bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity of Sulfa Drugs and Their Combinations against Stationary PhaseB. burgdorferiin vitro
Authors: Feng Jie , Zhang Shuo , Shi Wanliang , Zhang Ying 
Published: March 2017

AbstractLyme disease is a most common vector borne disease in the US. Although the majority of Lyme patients can be cured with the standard 2-4 week antibiotic treatment, at least 10-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, one possibility is that persisting organisms are not killed by current Lyme antibiotics. In our previous studies, we screened an FDA drug library and an NCI compound library onB. burgdorferiand found some drug hits including sulfa drugs as having good activity againstB. burgdorferistationary phase cells. In this study, we evaluated the relative activity of three commonly used sulfa drugs sulfamethoxazole (Smx), dapsone (Dps), sulfachlorpyridazine (Scp), and also trimethoprim (Tmp), and assessed their combinations with the commonly prescribed Lyme antibiotics for activities againstB. burgdorferistationary phase cells. Using the same molarity concentration, dapsone, sulfachlorpyridazine and trimethoprim showed very similar activity against stationary phaseB. burgdorferienriched in persisters, however, sulfamethoxazole was the least active drug among the three sulfa drugs tested. Interestingly, contrary to other bacterial systems, Tmp did not show synergy in drug combinations with the three sulfa drugs at their clinically relevant serum concentrations againstB. burgdorferi. We found that sulfa drugs combined with other antibiotics were more active than their respective single drugs and that four-drug combinations were more active than three-drug combinations. Four drug combinations dapsone+minocycline+cefuroxime+azithromycin and dapsone+minocycline+cefuroxime+rifampin showed best activity against stationary phaseB. burgdorferiin these sulfa drug combinations. However, these 4-sulfa drug containing combinations still had considerably less activity againstB. burgdorferistationary phase cells than the daptomycin+cefuroxime+doxycycline used as a positive control which completely eradicatedB. burgdorferistationary phase cells. Future studies are needed to evaluate and optimize the sulfa drug combinationsin vitroand also in animal models.
Socio-environmental and measurement factors drive spatial variation in influenza-like illness
Authors: Lee Elizabeth C. , Arab Ali , Goldlust Sandra , Viboud Cécile , Bansal Shweta 
Published: March 2017

AbstractThe mechanisms hypothesized to drive spatial heterogeneity in reported influenza activity include: environmental factors, contact patterns, population age structure, and socioeconomic factors linked to healthcare access and quality of life. Harnessing the large volume and high specificity of diagnosis codes in medical claims data for influenza seasons from 2002-2009, we estimate the importance of socio-environmental determinants and measurement-related factors on observed variation in influenza-like illness (ILI) across United States counties. We found that South Atlantic states tended to have higher ILI seasonal intensity, and a combination of transmission, environmental, influenza subtype, socioeconomic and measurement factors explained the variation in seasonal intensity across our study period. Moreover, our models suggest that sentinel surveillance systems should have fixed report locations across years for the most robust inference and prediction, and high volumes of data can offset measurement biases in opportunistic data samples.
Assessing the distribution and determinants of vaccine underutilization in the United States
Authors: Goldlust Sandra , Lee Elizabeth C. , Haran Murali , Rohani Pejman , Bansal Shweta 
Published: March 2017

AbstractDespite advances in sanitation and immunization, vaccine-preventable diseases remain a significant cause of morbidity and mortality worldwide. In high-income countries such as the United States, coverage rates for vaccination against childhood infections remains high. However, the phenomenon of vaccine hesitancy makes maintenance of herd immunity difficult, impeding global disease eradication efforts. Reaching the ‘last mile’ will require early detection of vaccine hesitancy (driven by philosophical or religious choices), identifying pockets of susceptibility due to underimmunization (driven by vaccine unavailability, costs ineligibility), determining the factors associated with the behavior and developing targeted strategies to ameliorate the concerns. Towards this goal, we harness high-resolution medical claims data to geographically localize vaccine refusal and underimmunization (collectively, ‘underutilization’) in the United States and identify the socio-economic determinants of the behaviors. Our study represents the first large-scale effort for vaccination behavior surveillance and has the potential to aid in the development of targeted public health strategies for optimizing vaccine uptake.
Genetic characterization of the Zika virus epidemic in the US Virgin Islands
Authors: Black Allison , Potter Barney , Dudas Gytis , Feldstein Leora , Grubaugh Nathan D , Andersen Kristian G , Ellis Brett R , Ellis Esther M , Bedford Trevor 
Published: March 2017

