bluuebunny/crossref_metadata_2025 huggingface dataset:
Utilizing random regression models for genomic prediction of a longitudinal trait derived from high-throughput phenotyping
Authors: Campbell Malachy , Walia Harkamal , Morota Gota
Published: May 2018

The accessibility of high-throughput phenotyping platforms in both the greenhouse and field, as well as the relatively low cost of unmanned aerial vehicles, have provided researchers with an effective means to characterize large populations throughout the growing season. These longitudinal phenotypes can provide important insight into plant development and responses to the environment. Despite the growing use of these new phenotyping approaches in plant breeding, the use of genomic prediction models for longitudinal phenotypes is limited in major crop species. The objective of this study is to demonstrate the utility of random regression (RR) models using Legendre polynomials for genomic prediction of shoot growth trajectories in rice (Oryza sativa). An estimate of shoot biomass, projected shoot area (PSA), was recored over a period of 20 days for a panel of 357 diverse rice accessions using an image-based greenhouse phenotyping platform. A RR that included a fixed second-order Legendre polynomial, a random second-order Legendre polynomial for the additive genetic effect, a first-order Legendre polynomial for the environmental effect, and heterogeneous residual variances was used to model PSA trajectories. The utility of the RR model over a single time point (TP) approach, where PSA is fit at each time point independently, is shown through four prediction scenarios. In the first scenario, the RR and TP approaches were used to predict PSA for a set of lines lacking phenotypic data. The RR approach showed a 11.6% increase in prediction accuracy over the TP approach. Much of this improvement could be attributed to the greater additive genetic variance captured by the RR approach. The remaining scenarios focused forecasting future phenotypes using a subset of early time points for known lines with phenotypic data, as well new lines lacking phenotypic data. In all cases, PSA could be predicted with high accuracy (r: 0.79 to 0.89 and 0.55 to 0.58 for known and unknown lines, respectively). This study provides the first application of RR models for genomic prediction of a longitudinal trait in rice, and demonstrates that RR models can be effectively used to improve the accuracy of genomic prediction for complex traits compared to a TP approach.
Transcriptome Analysis ofNeisseria gonorrhoeaeDuring Natural Infection Reveals Differential Expression of Antibiotic Resistance Determinants Between Men and Women
Authors: Nudel Kathleen , McClure Ryan , Moreau Matthew , Briars Emma , Abrams A. Jeanine , Tjaden Brian , Su Xiao-Hong , Trees David , Rice Peter A. , Massari Paola , Genco Caroline A.
Published: May 2018

Neisseria gonorrhoeaeis a bacterial pathogen responsible for the sexually transmitted infection, gonorrhea. Emergence of antimicrobial resistance (AMR) ofN. gonorrhoeaeworldwide has resulted in limited therapeutic choices for this infection. Men who seek treatment often have symptomatic urethritis; in contrast, gonococcal cervicitis in women is usually minimally symptomatic, but may progress to pelvic inflammatory disease. Previously, we reported the first analysis of gonococcal transcriptome expression determined in secretions from women with cervical infection. Here, we defined gonococcal global transcriptional responses in urethral specimens from men with symptomatic urethritis and compared these with transcriptional responses in specimens obtained from women with cervical infections, and ofin vitro-grown N. gonorrhoeaeisolates. This is the first comprehensive comparison of gonococcal gene expression in infected men and women. RNA sequencing analysis revealed that 9.4% of gonococcal genes showed increased expression exclusively in men and included genes involved in host immune cell interactions and 4.3% showed increased expression exclusively in women and included phage-associated genes. Infected men and women displayed comparable antibiotic resistant-genotypes andin vitro–phenotypes, but a 4-fold higher expression of the Mtr efflux pump-related genes was observed in men. These results suggest that expression of AMR genes is programmed genotypically, and also driven by sex-specific environments. Collectively, our results indicate that distinctN. gonorrhoeaegene expression signatures are detected during genital infection in men and women. We propose that therapeutic strategies could target sex specific differences in expression of antibiotic resistance genes.
C. albicans Zn Cluster Transcription Factors Tac1 and Znc1 are Activated by Farnesol to Up Regulate a Transcriptional Program Including the Multi-Drug Efflux Pump CDR1
Authors: Liu Zhongle , Rossi John M. , Myers Lawrence C.
Published: May 2018

