bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of mRNA translation by a photoriboswitch
Authors: Rotstan Kelly A. , Abdelsayed Michael M. , Passalacqua Luiz F. M. , Chizzolini Fabio , Sudarshan Kasireddy , Chamberlin A. Richard , Míšek Jiří , Lupták Andrej 
Published: September 2019

ABSTRACTOptogenetic tools have revolutionized the study of receptor-mediated biological processes, but such tools are lacking for the study of RNA-controlled systems. To fill this gap, we usedin vitroselection to isolate a novel RNA that selectively binds thetransisoform of a stiff-stilbene (amino-tSS), a rapidly and reversibly photoisomerizing small molecule. Structural probing revealed that the RNA binds amino-tSS about 100-times stronger than amino-cSS, giving the system robust selectivity for thetransisomer.In vitroandin vivofunctional analysis showed that the riboswitch, termed Werewolf-1 (Were-1), inhibits translation of a downstream open reading frame when bound to amino-tSS and photoisomerization of the ligand with a sub-millisecond pulse of light induced the protein expression. Similarly, bacterial culture containing thecisisoform (amino-cSS) supported protein expression, which was inhibited upon photoisomerization to amino-tSS. Reversible regulation of gene expression using a genetically encoded light-responsive RNA will broaden the analysis of complex RNA processes in living cells.
Reproducibility across single-cell RNA-seq protocols for spatial ordering analysis
Authors: Seirup Morten , Chu Li-Fang , Sengupta Srikumar , Leng Ning , Browder Hadley , Kapadia Kevin , Shafer Christina M. , Duffin Bret , Elwell Angela L. , Bolin Jennifer M. , Swanson Scott , Stewart Ron , Kendziorski Christina , Thomson James A. , Bacher Rhonda 
Published: September 2019

AbstractAs newer single-cell protocols generate increasingly more cells at reduced sequencing depths, the value of a higher read depth may be overlooked. Using data from three different single-cell RNA-seq protocols that lend themselves to having either higher read depth (Smart-seq) or many cells (MARS-seq and 10X), we evaluate their ability to recapitulate biological signals in the context of pseudo-spatial reconstruction. Overall, we find gene expression profiles after spatial-reconstruction analysis are highly reproducible between datasets despite being generated by different protocols and using different computational algorithms. While UMI based protocols such as 10X and MARS-seq allow for capturing more cells, Smart-seq’s higher sensitivity and read-depth allows for analysis of lower expressed genes and isoforms. Additionally, we evaluate trade-offs for each protocol by performing subsampling analyses, and find that optimizing the balance between sequencing depth and number of cells within a protocol is important for efficient use of resources. Our analysis emphasizes the importance of selecting a protocol based on the biological questions and features of interest.
DLO Hi-C Tool for Digestion-Ligation-Only Hi-C Chromosome Conformation Capture Data Analysis
Authors: Hong Ping , Jiang Hao , Xu Weize , Lin Da , Xu Qian , Cao Gang , Li Guoliang 
Published: September 2019

AbstractBackgroundIt is becoming increasingly important to understand the mechanism of regulatory elements on target genes in long-range genomic distance. 3C (Chromosome Conformation Capture) and its derived methods are now widely applied to investigate genome organizations and gene regulation. Digestion-Ligation-Only Hi-C (DLO Hi-C) is a new technology with high efficiency and effective cost for whole-genome chromosome conformation capture.ResultsHere, we introduce DLO Hi-C Tool, a flexible and versatile pipeline for processing DLO Hi-C data from raw sequencing reads to normalized contact maps and providing quality controls for different steps. It includes more efficient iterative mapping and linker filtering. We applied DLO Hi-C Tool to different DLO Hi-C datasets, and demonstrated its ability of processing large data in multi-threading.ConclusionsDLO Hi-C Tool is suitable for processing DLO Hi-C and in situ DLO Hi-C datasets. It is convenient and efficient for DLO Hi-C data processing.
Native plasmid-encoded mercury resistance genes are functional and demonstrate natural transformation in environmental bacterial isolates
Authors: Kothari Ankita , Soneja Drishti , Tang Albert , Carlson Hans , Deutschbauer Adam M. , Mukhopadhyay Aindrila 
Published: September 2019

