bluuebunny/crossref_metadata_2025_split huggingface dataset:
Locally Fixed Alleles: A method to localize gene drive to island populations
Authors: Sudweeks Jaye , Hollingsworth Brandon , Blondel Dimitri V. , Campbell Karl J. , Dhole Sumit , Eisemann John D. , Edwards Owain , Godwin John , Howald Gregg R. , Oh Kevin , Piaggio Antoinette J. , Prowse Thomas A. A. , Ross Joshua V. , Saah J. Royden , Shiels Aaron B. , Thomas Paul , Threadgill David W. , Vella Michael R. , Gould Fred , Lloyd Alun L. 
Published: January 2019

AbstractInvasive species pose a major threat to biodiversity on islands. While successes have been achieved using traditional removal methods, such as toxicants aimed at rodents, these approaches have limitations and various off-target effects on island ecosystems. Gene drive technologies designed to eliminate a population provide an alternative approach, but the potential for drive-bearing individuals to escape from the target release area and impact populations elsewhere is a major concern. Here we propose the “Locally Fixed Alleles” approach as a novel means for localizing elimination by a drive to an island population that exhibits significant genetic isolation from neighboring populations. Our approach is based on the assumption that in small island populations of rodents, genetic drift will lead to multiple genomic alleles becoming fixed. In contrast, multiple alleles are likely to be maintained in larger populations on mainlands. Utilizing the high degree of genetic specificity achievable using homing drives, for example based on the CRISPR/Cas9 system, our approach aims at employing one or more locally fixed alleles as the target for a gene drive on a particular island. Using mathematical modeling, we explore the feasibility of this approach and the degree of localization that can be achieved. We show that across a wide range of parameter values, escape of the drive to a neighboring population in which the target allele is not fixed will at most lead to modest transient suppression of the non-target population. While the main focus of this paper is on elimination of a rodent pest from an island, we also discuss the utility of the locally fixed allele approach for the goals of population suppression or population replacement. Our analysis also provides a threshold condition for the ability of a gene drive to invade a partially resistant population.
A 3-hydroxy-3-methylglutaryl-CoA synthase-based probe for the discovery of the acyltransferase-less type I polyketide synthases
Authors: Liang Haoyu , Jiang Lin , Jiang Qiyun , Shi Jie , Xiang Jingxi , Yan Xiaohui , Zhu Xiangcheng , Zhao Lixing , Shen Ben , Duan Yanwen , Huang Yong 
Published: January 2019

ABSTRACTAcyltransferase (AT)-less type I polyketide synthases (PKSs) produce complex natural products due to the presence of many unique tailoring enzymes. The 3-hydroxy-3-methylglutaryl coenzyme A synthases (HCSs) are responsible for β-alkylation of the growing polyketide intermediates in AT-less type I PKSs. In this study, we discovered a large group of HCSs, closely associated with the characterized and orphan AT-less type I PKSs throughin silicogenome mining, sequence and genome neighborhood network analysis. Using HCS-based probes, the survey of 1207 inhouse strains and 18 soil samples from different geological locations revealed the vast diversity of HCS-containing AT-less type I PKSs. The presence of HCSs in many AT-less type I PKSs suggests their co-evolutionary relationship. Our study should inspire future efforts to discover new polyketide natural products from AT-less type I PKSs.
Sensory feedback independent pre-song vocalizations correlate with current state of motor preparation
Authors: Rao Divya , Kojima Satoshi , Rajan Raghav 
Published: January 2019

