bluuebunny/crossref_metadata_2025_split huggingface dataset:
The FACTS model of speech motor control: fusing state estimation and task-based control
Authors: Parrell Benjamin , Ramanarayanan Vikram , Nagarajan Srikantan , Houde John 
Published: February 2019

ABSTRACTWe present a new computational model of speech motor control: the Feedback-Aware Control of Tasks in Speech orFACTSmodel. This model is based on a state feedback control architecture, which is widely accepted in non-speech motor domains. The FACTS model employs a hierarchical observer-based architecture, with a distinct higher-level controller of speech tasks and a lower-level controller of speech articulators. The task controller is modeled as a dynamical system governing the creation of desired constrictions in the vocal tract, based on the Task Dynamics model. Critically, both the task and articulatory controllers rely on an internal estimate of the current state of the vocal tract to generate motor commands. This internal state estimate is derived from initial predictions based on efference copy of applied controls. The resulting state estimate is then used to generate predictions of expected auditory and somatosensory feedback, and a comparison between predicted feedback and actual feedback is used to update the internal state prediction. We show that the FACTS model is able to qualitatively replicate many characteristics of the human speech system: the model is robust to noise in both the sensory and motor pathways, is relatively unaffected by a loss of auditory feedback but is more significantly impacted by the loss of somatosensory feedback, and responds appropriately to externally-imposed alterations of auditory and somatosensory feedback. The model also replicates previously hypothesized trade-offs between reliance on auditory and somatosensory feedback in speech motor control and shows for the first time how this relationship may be mediated by acuity in each sensory domain. These results have important implications for our understanding of the speech motor control system in humans.
Respiratory gas levels interact to control ventilatory motor patterns in isolated locust ganglia
Authors: Talal Stav , Ayali Amir , Gefen Eran 
Published: February 2019

AbstractLarge insects actively ventilate their tracheal system even at rest, using abdominal pumping movements, which are controlled by a central pattern generator (CPG) in the thoracic ganglia. We studied the effects of respiratory gases on the ventilatory rhythm by isolating the thoracic ganglia and perfusing its main tracheae with various respiratory gas mixtures. Fictive ventilation activity was recorded from motor nerves controlling spiracular and abdominal ventilatory muscles. Both hypoxia and hypercapnia increased the ventilation rate, with the latter being much more potent. Sub-threshold hypoxic and hypercapnic levels were still able to modulate the rhythm as a result of interactions between the effects of the two respiratory gases. Additionally, changing the oxygen levels in the bathing saline affected ventilation rate, suggesting a modulatory role for haemolymph oxygen. Central sensing of both respiratory gases as well as interactions of their effects on the motor output of the ventilatory CPG reported here indicate convergent evolution of respiratory control among terrestrial animals of distant taxa.Summary statementTight control over respiratory gas supply to the isolated locust CNS reveals interactions of oxygen and carbon dioxide effects on central ventilatory output.
Identifying Drug Sensitivity Subnetworks with NETPHLIX
Authors: Kim Yoo-Ah , Basso Rebecca Sarto , Wojtowicz Damian , Hochbaum Dorit S. , Vandin Fabio , Prztycka Teresa M. 
Published: February 2019

AbstractPhenotypic heterogeneity in cancer is often caused by different patterns of genetic alterations. Understanding such phenotype-genotype relationships is fundamental for the advance of personalized medicine. One of the important challenges in the area is to predict drug response on a personalized level. The pathway-centric view of cancer significantly advanced the understanding of genotype-phenotype relationships. However, most of network identification methods in cancer focus on identifying subnetworks that include general cancer drivers or are associated with discrete features such as cancer subtypes, hence cannot be applied directly for the analysis of continuous features like drug response. On the other hand, existing genome wide association approaches do not fully utilize the complex proprieties of cancer mutational landscape. To address these challenges, we propose a computational method, named NETPHLIX (NETwork-to-PHenotpe mapping LeveragIng eXlusivity), which aims to identify mutated subnetworks that are associated with drug response (or any continuous cancer phenotype). Utilizing properties such as mutual exclusivity and interactions among genes, we formulate the problem as an integer linear program and solve it optimally to obtain a set of genes satisfying the constraints. NETPHLIX identified gene modules significantly associated with many drugs, including interesting response modules to MEK1/2 inhibitors in both directions (increased and decreased sensitivity to the drug) that the previous method, which does not utilize network information, failed to identify. The genes in the modules belong to MAPK/ERK signaling pathway, which is the targeted pathway of the drug.
The role of mutational spectrum in the selection against mutator alleles
Authors: Couce Alejandro , Tenaillon Olivier 
Published: February 2019

