bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted gene correction and functional recovery in achondroplasia patient-derived iPSCs
Authors: Zou Huan , Guan Mingfeng , Li Yundong , Luo Fang , Wang Wenyuan , Qin Yiren 
Published: October 2019

AbstractBackgroundAchondroplasia (ACH) is the most common genetic form of dwarfism and belongs to dominant monogenic disorder caused by a gain-of-function point mutation in the transmembrane region of FGFR3. There are no effective treatments for ACH. Stem cells and gene-editing technology provide us with effective methods and ideas for ACH research and treatment.MethodsWe generated non-integrated iPSCs from an ACH girl’s skin and an ACH boy’s urine by Sendai virus. The mutation of ACH iPSCs was precisely corrected by CRISPR-Cas9.ResultsChondrogenic differentiation ability of ACH iPSCs was confined compared with that of healthy iPSCs. Chondrogenic differentiation ability of corrected ACH iPSCs could be restored. These corrected iPSCs displayed pluripotency, maintained normal karyotype, and demonstrated none of off-target indels.ConclusionsThis study may provide an important theoretical and experimental basis for the ACH research and treatment.
Mechanosensory neuron regeneration in adult Drosophila
Authors: Fernández-Hernández Ismael , Marsh Evan B. , Bonaguidi Michael A. 
Published: October 2019

ABSTRACTAuditory and vestibular mechanosensory hair cells do not regenerate following injury or aging in the adult mammalian inner ear, inducing irreversible hearing loss and balance disorders for millions of people. Research on model systems showing replacement of mechanosensory cells can provide mechanistic insights into developing new regenerative therapies. Here, we developed lineage tracing systems to reveal, for the first time, the generation of mechanosensory neurons in the Johnston’s Organ (JO) of intact adult Drosophila, which are the functional counterparts to hair cells in vertebrates. New JO neurons develop cilia, express an essential mechano-transducer gene and target central brain circuitry. Furthermore, we identified self-replication of JO neurons as an unexpected mechanism of neuronal plasticity, which is enhanced upon treatment with experimental and ototoxic compounds. Our findings introduce a new platform to expedite research about mechanisms and compounds mediating mechanosensory cell regeneration, with implications for hearing and balance restoration in humans.SUMMARY STATEMENTUsing refined lineage tracing and live imaging, we identified self-renewal of mechanosensory neurons in adult Drosophila, the functional counterparts to vertebrate hair cells, and their enhanced regeneration through pharmacological administration.
Probabilistic atlas of the lateral parabrachial nucleus, medial parabrachial nucleus, vestibular nuclei complex and medullary viscero-sensory-motor nuclei complex in living humans from 7 Tesla MRI
Authors: Singh Kavita , Indovina Iole , Augustinack Jean C. , Nestor Kimberly , García-Gomar María G. , Staab Jeffrey P , Bianciardi Marta 
Published: October 2019

AbstractThe lateral parabrachial nucleus, medial parabrachial nucleus, vestibular nuclei complex and medullary viscero-sensory-motor nuclei complex (the latter including among others the solitary nucleus, vagus nerve nucleus, and hypoglossal nucleus) are anatomically and functionally connected brainstem gray-matter structures that convey signals across multiple modalities between the brain and the spinal cord to regulate vital bodily functions. It is remarkably difficult to precisely extrapolate the location of these nuclei from ex vivo atlases to conventional 3 Tesla in vivo images; thus, a probabilistic brainstem atlas in stereotaxic neuroimaging space in living humans is needed. We delineated these nuclei using single-subject high contrast 1.1 mm isotropic resolution 7 Tesla MRI images. After precise coregistration of nuclei labels to stereotaxic space, we generated a probabilistic atlas of their anatomical locations. Finally, we validated the nuclei labels in the atlas by assessing their inter-rater agreement, consistency across subjects and volumes. We also performed a preliminary comparison of their location and microstructural properties to histologic sections of a postmortem human brainstem specimen. In future, the resulting probabilistic atlas of these brainstem nuclei in stereotaxic space may assist researchers and clinicians in evaluating autonomic, vestibular and viscero-sensory-motor nuclei structure, function and connectivity in living humans using conventional 3 Tesla MRI scanners.
Detecting and Isolating Mass Balance Errors in Reaction Based Models in Systems Biology
Authors: Shin Woosub , Hellerstein Joseph L. 
Published: October 2019

