bluuebunny/crossref_metadata_2025_split huggingface dataset:
Face Selective Neural Activity: Comparison Between Fixed and Free Viewing
Authors: Auerbach-Asch Carmel R. , Bein Oded , Deouell Leon Y. 
Published: August 2019

AbstractEvent Related Potentials (ERPs) are widely used to study category-selective EEG responses to visual stimuli, such as the face-selective N170 component. Typically, this is done by flashing stimuli abruptly at the point of static gaze fixation. While allowing for good experimental control, these paradigms ignore the dynamic role of eye-movements in natural vision. Fixation-related potentials (FRPs) obtained using simultaneous EEG and eye-tracking, overcome this limitation. Various studies have used FRPs to study processes such as lexical processing, target detection and attention allocation. The goal of this study was to compare face-sensitive activity evoked by stimulus abrupt appearance with that evoked by self-controlled gaze fixations on a stimulus. Twelve participants were studied in three experimental conditions: Free-viewing (FRPs), Cued-viewing (FRPs) and Control (ERPs). We used a multiple regression approach to disentangle overlapping activity components. Our results show that the N170 face effect (face vs. non-face) is evident for the first fixation on a stimulus, whether it follows a self-generated saccade or stimulus appearance at fixation point. Furthermore, the N170 exhibits category-specific adaptation in free viewing. The N170 face effect had similar topography across viewing conditions, but there were major differences within each stimulus category. We ascribe these differences to an overlap of the fixation-related Lambda response and the N170. We tested the plausibility of this account using dipole simulations. This study establishes the use of the N170 face effect as a signature of face detection in free-viewing experiments while highlighting the importance of accounting for eye-movement related effects.
Identification of RNA 3’ ends and termination sites in Haloferax volcanii
Authors: Berkemer Sarah J. , Maier Lisa-Katharina , Amman Fabian , Bernhart Stephan H. , Wörtz Julia , Märkle Pascal , Pfeiffer Friedhelm , Stadler Peter F. , Marchfelder Anita 
Published: August 2019

AbstractArchaeal genomes are densely packed; thus, correct transcription termination is an important factor for orchestrated gene expression. A systematic analysis of RNA 3’ termini, to identify transcription termination sites (TTS) using RNAseq data has hitherto only been performed in two archaea. In this study, only part of the genome had been investigated. Here, we developed a novel algorithm that allows an unbiased, genome-wide identification of RNA 3’ termini independent of annotation. In an RNA fraction enriched for primary transcripts by terminator exonuclease (TEX) treatment we identified 1,543 RNA 3’ termini. A strong sequence signature consistent with known termination events at intergenic loci indicates a clear enrichment for native TTS among them. Using these data we determined distinct putative termination motifs for intergenic (a T stretch) and coding regions (AGATC). In vivo reporter gene tests of selected TTS confirmed termination at these sites, which exemplify the different motifs. For several genes, more than one termination site was detected, resulting in transcripts with different lengths of the 3’ untranslated region.
An assessment of LRRK2 serine 935 phosphorylation in human peripheral blood mononuclear cells in idiopathic Parkinson’s disease and G2019S LRRK2 cohorts
Authors: Padmanabhan Shalini , Lanz Thomas A. , Gorman Donal , Wolfe Michele , Levers Najah , Joshi Neal , Liong Christopher , Narayan Sushma , Alcalay Roy N. , Hutten Samantha J. , Baptista Marco A. S. , Merchant Kalpana 
Published: August 2019

ABSTRACTThe phosphorylated form of LRRK2, pS935 LRRK2, has been proposed as a target modulation biomarker for LRRK2 inhibitors. To qualify the biomarker for therapeutic trials, we assessed pS935 LRRK2 levels in Peripheral Blood Mononuclear Cells (PBMCs). Analyses of PBMCs from healthy controls, idiopathic Parkinson’s disease (iPD), and G2019S carriers with and without PD showed significant reductions in pS935 LRRK2 levels normalized to total LRRK2 levels in G2019S carriers with PD compared to those without PD or iPD. Neither analyte correlated with age, gender, or disease severity. Thus, pS935 LRRK2 in PBMCs may reflect a state marker for G2019S LRRK2-driven PD.
Efficient whole genome sequencing of influenza A viruses
Authors: Escalera-Zamudio Marina , Cobián-Güemes Ana Georgina , Taboada Blanca , López-Martínez Irma , Vázquez-Pérez Joel Armando , Montalvo-Corral Maricela , Hernandez Jesus , Díaz-Quiñonez José Alberto , Badillo Gisela Barrera , López Susana , Arias Carlos F. , Iša Pavel 
Published: August 2019