AbstractRapidly adapting microbe and cancer cell populations often evolve high mutation rates. Yet, once adaptive opportunity declines, antimutator alleles are expected to take over as a result of indirect selection against deleterious mutations. Theory indicates that the most important determinant of antimutator invasions is the extent of mutation rate reduction. However, inconsistent results from evolution experiments suggest that additional factors may also play a major role in antimutator dynamics. Here we show that the idiosyncratic mutation bias exhibited by different mutators – a previously unrecognized factor – can greatly alter mutator susceptibility to antimutator invasions. Using a simulation model calibrated to mimic a well-known long-term evolution experiment with bacteria, we show that differences in average deleterious load can account for order-of-magnitude changes in antimutator fitness for a realistic range of parameters. Since these parameters are known to vary with the environment, our results reveal an unanticipated source of variability in antimutator dynamics. Finally, we estimated the genome-wide average disruptive effect on proteins of mutations caused by different mutators, and found marked and systematic differences emerging across mutators and species with different genomic GC compositions. Taken together, our results suggest that antimutator dynamics may be highly dependent on the specific genetic, ecological and evolutionary history of a given population. Such dependence reveals a more complex picture than anticipated, being relevant for understanding mutators in clinical settings, as well as how hypermutability shapes the evolution of bacterial genome size and composition.
Asymmetric Tug-of-War leads to Cooperative Transport of a Cargo by Multiple Kinesins
Authors: Tjioe Marco , Shukla Saurabh , Vaidya Rohit , Troitskaia Alice , Bookwalter Carol , Trybus Kathleen M. , Chemla Yann R. , Selvin Paul R. 
Published: February 2019

AbstractHow cargoes move within a crowded cell—over long distances and at speeds that are nearly the same as when moving on an unimpeded pathway—has long been mysterious. Through an in vitro gliding assay, which involves measuring nanometer displacement and piconewtons of force, we have evidence that when kinesins, a cytoplasmic molecular motor, operate in small groups, from 2-10, they can communicate among themselves through an asymmetric tug-of-war by inducing tension (up to 4 pN) on the cargo. Surprisingly, the primary role of approximately one-third of kinesins is to develop tension, which instantaneously slows forward motion but helps increase cargo run length. These hindering kinesins fall off rapidly when experiencing a forward tug. Occasionally, they may be ripped off from their anchors by other driving kinesins working in tandem. Furthermore, with roadblocks on the microtubule, multiple kinesins cooperate to overcome impediments. Hence, kinesin may employ an asymmetric tug-of-war and a cooperative motion to navigate through cellular environment.
Development of a quantitative PCR assay for the detection and enumeration of a potentially ciguatoxin-producing dinoflagellate, Gambierdiscus lapillus (Gonyaulacales, Dinophyceae)
Authors: Kretzschmar A.L. , Verma A. , Kohli G.S. , Murray S.A. 
Published: February 2019

