bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Autophagy in Acquired Cholesteatoma
Authors: Li Quancheng , Ao Yinjie , Yu Qi , Zhou Shuihong
Published: October 2019

Hypothesis:

Autophagy and its enhancement may have a role in the pathogenesis of acquired cholesteatoma.

Background:

The etiopathogenesis of acquired cholesteatoma remains unclear. Some clinical features of cholesteatoma are similar to those of cancer. The study of autophagy in cancer has indicated that enhanced autophagy enables tumor cell survival and growth.

Methods:

Cholesteatoma epithelium and normal external auditory canal (EAC) epithelium were obtained from patients with acquired cholesteatoma, and marginal epithelium of the tympanic membrane perforation was obtained from patients with chronic otitis media (COM). Immunohistochemistry (IHC) was performed to detect the expression of light chain 3 (LC3) in cholesteatoma and EAC epithelium. Western blotting (WB) was performed to detect the expression of LC3, Beclin-1, or the PI3K/AKT pathway in cholesteatoma, EAC, and COM epithelium.

Results:

LC3 staining of IHC was stronger in cholesteatoma epithelium compared with normal EAC epithelium. The ratios of LC3-II/I and Beclin-1 expression on WB were significantly higher in cholesteatoma epithelium compared with EAC epithelium or COM epithelium, and there was a significantly higher ratio of p-PI3K/PI3K and p-AKT/AKT in cholesteatoma epithelium compared with EAC epithelium.

Conclusions:

Enhanced autophagy might play a role in the pathogenesis of acquired cholesteatoma. PI3Ks might have different regulatory functions on autophagy in the cholesteatoma epithelium.
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

Background

Achondroplasia (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.

Methods

We 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.

Results

Chondrogenic 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.

Conclusions

This study may provide an important theoretical and experimental basis for the ACH research and treatment.
A simple method for spray-on gene editing in planta
Authors: Doyle Cara , Higginbottom Katie , Swift Thomas A. , Winfield Mark , Bellas Christopher , Benito-Alifonso David , Fletcher Taryn , Galan M. Carmen , Edwards Keith , Whitney Heather M.
Published: October 2019

Potential innovation in Plant research using gene-edited and genetically modified plants is currently being hindered by inefficient and costly plant transformation. We show that carbon dots formed from natural materials (quasi-spherical, <10nm nanoparticles) can act as a fast vehicle for carrying plasmids into mature plant cells, resulting in transient plant transformation in a number of important crop species with no negative impacts on photosynthesis or growth. We further show that GFP, Cas9, and gRNA introduced into wheat via foliar application (spraying on) of plasmid coated carbon dots are expressed and, in the case of Cas9, make genome edits in SPO11 genes. Therefore, we present a protocol for spray-on gene editing that is simple, inexpensive, fast, transforms in planta, and is applicable to multiple crop species. We believe this technique creates many opportunities for the future of plant transformation in research and shows great promise for plant protein production systems.
Mechanosensory neuron regeneration in adult Drosophila
Authors: Fernández-Hernández Ismael , Marsh Evan B. , Bonaguidi Michael A.
Published: October 2019

Auditory 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 STATEMENT

Using 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

The 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

Motivation

The 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).

Results

We 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 Implementation

Our 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.edu

Supplementary 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

Background

Genetic 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.

Methods

RNA-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.

Results

Networks 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.

