bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic expressions of confidence within an evidence accumulation framework
Authors: Desender Kobe , Donner Tobias H. , Verguts Tom 
Published: February 2020

AbstractHuman observers can reliably report their confidence in the choices they make. An influential framework conceptualizes decision confidence as the probability of a decision being correct, given the choice made and the evidence on which it was based. This framework accounts for three diagnostic signatures of human confidence reports, including an opposite dependence of confidence on evidence strength for correct and error trials. However, the framework does not account for the temporal evolution of these signatures, because it only describes the transformation of a static representation of evidence into choice and the associated confidence. Here, we combine this framework with another influential framework: dynamic accumulation of evidence over time, and build on the notion that confidence reflects the probability of being correct, given the choice and accumulated evidenceup until that point. Critically, we show that such a dynamic model predicts that the diagnostic signatures of confidence depend on time; most critically, it predicts a stronger opposite dependence of confidence on evidence strength and choice correctness as a function of time. We tested, and confirmed, these predictions in human behaviour during random dot motion discrimination, in which confidence judgments were queried at different points in time. We conclude that human confidence reports reflect the dynamics of the probability of being correct given the accumulated evidence and choice.
Differential Expression and Interaction network construction of Noncoding RNA and mRNA in Heart Tissue associated with Tetralogy of Fallot
Authors: Wang Hongdan , Cui Cunying , Li Yanan , Liu Yuanyuan , Fan Taibing , Peng Bangtian , Liu Lin 
Published: February 2020

ABSTRACTTetralogy of Fallot (TOF) is still the most common and complicated cyanotic congenital heart defect of all congenital heart diseases with a 10% incidence. Surgery repair is often necessary in infancy. The etiology of TOF is complex and genetic and epigenetic mechanisms such as chromosomal abnormalities, gene mutations, nucleic acid modifications, non-coding RNA, and circular RNA(circRNA) play an important role in its occurrence. RNA not only plays an auxiliary role of genetic information carrier, but also plays a more important role in various regulatory functions. There are few studies on the action mechanism of non-coding RNA. Aim to gain more in-depth knowledge of TOF, we collected tissue samples of the right ventricular outflow tract of 5 TOF children with no other intracardiac and extracardiac malformations and 5 normal fetuses. We systematically analyzed the specific long non-coding RNA (lncRNA), microRNA(miRNA), circRNA and messenger RNA(mRNA) profiles of TOF. To our knowledge, there are no reports of genome-wide study of transcriptome in TOF and we first obtained meaningful differentially expressed lncRNAs, miRNAs, circle RNA and mRNAs.
The genomic landscape of divergence across the speciation continuum in island-colonising silvereyes (Zosterops lateralis)
Authors: Sendell-Price Ashley T. , Ruegg Kristen C. , Anderson Eric C. , Quilodrán Claudio S. , Van Doren Benjamin M. , Underwood Vinh Le , Coulson Tim , Clegg Sonya. M. 
Published: February 2020

ABSTRACTA goal of the genomic era is to infer the evolutionary dynamics at play during the process of speciation by analysing the genomic landscape of divergence. However, empirical assessments of genomic landscapes under varying evolutionary scenarios are few, limiting the ability to achieve this goal. Here we combine RAD-sequencing and individual-based simulations to evaluate the genomic landscape in the silvereye (Zosterops lateralis). Using comparisons matched for divergence timeframe and gene flow context, we document how genomic patterns accumulate along the speciation continuum. In contrast to previous predictions, our results provide limited support for the idea that divergence accumulates around loci under divergent selection or that genomic islands widen with time. While a small number of genomic islands were found in populations diverging with and without gene flow, in few cases were SNPs putatively under selection tightly associated with genomic islands. Furthermore, we modelled the transition from localised to genome-wide levels of divergence using individual-based simulations that considered only neutral processes. Our results challenge the ubiquity of existing verbal models that explain the accumulation of genomic differences across the speciation continuum and instead support the idea that divergence both within and outside of genomic islands is important during the speciation process.DATA ACCESSION NUMBERSResequencing data from this study have been submitted to the National Center for Biotechnology Information (NCBI;https://www.ncbi.nlm.nih.gov) under accession number PRJNA489169.
Emergent properties of HNF4α-PPARγ network may drive consequent phenotypic plasticity in NAFLD
Authors: Sahoo Sarthak , Singh Divyoj , Chakraborty Priyanka , Jolly Mohit Kumar 
Published: February 2020

