bluuebunny/crossref_metadata_2025 huggingface dataset:
Common genetic variants and health outcomes appear geographically structured in the UK Biobank sample: Old concerns returning and their implications
Authors: Haworth Simon , Mitchell Ruth , Corbin Laura , Wade Kaitlin H , Dudding Tom , Budu-Aggrey Ashley , Carslake David , Hemani Gibran , Paternoster Lavinia , Smith George Davey , Davies Neil , Lawson Dan , Timpson Nicholas
Published: April 2018

Introductory paragraph

The inclusion of genetic data in large studies has enabled the discovery of genetic contributions to complex traits and their application in applied analyses including those using genetic risk scores (GRS) for the prediction of phenotypic variance. If genotypes show structure by location and coincident structure exists for the trait of interest, analyses can be biased. Having illustrated structure in an apparently homogeneous collection, we aimed to a) test for geographical stratification of genotypes in UK Biobank and b) assess whether stratification might induce bias in genetic association analysis.

We found that single genetic variants are associated with birth location within UK Biobank and that geographic structure in genetic data could not be accounted for using routine adjustment for study centre and principal components (PCs) derived from genotype data. We found that GRS for complex traits do appear geographically structured and analysis using GRS can yield biased associations. We discuss the likely origins of these observations and potential implications for analysis within large-scale population based genetic studies.
Enchained growth and cluster dislocation: a possible mechanism for microbiota homeostasis
Authors: Bansept Florence , Schumann-Moor Kathrin , Diard Médéric , Hardt Wolf-Dietrich , Slack Emma , Loverdo Claude
Published: April 2018

Immunoglobulin A is a class of antibodies produced by the adaptive immune system and secreted into the gut lumen to fight pathogenic bacteria. We recently demonstrated that the main physical effect of these antibodies is to enchain daughter bacteria, i.e. to cross-link bacteria into clusters as they divide, preventing them from interacting with epithelial cells, thus protecting the host. These links between bacteria may break over time. We study several models using analytical and numerical calculations. We obtain the resulting distribution of chain sizes, that we compare with experimental data. We study the rate of increase in the number of free bacteria as a function of the replication rate of bacteria. Our models show robustly that at higher replication rates, bacteria replicate before the link between daughter bacteria breaks, leading to growing cluster sizes. On the contrary at low growth rates two daughter bacteria have a high probability to break apart. Thus the gut could produce IgA against all the bacteria it has encountered, but the most affected bacteria would be the fast replicating ones, that are more likely to destabilize the microbiota. Linking the effect of the immune effectors (here the clustering) with a property directly relevant to the potential bacterial pathogeneicity (here the replication rate) could avoid to make complex decisions about which bacteria to produce effectors against.

Author Summary

Inside the organism, the immune system can fight generically against any bacteria. However, the lumen of the gut is home to a very important microbiota, so the host has to find alternative ways to fight dangerous bacteria while sparing beneficial ones. While many studies have focused on the complex molecular and cellular pathways that trigger an immune response, little is known about how the produced antibodies act once secreted into the intestinal lumen. We recently demonstrated that the main physical effect of these antibodies is to cross-link bacteria into clusters as they divide, preventing them from interacting with epithelial cells, thus protecting the host. These links between bacteria may break over time. Using analytical and numerical calculations, and comparing with experimental data, we studied the dynamics of these clusters. At higher replication rates, bacteria replicate before the link between daughter bacteria breaks, leading to growing cluster sizes, and conversely. Thus the gut could produce IgA against all the bacteria it has encountered, but the most affected bacteria would be the fast replicating ones, that are more likely destabilize the microbiota. Studying the mechanisms of the immune response may uncover more such processes that enable to target properties hard to escape through evolution.
Positive Cardiac Inotrope, Omecamtiv Mecarbil, Activates Muscle Despite Suppressing the Myosin Working Stroke
Authors: Woody Michael S. , Greenberg Michael J. , Barua Bipasha , Winkelmann Donald A. , Goldman Yale E. , Ostap E. Michael
Published: April 2018

