bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell transcriptome analysis reveals TOX as a promoting factor for T-cell exhaustion and a predictor for anti-PD1 responses in human cancer
Authors: Kim Kyungsoo , Park Seyeon , Park Seong Yong , Kim Gamin , Park Su Myeong , Cho Jae-Won , Kim Da Hee , Park Young Min , Koh Yoon Woo , Kim Hye Ryun , Ha Sang-Jun , Lee Insuk 
Published: May 2019

ABSTRACTBackgroundT cells exhibit heterogeneous functional states in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) can reinvigorate only the stem cell-like progenitor exhausted T cells, which suggests that inhibiting the exhaustion progress will improve the efficacy of immunotherapy. Thus, regulatory factors promoting T-cell exhaustion could serve as potential targets for delaying the process and improving ICI efficacy.MethodsWe analyzed the single-cell transcriptome data derived from human melanoma and non-small cell lung cancer (NSCLC) samples and classified the tumor-infiltrating (TI) CD8+ T-cell population based on PDCD1 (PD-1) levels, i.e. PDCD1-high and PDCD1-low cells. Additionally, we identified differentially expressed genes as candidate factors regulating intra-tumoral T-cell exhaustion. The co-expression of candidate genes with immune checkpoint (IC) molecules in the TI CD8+ T cells was confirmed by single-cell trajectory and flow-cytometry analyses. The loss-of-function effect of the candidate regulator was examined by a cell-based knockdown assay. The clinical effect of the candidate regulator was evaluated based on the overall survival and anti-PD-1 responses.ResultsWe retrieved many known factors for regulating T-cell exhaustion among the differentially expressed genes between PDCD1-high and PDCD1-low subsets of the TI CD8+ T cells in human melanoma and NSCLC. TOX was the only transcription factor (TF) predicted in both tumor types. TOX levels tend to increase as CD8+ T cells become more exhausted. Flow-cytometry analysis revealed a correlation between TOX expression and severity of intra-tumoral T-cell exhaustion. TOX knockdown in the human TI CD8+ T cells resulted in downregulation of PD-1, TIM-3, TIGIT, and CTLA-4, which suggests that TOX promotes intra-tumoral T-cell exhaustion by upregulating IC proteins in cancer. Finally, the TOX level in the TI T cells was found to be highly predictive of overall survival and anti-PD-1 efficacy in melanoma and NSCLC.ConclusionsWe predicted the regulatory factors involved in T-cell exhaustion using single-cell transcriptome profiles of human TI lymphocytes. TOX promoted intra-tumoral CD8+ T-cell exhaustion via upregulation of IC molecules. This suggested that TOX inhibition can potentially impede T-cell exhaustion and improve ICI efficacy. Additionally, TOX expression in the TI T cells can be used for patient stratification during anti-tumor treatments, including anti-PD-1 immunotherapy.
Metacognitive awareness of difficulty in action selection: the role of the cingulo-opercular network
Authors: Desender Kobe , Teuchies Martyn , Garcia Carlos Gonzalez , de Baene Wouter , Demanet Jelle , Brass Marcel 
Published: May 2019

AbstractThe question whether and how we are able to monitor our own cognitive states (metacognition) has been a matter of debate for decades. Do we have direct access to our cognitive processes or can we only infer them indirectly based on their consequences? In the current study, we wanted to investigate the brain circuits that underlie the metacognitive experience of fluency in action selection. To manipulate action-selection fluency we used a subliminal response priming paradigm. On each trial, both male and female human participants additionally engaged in the metacognitive process of rating how hard they felt it was to respond to the target stimulus. Despite having no conscious awareness of the prime, results showed that participants rated incompatible trials (during which subliminal primes interfered with the required response) to be more difficult than compatible trials (where primes facilitated the required response) reflecting metacognitive awareness of difficulty. This increased sense of subjective difficulty was mirrored by increased activity in the rostral cingulate zone (RCZ) and the anterior insula, two regions that are functionally closely connected. Importantly, this reflected activations that were unique to subjective difficulty ratings and were not explained by reaction times or prime-response compatibility. We interpret these findings in light of a possible grounding of the metacognitive judgement of fluency in action selection in interoceptive signals resulting from increased effort.
Acute Thiamethoxam exposure in Apis mellifera : Absence of both stress-induced changes in mRNA splicing and synergistic effects of common fungicide and herbicide
Authors: Decio Pâmela , Ustaoglu Pinar , Roat Thaisa C. , Malaspina Osmar , Devaud Jean-Marc , Stöger Reinhard , Soller Matthias 
Published: May 2019