AbstractPlasmid-mediated horizontal gene transfer (HGT) is a major driver of genetic diversity in bacteria. We experimentally validated the function of a putative mercury resistance operon present on an abundant 8 kilobase pair native plasmid found in groundwater samples without detectable levels of mercury. Phylogenetic analyses of the plasmid-encoded mercury reductases from the studied groundwater site show them to be distinct from those reported in proximal metal-contaminated sites. We synthesized the entire native plasmid and demonstrated that the plasmid was sufficient to confer functional mercury resistance inEscherichia coli. Given the possibility that natural transformation is a prevalent HGT mechanism in the low cell density environments of groundwaters, we also assayed bacterial strains from this environment for competence. We used the native plasmid-encoded metal resistance to design a screen and identified 17 strains positive for natural transformation. We selected 2 of the positive strains along with a model bacterium to fully confirm HGT via natural transformation. From an ecological perspective, the role of the native plasmid population in providing advantageous traits combined with the microbiome’s capacity to take up environmental DNA enables rapid adaptation to environmental stresses.ImportanceHorizontal transfer of mobile genetic elements via natural transformation has been poorly understood in environmental microbes. Here, we confirm the functionality of a native plasmid-encoded mercury resistance operon in a model microbe and then query for the dissemination of this resistance trait via natural transformation into environmental bacterial isolates. We identify seventeen strains including Gram-positive and Gram-negative bacteria to be naturally competent. These strains were able to successfully take up the plasmid DNA and obtain a clear growth advantage in the presence of mercury. Our study provides important insights into gene dissemination via natural transformation enabling rapid adaptation to dynamic stresses in groundwater environments.
SpineJ : A software tool for quantitative analysis of nanoscale spine morphology
Authors: Levet Florian , Tønnesen Jan , Nägerl Valentin , Sibarita Jean-Baptiste 
Published: September 2019

AbstractSuper-resolution microscopy provides diffraction-unlimited optical access to the intricate morphology of neurons in living brain tissue, resolving their finest structural details, which are critical for neuronal function. However, as existing image analysis software tools have been developed for diffraction-limited images, they are generally not well suited for quantifying nanoscale structures like dendritic spines. We present SpineJ, a semi-automatic ImageJ plugin that is specifically designed for this purpose. SpineJ comes with an intuitive and user-friendly graphical user interface, facilitating fast, accurate, and unbiased analysis of spine morphology.
Cell cycle-balanced expression of pluripotency regulators via cyclin-dependent kinase 1
Authors: Kasvandik Sergo , Schilf Reelika , Saarma Merilin , Loog Mart , Jääger Kersti 
Published: September 2019

ABSTRACTEmbryonic stem cells (ESCs) have a unique ability to remain pluripotent while undergoing rapid rounds of cell division required for self-renewal. However, it is not known how cell cycle and pluripotency regulatory networks co-operate in ESCs. Here, we used stable isotope labeling with amino acids in cell culture (SILAC) combined with mass spectrometry to determine pluripotency proteome dynamics during cell cycle in mouse ESCs. We found the S/G2M-fluctuating pluripotency transcription factors (ESRRB, REST), chromatin regulators (JARID2, TRIM24) and proteins with E3 ligase activity (NEDD4L, PIAS2) to peak in S phase. This expression balance was disrupted upon inhibition of cyclin-dependent kinase 1 (CDK1) activity resulting in the shift of the expression peak from S to G2M. Our results demonstrate that mouse ESCs require CDK1 activity to maintain high S to G2M ratio of pluripotency regulators revealing critical role of cell cycle dynamics in balancing ESC identity.
Genome-wide changes in genetic diversity in a population ofMyotis lucifugusaffected by white-nose syndrome
Authors: Lilley Thomas M. , Wilson Ian W. , Field Kenneth A. , Reeder DeeAnn M. , Vodzak Megan E. , Turner Gregory G. , Kurta Allen , Blomberg Anna S. , Hoff Samantha , Herzog Carl J. , Sewall Brent J. , Paterson Steve 
Published: September 2019

