bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatiotemporal analysis for detection of pre-symptomatic shape changes in neurodegenerative diseases: applied to GENFI study
Authors: Cury Claire , Durrleman Stanley , Cash David , Lorenzi Marco , Nicholas Jennifer M , Bocchetta Martina , van Swieten John C. , Borroni Barbara , Galimberti Daniela , Masellis Mario , Carmela Tartaglia Maria , Rowe James B , Graff Caroline , Tagliavini Fabrizio , Frisoni Giovanni B. , Laforce Robert , Finger Elizabeth , de Mendonca Alexandre , Sorbi Sandro , Ourselin Sebastien , Rohrer Jonathan D. , Modat Marc ,   on behalf of the Genetic FTD Initiative, GENFI
Published: August 2018

AbstractBrain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer’s disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure.In this paper we propose a spatiotemporal analysis pipeline based Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects.We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease.
pNeRF: Parallelized Conversion from Internal to Cartesian Coordinates
Authors: AlQuraishi Mohammed 
Published: August 2018

ABSTRACTThe conversion of polymer parameterization from internal coordinates (bond lengths, angles, and torsions) to Cartesian coordinates is a fundamental task in molecular modeling, often performed using the Natural Extension Reference Frame (NeRF) algorithm. NeRF can be parallelized to process multiple polymers simultaneously, but is not parallelizable along the length of a single polymer. A mathematically equivalent algorithm, pNeRF, has been derived that is parallelizable along a polymer’s length. Empirical analysis demonstrates an order-of-magnitude speed up using modern GPUs and CPUs. In machine learning-based workflows, in which partial derivatives are backpropagated through NeRF equations and neural network primitives, switching to pNeRF can reduce the fractional computational cost of coordinate conversion from over two-thirds to around 10%. An optimized TensorFlow-based implementation of pNeRF is available on GitHub.
Spatial autocorrelation: bane or bonus?
Authors: Pawley Matt. D. M. , McArdle Brian H. 
Published: August 2018

AbstractSpatial autocorrelation is a general phenomenon within biogeographical studies. However, considerable confusion exists about how to analyse spatially autocorrelated data collected using classical sampling methods (e.g. simple random sampling). We show that the two common discordant views about autocorrelated data depend upon the desired scale of inference. Although inferential statistics seeking to generalise to different unsampled spatial areas need to be adjusted for autocorrelation, if the inference is restricted to the area from which samples have been taken, then standard tests are applicable. In the latter case, incorporating autocorrelation into the model may actually improve the precision and power of the analysis. We found that the scale of spatial inference is rarely discussed, despite being of central importance to any spatial analysis. We suggest that spatial inference should rarely be formally generalised to unsampled areas, since it typically requires some assumption of stationarity, and is thus vulnerable to accusations of “pseudo-replication”.
Just the Two of Us? A Family of Pseudomonas Megaplasmids Offers a Rare Glimpse Into the Evolution of Large Mobile Elements
Authors: Smith Brian A. , Leligdon Courtney , Baltrus David A. 
Published: August 2018

AbstractPseudomonads are ubiquitous group of environmental proteobacteria, well known for their roles in biogeochemical cycling, in the breakdown of xenobiotic materials, as plant growth promoters, and as pathogens of a variety of host organisms. We have previously identified a large megaplasmid present within one isolate the plant pathogen Pseudomonas syringae, and here we report that a second member of this megaplasmid family is found within an environmental Pseudomonad isolate most closely related to P. putida. Many of the shared genes are involved in critical cellular processes like replication, transcription, translation, and DNA repair. We argue that presence of these shared pathways sheds new light on discussions about the types of genes that undergo horizontal gene transfer (i.e. the complexity hypothesis) as well as the evolution of pangenomes. Furthermore, although both megaplasmids display a high level of synteny, genes that are shared differ by over 30% on average at the amino acid level. This combination of conservation in gene order despite divergence in gene sequence suggests that this Pseudomonad megaplasmid family is relatively old, that gene order is under strong selection within this family, and that there are likely many more members of this megaplasmid family waiting to be found in nature.
GranatumX: A Community-engaging, Modularized, and Flexible Webtool for Single-cell Data Analysis
Authors: Garmire David , Zhu Xun , Mantravadi Aravind , Huang Qianhui , Yunits Breck , Liu Yu , Wolfgruber Thomas , Poirion Olivier , Zhao Tianying , Arisdakessian Cédric , Stanojevic Stefan , Garmire Lana X. 
Published: August 2018

