bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long noncoding RNA ANRIL supports proliferation of adult T-cell leukemia cells through cooperation with EZH2
Authors: Song Zaowen , Wu Wencai , Chen Mengyun , Cheng Wenzhao , Yu Juntao , Fang Jinyong , Xu Lingling , Yasunaga Jun-ichirou , Matsuoka Masao , Zhao Tiejun 
Published: May 2018

ABSTRACTAdult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA on HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression of the lncRNA ANRIL was elevated in HTLV-1 infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knocking down of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis in vitro and in vivo. As a mechanism for these actions, we found that ANRIL targeted EZH2, and activated the NF-κB pathway in ATL cells. This activation was independent of the histone methyltransferase (HMT) activity of EZH2, but required the formation of an ANRIL/EZH2/p65 ternary complex. Chromatin immunoprecipitation assay revealed that ANRIL/EZH2 enhanced p65 DNA binding capability. In addition, we observed that ANRIL/EZH2 complex repressed p21/CDKN1A transcription through H3K27 trimethylation of the p21/CDKN1A promoter. Taken together, our results implicate that lncRNA ANRIL, by cooperating with EZH2, supports the proliferation of HTLV-1 infected cells, which is thought to be critical for oncogenesis.IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) is the pathogen that causes adult T-cell leukemia (ATL), which is a unique malignancy of CD4+ T cells. A role for long noncoding RNA (lncRNA) in HTLV-1-mediated cellular transformation has not been described. In this study, we demonstrated that lncRNA ANRIL was important for maintaining proliferation of ATL cells in vitro and in vivo. ANRIL was shown to activate NF-κB signaling through forming a ternary complex with EZH2 and p65. Further, epigenetic inactivation of p21/CDKN1A was involved in the oncogenic function of ANRIL. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA ANRIL in ATL and provides an important clue to prevent or treat HTLV-1 associated human diseases.
Olive mild mosaic virus coat protein and p6 are suppressors of RNA silencing and their silencing confers resistance against OMMV
Authors: Varanda CMR , Materatski P , Campos MD , Clara MIE , Nolasco G , Félix MR 
Published: May 2018

AbstractRNA silencing is an important defense mechanism in plants, yet several plant viruses encode proteins that suppress it. Here the genome of Olive mild mosaic virus (OMMV) was screened for silencing suppressors using a green fluorescent based transient suppression assay. The full OMMV cDNA and 5 different OMMV open reading frames (ORFs) were cloned into Gateway binary destination vector pK7WG2, transformed into Agrobacterium tumefaciens C58C1 and agroinfiltrated into Nicotiana benthamiana 16C plants. Among all ORFs tested, CP and p6 showed suppressor activity, with CP showing a significant higher activity when compared to p6, yet lower than that of the full OMMV. This suggests that OMMV silencing suppression results from a complementary action of both CP and p6.Such discovery led to the use of those viral suppressors in the development of OMMV resistant plants through pathogen-derived resistance (PDR) based on RNA silencing. Two hairpin constructs targeting each suppressor were agroinfiltrated in N. benthamiana plants which were then inoculated with OMMV RNA. When silencing of both suppressors was achieved, a highly significant reduction in viral accumulation and symptom attenuation was observed as compared to that seen when each construct was used alone, and to the respective controls, thus showing clear effectiveness against OMMV infection. Data here obtained indicate that the use of both OMMV viral suppressors as transgenes is a very efficient and promising approach to obtain plants resistant to OMMV.ImportanceOMMV silencing suppressors were determined. Among all ORFs tested, CP and p6 showed suppressor activity, with CP showing a significant higher activity when compared to p6, yet lower than that of the full OMMV, suggesting a complementary action of both CP and p6 in silencing suppression.This is the first time that a silencing suppressor was found in a necrovirus and that two independent proteins act as silencing suppressors in a member of the Tombusviridae family.When silencing of both suppressors was achieved, a highly significant reduction in viral accumulation and symptom attenuation was observed as compared to that seen when each was used alone, thus showing clear effectiveness against OMMV infection. A high percentage of resistant plants was obtained (60%), indicating that the use of both OMMV viral suppressors as transgenes is a very efficient and promising approach to obtain plants resistant to OMMV.
In vitro and In vivo characterization of NOSO-502, a novel inhibitor of bacterial translation
Authors: Racine Emilie , Nordmann Patrice , Pantel Lucile , Sarciaux Matthieu , Serri Marine , Houard Jessica , Villain-Guillot Philippe , Demord Anthony , Lundberg Carina Vingsbo , Gualtieri Maxime 
Published: May 2018

ABSTRACTAntibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the Odilorhabdins, a novel antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a novel mechanism of action on ribosomes. A lead-optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 μg/ml against standard Enterobacteriaceae strains and carbapenem-resistant Enterobacteriaceae (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-β-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models against E. coli EN122 (ESBL) or E. coli ATCC BAA-2469 (NDM-1), achieving an ED50 of 3.5 mg/kg and 1-, 2- and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a UTI model of E. coli UTI89, urine, bladder and kidney burdens were reduced by 2.39, 1.96, and 1.36 log10 CFU/ml, respectively, after injecting 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or HRPT cells, no inhibition of hERG-CHO or Nav 1.5 -HEK current, and no increase of micronuclei at 512 μM. NOSO-502, a compound with a novel mechanism of action, is active against Enterobacteriaceae, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable in vitro safety profile.
When is a fish stock collapsed?
Authors: Yletyinen J , Butler WE , Ottersen G , Andersen KH , Bonanomi S , Diekert FK , Folke C , Lindegren M , Nordström MC , Richter A , Rogers L , Romagnoni G , Weigel B , Whittington JD , Blenckner T , Stenseth NC 
Published: May 2018

AbstractMarine fish stock collapses are a major concern for scientists and society due to the potentially severe impacts on ecosystem resilience, food security and livelihoods. Yet the general state of harvested fish populations has proven difficult to summarize, and the actual occurrence rate of stock collapses remains unclear. We have carried out a literature review and multi-stock analysis to show that numerous definitions exist for classifying stocks as collapsed, and that the classification of a stock’s status is sensitive to changes in the collapse definition’s formulation. We suggest that the lack of a unified definition has contributed to contrasting perceptions on the state of fish stocks. Therefore, we comprehensively define what constitutes a fish stock collapse and provide a time-series based method for collapse detection. Unlike existing definitions, our definition is process-based, because it links together three important phases of collapse events: the abrupt decline, an ensuing period of prolonged depletion, and potential recovery. Furthermore, these phases are specified in terms of population turnover. Through systematic evaluation, our definition can accurately distinguish collapses from less severe depletions or natural fluctuations for stocks with diverse life histories, helping identify the stocks in greatest need of reparatory measures. Our study advocates the consistent use of definitions to limit both alarmist and conservative narratives on the state of fish stocks, and to promote cooperation between conservation and fisheries scientists. This will facilitate clear and accurate communication of science to both the public and to policy-makers to ensure healthy fish stocks in the future.
ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks
Authors: Balmus Gabriel , Pilger Domenic , Coates Julia , Demir Mukerrem , Sczaniecka-Clift Matylda , Barros Ana , Woods Michael , Fu Beiyuan , Yang Fengtang , Chen Elisabeth , Ostermaier Matthias , Stankovic Tatjana , Ponstingl Hannes , Herzog Mareike , Yusa Kosuke , Munoz Martinez Francisco , Durant Stephen T. , Galanty Yaron , Beli Petra , Adams David J. , Bradley Allan , Metzakopian Emmanouil , Forment Josep V. , Jackson Stephen P. 
Published: May 2018