Omecamtiv mecarbil (OM) is a positive cardiac inotrope in phase-3 clinical trials for treatment of heart failure. Although initially described as a direct myosin activator, subsequent studies are at odds with this description and do not explain OM-mediated increases in cardiac output. Single-molecule, biophysical experiments on cardiac myosin show that OM suppresses myosin’s working stroke and prolongs actomyosin attachment 5-fold, which explain inhibitory actions of the drug observedin vitro. Surprisingly, the increased myocardial force output in the presence of OM can be explained by cooperative thin filament activation by OM-inhibited myosin molecules. Selective suppression of myosin is an unanticipated route to muscle activation that may guide future development of therapeutic drugs.
Multiplex Enrichment and Detection of Rare KRAS Mutations in Liquid Biopsy Samples using Digital Droplet Pre-Amplification
Authors: Pratt Erica D. , Cowan Robert W. , Manning Sara L. , Qiao Edmund , Cameron Heather , Schradle Kara , Simeone Diane , Zhen David B.
Published: April 2018

Oncology research is increasingly incorporating molecular detection of circulating tumor DNA (ctDNA) as a tool for cancer surveillance and early detection. However, non-invasive monitoring of conditions with low tumor burden remains challenging, as the diagnostic sensitivity of most ctDNA assays is inversely correlated with total DNA concentration and ctDNA abundance. Here we present the Multiplex Enrichment using Droplet Pre-Amplification (MED-Amp) method, which com-bines single-molecule emulsification and short-round PCR preamplification with digital droplet PCR (ddPCR) detection of mutant DNA template. The MED-Amp assay increased mutant signal by over 50-fold with minimal distortion in allelic frequency. We demonstrate detection of as few as 3 mutant copies in wild-type DNA concentrations ranging from 5 to 50ng. The MED-Amp assay successfully detected KRAS mutant ctDNA in 86% plasma samples obtained from patients with metastatic pancreatic ductal adenocarcinoma. This assay for high-sensitivity rare variant detection is appropriate for liquid biopsy samples, or other limited clinical biospecimens
Science Podcasts: Analysis of Global Production and Output From 2004 to 2018
Authors: MacKenzie Lewis E.
Published: April 2018

1.

Since 2004, podcasts have emerged as a decentralised medium for science communication to the global public. However, to-date, there have been no large-scale quantitative studies of the production and dissemination of science podcasts. This study identified 952 English language science podcasts available between January and February 2018 and analysed online textual and visual data related to the podcasts and classified and noted key production parameters. It was found that the total number of science podcast series available grew linearly between 2004 and 2010, and then exponentially between 2010 and 2018. 65% of science podcast series were hosted by scientists and 77% were targeted to public audiences. Although a wide range of primarily single-subject science podcasts series were noted, 34% of science podcast series were not dedicated to a science subject. Compared to biology and physics, chemistry may be under-represented by science podcasts. Only 24% of science podcast series had any overt financial income. 62% of science podcast series were affiliated to an organisation; producing a greater number of episodes (median = 24, average = 96) than independent science podcast series (median = 16, average = 48). This study provides the first ‘snapshot’ of how science podcasts are being used to communicate science to public audiences around the globe.
Cross-fostering in rodents causes region-specific alterations in entorhinal cortical gamma rhythms associated with NMDA receptor dysfunction
Authors: Hall Stephen , Hawkins Karen , Laws Grace , Akitt Thomas , Simon Anna , Davies Ceri H. , Whittington Miles A. , Cunningham Mark O.
Published: April 2018

There has recently been a large increase in the number of children placed in foster care in the United States and Europe. While this is ‘the least worst scenario’ for those with a lack of appropriate biological care, it is recognised that these children are exposed to major stressors correlated with behavioural changes, particularly in the realm of social cognition into adulthood. Here we model foster care in rodents: rat pups are removed from their biological mother and placed with a non-genetically related dam. This prevented the entorhinal cortex from generating patterns of gamma rhythms required for normal parahippocampal function relevant to social interaction. These changes correlated with a reduction in NMDA receptor-mediated excitation, and changes in parvalbumin expression in interneurons. These data suggest that early life care delivered by a non-biological parent may disrupt social behaviour but, in contrast, generate neurobiological changes antagonistic to those currently associated with psychosis.

