bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transmission dynamics and between-species interactions of multidrug-resistant Enterobacteriaceae
Authors: Crellen Thomas , Turner Paul , Pol Sreymom , Baker Stephen , Nguyen To Nguyen Thi , Stoesser Nicole , Day Nicholas P.J. , Cooper Ben S. 
Published: October 2018

AbstractWidespread resistance to antibiotics is among the gravest threats to modern medicine, and controlling the spread of multi-drug resistant Enterobacteriaceae has been given priority status by the World Health Organization. Interventions to reduce transmission within hospital wards may be informed by modifiable patient-level risk factors for becoming colonised, however understanding of factors that influence a patient’s risk of acquisition is limited. We analyse data from a one year prospective carriage study in a neonatal intensive care unit in Cambodia using Bayesian hierarchical models to estimate the daily probability of acquiring multi-drug resistant organisms, while accounting for patient-level time-varying covariates, including interactions between species, and interval-censoring of transmission events. We estimate the baseline daily probability for becoming colonised with third generation cephalosporin resistant (3GC-R) Klebsiella pneumoniae as 0.142 (95% credible interval [CrI] 0.066, 0.27), nearly ten times higher than the daily probability of acquiring 3GC-R Escherichia coli (0.016 [95% CrI 0.0038, 0.049]). Prior colonization with 3GC-R K. pneumoniae was associated with a greatly increased risk of a patient acquiring 3GC-R E. coli (odds ratio [OR] 6.4 [95% CrI 2.8, 20.9]). Breast feeding was associated with a reduced risk of colonization with both 3GC-R K. pneumoniae (OR 0.73 [95% CrI 0.38, 1.5]) and E. coli (OR 0.62 [95% CrI 0.28, 1.6]). The use of an oral probiotic (Lactobacillus acidophilus) did not show clear evidence of protection against colonization with either 3GC-R K. pneumoniae (OR 0.83 [95% CrI 0.51, 1.3]) or 3GC-R E. coli (OR 1.3 [95% CrI 0.77, 2.1]). Antibiotic consumption within the past 48 hours did not strongly influence the risk of acquiring 3GC-R K. pneumoniae. For 3GC-R E. coli, ceftriaxone showed the strongest effect for increasing the risk of acquisition (OR 2.2 [95% CrI 0.66, 6.2]) and imipenem was associated with a decreased risk (OR 0.31 [95% CrI 0.099, 0.76). Using 317 whole-genome assemblies of K. pneumoniae, we determined putatively related clusters and used a range of models to infer transmission rates. Model comparison strongly favored models with a time-varying force of infection term that increased in proportion with the number of colonized patients, providing evidence of patient-to-patient transmission, including among a cluster of Klebsiella quasipneumoniae. Our findings provide support for the hypothesis that K. pneumoniae can be spread person-to-person within ward settings. Subsequent horizontal gene transfer within patients from K. pneumoniae provides the most parsimonious explanation for the strong association between colonization with 3GC-R K. pneumoniae and acquisition of 3GC-R E. coli.
First detection of a highly invasive freshwater amphipod (Crangonyx floridanus) in the United Kingdom
Authors: Mauvisseau Quentin , Davy-Bowker John , Bryson David , Souch Graham R. , Burian Alfred , Sweet Michael 
Published: October 2018

AbstractThe freshwater gammarid, Crangonyx floridanus, originates from North America but has invaded and subsequently spread rapidly throughout Japan. We provide here the first genetic and microscopic evidence that C. floridanus has now also reached the United Kingdom. We found this species in two locations separated by more than 200 km (Lake Windermere in the North of the UK and Smestow Brook, West Midlands). The current distribution of C. floridanus is currently unknown, however both sites are well connected to other river and channel systems therefore the chance of further spread is high. Genetic analyses of C. floridanus indicate that British inland waters are colonised by the same linage, which also has invaded Japan. We recommend further work to assess the distribution of this species and its impact on the local fauna and flora.
Cytoscape stringApp: Network analysis and visualization of proteomics data
Authors: Doncheva Nadezhda T. , Morris John H. , Gorodkin Jan , Jensen Lars J. 
Published: October 2018