ABSTRACTNovel pathogens can cause massive declines in populations, and even extirpation of hosts. But disease can also act as a selective pressure on survivors, driving the evolution of resistance or tolerance. Bat white-nose syndrome (WNS) is a rapidly spreading wildlife disease in North America. The fungus causing the disease invades skin tissues of hibernating bats, resulting in disruption of hibernation behavior, premature energy depletion, and subsequent death. We used whole-genome sequencing to investigate changes in allele frequencies within a population ofMyotis lucifugusin eastern North America to search for genetic resistance to WNS. Our results show low FSTvalues within the population across time, i.e. prior to WNS (Pre-WNS) compared to the population that has survived WNS (Post-WNS). However, when dividing the population with a geographical cut-off between the states of Pennsylvania and New York, a sharp increase in values on scaffold GL429776 is evident in the Post-WNS samples. Genes present in the diverged area are associated with thermoregulation and promotion of brown fat production. Thus, although WNS may not have subjected the entireM. lucifuguspopulation to selective pressure, it may have selected for specific alleles in Pennsylvania through decreased gene flow within the population. However, the persistence of remnant sub-populations in the aftermath of WNS is likely due to multiple factors in bat life history.
Topoisomerase II inhibitors induce cGAS-STING dependent inflammation resulting in cytokine induction and immune checkpoint activation
Authors: Wilkinson R. D. A , McCabe N. , Parkes E. E. , Barros E.M. , Johnston D. I. , Ali R.M.M , Lappin K. , Greenberg R.A. , Harkin D. P. , McIntosh S. A. , Kennedy R. D. , Savage K. I. 
Published: September 2019

AbstractTumours with genomic instability demonstrate enhanced immunogenicity and potential for response to immune checkpoint blockade (ICB). We previously demonstrated activation of the cGAS-STING pathway following loss of DNA repair, resulting in cytokine induction, lymphocytic infiltration and immune checkpoint activation. Here we explore the role of chemotherapies in inducing this innate immune response, identifying topoisomerase II (topo-II) inhibitors, particularly doxorubicin and epirubicin, as potent inducers of a cGAS-STING dependent interferon response. Mechanistically, topo-II inhibition resulted in significant induction of cytoplasmic DNA and subsequent micronuclei formation, a requirement for efficient cGAS-STING activation and consequent cytokine and immune checkpoint gene induction. Importantly, increased cytokine and immune checkpoint gene expression, as well as increased immune cell infiltration, was also observed in patient derived breast tumour biopsies following topo-II inhibitor-based treatment. Taken together, this study indicates topo-II inhibitors such as doxorubicin, may be best placed to induce immunogenic inflammation, and thereby increase responses to ICB therapies.SignificanceThis work demonstrates how topo-II inhibitors induce STING-pathway activation, cytokine induction and immune checkpoint protein upregulation in cancer cells and provides a rationale for combining topo-II inhibitors with ICB therapy in early breast cancer.
A new high-throughput tool to screen mosquito-borne viruses in Zika virus endemic/epidemic areas
Authors: Moutailler Sara , Yousfi Lena , Mousson Laurence , Devillers Elodie , Vazeille Marie , Vega-Rúa Anubis , Perrin Yvon , Jourdain Frédéric , Chandre Fabrice , Cannet Arnaud , Chantilly Sandrine , Restrepo Johana , Guidez Amandine , Dusfour Isabelle , Santos de Abreu Filipe Vieira , Pereira dos Santos Taissa , Jiolle Davy , Visser Tessa M. , Koenraadt Constantianus J.M. , Wongsokarijo Merril , Diallo Mawlouth , Diallo Diawo , Gaye Alioune , Boyer Sébastien , Duong Veasna , Piorkowski Géraldine , Paupy Christophe , de Oliveira Ricardo Lourenco , de Lamballerie Xavier , Failloux Anna-Bella 
Published: September 2019

