bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptive coding for dynamic sensory inference
Authors: Młynarski Wiktor , Hermundstad Ann M. 
Published: September 2017

AbstractBehavior relies on the ability of sensory systems to infer properties of the environment from incoming stimuli. The accuracy of inference depends on the fidelity with which behaviorally-relevant properties of stimuli are encoded in neural responses. High-fidelity encodings can be metabolically costly, but low-fidelity encodings can cause errors in inference. Here, we discuss general principles that underlie the tradeoff between encoding cost and inference error. We then derive adaptive encoding schemes that dynamically navigate this tradeoff. These optimal encodings tend to increase the fidelity of the neural representation following a change in the stimulus distribution, and reduce fidelity for stimuli that originate from a known distribution. We predict dynamical signatures of such encoding schemes and demonstrate how known phenomena, such as burst coding and firing rate adaptation, can be understood as hallmarks of optimal coding for accurate inference.
Failure to reactivate salient episodic information during indirect and direct tests of memory retrieval
Authors: Price Mason H. , Johnson Jeffrey D. 
Published: September 2017

ABSTRACTSeveral fMRI and EEG studies have demonstrated that successful episodic retrieval is accompanied by the reactivation of cortical regions that were active during encoding. These findings are consistent with influential models of episodic memory that posit that conscious retrieval (recollection) relies on hippocampally-mediated cortical reinstatement. Evidence of reactivation corresponding to episodic information that is beyond conscious awareness at the time of memory retrieval, however, is limited. A recent exception is from an EEG study by Wimber, Maaβ, Staudigl, Richardson-Klavehn, and Hanslmayr (2012) in which words were encoded in the context of highly salient visual flicker entrainment and then presented at retrieval in the absence of any flicker. In that study, coherent (phase-locked) neural activity was observed at the corresponding entrained frequencies during retrieval, consistent with the notion that encoding representations were reactivated. Given the important implications of unconscious reactivation to past findings and the modeling literature, the current study set out to provide a direct replication of the previous study. Additionally, an attempt was made to extend such findings to intentional retrieval by acquiring EEG while subjects were explicitly asked to make memory judgments about the flicker frequency from encoding. Throughout a comprehensive set of analyses, the current study consistently failed to demonstrate evidence for unconscious reactivation, and instead provided support that test items were indistinguishable according to their prior encoding context. The findings thus establish an important boundary condition for the involvement of cortical reinstatement in episodic memory.
Transcription factor co-binding patterns drive conserved regulatory outcomes
Authors: Diehl Adam G. , Boyle Alan P. 
Published: September 2017

ABSTRACTThe mouse has been widely used as a model system in which to study human genetic mechanisms. However, part of the difficulty in translating findings from mouse is that, despite high levels of gene conservation, regulatory control networks between human and mouse have been extensively rewired. To understand common themes of regulatory control we look beyond physical sharing of regulatory sequence, where extensive turnover of individual transcription factor binding sites complicates cross-species prediction of specific functions, and instead look at conserved properties of the regulatory code itself. We define regulatory conservation in terms of a grammar with shared, species-specific, and tissue-specific segments, and show that this grammar is more predictive of shared chromatin states and gene expression profiles than shared occupancy alone. Furthermore, we demonstrate a marked enrichment of disease associated variation in conserved grammatical patterns. These findings offer new understanding of transcriptional regulatory mechanisms shared between human and mouse.
Biomarker evaluation of plasma microRNA-122, high-mobility group box-1 and keratin-18 in acute gallstone disease
Authors: Th’ng Francesca , Vliegenthart Bastiaan , Lea Jonathan D , Antoine Daniel J. , Dear James W , Mole Damian J. 
Published: September 2017