AbstractHere we release draft genome sequences of Zika virus (ZIKV) that were sequenced from PCR-positive diagnostic specimens collected by the United States Virgin Islands Department of Health (USVI DoH) as part of their ongoing response to the ZIKV outbreak. We will use these sequences to conduct a genomic epidemiological study of ZIKV transmission in the USVI. We are releasing these genomes in the hope that they are useful for those individuals involved in the public health response to ZIKV and to other groups working to understand Zika virus transmission and evolution.
DHX15 regulates CMTR1-dependent gene expression and cell proliferation
Authors: Inesta-Vaquera Francisco , Galloway Alison , Chandler Laurel , Rojas-Fernandez Alejandro , Chaugule Viduth K. , Weidlich Simone , Peggie Mark , Cowling Victoria H 
Published: March 2017

AbstractCMTR1 contributes to mRNA cap formation by methylating the O-2 position of the 1sttranscribed nucleotide ribose. mRNA cap O-2 methylation has roles in mRNA translation and self-RNA tolerance in innate immunity, however its role in cell physiology is unclear. We report that CMTR1 is recruited to Serine-5 phosphorylated RNA Pol II CTD, facilitating cotranscriptional methylation. We isolated CMTR1 in a complex with DHX15, an RNA helicase functioning in splicing and ribosome biogenesis, and characterised it as a regulator of CMTR1. When bound to DHX15, CMTR1 activity is repressed and prevented from binding to RNA pol II, thus constraining 1stnucleotide methylation to a co-transcriptional event. Conversely CMTR1 activates DHX15 helicase activity and influences its nuclear localisation, which is likely to impact on several nuclear functions. The impact of the CMTR1-DHX15 interaction is complex and will depend on the relative expression of these enzymes and their interactors, and the cellular dependency on different RNA processing pathways. In HCC1806 cells, the DHX15-CMTR1 interaction controls ribosome loading of a subset of mRNAs and impacts on cell proliferation.
Non-linear disease tolerance curves reveal distinct components of host responses to viral infection
Authors: Gupta Vanika , Vale Pedro F. 
Published: March 2017

AbstractThe ability to tolerate infection is a key component of host defence and offers potential novel therapeutic approaches for infectious diseases. To yield successful targets for therapeutic intervention, it is important that the analytical tools employed to measure disease tolerance are able to capture distinct host responses to infection. Here, we show that commonly used methods that estimate tolerance as a linear relationship may be inadequate, and that more flexible, non-linear estimates of this relationship may reveal variation in distinct components of host defence. To illustrate this, we measured the survival ofDrosophila melanogastercarrying either a functional or non-functional regulator of the JAK-STAT immune pathway (G9a) when challenged with a range of concentrations of Drosophila C Virus (DCV). While classical linear model analyses indicated thatG9aaffected tolerance only in females, a more powerful non-linear logistic model showed thatG9amediates viral tolerance to different extents in both sexes. This analysis also revealed thatG9aacts by changing the sensitivity to increasing pathogen burdens, but does not reduce the ultimate severity of infection. These results indicate that fitting non-linear models to host health-pathogen burden relationships may offer better and more detailed estimates of disease tolerance.
Despite reproductive interference, the net outcome of reproductive interactions among spider mite species is not necessarily costly
Authors: Clemente Salomé H. , Santos Inês , Ponce Rita , Rodrigues Leonor R. , Varela Susana A. M. , Magalhães Sara 
Published: March 2017