Farnesol, a quorum-sensing molecule, inhibits C. albicans hyphal formation, affects its biofilm formation and dispersal, and impacts its stress response. Several aspects of farnesol’s mechanism of action remain incompletely uncharacterized. Among these are a thorough accounting of the cellular receptors and transporters for farnesol. This work suggests these themes are linked through the Zn cluster transcription factors Tac1 and Znc1, and their induction of the multi-drug efflux pump Cdr1. Specifically, we have demonstrated that Tac1 and Znc1 are functionally activated by farnesol through a mechanism that mimics other means of hyperactivation of Zn cluster transcription factors. This is consistent with our observation that many genes acutely induced by farnesol are dependent on TAC1, ZNC1, or both. A related molecule, 1-dodecanol, invokes a similar TAC1/ZNC1 response, while several other proposed C. albicans quorum sensing molecules do not. TAC1 and ZNC1 both bind to and up-regulate the CDR1 promoter in response to farnesol. Differences in inducer and DNA binding specificity lead to Tac1 and Znc1 having overlapping, but non-identical, regulons. TAC1 and ZNC1 dependent farnesol induction of their target genes was inversely related to the level of CDR1 present in the cell, suggesting a model in which induction of CDR1 by Tac1 and Znc1 leads to an increase in farnesol efflux. Consistent with this premise, our results show that CDR1 expression, and its regulation by TAC1 and ZNC1, facilitates growth in the presence of high farnesol concentrations in C. albicans, and certain strains of its close relative C. dubliniensis.
Identification and Characterization of Human Monoclonal Antibodies for Immunoprophylaxis Against Enterotoxigenic Escherichia coli Infection
Authors: Giuntini Serena , Stoppato Matteo , Sedic Maja , Ejemel Monir , Pondish Jessica R. , Wisheart Danielle , Schiller Zachary A. , Thomas William D. , Barry Eileen M. , Cavacini Lisa A. , Klempner Mark S. , Wang Yang
Published: May 2018

Background

EnterotoxigenicEscherichia coli(ETEC) cause diarrheal illness in infants in the developing world and travelers to endemic countries including military personnel. ETEC infection of the host involves colonization of the small intestinal epithelium and toxin secretion leading to watery diarrhea. There is currently no vaccine licensed to prevent ETEC. CFA/I is one of the most common colonization factor antigens (CFAs). The CFA/I adhesin subunit, CfaE, is required for ETEC adhesion to host intestinal cells. Human antibodies against CfaE have potential to block colonization of ETEC and serve as an immunoprophylactic against ETEC-related diarrhea.

Methods

Mice transgenic for human immunoglobulin genes were immunized with CfaE to generate a panel of human monoclonal IgG1 antibodies (HuMAbs). The most potent IgG1 identified in thein vitrofunctional assays were selected and isotype switched to secretory IgA (sIgA) and tested in animal colonization assays via oral administration.

Results

Over 300 unique anti-CfaE IgG1 HuMabs were identified. The lead IgG1 anti-CfaE HuMAbs completely inhibited hemagglutination and blocked adhesion of ETEC to Caco-2 cells. Epitope mapping studies revealed that HuMAbs recognized epitopes in the N-terminal domain of CfaE near the putative receptor binding site. Oral administration of anti-CfaE antibodies in either IgG or secretory IgA isotypes inhibited intestinal colonization in mice challenged with ETEC. A two to four log decrease of colony forming units was observed as compared to irrelevant isotype controls.

Conclusions

We identified fully human monoclonal antibodies against CfaE adhesion domain that can be potentially employed as an immunoprophylaxis to prevent ETEC-related diarrhea.
Assembly of chloroplast genomes with long- and short-read data: a comparison of approaches using Eucalyptus pauciflora as a test case
Authors: wang weiwen , Schalamun Miriam , Morales Suarez Alejandro , Kainer David , Schwessinger Benjamin , Lanfear Robert
Published: May 2018

Background

Chloroplasts are organelles that conduct photosynthesis in plant and algal cells. Chloroplast genomes code for around 130 genes, and the information they contain is widely used in agriculture and studies of evolution and ecology. Correctly assembling complete chloroplast genomes can be challenging because the chloroplast genome contains a pair of long inverted repeats (10–30 kb). The advent of long-read sequencing technologies should alleviate this problem by providing sufficient information to completely span the inverted repeat regions. Yet, long-reads tend to have higher error rates than short-reads, and relatively little is known about the best way to combine long- and short-reads to obtain the most accurate chloroplast genome assemblies. Using Eucalyptus pauciflora, the snow gum, as a test case, we evaluated the effect of multiple parameters, such as different coverage of long (Oxford nanopore) and short (Illumina) reads, different long-read lengths, different assembly pipelines, and different genome polishing steps, with a view to determining the most accurate and efficient approach to chloroplast genome assembly.

Results

Hybrid assemblies combining at least 20x coverage of both long-reads and short-reads generated a single contig spanning the entire chloroplast genome with few or no detectable errors. Short-read-only assemblies generated three contigs representing the long single copy, short single copy and inverted repeat regions of the chloroplast genome. These contigs contained few single-base errors but tended to exclude several bases at the beginning or end of each contig. Long-read-only assemblies tended to create multiple contigs with a much higher single-base error rate, even after polishing. The chloroplast genome of Eucalyptus pauciflora is 159,942 bp, contains 131 genes of known function, and confirms the phylogenetic position of Eucalyptus pauciflora as a close relative of Eucalyptus regnans.