ABSTRACTBackgroundA biomarker that stratifies patients with complications of gallstone disease from the denominator pool of people with acute biliary-type symptoms is needed. Circulating microRNA-122 (miRNA-122), high-mobility group box1 (HMGB1), full-length keratin-18 (flk-18) and caspase-cleaved keratin-18 (cck-18) are established hepatocyte injury biomarkers. The aim of this study was to evaluate the discriminatory power of these biomarkers in plasma to identify potential biliary complications that may require acute intervention.MethodAn observational biomarker cohort study was carried out in a University teaching hospital for 12 months beginning 3rdSeptember 2014. Blood samples were collected from adults referred with acute biliary-type symptoms. miRNA-122 was measured by quantitative real-time polymerase chain reaction, and HMGB1, cck-18 and flk-18 by ELISA.Results300 patients were screened and 289 patients were included. Plasma miRNA-122, cck-18 and flk-18 concentrations were increased in patients with gallstones compared to those without (miRNA-122: median: 2.89 × 104copies/ml vs. 0.95 × 104copies/ml [P<0.001];cck-18:121.9 U/L vs. 104.6 U/L [P = 0.041];flk-18: 252.4 U/L vs. 151.8 U/L [P<0.001]). Uncomplicated gallstone disease was associated with higher miRNA-122 and cck-18 concentrations than complicated disease (miRNA-122: 5.72 × 104copies/ml vs. 2.26x104copies/ml [P=0.022];cck-18: 139.7 U/L vs. 111.4 U/L [P=0.049]). There was no significant difference in HMGB1 concentration between patients with and without gallstones [P=0.480]. Separation between groups for all biomarkers was modest.ConclusionmicroRNA-122 and keratin-18 plasma concentrations are elevated in patients with gallstones. However, these biomarkers were not sufficiently discriminatory to be progressed as clinically useful biomarkers in this context.
Dynamic changes in oligomeric complexes of UPR sensors induced by misfolded proteins in the ER
Authors: Sundaram Arunkumar , Appathurai Suhila , Mariappan Malaiyalam 
Published: September 2017

AbstractThe endoplasmic reticulum (ER) localized unfolded protein response (UPR) sensors, IRE1α, PERK, and ATF6α, are activated upon accumulation of misfolded proteins caused by ER stress. It is debated whether these UPR sensors are activated either by the release of their negative regulator BiP chaperone or directly binding to misfolded proteins during ER stress. Here we simultaneously examined oligomerization and activation of all three endogenous UPR sensors. We found that UPR sensors existed as preformed oligomers even in unstressed cells, which shifted to large oligomers for PERK and small oligomers for ATF6α, but little changed for IRE1α upon ER stress. Neither depletion nor overexpression of BiP had significant effects on oligomeric complexes of UPR sensors both in unstressed and stressed cells. Thus, our results find less evidence for the BiP-mediated activation of UPR sensors in mammalian cells and support that misfolded proteins bind and activate the preformed oligomers of UPR sensors.
ELMOD1 stimulates ARF6-GTP hydrolysis to stabilize apical structures in developing vestibular hair cells
Authors: Krey Jocelyn F. , Dumont Rachel A. , Wilmarth Philip A. , David Larry L. , Johnson Kenneth R. , Barr-Gillespie Peter G. 
Published: September 2017

