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COSSMO: predicting competitive alternative splice site selection using deep learning.

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COSSMO: predicting competitive alternative splice site selection using deep learning.

Bioinformatics. 2018 Jul 01;34(13):i429-i437

Authors: Bretschneider H, Gandhi S, Deshwar AG, Zuberi K, Frey BJ

Abstract
Motivation: Alternative splice site selection is inherently competitive and the probability of a given splice site to be used also depends on the strength of neighboring sites. Here, we present a new model named the competitive splice site model (COSSMO), which explicitly accounts for these competitive effects and predicts the percent selected index (PSI) distribution over any number of putative splice sites. We model an alternative splicing event as the choice of a 3' acceptor site conditional on a fixed upstream 5' donor site or the choice of a 5' donor site conditional on a fixed 3' acceptor site. We build four different architectures that use convolutional layers, communication layers, long short-term memory and residual networks, respectively, to learn relevant motifs from sequence alone. We also construct a new dataset from genome annotations and RNA-Seq read data that we use to train our model.
Results: COSSMO is able to predict the most frequently used splice site with an accuracy of 70% on unseen test data, and achieve an R2 of 0.6 in modeling the PSI distribution. We visualize the motifs that COSSMO learns from sequence and show that COSSMO recognizes the consensus splice site sequences and many known splicing factors with high specificity.
Availability and implementation: Model predictions, our training dataset, and code are available from http://cossmo.genes.toronto.edu.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 29949959 [PubMed - in process]



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Co-targeting ephrin receptor tyrosine kinases A2 and A3 in cancer stem cells reduces growth of recurrent glioblastoma.

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Co-targeting ephrin receptor tyrosine kinases A2 and A3 in cancer stem cells reduces growth of recurrent glioblastoma.

Cancer Res. 2018 Jun 26;:

Authors: Qazi MA, Vora P, Venugopal C, Adams J, Singh M, Hu AX, Gorelik M, Subapanditha MK, Savage N, Yang J, Chokshi C, London M, Gont A, Bobrowski D, Grinshtein N, Brown KR, Murty NK, Nilvebrant J, Kaplan DR, Moffat J, Sidhu S, Singh SK

Abstract
Glioblastoma (GBM) carries a dismal prognosis and inevitably relapses despite aggressive therapy. Many members of the Eph receptor tyrosine kinase (EphR) family are expressed by glioblastoma stem cells (GSC), which have been implicated in resistance to GBM therapy. In this study, we identify several EphR that mark a therapeutically targetable GSC population in treatment-refractory, recurrent GBM (rGBM). Using a highly specific EphR antibody panel and CyTOF (Cytometry by Time-Of-Flight), we characterized the expression of all 14 EphR in primary and recurrent patient-derived GSC to identify putative rGBM-specific EphR. EphA2 and EphA3 co-expression marked a highly tumorigenic cell population in rGBM that was enriched in GSC marker expression. Knockdown of EphA2 and EphA3 together led to increased expression of differentiation marker GFAP and blocked clonogenic and tumorigenic potential, promoting significantly higher survival in vivo. Treatment of rGBM with a bispecific antibody (BsAb) against EphA2/A3 reduced clonogenicity in vitro and tumorigenic potential of xenografted recurrent GBM in vivo via downregulation of Akt and Erk and increased cellular differentiation. In conclusion, we show that EphA2 and EphA3 together mark a GSC population in rGBM and that strategic co-targeting of EphA2 and EphA3 presents a novel and rational therapeutic approach for rGBM.

PMID: 29945963 [PubMed - as supplied by publisher]



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Biomaterials driving repair after stroke.

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Biomaterials driving repair after stroke.

Nat Mater. 2018 Jul;17(7):573-574

Authors: Tuladhar A, Shoichet MS

PMID: 29941949 [PubMed - in process]



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Mechanics-guided developmental fate patterning.

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Mechanics-guided developmental fate patterning.

Nat Mater. 2018 Jul;17(7):571-572

Authors: Tewary M, Zandstra PW

PMID: 29941948 [PubMed - in process]



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A multiprotein supercomplex controlling oncogenic signalling in lymphoma.

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A multiprotein supercomplex controlling oncogenic signalling in lymphoma.