ABSTRACTThe constant threat of emergence for novel pathogenic influenza A viruses with pandemic potential, makes full-genome characterization of circulating influenza viral strains a high priority, allowing detection of novel and re-assorting variants. Sequencing the full-length genome of influenza A virus traditionally required multiple amplification rounds, followed by the subsequent sequencing of individual PCR products. The introduction of high-throughput sequencing technologies has made whole genome sequencing easier and faster. We present a simple protocol to obtain whole genome sequences of hypothetically any influenza A virus, even with low quantities of starting genetic material. The complete genomes of influenza A viruses of different subtypes and from distinct sources (clinical samples of pdmH1N1, tissue culture-adapted H3N2 viruses, or avian influenza viruses from cloacal swabs) were amplified with a single multisegment reverse transcription-PCR reaction and sequenced using Illumina sequencing platform. Samples with low quantity of genetic material after initial PCR amplification were re-amplified by an additional PCR using random primers. Whole genome sequencing was successful for 66% of the samples, whilst the most relevant genome segments for epidemiological surveillance (corresponding to the hemagglutinin and neuraminidase) were sequenced with at least 93% coverage (and a minimum 10x) for 98% of the samples. Low coverage for some samples is likely due to an initial low viral RNA concentration in the original sample. The proposed methodology is especially suitable for sequencing a large number of samples, when genetic data is urgently required for strains characterization, and may also be useful for variant analysis.
Estimating rates and patterns of diversification with incomplete sampling: A case study in the rosids
Authors: Sun Miao , Folk Ryan A. , Gitzendanner Matthew A. , Guralnick Robert P. , Soltis Pamela S. , Chen Zhiduan , Soltis Douglas E. 
Published: August 2019

AbstractPremise of the StudyRecent advances in generating large-scale phylogenies enable broad-scale estimation of species diversification rates. These now-common approaches typically (1) are characterized by incomplete coverage without explicit sampling methodologies, and/or (2) sparse backbone representation, and usually rely on presumed phylogenetic placements to account for species without molecular data. Here we use an empirical example to examine effects of incomplete sampling on diversification estimation and provide constructive suggestions to ecologists and evolutionists based on those results.MethodsWe used a supermatrix for rosids, a large clade of angiosperms, and its well-sampled subclade Cucurbitaceae, as empirical case studies. We compared results using this large phylogeny with those based on a previously inferred, smaller supermatrix and on a synthetic tree resource with complete taxonomic coverage. Finally, we simulated random and representative taxon sampling and explored the impact of sampling on three commonly used methods, both parametric (RPANDA, BAMM) and semiparametric (DR).Key ResultsWe find the impact of sampling on diversification estimates is idiosyncratic and often strong. As compared to full empirical sampling, representative and random sampling schemes either depress or exaggerate speciation rates depending on methods and sampling schemes. No method was entirely robust to poor sampling, but BAMM was least sensitive to moderate levels of missing taxa.ConclusionsWe (1) urge caution in use of summary backbone trees containing only higher-level taxa, (2) caution against uncritical modeling of missing taxa using taxonomic data for poorly sampled trees, and (3) stress the importance of explicit sampling methodologies in macroevolutionary studies.
Insight into the genomic history of the Near East from whole-genome sequences and genotypes of Yemenis
Authors: Haber Marc , Saif-Ali Riyadh , Al-Habori Molham , Chen Yuan , Platt Daniel E. , Tyler-Smith Chris , Xue Yali 
Published: August 2019