AbstractMotivationThe growing complexity of reaction-based models necessitates early detection and resolution of model errors. This paper addresses mass balance errors, discrepancies between the mass of reactants and products in reaction specifications. One approach to detection is atomic mass analysis, which uses meta-data to expose atomic formulas of chemical species. Atomic mass analysis isolates errors to individual reactions. However, this approach burdens modelers with expressing model meta-data and writing excessively detailed reactions that include implicit chemical species (e.g., water). Moreover, atomic mass analysis has the shortcoming of not being applicable to large molecules because of the limitations of current annotation techniques. The second approach, Linear Programming (LP) analysis, avoids using model meta-data by checking for a weaker condition, stoichiometric inconsistency. But this approach suffers from false negatives and has large isolation sets (the set of reactions implicated in the stoichiometric inconsistency).ResultsWe propose alternatives to both approaches. Our alternative to atomic mass analysis is moiety analysis. Moiety analysis uses model meta-data in the form of moieties present in chemical species. Moiety analysis avoids excessively detailed reaction specifications, and can be used with large molecules. Our alternative to LP analysis is Graphical Analysis of Mass Equivalence Sets (GAMES). GAMES has a slightly higher false negative rate than LP analysis, but it provides much better error isolation. In our studies of the BioModels Repository, the average size of isolation sets for LP analysis is 55.5; for GAMES, it is 5.4. We have created open source codes for moiety analysis and GAMES.Availability and ImplementationOur project is hosted at https://github.com/ModelEngineering/ SBMLLint, which contains examples, documentation, source code files, and build scripts used to create SBMLLint. Our source code is licensed under the MIT open source license.Contact:jlheller@uw.eduSupplementary information: None.
Co-expression clustering across flower development identifies modules for diverse floral forms inAchimenes(Gesneriaceae)
Authors: Roberts Wade R , Roalson Eric H 
Published: October 2019

AbstractBackgroundGenetic pathways involved with flower color and shape are thought to play an important role in the development of flowers associated with different pollination syndromes, such as those associated with bee, butterfly, or hummingbird pollination. Because pollination syndromes are complex traits that are orchestrated by multiple genes and pathways, the gene networks have not been explored. Gene co-expression networks provide a systems level approach to identify important contributors to floral diversification.MethodsRNA-sequencing was used to assay gene expression across two stages of flower development (an early bud and an intermediate stage) in 10 species ofAchimenes(Gesneriaceae). Two stage-specific co-expression networks were created from 9503 orthologs and analyzed to identify module hubs and the network periphery. Module association with bee, butterfly, and hummingbird pollination syndromes was tested using phylogenetic mixed models. The relationship between network connectivity and evolutionary rates (dN/dS) was tested using linear models.ResultsNetworks contained 65 and 62 modules that were largely preserved between developmental stages and contained few stage-specific modules. Over a third of the modules in both networks were associated with flower color, shape, and pollination syndrome. Within these modules, several hub nodes were identified that related to the production of anthocyanin and carotenoid pigments and the development of flower shape. Evolutionary rates were decreased in highly connected genes and elevated in peripheral genes.DiscussionThis study aids in the understanding of the genetic architecture and network properties underlying the development of floral form and provides valuable candidate modules and genes for future studies.
Identification of Novel miRNAs in Mouse Embryonic Stem Cells, Embryonic Fibroblasts, and Reprogrammed Pluripotent Cells
Authors: Zhao Botao , Fan Chunsun 
Published: October 2019