Nature. 2018 Jun 20;:

Authors: Phelan JD, Young RM, Webster DE, Roulland S, Wright GW, Kasbekar M, Shaffer AL, Ceribelli M, Wang JQ, Schmitz R, Nakagawa M, Bachy E, Huang DW, Ji Y, Chen L, Yang Y, Zhao H, Yu X, Xu W, Palisoc MM, Valadez RR, Davies-Hill T, Wilson WH, Chan WC, Jaffe ES, Gascoyne RD, Campo E, Rosenwald A, Ott G, Delabie J, Rimsza LM, Rodriguez FJ, Estephan F, Holdhoff M, Kruhlak MJ, Hewitt SM, Thomas CJ, Pittaluga S, Oellerich T, Staudt LM

Abstract
B cell receptor (BCR) signaling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients1. Gene expression profiling identified two major DLBCL subtypes, known as germinal center (GC) B cell-like (GCB) and activated B cell-like (ABC)2,3, with inferior outcomes following immunochemotherapy in ABC. Autoantigens drive BCR-dependent activation of NF-κB in ABC DLBCL through a kinase cascade of SYK, BTK and PKCβ to promote the assembly of the CARD11-BCL10-MALT1 (CBM) adapter complex that recruits and activates IκB kinase (IKK)4-6. Genome sequencing revealed gain-of-function mutations targeting the CD79A and CD79B BCR subunits and the Toll-like receptor (TLR) signaling adapter MYD885,7, with MYD88L265P being the most prevalent isoform. In a clinical trial, the BTK inhibitor, ibrutinib, produced responses in 37% of ABC cases1. The most striking response rate (80%) was observed in tumors with both CD79B and MYD88L265P mutations, but how these mutations cooperate to promote dependence on BCR signaling remains unclear. Herein, we used genome-wide CRISPR-Cas9 screening and functional proteomics to understand the molecular basis of exceptional clinical responses to ibrutinib. We discovered a new mode of oncogenic BCR signaling in ibrutinib-responsive cell lines and biopsies, coordinated by a multiprotein supercomplex formed by MYD88, TLR9, and the BCR (My-T-BCR). The My-T-BCR co-localizes with mTOR on endolysosomes, where it drives pro-survival NF-κB and mTOR signaling. Inhibitors of BCR and mTOR signaling cooperatively decreased My-T-BCR supercomplex formation and function, providing mechanistic insight into their synergistic toxicity for My-T-BCR+ DLBCL cells. My-T-BCR complexes characterized ibrutinib-responsive malignancies and distinguished ibrutinib responders from non-responders. Our data provide a roadmap for the rational deployment of oncogenic signaling inhibitors in molecularly-defined subsets of DLBCL.

PMID: 29925955 [PubMed - as supplied by publisher]



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Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

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Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities.

J Cell Biol. 2018 Jun 19;:

Authors: Casey AE, Sinha A, Singhania R, Livingstone J, Waterhouse P, Tharmapalan P, Cruickshank J, Shehata M, Drysdale E, Fang H, Kim H, Isserlin R, Bailey S, Medina T, Deblois G, Shiah YJ, Barsyte-Lovejoy D, Hofer S, Bader G, Lupien M, Arrowsmith C, Knapp S, De Carvalho D, Berman H, Boutros PC, Kislinger T, Khokha R

Abstract
The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin-DNA-RNA-protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor-positive and -negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology.

PMID: 29921600 [PubMed - as supplied by publisher]



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GeneMANIA update 2018.

GeneMANIA update 2018.

Nucleic Acids Res. 2018 Jun 15;:

Authors: Franz M, Rodriguez H, Lopes C, Zuberi K, Montojo J, Bader GD, Morris Q

Abstract
GeneMANIA (http://genemania.org) is a flexible user-friendly web site for generating hypotheses about gene function, analyzing gene lists and prioritizing genes for functional assays. Given a query gene list, GeneMANIA finds functionally similar genes using a wealth of genomics and proteomics data. In this mode, it weights each functional genomic dataset according to its predictive value for the query. Another use of GeneMANIA is gene function prediction. Given a single query gene, GeneMANIA finds genes likely to share function with it based on their interactions with it. Enriched Gene Ontology categories among this set can point to the function of the gene. Nine organisms are currently supported (Arabidopsis thaliana, Caenorhabditis elegans, Danio rerio, Drosophila melanogaster, Escherichia coli, Homo sapiens, Mus musculus, Rattus norvegicus and Saccharomyces cerevisiae). Hundreds of data sets and hundreds of millions of interactions have been collected from GEO, BioGRID, IRefIndex and I2D, as well as organism-specific functional genomics data sets. Users can customize their search by selecting specific data sets to query and by uploading their own data sets to analyze. We have recently updated the user interface to GeneMANIA to make it more intuitive and make more efficient use of visual space. GeneMANIA can now be used effectively on a variety of devices.

