bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcome of TMS-based motor mapping depends on TMS current direction
Authors: Vink Jord JT , Petrov Petar I , Mandija Stefano , Dijkhuizen Rick M , Neggers Sebastiaan FW 
Published: July 2018

ABSTRACTNavigated transcranial magnetic stimulation (TMS) in combination with electromyography (EMG) recordings can be used to map the brain regions in which TMS evokes motor-evoked potentials (MEPs) in certain muscles. Navigated TMS (nTMS) is used increasingly to identify the functional motor area of different muscles for clinical applications, including neurosurgical planning. However, the accuracy of TMS-based mapping of functional motor areas may depend on the TMS-induced current direction due to anisotropic cortical morphology, complicating association of the functional motor maps with neuroanatomical structures. Furthermore, it is not clear how well nTMS can distinguish nearby muscle representations on the cortical surface. We therefore investigated the functional motor maps obtained with posterior-to-anterior (PA) and lateral-to-medial (LM) TMS-induced currents within a spatially defined area by stimulating targets in a grid of locations over the left primary motor cortex in 8 healthy participants. Results were compared to functional MRI (fMRI) activation maps obtained using a voluntary opposing thumb movement task. We found that TMS applied with PA-induced currents identifies a motor area that is located significantly more anterior (8.7 – 10.4 mm depending on the muscle) with respect to an MEP motor area identified using LM-induced currents for the same muscle. Motor maps obtained with LM-induced currents show more overlap with the motor map identified using fMRI compared to PA-induced currents. In conclusion, the spatial representation of the MEP motor map identified by TMS is dependent on the direction of the induced current. These findings suggest that the application of nTMS using an LM-induced current direction corresponds best with the hand motor area as measured with fMRI.
MetaMaps – Strain-level metagenomic assignment and compositional estimation for long reads
Authors: Dilthey Alexander , Jain Chirag , Koren Sergey , Phillippy Adam M. 
Published: July 2018

AbstractMetagenomic sequence classification should be fast, accurate and information-rich. Emerging long-read sequencing technologies promise to improve the balance between these factors but most existing methods were designed for short reads. MetaMaps is a new method, specifically developed for long reads, that combines the accuracy of slower alignment-based methods with the scalability of faster k-mer-based methods. Using an approximate mapping algorithm, it is capable of mapping a long-read metagenome to a comprehensive RefSeq database with >12,000 genomes in <30 GB or RAM on a laptop computer. Integrating these mappings with a probabilistic scoring scheme and EM-based estimation of sample composition, MetaMaps achieves >95% accuracy for species-level read assignment and r2 > 0.98 for the estimation of sample composition on both simulated and real data. Uniquely, MetaMaps outputs mapping locations and qualities for all classified reads, enabling functional studies (e.g. gene presence/absence) and the detection of novel species not present in the current database.Availability and ImplementationMetaMaps is implemented in C++/Perl and freely available from https://github.com/DiltheyLab/MetaMaps (GPL v3).
Evidence for Miocene overwater colonization in CaribbeanCyrtognathaspiders
Authors: Čandek Klemen , Agnarsson Ingi , Binford Greta , Kuntner Matjaž 
Published: July 2018

AbstractIsland systems provide excellent arenas to test evolutionary hypotheses pertaining to gene flow and diversification of dispersal-limited organisms. Here we focus on an orbweaver spider genusCyrtognatha(Tetragnathidae) from the Caribbean, with the aims to reconstruct its evolutionary history, describe its biogeographic history in the archipelago, and to estimate the timing and route of Caribbean colonization. Specifically, we test ifCyrtognathabiogeographic history is consistent with an ancient vicariant scenario (the GAARlandia landbridge hypothesis) or overwater dispersal. We reconstructed a species level phylogeny based on one mitochondrial (CO1) and one nuclear (28S) marker. We then used this topology to constrain a time-calibrated mtDNA phylogeny, for subsequent biogeographical analyses of over 100 originally sampledCyrtognathaindividuals. Our results suggest a monophyletic radiation of CaribbeanCyrtognatha, containing 11 to 14 species that are exclusively single island endemics. Our analyses refute vicariance and instead support an overwater colonization to the Caribbean in mid-Miocene. Having colonized Hispaniola first,Cyrtognathasubsequently dispersed to, and diversified on, the other islands of the Greater, and Lesser Antilles.
Helmsman: fast and efficient generation of input matrices for mutation signature analysis
Authors: Carlson Jedidiah , Li Jun Z , Zöllner Sebastian 
Published: July 2018