AbstractProtein networks have become a popular tool for analyzing and visualizing the often long lists of proteins or genes obtained from proteomics and other high-throughput technologies. One of the most popular sources of such networks is the STRING database, which provides protein networks for more than 2000 organisms, including both physical interactions from experimental data and functional associations from curated pathways, automatic text mining, and prediction methods. However, its web interface is mainly intended for inspection of small networks and their underlying evidence. The Cytoscape software, on the other hand, is much better suited for working with large networks and offers greater flexibility in terms of network analysis, import and visualization of additional data. To include both resources in the same workflow, we created stringApp, a Cytoscape app that makes it easy to import STRING networks into Cytoscape, retains the appearance and many of the features of STRING, and integrates data from associated databases. Here, we introduce many of the stringApp features and show how they can be used to carry out complex network analysis and visualization tasks on a typical proteomics dataset, all through the Cytoscape user interface. stringApp is freely available from the Cytoscape app store:http://apps.cytoscape.org/apps/stringapp.
Population-scale proteome variation in human induced pluripotent stem cells
Authors: Mirauta Bogdan A , Seaton Daniel D , Bensaddek Dalila , Brenes Alejandro , Bonder Marc J , Kilpinen Helena ,   HipSci Consortium, Stegle Oliver , Lamond Angus I 
Published: October 2018

AbstractRealising the potential of human induced pluripotent stem cell (iPSC) technology for drug discovery, disease modelling and cell therapy requires an understanding of variability across iPSC lines. While previous studies have characterized iPS cell lines genetically and transcriptionally, little is known about the variability of the iPSC proteome. Here, we present the first comprehensive proteomic iPSC dataset, analysing 202 iPSC lines derived from 151 donors. We characterise the major genetic determinants affecting proteome and transcriptome variation across iPSC lines and identify key regulatory mechanisms affecting variation in protein abundance. Our data identified >700 human iPSC protein quantitative trait loci (pQTLs). We mapped trans regulatory effects, identifying an important role for protein-protein interactions. We discovered that pQTLs show increased enrichment in disease-linked GWAS variants, compared with RNA-based eQTLs.
AMON: Annotation of metabolite origins via networks to better integrate microbiome and metabolome data
Authors: Shaffer M. , Quinn K. , Doenges K. , Zhang X. , Bokatzian S. , Reisdorph N. , Lozupone CA. 
Published: October 2018

ABSTRACTMotivationUntargeted metabolomics of host-associated samples has yielded insights into mechanisms by which microbes modulate health. However, data interpretation is challenged by the complexity of origins of the small molecules measured, which can come from the host, microbes that live with the host, or from other exposures such as diet or the environment.ResultsWe address this challenge through development of AMON: Annotation of Metabolite Origins via Networks. AMON is an open-source bioinformatics application that can be used to determine the degree to which annotated compounds in the metabolome may have been produced by bacteria present, the host, either (i.e. both the bacteria and host are capable of production), or neither (i.e. neither the human or the fecal microbiome are predicted to be capable of producing the observed metabolite).Availability and ImplementationThis software is available at https://github.com/lozuponelab/AMON as well as via pip.Contactcatherine.lozupone@ucdenver.edu
Vitamin D3 regulates estrogen’s action and affects mammary epithelial organization in 3D cultures
Authors: Hasan Nafis , Sonnenschein Carlos , Soto Ana M. 
Published: October 2018