AbstractThis preprint has been reviewed and recommended by Peer Community in Evolutionary Biology (http://dx.doi.org/10.24072/pci.evolbiol.100025). Reproductive interference is considered a strong ecological force, potentially leading to species exclusion. This supposes that the net effect of reproductive interactions is strongly negative for one of the species involved. Testing this requires a comprehensive analysis of interspecific reproductive interactions, accounting for the order and timing of mating events, and for their effects on either fertility or fecundity. To this aim, we measured reproductive interactions between a focal species,Tetranychus urticae, and an invasive (T.evansi) and a resident (T. ludeni) species, varying the mating sequence and interval, and measuring the effect of such crosses on fecundity and offspring sex ratio (a measure of fertility, as these species are haplodiploid). We found that mating with heterospecifics affected fecundity and sex ratio negatively, but also positively, depending on the species involved, and on the order and timing of mating events. Overall, the net effect of reproductive interactions was weak despite strong effects of particular events. In natural situations, the outcome of reproductive interactions will thus hinge upon the frequency of each event.
Contractility, Differential Tension and Membrane Removal direct zebrafish Epiboly Biomechanics
Authors: Marsal Maria , Martin-Blanco Enrique 
Published: March 2017

ABSTRACTPrecise tissue remodeling during development is essential for shaping embryos and for optimal organ function. Epiboly is an early gastrulation event by which the blastoderm expands around the yolk to engulf it. Three different layers are involved, an epithelial layer (the enveloping layer, EVL), the embryo proper, constituted by the deep cells (DCs), and the yolk cell. Although teleost epiboly has been studied for many years, a clear understanding of its mechanics was still missing. Here we present new information on the cellular, molecular and mechanical elements involved in epiboly that, together with some other recent data and upon comparison with previous biomechanical models, lets conclude that the expansion of the epithelia is passive and driven by cortical contraction and membrane removal in the adjacent layer, the External Yolk Syncytial Layer (E-YSL). The isotropic actomyosin contraction of the E-YSL generates an anisotropic stress pattern and a directional net movement as a result of the differences in the deformation response of two opposites adjacent domains (the EVL and the Yolk Cytoplasmic Layer - YCL). Contractility is accompanied by the local formation of membrane folds and the membrane removal by Rab5ab dependent macropinocytosis. The increase in area of the epithelia during the expansion is achieved by cell-shape changes (flattening) responding to spherical geometrical cues. The counterbalance between the geometry of the embryo and forces dissipation is therefore essential for epiboly global coordination.
A climosequence of chronosequences in southwestern Australia
Authors: Turner Benjamin L. , Hayes Patrick E. , Laliberté Etienne 
Published: March 2017

AbstractTo examine how climate affects soil development and nutrient availability over long timescales, we studied a series of four long-term chronosequences along a climate gradient in southwestern Australia. Annual rainfall ranged from 533 mm to 1185 mm (water balance from –900 mm to +52 mm) and each chronosequence included Holocene (≤6.5 ka), Middle Pleistocene (120–500 ka), and Early Pleistocene (∼2000 ka) dunes. Vegetation changed markedly along the climosequence, from shrubland at the driest site toEucalyptusforest at the wettest. The carbonate and P content of the parent sand declined along the climosequence, presumably linked to variation in offshore productivity. However, soil development and associated nutrient status followed remarkably consistent patterns along the four chronosequences. Pedogenesis involved decalcification and secondary carbonate precipitation in Holocene soils and leaching of iron oxides from Middle Pleistocene soils, ultimately yielding bleached quartz sands on the oldest soils. Along all chronosequences soil pH and total P declined, while C:P and N:P ratios increased, consistent with the predicted shift from N to P limitation of vegetation during ecosystem development. The expected unimodal pattern of leaf area index was most pronounced along wetter chronosequences, suggesting an influence of climate on the expression of retrogression. The four chronosequences do not appear to span a pedogenic climate threshold, because exchangeable phosphate and base cations declined consistently during long-term pedogenesis. However, the proportion of the total P in organic form was greater along wetter chronosequences. We conclude that soils and nutrient availability on the coastal sand plains of southwestern Australia change consistently during long-term pedogenesis, despite marked variation in modern vegetation and climate. The four chronosequences provide a rare soil-age × climate framework within which to study long-term ecosystem development.
Targeted genomic screen reveals focal long non-coding RNA copy number alterations in cancer
Authors: Volders Pieter-Jan , Vandesompele Jo , Lefever Steve , Baute Shalina , Nuytens Justine , Vanderheyden Katrien , Menten Björn , Mestdagh Pieter 
Published: March 2017