Conclusions

Our results suggest that very accurate assemblies of chloroplast genomes can be achieved using a combination of at least 20x coverage of long- and short-reads respectively, provided that the long-reads contain at least ~5x coverage of reads longer than the inverted repeat region. We show that further increases in coverage give little or no improvement in accuracy, and that hybrid assemblies are more accurate than long-read-only or short-read-only assemblies.
Detection and quantification of the heterogeneity of S. aureus bacterial populations to identify antibiotic-induced persistence
Authors: Hassan Marwa M. , Butler Mark S. , Ranzoni Andrea , Cooper Matthew A.
Published: May 2018

Objectives

Persister cells are characterised as being viable but non-culturable, a state that preserves their metabolic energy to survive the environmental stress, which allows for recurrent infections. Detection of persisters is, therefore, not possible with standard culture-dependent methods. Furthermore, the effect of antibiotics on the induction of persisters has not been assessed. This study aimed to identify antibiotic-induced persistence and determine the percentage of heterogeneity.

Methods

Vancomycin, daptomycin and dalbavancin were assessed by standard MIC methods against selected Staphylococcus aureus strains. Replicates of MIC assays were stained with propidium iodide to quantify live/dead and a reactive oxygen species (ROS) dye to detect and quantify persisters using culture-independent single-cell sorting, independently. A comparative analysis was then performed.

Results

Dalbavancin showed the lowest MIC values against tested S. aureus strains followed by daptomycin and vancomycin. Cell sorting of vancomycin-, daptomycin- and dalbavancin-treated S. aureus strains showed a range of 1.9–10.2%, 17.7–62.9% and 7.5–77.6% live cells based on the strain, respectively, in which daptomycin, in particular, was a strong inducer of a persister population. Persisters represented 3.7–16% of the bacterial population.

Conclusions

The culture-independent identification of antibiotic-induced persistence through studying at the single-cell level showed different efficacy of antibiotics than standard MIC. Vancomycin was the most effective antibiotic against tested strains followed by dalbavancin then daptomycin as assessed by cell sorting. Therefore, re-evaluation of standard MIC methods may be required to assess the efficacy of antibiotics. Additionally, the detection of daptomycin-associated persisters may provide an elucidation to the reported rapid resistance development in vivo.
Post-reactivation new learning impairs and updates human episodic memory through dissociable processes
Authors: Zhu Zijian , Wang Yingying , Jia Jianrong , Huang Liqiang , Rao Yi , Wu Yanhong
Published: May 2018

Learning of competing information after reactivation has the potential to disrupt memory reconsolidation and thus impair a consolidated memory. Yet this effect has rarely been detected in episodic memory. By introducing an additional retrieving cue to the target memory, the current study detected significant impairment on the reactivated episodic memory, in addition to an integration of new information to the old memory. However, while the integration effect followed the time window of reconsolidation disruption, the impairment effect did not. MEG measurements further revealed alpha power change during reactivation and post-reactivation learning which showed different correlation patterns with the integration and impairment effects, confirming that the two effects relied on different processes. Therefore, post-reactivation new learning disrupts episodic memory but not through reconsolidation disruption. Further findings that the impairment effect was correlated with participants’ voluntary inhibition ability suggest an inhibition-based memory updating process underlying post-reactivation new learning.
Integrated Clinical and Omics Approach to Rare Diseases: Novel Genes and Oligogenic Inheritance in Holoprosencephaly
Authors: Kim Artem , Savary Clara , Dubourg Christèle , Carré Wilfrid , Mouden Charlotte , Hamdi-Rozé Houda , Guyodo Hélène , Le Douce Jerome , Pasquier Laurent , Flori Elisabeth , Gonzales Marie , Bénéteau Claire , Boute Odile , Attié-Bitach Tania , Roume Joelle , Goujon Louise , Akloul Linda , Watrin Erwan , Dupé Valérie , Odent Sylvie , de Tayrac Marie , David Véronique
Published: May 2018

Purpose

Holoprosencephaly (HPE) is a pathology of forebrain development characterized by high phenotypic and locus heterogeneity. Seventeen genes are known so far in HPE but the understanding of its genetic architecture remains to be refined. Here, we investigated the oligogenic nature of HPE resulting from accumulation of variants in different relevant genes.

Methods

Exome data from 29 patients diagnosed with HPE and 51 relatives from 26 unrelated families were analyzed. Standard variant classification approach was improved with a gene prioritization strategy based on clinical ontologies and gene co-expression networks. Clinical phenotyping and exploration of cross-species similarities were further performed on a family-by-family basis.

Results

We identified 232 rare deleterious variants in HPE patients representing 180 genes significantly associated with key pathways of forebrain development including Sonic Hedgehog (SHH) and Primary Cilia. Oligogenic events were observed in 10 families and involved novel HPE genes including recurrently mutated genes (FAT1, NDST1, COL2A1 and SCUBE2) and genes implicated in cilia function.