AbstractCiguatera fish poisoning is an illness contracted through the ingestion of seafood containing ciguatoxins. It is prevalent in tropical regions worldwide, including in Australia. Ciguatoxins are produced by some species of Gambierdiscus. Therefore, screening of Gambierdiscus species identification through quantitative PCR (qPCR), along with the determination of species toxicity, can be useful in monitoring potential ciguatera risk in these regions. In Australia, the identity, distribution and abundance of ciguatoxin producing Gambierdiscus spp. is largely unknown. In this study we developed a rapid qPCR assay to quantify the presence and abundance of Gambierdiscus lapillus, a likely ciguatoxic species. We assessed the specificity and efficiency of the qPCR assay. The assay was tested on 25 environmental samples from the Heron Island reef in the southern Great Barrier Reef, a ciguatera endemic region, in triplicate to determine the presence and patchiness of these species across samples from Chnoospora sp., Padina sp. and Sargassum macroalgal hosts.Author’s summaryCiguatera fish poisoning is a human disease contracted by ingesting seafood contaminated with a group of neurotoxins. The group of neurotoxins, named ciguatoxins, are synthesised by species of single celled marine algae from the genus Gambierdiscus.Ciguatera fish poisoning occurs worldwide, particularly in tropical nations. Pacific Island nations are disproportionately impacted, and this impact is predicted to increase as the effects of climate change unfold. Few effective monitoring and mitigation strategies exist for ciguatera fish poisoning, and reporting rates of the disease are estimated to be approximately 20% at best. A global ciguatera strategy was developed by a group of researchers coordinated by UNESCO’s Intergovernmental Oceanographic Commission to characterise the cause and mode of action of ciguatera fish poisoning, as a matter of urgency.In this study, we designed a qPCR assay to detect a species of microalgae, Gambierdiscus lapillus. Gambierdiscus lapillus produces compounds with ciguatoxin-like properties, which may lead to ciguatoxin uptake in fish in the Australian region. This assay was sensitive and able to detect the presence of Gambierdiscus lapillus in a range of environmental samples from the Great Barrier Reef region, Australia.
Influence of Mismarking Fiducial Locations on EEG Source Estimation
Authors: Shirazi Seyed Yahya , Huang Helen J. 
Published: February 2019

AbstractMismarking locations of the fiducials can have a significant influence on the digitized electrode locations and cortical source estimation using high-density EEG. Under-standing and quantifying how uncertainties in the fiducial locations affect the locations of cortical sources is important for interpreting EEG analyses. We systematically shifted fiducial locations to investigate the relationship between variations of fiducial locations and the corresponding estimations of the source locations. We quantified the uncertainty of the dipole locations using the enclosing volume of the dipole locations and the maximum width of the dipole cluster. Shifting fiducial locations 1.5 cm increased the uncertainty of the dipole locations to span a volume >1 cm3 and about 2.5 cm wide. Results suggest that the fiducials need to be digitized accurately within at least 0.5 cm of the absolute actual fiducial location to limit the uncertainty of a dipole location to <1 cm. Additionally, we used random fiducial shift combinations to estimate the effects of combinations of the fiducial shifts on dipole location estimation. This analysis showed that dipole locations were within the bounds of our dipole estimation uncertainty volumes. Based on the outcomes, we suggest marking fiducials carefully before placement of the cap and to use a digitization method with an accuracy of <0.5 cm.
The mycobacterial cell wall partitions the plasma membrane to organize its own synthesis
Authors: García-Heredia Alam , Kado Takehiro , Sein Caralyn E. , Puffal Julia , Osman Sarah H. , Judd Julius , Gray Todd A. , Morita Yasu S. , Siegrist M. Sloan 
Published: February 2019

AbstractMany antibiotics target the assembly of cell wall peptidoglycan, an essential, heteropolymeric mesh that encases most bacteria. Different species have characteristic subcellular sites of peptidoglycan synthesis that they must carefully maintain for surface integrity and, ultimately, viability. In rod-shaped bacteria, cell wall elongation is spatially precise yet relies on a limited pool of lipid-linked precursors that generate and are attracted to membrane disorder. By tracking enzymes, substrates and products of peptidoglycan biosynthesis inMycobacterium smegmatis, we show that precursors are made in plasma membrane domains that are laterally and biochemically distinct from sites of cell wall assembly. Membrane partitioning is required for robust, orderly peptidoglycan synthesis, indicating that these domains help template peptidoglycan synthesis. The cell wall-organizing protein DivIVA and the cell wall itself are essential for domain homeostasis. Thus, the peptidoglycan polymer feeds back on its membrane template to maintain an environment conducive to directional synthesis. We further show that our findings are applicable to rod-shaped bacteria that are phylogenetically distant fromM. smegmatis, demonstrating that horizontal compartmentalization of precursors is a general feature of bacillary cell wall biogenesis.
netNMF-sc: Leveraging gene-gene interactions for imputation and dimensionality reduction in single-cell expression analysis
Authors: Elyanow Rebecca , Dumitrascu Bianca , Engelhardt Barbara E. , Raphael Benjamin J. 
Published: February 2019