AbstractThe landscape of somatic copy-number alterations (SCNAs) affecting long non-coding RNAs (lncRNAs) in human cancer remains largely unexplored. While the majority of lncRNAs remains to be functionally characterized, several have been implicated in cancer development and metastasis. Considering the plethora of lncRNAs genes that is currently reported, it is conceivable that several lncRNAs might function as oncogenes or tumor suppressor genes.We devised a strategy to detect focal lncRNA SCNAs using a custom DNA microarray platform probing 20 418 lncRNA genes. By screening a panel of 80 cancer cell lines, we detected numerous focal aberrations targeting one or multiple lncRNAs without affecting neighboring protein-coding genes. These focal aberrations are highly suggestive for a tumor suppressive or oncogenic role of the targeted lncRNA gene. Although functional validation remains an essential step in the further characterization of the involved candidate cancer lncRNAs, our results provide a direct way of prioritizing candidate lncRNAs involved in cancer pathogenesis.
Negative frequency-dependent selection is frequently confounding
Authors: Brisson Dustin 
Published: March 2017

AbstractThis preprint has been reviewed and recommended by Peer Community in Evolutionary Biology (http://dx.doi.org/10.24072/pci.evolbiol.100024).The existence of persistent genetic variation within natural populations presents an evolutionary problem as natural selection and genetic drift tend to erode genetic diversity. Models of balancing selection were developed to account for the high and sometimes extreme levels of polymorphism found in many natural populations. Negative frequency-dependent selection may be the most powerful selective force maintaining balanced natural polymorphisms but it is also commonly misinterpreted. The aim of this review is to clarify the processes underlying negative frequency-dependent selection, describe classes of natural polymorphisms that can and cannot result from these processes, and discuss observational and experimental data that can aid in accurately identifying the processes that generated or are maintain diversity in nature. Finally, I consider the importance of accurately describing the processes affecting genetic diversity within populations as it relates to research progress.
An indicator cell assay for blood-based diagnostics
Authors: Danziger Samuel A. , Miller Leslie R. , Singh Karanbir , Whitney G. Adam , Peskind Elaine R. , Li Ge , Lipshutz Robert J. , Aitchison John D. , Smith Jennifer J. 
Published: March 2017

AbstractWe have established proof of principle for the Indicator Cell Assay Platform™ (iCAP™), a broadly applicable tool for blood-based diagnostics that uses specifically-selected, standardized cells as biosensors, relying on their innate ability to integrate and respond to diverse signals present in patients’ blood. To develop an assay, indicator cells are exposedin vitroto serum from case or control subjects and their global differential response patterns are used to train reliable, cost-effective disease classifiers based on a small number of features. In a feasibility study, the iCAP detected pre-symptomatic disease in a murine model of amyotrophic lateral sclerosis (ALS) with 94% accuracy (p-Value=3.81E-6) and correctly identified samples from a murine Huntington’s disease model as non-carriers of ALS. In a preliminary human disease assay, the iCAP detected early stage Alzheimer’s disease with 72% cross-validated accuracy (p-Value=3.10E-3). For both assays, iCAP features were enriched for disease-related genes, supporting the assay’s relevance for disease research.
The exported chaperone PfHsp70x is dispensable for thePlasmodium falciparumintraerythrocytic lifecycle
Authors: Cobb David W. , Florentin Anat , Fierro Manuel A. , Krakowiak Michelle , Moore Julie M. , Muralidharan Vasant 
Published: March 2017