ABSTRACTNon-Alcoholic Fatty Liver Disease (NAFLD) is the most common form of chronic liver disease in adults and children. It is characterized by excessive accumulation of lipids in the hepatocytes of patients without any excess alcohol intake. With a global presence of 24% and limited therapeutic options, the disease burden of NAFLD is increasing. Thus, it becomes imperative to attempt to understand the dynamics of disease progression at a systems-level. Here, we decode the emergent dynamics of underlying gene regulatory networks that have been identified to drive the initiation and progression of NAFLD. We have developed a mathematical model to elucidate the dynamics of the HNF4α-PPARγ gene regulatory network. Our simulations reveal that this network can enable multiple co-existing phenotypes under certain biological conditions: an adipocyte, a hepatocyte, and a “hybrid” adipocyte-like state of the hepatocyte. These phenotypes may also switch among each other, thus enabling phenotypic plasticity and consequently leading to simultaneous deregulation of the levels of molecules that maintain a hepatic identity and/or facilitate a partial or complete acquisition of adipocytic traits. These predicted trends are supported by the analysis of clinical data, further substantiating the putative role of phenotypic plasticity in driving NAFLD. Our results unravel how the emergent dynamics of underlying regulatory networks can promote phenotypic plasticity, thereby propelling the clinically observed changes in gene expression often associated with NAFLD.
Comparative Genome Analysis ofScutellaria baicalensisandScutellaria barbataReveals the Evolution of Active Flavonoid Biosynthesis
Authors: Xu Zhichao , Gao Ranran , Pu Xiangdong , Xu Rong , Wang Jiyong , Zheng Sihao , Zeng Yan , Chen Jun , He Chunnian , Song Jingyuan 
Published: February 2020

AbstractScutellaria baicalensisandScutellaria barbata, common medicinal plants of the Lamiaceae family, produce specific flavonoid compounds with antioxidant and antitumor activities, including baicalein, scutellarein, norwogonin, wogonin, and their glycosides. Here, we reported two chromosome-level genome assemblies ofS. baicalensisandS. barbatawith significant quantitative chromosomal variation (2n = 18 and 2n = 26, respectively). The divergence ofS. baicalensisandS. barbataoccurred far earlier than previously reported, and a whole-genome duplication event was identified. The insertion of long terminal repeat elements after speciation might be responsible for the observed chromosomal expansion and rearrangement. The comparative genome analysis of congeneric species elucidated the species-specific evolution of chrysin and apigenin biosynthetic genes, such as theS. baicalensis-specific tandem duplication of the phenylalanine ammonia lyase (PAL) and chalcone synthase (CHS) genes, and theS. barbata-specific duplication of 4-CoA ligase (4CL) genes. In addition, the paralogous duplication, collinearity, and expression diversity of CYP82D subfamily members revealed the functional divergence of flavone hydroxylase genes betweenS. baicalensisandS. barbata. TheseScutellariagenomes highlight the common and species-specific evolution of flavone biosynthetic genes, promoting the development of molecular breeding and the study of the biosynthesis and regulation of bioactive compounds.
Comparison of three glycoproteomic methods for the analysis of CHO cells treated with 1,3,4-O-Bu3ManNAc
Authors: Mertz Joseph L. , Sun Shisheng , Yin Bojiao , Betenbaugh Michael J. , Yarema Kevin J. , Zhang Hui 
Published: February 2020

AbstractComprehensive analysis of the glycoproteome is critical due to the widespread importance of this post-translational modification to protein function, and difficult because of the tremendous complexity it exhibits. Here we compared three glycoproteomic analysis methods, a recently described chemoenzymatic glycoproteome analysis methods, N-linked glycans and glycosite containing peptides (NGAG), Solid-phase extraction of N-linked glycoproteins (SPEG), and hydrophilic interaction liquid chromatography (HILIC), for the analysis of N-linked glycosites of Chinese hamster ovarian (CHO) cells treated with 1,3,4-O-Bu3ManNAc. The NGAG protocol resulted in substantially increased glycosite identifications over both SPEG and HILIC. Interestingly, while the glycosites identified by SPEG and HILIC overlapped strongly, NGAG identified many glycosites not observed in either of the other two methods. Further, utilizing the enhanced intact glycopeptide identification afforded by the NGAG workflow, we also found that of the sugar analog 1,3,4-O-Bu3ManNAc increases sialylation of proteins secreted by CHO cells, including an ectopically expressed human proteins.
A lipocalin mediates unidirectional haem biomineralization in malaria parasites
Authors: Matz Joachim M. , Drepper Benjamin , Blum Thorsten B. , van Genderen Eric , Burrell Alana , Martin Peer , Stach Thomas , Collinson Lucy , Abrahams Jan Pieter , Matuschewski Kai , Blackman Michael J. 
Published: February 2020