Conclusions

This study reports novel HPE-relevant genes and reveals the existence of oligogenic cases resulting from several mutations in SHH-related genes. It also underlines that integrating clinical phenotyping in genetic studies will improve the identification of causal variants in rare disorders.
Dlk1-Dio3Locus-Derived LncRNAs Perpetuate Postmitotic Motor Neuron Cell Fate and Subtype Identity
Authors: Yen Ya-Ping , Hsieh Wen-Fu , Lu Ya-Lin , Liau Ee Shan , Hsu Ho-Chiang , Chen Yen-Chung , Liu Ting-Chun , Chang Mien , Li Joye , Lin Shau-Ping , Hung Jui-Hung , Chen Jun-An
Published: May 2018

The mammalian imprintedDlk1-Dio3locus produces multiple long non-coding RNAs (lncRNAs) from the maternally inherited allele, includingMeg3(i.e.Gtl2) in the mammalian genome. Although this locus has well-characterized functions in stem cell and tumor contexts, its role during neural development is unknown. By transcriptome profiling cell types at each stage of spinal cord development, we uncovered that lncRNAs expressed from theDlk1-Dio3locus are predominantly and gradually enriched in rostral motor neurons (MNs). Mechanistically,Meg3and otherDlk1-Dio3locus-derived lncRNAs facilitate Jarid2-Ezh2 interactions. Loss of these lncRNAs compromises the H3K27me3 landscape, leading to aberrant expression of progenitor and caudalHoxgenes in postmitotic MNs. Our data illustrate that these lncRNAs in theDlk1-Dio3locus play a critical role in maintaining postmitotic MN cell fate by repressing progenitor genes and they shape MN subtype identity by regulatingHoxgenes, providing strong evidence of how lncRNAs function during embryonic development.
Transcription apparatus of the yeast killer DNA plasmids: Architecture, function, and evolutionary origin
Authors: Sýkora Michal , Pospíšek Martin , Novák Josef , Mrvová Silvia , Krásný Libor , Vopálenský Václav
Published: May 2018

Transcription of extrachromosomal elements such as organelles, viruses, and plasmids is dependent on cellular RNA polymerase (RNAP) or intrinsic RNAP encoded by these elements. The yeastKluyveromyces lactiscontains killer DNA plasmids that bear putative non-canonical RNAP genes. Here, we describe the architecture and evolutionary origin of this transcription machinery. We show that the two RNAP subunits interactin vivo, and this complex interacts with another two plasmid-encoded proteins - the mRNA capping enzyme, and a putative helicase which interacts with plasmid-specific DNA. Further, we identify a promoter element that causes 5’ polyadenylation of plasmid-specific transcriptsviaRNAP slippage during transcription initiation, and structural elements that precede the termination sites. As a result, we present a first model of the yeast killer plasmid transcription initiation and intrinsic termination. Finally, we demonstrate that plasmid RNAP and its promoters display high similarity to poxviral RNAP and promoters of early poxviral genes, respectively.
Telomeres as integrative markers of exposure to stress and adversity: A systematic review and meta-analysis
Authors: Pepper Gillian V. , Bateson Melissa , Nettle Daniel
Published: May 2018

Telomeres have been proposed as a biomarker that integrates the impacts of different kinds of stress and adversity into a common currency. There has as yet been no overall comparison of how different classes of exposure associate with telomeres. We present a meta-analysis of the literature relating telomere measures to stresses and adversities in humans. The analysed dataset contained 543 associations from 138 studies involving 402,116 people. Overall, there was a weak association between telomere variables and exposures (greater adversity, shorter telomeres:r= −0.15, 95% CI - 0.18 to −0.11). This was not driven by any one type of exposure, since significant associations were found separately for physical diseases, environmental hazards, nutrition, psychiatric illness, smoking, physical activity, psychosocial and socioeconomic exposures. Methodological features of the studies did not explain any substantial proportion of the heterogeneity in association strength. There was, however, evidence consistent with publication bias, with unexpectedly strong negative associations reported by studies with small samples. Restricting analysis to sample sizes greater than 100 attenuated the overall association substantially (r= −0.09, 95% CI −0.13 to −0.05). Most studies were underpowered to detect the typical association magnitude. The literature is dominated by cross-sectional and correlational studies which makes causal interpretation problematic.
Highly differentiated CD4 T cells Unequivocally Identify Primary Resistance and Risk of Hyperprogression to PD-L1/PD-1 Immune Checkpoint Blockade in Lung Cancer
Authors: Zuazo-Ibarra Miren , Arasanz Hugo , Fernández-Hinojal Gonzalo , María Gato-Cañas , Hernández-Marín Berta , Martínez-Aguillo Maite , Jose Lecumberri Maria , Fernández Angela , Teijeira Lucía , Vera Ruth , Kochan Grazyna , Escors David
Published: May 2018

The majority of lung cancer patients are refractory to PD-L1/PD-1 blockade monotherapy. This therapy may even accelerate progression and death in a group of patients called hyperprogressors. Here we demonstrate that the efficacy of PD-L1/PD-1 blockade therapy relies on baseline circulating highly-differentiated CD28−CD27−CD4 T cells (THDcells), which segregate patients in two non-overlapping groups. THDcells in cancer patients mostly comprised of central memory subsets that potently co-upregulated PD-1 and LAG3 upon antigen recognition. Low baseline THDnumbers unequivocally identified intrinsic non-responders and hyperprogressors, whom aberrantly responded to therapy with a potent systemic proliferative THDcell burst. Responder patients showed significant reductions in systemic CD4 THDcells throughout therapy linked to expansion of the CD28+ CD27+ CD4 T cell compartment. Quantification of THDcells from peripheral blood samples prior to therapy allows identification of non-responders, hyperprogressors and responders, a critical issue in clinical oncology. These results place CD4 T cell responses at the center of anti-tumor immunity.
Identification of a divergent cytochrome c oxidase complex in the mitochondrial proteome of Toxoplasma gondii
Authors: Seidi Azadeh , Muellner-Wong Linden S. , Rajendran Esther , Tjhin Edwin T. , Dagley Laura F. , Vincent Aw Y.T. , Webb Andrew I. , Tonkin Christopher J. , van Dooren Giel G.
Published: May 2018