AbstractMicroRNAs (miRNAs) are a class of non-coding small RNAs that function in almost every known cellular activity. MiRNAs play an important role in gene regulation that controls embryonic stem cell (ESC) pluripotency and differentiation, as well as induced pluripotent stem cell (iPSC) reprogramming. In this study, we identified nine novel miRNAs by mining the deep sequencing dataset from mouse embryonic stem cells, mouse embryonic fibroblasts (MEF) and three kinds of reprogrammed pluripotent cells. Most of them are non-conserved but species-specific and cell-specific miRNAs. Eight miRNAs are derived from gene introns, including a “mirtron” miRNA, miR-novel-41. We also showed that miR-novel-27 is a mouse-specific miRNA and the 5′ arm of its precursor hairpin, embedding the mature miR-novel-27, uniquely exists in mouse species but not in any other Placentalia animals. Notably, the 5′ arm of the pre-miR-novel-27 hairpin shows nearly perfect palindrome to the 3′ arm suggesting that it was generated by inverted duplication of the 3′ arm. By this mechanism, the pre-miR-novel-27 hairpin was de novo gained in the mouse genome. This is a new type of de novo miRNA emergence mechanism in animals, which we called “inverted local half hairpin duplication” here. In addition, very limited nucleotide mutants accumulated on the newly emerged 5′ arm since its birth suggesting an especially young evolutionary history of the miR-novel-27 gene.
Selective loss of diversity in doubled-haploid lines from European maize landraces
Authors: Zeitler Leo , Ross-Ibarra Jeffrey , Stetter Markus G 
Published: October 2019

ABSTRACTMaize landraces are well adapted to their local environments and present valuable sources of genetic diversity for breeding and conservation. But the maintenance of open-pollinated landraces inex-situprograms is challenging, as regeneration of seed can often lead to inbreeding depression and the loss of diversity due to genetic drift. Recent reports suggest that the production of doubled-haploid (DH) lines from landraces may serve as a convenient means to preserve genetic diversity in a homozygous form that is immediately useful for modern breeding. The production of doubled-haploid (DH) lines presents an extreme case of inbreeding which results in instantaneous homozygosity genome-wide. Here, we analyzed the effect of DH production on genetic diversity, using genome-wide SNP data from hundreds of individuals of five European landraces and their related DH lines. In contrast to previous findings, we observe a dramatic loss of diversity at both the haplotype level and that of individual SNPs. We identify thousands of SNPs that exhibit allele frequency differences larger than expected under models of neutral genetic drift and document losses of shared haplotypes. We find evidence consistent with selection at functional sites that are potentially involved in the diversity differences between landrace and DH populations. Although we were unable to uncover more details about the mode of selection, we conclude that landrace DH lines may be a valuable tool for the introduction of variation into maize breeding programs but come at the cost of decreased genetic diversity and increased genetic load.
Caenorhabditis elegansAF4/FMR2 family homologaffl-2is required for heat shock induced gene expression
Authors: Walton Sophie J. , Wang Han , Quintero-Cadena Porfirio , Bateman Alex , Sternberg Paul W. 
Published: October 2019

AbstractTo mitigate the deleterious effects of temperature increases on cellular organization and proteotoxicity, organisms have developed mechanisms to respond to heat stress. In eukaryotes, HSF1 is the master regulator of the heat shock transcriptional response, but the heat shock response pathway is not yet fully understood. From a forward genetic screen for suppressors of heat shock induced gene expression inC. elegans, we identified a new allele ofhsf-1that alters its DNA-binding domain, and three additional alleles ofsup-45,a previously uncharacterized genetic locus. We identifiedsup-45as one of the two hitherto unknownC. elegansorthologs of the human AF4/FMR2 family proteins, which are involved in regulation of transcriptional elongation rate. We thus renamedsup-45asaffl-2(AF4/FMR2-Like).affl-2mutants are egg-laying defective and dumpy, but worms lacking its sole paralog (affl-1) appear wild-type. AFFL-2 is a broadly expressed nuclear protein, and nuclear localization of AFFL-2 is necessary for its role in heat shock response.affl-2and its paralog are not essential for proper HSF-1 expression and localization after heat shock, which suggests thataffl-2may function downstream or parallel ofhsf-1. Our characterization ofaffl-2provides insights into the complex processes of transcriptional elongation and regulating heat shock induced gene expression to protect against heat stress.
Insights into the origin of metazoan multicellularity from predatory unicellular relatives of animals
Authors: Tikhonenkov Denis V. , Hehenberger Elisabeth , Esaulov Anton S. , Belyakova Olga I. , Mazei Yuri A. , Mylnikov Alexander P. , Keeling Patrick J. 
Published: October 2019