ABSTRACTMany self-initiated, learned, motor sequences begin by repeating a simple movement, like ball-bouncing before a tennis serve, and this repetition is thought to represent motor preparation. Do these simple movements provide real-time sensory feedback used by the brain for getting ready or do they simply reflect internal neural preparatory processes? Here, we addressed this question by examining the introductory notes (INs) that zebra finches repeat before starting their learned song sequence. INs progress from a variable initial state to a stereotyped final state before each song and are thought to represent motor preparation before song. Here, we found that the mean number of INs before song and the progression of INs to song were not affected by removal of two sensory feedback pathways (auditory and proprioceptive). In both feedback-intact and feedback-deprived birds, the presence of calls (other non-song vocalizations), just before the first IN, was correlated with fewer INs before song and an initial state closer to song. Finally, the initial IN state correlated with the time to song initiation. Overall, these results show that INs do not provide real-time sensory feedback for preparing the motor system. Rather, repetition of INs, and possibly, other such simple movements, may reflect the “current” state of internal neural preparatory processes involved in getting the brain ready to initiate a learned movement sequence.SUMMARY STATEMENTThe number and progression of introductory notes to song in the zebra finch are not affected by removal of sensory feedback.
Neural differentiation is increased by GSK-3β inhibition and decreased by tankyrase inhibition in human neural precursor cells
Authors: Telias Michael , Ben-Yosef Dalit 
Published: January 2019

AbstractGlycogen synthase kinase-3β (GSK-3β) and tankyrase-1/2 (TANK) are two enzymes known to play multiple roles in cell biology, including regulation of proliferation, differentiation and metabolism. Both of them act on the canonical Wnt/β-Catenin pathway, but are also involved in many other independent intracellular mechanisms. More importantly, GSK-3β and TANK have been shown to play crucial roles in different diseases, including cancer and neurological disorders. The GSK-3β-inhibitor ‘CHIR’ and the TANK-inhibitor ‘XAV’ are two pyrimidine molecules, holding high potential as possible therapeutic drugs. However, their effect on neural tissue is poorly understood. In this study, we tested the effects of CHIR and XAV on human neural precursor cells (hNPCs) derived from human embryonic stem cells. We found that CHIR-mediated inhibition of GSK-3β promotes neural differentiation. In contrast, XAV-mediated inhibition of TANK leads to de-differentiation. These results highlight the relative importance of these two enzymes in determining the neurodevelopmental status of hNPCs. Furthermore, they shed light on the roles of Wnt signaling during early human neurogenesis.
History-dependent perturbation response in limb muscle
Authors: Libby Thomas , Chukwueke Chidinma , Sponberg Simon 
Published: January 2019

1AbstractMuscle mediates movement but movement is typically unsteady and perturbed. Muscle is known to behave non-linearly and with history dependent properties during steady locomotion, but the importance of history dependence in mediating muscles function during perturbations remains less clear. To explore muscle’s capacity to mitigate perturbations, we constructed a series of perturbations that varied only in kinematic history, keeping instantaneous position, velocity and time from stimulation constant. We discovered that muscle’s perturbation response is profoundly history dependent, varying by four fold as baseline frequency changes, and dissipating energy equivalent to ~ 6 times the kinetic energy of all the limbs (nearly 2400 WKg−1). Muscle’s energy dissipation during a perturbation is predicted primarily by the force at the onset of the perturbation. This relationship holds across different frequencies and timings of stimulation. This history dependence behaves like a viscoelastic memory producing perturbation responses that vary with the frequency of the underlying movement.Summary StatementThe response of muscles to rapid, identical strain perturbations is history dependent, but is captured by a viscoelastic model with memory. Muscle function during perturbations therefore depends on locomotor frequency.
Genetic interactions of histone acetyl-transferase enzymes encoding genesGcn5andMofwithhsrωlncRNA gene
Authors: Chaturvedi Deo Prakash 
Published: January 2019