Discussion

This 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

MicroRNAs (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

Maize 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

To 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

The 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

Human 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

Hyperactivity/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

The 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

Coenzyme 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.
Sexually antagonistic coevolution between the sex chromosomes of Drosophila melanogaster
Authors: Lund-Hansen Katrine K. , Olito Colin , Morrow Edward H. , Abbott Jessica K.
Published: October 2019

Antagonistic interactions between the sexes are important drivers of evolutionary divergence. Interlocus sexual conflict is generally described as a conflict between alleles at two interacting loci whose identity and genomic location are arbitrary. Here we build on previous theory and suggest that when these two loci are located on the sex chromosomes it can lead to cycles of antagonistic coevolution between them, and therefore between the sexes. We tested this hypothesis by performing experimental crosses using Drosophila melanogaster in which we reciprocally exchanged the sex chromosomes between five wild-type populations in a round-robin design. Disrupting putatively coevolved sex chromosome pairs resulted in increased male reproductive success in 16 out of 20 experimental populations (10 of which were significant), but also resulted in lower offspring egg-to-adult viability that affected both male and female fitness. After 25 generations of experimental evolution these sexually antagonistic fitness effects appeared to have been resolved. To help formalise our hypothesis, we developed population genetic models of antagonistic coevolution using fitness expressions based on our empirical results. Our models support the conclusion that antagonistic coevolution between the sex chromosomes is plausible under the fitness effects observed in our experiments. Together, our results lend both empirical and theoretical support to the idea that a cycle of antagonistic coevolution can occur between sex chromosomes and illustrates how this process may drive genetic and phenotypic divergence between populations.

Significance

Sex chromosomes are not only involved in genetic sex determination – they are also important factors in sexual conflict and speciation. Here, using a combination of experiments and population genetic models, we show that the sex chromosomes in Drosophila melanogaster can coevolve antagonistically. We found that swapping sex chromosomes between five Drosophila melanogaster populations increased male fitness at the cost of reduced offspring survival. After 25 generations, the increase had disappeared, consistent with the completion of a cycle of antagonistic coevolution. Using parameter values based on these empirical data, our models show that antagonistic coevolution between the sex chromosomes is a biologically plausible explanation for the results. Thus, our results point to a potentially important path to speciation through sexual conflict.
PLETHORA-WOX5 interaction and subnuclear localisation controlArabidopsisroot stem cell maintenance
Authors: Burkart Rebecca C. , Strotmann Vivien I. , Kirschner Gwendolyn K. , Akinci Abdullah , Czempik Laura , Dolata Anika , Maizel Alexis , Weidtkamp-Peters Stefanie , Stahl Yvonne
Published: October 2019

Maintenance and homeostasis of the stem cell niche (SCN) in theArabidopsisroot is essential for growth and development of all root cell types. The SCN is organized around a quiescent center (QC) maintaining the stemness of cells in direct contact. The key transcription factors (TFs) WUSCHEL-RELATED HOMEOBOX 5 (WOX5) and PLETHORAs (PLTs) are expressed in the SCN where they maintain the QC and regulate distal columella stem cell (CSC) fate. Here, we describe the concerted mutual regulation of the key TFs WOX5 and PLTs on a transcriptional and protein interaction level. Additionally, by applying a novel SCN staining method, we demonstrate that both WOX5 and PLTs regulate root SCN homeostasis as they control QC quiescence and CSC fate interdependently. Moreover, we uncover that some PLTs, especially PLT3, contain intrinsically disordered prion-like domains (PrDs) that are necessary for complex formation with WOX5 and its recruitment to subnuclear microdomains/nuclear bodies (NBs) in the CSCs. We propose that this partitioning of PLT-WOX5 complexes to NBs, possibly by phase separation, is important for CSC fate determination.
The Dynamics of Resting-State Alpha Oscillations Predict Individual Differences in Creativity
Authors: Prent Naomi , Smit Dirk J.A.
Published: October 2019