AbstractMotivationSingle-cell RNA-sequencing (scRNA-seq) enables high throughput measurement of RNA expression in individual cells. Due to technical limitations, scRNA-seq data often contain zero counts for many transcripts in individual cells. These zero counts, ordropout events, complicate the analysis of scRNA-seq data using standard analysis methods developed for bulk RNA-seq data. Current scRNA-seq analysis methods typically overcome dropout by combining information across cells, leveraging the observation that cells generally occupy a small number of RNA expression states.ResultsWe introduce netNMF-sc, an algorithm for scRNA-seq analysis that leverages information acrossbothcells and genes. netNMF-sc combines network-regularized non-negative matrix factorization with a procedure for handling zero inflation in transcript count matrices. The matrix factorization results in a low-dimensional representation of the transcript count matrix, which imputes gene abundance for both zero and non-zero entries and can be used to cluster cells. The network regularization leverages prior knowledge of gene-gene interactions, encouraging pairs of genes with known interactions to be close in the low-dimensional representation. We show that netNMF-sc outperforms existing methods on simulated and real scRNA-seq data, with increasing advantage at higher dropout rates (e.g. above 60%). Furthermore, we show that the results from netNMF-sc – including estimation of gene-gene covariance – are robust to choice of network, with more representative networks leading to greater performance gains.AvailabilitynetNMF-sc is available atgithub.com/raphael-group/netNMF-sc.Contactbraphael@princeton.edu
Multivariate genome-wide association analysis of a cytokine network reveals variants with widespread immune, haematological and cardiometabolic pleiotropy
Authors: Nath Artika P. , Ritchie Scott C. , Grinberg Nastasiya F. , Tang Howard Ho-Fung , Huang Qin Qin , Teo Shu Mei , Ahola-Olli Ari V. , Würtz Peter , Havulinna Aki S. , Aalto Kristiina , Pitkänen Niina , Lehtimäki Terho , Kähönen Mika , Lyytikäinen Leo-Pekka , Raitoharju Emma , Seppälä Ilkka , Sarin Antti-Pekka , Ripatti Samuli , Palotie Aarno , Perola Markus , Viikari Jorma S , Jalkanen Sirpa , Maksimow Mikael , Salmi Marko , Wallace Chris , Raitakari Olli T. , Salomaa Veikko , Abraham Gad , Kettunen Johannes , Inouye Michael 
Published: February 2019

AbstractCytokines are essential regulatory components of the immune system and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlie them, remain unknown. Here we aimed to identify and characterise genetic variants with pleiotropic effects on cytokines – to do this we performed a multivariate genome-wide association study on a correlation network of 11 circulating cytokines measured in 9,263 individuals. Meta-analysis identified a total of 8 loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. Bayesian colocalisation analysis revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins; on metabolic traits such as lipoprotein and lipid levels; on blood-cell related traits such as platelet count; and on disease traits such as coronary artery disease and type 2 diabetes.
Non-canonical Features of Pentatricopeptide Repeat Protein-Facilitated RNA Editing in Arabidopsis Chloroplasts
Authors: Kelly Sun Yueming , Gutmann Bernard , Small Ian 
Published: February 2019

AbstractCytosine (C) to uracil (U) RNA editing in plant mitochondria and chloroplasts is facilitated by site-specific pentatricopeptide repeat (PPR) editing factors. PPR editing factors contain multiple types of PPR motifs, and PPR motifs of the same type also show sequence variations. Therefore, no PPR motifs are invariant within a PPR protein or between different PPR proteins. This work evaluates the functional diversity of PPR motifs in CHLOROPLAST RNA EDITING FACTOR 3 (CREF3). The results indicate that previously overlooked features of PPR editing factors could also contribute to RNA editing activity. In particular, the N-terminal degenerated PPR motifs and the two L1-type PPR motifs in CREF3 are functionally indispensable. Furthermore, PPR motifs of the same type in CREF3 are not interchangeable. These non-canonical features of CREF3 have important implications on the understanding of PPR-facilitated RNA editing in plant organelles.
Characterization of Peripheral Blood Mononuclear Cells Gene Expression Profiles of PediatricStaphylococcus aureusPersistent and Non-Carriers Using a Targeted Assay
Authors: Israelsson Elisabeth , Chaussabel Damien , Fischer Rebecca S.B. , Moore Heather C. , Robinson D. Ashley , Essigmann Heather T. , Brown Eric L. 
Published: February 2019