AbstractSensory hair cells require control of physical properties of their apical plasma membranes for normal development and function. Members of the ARF small GTPase family regulate membrane trafficking and cytoskeletal assembly in many cells. We identified ELMOD1, a guanine nucleoside triphosphatase activating protein (GAP) for ARF6, as the most highly enriched ARF regulator in hair cells. To characterize ELMOD1 control of trafficking, we used a mouse strain lacking functional ELMOD1 (roundabout; rda). In rda/rda mice, cuticular plates of utricle hair cells initially formed normally, then degenerated after postnatal day 5 (P5); large numbers of vesicles invaded the compromised cuticular plate. Hair bundles initially developed normally, but the cell’s apical membrane lifted away from the cuticular plate, and stereocilia elongated and fused. Membrane trafficking in type I hair cells, measured by FM1-43 dye labeling, was altered in rda/rda mice. Consistent with the proposed GAP role for ELMOD1, the ARF6 GTP/GDP ratio was significantly elevated in rda/rda utricles as compared to controls, and the level of ARF6-GTP was correlated with the severity of the rda/rda phenotype. These results suggest that conversion of ARF6 to its GDP-bound form is necessary for final stabilization of the hair bundle.Significance StatementAssembly of the mechanically sensitive hair bundle of sensory hair cells requires growth and reorganization of apical actin and membrane structures. Hair bundles and apical membranes in mice with mutations in theElmod1gene degenerate after formation, suggesting that the ELMOD1 protein stabilizes these structures. We show that ELMOD1 is a GTPase-activating protein in hair cells for the small GTP-binding protein ARF6, known to participate in actin assembly and membrane trafficking. We propose that conversion of ARF6 into the GDP-bound form in the apical domain of hair cells is essential for stabilizing apical actin structures like the hair bundle and ensuring that the apical membrane forms appropriately around the stereocilia.
EIF4A3 associated splicing and nonsense mediated decay defined by a systems analysis with novel small molecule inhibitors
Authors: Mazloomian Alborz , Araki Shinsuke , Ohori Momoko , Yap Damian , Nakao Shoichi , Nakanishi Atsushi , Shah Sohrab , Aparicio Samuel 
Published: September 2017

AbstractChemical biology approaches to the global functions of splicing reactions are gaining momentum, with an increasing repertoire of small molecule probes becoming available. Here we map the association of eIF4A3 with transcript expression, NMD and alternative splicing using a set of selective novel small molecule allosteric helicase inhibitors whose synthesis and chemical properties we have recently described. We show through analysis of dose monotonic transcriptional responses to increasing inhibition that both full length and NMD prone transcripts link eIF4A3 to normal functioning of cell division including chromosome segregation and cell cycle checkpoints, pointing to a conserved role of splicing and transcript quality processing in cell cycle functions. Cell cycle analysis and microscopy of inhibitor treated cells demonstrates chromosome mis-segregation and spindle defects, associated with a G2/M arrest, validating this observation. Through analysis of conserved alternative splicing patterns exhibiting monotonic responses, we find that eIF4A3 dependent alternative splicing involves exons that are longer and introns that are shorter than transcripts not modulated by eIF4A3. Moreover we observe conservation of over/under representation of RBP binding motif density over introns and exons implicated eIF4A3 modulated skipped exon and retained introns. The distribution of motif densities over 5’ and branch intron sites and 5’ exons is consistent with function of the exon-junction complex. Taken together we have defined a fraction of the transcrip-tome dependent on eIF4A3 functions and revealed a link between eIF4A3 and cell cycle regulation. The systems approach described here suggests additional avenues for therapeutic exploitation of eIF4A3 functions in cancer and related diseases.
NF90/ILF3 is a transcription factor that promotes proliferation over differentiation by hierarchical regulation in K562 erythroleukemia cells
Authors: Wu Ting-Hsuan , Shi Lingfang , Adrian Jessika , Shi Minyi , Nair Ramesh V. , Snyder Michael P. , Kao Peter N. 
Published: September 2017

ABSTRACTNF90 and splice variant NF110 are DNA‐ and RNA-binding proteins encoded by the Interleukin enhancer-binding factor 3 (ILF3) gene that regulate RNA splicing, stabilization and export. The role of NF90 in regulating transcription as a DNA-binding protein has not been comprehensively characterized. Here, ENCODE ChIP-seq identified 9,081 genomic sites specifically bound by NF90/110 in K562 cells. One third of binding sites occurred at promoters of annotated genes. NF90/110 binding colocalized with chromatin marks associated with active promoters and strong enhancers. Comparison with 150 ENCODE ChIP-seq experiments revealed that NF90 clustered with transcription factors exhibiting preference for promoters over enhancers (POLR2A,MYC,YY1). Differential gene expression analysis following shRNA knockdown of NF90 in K562 cells revealed that NF90 directly activates transcription factors that drive growth and proliferation (EGR1,MYC), while attenuating differentiation along erythroid lineage (KLF1). NF90/110 binds chromatin to hierarchically regulate transcription factors to promote proliferation and suppress differentiation.
High-throughput identification of RNA nuclear enrichment sequences
Authors: Shukla Chinmay J , McCorkindale Alexandra L , Gerhardinger Chiara , Korthauer Keegan D , Cabili Moran N , Shechner David M , Irizarry Rafael A , Maass Philipp G , Rinn John L 
Published: September 2017