The neuronal mechanisms underlying creativity are poorly understood. Here, we investigated whether temporal dynamics of functional brain activity is a biomarker of creative ideation. Specifically, we investigated whether long-range temporal correlations in fluctuating resting-state alpha oscillations predict human creativity. Because lower temporal correlations reflect faster brain state switching, and faster state switching may be associated with increased flexibility of mind, we hypothesized that subjects with lower temporal correlations would show higher creativity. Creativity was measured by self-rating, examiner-rating and the alternative uses task in 40 healthy young adults, and scored on dimensions of verbal fluency, originality, elaboration, usefulness, and flexibility. For each dimension, the total number of subject-reported alternative uses that matched the criterium was noted (the quantity measure), as well as the proportion of uses that matched the dimensional criterium. A principal components analysis confirmed the two-component structure of quantity and quality. Eyes-open resting-state brain activity was measured by electroencephalogram (EEG) with 128 channels. Scaling exponents β were derived from spectral analysis of the amplitude modulation of 8-13 Hz oscillations, where high exponents β reflect lower decay of autocorrelation and slower switching of brain. Partial correlation analysis was used controlling for gender and age, and a cluster permutation test was performed correcting for multiple testing. Significant negative correlations between creativity and temporal correlations were observed, most prominent in right central/temporal brain areas. To our knowledge, this is the first demonstration that individual variation in the intrinsic dynamics of the brain may offer a neuronal explanation for individual variation in both the quality and quantity of creative ideation.
MicroCT optimisation for imaging fascicular anatomy in peripheral nerves
Authors: Thompson Nicole , Ravagli Enrico , Mastitskaya Svetlana , Iacoviello Francesco , Aristovich Kirill , Perkins Justin , Shearing Paul R , Holder David
Published: October 2019

Vagus nerve stimulation (VNS) is a promising therapy for treatment of various conditions resistant to standard therapeutics. However, due to the lack of understanding of the fascicular organisation of the vagus nerve, VNS leads to unwanted off-target effects. Micro-computed tomography (microCT) can be used to trace fascicles from periphery and image fascicular anatomy. In this work we optimised the microCT protocol of the rat sciatic and subsequent pig vagus nerves.

After differential staining, the optimal staining time was selected and scanning parameters were altered in subsequent scans. Scans were reconstructed, visualised in ImageJ and fascicles segmented with a custom algorithm in Matlab to determine ultimate parameters for tracking of the nerve. Successful segmentation for tracking of individual fascicles was achieved after 24 hours and 120 hours of staining with Lugol’s solution (1% total iodine) for rat sciatic and pig vagus nerves, respectively, and the following scanning parameters: 4 µm voxel size, 35 kVp energy, 114 µA current, 4 W power, 0.25 fps in 4 s exposure time, 3176 projections and a molybdenum target.

The optimised microCT protocol allows for segmentation and tracking of the fascicles within the nerve. This will be used to scan the full length of the pig, and possibly, the human vagus nerves. The resulting segmentation map of the functional anatomical organisation of the vagus nerve will enable selective VNS ultimately allowing for the avoidance of the off-target effects and improving its therapeutic efficacy.
Exploration of the role of CHRNA5-A3-B4 genotype in smoking behaviours
Authors: Lassi Glenda , Tan Vanessa , Mahedy Liam , Oliveira Ana Sofia F. , Dyer Maddy L. , Drax Katie , Dawkins Lynne , Rennard Stephen , Matcham James , Timpson Nicholas J. , Eisen Tim , Munafò Marcus R.
Published: October 2019

Genome-wide association studies have identified associations between variation at rs16969968/rs1051730 in the CHRNA5–A3–B4 gene cluster and smoking related outcomes. Experiments in rodents have described the nicotinic acetylcholine receptors (nAChRs) subunits encoded by this gene cluster and showed a lack of nicotine aversion in nAChRs deficient animal models. We conducted a nicotine challenge and a smoking topography study in humans, hypothesising that: 1. responses to a nicotine challenge would differ according to the rs16969968/rs1051730 genotype and 2. genotype may influence nicotine intake via smoking topography.