AbstractSecuring food supply for a growing population is one of the current major challenges and heavily relies on the use of agrochemicals to maximize crop yield. Neonicotinoids are globally one of the most widely used insecticides. It is increasingly recognized, that neonicotinoids have a negative impact on non-target organisms, including important pollinators such as the European honey bee Apis mellifera. Toxicity of neonicotinoids may be enhanced through simultaneous exposure with additional pesticides, which could help explain, in part, the global decline of honey bee colonies. Here we examined whether exposure effects of the neonicotinoid Thiamethoxam are enhanced by the commonly used fungicide Carbendazim and the herbicide Glyphosate. For the first time, we also analysed alternative splicing changes upon pesticide exposure in the honey bee. In particular, we examined transcripts of three genes: i) the stress sensor gene X box binding protein-1 (Xbp1), ii) the Down Syndrome Cell Adhesion Molecule (Dscam) gene and iii) the embryonic lethal/abnormal visual system (elav) gene, both important genes for neuronal function. Our results indicate that neonicotinoid toxicity applied at sub-lethal doses is not enhanced by Carbendazim nor Glyphosate. Likewise, toxicity of these compounds did not impact on the complex process of spliceosomal-directed joining of exons and non-spliceosomal intron excision in the analysed mRNAs.
mitoXplorer, a visual data mining platform to systematically analyze and visualize mitochondrial expression dynamics and mutations
Authors: Yim Annie , Koti Prasanna , Bonnard Adrien , Duerrbaum Milena , Mueller Cecilia , Villaveces Jose , Gamal Salma , Cardone Giovanni , Perocchi Fabiana , Storchova Zuzana , Habermann Bianca H. 
Published: May 2019

AbstractBackgroundMitochondria produce cellular energy in the form of ATP and are involved in various metabolic and signaling processes. However, the cellular requirements for mitochondria are different depending on cell type, cell state or organism. Information on the expression dynamics of genes with mitochondrial functions (mito-genes) is embedded in publicly available transcriptomic or proteomic studies and the variety of available datasets enables us to study the expression dynamics of mito-genes in many different cell types, conditions and organisms. Yet, we lack an easy way of extracting these data for gene groups such as mito-genes.ResultsHere, we introduce the web-based visual data mining platform mitoXplorer, which systematically integrates expression and mutation data of mito-genes. The central part of mitoXplorer is a manually curated mitochondrial interactome containing ∼1200 genes, which we have annotated in 35 different mitochondrial processes. This mitochondrial interactome can be integrated with publicly available transcriptomic, proteomic or mutation data in a user-centric manner. A set of analysis and visualization tools allows the mining and exploration of mitochondrial expression dynamics and mutations across various datasets from different organisms and to quantify the adaptation of mitochondrial dynamics to different conditions. We apply mitoXplorer to quantify expression changes of mito-genes of a set of aneuploid cell lines that carry an extra copy of chromosome 21. mitoXplorer uncovers remarkable differences in the regulation of the mitochondrial transcriptome and proteome due to the dysregulation of the mitochondrial ribosome in retinal pigment epithelial trisomy 21 cells which results in severe defects in oxidative phosphorylation.ConclusionsWe demonstrate the power of the visual data mining platform mitoXplorer to explore expression data in a focused and detailed way to uncover underlying potential mechanisms for further experimental studies. We validate the hypothesis-creating power of mitoXplorer by testing predicted phenotypes in trisomy 21 model systems. MitoXplorer is freely available athttp://mitoxplorer.ibdm.univ-mrs.fr. MitoXplorer does not require installation nor programming knowledge and is web-based. Therefore, mitoXplorer is accessible to a wide audience of experimental experts studying mitochondrial dynamics.
Modelling the population dynamics of Plasmodium falciparum gametocytes in humans during malaria infection
Authors: Cao Pengxing , Collins Katharine A. , Zaloumis Sophie , Wattanakul Thanaporn , Tarning Joel , Simpson Julie A. , McCarthy James S. , McCaw James M. 
Published: May 2019

AbstractEvery year over two hundred million people are infected with the malaria parasite. Renewed efforts to eliminate malaria has highlighted the potential to interrupt transmission from humans to mosquitoes which is mediated through the gametocytes. Reliable prediction of transmission requires an improved understanding of in vivo kinetics of gametocytes. Here we study the population dynamics of Plasmodium falciparum gametocytes in human hosts by establishing a framework which incorporates improved measurements of parasitaemia in humans, a novel mathematical model of gametocyte dynamics, and model validation using a Bayesian hierarchical inference method. We found that the novel mathematical model provides an excellent fit to the available clinical data from 17 volunteers infected with P. falciparum, and reliably predicts observed gametocyte levels. We estimated the P. falciparum’s sexual commitment rate and gametocyte sequestration time in humans to be 0.54% (95% credible interval: 0.30-1.00) per life cycle and 8.39 (6.54-10.59) days respectively. Furthermore, we used the data-calibrated model to predict the effects of those gametocyte dynamics parameters on human-to-mosquito transmissibility, providing a method to link within-human host kinetics of malaria infection to epidemiological-scale infection and transmission patterns.
Benchmarking software tools for detecting and quantifying selection in Evolve and Resequencing studies
Authors: Vlachos Christos , Burny Claire , Pelizzola Marta , Borges Rui , Futschik Andreas , Kofler Robert , Schlötterer Christian 
Published: May 2019