AbstractMosquitoes are vectors of arboviruses affecting animal and human health. Arboviruses circulate primarily within an enzootic cycle and recurrent spillovers contribute to the emergence of human-adapted viruses able to initiate an urban cycle involving anthropophilic mosquitoes. The increasing volume of travel and trade offers multiple opportunities for arbovirus introduction in new regions. This scenario has been exemplified recently with the Zika pandemic. To incriminate a mosquito as vector of a pathogen, several criteria are required such as the detection of natural infections in mosquitoes. In this study, we used a high-throughput chip based on the BioMarkTM Dynamic arrays system capable of detecting 64 arboviruses in a single experiment. A total of 17,958 mosquitoes collected in Zika-endemic/epidemic countries (Brazil, French Guiana, Guadeloupe, Suriname, Senegal, and Cambodia) were analyzed. Here we show that this new tool can detect endemic and epidemic viruses in different mosquito species in an epidemic context. Thus, this fast and low-cost method can be suggested as a novel epidemiological surveillance tool to identify circulating arboviruses.
Hispanic/Latino gastric adenocarcinoma patients have distinct molecular profiles including a high rate of germline CDH1 mutations
Authors: Wang Sam C. , Yeu Yunku , Hammer Suntrea T.G. , Xiao Shu , Zhu Min , Hong Changjin , Yoon Lynn Y. , Nassour Ibrahim , Shen Jeanne , Agarwal Deepak , Reznik Scott I. , Mansour John C. , Yopp Adam C. , Zhu Hao , Hwang Tae Hyun , Porembka Matthew R. 
Published: September 2019

AbstractHispanic/Latino patients have a higher incidence of gastric cancer and worse cancer-related outcomes as compared to patients of other backgrounds. Whether there is a molecular basis for these disparities is unknown, as very few Hispanic/Latino patients were included in previous studies. We performed a large, integrated genomic analysis of gastric cancer samples from Hispanic/Latino patients. Whole-exome sequencing (WES) and RNA sequencing were performed on 57 Hispanic/Latino gastric cancer patient samples. Germline analysis was conducted on 83 patients. Functional testing of CDH1 germline mutations was performed in Chinese hamster ovary cells. Tumors from Hispanic/Latino patients were significantly enriched for the genomically-stable subtype (as defined by The Cancer Genome Atlas), compared to Asians and Whites (65% vs 21% vs 20%, P < 0.001). Transcriptomic analysis identified molecular signatures that were prognostic. Of the 43 Hispanic/Latino patients with diffuse-type gastric cancer, 7 (16%) had germline mutations in CDH1. Mutation carriers were significantly younger than non-carriers (41 vs 50 years, P < 0.05). E-cadherin expression was reduced in 5 of 6 mutation carrier tumor samples available for analysis. In silico algorithms predicted 5 variants were deleterious. For the two variants that were predicted to be benign, we demonstrated that the mutations conferred increased migratory capability, suggesting pathogenicity. Hispanic/Latino gastric cancer patients possess unique genomic landscapes. This includes a high rate of CDH1 germline mutations that may partially explain their aggressive clinical phenotypes. Individualized screening, genetic counseling, and treatment protocols based on patient ethnicity and race may be necessary.
Animacy modulates gender agreement computation in Hindi: An ERP study
Authors: Bhattamishra Shikha , Muralikrishnan R. , Choudhary Kamal Kumar 
Published: September 2019