AbstractVitamin D3 (vitD3) and its active metabolite, calcitriol (1,25-(OH)2D3), affect multiple tissue types by interacting with the vitamin D receptor (VDR). Although vitD3 deficiency has been correlated with increased incidence of breast cancer and less favorable outcomes across ethnic groups and latitudes, randomized human clinical trials have yet to provide conclusive evidence on the efficacy of vitD3 in treating and/or preventing breast cancer. When considering that carcinogenesis is “development gone awry”, it becomes imperative to understand the role of vitD3 during breast development. Mammary gland development in VDR KO mice is altered by increased ductal elongation and lateral branching during puberty, precocious and increased alveologenesis at pregnancy and delayed post-lactational involution. These developmental processes are largely influenced by mammotropic hormones, i.e., ductal elongation by estrogen, branching by progesterone and alveologenesis by prolactin. However, research on vitD3’s effects on mammary gland morphogenesis focused on cell proliferation and apoptosis in 2D culture models and utilized supra-physiological doses of vitD3, conditions that spare the microenvironment in which morphogenesis takes place. Here, using two 3D culture models, we investigated the role of vitD3 in mammary epithelial morphogenesis. We found that vitD3 interferes with estrogen’s actions on T47D human breast cancer cells in 3D differently at different doses, and recapitulates what is observedin vivo. Also, vitD3 can act autonomously and affect the organization of MCF10A cells in 3D collagen matrix by influencing collagen fiber organization. Thus, we uncovered how vitD3 modulates mammary tissue organization independent of its already known effects on cell proliferation.
NetGO: Improving Large-scale Protein Function Prediction with Massive Network Information
Authors: You Ronghui , Yao Shuwei , Huang Xiaodi , Sun Fengzhu , Mamitsuka Hiroshi , Zhu Shanfeng 
Published: October 2018

AbstractAutomated function prediction (AFP) of proteins is of great significance in biology. In essence, AFP is a large-scale multi-label classification over pairs of proteins and GO terms. Existing AFP approaches, however, have their limitations on both sides of proteins and GO terms. Using various sequence information and the robust learning to rank (LTR) framework, we have developed GOLabeler, a state-of-the-art approach of CAFA3, which overcomes the limitation of the GO term side, such as imbalanced GO terms. Unfortunately, for the protein side issue, available abundant protein information, except for sequences, have not been effectively used for large-scale AFP in CAFA. We propose NetGO that is able to improve large-scale AFP with massive network information. The novelties of NetGO have threefold in using network information: 1) the powerful LTR framework of NetGO efficiently and effectively integrates both sequence and network information, which can easily make large-scale AFP; 2) NetGO can use whole and massive network information of all species (>2000) in STRING (other than only high confidence links and/or some specific species); and 3) NetGO can still use network information to annotate a protein by homology transfer even if it is not covered in STRING. Under numerous experimental settings, we examined the performance of NetGO, such as general performance comparison, species-specific prediction, and prediction on difficult proteins, by using training and test data separated by time-delayed settings of CAFA. Experimental results have clearly demonstrated that NetGO outperforms GOLabeler, DeepGO, and other compared baseline methods significantly. In addition, several interesting findings from our experiments on NetGO would be useful for future AFP research.
In vivo phosphoproteomics reveals pathogenic signaling changes in diabetic islets
Authors: Sacco Francesca , Seelig Anett , Humphrey Sean J. , Krahmer Natalie , Volta Francesco , Reggio Alessio , Gerdes Jantje , Mann Matthias 
Published: October 2018

SUMMARYProgressive decline of pancreatic beta cells function is key to the pathogenesis of type 2 diabetes. Protein phosphorylation is the central mechanism controlling glucose-stimulated insulin secretion in beta cells. However, if and how signaling networks are remodeled in diabetic isletsin vivoremain unknowns. Here we applied high-sensitivity mass spectrometry-based proteomics and quantified the levels of about 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls. This highlighted drastic remodeling of key kinase hubs and signaling pathways. We integrated our phosphoproteomic dataset with a literature-derived signaling network, which revealed a crucial and conserved role of GSK3 kinase in the control of the beta cells-specific transcription factor PDX1 and insulin secretion, which we functionally verified. Our resource will enable the community to investigate potential mechanisms and drug targets in type 2 diabetes.
Phylogenetically based establishment of a dengue virus panel, representing all available genotypes, as a tool in dengue drug discovery
Authors: Touret Franck , Baronti Cécile , Goethals Olivia , Van Loock Marnix , de Lamballerie Xavier , Querat Gilles 
Published: October 2018