We used linear regressions to examine associations between rs16969968/rs1051730 genotype and subjective (questionnaires) and objective (physiological parameters) responses following acute nicotine exposure in never smokers (hypothesis 1) or cigarette smoking in current smokers (hypothesis 2). There was evidence to suggest nicotine exposure increases blood pressure and heart rate, and negatively affects mood, but insufficient evidence that these effects differ by genotype. Carriers of the minor allele following smoking one cigarette, exhibited reduced cravings (b=-2.46, 95% CI -4.87 to - 0.06, p=0.04) and inhaled less smoke per cigarette (b=-0.24, 95% CI - 0.43 to - 0.06, p=0.01) and per puff (b=-0.18, 95% CI -0.32 to -0.01, p=0.02). These results suggest that we need to carefully consider the translational value of the findings of aversion behaviour in nAChRs rodent models, and that deeper inhalation does not explain the strong association between rs16969968/rs1051730 genotype and objective biomarkers of tobacco exposure.
Extensive In Silico Analysis of ATL1 Gene: Discovered Five Mutations that may Cause Hereditary Spastic Paraplegia Type 3A
Authors: Mustafa Mujahed I. , Murshed Naseem S. , Abdelmoneim Abdelrahman H. , Abdelmageed Miysaa I. , Elfadol Nafisa M. , Makhawi Abdelrafie M.
Published: October 2019

BACKGROUND

Hereditary spastic paraplegia type 3A (SPG3A) is a neurodegenerative disease inherited type of Hereditary spastic paraplegia (HSP). It is the second most frequent type of HSP; which Characterized by muscle stiffness with paraplegia and early-onset of symptoms. This is the first translational bioinformatics analysis in a coding region of ATL1 gene which aims to categorize nsSNPs to be used as genomic biomarkers; also it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.

METHODS

The raw data of ATL1 gene were retrieved from dbSNP database, and then run into numerous computational analysis tools. Additionally; we submitted the common six deleterious outcomes from the previous functional analysis tools to I-mutant 3.0, and MUPro respectively, to investigate their effect on structural level. The 3D structure of ATL1 was predicted by RaptorX and modeled using UCSF Chimera to compare the differences between the native and the mutant amino acids.

RESULTS

Five nsSNPs out of 249 were classified as the most deleterious (rs746927118, rs979765709, rs119476049, rs864622269, rs1242753115).

CONCLUSIONS

In this study the impact of nsSNPs in the ATL1 gene was investigated by various bioinformatics tools, that revealed five nsSNPs (V67F, T120I, R217Q, R495W and G504E) are deleterious SNPs, which have a functional impact on ATL1 protein; and therefore, can be used as genomic biomarkers specifically before 4 years old; also it may play a key role in pharmacogenomics by evaluating drug response for this disabling disease.
Liver X Receptor regulates Th17 and RORγt+ Treg cells by distinct mechanisms
Authors: Parigi Sara M. , Das Srustidhar , Frede Annika , Cardoso Rebeca F. , Tripathi Kumar Parijat , Doñas Cristian , Hu Yue O. O. , Antonson Per , Engstrand Lars , Gustafsson Jan-Åke , Villablanca Eduardo J.
Published: October 2019

The gastrointestinal microenvironment, dominated by dietary compounds and the commensal bacteria, is a major driver of intestinal CD4+ T helper (Th) cell differentiation. Dietary compounds can be sensed by nuclear receptors (NRs) that consequently exerts pleiotropic effects including immune modulation. However, how NRs regulate distinct intestinal Th subsets remain poorly understood. Here, we found that under homeostatic condition Liver X receptor (LXR), a sensor of cholesterol metabolites, controls RORγt+ Treg and Th17 cells in the intestine draining mesenteric lymph node (MLN). Mechanistically, while lack of LXR signaling in CD11c+ myeloid cells led to an increase in RORγt+ Treg, modulation of MLN Th17 was independent of LXR signaling in either immune or epithelial cells. Of note, LXRα modulated only the Th17 cells, but not RORγt+ Treg in the MLN and horizontal transfer of microbiota between LXRα−/− and WT mice was sufficient to partially increase the MLN Th17 in WT mice. While LXRα deficiency increased the abundance of Ruminococcaceae and Lachnospiraceae bacterial families compared to the WT littermates, microbiota ablation including ablation of SFB was not sufficient to dampen LXRα-mediated expansion of MLN Th17. Altogether, our results suggest that LXR modulates RORγt+ Treg and Th17 cells in the MLN through distinct mechanisms.
A meta-analysis reveals temperature, dose, life stage, and taxonomy influence host susceptibility to a fungal parasite
Authors: Sauer Erin L. , Cohen Jeremy M. , Lajeunesse Marc J. , McMahon Taegan A. , Civitello David J. , Knutie Sarah A. , Nguyen Karena , Roznik Elizabeth A. , Sears Brittany F. , Bessler Scott , Delius Bryan K. , Halstead Neal , Ortega Nicole , Venesky Matthew D. , Young Suzanne , Rohr Jason R.
Published: October 2019