ABSTRACTDuring blood stage development, malaria parasites are challenged with the detoxification of enormous amounts of haem released during the proteolytic catabolism of erythrocytic haemoglobin. They tackle this problem by sequestering haem into bioinert crystals known as haemozoin. The mechanisms underlying this biomineralization process remain enigmatic. Here, we demonstrate that both rodent and human malaria parasite species secrete and internalize a lipocalin-like protein, PV5, to control haem crystallization. Transcriptional deregulation ofPV5in the rodent parasitePlasmodium bergheiresults in inordinate elongation of haemozoin crystals, while conditionalPV5inactivation in the human malaria agentPlasmodium falciparumcauses excessive multi-directional crystal branching. Although haemoglobin processing remains unaffected, PV5-deficient parasites generate less haemozoin. Electron diffraction analysis indicates that despite the distinct changes in crystal morphology neither the crystalline order nor unit cell of haemozoin are affected by impaired PV5 function. Deregulation ofPV5expression rendersP. bergheihypersensitive to the antimalarial drugs artesunate, chloroquine, and atovaquone, resulting in accelerated parasite clearance following drug treatmentin vivo. Together, our findings demonstrate thePlasmodium-tailored role of a lipocalin family member in haemozoin formation and underscore the haem biomineralization pathway as an attractive target for therapeutic exploitation.SIGNIFICANCEDuring blood stage development, the malaria parasite replicates inside erythrocytes of the vertebrate host, where it engulfs and digests most of the available haemoglobin. This results in release of the oxygen-binding prosthetic group haem, which is highly toxic in its unbound form. The parasite crystallizes the haem into an insoluble pigment called haemozoin, a process that is vital for parasite survival and which is exploited in antimalarial therapy. We demonstrate that the parasite uses a protein called PV5 in haemozoin formation and that interfering with PV5 expression can increase the parasite’s sensitivity to antimalarial drugs during blood infection. An improved understanding of the mechanisms underlying haem sequestration will provide valuable insights for future drug development efforts.
Subjective value and decision entropy are jointly encoded by aligned gradients across the human brain
Authors: Bobadilla-Suarez Sebastian , Guest Olivia , Love Bradley C. 
Published: February 2020

AbstractRecent work has considered the relationship between value and confidence in both behavior and neural representation. Here we evaluated whether the brain organizes value and confidence signals in a systematic fashion that reflects the overall desirability of options. If so, regions that respond to either increases or decreases in both value and confidence should be widespread. We strongly confirmed these predictions through a model-based fMRI analysis of a mixed gambles task that assessed subjective value (SV) and inverse decision entropy (iDE), which is related to confidence. Purported value areas more strongly signalled iDE than SV, underscoring how intertwined value and confidence are. A gradient tied to the desirability of actions transitioned from positive SV and iDE in ventromedial prefrontal cortex to negative SV and iDE in dorsal medial prefrontal cortex. This alignment of SV and iDE signals could support retrospective evaluation to guide learning and subsequent decisions.
Fine-tuning of the PAX-SIX-EYA-DACH network by multiple microRNAs controls embryo myogenesis
Authors: Viaut Camille , Münsterberg Andrea 
Published: February 2020