AbstractDengue fever is the most widespread of the human arbovirus diseases, with approximately one third of the world’s population at risk of infection. Dengue viruses are members of the genus Flavivirus (family Flaviviridae) and, antigenically, they separate as four closely related serotypes (1-4) that share 60 to 75 % amino acid homology. This genetic diversity complicates the process of antiviral drug discovery. Thus, currently no approved dengue-specific therapeutic treatments are available. With the aim of providing an efficient tool for dengue virus drug discovery, a collection of nineteen dengue viruses, representing the genotypic diversity within the four serotypes, was developed. After phylogenetic analysis of the full-length genomes, we selected relevant strains from the EVAg collection at Aix-Marseille University and completed the virus collection, using a reverse genetic system based on the infectious sub-genomic amplicons technique. Finally, we evaluated this dengue virus collection against three published dengue inhibitory compounds. NITD008, which targets the highly conserved active site of the viral NS5 polymerase enzyme, exhibited similar antiviral potencies against each of the different dengue genotypes in the panel. Compounds targeting less conserved protein subdomains, such as the capsid inhibitor ST-148, or SDM25N, a ∂ opioid receptor antagonist which indirectly targets NS4B, exhibited larger differences in potency against the various genotypes of dengue viruses. These results illustrate the importance of a phylogenetically based dengue virus reference panel for dengue antiviral research. The collection developed in this study, which includes such representative dengue viruses, has been made available to the scientific community through the European Virus Archive to evaluate novel DENV antiviral candidates.
Expanding the bioluminescence reporter toolkit for plant chronobiology with NanoLUC
Authors: Urquiza-García Uriel , Millar Andrew J. 
Published: October 2018

AbstractBioluminescence has been an important tool for gathering circadian data with the main reporter gene exploited firefly luciferase (LUC). In some circumstances the rapid inactivation of LUC could be disadvantageous, e.g. reporting total protein levels through reporter translational fusions. In the latter scenario the commercially available Nano luciferase (NanoLUC) might offer and advantage, however no data in plant has been provided so far. We tested NanoLUC under different research scenarios were LUC has been used, for example enzyme purification, expression in transient plant systems and in stable transgenic lines. We show that NanoLUC is active in these experimental scenarios. We also created a set of NanoLUC variants for example MBP-NanoLUC-3xFlag-10xHis version of NanoLUC can be easily purified and stable for several days (half-life 37.2 at 4°C) and can be used for generating calibration curves for quantifying protein as the signal is linear over a large dynamic range. In addition, we show that NanoLUC can report in-planta protein levels on circadian time scale thanks to the stability of furimazine. Therefore, opening the possibility of using NanoLUC for reporting protein dynamics in seedlings. With this new technology, we explored the dynamics of protein BROTHER OF LUX ARRHYTHMO (BOA), which has been suggested in mathematical models to be a rhythmic protein from RNA data. Using an automatic plate-reader, we were able to track BOAp:BOA-NL for an extended period of time by just adding a mix of furimazine with Triton X-100, as it is done with LUC-reporter lines. In our experimental context BOA protein does not present strong oscillatory dynamics similar to what has been reported for Phytocrhome B for which rhythmic accumulation of transcript can be observed while total protein levels remain constant under diurnal conditions. Our results support the use NanoLUC for studying the dynamics of plant proteins for extended period of time under different circumstances.
Anticipatory neural activity improves the decoding accuracy for dynamic head-direction signals
Authors: Zirkelbach Johannes , Stemmler Martin , Herz Andreas V.M. 
Published: October 2018