AbstractExport of parasite proteins into the host erythrocyte is essential for survival ofPlasmodium falciparumduring its asexual lifecycle. While several studies described key factors within the parasite that are involved in protein export, the mechanisms employed to traffic exported proteins within the host cell are currently unknown. Members of the Hsp70 family of chaperones, together with their Hsp40 co-chaperones, facilitate protein trafficking in other organisms, and are thus likely used byP. falciparumin the trafficking of its exported proteins. A large group of Hsp40 proteins is encoded by the parasite and exported to the host cell, but only one Hsp70, PfHsp70x, is exported with them.PfHsp70x is absent from mostPlasmodiumspecies and is found only inP. falciparumand closely-related species that infect Apes. Herein, we have utilized CRISPR/Cas9 genome editing inP. falciparumto investigate the essentiality of PfHsp70x. We show that parasitic growth was unaffected by knockdown of PfHsp70x using both the DHFR-based Destabilization Domain and theglmSribozyme system. Similarly, a complete gene knockout of PfHsp70x did not affect the ability ofP. falciparumto proceed through its intraerythrocytic lifecycle. The effect of PfHsp70x knockdown/knockout on the export of proteins to the host RBC, including the critical virulence factor PfEMP1, was tested and we found that this process was unaffected. These data show that although PfHsp70x is the sole exported Hsp70, it is not essential for the asexual development ofP. falciparum.ImportanceHalf of the world’s population lives at risk for malaria. The intraerythrocytic lifecycle ofPlasmodiumspp. is responsible for clinical manifestations of malaria; therefore, knowledge of the parasite’s ability to survive within the erythrocyte is needed to combat the deadliest agent of malaria,P. falciparum. An outstanding question in the field is howP. falciparumundertakes the essential process of trafficking its proteins within the host cell. In most organisms, chaperones such as Hsp70 are employed in protein trafficking. Of the human-disease causing Plasmodium species, the chaperone PfHsp70x is unique toP. falciparum,and it is the only parasite protein of its kind exported to the host (1). This has placed PfHsp70x as an ideal target to inhibit protein trafficking and kill the parasite. However, we show that PfHsp70x is not required for export of parasite effectors nor is it essential for parasite survival inside of the RBC.
Individual differences in frequency and topography of slow and fast sleep spindles
Authors: Cox Roy , Schapiro Anna C. , Manoach Dara S. , Stickgold Robert 
Published: March 2017

AbstractSleep spindles are transient oscillatory waveforms occurring during non-rapid eye movement (NREM) sleep and are implicated in plasticity and memory processes. In humans, spindles can be classified as either slow or fast, but large individual differences in spindle frequency as well as methodological difficulties have hindered progress towards understanding their function. Using two nights of high-density electroencephalography recordings from healthy individuals, we first characterize the individual variability of NREM spectra and demonstrate the difficulty of determining subject-specific spindle frequencies. We then introduce a novel spatial filtering approach that can reliably separate subject-specific spindle activity into slow and fast components that are stable across nights and across N2 and N3 sleep. We then proceed to provide detailed analyses of the topographical expression of individualized slow and fast spindle activity. Group-level analyses conform to known spatial properties of spindles, but also uncover novel differences between sleep stages and spindle classes. Moreover, subject-specific examinations reveal that individual topographies show considerable variability that is stable across nights. Finally, we demonstrate that topographical maps depend nontrivially on the spindle metric employed. In sum, our findings indicate that group-level approaches mask substantial individual variability of spindle dynamics, in both the spectral and spatial domains. We suggest that leveraging, rather than ignoring, such differences may prove useful to further our understanding of the physiology and functional role of sleep spindles.
Image processing techniques for high-resolution structure determination from badly ordered 2D crystals
Authors: Biyani Nikhil , Scherer Sebastian , Righetto Ricardo D. , Kowal Julia , Chami Mohamed , Stahlberg Henning 
Published: March 2017

Abstract2D electron crystallography can be used to study small membrane proteins in their native environment. Obtaining highly ordered 2D crystals is difficult and time-consuming. However, 2D crystals diffracting to only 10-12 Å can be prepared relatively conveniently in most cases. We have developed image-processing algorithms allowing to generate a high resolution 3D structure from cryo-electron crystallography images of badly ordered crystals. These includemovie-mode unbending, refinement over sub-tiles of the images in order to locally refine the sample tilt geometry; implementation of different CTF correction schemes; and an iterative method to apply known constraints in the real and reciprocal space to approximate amplitudes and phases in the so-called missing cone regions. These algorithms applied to a dataset of the potassium channel MloK1 show significant resolution improvements to approximately 5Å.Abbreviations2Dtwo dimensions / dimensional3Dthree dimensions / dimensionalAmpamplitudecAMPcyclic adenosine monophosphateCCDcharge coupled devicesCMOScomplementary metal-oxide-semiconductorCNBDcyclic nucleotide-binding domaincryo-EMcryo-electron microscopyCTFcontrast transfer functionDEDdirect electron detectorDQEdetector quantum efficiencyEMelectron microscopeFOMfigure-of-meritPhaphaseSNRsignal-to-noise ratio