bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunization by replication-competent controlled herpesvirus vectors
Authors: Bloom David C. , Tran Robert K. , Feller Joyce , Voellmy Richard 
Published: April 2018

ABSTRACTReplication-competent controlled virus vectors were derived from virulent HSV-1 wildtype strain 17syn+ by placing one or two replication-essential genes under the stringent control of a gene switch that is co-activated by heat and an antiprogestin. Upon activation of the gene switch, the vectors replicate in infected cells with an efficacy that approaches that of the wildtype virus from which they were derived. Essentially no replication occurs in the absence of activation. When administered to mice, localized application of a transient heat treatment in the presence of systemic antiprogestin results in efficient but limited virus replication at the site of administration. The immunogenicity of these viral vectors was tested in a mouse footpad lethal challenge model. Unactivated viral vectors - which may be regarded as equivalents of inactivated vaccines - induced detectable protection against lethality caused by wildtype virus challenge. Single activation of the viral vectors at the site of administration (rear footpads) greatly enhanced protective immune responses, and second immunization resulted in complete protection. Once activated vectors also induced far better neutralizing antibody and HSV-1-specific T cells responses than unactivated vectors. To find out whether the immunogenicity of a heterologous antigen was also enhanced in the context of efficient transient vector replication, a virus vector constitutively expressing an equine influenza virus hemagglutinin was constructed. Immunization of mice with this recombinant induced detectable antibody-mediated neutralization of equine influenza virus as well as a hemagglutinin-specific T cell response. Single activation of viral replication resulted in a several-fold enhancement of this immune response.IMPORTANCEWe hypothesized that vigorous replication of a pathogen may be critical for eliciting the most potent and balanced immune response against it. Hence, attenuation/inactivation (as in conventional vaccines) should be avoided. Instead, necessary safety should be provided by placing replication of the pathogen under stringent control and of activating time-limited replication of the pathogen strictly in an administration region in which pathology cannot develop. Immunization will then occur in the context of highly efficient pathogen replication and uncompromised safety. We found that localized activation in mice of efficient but limited replication of a replication-competent controlled herpesvirus vector resulted in a greatly enhanced immune response to the virus or an expressed heterologous antigen. This finding supports the above hypothesis as well as suggests that the vectors may be promising novel agents worth exploring for the prevention/mitigation of infectious diseases for which efficient vaccination is lacking, in particular in immunocompromised patients.
Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation
Authors: Ye Zhizhou , Ayer Donald E. 
Published: April 2018

ABSTRACTOncogenic Ras upregulates aerobic glycolysis to meet the bioenergetic and biosynthetic demands of rapidly growing cells. In contrast, Thioredoxin interacting protein (TXNIP) is a potent inhibitor of glucose uptake and is frequently downregulated in human cancers. Our lab previously discovered that Ras activation suppresses TXNIP transcription and translation. In this report, we developed a system to study how Ras affects TXNIP translation in the absence of transcriptional affects. We show that whereas Ras drives a global increase in protein translation, it suppresses TXNIP protein synthesis by reducing the rate at which ribosomes transit the coding region of TXNIP mRNA. To investigate the underlying mechanism(s), we randomized or optimized the codons in the TXNIP message without altering the TXNIP primary amino acid sequence. Translation from these mRNA variants is still repressed by Ras, intimating that mRNA secondary structure, miRNAs, RNA binding proteins, or codon usage do not contribute to the blockade of TXNIP synthesis. Rather, we show that the N-terminus of the growing TXNIP polypeptide is the target for Ras-dependent translational repression. Our work demonstrates how Ras suppresses TXNIP translation elongation in the face of a global upregulation of protein synthesis and provides new insight into Ras-dependent metabolic reprogramming.
Taking sharper pictures of malaria with CAMERAs: Combined Antibodies to Measure Exposure Recency Assays
Authors: Greenhouse Bryan , Smith David L. , Rodríguez-Barraquer Isabel , Mueller Ivo , Drakeley Chris J. 
Published: April 2018

