bluuebunny/crossref_metadata_2025_split huggingface dataset:
PIK3C2Bpromotes epithelial to mesenchymal transition and EGFR inhibitors insensitivity in epidermal squamous cell carcinoma
Authors: Pomar Silvia Crespo , Borgström Anna , Arcaro Alexandre , Charles Roch-Philippe 
Published: July 2018

AbstractWhile the class I of PI3Ks has been deeply studied due to its clear implication in cancer development, little is known about the class II of PI3Ks. However, recent accumulation of data is now revealing that PI3KC2β, one isoform of this class of PI3Ks, may also play a role in cancer. Specifically, recent studies have suggested an implication of PI3KC2β in metastasis formation through the promotion of epithelial to mesenchymal transition (EMT). Here, we report that the overexpression of PI3KC2β in the epidermal squamous cell carcinoma (ESCC) cells A431 promotes apparent EMT transformation. We further confirm this EMT by showing modification in several biochemical markers (E-cadherin, β-catenin, Snail, Twist1 and Vimentin). Furthermore, an intracellular co-localization of E-cadherin, β-catenin and EGFR was observed. This transformation decreased EGFR signaling and the sensitivity to inhibitors targeting this receptor. To confirm our results, we have used the colon adenocarcinoma cells HT29 and induced overexpression of PI3KC2β in these cells. We could recapitulate in this model some of our major findings regarding EMT in the PI3KC2β overexpressing A431 cells. Taken together, these data support a role of PI3KC2β in promoting EMT.
Scoring of pathogenic non-coding variants in Mendelian diseases through supervised learning on ancient, recent and ongoing purifying selection signals in human
Authors: Caron Barthélémy , Luo Yufei , Rausell Antonio 
Published: July 2018

AbstractThe study of rare Mendelian diseases through exome sequencing typically yields incomplete diagnostic rates, ~8-70% depending on the disease type. Whole genome sequencing of the unresolved cases allows addressing the hypothesis that causal variants could lay in non-coding regions with damaging regulatory consequences. The large amount of rare and singleton variants found in each individual genome requires computational filtering and scoring strategies to gain power in downstream statistical genetics tests. However, state-of-the-art methods estimating the functional relevance of non-coding genomic regions have been mostly characterized on sets of variants largely composed of trait-associated polymorphisms and associated to common diseases, yet with modest accuracy and strong positional biases. In this work we first curated a collection of n=737 high-confidence pathogenic non-coding single-nucleotide variants in proximalcis-regulatory genomic regions associated to monogenic Mendelian diseases. We then systematically evaluated the ability to predict causal variants of a comprehensive set of natural selection features extracted at three genomic levels: the affected position, the flanking region and the associated gene. In addition to inter-species conservation, a comprehensive set of recent and ongoing purifying selection signals in human was explored, allowing to capture potential constraints associated to recently acquired regulatory elements in the human lineage. A supervised learning approach using gradient tree boosting on such features reached a high predictive performance characterized by an area under the ROC curve = 0.84 and an area under the Precision-Recall curve = 0.47. The figures represent a relative improvement of >10% and >34% respectively upon the performance of current state-of-the-art methods for prioritizing non-coding variants. Performance was consistent under multiple configurations of the sets of variants used for learning and for independent testing. The supervised learning design allowed the assessment of newly seen non-coding variants overcoming gene and positional bias. The scores produced by the approach allow a more consistent weighting and aggregation of candidate pathogenic variants from diverse non-coding regions within and across genes in the context of statistical tests for rare variant association analysis.
Lineage tracing of Notch1-expressing cells in intestinal tumours reveals a distinct population of cancer stem cells
Authors: Mourao Larissa , Jacquemin Guillaume , Huyghe Mathilde , Nawrocki Wojciech J. , Menssouri Naoual , Servant Nicolas , Fre Silvia 
Published: July 2018