SummaryOne of the biggest surprises since the sequencing of the human genome has been the discovery of thousands of long noncoding RNAs (lncRNAs)1–6. Although lncRNAs and mRNAs are similar in many ways, they differ with lncRNAs being more nuclear-enriched and in several cases exclusively nuclear7,8. Yet, the RNA-based sequences that determine nuclear localization remain poorly understood9–11. Towards the goal of systematically dissecting the lncRNA sequences that impart nuclear localization, we developed a massively parallel reporter assay (MPRA). Unlike previous MPRAs12–15that determine motifs important for transcriptional regulation, we have modified this approach to identify sequences sufficient for RNA nuclear enrichment for 38 human lncRNAs. Using this approach, we identified 109 unique, conserved nuclear enrichment regions, originating from 29 distinct lncRNAs. We also discovered two shorter motifs within our nuclear enrichment regions. We further validated the sufficiency of several regions to impart nuclear localization by single molecule RNA fluorescencein situhybridization (smRNA-FISH). Taken together, these results provide a first systematic insight into the sequence elements responsible for the nuclear enrichment of lncRNA molecules.
S1-seq assay for mapping processed DNA ends
Authors: Mimitou Eleni P. , Keeney Scott 
Published: September 2017

AbstractDuring meiosis, the specialized cell division giving rise to gametes, numerous DNA doublestrand breaks (DSBs) are introduced at multiple places throughout the genome by the topoisomerase-like protein Spo11. Homologous recombination, a highly-conserved DSB repair pathway, is employed for their repair and ensures the formation of chiasmata and the proper segregation of homologous chromosomes. In the initial steps of recombination, end resection takes place, wherein Spo11 is endonucleolytically released and the 5′-terminal strands of each DSB are exonucleolytically processed, exposing the ssDNA necessary to identify a homologous repair template. DNA removed by DSB processing is reconstituted by DNA synthesis, which copies genetic information from the intact homologous template. We developed a next-generation sequencing assay, termed S1-seq, to study DNA end resection genome-wide at high spatial resolution during yeast meiotic recombination. The assay relies on the fact that removal of the ssDNA tails of resected DSBs marks the position where resection stopped. Molecular features of resection are revealed by sequencing of these ssDNA-to-dsDNA junctions and comparison to high-resolution Spo11 DSB maps. We describe the experimental and computational methods for S1-seq as applied to meiosis in the SK1 strain of budding yeastSaccharomyces cerevisiae, and discuss how it can also be applied to map DSBs and recombination intermediates.
Turning vice into virtue: Using Batch-Effects to Detect Errors in Large Genomic Datasets
Authors: Mafessoni Fabrizio , Prasad Rashmi B , Groop Leif , Hansson Ola , Prüfer Kay 
Published: September 2017

AbstractIt is often unavoidable to combine data from different sequencing centers or sequencing platforms when compiling datasets with a large number of individuals. However, the different data are likely to contain specific systematic errors that will appear as SNPs. Here, we devise a method to detect systematic errors in combined datasets. To measure quality differences between individual genomes, we study pairs of variants that reside on different chromosomes and co-occur in individuals. The abundance of these pairs of variants in different genomes is then used to detect systematic errors due to batch effects. Applying our method to the 1000 Genomes dataset, we find that coding regions are enriched for errors, where about 1% of the higher-frequency variants are predicted to be erroneous, whereas errors outside of coding regions are much rarer (<0.001%). As expected, predicted errors are less often found than other variants in a dataset that was generated with a different sequencing technology, indicating that many of the candidates are indeed errors. However, predicted 1000 Genomes errors are also found in other large datasets; our observation is thus not specific to the 1000 Genomes dataset. Our results show that batch effects can be turned into a virtue by using the resulting variation in large scale datasets to detect systematic errors.
Inferring continuous and discrete population genetic structure across space
Authors: Bradburd Gideon S. , Coop Graham M. , Ralph Peter L. 
Published: September 2017