AbstractWe present GranatumX, a next-generation software environment for single-cell data analysis. GranatumX is inspired by the interactive web tool Granatum. It enables biologists to access the latest single-cell bioinformatics methods in a web-based graphical environment. It also offers software developers the opportunity to rapidly promote their own tools with others in customizable pipelines. The architecture of GranatumX allows for easy inclusion of plugin modules, named Gboxes, that wrap around bioinformatics tools written in various programming languages and on various platforms. GranatumX can be run on the cloud or private servers and generate reproducible results. It is a community-engaging, flexible, and evolving software ecosystem for scRNA-Seq analysis, connecting developers with bench scientists. GranatumX is freely accessible at http://garmiregroup.org/granatumx/app.
Drug repurposing through joint learning on knowledge graphs and literature
Authors: Alshahrani Mona , Hoehndorf Robert 
Published: August 2018

AbstractMotivationDrug repurposing is the problem of finding new uses for known drugs, and may either involve finding a new protein target or a new indication for a known mechanism. Several computational methods for drug repurposing exist, and many of these methods rely on combinations of different sources of information, extract hand-crafted features and use a computational model to predict targets or indications for a drug. One of the distinguishing features between different drug repurposing systems is the selection of features. Recently, a set of novel machine learning methods have become available that can efficiently learn features from datasets, and these methods can be applied, among others, to text and structured data in knowledge graphs.ResultsWe developed a novel method that combines information in literature and structured databases, and applies feature learning to generate vector space embeddings. We apply our method to the identification of drug targets and indications for known drugs based on heterogeneous information about drugs, target proteins, and diseases. We demonstrate that our method is able to combine complementary information from both structured databases and from literature, and we show that our method can compete with well-established methods for drug repurposing. Our approach is generic and can be applied to other areas in which multi-modal information is used to build predictive models.Availabilityhttps://github.com/bio-ontology-research-group/multi-drug-embeddingContactrobert.hoehndorf@kaust.edu.sa
Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
Authors: Qu Yue , Hahn Ines , Lees Meredith , Parkin Jill , Voelzmann André , Dorey Karel , Rathbone Alex , Friel Claire , Allan Viki , Okenve-Ramos Pilar , Sanchez-Soriano Natalia , Prokop Andreas 
Published: August 2018