AbstractAntibodies directed against malaria parasites are easy and inexpensive to measure but remain an underutilized surveillance tool due to a lack of consensus on what to measure and how to interpret results. High throughput screening of antibodies from well-characterized cohorts offers a means to substantially improve existing assays by rationally choosing the most informative sets of responses and analytical methods. Recent data suggest that high-resolution data on malaria exposure can be obtained from a small number of samples by measuring a handful of properly chosen antibody responses. In this review, we will discuss how standardized multi-antibody assays can be developed and efficiently integrated into existing surveillance activities, with great potential to greatly augment the breadth and quality of information available to direct and monitor malaria control and elimination efforts.
A multi-scale model of the yeast chromosome-segregation system
Authors: Ng Cai Tong , Deng Li , Chen Chen , Lim Hong Hwa , Shi Jian , Surana Uttam , Gan Lu 
Published: April 2018

ABSTRACTIn dividing cells, depolymerizing spindle microtubules move chromosomes by pulling at their kinetochores. While kinetochore subcomplexes have been studied extensively in vitro, little is known about their in vivo structure and interactions with microtubules or their response to spindle damage. Here we combine electron cryotomography of serial cryosections with genetic and pharmacological perturbation to study the yeast chromosome-segregation machinery at molecular resolution in vivo. Each kinetochore microtubule has one (rarely, two) Dam1C/DASH outer-kinetochore assemblies.Dam1C/DASH only contacts the flat surface of the microtubule and does so with its flexible “bridges”. In metaphase, 40% of the Dam1C/DASH assemblies are complete rings; the rest are partial rings. Ring completeness and binding position along the microtubule are sensitive to kinetochore attachment and tension, respectively. Our study supports a model in which each kinetochore must undergo cycles of conformational change to couple microtubule depolymerization to chromosome movement.
Heterogeneous Exposure and Hotspots for Malaria Vectors at Three Study Sites in Uganda
Authors: Kang Su Yun , Battle Katherine E. , Gibson Harry S. , Cooper Laura V. , Maxwell Kilama , Kamya Moses , Lindsay Steven W. , Dorsey Grant , Greenhouse Bryan , Rodriguez-Barraquer Isabel , Reiner Robert C. , Smith David L. , Bisanzio Donal 
Published: April 2018

AbstractHeterogeneity in malaria transmission has household, temporal, and spatial components. These factors are relevant for improving the efficiency of malaria control by targeting heterogeneity. To quantify variation, we analyzed mosquito counts from entomological surveillance conducted at three study sites in Uganda that varied in malaria transmission intensity. Using a Bayesian zero-inflated negative binomial model, validated via a comprehensive simulation study, we quantified household differences in malaria exposure and examined its spatial distribution. We found that housing quality explained large variation among households in mosquito counts. In each site, there was evidence for hot and cold spots, spatial patterns associated with urbanicity, elevation, or other environmental covariates. We also found some differences in the hotspots in rainy vs. dry seasons or before vs. after control. This work identified methods for quantifying heterogeneity in malaria exposure and offered a critical evaluation of spatially targeting interventions at malaria hotspots.
Imagery of movements immediately following performance allows learning of motor skills that interfere
Authors: Sheahan Hannah R. , Ingram James N. , Žalalytė Goda M. , Wolpert Daniel M. 
Published: April 2018

AbstractMotor imagery, that is the mental rehearsal of a motor skill, can lead to improvements when performing the same skill. Here we show a powerful and complementary role, in which motor imagery of movements after actually performing a skill allows learning that is not possible without imagery. We leverage a well-studied motor learning task in which subjects reach in the presence of a dynamic (force-field) perturbation. When two opposing perturbations are presented alternately for the same physical movement, there is substantial interference, preventing any learning. However, when the same physical movement is associated with follow-through movements that differ for each perturbation, both skills can be learned. Here we show that when subjects perform the skill and only imagine the follow-through, substantial learning occurs. In contrast, without such motor imagery there was no learning. Therefore, motor imagery can have a profound effect on skill acquisition even when the imagery is not of the skill itself. Our results suggest that motor imagery may evoke different neural states for the same physical
state, thereby enhancing learning.
TAF-ChIP: An ultra-low input approach for genome wide chromatin immunoprecipitation assay
Authors: Akhtar Junaid , More Piyush , Albrecht Steffen , Marini Federico , Kaiser Waldemar , Kulkarni Apurva , Wojnowski Leszek , Fontaine Jean-Fred , Andrade-Navarro Miguel A. , Silies Marion , Berger Christian 
Published: April 2018