AbstractA classic problem in population genetics is the characterization of discrete population structure in the presence of continuous patterns of genetic differentiation. Especially when sampling is discontinuous, the use of clustering or assignment methods may incorrectly ascribe differentiation due to continuous processes (e.g., geographic isolation by distance) to discrete processes, such as geographic, ecological, or reproductive barriers between populations. This reflects a shortcoming of current methods for inferring and visualizing population structure when applied to genetic data deriving from geographically distributed populations. Here, we present a statistical framework for the simultaneous inference of continuous and discrete patterns of population structure. The method estimates ancestry proportions for each sample from a set of two-dimensional population layers, and, within each layer, estimates a rate at which relatedness decays with distance. This thereby explicitly addresses the “clines versus clusters” problem in modeling population genetic variation. The method produces useful descriptions of structure in genetic relatedness in situations where separated, geographically distributed populations interact, as after a range expansion or secondary contact. We demonstrate the utility of this approach using simulations and by applying it to empirical datasets of poplars and black bears in North America.Author summaryOne of the first steps in the analysis of genetic data, and a principal mission of biology, is to describe and categorize natural variation. A continuous pattern of differentiation (isolation by distance), where individuals found closer together in space are, on average, more genetically similar than individuals sampled farther apart, can confound attempts to categorize natural variation into groups. This is because current statistical methods for assigning individuals to discrete clusters cannot accommodate spatial patterns, and so are forced to use clusters to describe what is in fact continuous variation. As isolation by distance is common in nature, this is a substantial shortcoming of existing methods. In this study, we introduce a new statistical method for categorizing natural genetic variation - one that describes variation as a combination of continuous and discrete patterns. We demonstrate that this method works well and can capture patterns in population genomic data without resorting to splitting populations where they can be described by continuous patterns of variation.
The drivers and consequences of unstablePlasmodiumdynamics: A long-term study of three malaria species infecting a tropical lizard
Authors: Otero Luisa , Schall Jos. J. , Cruz Virnaliz , Aaltonen Kristen , Acevedo Miguel A. 
Published: September 2017

ABSTRACTThe dynamics of vector-borne parasites are driven by interactions between factors intrinsic to the parasite, its host, as well as environmental fluctuations. Understanding these interactions requires a long-term view, especially to predict the consequences of climate change on parasite dynamics.The goal of this study is to evaluate temporal fluctuations in individual probability of infection, its environmental drivers and consequences for host body condition, of three malaria parasites (Plasmodium azurophilum,P. leucocytica, andP. floridense) infecting the lizard,Anolis gundlachi, in the rainforest of Puerto Rico.We conducted 13 surveys totalingN> 8000 lizards over 26 years. During the early years of the study, the lizard’s probability of infection by all threePlasmodiumspecies appeared stable despite disturbances from short droughts and small to moderate hurricanes.Over a longer timescale, we found that the individual lizard probability of infection and overall prevalence varied significantly over the years, and this fluctuation was driven in non-linear ways by variations in temperature and rainfall. The probability of infection was maximized at intermediate levels of temperature and precipitation. This temporal variability inPlasmodiumprevalence driven by environmental factors had two important consequences. First, temperature-mediated a decrease in body condition in infected female lizards relative to non-infected ones. Second,Plasmodiumparasite species composition varied through time.Overall, the results show how environmental conditions, such a severe drought, can drive disease dynamics outside of their apparent stable equilibrium and mediate the potential negative effects of parasite infection on the host. Our results also emphasize the need for long-term studies to reveal host-parasite dynamics, their drivers and consequences.