Wong Kam-Tak , Dissanayake N. , Ip Margaret 
Published: May 2018

ABSTRACTWhole genome sequencing of carbapenem-resistant Enterobacteriaceae from the intensive care units of a Sri Lankan teaching hospital revealed the presence of carbapenemase gene, blaOXA-181 among isolates of carbapenase-producing Klebsiella pneumoniae belonging to ST437 (2 strains) and ST147 (8 strains) in 2015. blaOXA-181 genes were carried in three variants of ColE-type plasmids. Elevated carbapemen resistance were observed in ompK36 mutant strains. ESBL genes, plasmid–mediated quinolone resistance (PMQR) determinants (qnr, aac(6’)-Ib-cr, oqxAB) and mutations on chromosomal quinolone resistance-determining regions (QRDRs) with substitutions at ser83→I of gyrA and ser80→I of parC were observed. All strains possessed yersiniabactin on the mobile element ICEkp and other virulence determinants. Strict infection control and judicious use of antibiotics are warranted to prevent further spread of multidrug-resistant Klebsiella pneumoniae in the intensive care units.
Pathways of pathogenicity: The transcriptional stages of germination in the fatal fungal pathogen Rhizopus delemar
Authors: Sephton Clark Poppy C. S. , Muñoz Jose F. , Ballou Elizabeth R. , Cuomo Christina A. , Voelz Kerstin 
Published: May 2018

AbstractRhizopus delemar is an invasive fungal pathogen, responsible for the frequently fatal disease mucormycosis. Germination, a crucial mechanism by which spores of Rhizopus delemar infect and cause disease, is a key developmental process that transforms the dormant spore state into a vegetative one. Understanding the molecular mechanisms which underpin this transformation may be key to controlling mucormycosis, however the regulation of germination remains poorly understood. This study describes the phenotypic and transcriptional changes which take place over the course of germination. This process is characterised by four distinct stages: dormancy, isotropic swelling, germ tube emergence and hyphal growth. Dormant spores are shown to be transcriptionally unique, expressing a subset of transcripts absent in later developmental stages. A large shift in the expression profile is prompted by the initiation of germination, with genes involved in respiration, chitin, cytoskeleton and actin regulation appearing to be important for this transition. A period of transcriptional consistency can be seen throughout isotropic swelling, before the transcriptional landscape shifts again at the onset of hyphal growth. This study provides a greater understanding of the regulation of germination and highlights processes involved in transforming Rhizopus delemar from a single to a multicellular organism.ImportanceGermination is key to the growth of many organisms, including fungal spores. Mucormycete spores exist abundantly within the environment and germinate to form hyphae. These spores are capable of infecting immunocompromised individuals, causing the disease mucormycosis Germination from spore to hyphae within patients leads to angioinvasion, tissue necrosis and often fatal infections. This study advances our understanding of how spore germination occurs in the mucormycetes, identifying processes we may be able to inhibit to help prevent or treat mucormycosis.
Analysis of Transcripts and splice isoforms in Red Clover (Trifolium pratense L.) by single-molecule long-read sequencing
Authors: Chao Yuehui , Yuan Jianbo , Li Sifeng , Jia Siqiao , Han Liebao , Xu Lixin 
Published: May 2018

AbstractRed clover (Trifolium pratense L.) is an important cool-season legume plant, which is the most widely planted forage legume after alfalfa. Although a draft genome sequence was published already, the sequences and completed structure of mRNA transcripts remain unclear, which limit further explore on red clover. In this study, the red clover transcriptome was sequenced using single-molecule long-read sequencing to identify full-length splice isoforms, and 29,730 novel isoforms from known genes and 2,194 novel isoforms from novel genes were identified. A total of 5,492 alternative splicing events was identified and the majority of alter spliced events in red clover was corrected as intron retention. In addition, of the 15,229 genes detected by SMRT, 8,719 including 1,86,517 transcripts have at least one poly(A) site. Furthermore, we identified 4,333 long non-coding RNAs and 3,762 fusion transcripts. Our results show the feasibility of deep sequencing full-length RNA from red clover transcriptome on a single-molecule level.