AbstractWe report high-coverage whole-genome sequencing data from 46 Yemeni individuals as well as genome-wide genotyping data from 169 Yemenis from diverse locations. We use this dataset to define the genetic diversity in Yemen and how it relates to people elsewhere in the Near East. Yemen is a vast region with substantial cultural and geographic diversity, but we found little genetic structure correlating with geography among the Yemenis – probably reflecting continuous movement of people between the regions. African ancestry from admixture in the past 800 years is widespread in Yemen and is the main contributor to the country’s limited genetic structure, with some individuals in Hudayda and Hadramout having up to 20% of their genetic ancestry from Africa. In contrast, individuals from Maarib appear to have been genetically isolated from the African gene flow and thus have genomes likely to reflect Yemen’s ancestry before the admixture. This ancestry was comparable to the ancestry present during the Bronze Age in the distant Northern regions of the Near East. After the Bronze Age, the South and North of the Near East therefore followed different genetic trajectories: in the North the Levantines admixed with a Eurasian population carrying steppe ancestry whose impact never reached as far south as the Yemen, where people instead admixed with Africans leading to the genetic structure observed in the Near East today.
Structure-guided design of a synthetic mimic of an EPCR-binding PfEMP1 protein
Authors: Barber Natalie M. , Lau Clinton K. Y. , Turner Louise , Watson Gareth , Thrane Susan , Lusingu John P.A. , Lavstsen Thomas , Higgins Matthew K. 
Published: August 2019

AbstractStructure-guided vaccine design provides a route to elicit a focused immune response against the most functionally important regions of a pathogen surface. This can be achieved by identifying epitopes for neutralizing antibodies through structural methods and recapitulating these epitopes by grafting their core structural features onto smaller scaffolds. In this study, we have conducted a modified version of this protocol. We focused on the PfEMP1 protein family found on the surfaces of erythrocytes infected withPlasmodium falciparum. A subset of PfEMP1 proteins bind to endothelial protein C receptor (EPCR), and their expression correlates with development of the symptoms of severe malaria. Structural studies revealed the PfEMP1 to present a helix-kinked-helix motif which forms the core of the EPCR binding site. Using Rosetta-based design we successfully grafted this motif onto a three-helical bundle scaffold. We show that this synthetic binder interacts with EPCR with nanomolar affinity and adopts the expected structure. We also assessed its ability to bind to antibodies found in immunized animals and in humans from malaria endemic regions. Finally, we tested its capacity to effectively elicit antibodies that prevent EPCR binding and analysed the degree of cross-reactivity of these antibodies across a diverse repertoire of EPCR-binding PfEMP1. This provides a case study of immunogen design, assessing the effect of designing a focused immunogen that contains the core features of a ligand binding site, rather than those of a neutralizing antibody epitope.
Functional genetic validation of key genes conferring insecticide resistance in the major African malaria vector, Anopheles gambiae
Authors: Adolfi Adriana , Poulton Beth , Anthousi Amalia , Macilwee Stephanie , Ranson Hilary , Lycett Gareth J 
Published: August 2019

ABSTRACTResistance in Anopheles gambiae to members of all four major classes (pyrethroids, carbamates, organochlorines and organophosphates) of public health insecticides limits effective control of malaria transmission in Africa. Increased expression of detoxifying enzymes has been associated with resistance, but direct functional validation in An. gambiae has been lacking. Here we perform transgenic analysis using the GAL4/UAS system to examine insecticide resistance phenotypes conferred by increased expression of the three genes - Cyp6m2, Cyp6p3 and Gste2 - most often found upregulated in resistant An. gambiae. We report the first evidence in An. gambiae that organophosphate and organochlorine resistance is conferred by overexpression of GSTE2 in a broad tissue profile. Pyrethroid and carbamate resistance is bestowed by similar Cyp6p3 overexpression, and Cyp6m2 confers only pyrethroid resistance when overexpressed in the same tissues. Conversely, such Cyp6m2 overexpression increases susceptibility to the organophosphate malathion, presumably due to conversion to a more toxic metabolite. No resistant phenotypes are conferred when either Cyp6 gene overexpression is restricted to the midgut or oenocytes, answering long standing questions related to the importance of these tissues in resistance to contact insecticides. Validation of genes conferring resistance provides markers to guide control strategies, and the observed negative cross-resistance due to Cyp6m2 gives credence to proposed dual insecticide strategies to overcome pyrethroid resistance. These trasnsgenic An. gambiae resistant lines are being used to test potential liabilities in new active compounds early in development.SIGNIFICANCE STATEMENTInsecticide resistance in Anopheles gambiae mosquitoes can derail malaria control programs, and to overcome it we need to discover the underlying molecular basis. Here, for the first time, we characterise three genes most often associated with insecticide resistance directly by their overproduction in genetically modified An. gambiae. We show that overexpression of each gene confers resistance to representatives of at least one insecticide class and, taken together, the three genes provide cross-resistance to all four major insecticide classes currently used in public health. These data validate the candidate genes as markers to monitor the spread of resistance in mosquito populations. The modified mosquitoes produced are also valuable tools to pre-screen new insecticides for potential liabilities to existing resistance mechanisms.
Population-specific sequence and expression differentiation in Europeans
Authors: Jiang Xueyuan , Assis Raquel 
Published: August 2019