AbstractThe hsrω lncRNAs are known to interact with the Iswi chromatin remodeler while Iswi is known to interact with Gcn5, a general histone acetyl transferase, and Mof, a male-specific HAT essential for H4K16 acetylation and consequent hyperactivity of the single X-chromosome in maleDrosophila. We show here thathsrωgenetically interacts with Gcn5 as well as Mof, but unlike the suppression of phenotypes due to down-regulation or absence of Iswi, those following down-regulation of Gcn5 or Mof are suppressed by over-expression ofhsrω. General lethality caused byAct-GAL4driven global expression ofGcn5-RNAiand the male-specific lethality followingMof-RNAitransgene expression were partially suppressed by over-expression ofhsrω, but not by down regulation throughhsrω-RNAi. Likewise, eye phenotypes followingey-GAL4driven down-regulation of Gcn5 or Mof were also partially suppressed by over-expression ofhsrω. Act-GAL4driven global over-expression ofhsrωalong withGcn5-RNAitransgene substantially restored levels of Gcn5 RNA as well as protein that were reduced by Gcn5-RNAi.Mof-RNAitransgene expression reduced Megator and Msl-2 levels and their nuclear distribution patterns; over-expression ofhsrωalong withMof-RNAisubstantially restored Megator levels and its distribution at the nuclear rim and in nucleoplasmic speckles and at the same time restored the male X-chromosome specific localization of Msl-2. Earlier reported antagonistic interactions of Mof with Iswi and interaction of hsrω transcripts with Megator appear to underlie the suppression of Gcn5 and Mof phenotypes by over-expression of the lncRNAs. Present results add the dosage compensation pathway to the list of diverse pathways in which the multiple lncRNAs produced by thehsrωare known to have important roles.
BjuWRR1, a CC-NB-LRR gene identified in Brassica juncea, confers resistance to white rust caused by Albugo Candida
Authors: Arora Heena , Padmaja K. Lakshmi , Paritosh Kumar , Mukhi Nitika , Tewari A. K. , Mukhopadhyay Arundhati , Gupta Vibha , Pradhan Akshay K , Pental Deepak 
Published: January 2019

AbstractWhite rust caused by oomycete pathogen Albugo candida is a significant disease of crucifer crops including Brassica juncea (mustard), a major oilseed crop of the Indian subcontinent. Earlier a resistance-conferring locus named AcB1-A5.1 was mapped in an east European gene pool line of B. juncea – Donskaja-IV. This line was tested along with some other lines of B. juncea (AABB), B. rapa (AA) and B. nigra (BB) for resistance to six isolates of A. candida collected from different mustard growing regions of India. Donskaja-IV was found to be completely resistant to all the tested isolates. Sequencing of a BAC spanning the locus AcB1-A5.1 showed the presence of a single CC-NB-LRR protein encoding R gene. The genomic sequence of the putative R gene with its native promoter and terminator was used for the genetic transformation of a susceptible Indian gene pool line Varuna and was found to confer complete resistance to all the isolates. This is the first white rust resistance-conferring gene described from Brassica species and has been named BjuWRR1. Allelic variants of the gene in B. juncea germplasm and orthologues in the Brassicaceae genomes were studied to understand the evolutionary dynamics of the BjuWRR1 gene.HighlightBjuWRR1, a CNL type R gene, was identified from an east European gene pool line of Brassica juncea and validated for conferring resistance to white rust by genetic transformation.
Disparate evolution of virus populations in upper and lower airways of mechanically ventilated patients
Authors: Koel Björn F. , van Someren Gréve Frank , Vigeveno René M. , Pater Maarten , Russell Colin A. , de Jong Menno D. 
Published: January 2019

AbstractIn routine surveillance and diagnostic testing, influenza virus samples are typically collected only from the upper respiratory tract (URT) due to the invasiveness of sample collection from the lower airways. Very little is known about virus variation in the lower respiratory tract (LRT) and it remains unclear if the virus populations at different sites of the human airways may develop to have divergent genetic signatures. We used deep sequencing of serially obtained matched nasopharyngeal swabs and endotracheal aspirates from four mechanically ventilated patients with influenza A/H3N2 infections. A physical barrier separating both compartments of the respiratory tract introduced as part of the medical procedures enabled us to track and compare the genetic composition of the virus populations during isolated evolution in the same host. Amino acid variants reaching majority proportions emerged during the course of infection in both nasopharyngeal swabs and endotracheal aspirates, and amino acid variation was observed in all influenza virus proteins. Genetic variation of the virus populations differed between the URT and LRT and variants were frequently uniquely present in either URT or LRT virus populations of a patient. These observations indicate that virus populations in spatially distinct parts of the human airways may follow different evolutionary trajectories. Selectively sampling from the URT may therefore fail to detect potentially important emerging variants.ImportanceInfluenza viruses are rapidly mutating pathogens that easily adapt to changing environments. Although advances in sequencing technology make it possible to identify virus variants at very low proportions of the within-host virus population, several aspects of intrahost viral evolution have not been studied because sequentially collected samples and samples from the lower respiratory tract are not routinely obtained for influenza surveillance or clinical diagnostic purposes. Importantly, how virus populations evolve in different parts of the human respiratory tract remains unknown. Here we used serial clinical specimens collected from mechanically ventilated influenza patients to compare how virus populations develop in the upper and lower respiratory tract. We show that virus populations in the upper and lower respiratory tract may evolve along distinct evolutionary pathways, and that current sampling and surveillance regimens likely capture only part of the complete intrahost virus variation.
The respiratory virome and exacerbations in patients with chronic obstructive pulmonary disease
Authors: van Rijn Anneloes L. , van Boheemen Sander , Carbo Ellen C. , Pappas Nikos , Sidorov Igor , Mei Hailiang , Aanerud Marianne , Bakke Per , Claas Eric C.J. , Eagan Tomas M. , Hiemstra Pieter S. , Kroes Aloys C.M. , de Vries Jutte J.C. 
Published: January 2019