The mitochondrion of apicomplexan parasites is critical for parasite survival, although the full complement of proteins that localize to this organelle has not been defined. Here we undertake two independent approaches to elucidate the mitochondrial proteome of the apicomplexan Toxoplasma gondii. We identify 421 mitochondrial proteins, many of which lack homologs in the animals that these parasites infect, and most of which are important for parasite growth. We demonstrate that one such protein, termed TgApiCox25, is an important component of the parasite cytochrome c oxidase (COX) complex. We identify numerous other apicomplexan-specific components of COX, and conclude that apicomplexan COX, and apicomplexan mitochondria more generally, differ substantially in their protein composition from the hosts they infect. Our study highlights the diversity that exists in mitochondrial proteomes across the eukaryotic domain of life, and provides a foundation for defining unique aspects of mitochondrial biology in an important phylum of parasites.
Binocular modulation of monocular V1 neurons
Authors: Dougherty Kacie , Cox Michele A. , Westerberg Jacob A. , Maier Alexander
Published: May 2018

In humans and other primates, sensory signals from each eye remain separated until they arrive in the primary visual cortex (V1), but their exact meeting point is unknown. In V1, some neurons are activated by stimulation of only one eye (monocular neurons) while most neurons are driven by stimulation of either eye (binocular neurons). Monocular neurons are most prevalent in the main input layers of V1 while binocular neurons dominate the layers above and below. This observation has given rise to the idea that the two eyes’ signals remain separate until they converge outside V1’s input layers. Here, we show that despite responding to only one eye, monocular neurons in all layers, including the input layers, of V1 discriminate between stimulation of their driving eye alone and stimulation of both eyes. This finding suggests that binocular signals occur at an earlier processing stage than previously appreciated as even so-called monocular neurons across all V1 layers encode what is shown to both eyes.
Adaptation of Intracortical Signaling Concurs with Enhanced Encoding Efficiency
Authors: Westerberg Jacob A. , Cox Michele A. , Dougherty Kacie , Maier Alexander
Published: May 2018

Stimulus repetitions improve performance despite decreased brain responses, suggesting that the brain is more efficient when processing familiar stimuli. Previous work demonstrated that stimulus repetition enhances encoding efficiency in primary visual cortex (V1) by increasing synchrony and sharpening the orientation tuning of neurons. Here we show that these adaptive changes are supported by an altered flow of sensory activation across the V1 laminar microcircuit. Using a repeating stimulus sequence, we recorded laminar responses in V1 of two fixating monkeys. We found repetition-related response reductions that were most pronounced outside V1 layers that receive the main retinogeniculate input. This repetition-induced suppression was robust to alternating stimuli between the eyes, in line with the notion that repetition suppression is predominantly of cortical origin. Congruent with earlier reports, we found that V1 adaptation to repeating stimuli is accompanied by sharpened neural tuning as well as increased neural synchrony. Current source density (CSD) analysis, which provides an estimate of net synaptic activation, revealed that the responses to repeated stimuli were most profoundly affected within layers that harbor the bulk of cortico-cortical connections. Together, these results suggest that stimulus repetition induces an altered state of intracortical processing resulting in enhanced encoding efficiency of sensory stimuli.
Endothelial and non-endothelial responses to estrogen excess during development lead to vascular malformations
Authors: Parajes Silvia , Ramas Sophie , Stainier Didier Y.R.
Published: May 2018

Excess estrogen signaling is associated with vascular malformations and pathologic angiogenesis, as well as tumor progression and metastasis. Yet, how dysregulated estrogen signaling impacts vascular morphogenesis in vivo remains elusive. Here we use live imaging of zebrafish embryos to determine the effects of excess estrogen signaling on the developing vasculature. We find that excess estrogens during development induce intersegmental vessel defects, endothelial cell-cell disconnections, and a shortening of the circulatory loop due to arterial-venous segregation defects. Whole-mount in situ hybridization and qPCR analyses reveal that excess estrogens negatively regulate Sonic hedgehog (Hh)/Vegf/Notch signaling. Activation of Hh signaling with SAG partially rescues the estrogen-induced vascular defects. Similarly, increased vegfaa bioavailability, using flt1/vegfr1 mutants or embryos overexpressing vegfaa165, also partially rescues the estrogen-induced vascular defects. We further find that excess estrogens promote aberrant endothelial cell (EC) migration, possibly as a result of increased PI3K and Rho GTPase signaling. Using estrogen receptor mutants and pharmacological studies, we show that Esr1 and the G-protein coupled estrogen receptor (Gper1) are the main receptors driving the estrogen-induced vascular defects. Mosaic overexpression of gper1 in ECs promotes vascular disconnections and aberrant migration, whereas no overt vascular defects were observed in mosaic embryos overexpressing wild-type or constitutively active nuclear estrogen receptors in their ECs. In summary, developmental estrogen excess leads to a mispatterning of the forming vasculature. Gper1 can act cell-autonomously in ECs to cause disconnections and aberrant migration, whilst Esr signaling predominantly downregulates Hh/Vegf/Notch signaling leading to impaired angiogenesis and defective arterial-venous segregation.