SummaryMutations in the ATM tumor suppressor confer hypersensitivity to DNA-damaging agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase poison topotecan. Thus, we establish that loss of terminal components of the non-homologous end-joining (NHEJ) machinery or the BRCA1-A complex specifically confers topotecan resistance to ATM-deficient cells. We show that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase inhibitor olaparib is due to delayed homologous recombination repair at DNA-replication-fork-associated double-strand breaks (DSBs), resulting in toxic NHEJ-mediated chromosome fusions. Accordingly, restoring legitimate repair in ATM-deficient cells, either by preventing NHEJ DNA ligation or by enhancing DSB-resection by BRCA1-A complex inactivation, markedly suppresses this toxicity. Our work suggests opportunities for patient stratification in ATM-deficient cancers and when using ATM inhibitors in the clinic, and identifies additional therapeutic vulnerabilities that might be exploited when such cancers evolve drug resistance.One Sentence SummaryATM counteracts toxic NHEJ at broken replication forks
Critical role for Piccolo in Synaptic Vesicle Retrieval
Authors: Ackermann Frauke , Schink Kay O. , Bruns Christine , Izsvák Zsuzsanna , Hamra F. Kent , Rosenmund Christian , Garner Craig C. 
Published: May 2018

AbstractLoss of function of the presynaptic active zone protein Piccolo has recently been linked to a devastating disease causing brain atrophy. Here, we address how Piccolo inactivation adversely affects synaptic function and thus may contributes to neuronal loss. Our analysis shows that Piccolo is critical for the activity dependent recycling and maintenance of synaptic vesicles (SVs). Specifically, we find that boutons lacking Piccolo have deficits in the Rab5/EEA1 dependent formation of early endosomes and thus the recycling of SVs. Mechanistically, impaired Rab5 function was caused by the reduced synaptic recruitment of Pra1, known to interact selectively with the zinc fingers of Piccolo. Importantly, over-expression of GTPase deficient Rab5 or the Znf1 domain of Piccolo restores the size and recycling of SV pools. These data provide a molecular link between the active zone and endosome sorting at synapses providing hints to how Piccolo contributes to both developmental and psychiatric disorders.Impact StatementThe efficient recycling of synaptic vesicle proteins is critical for the integrity and reliability of synaptic transmission. Increasingly genetic and environmental insults have been shown to affect this recycling pathway, resulting in both cognitive impairment in humans and neurodegenerative diseases, yet the underlying mechanisms are poorly understood. Here we could show that the presynaptic active zone protein Piccolo regulates efficient recycling of synaptic vesicles via Pra1 and Rab5, perhaps explaining why Piccolo loss of function contributes to Pontocerebellar Hypoplasia and major depressive disorders.
mitoNEET Regulates Mitochondrial Iron Homeostasis Interacting with Transferrin Receptor
Authors: Furihata Takaaki , Takada Shingo , Maekawa Satoshi , Mizushima Wataru , Watanabe Masashi , Takahashi Hidehisa , Fukushima Arata , Tsuda Masaya , Matsumoto Junichi , Kakutani Naoya , Yokota Takashi , Matsushima Shouji , Otsuka Yutaro , Matsumoto Masaki , Nakayama Keiichi I. , Nio-Kobayashi Junko , Iwanaga Toshihoko , Sabe Hisataka , Hatakeyama Shigetsugu , Tsutsui Hiroyuki , Kinugawa Shintaro 
Published: May 2018