AbstractMuch of the enormous phenotypic variation observed across human populations is thought to have arisen from events experienced as our ancestors peopled different regions of the world. However, little is known about the genes involved in these population-specific adaptations. Here we explore this problem by simultaneously examining population-specific sequence and expression differentiation in four human populations. In particular, we design a branch-based statistic to estimate population-specific differentiation in four populations, and apply this statistic to single nucleotide polymorphism (SNP) and RNA-seq data from Italian, British, Finish, and Yoruban populations. As expected, genome-wide estimates of sequence and expression differentiation each independently recapitulate the known demographic history of these four human populations, highlighting the utility of our statistic for identifying genic targets of population-specific adaptations. Application of our statistic reveals that genes containing large copy number variations (CNVs) have elevated levels of population-specific sequence and expression differentiation, consistent with the hypothesis that gene turnover is a key reservoir of adaptive variation. Further, European genes displaying population-specific sequence and expression differentiation are enriched for functions related to epigenetic regulation, immunity, and reproduction. Together, our findings illustrate that population-specific sequence and expression differentiation in humans may preferentially target genes with CNVs and play important roles in a diversity of adaptive and disease-related phenotypes.
Microbial Community Dissimilarity for Source Tracking with Application in Forensic Studies
Authors: Carter Kyle M. , Lu Meng , Jiang Hongmei , An Lingling 
Published: August 2019

AbstractMicrobial source-tracking is a useful tool for trace evidence analysis in Forensics. Community-wide massively parallel sequencing profiles can bypass the need for satellite microbes or marker sets which are unreliable when handling unstable samples. We propose a method utilizing Aitchison distance to select important suspects/sources and then propose several methods to estimate the proportions of microbial communities/samples coming from important suspects/sources. A series of comprehensive simulation studies show that these methods are capable of accurate selection and improve the performance of current methods Bayesian SourceTracker and FEAST in the presence of noise microbial sources.
Functional effects of chimeric antigen receptor co-receptor signaling domains in human Tregs
Authors: Dawson Nicholas A.J. , Rosado-Sánchez Isaac , Novakovsky German E. , Fung Vivian C.W. , Huang Qing , McIver Emma , Sun Grace , Gillies Jana , Speck Madeleine , Orban Paul C. , Mojibian Majid , Levings Megan K 
Published: August 2019

SummaryAntigen-specific regulatory T cells (Tregs) engineered with chimeric antigen receptor (CARs) are a potent immunosuppressive cellular therapy in multiple disease models. To date the majority of CAR Treg studies employed second generation CARs, encoding a CD28 or 4-1BB co-receptor signaling domain and CD3ζ, but it was not known if this CAR design was optimal for Tregs. Using an HLA-A2-specific CAR platform and human Tregs, we compared ten CARs with different co-receptor signaling domains and systematically tested their function. Tregs expressing a CAR encoding wild-type CD28 were markedly superior to all other CARs tested in anin vivomodel of graft-versus-host disease. In vitro assays revealed stable expression of Helios and ability to suppress CD80 expression on DCs as keyin vitropredictors ofin vivofunction. This comprehensive study of CAR signaling-domain variants in Tregs can be leveraged to optimize CAR design for use in antigen-specific Treg therapy.
Acute effects of Adaptive Deep Brain Stimulation in Parkinson’s disease
Authors: Piña-Fuentes Dan , van Dijk J. Marc C. , van Zijl Jonathan C. , Moes Harmen R. , Oterdoom D. L. Marinus , Little Simon , Brown Peter , Beudel Martijn 
Published: August 2019