AbstractThe diversity and biology of unicellular relatives of animals has strongly informed our understanding of the transition from single-celled organisms to the multicellular Metazoa. Here we analyse the cellular structures and complex life cycles of the novel unicellular holozoans Pigoraptor and Syssomonas (Opisthokonta). Both lineages are characterized by complex life cycles with a variety of cell types, the formation of multicellular aggregations and syncytium-like structures, and an unusual diet for single-celled opisthokonts (partial cell fusion and joint sucking of a large eukaryotic prey), all of which provide new insights into the origin of multicellularity in Metazoa. The ability to feed on large eukaryotic prey could have been a powerful trigger in the formation and development both aggregative (e.g., joint feeding, which also implies signalling) and clonal (e.g., hypertrophic growth followed by palintomy) multicellular stages that played important roles in the emergence of multicellular animals.
Temporal structure in sensorimotor variability: a stable trait, but what for?
Authors: Perquin Marlou Nadine , van Vugt Marieke K. , Hedge Craig , Bompas Aline 
Published: October 2019

AbstractHuman performance shows substantial endogenous variability over time, and this variability is a robust marker of individual differences. Of growing interest to psychologists is the realisation that variability is not fully random, but often exhibits temporal dependencies. However, their measurement and interpretation come with several controversies. Furthermore, their potential benefit for studying individual differences in healthy and clinical populations remains unclear. Here we gather new and archival datasets featuring 11 sensorimotor and cognitive tasks across 526 participants, to examine individual differences in temporal structures. We first investigate intra-individual repeatability of the most common measures of temporal structures – to test their potential for capturing stable individual differences. Secondly, we examine inter-individual differences in these measures using: 1) task performance assessed from the same data, 2) meta-cognitive ratings of on-taskness from thought probes occasionally presented throughout the task, and 3) self-assessed attention-deficit related traits. Across all datasets, autocorrelation at lag 1 and Power Spectra Density slope showed high intra-individual repeatability across sessions and correlated with task performance. The Detrended Fluctuation Analysis slope showed the same pattern, but less reliably. The long-term component (d) of the ARFIMA(1,d,1) model showed poor repeatability and no correlation to performance. Overall, these measures failed to show external validity when correlated with either mean subjective attentional state or self-assessed traits between participants. Thus, some measures of serial dependencies may be stable individual traits, but their usefulness in capturing individual differences in other constructs typically associated with variability in performance seems limited. We conclude with comprehensive recommendations for researchers.
Hyperactive/impulsive and inattention symptoms are associated with reduced ERP activity during different reward processing stages: Evidence from the electrophysiological Monetary Incentive Delay Task in adult ADHD
Authors: Bennett M. P. , Kiiski H. , Cao Z. , Farina F. R. , Knight R. , Sweeney A. , Roddy D. , Kelly C. , Whelan R. 
Published: October 2019

AbstractHyperactivity/impulsivity and inattention are core symptoms dimensions in attention-deficit/hyperactivity disorder. Some approaches suggest that these symptoms arise from deficits in the ability to anticipate and process rewards. However, evidence is equivocal with regard to ADHD-related differences in brain activity during reward processing. The aim of this study was to investigate when, and how, reward-related ERP activity was associated with hyperactive/impulsive symptoms and inattention symptoms. Adults with ADHD (n=34) and matched comparison participants (n=36) completed an electrophysiological version of the Monetary Incentive Delay task. This task separates reward processing into two stages-namely, an anticipation stage and a delivery stage. During the anticipation stage, visual cues signalled a possible monetary incentive (i.e. a reward or loss). After a brief delay, the delivery stage began, and incentives were delivered contingent on a speeded button-press. Electroencephalogram activity was simultaneously sampled and incentive-related event relate potentials (ERPs) calculated. These data were then analysed by calculating multiple regression models, at each sample point, wherein the correlation between incentive-related ERPs and ADHD symptoms was estimated. Linear and curvilinear associations between ERP activity and ADHD symptoms were tested in each regression mode. Findings suggest that ADHD symptoms were associated ERP activity at different reward processing stages. Hyperactive/impulsive symptoms were associated with reduced ERP activity during the initial anticipation of rewards from 224-329 ms post-reward cue. Inattention symptoms were associated with reduced ERP activity during the initial delivery of rewards from 251-280 ms post-reward onset. Finally, extreme ends of hyperactive/impulsive and inattention symptoms were associated with reduced ERP activity towards the end of the anticipation stage from 500 ms post-reward cue onwards. These results support the idea that reward processing is disrupted in ADHD while also shedding new light on the dynamic relationship between ADHD symptom dimensions and the neurological mechanisms of reward processing.
A discrete approach to the external branches of a Kingman coalescent tree. Theoretical results and practical applications
Authors: Disanto Filippo , Wiehe Thomas 
Published: October 2019