AbstractIntroductionExacerbations are major contributors to morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD), and respiratory bacterial and viral infections are an important trigger for the occurrence of such exacerbations. However, using conventional diagnostic techniques, a causative agent is not always found. Metagenomic next-generation sequencing (mNGS) allows analysis of the complete virome, but has not yet been applied in COPD exacerbations.ObjectivesTo study the respiratory virome in nasopharyngeal samples during COPD exacerbations using mNGS.Study design88 nasopharyngeal swabs from 63 patients from the Bergen COPD Exacerbation Study (2006-2010) were analysed by mNGS and in-house qPCR for respiratory viruses. Both DNA and RNA were sequenced simultaneously using an lllumina library preparation protocol with in-house adaptations.ResultsBy mNGS, 23/88 samples tested positive. Sensitivity and specificity were both 96% for diagnostic targets (23/24 and 1067/1120, respectively). Viral pathogens only detected by mNGS were herpes simplex virus type 1 and coronavirus OC43. A positive correlation was found between Cq value and mNGS viral species reads (p=0.008). Patients with viral pathogens had lower percentages of bacteriophages (p<0.000). No correlation was found between viral reads (species and genus level) and clinical markers.ConclusionsThe mNGS protocol used was highly sensitive and specific for semi-quantitative detection of respiratory viruses. Excellent negative predictive value implicates the power of mNGS to exclude any infectious cause in one test, with consequences for clinical decision making. Reduced abundance of bacteriophages in COPD patients with viral pathogens implicates skewing of the virome, and speculatively the bacterial population, during infection.
MetaDome: Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains
Authors: Wiel Laurens , Baakman Coos , Gilissen Daan , Veltman Joris A. , Vriend Gerrit , Gilissen Christian 
Published: January 2019

AbstractThe growing availability of human genetic variation has given rise to novel methods of measuring genetic tolerance that better interpret variants of unknown significance. We recently developed a novel concept based on protein domain homology in the human genome to improve variant interpretation. For this purpose we mapped population variation from the Exome Aggregation Consortium (ExAC) and pathogenic mutations from the Human Gene Mutation Database (HGMD) onto Pfam protein domains. The aggregation of these variation data across homologous domains into meta-domains allowed us to generate base-pair resolution of genetic intolerance profiles for human protein domains.Here we developed MetaDome, a fast and easy-to-use web service that visualizes meta-domain information and gene-wide profiles of genetic tolerance. We updated the underlying data of MetaDome to contain information from 56,319 human transcripts, 71,419 protein domains, 12,164,292 genetic variants from gnomAD, and 34,076 pathogenic mutations from ClinVar. MetaDome allows researchers to easily investigate their variants of interest for the presence or absence of variation at corresponding positions within homologous domains. We illustrate the added value of MetaDome by an example that highlights how it may help in the interpretation of variants of unknown significance. The MetaDome web server is freely accessible at https://stuart.radboudumc.nl/metadome.
STAM Interaction with Hrs Controls JAK/STAT Activation by Interferon-α at the Early Endosome
Authors: Zanin Natacha , Blouin Cédric M. , de Lesegno Christine Viaris , Chmiest Daniela , Johannes Ludger , Lamaze Christophe 
Published: January 2019

ABSTRACTActivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway by type I interferons (IFN) requires clathrin-dependent endocytosis of the IFN-α/β receptor (IFNAR). The molecular machinery that brings about the selective activation of IFN-α/β-induced JAK/STAT signaling on endosomes remains unknown. Here we show that the constitutive association of STAM with IFNAR1 and the TYK2 Janus kinase at the plasma membrane prevents the activation of TYK2 by type I IFNs. IFN-α stimulated endocytosis leads to the interaction of IFNAR1 with Hrs on early endosomes, which then relieves TYK2 inhibition by STAM and thereby allows for TYK2 and IFNAR signaling. In contrast, IFN-β stimulation results in sorting of IFNAR to a distinct endosomal subdomain where the receptor is activated independently from Hrs. Our results identify the molecular machinery that controls the spatiotemporal activation of TYK2 and establish the central role of endosomal sorting in the differential regulation of JAK/STAT signaling by IFN-α and IFN-β.SummaryThe spatiotemporal activation of JAK/STAT signaling by IFN-α is controlled by STAM association with Hrs at the early endosome.
Self-determination motivation theory in R: The software package S D T
Authors: Ünlü Ali 
Published: January 2019

AbstractThis paper presents the technical details of the software package SDT in the R computing and graphics environment, implementing a convex quadratic program that was recently proposed in the literature on self-determination theory of human motivation. Three main features are addressed, with their accompanying code for computation in R: first, the application of the quadratic program and corresponding code for the analysis of the extent of motivation internalization or externalization; second, for exploring the simplex structure assumption of motivation; and third, for adjusting the confounded scoring protocol, called the self-determination or relative autonomy index, to account for the mixture of internal motivation and external motivation. We describe the functions of the R package SDT. The computations are demonstrated with example data accompanying the package, so researchers can run the methodology on their own datasets.
The influence of kinesthetic motor imagery and effector specificity on the long-latency stretch response
Authors: Forgaard Christopher J. , Franks Ian M. , Maslovat Dana , Chua Romeo 
Published: January 2019

AbstractThe long-latency “reflexive” response (LLR) following an upper-limb mechanical disturbance is generated by neural circuitry shared with voluntary control. This feedback response supports many task-dependent behaviours and permits the expression of goal-directed corrections at latencies shorter than voluntary reaction time. An extensive body of literature has demonstrated that the LLR shows flexibility akin to voluntary control, but it has never been tested whether instruction-dependent LLR changes can also occur in the absence of an overt voluntary response. The present study used kinesthetic motor imagery (Experiment 1) and instructed participants to execute a voluntary response in a non-stretched contralateral muscle (Experiment 2) to explore the relationship between the overt production of a voluntary response and LLR facilitation. Activity in stretched right wrist flexors were compared to standard “not-intervene” and “compensate” conditions. Our findings revealed that on ~40% of imagery and ~50% of contralateral trials, a partial voluntary response “leaked-out” into the stretched right wrist flexor muscle. On these “leaked” trials, the early portion of the LLR (R2) was facilitated and displayed a similar increase to compensate trials. The latter half of the LLR (R3) showed further modulation, mirroring the patterns of voluntary response activity. By contrast, the LLR on “non-leaked” imagery and contralateral trials did not modulate. We suggest that even though a hastened voluntary response cannot account for all instruction-dependent LLR modulation, the overt execution of a voluntary response in the same muscle(s) as the LLR is a pre-requisite for facilitation of this rapid feedback response.New and NoteworthyWe examined volitional modulation of the long-latency stretch response (LLR) using two novel approaches: motor imagery and the execution of contralateral movements. The LLR was only facilitated on imagery or contralateral trials when a voluntary response “leaked-out” into stretched muscle suggesting that a voluntary response in the same muscle as the LLR is a prerequisite for facilitation. Our findings also demonstrate an important distinction between the early (R2) and late (R3) portions of the LLR.