AbstractColon tumours are hierarchically organized and contain multipotent self-renewing cells, called Cancer Stem Cells (CSCs). We have previously shown that the Notch1 receptor is expressed in Intestinal Stem Cells (ISCs); given the critical role played by Notch signalling in promoting intestinal tumourigenesis, we explored Notch1 expression in tumours. Combining lineage tracing in two tumour models with transcriptomic analyses, we found that Notch1 + tumour cells are undifferentiated, proliferative and capable of indefinite self-renewal and of generating a heterogeneous clonal progeny. Molecularly, the transcriptional signature of Notch1+ tumour cells highly correlates with ISCs, suggestive of their origin from normal crypt cells. Surprisingly, Notch1+ expression labels a subset of CSCs that show reduced levels of Lgr5, a reported CSCs marker. The existence of distinct stem cell populations within intestinal tumours highlights the necessity of better understanding their hierarchy and behaviour, to identify the correct cellular targets for therapy.
CancerMine: A literature-mined resource for drivers, oncogenes and tumor suppressors in cancer
Authors: Lever Jake , Zhao Eric Y. , Grewal Jasleen , Jones Martin R. , Jones Steven J. M. 
Published: July 2018

AbstractUnderstanding a mutation in cancer requires knowledge of the different roles that genes play in cancer as drivers, oncogenes and tumor suppressors. We present CancerMine, a high-quality text-mined knowledgebase that catalogues over 856 genes as drivers, 2,421 as oncogenes and 2,037 as tumor suppressors in 426 cancer types. We compile 3,485 genes that are not in the IntOGen resource of drivers and complement the Cancer Gene Census with 3,136 new genes identified as oncogenes and tumor suppressors. CancerMine provides a method for gene-centric clustering of cancer types illustrating genetic similarities between cancer types of different organs and was validated against data from the Cancer Genome Atlas (TCGA) project. Finally with 178 novel cancer gene mentions in publications each month, this resource will be updated monthly, pre-empting the need to manually curate the ever-increasing number of novel cancer associated genes. CancerMine is viewable through a web portal (http://bionlp.bcgsc.ca/cancermine/) and available for download (https://github.com/jakelever/cancermine).
Factors Related to Dental Caries, Periodontal Disease, and Psychological effect of those diseases: A Structural Equation Modeling and Artificial Neural Network model comparative approach
Authors: Ghosh Capt Sirsendu 
Published: July 2018

AbstractExceptional growth in the development of oral health of various populations worldwide over the last three decades cannot lessen tribulations in dental caries, periodontal disease, and psychological problems, which are still prevalent in many communities, especially among the poor socioeconomic groups in developing countries like India. Dental caries and periodontal disease are exceedingly related to the lifestyle associated risk factors and various daily habits including smoking and tobacco chewing. Dietary habit is one of the prime causative behind the formation of dental caries and simultaneously the dietary habit is greatly influenced by the person’s socio-economic status. In this study to explore the factors related to dental caries and periodontal disease and how these diseases manipulate the mental health of the people, some SEMs and some ANN models are also formed. At last both models are compared and explained about their purposes and usability for further applications.
pymfinder: a tool for the motif analysis of binary and quantitative complex networks
Authors: Mora Bernat Bramon , Cirtwill Alyssa R. , Stouffer Daniel B. 
Published: July 2018

AbstractWe developed pymfinder, a new software to analyze multiple aspects of the so-called network motifs—distinct n-node patterns of interaction—for any directed, undirected, unipartite or bipartite network. Unlike existing software for the study of network motifs, pymfinder allows the computation of node- and link-specific motif profiles as well as the analysis of weighted motifs. Beyond the overall characterization of networks, the tools presented in this work therefore allow for the comparison of the “roles” of either nodes or links of a network. Examples include the study of the roles of different species and/or their trophic/mutualistic interactions in ecological networks or the roles of specific proteins and/or their activation/inhibition relationships in protein-protein interaction networks. Here, we show how to apply the main tools from pymfinder using a predator-prey interaction network from a marine food web. pymfinder is open source software that can be freely and anonymously downloaded from https://github.com/stoufferlab/pymfinder, distributed under the MIT License (2018).
Comprehensive transcriptional profiling of the gastrointestinal tract of ruminants from birth to adulthood reveals strong developmental stage specific gene expression
Authors: Bush S. J. , McCulloch M. E. B. , Muriuki C. , Salavati M. , Davis G. M. , Farquhar I. L. , Lisowski Z. M. , Archibald A. L. , Hume D. A. , Clark E. L. 
Published: July 2018