AbstractInsects and vertebrates harbor specific neurons that encode the animal’s head direction (HD) and provide an internal compass for spatial navigation. Each HD cell fires most strongly in one preferred direction. As the animal turns its head, however, HD cells in rat anterodorsal thalamic nucleus (ADN) and other brain areas fire already before their preferred direction is reached, as if the neurons anticipated the future head direction. This phenomenon has been explained at a mechanistic level but a functional interpretation is still missing. To close this gap, we use a computational approach based on the animal’s movement statistics and a simple model for the behavior of the ADN head-direction network. Network activity is read out using population vectors in a biologically plausible manner, so that only past spikes are taken into account. We find that anticipatory firing improves the representation of the present HD by reducing the motion-induced temporal bias inherent in causal decoding. The amount of anticipation observed in ADN enhances the precision of the HD compass read-out by up to 40%. In addition, our framework predicts that neural integration times not only reflect biophysical constraints, but also the statistics of natural stimuli; anticipatory tuning should be found whenever neurons encode sensory signals that change gradually in time.Significance statementAcross different brain regions, populations of noisy neurons encode dynamically changing stimuli. Decoding a time-varying stimulus from the population response involves a trade-off: For short read-out times, stimulus estimates are unreliable as the number of stochastic spikes will be small; for long read-out times, estimates are biased because they lag behind the true stimulus. We show that optimal decoding relies not only on finding the right read-out time window, but requires neurons to anticipate future stimulus values. We apply this framework to the rodent head-direction system and show that the experimentally observed anticipation of future head directions can be explained at a quantitative level from the neuronal tuning properties, the network size, and the animal’s head-movement statistics.
Single step, high efficiency CRISPR-Cas9 genome editing in primary human disease-derived fibroblasts
Authors: Martufi Matteo , Good Robert B. , Rapiteanu Radu , Schmidt Tobias , Patili Eleni , Tvermosegaard Ketil , Nanthakumar Carmel B. , Betts Joanna , Blanchard Andy D. , Maratou Klio 
Published: October 2018

AbstractGenome editing is a tool that has many applications including the validation of potential drug targets. However, performing genome editing in low passage, primary human cells with the greatest physiological relevance, is notoriously difficult. High editing efficiency is desired because it enables gene knock outs (KO) to be generated in bulk cellular populations and circumvents the problem of having to generate clonal cell isolates. Here, we describe a single step workflow enabling >90% KO generation in primary human lung fibroblasts via CRISPR ribonucleoprotein delivery, in the absence of antibiotic selection or clonal expansion. As proof of concept, we performed a disease relevant phenotypic assay measuring collagen deposition in response to TGFβ and demonstrated SMAD3 but not SMAD2 dependent deposition of type I collagen following knockout of each using our single step methodology. The optimization of this workflow can readily be transferred to other primary cell types.
The River Runs Through It: the Athabasca River Delivers Mercury to Aquatic Birds Breeding Far Downstream
Authors: Hebert Craig E. 
Published: October 2018

AbstractThis study examined factors contributing to temporal variability (2009-2017) in total mercury (THg) concentrations in aquatic bird eggs collected in the Peace-Athabasca Delta and Lake Athabasca in northern Alberta. Factors examined included annual changes in oil sands production, bird diets, forest fires, and flow of the Athabasca River. Surface mining activities associated with Alberta’s Athabasca oil sands are centered north of Fort McMurray, Alberta, adjacent to the northward-flowing Athabasca River. Previous studies have found that oil sands industrial operations release mercury into the local (within ~50 km) environment. However, temporal trends in egg THg levels did not track trends in synthetic oil production from the oil sands. Intraspecific fluctuations in bird diet also could not explain annual variability in egg THg levels. Annual extent of forest fires in Alberta was only related to egg THg concentrations in California Gulls from Lake Athabasca; annual levels in other species showed no relationship with fire extent. The inclusion of more terrestrial foods in gull diets may have contributed to this difference. For the majority of species, annual fluctuations in maximal flow of the Athabasca River were important in influencing annual egg THg levels. Eggs collected following years of high flow had higher THg concentrations with distinct stable Hg isotope compositions. Riverine processes associated with suspended sediment were likely critical in regulating Hg availability to nesting birds. This study highlights the importance of the Athabasca River as a conduit for Hg transport to ecologically-sensitive downstream ecosystems such as the Peace-Athabasca Delta and Wood Buffalo National Park (a UNESCO World Heritage Site). Human activities that increase atmospheric Hg deposition to the Athabasca River watershed, or that enhance Hg releases to the river through erosion of Hg-bearing soils, will likely increase the availability of Hg to organisms inhabiting downstream areas.