AbstractDefects in innate immunity affect many different physiologic systems and several studies of patients with primary immunodeficiency disorders demonstrated the importance of innate immune system components in disease prevention or colonization of bacterial pathogens. To assess the role of the innate immune system on nasal colonization withStaphylococcus aureus, innate immune responses in pediatricS. aureusnasal persistent carriers (n=15) and non-carriers (n=15) were profiled by analyzing co-clustered gene sets (modules) identified through large-scale transcriptome data analysis as the basis for the development of a targeted assay. We stimulated previously frozen peripheral blood mononuclear cells (PBMCs) from these subjects with i) a panel of TLR ligands, ii) liveS. aureus(either a mixture of strains or stimulation with respective carriage isolates), or iii) heat-killedS. aureus. We found no difference in responses between carriers and non-carriers when PBMCs were stimulated with a panel of TLR ligands. However, PBMCs stimulated with liveS. aureuselicited a significantly different response that also differed from the response elicited following stimulation with deadS. aureus. Furthermore, we observed a distinct stimulation profile for PBMCs isolated from persistent carriers stimulated with their respective live or dead carriage strains compared to responses observed for PBMCs isolated from non-carriers that were similar regardless of whether or not the bacteria were alive or not. These data suggested that innate pathway signaling is different between persistent and non-carriers ofS. aureus.
Electrophysiological correlates of state transition prediction errors
Authors: Shahnazian Danesh , Ribas-Fernandes José J.F , Holroyd Clay B. 
Published: February 2019

AbstractPlanning behavior depends crucially on the ability to distinguish between the likely and unlikely consequences of an action. Formal computational models of planning postulate the existence of a neural mechanism that tracks the transition model of the environment, i.e., a model that explicitly represents the probabilities of action consequences. However, empirical findings relating to such a mechanism are scarce. Here we report the results of two electroencephalographic experiments examining the neural correlates of transition model learning. The results implicate fronto-midline theta and delta oscillations in this process and suggest a role of the anterior midcingulate cortex in planning behavior.
A genetically-encoded toolkit of functionalized nanobodies against fluorescent proteins for visualizing and manipulating intracellular signalling
Authors: Prole David L. , Taylor Colin W. 
Published: February 2019

AbstractBackgroundIntrabodies enable targeting of proteins in live cells, but it remains a huge task to generate specific intrabodies against the thousands of proteins in a proteome. We leverage the widespread availability of fluorescently labelled proteins to visualize and manipulate intracellular signalling pathways in live cells by using nanobodies targeting fluorescent protein tags.ResultsWe generated a toolkit of plasmids encoding nanobodies against red and green fluorescent proteins (RFP and GFP variants), fused to functional modules. These include fluorescent sensors for visualization of Ca2+, H+ and ATP/ADP dynamics; oligomerizing or heterodimerizing modules that allow recruitment or sequestration of proteins and identification of membrane contact sites between organelles; SNAP tags that allow labelling with fluorescent dyes and targeted chromophore-assisted light inactivation; and nanobodies targeted to lumenal sub-compartments of the secretory pathway. We also developed two methods for crosslinking tagged proteins: a dimeric nanobody, and RFP-targeting and GFP-targeting nanobodies fused to complementary hetero-dimerizing domains. We show various applications of the toolkit and demonstrate, for example, that IP3 receptors deliver Ca2+ to the outer membrane of only a subset of mitochondria, and that only one or two sites on a mitochondrion form membrane contacts with the plasma membrane.ConclusionsThis toolkit greatly expands the utility of intrabodies for studying cell signalling in live cells.