AbstractMotivationThe spectrum of somatic single-nucleotide variants in cancer genomes often reflects the signatures of multiple distinct mutational processes, which can provide clinically actionable insights into cancer etiology. Existing software tools for identifying and evaluating these mutational signatures do not scale to analyze large datasets containing thousands of individuals or millions of variants.ResultsWe introduce Helmsman, a program designed to rapidly generate mutation spectra matrices from arbitrarily large datasets. Helmsman is up to 300 times faster than existing methods and can provide more than a 100-fold reduction in memory usage, making mutation signature analysis tractable for any collection of single nucleotide variants, no matter how large.AvailabilityHelmsman is freely available for download at https://github.com/carjed/helmsman under the MIT license. Detailed documentation can be found at https://www.jedidiahcarlson.com/docs/helmsman/, and an interactive Jupyter notebook containing a guided tutorial can be accessed at https://mybinder.org/v2/gh/carjed/helmsman/master.Contactjedidiah@umich.eduSupplementary informationSupplementary information for this article is available.
A new lipid force field (FUJI)
Authors: Kamiya Nozomu , Shinoda Keiko , Fujitani Hideaki 
Published: July 2018

AbstractTo explore inhomogeneous and anisotropic systems such as lipid bilayers, the Lennard-Jones particle mesh Ewald (LJ-PME) method was applied without a traditional isotropic dispersion correction. As the popular AMBER and CHARMM lipid force fields were developed using a cutoff scheme, their lipid bilayers unacceptably shrank when using LJ-PME method. A new lipid force field (FUJI) was developed on the basis of the AMBER force field scheme including the Lipid14 van der Waals parameters. Point charges were calculated by the restrained electrostatic potentials of many lipid conformers. The torsion energy profiles were calculated by high level ab initio molecular orbitals (LCCSD(T)/Aug-cc-pVTZ//LMP2/Aug-cc-pVTZ); then, the molecular mechanical dihedral parameters were derived by means of a fast Fourier transform. Incorporating these parameters into a new lipid force field without any fittings to experimental data, desirable lipid characteristics such as the area per lipid and lateral diffusion coefficients were obtained by GROMACS molecular dynamics simulations using the LJ-PME method and hydrogen virtual sites. The stability and structures of large membranes with undulatory fluctuations were studied by a multidrug efflux transporter (AcrABZ-TolC) with inner and outer membranes.
Inferring the nature of missing heritability in human traits
Authors: López-Cortegano Eugenio , Caballero Armando 
Published: July 2018