AbstractThe Kingman coalescent process is a classical model of gene genealogies in population genetics. It generates Yule-distributed, binary ranked tree topologies—also calledhistories—with a finite number ofnleaves, together withn−1 exponentially distributed time lengths: one for each each layer of the history. Using a discrete approach, we study the lengths of the external branches of Yule distributed histories, where the length of an external branch is defined as the rank of its parent node. We study the multiplicity of external branches of given length in a random history ofnleaves. A correspondence between the external branches of the ordered histories of sizenand the non-peak entries of the permutations of sizen−1 provides easy access to the length distributions of the first and second longest external branch in a random Yule history and coalescent tree of sizen. The length of the longest external branch is also studied in dependence of root balance of a random tree. As a practical application, we compare the observed and expected number of mutations on the longest external branches in samples from natural populations.
Prolonged oral coenzyme Q10-β-cyclodextrin supplementation increases plasma CoQ10concentration and skeletal muscle complex I+III activity in young, untrained healthy Thoroughbreds
Authors: Rooney Mary F. , Curley Caitriona E. , Sweeney James , Griffin Michael E. , Porter Richard K. , Hill Emmeline W. , Katz Lisa M. 
Published: October 2019

AbstractCoenzyme Q10(CoQ10) is an essential component of the mitochondrial electron transport chain (ETC). Decreased skeletal muscle CoQ10content may result in decreased ETC activity and energy production. This study aimed to test the hypothesis that prolonged supplementation with oral CoQ10will increase plasma CoQ10concentrations and skeletal muscle CoQ10content in young, healthy untrained Thoroughbreds. Nineteen Thoroughbreds (27.5±9.7 months old; 11 males, 8 females) from one farm and maintained on a grass pasture with one grain meal per day were supplemented orally once per day for 9 weeks with 1.5 mg/kg body weight of a CoQ10-β-cyclodextrin inclusion complex. Whole-blood and skeletal muscle biopsies were collected before (T0) and after (T1) 9 weeks of supplementation. Plasma CoQ10concentrations were determined via high-performance liquid chromatography. Skeletal muscle mitochondrial ETC combined complex I+III enzyme activity (an indirect measurement of CoQ10content) was assessed spectrophotometrically and normalised to mitochondrial abundance. Results were analysed using a paired two-tailed Studentst-test withP≤0.05 significant. Horses accepted supplementation with no adverse effects. The mean change in plasma CoQ10concentration from T0to T1was significantly greater than zero (0.13±0.02vs. 0.25±0.03 µg/ml, mean difference 0.12±0.03;P=0.004), although variability in absorbance resulted in only a 58% response rate. The mean change in skeletal muscle complex I+III activity from T0to T1was significantly greater than zero (0.36±0.04vs. 0.59±0.05 pmol/min/mg of muscle, mean difference 0.23±0.05;P=0.0004), although T1values for 3/19 horses decreased on average by 23% below T0values. In conclusion, prolonged oral supplementation of the diet of young, healthy untrained Thoroughbreds with CoQ10increased mean plasma CoQ10concentration by 99% and mean skeletal muscle complex I+III activity by 65% with variability in absorbance among horses. Additional research is warranted investigating training and exercise effects on skeletal muscle CoQ10content in CoQ10supplemented and un-supplemented Thoroughbreds.