AbstractCortical collapse factors affect microtubule (MT) dynamics at the plasma membrane. They play important roles in neurons, as suggested by inhibition of axon growth and regeneration through the Arf activator Efa6 inC. elegans, and by neurodevelopmental disorders linked to the mammalian kinesin Kif21A. How cortical collapse factors influence axon growth is little understood. Here we studied them, focussing on the function ofDrosophilaEfa6 in experimentally and genetically amenable fly neurons. First, we show thatDrosophilaEfa6 can inhibit MTs directly without interacting molecules via an N-terminal 18 amino acid motif (MT elimination domain/MTED) that binds tubulin and inhibits microtubule growthin vitroand cells. If N-terminal MTED-containing fragments are in the cytoplasm they abolish entire microtubule networks of mouse fibroblasts and whole axons of fly neurons. Full-length Efa6 is membrane-attached, hence primarily blocks MTs in the periphery of fibroblasts, and explorative MTs that have left axonal bundles in neurons. Accordingly, loss of Efa6 causes an increase of explorative MTs: in growth cones, they enhance axon growth, in axon shafts, explorative MTs cause excessive branching, as well as atrophy through perturbations of MT bundles. Efa6 over-expression causes the opposite phenotypes. Taken together, our work conceptually links molecular and sub-cellular functions of cortical collapse factors to axon growth regulation and reveals new roles in axon branching and in the prevention of axonal atrophy. Furthermore, the MTED delivers a promising tool that can be used to inhibit MTs in a compartmentalised fashion when fusing it to specifically localising protein domains.Summary statementThe cortical collapse factor Efa6 inhibits microtubule polymerising outside axonal bundles. Thereby it limits axon growth and branching, but preserves microtubule bundle organisation crucial for axon maintenance.
The RopGEF KARAPPO is Essential for the Initiation of Vegetative Reproduction in Marchantia
Authors: Hiwatashi Takuma , Quan Koh Li , Yasui Yukiko , Takami Hideyuki , Kajikawa Masataka , Kirita Hiroyuki , Sato Mayuko , Wakazaki Mayumi , Yamaguchi Katsushi , Shigenobu Shuji , Fukaki Hidehiro , Mimura Tetsuro , Yamato Katsuyuki T. , Toyooka Kiminori , Sawa Shinichiro , Urano Daisuke , Kohchi Takayuki , Ishizaki Kimitsune 
Published: August 2018

SummaryMany plants can reproduce vegetatively, producing clonal progeny from vegetative cells; however, little is known about the molecular mechanisms underlying this process. Liverwort (Marchantia polymorpha), a basal land plant, propagates asexually via gemmae, which are clonal plantlets formed in gemma cups on the dorsal side of the vegetative thallus [1]. The initial stage of gemma development involves elongation and asymmetric divisions of a specific type of epidermal cell, called a gemma initial, which forms on the floor of the gemma cup [2, 3]. To investigate the regulatory mechanism underlying gemma development, we focused on two allelic mutants in which no gemma initial formed; these mutants were named karappo, meaning “empty”. We used whole-genome sequencing of both mutants, and molecular genetic analyses to identify the causal gene, KARAPPO (KAR), which encodes a Rop guanine nucleotide exchange factor (RopGEF) carrying a PRONE catalytic domain. In vitro GEF assays showed that the full-length KAR protein and the PRONE domain have significant GEF activity toward MpRop, the only Rop GTPase in M. polymorpha. Moreover, genetic complementation experiments showed a significant role for the N- and C-terminal variable regions in gemma development. Our investigation demonstrated an essential role for KAR/RopGEF in the initiation of plantlet development from a differentiated cell, which may involve cell polarity formation and subsequent asymmetric cell division via activation of Rop signaling, implying a similar developmental mechanism in vegetative reproduction of various land plants.
Triparental inheritance inDictyostelium
Authors: Bloomfield Gareth , Paschke Peggy , Okamoto Marina , Stevens Tim J. , Urushihara Hideko 
Published: August 2018

AbstractSex promotes the recombination and reassortment of genetic material and is prevalent across eukaryotes. In social amoebae sex involves a promiscuous mixing of cytoplasm before zygotes consume the majority of cells. We report here the first genomewide characterisation of meiotic progeny inDictyostelium discoideum. We find that recombination occurs at high frequency in pairwise crosses between all three mating types, despite the absence of the SPO11 enzyme that is normally required to initiate crossover formation. In crosses involving three strains, transient fusions involving more than two gametes frequently lead to triparental inheritance, with recombined nuclear haplotypes inherited from two parents and the mitochondrial genome from a third. Cells that do not contribute genetically to theDictyosteliumzygote nucleus thereby have a stake in the next haploid generation. We suggest that this lateral transfer helps to enforce cooperation in this confictual system.
Heat stress modifies the lactational performances and the urinary metabolomic profile related to gastrointestinal microbiota of dairy goats
Authors: Contreras-Jodar Alexandra , Nayan Nazri , Hamzaoui Soufiane , Caja Gerardo , Salama Ahmed A.K. 
Published: August 2018