Significance Statement

Cross fostering is an effective approach for delineating the effect of environment from genetic influences upon behavior. This involves removal of pups from one mother and transfer to another lactating dam. This manipulation is considered as a mild form of early life stress, producing neurobehavioral changes such as alterations in social interaction. We demonstrate that cross fostering produces changes in the ability of cortical microcircuits to generate oscillatory rhythms, in particular the gamma rhythm, in brain regions important for social cognition. This reduction in gamma rhythmogenesis is related to a reduction in synaptic drive provided by the NMDA receptor. One implication of this work is that the modulation of NMDA receptors offers a potential therapeutic strategy for disorders involving impaired sociability.
Reproducible genomics analysis pipelines with GNU Guix
Authors: Wurmus Ricardo , Uyar Bora , Osberg Brendan , Franke Vedran , Gosdschan Alexander , Wreczycka Katarzyna , Ronen Jonathan , Akalin Altuna
Published: April 2018

In bioinformatics, as well as other computationally-intensive research fields, there is a need for workflows that can reliably produce consistent output, independent of the software environment or configuration settings of the machine on which they are executed. Indeed, this is essential for controlled comparison between different observations or for the wider dissemination of workflows. Providing this type of reproducibility, however, is often complicated by the need to accommodate the myriad dependencies included in a larger body of software, each of which generally come in various versions. Moreover, in many fields (bioinformatics being a prime example), these versions are subject to continual change due to rapidly evolving technologies, further complicating problems related to reproducibility. Here, we propose a principled approach for building analysis pipelines and managing their dependencies. As a case study to demonstrate the utility of our approach, we present a set of highly reproducible pipelines for the analysis of RNA-seq, ChIP-seq, Bisulfite-seq, and single-cell RNA-seq. All pipelines process raw experimental data, and generate reports containing publication-ready plots and figures, with interactive report elements and standard observables. Users may install these highly reproducible packages and apply them to their own datasets without any special computational expertise beyond the use of the command line. We hope such a toolkit will provide immediate benefit to laboratory workers wishing to process their own data sets or bioinformaticians seeking to automate all, or parts of, their analyses. In the long term, we hope our approach to reproducibility will serve as a blueprint for reproducible workflows in other areas. Our pipelines, along with their corresponding documentation and sample reports, are available at http://bioinformatics.mdc-berlin.de/pigx
Multiple brain networks mediating stimulus-pain relationships in humans
Authors: Geuter Stephan , Losin Elizabeth A. Reynolds , Roy Mathieu , Atlas Lauren Y. , Schmidt Liane , Krishnan Anjali , Koban Leonie , Wager Tor D. , Lindquist Martin A.
Published: April 2018

The brain transforms nociceptive input into a complex pain experience comprised of sensory, affective, motivational, and cognitive components. However, it is still unclear how pain arises from nociceptive input, and which brain networks coordinate to generate pain experiences. We introduce a new high-dimensional mediation analysis technique to estimate distributed, network-level patterns mediating the relationship between stimulus intensity and pain. In a large-scale analysis of functional magnetic resonance imaging data (N=284), we identify both traditional mediators in somatosensory brain regions and additional mediators located in prefrontal, midbrain, striatal, and default-mode regions unrelated to nociception in standard analyses. The whole brain mediators are specific for pain vs. aversive sounds and are organized in five functional networks. Brain mediators explain 32% more within-subject variance of single-trial pain ratings than previous brain-based models. Our results provide a new, broader view of the networks underlying pain experience, as well as distinct targets for interventions.
Test-retest reliability and convergent validity of (R)-[11C]PK11195 outcome measures without arterial input function
Authors: Plavén-Sigray Pontus , Matheson Granville James , Cselényi Zsolt , Jučaite Aurelija , Farde Lars , Cervenka Simon
Published: April 2018

Background

The positron emission tomography radioligand (R)-[11C]PK11195 can be used to quantify the expression of translocator protein (TSPO), which is considered a marker for activation of glial cells. TSPO is expressed throughout the brain, and for this reason no true reference region exists. When a radioligand does not have a reference region, an arterial input function (AIF) is usually required in order to quantify binding. However, obtaining an AIF can be difficult as well as uncomfortable for participants. Alternative methods have therefore been proposed with the aim of estimating (R)-[11C]PK11195 binding without arterial measurements, such as standardized uptake values (SUVs), supervised-cluster analysis (SVCA), or the use of a pseudo-reference region. The objective of this study was to evaluate the test-retest reliability and convergent validity of these techniques.