AbstractMicroRNAs (miRNAs), short non-coding RNAs, which act post-transcriptionally to regulate gene expression, are of widespread significance during development and disease, including muscle disease. Advances in sequencing technology and bioinformatics led to the identification of a large number of miRNAs in vertebrates and other species, however, for many of these miRNAs specific roles have not yet been determined. LNAin situhybridisation has revealed expression patterns of somite-enriched miRNAs, here we focus on characterising the functions of miR-128. We show that antagomir-mediated knock-down (KD) of miR-128 in developing chick somites has a negative impact on skeletal myogenesis. Computational analysis identified the transcription factorEYA4as a candidate target consistent with the observation that miR-128 andEYA4display similar expression profiles. Luciferase assays confirmed that miR-128 interacts with theEYA43’UTR. Furthermore,in vivoexperiments suggest thatEYA4is regulated by miR-128, asEYA4expression is derepressed after antagomir-mediated inhibition of miR-128. EYA4 is a member of the PAX-SIX-EYA-DACH (PSED) network of transcription factors. Therefore, we identified additional candidate miRNA binding sites in the 3’UTR ofSIX1/4, EYA1/2/3andDACH1. Using the miRanda algorithm, we found sites for miR-128, as well as for other myogenic miRNAs, miR-1a, miR-206 and miR-133a, some of these were experimentally confirmed as functional miRNA-target sites. Our results reveal that miR-128 is involved in regulating skeletal myogenesis by targetingEYA4transcripts and moreover that the PSED network of transcription factors is co-regulated by multiple muscle-enriched microRNAs.
An Envelope Protein of a Prokaryotic Organelle Function towards Conserving Catalytic Activity of the Native Enzyme at Higher Temperatures
Authors: Kumar Gaurav , Bari Naimat K. , Hazra Jagadish P. , Sinha Sharmistha 
Published: February 2020

AbstractA classic example of an all-protein natural nano-bioreactor, the bacterial microcompartments are a special kind of prokaryotic organelles that confine enzymes within a small volume enveloped by an outer layer of shell proteins. This arrangement provides conditional metabolic aid to the bacteria. The outer shell allows selective diffusion of small molecules and sequesters toxic metabolites. In this work we use 1,2-propanediol utilization microcompartment as a model to study the effect of molecular confinement on the stability and catalytic activity of native enzymes in microcompartment. We observe a 50% decrease in the activity of free enzyme PduCDE at 45°C, while PduMCP retains its optimum activity till 50°C followed by more than 40% reduced activity at 55°C. PduBB’, the major component of the outer shell contributes to the increased catalytic activity of PduCDE. PduBB’ also prevents the unfolding and aggregation of PduCDE under thermal stress. Using a combination of experimental and theoretical studies we probe the interactions of the shell proteins PduBB’, N-terminal truncated PduB and single mutant PduB’M38L with PduCDE. We observe that all the three variants of PduB* shell proteins interact with the enzyme in vitro, but only PduBB’ influences its activity and stability, underscoring the significance of the unique combination of PduB and PduB’ in PduMCP assembly.
ASH1L REGULATES THE STRUCTURAL DEVELOPMENT OF NEURONAL CIRCUITRY BY MODULATING BDNF/TrkB SIGNALING IN HUMAN NEURONS
Authors: Cheon Seon Hye , Culver Allison M. , Bagnell Anna M. , Ritchie Foster D. , Clytus Janay M. , McCord Mikayla , Papendorp Carin M. , Chukwurah Evelyn , Smith Austin J. , Cowen Mara H. , Ghate Pankaj S. , Davis Shannon W. , Liu Judy S. , Lizarraga Sofia B. 
Published: February 2020

SUMMARYAutism spectrum disorders (ASD) are associated with defects in neuronal connectivity and are highly heritable. Genetic findings suggest that there is an overrepresentation of chromatin regulatory genes among the genes associated with ASD. ASH1 like histone lysine methyltransferase (ASH1L) was identified as a major risk factor for autism. ASH1L methylates Histone H3 on Lysine 36, which is proposed to result primarily in transcriptional activation. However, how mutations in ASH1L lead to deficits in neuronal connectivity associated with autism pathogenesis is not known. We report that ASH1L regulates neuronal morphogenesis by counteracting the catalytic activity of Polycomb Repressive complex 2 group (PRC2) in stem cell-derived human neurons. Depletion of ASH1L decreases neurite outgrowth and decreases expression of the gene encoding the neurotrophin receptor TrkB whose signaling pathway is linked to neuronal morphogenesis. This is overcome by inhibition of PRC2 activity, indicating a balance between the Trithorax group protein ASH1L and PRC2 activity determines neuronal morphology and connectivity. Thus, ASH1L epigenetically regulates neuronal connectivity by modulating the BDNF-TrkB signaling pathway, which likely contributes to the neurodevelopmental pathogenesis associated with ASD in patients with ASH1L mutations.eTOC BLURBCheon et al. report a novel epigenetic mechanism that implicates the counteracting activities of the evolutionarily conserved Trithorax (ASH1L) and Polycomb (PRC2) chromatin regulators, in the modulation of human neuronal connectivity by regulating the developmentally important TrkB-BDNF signaling pathway.HIGHLIGHTSASH1L regulates neuronal morphogenesis by modulating neurotrophin signalingCounteracting activities of Trithorax (ASH1L) and Polycomb (PRC2) affect neuronal arborizationLoss of ASH1L modulates growth cone size in human neurons
Discovering and exploiting multiple types of DNA methylation from individual bacteria and microbiome using nanopore sequencing
Authors: Tourancheau Alan , Mead Edward A. , Zhang Xue-Song , Fang Gang 
Published: February 2020