ABSTRACTThousands of genes responsible for many diseases and other common traits in humans have been detected by Genome Wide Association Studies (GWAS) in the last decade. However, candidate causal variants found so far usually explain only a small fraction of the heritability estimated by family data, the rest remaining ‘missing’. The most common explanation for this observation is that the missing heritability corresponds to variants, either rare or common, with very small effect, which pass undetected due to a lack of statistical power. We carried out a meta-analysis using data from the NHGRI-EBI GWAS Catalog in order to explore the distribution of gene effects for a set of 59 complex traits, to investigate the factors related to new gene discovery and to quantify their contributions to heritability. With the data obtained we were able to predict the expected distribution of gene effects for 16 traits and diseases including cancer and immune disorders, the missing number of genes yet to be discovered, and the additive contribution of common variants to heritability. Our results indicate that, for most traits, the additive contribution of hundreds or thousands of genes is able to explain the familiar heritability. However, for some traits, the predicted heritability is lower than the familiar one, so that part of the missing heritability cannot be explained by the contribution of common variants with additive effects, and other phenomena (e.g. dominance or epistasis) should be invoked.AUTHOR SUMMARYThe heritability of biological traits refers to the fraction of the phenotypic (i.e.visible or diagnosable) variability that is explained by the underlying genetic variability. Despite the efforts made to find the genes responsible for complex traits and diseases, most of the heritability explained by the variants found explains only a small fraction of that measured by population and family studies. The remaining ‘missing’ heritability is usually assumed to be due to the additive effect of undetected variants. Here we carried out a meta-analysis using records from a publicly available database of genome-wide studies on humans. With these data, we were able to investigate and make inferences on the nature of heritability and the factors associated to new gene discovery. Our results indicate that increasing population sample size, as well as its diversity, enhances the discovery of new genes, but these have lower and lower effects, contributing little to heritability. We were also able to predict the distribution of gene effects for many traits and the number of variants needed to fully explain the heritability. For some traits, the additive effects of single variants yet to be discovered cannot explain the heritability, suggesting that other sources of variation are involved.
The taxonomic and functional biogeographies of phytoplankton and zooplankton communities across boreal lakes
Authors: St-Gelais Nicolas F. , Vogt Richard J. , del Giorgio Paul A. , Beisner Beatrix E. 
Published: July 2018

AbstractStrong trophic interactions link primary producers (phytoplankton) and consumers (zooplankton) in lakes. However, the influence of such interactions on the biogeographical distribution of the taxa and functional traits of planktonic organisms in lakes has never been explicitly tested. To better understand the spatial distribution of these two major aquatic groups, we related composition across boreal lakes (104 for zooplankton and 48 for phytoplankton) in relation to a common suite of environmental and spatial factors. We then directly tested the degree of coupling in their taxonomic and functional distributions across the subset of common lakes. Although phytoplankton composition responded mainly to properties related to water quality while zooplankton composition responded more strongly to lake morphometry, we found significant coupling between their spatial distributions at taxonomic and functional levels based on a Procrustes test. This coupling was not significant after removing the effect of environmental drivers (water quality and morphometry) on the spatial distributions of the two groups. This result suggests that top-down and bottom-up effects (e.g. nutrient concentration and predation) drove trophic interactions at the landscape level. We also found a significant effect of dispersal limitation on the distribution of taxa, which could explain why coupling was stronger for taxa than for traits at the scale of this study, with a turnover of species observed between regions, but no trait turnover. Our results indicate that landscape pelagic food web responses to anthropogenic changes in ecosystem parameters should be driven by a combination of top-down and bottom-factors for taxonomic composition, but with a relative resilience in functional trait composition of lake communities.
Evaluating the diversity of maternal age effects upon neonatal survival across animal species
Authors: Ivimey-Cook Edward , Moorad Jacob 
Published: July 2018

AbstractMaternal effect senescence is the detrimental effect of increased maternal age on offspring performance. Despite much recent interest given to describing this phenomenon, its origins and distribution across the tree-of-life are poorly understood. We find that age affects neonatal survival in 83 of 90 studies across 51 species, but we observed a puzzling difference between groups of animal species. Amongst wild bird populations, the average effect of age was only −0.7% per standardized unit of increasing age, but maternal effects clearly senesced in laboratory invertebrates (−67.1%) and wild mammals (−57.8%). Comparisons amongst demographic predictions derived from evolutionary theory and conventional demographic models suggest that natural selection has shaped maternal effect senescence in the natural world. These results emphasize both the general importance of maternal age effects and the potential for evolutionary genetics to provide a valuable framework for understanding the diversity of this manifestation of ageing in animal species.
Quantitative single-cell live imaging links HES5 dynamics with cell-state and fate in murine neurogenesis
Authors: Manning Cerys S , Biga Veronica , Boyd James , Kursawe Jochen , Ymisson Bodvar , Spiller David G , Sanderson Christopher M , Galla Tobias , Rattray Magnus , Papalopulu Nancy 
Published: July 2018