Methods

Data from a previously published (R)-[11C]PK11195 test-retest study in six healthy male subjects were reanalysed. Non-displaceable binding potential (BPND) was calculated for a set of cortical and subcortical brain regions using the simplified reference tissue model, with either cerebellum as reference region or a reference input derived using SVCA. SUVs were estimated for the time interval of 40-60 minutes. For comparison, total distribution volume (VT), specific distribution volume (VS) and BPNDwere estimated from the two-tissue-compartment model (2TCM) using AIF. Test-retest reliability was then assessed for all outcome measures. Convergent validity was examined by correlating all measures derived without an AIF to those derived using 2TCM.

Results

Test-retest reliability for BPNDestimates were poor (80% of all regional ICCs<0.5). SUVs showed, on average, moderate reliability. BPNDestimates derived without an AIF were not correlated with VT, VSor BPNDfrom the 2TCM (all R2<12%). SUVs were not correlated with any other outcome (all R2<9%).

Discussion

BPNDestimated using cerebellum or SVCA as reference input showed poor reliability and little to no convergent validity with outcomes derived using an AIF. SUVs showed moderate reliability but no convergent validity with any other outcome. Caution is warranted for interpreting patient-control comparisons employing (R)-[11C]PK11195 outcome measures obtained without an AIF.
A Cut/cohesin axis alters the chromatin landscape to facilitate neuroblast death
Authors: Arya Richa , Gyonjyan Seda , Harding Katherine , Sarkissian Tatevik , Li Ying , Zhou Lei , White Kristin
Published: April 2018

Precise control of cell death in the nervous system is essential for development. Spatial and temporal factors activate the death of Drosophila neural stem cells (neuroblasts) by controlling the transcription of multiple cell death genes through a shared enhancer, enh1. The activity of enh1 is controlled byabdominalAandNotch, but additional inputs are needed for proper specificity. Here we show that the Cut DNA binding protein is required for neuroblast death, acting downstream of enh1. In the nervous system, Cut promotes an open chromatin conformation in the cell death gene locus, allowing cell death gene expression in response toabdominalA. We demonstrate a temporal increase in global H3K27me3 levels in neuroblasts, which is enhanced bycutknockdown. Furthermore,cutregulates the expression of the cohesin subunit Stromalin in the nervous system. The cohesin components Stromalin and NippedB are required for neuroblast death, and knockdown of Stromalin increases repressive histone modifications in neuroblasts. Thus Cut and cohesin regulate apoptosis in the developing nervous system by altering the chromatin landscape.

Summary statement

Cut regulates the programmed death of neural stem cells by altering cohesin levels and promoting a more open chromatin conformation to allow cell death gene expression.
Marginal Effects of Systemic CCR5 Blockade with Maraviroc on Oral Simian Immunodeficiency Virus Transmission to Infant Macaques
Authors: Brocca-Cofano Egidio , Xu Cuiling , Wetzel Katherine S. , Cottrell Mackenzie L. , Policicchio Benjamin B. , Raehtz Kevin D. , Ma Dongzhu , Dunsmore Tammy , Haret-Richter George S. , Musaitif Karam , Keele Brandon F. , Kashuba Angela D. , Collman Ronald G. , Pandrea Ivona , Apetrei Cristian
Published: April 2018