AbstractChromatin immunoprecipitation (ChIP) followed by next generation sequencing (ChIP-Seq) is powerful technique to study transcriptional regulation. However, the requirement of millions of cells to generate results with high signal-to-noise ratio precludes it in the study of small cell populations. Here, we present a Tagmentation-Assisted Fragmentation ChIP (TAF-ChIP) and sequencing method to generate high-quality results from low cell numbers. The data obtained from the TAF-ChIP approach is amenable to standard tools for ChIP-Seq analysis, owing to its high signal-to-noise ratio. The epigenetic profiles from TAF-ChIP approach showed high agreement with conventional ChIP-Seq datasets, thereby underlining the utility of this approach.
A planarian nidovirus expands the limits of RNA genome size
Authors: Saberi Amir , Gulyaeva Anastasia A. , Brubacher John L. , Newmark Phillip A. , Gorbalenya Alexander E. 
Published: April 2018

AbstractRNA viruses are the only known RNA-protein (RNP) entities capable of autonomous replication (albeit within a permissive environment). A 33.5-kb nidovirus has been considered close to the upper size limit for such entities; conversely, the minimal cellular DNA genome is ~200 kb. This large difference presents a daunting gap for the transition from primordial RNP to contemporary DNA-RNP-based life. Whether or not RNA viruses represent transitional steps on the road to DNA-based life, studies of larger RNA viruses advance our understanding of size constraints on RNP entities. For example, emergence of the largest previously known RNA genomes (20-34 kb in positive-stranded nidoviruses, including coronaviruses) is associated with a proofreading exoribonuclease encoded in the nidoviral open reading frame 1b (ORF1b). However, apparent constraints on the size of ORF1b, which encodes this and other key replicative enzymes, have been hypothesized to limit further expansion of viral RNA genomes. Here, we characterize a novel nidovirus (planarian secretory cell nidovirus; PSCNV) whose disproportionately large ORF1b-like region, and overall 41.1 kb genome, substantially extend the presumed limits on RNA genome size. This genome encodes a predicted 13,556-aa polyprotein in an unconventional single ORF, yet retains canonical nidoviral genome organization and expression, and key replicative domains. Our evolutionary analysis suggests that PSCNV diverged early from multi-ORF nidoviruses, and subsequently acquired additional genes, including those typical of large DNA viruses or hosts. PSCNV’s greatly expanded genome, proteomic complexity, and unique features – impressive in themselves – attest to the likelihood of still-larger RNA genomes awaiting discovery.Significance StatementRNA viruses are the only known RNA-protein (RNP) entities capable of autonomous replication. The upper genome size for such entities was assumed to be <35 kb; conversely, the minimal cellular DNA genome is ~200 kb. This large difference presents a daunting gap for the proposed evolution of contemporary DNA-RNP-based life from primordial RNP entities. Here, we describe a nidovirus from planarians, whose 41.1 kb genome is 23% larger than the largest known of RNA virus. The planarian secretory cell nidovirus has broken apparent constraints on the size of the genomic subregion that encodes core replication machinery, and has acquired genes not previously observed in RNA viruses. This virus challenges and advances our understanding of the limits to RNA genome size.
Methods for Automatic Reference Trees and Multilevel Phylogenetic Placement
Authors: Czech Lucas , Stamatakis Alexandros 
Published: April 2018