AbstractOne of the most significant physiological challenges to neonatal and juvenile ruminants is the development and establishment of the rumen. Using a subset of RNA-Seq data from our high-resolution atlas of gene expression in sheep (Ovis aries) we have provided the first comprehensive characterisation of transcription of the entire the gastrointestinal (GI) tract during the transition from pre-ruminant to ruminant. The dataset comprises 168 tissue samples from sheep at four different time points (birth, one week, 8 weeks and adult). Using network cluster analysis we illustrate how the complexity of the GI tract is reflected in tissue- and developmental stage-specific differences in gene expression. The most significant transcriptional differences between neonatal and adult sheep were observed in the rumen complex. Differences in transcription between neonatal and adult sheep were particularly evident in macrophage specific signatures indicating they might be driving the observed developmental stage-specific differences. Comparative analysis of gene expression in three GI tract tissues from age-matched sheep and goats revealed species-specific differences in genes involved in immunity and metabolism. This study improves our understanding of the transcriptomic mechanisms involved in the transition from pre-ruminant to ruminant. It highlights key genes involved in immunity, microbe recognition, metabolism and cellular differentiation in the GI tract. The results form a basis for future studies linking gene expression with microbial colonisation of the developing GI tract and will contribute towards identifying genes that underlie immunity in early development, which could be utilised to improve ruminant efficiency and productivity.Reference Numbers for Data in the Public RepositoriesThe raw RNA-Sequencing data are deposited in the European Nucleotide Archive (ENA) under study accessions PRJEB19199 (sheep) and PRJEB23196 (goat). Metadata for all samples is deposited in the EBI BioSamples database under group identifiers SAMEG317052 (sheep) and SAMEG330351 (goat).
Expression and role of Galectin-3 in the postnatal development of the cerebellum
Authors: González-Calvo Inés , Selimi Fekrije 
Published: July 2018

AbstractMany proteins initially identified in the immune system play roles in neurogenesis, neuronal migration, axon guidance, synaptic plasticity and other processes related to the formation and refinement of neural circuits. Although the function of the immune-related protein Galectin-3 (LGALS3) has been extensively studied in the regulation of inflammation, cancer and microglia activation, little is known about its role in the development of the brain. In this study, we identified that LGALS3 is expressed in the developing postnatal cerebellum. More precisely, LGALS3 is expressed by cells in meninges and in the choroid plexus, and in subpopulations of astrocytes and of microglial cells in the cerebellar cortex. Analysis ofLgals3knockout mice showed thatLgals3is dispensable for the development of cerebellar cytoarchitecture and Purkinje cell excitatory synaptogenesis in the mouse.
Alternative (backdoor) androgen production and masculinization in the human fetus
Authors: O’Shaughnessy Peter J , Antignac Jean Philippe , Bizec Bruno Le , Morvan Marie-Line , Svechnikov Konstantin , Söder Olle , Savchuk Iuliia , Monteiro Ana , Soffientini Ugo , Johnston Zoe C , Bellingham Michelle , Hough Denise , Bhattacharya Siladitya , Walker Natasha , Filis Panagiotis , Fowler Paul A 
Published: July 2018

AbstractMasculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway. The fetal testes are essential for canonical androgen production but little is known about the synthesis of backdoor androgens despite their known critical role in masculinization. In this study, we have measured plasma and tissue levels of endogenous steroids in second trimester human male fetuses using multi-dimensional and high-resolution mass-spectrometry. Results show that androsterone is the principal backdoor androgen in the fetal circulation and that DHT is undetectable (<1ng/ml). Backdoor pathway intermediates are found primarily in the placenta and fetal liver with significant androsterone levels also in the fetal adrenal. Backdoor intermediates, including androsterone, are mostly undetectable in the fetal testes. This is consistent with transcript levels of enzymes involved in the backdoor pathway (SRD5A1, AKR1C2/4, CYP17A1), as measured by qPCR. These data identify androsterone as the predominant backdoor androgen in the human fetus and show that it is formed primarily in non-gonadal tissue with placental progesterone the likely substrate. Masculinization of the human fetus depends, therefore, on androgen synthesis by both the fetal testes and non-gonadal tissues leading to DHT formation at the genital tubercle. Our findings provide, for the first time, a solid basis to explain why placental insufficiency is associated with disorders of sex development in humans
Inferring the presence of aflatoxin-producingAspergillus flavusstrains using RNA sequencing and electronic probes as a transcriptomic screening tool
Authors: Espindola Andres S. , Schneider William , Cardwell Kitty F. , Carrillo Yisel , Hoyt Peter R. , Marek Stephen M. , Melouk Hassan , Garzon Carla D. 
Published: July 2018