Current approaches do not eliminate all HIV-1 maternal-to-infant transmissions (MTIT); new prevention paradigms might help avert new infections. We administered Maraviroc (MVC) to rhesus macaques (RMs) to block CCR5-mediated entry, followed by repeated oral exposure of a CCR5-dependent clone of simian immunodeficiency virus (SIV)mac251 (SIVmac766). MVC significantly blocked the CCR5 coreceptor in peripheral blood mononuclear cells and tissue cells. All control animals and 60% of MVC-treated infant RMs became infected by the 6th challenge, with no significant difference between the number of exposures (p=0.15). At the time of viral exposures, MVC plasma and tissue (including tonsil) concentrations were within the range seen in humans receiving MVC as a therapeutic. Both treated and control RMs were infected with only a single transmitted/founder variant, consistent with the dose of virus typical of HIV-1 infection. The uninfected RMs expressed the lowest levels of CCR5 on the CD4+ T cells. Ramp-up viremia was significantly delayed (p=0.05) in the MVC-treated RMs, yet peak and postpeak viral loads were similar in treated and control RMs. In conclusion, in spite of apparent effective CCR5 blockade in infant RMs, MVC had marginal impact on acquisition and only a minimal impact on post infection delay of viremia following oral SIV infection. Newly developed, more effective CCR5 blockers may have a more dramatic impact on oral SIV transmission than MVC.

Importance

We have previously suggested that the very low levels of simian immunodeficiency virus (SIV) maternal-to-infant transmissions (MTIT) in African nonhuman primates that are natural hosts of SIVs are due to a low availability of target cells (CCR5+ CD4+ T cells) in the oral mucosa of the infants, rather than maternal and milk factors. To confirm this new MTIT paradigm, we performed a proof of concept study, in which we therapeutically blocked CCR5 with maraviroc (MVC) and orally exposed MVC treated and naïve infant rhesus macaques to SIV. MVC had only a marginal effect on oral SIV transmission. However, the observation that the infant RMs that remained uninfected at the completion of the study, after 6 repeated viral challenges, had the lowest CCR5 expression on the CD4+ T cells prior to the MVC treatment, appear to confirm our hypothesis, also suggesting that the partial effect of MVC is due to a limited efficacy of the drug. Newly, more effective CCR5 inhibitors may have a better effect in preventing SIV and HIV transmission.
Immunization by replication-competent controlled herpesvirus vectors
Authors: Bloom David C. , Tran Robert K. , Feller Joyce , Voellmy Richard
Published: April 2018

Replication-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.

IMPORTANCE

We 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

Oncogenic 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

Antibodies 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.
Spatial soft sweeps: patterns of adaptation in populations with long-range dispersal
Authors: Paulose Jayson , Hermisson Joachim , Hallatschek Oskar
Published: April 2018

Adaptation in extended populations often occurs through multiple independent mutations responding in parallel to a common selection pressure. As the mutations spread concurrently through the population, they leave behind characteristic patterns of polymorphism near selected loci—so-called soft sweeps—which remain visible after adaptation is complete. These patterns are well-understood in two limits of the spreading dynamics of beneficial mutations: the panmictic case with complete absence of spatial structure, and spreading via short-ranged or diffusive dispersal events, which tessellates space into distinct compact regions each descended from a unique mutation. However, spreading behaviour in most natural populations is not exclusively panmictic or diffusive, but incorporates both short-range and long-range dispersal events. Here, we characterize the spatial patterns of soft sweeps driven by dispersal events whose jump distances are broadly distributed, using lattice-based simulations and scaling arguments. We find that mutant clones adopt a distinctive structure consisting of compact cores surrounded by fragmented “haloes” which mingle with haloes from other clones. As long-range dispersal becomes more prominent, the progression from diffusive to panmictic behaviour is marked by two transitions separating regimes with differing relative sizes of halo to core. We analyze the implications of the core-halo structure for the statistics of soft sweep detection in small genomic samples from the population, and find opposing effects of long-range dispersal on the expected diversity in global samples compared to local samples from geographic subregions of the range. We also discuss consequences of the standing genetic variation induced by the soft sweep on future adaptation and mixing.
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

In 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

Heterogeneity 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

Motor 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

Chromatin 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

RNA 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 Statement

RNA 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

Motivation

In 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.

Results

We 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.

Implementation

Freely available under GPLv3 at http://github.com/lczech/gappa.

Contact

lucas.czech@h-its.org

Supplementary Information

Supplementary 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

Electrophysiological 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

We 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

Candida 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

The 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

Standard 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.