AbstractMotivationIn most metagenomic sequencing studies, the initial analysis step consists in assessing the evolutionary provenance of the sequences. Phylogenetic (or Evolutionary) Placement methods can be employed to determine the evolutionary position of sequences with respect to a given reference phylogeny. These placement methods do however face certain limitations: The manual selection of reference sequences is labor-intensive; the computational effort to infer reference phylogenies is substantially larger than for methods that rely on sequence similarity; the number of taxa in the reference phylogeny should be small enough to allow for visually inspecting the results.ResultsWe present algorithms to overcome the above limitations. First, we introduce a method to automatically construct representative sequences from databases to infer reference phylogenies. Second, we present an approach for conducting large-scale phylogenetic placements on nested phylogenies. Third, we describe a preprocessing pipeline that allows for handling huge sequence data sets. Our experiments on empirical data show that our methods substantially accelerate the workflow and yield highly accurate placement results.ImplementationFreely available under GPLv3 at http://github.com/lczech/gappa.Contactlucas.czech@h-its.orgSupplementary InformationSupplementary data are available at Bioinformatics online.
Parameterizing neural power spectra
Authors: Haller Matar , Donoghue Thomas , Peterson Erik , Varma Paroma , Sebastian Priyadarshini , Gao Richard , Noto Torben , Knight Robert T. , Shestyuk Avgusta , Voytek Bradley 
Published: April 2018

AbstractElectrophysiological signals across species and recording scales exhibit both periodic and aperiodic features. Periodic oscillations have been widely studied and linked to numerous physiological, cognitive, behavioral, and disease states, while the aperiodic “background” 1/f component of neural power spectra has received far less attention. Most analyses of oscillations are conducted on a priori, canonically-defined frequency bands without consideration of the underlying aperiodic structure, or verification that a periodic signal even exists in addition to the aperiodic signal. This is problematic, as recent evidence shows that the aperiodic signal is dynamic, changing with age, task demands, and cognitive state. It has also been linked to the relative excitation/inhibition of the underlying neuronal population. This means that standard analytic approaches easily conflate changes in the periodic and aperiodic signals with one another because the aperiodic parameters—along with oscillation center frequency, power, and bandwidth—are all dynamic in physiologically meaningful, but likely different, ways. In order to overcome the limitations of traditional narrowband analyses and to reduce the potentially deleterious effects of conflating these features, we introduce a novel algorithm for automatic parameterization of neural power spectral densities (PSDs) as a combination of the aperiodic signal and putative periodic oscillations. Notably, this algorithm requires no a priori specification of band limits and accounts for potentially-overlapping oscillations while minimizing the degree to which they are confounded with one another. This algorithm is amenable to large-scale data exploration and analysis, providing researchers with a tool to quickly and accurately parameterize neural power spectra.
Evidence against preserved syntactic comprehension in healthy aging
Authors: Poulisse Charlotte , Wheeldon Linda , Segaert Katrien 
Published: April 2018

AbstractWe investigated age-related differences in syntactic comprehension in young and older adults. Most previous research found no evidence of age-related decline in syntactic processing. We investigated elementary syntactic comprehension of minimal sentences (e.g. I cook), minimizing the influence of working memory. We also investigated the contribution of semantic processing by comparing sentences containing real verbs (e.g. I cook) versus pseudoverbs (e.g. I spuff). We measured the speed and accuracy of detecting syntactic agreement errors (e.g. I cooks, I spuffs). We found that older adults were slower and less accurate than younger adults in detecting syntactic agreement errors for both real and pseudoverb sentences, suggesting there is age-related decline in syntactic comprehension. The age-related decline in accuracy was smaller for the pseudoverb sentences, and the decline in speed was larger for the pseudoverb sentences, compared to real verb sentences. We suggest that syntactic comprehension decline is stronger in the absence of semantic information, which causes older adults to produce slower responses in order to make more accurate decisions. In line with these findings, performance for older adults was positively related to a measure of processing speed capacity. Taken together, we found evidence that elementary syntactic processing abilities decline in healthy ageing.
Genomic basis of multidrug-resistance, mating, and virulence inCandida aurisand related emerging species
Authors: Muñoz José F. , Gade Lalitha , Chow Nancy A. , Loparev Vladimir N. , Juieng Phalasy , Berkow Elizabeth L. , Farrer Rhys A. , Litvintseva Anastasia P. , Cuomo Christina A. 
Published: April 2018