AbstractNanopore sequencing provides a great opportunity for direct detection of chemical DNA modification. However, existing computational methods were either trained for detecting a specific form of DNA modification from one, or a few, specific sequence contexts (e.g.5-methylcytosine from CpG dinucleotides) or for allowingde novodetection without effectively differentiating between different forms of DNA modifications. As a result, none of these methods supportsde novo, systematic study of unknown bacterial methylomes. In this work, by examining three types of DNA methylation in a large diversity of sequence contexts, we observed that nanopore sequencing signal displays complex heterogeneity across methylation events of the same type. To capture this complexity and enable nanopore sequencing for broadly applicable methylation discovery, we generated a training dataset from an assortment of bacterial species and developed a novel method that couples the identification and fine mapping of the three forms of DNA methylation into a multi-label classification design. We evaluated the method and then applied it to individual bacteria and mouse gut microbiome for reliable methylation discovery. In addition, we demonstrated in the microbiome analysis the use of DNA methylation for binning metagenomic contigs, associating mobile genetic elements with their host genomes, and for the first time, identifying misassembled metagenomic contigs. This novel method has broad utility for discovering different forms of DNA methylation from bacteria, assisting functional studies of epigenetic regulation in bacteria, and exploiting bacterial epigenomes for more effective metagenomic analyses.
Spatial segregation and cooperation in radially expanding microbial colonies under antibiotic stress
Authors: Sharma Anupama , Wood Kevin B. 
Published: February 2020

ABSTRACTAntibiotic resistance in microbial communities reflects a combination of processes operating at different scales. The molecular mechanisms underlying antibiotic resistance are increasingly understood, but less is known about how these molecular events give rise to spatiotemporal behavior on longer length scales. In this work, we investigate the population dynamics of bacterial colonies comprised of drug-resistant and drug-sensitive cells undergoing range expansion under antibiotic stress. Using the opportunistic pathogenE. faecaliswith plasmid-encoded (β-lactamase) resistance as a model system, we track colony expansion dynamics and visualize spatial pattern formation in fluorescently labeled populations exposed to ampicillin, a commonly-usedβ-lactam antibiotic. We find that the radial expansion rate of mixed communities is approximately constant over a wide range of drug concentrations and initial population compositions. Fluorescence imaging of the final populations shows that resistance to ampicillin is cooperative, with sensitive cells surviving in the presence of resistant cells even at drug concentrations lethal to sensitive-only communities. Furthermore, despite the relative invariance of expansion rate across conditions, the populations exhibit a diverse range of spatial segregation patterns, with both the spatial structure and the population composition depending on drug concentration, initial composition, and initial population size. Agent based models indicate that the observed dynamics are consistent with long-range cooperation, despite the fact thatβ-lactamase remains cell-associated inE. faecalis, and experiments confirm that resistant colonies provide a protective effect to sensitive cells on length scales multiple times the size of a single colony. Furthermore, in the limit of small inoculum sizes, we experimentally show that populations seeded with (on average) no more than a single resistant cell can produce mixed communities in the presence of drug. While biophysical models of diffusion-limited drug degradation suggest that individual resistant cells offer only short-range protection to neighboring sensitive cells, we show that long-range protection may arise from synergistic effects of multiple resistant cells, even when they represent only a small fraction of a colony’s surface area. Our results suggest thatβ-lactam resistance can be cooperative even in spatially extended systems where genetic segregation typically disfavors exploitation of locally produced public goods.