AbstractThe combination of experimental evolution with whole genome re-sequencing of pooled individuals, also called Evolve and Resequence (E&R) is a powerful approach to study selection processes and to infer the architecture of adaptive variation. Given the large potential of this method, a range of software tools were developed to identify selected SNPs and to measure their selection coefficients. In this benchmarking study, we are comparing 15 test statistics implemented in 10 software tools using three different scenarios. We demonstrate that the power of the methods differs among the scenarios, but some consistently outperform others. LRT-1, which takes advantage of time series data consistently performed best for all three scenarios. Nevertheless, the CMH test, which requires only two time points had almost the same performance. This benchmark study will not only facilitate the analysis of already existing data, but also affect the design of future data collections.
MicroRNA miR-1002 enhances NMNAT-mediated stress response by modulating alternative splicing
Authors: Park Joun , Zhu Yi , Tao Xianzun , Brazill Jennifer M. , Li Chong , Wuchty Stefan , Zhai R. Grace 
Published: May 2019

SUMMARYUnderstanding endogenous regulation of stress resistance and homeostasis maintenance is critical to developing neuroprotective therapies. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved essential enzyme that confers extraordinary protection and stress resistance in many neurodegenerative disease models. Drosophila Nmnat is alternatively spliced to two mRNA variants, RA and RB. RB translates to protein isoform PD with robust protective activity and is upregulated upon stress to confer enhanced neuroprotection. The mechanisms regulating alternative splicing and stress response of NMNAT remain unclear. We have discovered a Drosophila microRNA, dme-miR-1002, which promotes the splicing of NMNAT pre-mRNA to RB by disrupting a pre-mRNA stem-loop structure. While NMNAT pre-mRNA is preferentially spliced to RA in basal conditions, miR-1002 enhances NMNAT PD-mediated stress protection by binding via RISC component Argonaute1 to the pre-mRNA, facilitating the splicing switch to RB. These results outline a new process for microRNAs in regulating alternative splicing and modulating stress resistance.
Bimodal Regulation of the PRC2 Complex by USP7 Underlies Melanomagenesis
Authors: Su Dongxue , Wang Wenjuan , Hou Yongqiang , Wang Liyong , Wang Yue , Yang Chao , Liu Beibei , Chen Xing , Wu Xiaodi , Wu Jiajing , Yan Dong , Wei Shuqi , Han Lu , Liu Shumeng , Shi Lei , Shan Lin 
Published: May 2019

ABSTRACTAlthough overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in melanoma cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives melanoma cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during melanoma progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of melanoma patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for melanoma.
Toxoplasma gondiiInfection Drives Conversion of NK Cells into ILC1s
Authors: Park Eugene , Patel Swapneel J. , Wang Qiuling , Andhey Prabhakar S. , Zaitsev Konstantin , Porter Sofia I. , Hershey Maxwell L. , Bern Michael D. , Plougastel-Douglas Beatrice , Collins Patrick L. , Colonna Marco , Murphy Kenneth M. , Oltz Eugene M. , Artyomov Maxim N. , Sibley L. David , Yokoyama Wayne M. 
Published: May 2019

AbstractInnate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here we describeToxoplasma gondiiinfection converts NK cells into cells resembling steady-state ILC1s that are heterogeneous and distinct from both steady-state NK cells and ILC1s in uninfected mice. Most toxoplasma-induced ILC1s were Eomes-dependent, indicating that NK cells can give rise to Eomes−Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.
Deep evolutionary origin of nematode SL2
trans-splicing revealed by genome-wide
analysis of the Trichinella spiralis
transcriptome
Authors: Wenzel Marius , Johnston Christopher , Müller Berndt , Pettitt Jonathan , Connolly Bernadette 
Published: May 2019