AbstractCandida aurisis an emergent fungal pathogen of rising public health concern due to increasing reports of outbreaks in healthcare settings and resistance to multiple classes of antifungal drugs. While distantly related to the more common pathogensC. albicansandC. glabrata,C. aurisis closely related to three rarely observed and often multidrug-resistant species,C. haemulonii, C. duobushaemulonii and C. pseudohaemulonii. Here, we generated and analyzed near complete genome assemblies and RNA-Seq-guided gene predictions for isolates from each of the four majorC. aurisclades and forC. haemulonii, C. duobushaemulonii and C. pseudohaemulonii. Our analyses mapped seven chromosomes and revealed chromosomal rearrangements betweenC. aurisclades and related species. We found conservation of genes involved in mating and meiosis and identified bothMTLaandMTLαC. aurisisolates, suggesting the potential for mating between clades. Gene conservation analysis highlighted that many genes linked to drug resistance and virulence in other pathogenicCandidaspecies are conserved inC. aurisand related species including expanded families of transporters and lipases, as well as mutations and copy number variants inERG11that confer drug resistance. In addition, we found genetic features of the emerging species that likely underlie differences in virulence and drug response between these and otherCandidaspecies, including genes involved in cell wall structure. To begin to characterize the species-specific genes important for antifungal response, we profiled the gene expression ofC. aurisin response to voriconazole and amphotericin B and found induction of several transporters and metabolic regulators that may play a role in drug resistance. This study provides a comprehensive view of the genomic basis of drug resistance, potential for mating, and virulence in this emerging fungal clade.
Distinct cortical-amygdala projections drive reward value encoding and retrieval
Authors: Malvaez Melissa , Shieh Christine , Murphy Michael D. , Greenfield Venuz Y. , Wassum Kate M. 
Published: April 2018

ABSTRACTThe value of an anticipated rewarding event is crucial information in the decision to engage in its pursuit. The networks responsible for encoding and retrieving this value are largely unknown. Using glutamate biosensors and pharmacological manipulations, we found that basolateral amygdala (BLA) glutamatergic activity tracks and mediates both the encoding and retrieval of the state-dependent incentive value of a palatable food. Projection-specific and bidirectional chemogenetic and optogenetic manipulations revealed the orbitofrontal cortex (OFC) supports the BLA in these processes. Critically, the function of ventrolateral (lOFC) and medial (mOFC) OFC→BLA projections was found to be doubly dissociable. Whereas activity in lOFC→BLA projections is necessary for and sufficient to drive encoding of a positive change in the value of a reward, mOFC→BLA projections are necessary and sufficient for retrieving this value from memory to guide its pursuit. These data reveal a new circuit for adaptive reward valuation and pursuit, indicate dissociability in the encoding and retrieval of reward memories, and provide insight into the dysfunction in these processes that characterizes myriad psychiatric diseases.
Controlling fluid flow to improve cell seeding uniformity
Authors: Reynolds Paul M. , Rasmussen Camilla Holzmann , Hansson Mathias , Dufva Martin , Riehle Mathis O. , Gadegaard Nikolaj 
Published: April 2018

AbstractStandard methods for seeding monolayer cell cultures in a multiwell plate or dish do not uniformly distribute cells on the surface. With traditional methods, users find aggregation around the circumference, in the centre, or a combination of the two. This variation is introduced due to the macro scale flow of the cell seeding suspension, and movement of the dish before cells can settle and attach to the surface. Reproducibility between labs, users, and experiments is hampered by this variability in cell seeding. We present a simple method for uniform and user-independent cell seeding using an easily produced uniform cell seeder (UCS) device. This allows precise control of cell density in a reproducible manner. By containing the cell seeding suspension in a defined volume above the culture surface with the UCS, fluctuations in cell density are minimised. Seeding accuracy, as defined by the actual cell density versus the target seeding density is improved dramatically across users with various levels of expertise. We go on to demonstrate the impact of local variation in cell density on the lineage commitment of human embryonic stem cells (hESCs) towards pancreatic endoderm (PE). Variations in the differentiation profile of cells across a culture well closely mirror variations in cell density introduced by seeding method – with the UCS correcting variations in differentiation efficiency. The UCS device provides a simple and reproducible method for uniform seeding across multiple culture systems.