PMID: 29912392 [PubMed - as supplied by publisher]



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Lipophilicity of the Cystic Fibrosis drug, Ivacaftor, and its destabilizing effect on the major CF-causing mutation: F508del.

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Lipophilicity of the Cystic Fibrosis drug, Ivacaftor, and its destabilizing effect on the major CF-causing mutation: F508del.

Mol Pharmacol. 2018 Jun 14;:

Authors: Chin S, Hung M, Won A, Wu YS, Ahmadi S, Yang D, Elmallah S, Toutah K, Hamilton CM, Young RN, Viirre RD, Yip CM, Bear CE

Abstract
The major Cystic Fibrosis (CF) causing mutation, the deletion of phenylalanine at position 508 (F508del) at the cystic fibrosis transmembrane conductance regulator (CFTR), occurs in approximately 90% of the CF population. Recently, a combination therapy, comprising a corrector (VX-809) that rescues the processing defects of F508del-CFTR and a potentiator (VX-770) that rescues mutant channel activity, was approved for CF patients homozygous for this mutation. However, clinical studies revealed that the efficacy of this drug on lung function was modest and variable amongst patients. It has been proposed that this modest effect may partially relate to a destabilizing effect of VX-770 on mutant protein. In the current studies, we observed a similar concentration-dependent destabilizing effect of VX-770 on F508del-CFTR and on other ion transporters. We found that the relative destabilizing effect of a panel of VX-770 derivatives correlated with their predicted lipophilicity. Given the importance of CFTR association with lipid rafts, we were prompted to determine if VX-770 directly disrupted lipid rafts. Polarized total internal reflection fluorescence microscopy on a supported lipid bilayer model shows that VX-770, and not its less lipophilic derivative, increased the fluidity of and reorganized the membrane. In summary, our findings support the claim that VX-770 modulates CFTR stability via interaction with membrane lipids.

PMID: 29903751 [PubMed - as supplied by publisher]



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Genetic Network Complexity Shapes Background-Dependent Phenotypic Expression.

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Genetic Network Complexity Shapes Background-Dependent Phenotypic Expression.

Trends Genet. 2018 Jun 11;:

Authors: Hou J, van Leeuwen J, Andrews BJ, Boone C

Abstract
The phenotypic consequences of a given mutation can vary across individuals. This so-called background effect is widely observed, from mutant fitness of loss-of-function variants in model organisms to variable disease penetrance and expressivity in humans; however, the underlying genetic basis often remains unclear. Taking insights gained from recent large-scale surveys of genetic interaction and suppression analyses in yeast, we propose that the genetic network context for a given mutation may shape its propensity of exhibiting background-dependent phenotypes. We argue that further efforts in systematically mapping the genetic interaction networks beyond yeast will provide not only key insights into the functional properties of genes, but also a better understanding of the background effects and the (un)predictability of traits in a broader context.

PMID: 29903533 [PubMed - as supplied by publisher]



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Neural stem cell heterogeneity in the mammalian forebrain.

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Neural stem cell heterogeneity in the mammalian forebrain.

Prog Neurobiol. 2018 Jun 11;:

Authors: Adams KV, Morshead CM

Abstract
The brain was long considered an organ that underwent very little change after development. It is now well established that the mammalian central nervous system contains neural stem cells that generate progeny that are capable of making new neurons, astrocytes, and oligodendrocytes throughout life. The field has advanced rapidly as it strives to understand the basic biology of these precursor cells, and explore their potential to promote brain repair. The purpose of this review is to present current knowledge about the diversity of neural stem cells in vitro and in vivo, and highlight distinctions between neural stem cell populations, throughout development, and within the niche. A comprehensive understanding of neural stem cell heterogeneity will provide insights into the cellular and molecular regulation of neural development and lifelong neurogenesis, and will guide the development of novel strategies to promote regeneration and neural repair.

PMID: 29902499 [PubMed - as supplied by publisher]



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