AbstractBackgroundBeta-based adaptive Deep Brain Stimulation (aDBS) is effective in Parkinson’s disease (PD), when assessed in the immediate post-implantation phase. However, the potential benefits of aDBS in patients with electrodes chronically implanted, in whom the benefits of the microlesion effect have disappeared, are yet to be assessed.MethodsTo determine the acute effectiveness and side-effect profile of aDBS in PD compared to conventional continuous DBS (cDBS) and no stimulation (NoStim), years after DBS implantation. 13 PD patients undergoing battery replacement were pseudo-randomised in a crossover fashion, in- to three conditions (NoStim, aDBS or cDBS). Patient videos were blindly evaluated using a short version of the Unified Parkinson’s Disease Rating Scale (subUPDRS) and the Speech Intelligibility Test (SIT).ResultsPatients had a mean disease duration of 16 years, and the mean time since DBS implantation was 6.9 years. subUPDRS scores (11 patients tested) were significantly lower both in aDBS (p=<.001), and cDBS (p=.001), when compared to NoStim. Bradykinesia subscores were significantly lower in aDBS (p=.002), but not in cDBS (p=.08), when compared to NoStim. Two patients presented re-emerging tremor during NoStim. SIT scores of patients with stimulation-induced dysarthria (11 patients tested) significantly worsened in cDBS (p=.009), but not in aDBS (p=.407), when compared to NoStim. Overall, stimulation was applied 48.8% of the time during aDBS.ConclusionBeta oscillations is effective in PD patients with bradykinetic phenotypes, delivers less stimulation than cDBS, and potentially has a more favourable speech side-effect profile. Patients with prominent tremor may require a modified adaptive control strategy.
Multi-shanks SiNAPS Active Pixel Sensor CMOS probe: 1024 simultaneously recording channels for high-density intracortical brain mapping
Authors: Boi Fabio , Perentos Nikolas , Lecomte Aziliz , Schwesig Gerrit , Zordan Stefano , Sirota Anton , Berdondini Luca , Angotzi Gian Nicola 
Published: August 2019

AbstractThe advent of implantable active dense CMOS neural probes opened a new era for electrophysiology in neuroscience. These single shank electrode arrays, and the emerging tailored analysis tools, provide for the first time to neuroscientists the neurotechnology means to spatiotemporally resolve the activity of hundreds of different single-neurons in multiple vertically aligned brain structures. However, while these unprecedented experimental capabilities to study columnar brain properties are a big leap forward in neuroscience, there is the need to spatially distribute electrodes also horizontally. Closely spacing and consistently placing in well-defined geometrical arrangement multiple isolated single-shank probes is methodologically and economically impractical. Here, we present the first high-density CMOS neural probe with multiple shanks integrating thousand’s of closely spaced and simultaneously recording microelectrodes to map neural activity across 2D lattice. Taking advantage from the high-modularity of our electrode-pixels-based SiNAPS technology, we realized a four shanks active dense probe with 256 electrode-pixels/shank and a pitch of 28 µm, for a total of 1024 simultaneously recording channels. The achieved performances allow for full-band, whole-array read-outs at 25 kHz/channel, show a measured input referred noise in the action potential band (300-7000 Hz) of 6.5 ± 2.1µVRMS, and a power consumption <6 µW/electrode-pixel. Preliminary recordings in awake behaving mice demonstrated the capability of multi-shanks SiNAPS probes to simultaneously record neural activity (both LFPs and spikes) from a brain area >6 mm2, spanning cortical, hippocampal and thalamic regions. High-density 2D array enables combining large population unit recording across distributed networks with precise intra- and interlaminar/nuclear mapping of the oscillatory dynamics. These results pave the way to a new generation of high-density and extremely compact multi-shanks CMOS-probes with tunable layouts for electrophysiological mapping of brain activity at the single-neurons resolution.