ABSTRACT
Spliced leader
trans-splicing is
intimately associated with the presence of
eukaryotic operons, allowing the processing of
polycistronic RNAs into individual mRNAs. Most of
our understanding of spliced leader
trans-splicing as it
relates to operon gene expression comes from
studies in C. elegans.
In this organism, two distinct spliced leader
trans-splicing events
are recognised: SL1, which is used to replace the
5’ ends of pre-mRNAs that have a nascent
monomethyl guanosine cap; and SL2, which provides
the 5’ end to uncapped pre-mRNAs derived from
polycistronic RNAs. Limited data on operons and
spliced leader
trans-splicing in other
nematodes suggested that SL2-type
trans-splicing is a
relatively recent innovation, associated with
increased efficiency of polycistronic processing,
and confined to only one of the five major
nematode clades, Clade V. We have conducted the
first transcriptome-wide analysis of spliced
leader trans-splicing
in a nematode species, Trichinella
spiralis, which belongs to a clade
distantly related to Clade V. Our work identifies
a set of T. spiralis
SL2-type spliced leaders that are specifically
used to process polycistronic RNAs, the first
examples of specialised spliced leaders that have
been found outside of Clade V. These
T. spiralis spliced
leader RNAs possess a perfectly conserved
stem-loop motif previously shown to be essential
for polycistronic RNA processing in
C. elegans. We show
that this motif is found in specific sets of
spliced leader RNAs broadly distributed across the
nematode phylum. This work substantially revises
our understanding of the evolution of nematode
spliced leader
trans-splicing, showing
that the machinery for SL2
trans-splicing evolved
much earlier during nematode evolution than was
previously appreciated, and has been conserved
throughout the radiation of the nematode
phylum.
Synthesizing the effects of large, wild herbivore exclusion on ecosystem function
Authors: Forbes Elizabeth S. , Cushman J. Hall , Burkepile Deron E. , Young Truman P. , Klope Maggie , Young Hillary S. 
Published: May 2019

AbstractWild large herbivores are declining worldwide. Despite extensive use of exclosure experiments to investigate herbivore impacts, there is little consensus on the effects of wild large herbivores on ecosystem function.Of the ecosystem functions likely impacted, we reviewed the five most‐studied in exclosure experiments: ecosystem resilience/resistance to disturbance, nutrient cycling, carbon cycling, plant regeneration, and primary productivity.Experimental data on large wild herbivores' effects on ecosystem functions were predominately derived from temperate grasslands (50% grasslands, 75% temperate zones). Additionally, data were from experiments that may not be of adequate size (median size 400 m2despite excluding all experiments below 25 m2) or duration (median duration 6 years) to capture ecosystem‐scale responses to these low‐density and wide‐ranging taxa.Wild herbivore removal frequently impacted ecosystem functions; for example, net carbon uptake increased by three times in some instances. However, the magnitude and direction of effects, even within a single function, were highly variable.A focus on carbon cycling highlighted challenges in interpreting effects on a single function. While the effect of large herbivore exclusion on carbon cycling was slightly positive when its components (e.g. pools vs. fluxes of carbon) were aggregated, effects on individual components were variable and sometimes opposed.Given modern declines in large wild herbivores, it is critical to understand their effects on ecosystem function. However, this synthesis highlights strong variability in direction, magnitude, and modifiers of these effects. Some variation is likely due to disparity in what components are used to describe a given function. For example, for the carbon cycle we identified eight distinctly meaningful components, which are not easily combined yet are potentially misrepresentative of the larger cycle when considered alone. However, much of the observed difference in responses likely reflects real ecological variability across complex systems.To move towards a general predictive framework we must identify where variation in effect is due to methodological differences and where due to ecosystem context. Two critical steps forward are (a) additional quantitative synthetic analyses of large herbivores' effects on individual functions, and (b) improved, increased systematic exclosure research focusing on effects of large herbivores' exclusion on functions.A freePlain Language Summarycan be found within the Supporting Information of this article.
Tropodithietic acid induces oxidative stress response, cell envelope biogenesis and iron uptake in Vibrio vulnificus
Authors: Dittmann Karen K. , Porsby Cisse H. , Goncalves Priscila , Mateiu Ramona Valentina , Sonnenschein Eva C. , Bentzon‐Tilia Mikkel , Egan Suhelen , Gram Lone 
Published: May 2019

SummaryThe Roseobacter group is a widespread marine bacterial group, of which some species produce the broad‐spectrum antibiotic tropodithietic acid (TDA). A mode of action for TDA has previously been proposed in Escherichia coli, but little is known about its effect on non‐producing marine bacteria at in situ concentrations. The purpose of this study was to investigate how a sub‐lethal level of TDA affects Vibrio vulnificus at different time points (30 and 60 min) using a transcriptomic approach. Exposure to TDA for as little as 30 min resulted in the differential expression of genes associated with cell regeneration, including the up‐regulation of those involved in biogenesis of the cell envelope. Defence mechanisms including oxidative stress defence proteins and iron uptake systems were also up‐regulated in response to TDA, while motility‐related genes were down‐regulated. Gene expression data and scanning electron microscopy imaging revealed a switch to a biofilm phenotype in the presence of TDA. Our study shows that a low concentration of this antibiotic triggers a defence response to reactive oxygen species and iron depletion in V. vulnificus, which indicates that the mode of action of TDA is likely more complex in this bacterium than what is known for E. coli.