AbstractDuring embryogenesis cells make fate decisions within complex tissue environments. The levels and dynamics of transcription factor expression regulate these decisions. Here we use single cell live imaging of an endogenous HES5 reporter and absolute protein quantification to gain a dynamic view of neurogenesis in the embryonic mammalian spinal cord. We report that dividing neural progenitors show both aperiodic and periodic HES5 protein fluctuations. Mathematical modelling suggests that in progenitor cells the HES5 oscillator operates close to its bifurcation boundary where stochastic conversions between dynamics are possible. HES5 expression becomes more frequently periodic as cells transition to differentiation which, coupled with an overall decline in HES5 expression, creates a transient period of oscillations with higher fold expression change. This increases the decoding capacity of HES5 oscillations and correlates with interneuron versus motor neuron cell fate. Thus, HES5 undergoes complex changes in gene expression dynamics as cells differentiate.
Y-profile evidence: close paternal relatives and mixtures
Authors: Andersen Mikkel M , Balding David J 
Published: July 2018

AbstractWe recently introduced a new approach to the evaluation of weight of evidence (WoE) for Y-chromosome profiles. Rather than attempting to calculate match probabilities, which is particularly problematic for modern Y-profiles with high mutation rates, we proposed using simulation to describe the distribution of the number of males in the population with a matching Y-profile, both the unconditional distribution and conditional on a database frequency of the profile. Here we further validate the new approach by showing that our results are robust to assumptions about the allelic ladder and the founder haplotypes, and we extend the approach in two important directions. Firstly, forensic databases are not the only source of background data relevant to the evaluation of Y-profile evidence: in many cases the Y-profiles of one or more relatives of the accused are also available. To date it has been unclear how to use this additional information, but in our simulation-based approach its effect is readily incorporated. We describe this approach and illustrate how the WoE that a man was the source of an observed Y-profile changes when the Y-profiles of some of his male-line relatives are also available. Secondly, we extend our new approach to mixtures of Y-profiles from two or more males. Surprisingly, our simulation-based approach reveals that observing a 2-male mixture that includes an alleged contributor’s profile is almost as strong evidence as observing a matching single-contributor evidence sample, and even 3-male and 4-male mixtures are only slightly weaker.
Human Cervical Keratinocyte-Derived Monolayer and Organoid Cultures for Disease Modelling and Drug Screening
Authors: Villa Peter L. , Jackson Robert , Eade Statton , Escott Nicholas , Zehbe Ingeborg 
Published: July 2018

AbstractThe successful isolation and propagation of patient-derived keratinocytes from cervical lesions constitute a more appropriate model of cervical disease than traditional cervical cancer-derived cell lines such as SiHa and CaSki. Our aim was to streamline the growth of patient-obtained, cervical keratinocytes into a reproducible process. We performed an observational case series study with 60 women referred to colposcopy for a diagnostic biopsy. Main outcome measures were how many samples could be passaged at least once, and where enough cells could be established, to precisely define their proliferation profile over time. Altering cell culture conditions over those reported by other groups markedly improved outcomes. We were also successful in making freeze backs which could be resuscitated for additional experiments. For best results, biopsy-intrinsic factors such as size and tissue digestion appear to be major variables. This seems to be the first systematic report with a well characterized and defined sample size, detailed protocol, carefully assessed cell yield and performance, and to successfully grow multi-layered, organoid cultures from cervical keratinocytes. This research is particularly impactful for constituting a sample repository-on-demand for appropriate disease modelling and drug screening under the umbrella of personalized health.
An alternative membrane topology permits lipid droplet localization of peroxisomal fatty acyl-CoA reductase 1
Authors: Exner Tarik , Romero-Brey Inés , Yifrach Eden , Rivera-Monroy Jhon , Schrul Bianca , Zouboulis Christos C. , Stremmel Wolfgang , Honsho Masanori , Bartenschlager Ralf , Zalckvar Einat , Poppelreuther Margarete , Füllekrug Joachim 
Published: July 2018