Complex ecological relationships, such as host-parasite interactions, are often modeled with laboratory experiments. However, some experimental laboratory conditions, such as temperature or infection dose, are regularly chosen based on convenience or convention and it is unclear how these decisions systematically affect experimental outcomes. Here, we conducted a meta-analysis of 58 laboratory studies that exposed amphibians to the pathogenic fungusBatrachochytrium dendrobatidis(Bd) to better understand how laboratory temperature, host life stage, infection dose, and host species affect host mortality. We found that host mortality was driven by thermal mismatches: hosts native to cooler environments experienced greater Bd-induced mortality at relatively warm experimental temperatures and vice versa. We also found that Bd dose positively predicted Bd-induced host mortality and that the superfamilies Bufonoidea and Hyloidea were especially susceptible to Bd. Finally, the effect of Bd on host mortality varied across host life stages, with larval amphibians experiencing lower risk of Bd-induced mortality than adults or metamorphs. Metamorphs were especially susceptible and experienced mortality when inoculated with much smaller Bd doses than the average dose used by researchers. Our results suggest that when designing experiments on species interactions, researchers should carefully consider the experimental temperature, and inoculum dose, and life stage and taxonomy of the host species.
Behavioral and physiological evidence that increasing group size ameliorates the impacts of social disturbance
Authors: Anderson Hannah M. , Little Alexander G. , Fisher David N. , McEwen Brendan L. , Culbert Brett M. , Balshine Sigal , Pruitt Jonathan N.
Published: October 2019

Intra-group social stability is important for the long-term productivity and health of social organisms. We evaluated the effect of group size on group stability in the face of repeated social perturbations using a cooperatively breeding fish, Neolamprologus pulcher. In a laboratory study, we compared both the social and physiological responses of individuals from small versus large groups to the repeated removal and replacement of the most dominant group member (the breeder male). Individuals living in large groups were overall more resistant to instability but were seemingly slower to recover from perturbation. Members of small group were more vulnerable to instability but recovered faster. Breeder females in smaller groups also showed greater physiological preparedness for instability following social perturbations. In sum, we recover both behavioral and physiological evidence that living in larger groups helps to dampen the impacts of social instability in this system.

Summary Statement

Social stability is vital for group productivity and long-term persistence. Here, both behavioral and physiological evidence conveys that larger groups are less susceptible to social disturbance.
Disruption of Nrxn1α within excitatory forebrain circuits drives value-based dysfunction
Authors: Alabi Opeyemi , Robinson Mara , Fortunato Michael , Kable Joe W. , Fuccillo Marc V.
Published: October 2019