AbstractGender has been investigated in psycholinguistics research both with respect to how it is retrieved when a noun is encountered and the computation of its agreement dependencies between different elements in a sentence. The literature is abound with differences as to the processing of gender agreement computations across languages and constructs. Similarly, neurophysiological evidence with respect to gender retrieval mechanisms differ wherein languages differ in the way the gender feature is retrieved when a noun is encountered based on different properties. The present study aims to scrutinize gender agreement computations in verb-agreement relations in Hindi and to ascertain if the intrinsic property (i.e. the animacy) of a noun participating in the relation plays a role in processing agreement dependencies. In addition, it also looks into the issue of whether the gender retrieval mechanism in the language influences agreement comprehension. Results revealed a positivity for the animate subject agreement and a negativity for the inanimate subject agreement violations at the position of the verb respectively. The results are suggestive of distinct processing mechanisms underlying semantic and syntactic gender. Further, the results also suggest that gender agreement computation in Hindi is modulated by the way gender is retrieved at the position of the noun.
Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains
Authors: Khrameeva Ekaterina , Kurochkin Ilia , Han Dingding , Guijarro Patricia , Kanton Sabina , Santel Malgorzata , Qian Zhengzong , Rong Shen , Mazin Pavel , Bulat Matvei , Efimova Olga , Tkachev Anna , Guo Song , Sherwood Chet C. , Camp J. Gray , Paabo Svante , Treutlein Barbara , Khaitovich Philipp 
Published: September 2019

ABSTRACTIdentification of gene expression traits unique to the human brain sheds light on the mechanisms of human cognition. Here we searched for gene expression traits separating humans from other primates by analyzing 88,047 cell nuclei and 422 tissue samples representing 33 brain regions of humans, chimpanzees, bonobos, and macaques. We show that gene expression evolves rapidly within cell types, with more than two-thirds of cell type-specific differences not detected using conventional RNA sequencing of tissue samples. Neurons tend to evolve faster in all hominids, but non-neuronal cell types, such as astrocytes and oligodendrocyte progenitors, show more differences on the human lineage, including alterations of spatial distribution across neocortical layers.
GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer
Authors: Wu Qin , ba-alawi Wail , Deblois Genevieve , Cruickshank Jennifer , Duan Shili , Lima-Fernandes Evelyne , Haight Jillian , Tonekaboni Seyed Ali Madani , Fortier Anne-Marie , Kuasne Hellen , McKee Trevor D. , Mahmoud Hassan , Cameron Sarina , Dogan-Artun Nergiz , Chen WenJun , Vellanki Ravi N. , Zhou Stanley , Done Susan J. , Park Morag , Cescon David W. , Haibe-Kains Benjamin , Lupien Mathieu , Arrowsmith Cheryl H. 
Published: September 2019

AbstractTriple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data implicates E2F Targets pathway activity as a surrogate of OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) are strongly correlated with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.
Disruption of NOX2-dependent Oxidative Injury with a Targeted Gene-Therapy Approach Prevents Atrial Fibrillation in a Canine Model
Authors: Yoo Shin , Pfenniger Anna , Hoffman Jacob , Zhang Wenwei , Ng Jason , Burrell Amy , Johnson David A. , Gussak Georg , Waugh Trent , Bull Suzanne , Benefield Brandon , Knight Bradley P. , Passman Rod , Wasserstrom J. Andrew , Aistrup Gary L. , Arora Rishi 
Published: September 2019

AbstractAtrial fibrillation is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal as they are not targeted to the molecular mechanisms underlying AF. In this study, we demonstrated using a novel gene-based strategy in a clinically relevant large animal of AF that oxidative injury is a key mechanism underlying the onset and perpetuation of AF. First, we demonstrated that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through induction of NADPH oxidase 2 (NOX2) and generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electrical remodeling in AF by upregulating a constitutively active form of acetylcholine-dependent K+current (IKACh) – calledIKH- by a mechanism involving frequency-dependent activation of protein kinase C epsilon (PKCε). To understand the mechanism by which oxidative injury promotes the genesis and/or maintenance of AF, we performed targeted injection of NOX2 shRNA in atria of normal dogs followed by rapid atrial pacing. The time to onset of non-sustained AF increased by more than 5-fold in NOX2 shRNA treated dogs. Furthermore, animals treated with NOX2 shRNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, with attenuated activation of PKCε, a likely molecular mechanism underlying this beneficial electrophysiological remodeling. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.One Sentence SummaryTargeted disruption of NOX2-dependent oxidative injury with a novel gene therapy approach prevents onset as well as perpetuation of atrial fibrillation.