AbstractThe aim of the study was to identify the candidate biomarkers of heat stress (HS) in the urine of lactating dairy goats through the application of proton Nuclear Magnetic Resonance (1H NMR)-based metabolomic analysis. Dairy does (n = 16) in mid-lactation were submitted to thermal neutral (TN; indoors; 15 to 20°C; 40 to 45% humidity) or HS (climatic chamber; 37°C day, 30°C night; 40% humidity) conditions according to a crossover design (2 periods of 21 days). Thermophysiological traits and lactational performances were recorded and milk composition analyzed during each period. Urine samples were collected at day 15 of each period for 1H NMR spectroscopy analysis. Principal component analysis (PCA) and partial least square–discriminant analysis (PLS-DA) assessment with cross validation were used to identify the goat urinary metabolome from Human Metabolome Data Base. HS increased rectal temperature (1.2°C), respiratory rate (3.5-fold) and water intake (74%), but decreased feed intake (35%) and body weight (5%) of the lactating does. No differences were detected in milk yield, but HS decreased the milk contents of fat (9%), protein (16%) and lactose (5%). Metabolomics allowed separating TN and HS urinary clusters by PLS-DA. Most discriminating metabolites were hippurate and other phenylalanine (Phe) derivative compounds, which increased in HS vs. TN does. The greater excretion of these gut-derived toxic compounds indicated that HS induced a harmful gastrointestinal microbiota overgrowth, which should have sequestrated aromatic amino acids for their metabolism and decreased the synthesis of neurotransmitters and thyroid hormones, with negative impact on milk yield and composition. In conclusion, HS markedly changed the thermophysiological traits and lactational performances of dairy goats, which were translated into their urinary metabolomic profile through the presence of gut-derived toxic compounds. Hippurate and other Phe-derivative compounds are suggested as urinary biomarkers to detect heat stressed dairy animals in practice.
Oral iron exacerbates colitis and influences the intestinal microbiome
Authors: Mahalhal Awad , Williams Jonathan M. , Johnson Sophie , Ellaby Nicholas , Duckworth Carrie A. , Burkitt Michael D. , Liu Xuan , Hold Georgina L. , Campbell Barry J. , Pritchard D. Mark , Probert Chris S. 
Published: August 2018

AbstractInflammatory bowel disease (IBD) is associated with anaemia and oral iron replacement to correct this can be problematic, intensifying inflammation and tissue damage. The intestinal microbiota also plays a key role in the pathogenesis of IBD, and iron supplementation likely influences gut bacterial diversity in patients with IBD. Here, we assessed the impact of dietary iron, using chow diets containing either 100, 200 or 400 ppm, fed ad libitum to adult female C57BL/6 mice in the presence or absence of colitis induced using dextran sulfate sodium (DSS), on (i) clinical and histological severity of acute DSS-induced colitis, and (ii) faecal microbial diversity, as assessed by sequencing the V4 region of 16S rRNA. Increasing or decreasing dietary iron concentration from the standard 200 ppm exacerbated both clinical and histological severity of DSS-induced colitis. DSS-treated mice provided only half the standard levels of iron ad libitum (i.e. chow containing 100 ppm iron) lost more body weight than those receiving double the amount of standard iron (i.e. 400 ppm); p<0.01. Faecal calprotectin levels were significantly increased in the presence of colitis in those consuming 100 ppm iron at day 8 (5.94-fold) versus day-10 group (4.14-fold) (p<0.05), and for the 400 ppm day-8 group (8.17-fold) versus day-10 group (4.44-fold) (p<0.001). In the presence of colitis, dietary iron at 400 ppm resulted in a significant reduction in faecal abundance of Firmicutes and Bacteroidetes, and increase of Proteobacteria, changes which were not observed with lower dietary intake of iron at 100 ppm. Overall, altering dietary iron intake exacerbated DSS-induced colitis; increasing the iron content of the diet also led to changes in intestinal bacteria diversity and composition after colitis was induced with DSS.
3D Images of Neuronal Adhesion Molecule Contactin-2 Reveal an Unanticipated Two-State Architecture
Authors: Lu Z. , Lei D. , Seshadrinathan S. , Szwed A. , Liu J. , Liu J. , Rudenko G. , Ren G. 
Published: August 2018