Goal-directed behaviors, complex action sequences that maximize reward, are essential for normal function and are significantly impaired across neuropsychiatric disorders. Despite extensive associations between genetic mutations and these brain disorders, the mechanisms by which candidate genes contribute to goal-directed dysfunction remains unclear, owing to challenges in (1) describing aspects of reward processing that drive goal-directed dysfunction, (2) localizing these deficits to specific brain circuits and (3) relating changes in physiology to behavioral alterations. Here we examined mice with mutations in Neurexin1α, a presynaptically-localized adhesion molecule with widespread neuropsychiatric dis ease association, in value-based decision-making paradigms. We found that Neurexin1α knockout animals exhibited blunted choice bias towards outcomes associated with greater benefits. Mutant mice were similarly impaired in avoiding costlier, benefit-neutral actions. Analysis of trial-by-trial choice data via reinforcement learning models suggested these behavioral patterns were driven largely by deficits in the updating and representation of choice values. Employing conditional gene ablation and region-specific Cre-recombinase strains, we revealed that Neurexin1α disruption within forebrain excitatory projection neurons, but not thalamic population s, recapitulated most aspects of the whole-brain knockout phenotype. Finally, utilizing in vivo recordings of direct pathway spiny neuron population calcium activity, we demonstrated that selective knockout of Neurexin1α within forebrain excitatory neurons disrupts reward-associated neural signals within striatum, a major site of feedback-based learning. By relating deficits in value-based decision-making to region-specific Nrxn1α disruption and changes in reward-associated neural activity, we reveal potential neural substrates for the pathophysiology of neuropsychiatric disease-associated cognitive dysfunction.
A portable and cost-effective microfluidic system for massively parallel single-cell transcriptome profiling
Authors: Liu Chuanyu , Wu Tao , Fan Fei , Liu Ya , Wu Liang , Junkin Michael , Wang Zhifeng , Yu Yeya , Wang Weimao , Wei Wenbo , Yuan Yue , Wang Mingyue , Cheng Mengnan , Wei Xiaoyu , Xu Jiangshan , Shi Quan , Liu Shiping , Chen Ao , Wang Ou , Ni Ming , Zhang Wenwei , Shang Zhouchun , Lai Yiwei , Guo Pengcheng , Ward Carl , Volpe Giacomo , Wang Lei , Zheng Huan , Liu Yang , Peters Brock A. , Beecher Jody , Zhang Yongwei , Esteban Miguel A. , Hou Yong , Xu Xun , Chen I-Jane , Liu Longqi
Published: October 2019

Single-cell technologies are becoming increasingly widespread and have been revolutionizing our understanding of cell identity, state, diversity and function. However, current platforms can be slow to apply to large-scale studies and resource-limited clinical arenas due to a variety of reasons including cost, infrastructure, sample quality and requirements. Here we report DNBelab C4 (C4), a negative pressure orchestrated, portable and cost-effective device that enables high-throughput single-cell transcriptional profiling. C4 system can efficiently allow discrimination of species-specific cells at high resolution and dissect tissue heterogeneity in different organs, such as murine lung and cerebral cortex. Finally, we show that the C4 system is comparable to existing platforms but has huge benefits in cost and portability and, as such, it will be of great interest for the wider scientific community.
Glutamate-ammonia ligase promotes lung cancer cell growth through an enzyme-independent upregulation of CaMK2G under a glutamine-sufficient condition
Authors: Zhao Jiangsha , Zeng Xiankun , Hou Steven X.
Published: October 2019

Glutamate-ammonia ligase (GLUL) is highly expressed in many cancer cells. Synthesizing glutamine by its enzyme function has been found to be important for supporting cancer cell survival and growth under glutamine restriction. However, GLUL’s functions under a glutamine-sufficient condition still have not been uncovered. Here we find that GLUL is highly expressed in lung cancer cells and provides survival and growth advantages under both glutamine restriction and adequacy conditions. Knocking down GLUL can block lung cancer cell growth in an enzyme-independent way when glutamine is sufficient. Mechanistically, GLUL regulates Calcium/Calmodulin Dependent Protein Kinase II Gamma (CaMK2G) expression at the transcription level, and CaMK2G is a major mediator in controlling cell growth under GLUL. The transcriptional regulation of CaMK2G is partially mediated by SMAD4. Our data unveil a new enzyme-independent function of GLUL in lung cancer cells under a glutamine-sufficient condition.