Subject codes: angiogenesis, animal models of human disease, mechanisms, vascular biology.
Oculomotor capture reveals trial-by-trial neural correlates of attentional guidance by contents of visual working memory
Authors: Beck Valerie M. , Vickery Timothy J.
Published: May 2018

Evidence from attentional and oculomotor capture, contingent capture, and other paradigms suggests that mechanisms supporting human visual working memory (VWM) and visual attention are intertwined. Features held in VWM bias guidance toward matching items even when those features are task irrelevant. However, the neural basis of this interaction is underspecified. Prior examinations using fMRI have primarily relied on coarse comparisons across experimental conditions that produce varying amounts of capture. To examine the neural dynamics of attentional capture on a trial-by-trial basis, we applied an oculomotor paradigm that produced discrete measures of capture. On each trial, subjects were shown a memory item, followed by a blank retention interval, then a saccade target that appeared to the left or right. On some trials, an irrelevant distractor appeared above or below fixation. Once the saccade target was fixated, subjects completed a forced-choice memory test. Critically, either the target or distractor could match the feature held in VWM. Although task irrelevant, this manipulation produced differences in behavior: participants were more likely to saccade first to an irrelevant VWM-matching distractor compared with a non-matching distractor – providing a discrete measure of capture. We replicated this finding while recording eye movements and scanning participants’ brains using fMRI. To examine the neural basis of oculomotor capture, we separately modeled the retention interval for capture and non-capture trials within the distractor-match condition. We found that frontal activity, including anterior cingulate cortex and superior frontal gyrus regions, differentially predicted subsequent oculomotor capture by a memory-matching distractor. Other regions previously implicated as involved in attentional capture by VWM-matching items showed no differential activity across capture and no-capture trials, even at a liberal threshold. Our findings demonstrate the power of trial-by-trial analyses of oculomotor capture as a means to examine the underlying relationship between VWM and attentional guidance systems.
A community-level investigation of the yellow fever virus outbreak in South Omo Zone, South-West Ethiopia, 2012–2014
Authors: Mulchandani Ranya , Massebo Fekadu , Bocho Fekadu , Jeffries Claire L , Walker Thomas , Messenger Louisa A
Published: May 2018

Background

A yellow fever (YF) outbreak occurred in South Omo Zone, Ethiopia in 2012-2014. This study aimed to analyse historical epidemiological data, to assess the risk for future YF outbreaks through entomological surveillance, including mosquito species identification and molecular screening for arboviruses, and finally to determine the knowledge, attitudes and current preventative practices within the affected communities.

Methodology/Principal Findings

From October 2012 to March 2014, 165 cases and 62 deaths were reported, principally in rural areas of South Ari region (83.6%), south-west Ethiopia. The majority of patients were 15-44 years old (74.5%) and most case deaths were males (76%). Between June and August 2017, 688 containers were sampled from across 177 households to identify key breeding sites forAedesmosquitoes.Ensete ventricosum(“false banana”) was identified as the primary natural breeding site, and clay pots outside the home as the most productive artificial breeding site. Entomological risk indices from the majority of sites were classified as “high risk” for future outbreaks under current World Health Organization criteria. Adult trapping resulted in the identification of members of theAedes simpsonicomplex in and around households. Screening of adult females revealed no detection of yellow fever virus (YFV) or other arboviruses. 88% of 177 participants had heard of YF, however many participants easily confused transmission and symptoms of YF with malaria, which is also endemic in the area.

Conclusions/Significance

Study results emphasise the need for further entomological studies to improve our understanding of local vector species and transmission dynamics. Disease surveillance systems and in-country laboratory capacity also need to be strengthened to facilitate more rapid responses to future YF outbreaks.

Author Summary

Despite the availability of a highly effective vaccine, yellow fever virus (YFV) remains an important public health problem across Africa and South America due to its high case-fatality rate. This study aimed to assess and reduce the risk for future outbreaks. During this study, historical data analysis was conducted to understand the epidemiology of the recent outbreak in 2012-2014. Entomological surveillance was also carried out, including both mosquito species identification and molecular screening for arboviruses, as well as a household survey to understand the knowledge and attitudes towards yellow fever (YF) within the affected areas and to assess community-level practices for YF prevention. We found a high abundance ofAedes simpsonicomplex in the context of low vaccination coverage. Community knowledge and practice levels were low for reducing potential breeding sites, highlighting the need for increased dissemination of information to community members on how to reduce their risk of exposure to mosquito vectors of arboviruses.
Examining food intake and eating out of home patterns among university students
Authors: Llanaj Erand , Àdàny Róza , Lachat Carl , D’Haese Marijke
Published: May 2018