AbstractE-probe Diagnostic for Nucleic acid Analysis (EDNA) is a bioinformatic tool originally developed to detect plant pathogens in metagenomic databases. However, enhancements made to EDNA increased its capacity to conduct hypothesis directed detection of specific gene targets present in transcriptomic databases. To target specific pathogenicity factors used by the pathogen to infect its host or other targets of interest, e-probes need to be developed for transcripts related to that function. In this study, EDNA transcriptomics (EDNAtran) was developed to detect the expression of genes related to aflatoxin production at the transcriptomic level. E-probes were designed from genes up-regulated duringA.flavusaflatoxin production. EDNAtran detected gene transcripts related to aflatoxin production in a transcriptomic database from corn, where aflatoxin was produced. The results were significantly different from e-probes being used in the transcriptomic database where aflatoxin was not produced (atoxigenic AF36 strain and toxigenic AF70 in Potato Dextrose Broth).
Design, optimization and validation of genes commonly used in expression studies on DMH/AOM rat colon carcinogenesis model
Authors: Bars-Cortina David , Riera Antoni , Gou Gemma , Piñol-Felis Carme , Motilva Maria-José 
Published: July 2018

AbstractColorectal cancer (CRC), also known as colon cancer, is the third most common form of cancer worldwide in men and the second in women and is characterized by several genetic alterations, among them the expression of several genes. 1,2-dimethylhydrazine (DMH) and its metabolite azoxymethane (AOM) are procarcinogens commonly used to induce colon cancer in rats (DMH/AOM rat model). This rat model has been used to study changes in mRNA expression in genes involved in this pathological condition. However, a lack of proper detailed PCR primer design in the literature limits the reproducibility of the published data.The present study aims to design, optimize and validate the qPCR, in accordance with the MIQE (Minimum Information for Publication of Quantitative Real-Time PCR Experiments) guidelines, for seventeen genes commonly used in the DMH/AOM rat model of CRC (Apc, Aurka, Bax, Bcl2, β-catenin, Ccnd1, Cdnk-1A, Cox2, Gsk3beta, IL-33, iNOs, Nrf2, p53, RelA, Smad4, Tnfa and Vegfa) and two reference genes (Actb or β-actin and B2m). The specificity of all primer pairs was empirically validated on agarose gel, and furthermore, the melting curve inspection was checked as was their efficiency (%) ranging from 90 to 110 with a correlation coefficient of r2 > 0.980. Finally, a pilot study was performed to compare the robustness of two candidate reference genes.
Circadian gene Clock regulates mitochondrial morphology and functions by posttranscriptional way
Authors: Xu Lirong , Cheng Qianyun , Hua Bingxuan , Cai Tingting , Lin Jiaxin , Yuan Gongsheng , Yan Zuoqin , Li Xiaobo , Sun Ning , Lu Chao , Qian Ruizhe 
Published: July 2018

AbstractMany daily activities are under the control of circadian clock, including nutrition metabolism and energy generation. Mitochondria, as the core factories of oxidizing substrates and producing ATP, undergo changes in quantity and morphology to adapt to the demand for energy. It has been demonstrated that mitochondrial gene expression, dynamics and functions are all affected by circadian clock. Here, we demonstrated that circadian gene Clock affects the number, architecture and function of mitochondria via posttranscriptional regulation of Drp1. ClockΔ19 leads to fragmented mitochondria accompanied with the loss of membrane potential, excessive ROS accumulation and decreased mitochondrial respiration and ATP generation. ClockΔ19 mice exhibit disordered lipid metabolism and evident nonalcoholic fatty liver disease (NAFLD), which are rescued by treatment with the mitochondrial fission inhibitor Mdivi-1. These results suggest a strong relationship between Clock, mitochondrial dynamics and metabolic diseases and provide a new perspective on disordered circadian clock and related diseases.
Effects of passive phospholipid flip-flop and asymmetric external fields on bilayer phase equilibria
Authors: Williamson J. J. , Olmsted P. D. 
Published: July 2018