AbstractIron is an essential trace element for regulation of redox and mitochondrial function, and then mitochondrial iron content is tightly regulated in mammals. We focused on a novel protein localized at the outer mitochondrial membrane. Immunoelectron microscopy revealed transferrin receptor (TfR) displayed an intimate relationship with the mitochondria, and mass spectrometry analysis also revealed mitoNEET interacted with TfR in vitro. Moreover, mitoNEET was endogenously coprecipitated with TfR in the heart, which indicates that mitoNEET also interacts with TfR in vivo. We generated mice with cardiac-specific deletion of mitoNEET (mitoNEET-knockout). Iron contents in isolated mitochondria were significantly increased in mitoNEET-knockout mice compared to control mice. Mitochondrial reactive oxygen species (ROS) were higher, and mitochondrial maximal capacity and reserve capacity were significantly decreased in mitoNEET-knockout mice, which was consistent with cardiac dysfunction evaluated by echocardiography. The complex formation of mitoNEET with TfR may regulate mitochondrial iron contents via an influx of iron. A disruption of mitoNEET could thus be involved in mitochondrial ROS production by iron overload in the heart.
Transcranial alternating current stimulation at 10 Hz modulates response bias in the Somatic Signal Detection Task
Authors: Craddock Matt , Klepousniotou Ekaterini , el-Deredy Wael , Poliakoff Ellen , Lloyd Donna 
Published: May 2018

AbstractBackgroundOngoing, pre-stimulus oscillatory activity in the 8-13 Hz alpha range has been shown to correlate with both true and false reports of peri-threshold somatosensory stimuli. However, to directly test the role of such oscillatory activity in behaviour, it is necessary to manipulate it. Transcranial alternating current stimulation (tACS) offers a method of directly manipulating oscillatory brain activity using a sinusoidal current passed to the scalp.ObjectiveWe tested whether alpha tACS would change somatosensory sensitivity or response bias in a signal detection task in order to test whether alpha oscillations have a causal role in behaviour.MethodsActive 10 Hz tACS or sham stimulation was applied using electrodes placed bilaterally at positions CP3 and CP4 of the 10-20 electrode placement system. Participants performed the Somatic Signal Detection Task (SSDT), in which they must detect brief somatosensory targets delivered at their detection threshold. These targets are sometimes accompanied by a light flash, which could also occur alone.ResultsActive tACS did not modulate sensitivity to targets but did modulate response criterion. Specifically, we found that active stimulation generally increased touch reporting rates, but particularly increased responding on light trials. Stimulation did not interact with the presence of touch, and thus increased both hits and false alarms.ConclusionstACS stimulation increased reports of touch in a manner consistent with our observational reports, changing response bias, and consistent with a role for alpha activity in somatosensory detection.
Gene function contributes to gene expression levels inS. cerevisiae
Authors: Hickman Mark J. , Jackson Andrea , Smith Abigail , Thornton Julianne , Tursi Amanda 
Published: May 2018

ABSTRACTIt is not understood what evolutionary factors drive some genes to be expressed at a higher level than others. Here, we hypothesized that a gene’s function plays an important role in setting expression level. First, we established that eachS. cerevisiaegene is maintained at a specific expression level by analyzing RNA-seq data from multiple studies. Next, we found that mRNA and protein levels were maintained for the orthologous genes inS. pombe, showing that gene function, conserved in orthologs, is important in setting expression level. To further explore the role of gene function in setting expression level, we analyzed mRNA and protein levels ofS. cerevisiaegenes within gene ontology (GO) categories. The GO framework systematically defines gene function based on experimental evidence. We found that several GO categories contain genes with statistically significant expression extremes; for example, genes involved in translation or energy production are highly expressed while genes involved in chromosomal activities, such as replication and transcription, are weakly expressed. Finally, we were able to predict expression levels using GO information alone. We created and optimized a linear equation that predicted a gene’s expression based on the gene’s membership in 161 GO categories. The greater number of GO categories with which a gene is associated, the more accurately expression could be predicted. Taken together, our analysis systematically demonstrates that gene function is an important determinant of expression level.
Examining the Role of the Surfactant Family Member SFTA3 in Interneuron Specification
Authors: Chen Christopher Y. , Anderson Nickesha C. , Becker Sandy , Schicht Martin , Stoddard Christopher , Bräuer Lars , Paulsen Friedrich , Grabel Laura 
Published: May 2018