Eating out of home (OH) is increasingly popular in Balkan countries, among them Albania. To date there is only anecdotal evidence regarding nutritional quality of food consumed OH and the contribution to diet. This study assessed intake of foods and drinks consumed OH and at home (AH), as well as their nutritional contribution to the daily diet of university students in Tirana, Albania. Using a single day Automated Multiple Pass Method (AMPM) 24-hour dietary recall, we examined food intake among 289 students aged 18-24 years old, from three major universities in Albania. Contribution of eating OH to total energy intake per day, as well as to daily consumption of macronutrients by eating OH intensity tertiles were assessed. Foods and drinks consumed OH contributed 46.9% [95%CI:41.4-52.8] of total daily energy intake, representing, on average, 1169.1kcal [95%CI:1088.3-1249.9]. Sweets, soft drinks and meat products were more frequently consumed OH, while fruits and vegetables consumption was extremely low. The average quantity of sugars and dietary fats per day was higher AH, 76.9g [95%CI:70.3-83.5] and 173.7g [95%CI:163.2-184.2] respectively, compared to OH, 33.7g [95%CI:30.4-37.0] and 142.0g [95%CI:131.5-152.5] respectively. Dietary composition of AH intake was richer in sugars, total fats and proteins, while OH intake was richer in saturated fats. The overall diet appeared unhealthy, when nutrients were assessed as energy percentage against WHO proposed nutrient standards for sugar and saturated fats. Eating OH, even though was associated with lower fruits and vegetables intake, was not clearly associated with poor diet quality, as AH foods were also characterized by increased saturated fats and sugars intake as energy percentage. This study provides data on the first assessment of current dietary patterns of the studied population and can be used as baseline for designing and conducting future studies and interventions targeting malnutrition in all its forms.
Human genomics of acute liver failure due to hepatitis B virus infection: an exome sequencing study in liver transplant recipients
Authors: Asgari Samira , Chaturvedi Nimisha , Scepanovic Petar , Hammer Christian , Semmo Nasser , Giostra Emiliano , Müllhaupt Beat , Angus Peter , Thompson Alexander J , Moradpour Darius , Fellay Jacques
Published: May 2018

Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life-threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen-specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti-HBc and anti-HBs antibodies but had no clinical history of jaundice or liver disease. After a series of hypothesis-driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case-control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV-related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals.

Author Summary

Infection with hepatitis B virus (HBV) is very common and causes a variety of liver diseases including acute and chronic hepatitis, cirrhosis and liver carcinoma. Acute HBV infection is often asymptomatic, still about 1% of newly infected people develop a rapid and severe disease known as acute liver failure or fulminant hepatitis. Acute liver failure has a high mortality rate and is an indication for urgent liver transplantation. It is not clear why some people, who are otherwise healthy, develop such severe symptoms upon infection with a common pathogen. Here, we hypothesized that rare DNA variants in the human genome could contribute to this unusual susceptibility. We sequenced the exome (i.e. the regions of the genome that encode the proteins) of 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and searched for rare genetic variants that could explain the clinical presentation. We did not identify any variant that could be convincingly linked to the extreme susceptibility to HBV observed in the study participants. This suggests that HBV-induced acute liver failure is more likely to result from the combined influence of multiple genetic and environmental factors.
The protozoanTrichomonas vaginalistargets bacteria with laterally-acquired NlpC/P60 peptidoglycan hydrolases
Authors: Pinheiro Jully , Biboy Jacob , Vollmer Waldemar , Hirt Robert P. , Keown Jeremy R. , Artuyants Anastasiia , Goldstone David C. , Simoes-Barbosa Augusto
Published: May 2018

Trichomonas vaginalisis a human eukaryotic pathogen and the causative agent of trichomoniasis, the most prevalent non-viral sexually transmitted infection worldwide. This extracellular protozoan parasite is intimately associated with the human vaginal mucosa and microbiota but key aspects of the complex interactions between the parasite and the vaginal bacteria remain elusive. We report thatT. vaginalishas acquired, by lateral gene transfer from bacteria, genes encoding peptidoglycan hydrolases of the NlpC/P60 family. Two of theT. vaginalisenzymes were active against bacterial peptidoglycan, retaining the active site fold and specificity as DL-endopeptidases. The endogenous NlpC/P60 genes are transcriptionally up regulated inT. vaginaliswhen in the presence of bacteria. The over-expression of an exogenous copy produces a remarkable phenotype where the parasite is capable of competing out bacteria from mixed cultures, consistent with the biochemical activity of the enzymein vitro. Our study highlights the relevance of the interactions of this eukaryotic pathogen with bacteria, a poorly understood aspect on the biology of this important human parasite.

