bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractNeisseria 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

AbstractFarnesol, 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

AbstractBackgroundEnterotoxigenicEscherichia 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.MethodsMice 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.ResultsOver 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.ConclusionsWe 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

AbstractBackgroundChloroplasts 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.ResultsHybrid 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.ConclusionsOur 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

AbstractObjectivesPersister 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.MethodsVancomycin, 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.ResultsDalbavancin 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.ConclusionsThe 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

AbstractLearning 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

AbstractPurposeHoloprosencephaly (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.MethodsExome 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.ResultsWe 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.ConclusionsThis 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.
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

ABSTRACTTranscription 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

AbstractTelomeres 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

AbstractThe 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

ABSTRACTThe 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

SUMMARYIn 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

AbstractStimulus 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.