AbstractFatty acyl-CoA reductase 1 (Far1) is an ubiquitously expressed peroxisomal membrane protein generating fatty alcohols required for the biosynthesis of ether lipids.Lipid droplet localization of human Far1 was observed by fluorescence microscopy under conditions of increased triglyceride synthesis in tissue culture cells. This unexpected finding was supported further by correlative light electron microscopy and subcellular fractionation. Selective permeabilization and N-glycosylation tagging suggest that Far1 is able to assume two different membrane topologies, differing in the orientation of the short hydrophilic C-terminus towards the lumen or the cytosol, respectively. Two closely spaced hydrophobic domains are contained within the C-terminal region. When analyzed separately, the second domain was sufficient for the localization of a fluorescent reporter to lipid droplets. Targeting of Far1 to lipid droplets was not impaired in either pex19 or TRC40/ASNA1 CRISPR/Cas9 knockout cells.In conclusion, our data suggest that Far1 is a novel member of the rather exclusive group of dual topology membrane proteins. At the same time, Far1 shows lipid metabolism-dependent differential subcellular localizations to peroxisomes and lipid droplets.
Pkd2l1 is required for mechanoception in cerebrospinal fluid-contacting neurons and maintenance of spine curvature
Authors: Sternberg Jenna R. , Prendergast Andrew E. , Brosse Lucie , Cantaut-Belarif Yasmine , Thouvenin Olivier , Orts-Del’Immagine Adeline , Castillo Laura , Djenoune Lydia , Kurisu Shusaku , McDearmid Jonathan R. , Bardet Pierre-Luc , Boccara Claude , Okamoto Hitoshi , Delmas Patrick , Wyart Claire 
Published: July 2018

AbstractFlow of cerebrospinal fluid (CSF) may contribute to spine morphogenesis, as mutations affecting both cilia motility and CSF flow lead to scoliosis1. However, the mechanisms underlying detection of the CSF flow in the central canal of the spinal cord remain elusive. Here we used full-field optical coherence tomography (FF-OCT) and bead tracking to demonstrate that CSF flows bidirectionally along the antero-posterior axis in the central canal of zebrafish embryos. In the zebrafish mutantcfap298tm304, previously known askurly, reduction of cilia motility slows transport down the length of central canal. To investigate downstream mechanisms that could transduce CSF flow, we performed calcium imaging in sensory neurons contacting the CSF (CSF-cNs) and found that disruption in cilia motility impaired the activity of CSF-cNs. CSF-cNs across species express the transient receptor potential channel PKD2L1, also known as TRPP3, which contributes to CSF-cN chemosensory properties. Using calcium imaging and whole-cell patch clamp recordings, we found that the loss of the Pkd2l1 channel inpkd2l1mutant embryos also abolished CSF-cN activity. Whole-cell recordings further demonstrated that opening of a single channel is sufficient to trigger action potentials in wild type CSF-cNs. Recording from isolated cellsin vitro,we showed that CSF-cNs are mechanosensory cells that respond to pressure in a Pkd2l1-dependent manner. Interestingly, adultpkd2l1mutant zebrafish develop an exaggerated spine curvature, reminiscent of kyphosis in humans. Our study indicates that CSF-cNs are mechanosensory cells whose spontaneous activity reflects CSF flowin vivo. Furthermore, Pkd2l1 in CSF-cNs contributes to the maintenance of the natural curvature of the spine.
Coordinative Metabolism of Glutamine Carbon and Nitrogen in proliferating Cancer Cells Under Hypoxia
Authors: Wang Yuanyuan , Bai Changsen , Ruan Yuxia , Liu Miao , Chu Qiaoyun , Qiu Li , Yang Chuanzhen , Li Binghui 
Published: July 2018

ABSTRACTUnder hypoxia, most of glucose is converted to secretory lactate, which leads to the lack of carbon source from glucose and thus the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid releasing potentially toxic ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate under hypoxia. We found that glutamine nitrogen is indispensable to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. The specific metabolic pathway occurs in vivo and is required for tumor growth. Such a metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism.SignificanceTumor cells often addict to glutamine, and particularly utilize its carbon for lipogenesis under hypoxia. We reveal that tumor cells package the excessive glutamine-nitrogen into secretory dihydroorotate, instead of toxic ammonia. This specifically reprogrammed pathway supports in vivo tumor growth, and could offer diagnostic markers and therapeutic targets for cancers.