Author summary

Trichomonas vaginalisis a protozoan parasite that causes a very common sexually transmitted disease known as trichomoniasis. This extracellular parasite resides in the vagina where it is in close association with the mucosa and the local microbiota. Very little is known about the nature of the parasite-bacteria interactions. Here, we report that this parasite had acquired genes from bacteria which retained their original function producing active enzymes capable of degrading peptidoglycan, a polymer that is chemically unique to the cell envelope of bacteria. Our results indicate that these enzymes help the parasite compete out bacteria in mixed cultures. These observations suggest that these enzymes may be critical for the parasite to establish infection in the vagina, a body site that is densely colonised with bacteria. Our study further highlights the importance of understanding the interactions between pathogens and microbiota, as the outcomes of these interactions are increasingly understood to have important implications on health and disease.
Robust associative learning is sufficient to explain structural and dynamical properties of local cortical circuits
Authors: Zhang Danke , Zhang Chi , Stepanyants Armen
Published: May 2018

The ability of neural networks to associate successive states of network activity lies at the basis of many cognitive functions. Hence, we hypothesized that many ubiquitous structural and dynamical properties of local cortical networks result from associative learning. To test this hypothesis, we trained recurrent networks of excitatory and inhibitory neurons on memory sequences of varying lengths and compared network properties to those observed experimentally. We show that when the network is robustly loaded with near-maximum amount of associations it can support, it develops properties that are consistent with the observed probabilities of excitatory and inhibitory connections, shapes of connection weight distributions, overrepresentations of specific 3-neuron motifs, distributions of connection numbers in clusters of 3–8 neurons, sustained, irregular, and asynchronous firing activity, and balance of excitation and inhibition. What is more, memories loaded into the network can be retrieved even in the presence of noise comparable to the baseline variations in the postsynaptic potential. Confluence of these results suggests that many structural and dynamical properties of local cortical networks are simply a byproduct of associative learning.
DOT1L suppresses nuclear RNAi originating from enhancer elements in Caenorhabditis elegans
Authors: Esse Ruben , Gushchanskaia Ekaterina , Lord Avery , Grishok Alla
Published: May 2018

Methylation of histone H3 on lysine 79 (H3K79) by DOT1L is associated with actively transcribed genes. Earlier, we described that DOT-1.1, the Caenorhabditis elegans DOT1L homologue, cooperates with the chromatin-binding protein ZFP-1 (AF10 homologue) to negatively modulate transcription of highly and widely expressed target genes. Also, reduction in ZFP-1 levels has long been associated with lower efficiency of RNA interference (RNAi) triggered by exogenous double-stranded RNA (dsRNA), but the reason for this is not clear. Here, we demonstrate that DOT1L suppresses bidirectional transcription, including that producing enhancer RNAs, thereby preventing dsRNA formation and ectopic RNAi. This ectopic elevation of endogenous dsRNA may engage the Dicer complex and, therefore, limit efficiency of exogenous RNAi. Our insight provides a novel perspective on the underlying mechanisms of DOT1L function in development, neural activity, and cancer.
Poor coherence in older people's speech is explained by impaired semantic and executive processes
Authors: Hoffman Paul , Loginova Ekaterina , Russell Asatta
Published: May 2018

The ability to speak coherently is essential for effective communication but declines with age: older people more frequently produce tangential, off-topic speech. The cognitive factors underpinning this decline are poorly understood. We predicted that maintaining coherence relies on effective regulation of activated semantic knowledge about the world, and particularly on the selection of currently relevant semantic representations to drive speech production. To test this, we collected 840 speech samples along with measures of executive and semantic ability from 60 young and older adults, using a novel computational method to quantify coherence. Semantic selection ability predicted coherence, as did level of semantic knowledge and a measure of domain-general executive ability. These factors fully accounted for the age-related coherence deficit. Our results indicate that maintaining coherence in speech becomes more challenging as people age because they accumulate more knowledge but are less able to effectively regulate how it is activated and used.
Innate potential of random genetic oligomer pools for recombination
Authors: Mutschler Hannes , Taylor Alexander I. , Lightowlers Alice , Houlihan Gillian , Abramov Mikhail , Herdewijn Piet , Holliger Philipp
Published: May 2018

The spontaneous emergence of function from prebiotic pools of informational polymers is a central conjecture of current origin of life scenarios. However, the innate functional capacity of random genetic polymer pools is unknown. Here, we have examined the ab initio activity of random and semi-random eicosamer pools of RNA, DNA and the unnatural genetic polymers ANA (arabino-), HNA (hexitol-) and AtNA (altritol-nucleic acids) with respect to a simple functional test: the capacity for intermolecular ligation and recombination. While DNA, ANA and HNA pools proved inert, naïve RNA and AtNA pools displayed diverse modes of intermolecular recombination in eutectic ice phases. Recombination appears linked to the vicinal ring cis-diol shared by RNA and AtNA. Thus, the chemical configuration that renders both susceptible to hydrolysis also enables substantial spontaneous intrapool recombination in the absence of activation chemistry with a concomitant increase in the compositional and structural complexity of recombined pools.
Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology and Hebbian plasticity in the mouse hippocampus
Authors: Moulin Thiago C. , Petiz Lyvia L. , Rayêe Danielle , Winne Jessica , Maia Roberto G. , Cruz Rafael V. Lima da , Amaral Olavo B. , Leão Richardson N.
Published: May 2018

Prolonged increases in excitation can trigger cell-wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely-moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 h of stimulation with 15-ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin-2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2-expressing mice immediately after the end of stimulation. Lastly, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.