AbstractCompositional asymmetry between the leaflets of bilayer membranes is known to couple strongly to their phase behaviour, in addition to having important effects on, e.g., mechanical properties and protein activity. We address how phase behaviour is affected by passive phospholipid flip-flop, such that the compositional asymmetry is not fixed. We predict transitions from “pre flip-flop” behaviour to a restricted set of phase equilibria that can persist in the presence of passive flip-flop. Surprisingly, such states are not necessarily symmetric. We further account for external symmetry-breaking, such as a preferential substrate interaction, and show how this can stabilise strongly asymmetric equilibrium states. Our theory explains several experimental observations of flip-flop mediated changes in phase behaviour, and shows how domain formation and compositional asymmetry can be controlled in concert, by manipulating passive flip-flop rates and applying external fields.
Pharmacologic activation of the G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma
Authors: Natale Christopher A. , Li Jinyang , Dentchev Tzvete , Capell Brian C. , Seykora John T. , Stanger Ben Z. , Ridky Todd W. 
Published: July 2018

AbstractFemale sex is associated with lower incidence and improved clinical outcomes for many cancer types, including pancreatic ductal adenocarcinoma (PDAC). Although the mechanisms responsible for this sex difference are unknown, recent data suggests nonclassical estrogen signaling through the G Protein-coupled Estrogen Receptor (GPER) is likely involved. Here we used murine syngeneic tumor models and human xenografts to test whether GPER signaling inhibits pancreatic ductal adenocarcinoma (PDAC). Activation of GPER with the specific, small molecule agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically delivered G-1 was well tolerated in PDAC bearing mice, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. We detected GPER protein in a majority of spontaneous human PDAC tumors. These data, coupled with the wide tissue distribution of GPER, and our previous work showing that G-1 inhibits melanoma, suggest that GPER agonists may be useful against many different cancer types.
Proteolytic processing of LRP2 on RPE cells regulates BMP activity to control eye size and refractive error
Authors: Collery Ross F. , Link Brian A. 
Published: July 2018

AbstractMutations in LRP2, a transmembrane receptor, cause ocular enlargement and high-myopia. LRP2 is expressed by the RPE and eye ciliary epithelia, binding many extracellular ligands, including Bmp4 and Shh. Signaling mediated by LRP2 is very context-dependent, and how multiple pathways are coordinated is unknown. Transcriptome analyses of ocular tissues revealed that controlled, sustained BMP signaling from the RPE is critical for normal eye growth and emmetropia (proper refraction). Using zebrafish, we demonstrate that BACE sheddase-dependent LRP2 cleavage produces a soluble domain that binds BMP4, inhibiting its signaling. We propose that controlled proteolytic cleavage of LRP2 makes two ligand-binding receptor forms available: a soluble BMP trap, and a membrane-bound RPE signaling facilitator. By modulating LRP2 cleavage, cells can fine-tune and coordinate multiple signaling pathways, as well as growth and turnover of the extracellular matrix, control of which is important to maintain proper eye size. This data supports the concept that LRP2 acts as a homeostasis node that buffers and integrates diverse signaling to regulate emmetropic eye growth.Author SummaryFor proper focusing and normal vision, the axial length of the eye needs to match the refractive power of the lens. This is achieved by fine-tuning multiple signaling pathways to regulate the shape of the eye primarily by remodeling of the sclera, the outermost layer of the eye. This process is termed emmetropization. Emmetropization cues are initiated by visual input, but how signals are transduced from the photoreceptors across the retinal pigment epithelium to the sclera is incompletely understood. Here we show that cleavage of Lrp2, a large receptor expressed on RPE cells in the eye, alters BMP signaling, which contributes to proper eye size control. Dysregulation of BMP signaling by a) absence of Lrp2 in mutant zebrafish or b) overexpression of BMP antagonists from the RPE both cause eye enlargement and myopia. Understanding how regulated cleavage of Lrp2 affects paracrine signaling provides critical insight to emmetropization, raising the possibility for development of therapeutic agents to combat the epidemic incidence of refractive error.