ABSTRACTContactins (CNTNs) are important cell adhesion molecules that mediate neuronal and axoglial contacts, and lesions in these molecules are linked to neuropsychiatric disorders. The extracellular domain of CNTNs contains six Ig domains and four FNIII domains. Crystal structures have shown that Ig1-Ig4 forms a horseshoe-shaped headpiece, in which the N-terminal domains might fold back on the C-terminal domains to form molecular super-U shaped architecture. The arrangement of these domains has been controversial, which may due to the structural dynamics and conformation heterogeneity of the protein. Here, we used a single-molecule 3D imaging method, individual-particle electron tomography (IPET), to study the extracellular domain of CNTN2 that forms monomers with a broad spectrum of conformations, and obtained 60 three-dimensional (3D) reconstructions. In addition to the known horseshoe-shaped headpiece, ~75% headpieces unexpectedly adopt an open (elongated) or a semi-open conformations contributed to our understanding about structural dynamics. The ectodomains formed curve but not double-back in any uniform way, with an averaged molecular dimension of ~255 Å. The first-time demonstration of the dynamic nature and conformational preferences of the full-length CNTN2 ectodomain suggest that the headpiece exists in equilibrium in the ‘closed’ or ‘not-closed’ states. The important architecture may provide a structural platform for protein partners to influence this balance regulating the function of CNTN2. Encoding the ability of this neural adhesion molecule to form both homomers with itself, as well as recruit different protein partner to neuronal and axoglial contact points play the key role in mediating cell-cell interactions.
Programmed mutation of liver fluke granulin using CRISPR/Cas9 attenuates virulence of infection-induced hepatobiliary morbidity
Authors: Arunsan Patpicha , Ittiprasert Wannaporn , Smout Michael J. , Cochran Christina J. , Mann Victoria H. , Chaiyadet Sujittra , Karinshak Shannon E. , Sripa Banchob , Young Neil D. , Sotillo Javier , Loukas Alex , Brindley Paul J. , Laha Thewarach 
Published: August 2018

AbstractInfections with several flatworm parasites represent group 1 biological carcinogens, i.e. definite causes of cancer. Infection with the food-borne liver fluke Opisthorchis viverrini causes cholangiocarcinoma (CCA). Whereas the causative agent for most cancers, including CCA in the West, remains obscure, the principal risk factor for CCA in Thailand is opisthorchiasis. We exploited this established link to explore the role of the secreted parasite growth factor termed liver fluke granulin (Ov-GRN-1) in pre-malignant lesions of the biliary tract. We targeted the Ov-grn-1 gene for programmed knockout and investigated gene-edited parasites in vitro and in experimentally infected hamsters. Both adult and juvenile stages of the liver fluke were transfected with a plasmid encoding a guide RNA sequence specific for exon 1 of Ov-grn-1 and the Cas9 nuclease. Deep sequencing of amplicon libraries from genomic DNA from gene-edited parasites exhibited programmed, Cas9-catalyzed mutations within the Ov-grn-1 locus, and tandem analyses by RT-PCR and western blot revealed rapid depletion of Ov-grn-1 transcripts and protein. Newly excysted juvenile flukes that had undergone editing of Ov-grn-1 colonized the biliary tract, grew and developed over a period of 60 days, were active and motile, and induced a clinically relevant pathophysiological tissue phenotype of attenuated biliary hyperplasia and fibrosis in comparison to infection with wild type flukes. This is the first report of gene knock-out using CRISPR/Cas9 in a parasitic flatworm, demonstrating the activity and utility of the process for functional genomics in these pathogens. The striking clinical phenotype highlights the role in virulence that liver fluke growth factors play in biliary tract morbidity during chronic opisthorchiasis.