AbstractThe transcription factorNKX2.1, expressed at high levels in the medial ganglionic eminence (MGE), is a master regulator of cortical interneuron progenitor development. To identify gene candidates with expression profiles similar toNKX2.1, previous transcriptome analysis of human embryonic stem cell (hESC)-derived MGE-like progenitors revealedSFTA3as the strongest candidate. Quantitative real-time PCR analysis of hESC-derived NKX2.1-positive progenitors and transcriptome data available from the Allen Institute for Brain Science revealed comparable expression patterns forNKX2.1andSFTA3during interneuron differentiationin vitroand demonstrated highSFTA3expression in the human MGE. AlthoughSFTA3has been well studied in the lung, the possible role of this surfactant protein in the MGE during embryonic development remains unexamined. To determine ifSFTA3plays a role in MGE specification,SFTA3-/- andNKX2.1 -/-hESC lines were generated using custom designed CRISPRs. We show thatNKX2.1KOs have a significantly diminished capacity to differentiate into MGE interneuron subtypes.SFTA3KOs also demonstrated a somewhat reduced ability to differentiate down the MGE-like lineage, although not as severe relative toNKX2.1deficiency. These results suggestNKX2.1andSFTA3are co-regulated genes, and that deletion ofSFTA3does not lead to a major change in the specification of MGE derivatives.
Automated High-Throughput Light-Sheet Fluorescence Microscopy of Larval Zebrafish
Authors: Logan Savannah L. , Dudley Christopher , Baker Ryan P. , Taormina Michael J. , Hay Edouard A. , Parthasarathy Raghuveer 
Published: May 2018

ABSTRACTLight sheet fluorescence microscopy enables fast, minimally phototoxic, three-dimensional imaging of live specimens, but is currently limited by low throughput and tedious sample preparation. Here, we describe an automated high-throughput light sheet fluorescence microscope in which specimens are positioned by and imaged within a fluidic system integrated with the sheet excitation and detection optics. We demonstrate the ability of the instrument to rapidly examine live specimens with minimal manual intervention by imaging fluorescent neutrophils over a nearly 0.3 mm3 volume in dozens of larval zebrafish. In addition to revealing considerable inter-individual variability in neutrophil number, known previously from labor-intensive methods, three-dimensional imaging allows assessment of the correlation between the bulk measure of total cellular fluorescence and the spatially resolved measure of actual neutrophil number per animal. We suggest that our simple experimental design should considerably expand the scope and impact of light sheet imaging in the life sciences.
Can I have more of these please?
Authors: Sesagiri Raamkumar Aravind , Foo Schubert , Pang Natalie 
Published: May 2018

Purpose
During the literature review phase, the task of finding similar research papers can be a difficult proposition for researchers due to the procedural complexity of the task. Current systems and approaches help in finding similar papers for a given paper, even though researchers tend to additionally search using a set of papers. This paper aims to focus on conceptualizing and developing recommendation techniques for key literature review and manuscript preparatory tasks that are interconnected. In this paper, the user evaluation results of the task where seed basket-based discovery of papers is performed are presented.

Design/methodology/approach
A user evaluation study was conducted on a corpus of papers extracted from the ACM Digital Library. Participants in the study included 121 researchers who had experience in authoring research papers. Participants, split into students and staff groups, had to select one of the provided 43 topics and run the tasks offered by the developed assistive system. A questionnaire was provided at the end of each task for evaluating the task performance.

Findings
The results show that the student group evaluated the task more favourably than the staff group, even though the difference was statistically significant for only 5 of the 16 measures. The measures topical relevance, interdisciplinarity, familiarity and usefulness were found to be significant predictors for user satisfaction in this task. A majority of the participants, who explicitly stated the need for assistance in finding similar papers, were satisfied with the recommended papers in the study.

Originality/value
The current research helps in bridging the gap between novices and experts in terms of literature review skills. The hybrid recommendation technique evaluated in this study highlights the effectiveness of combining the results of different approaches in finding similar papers.