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  1. Article ; Online: Adaptation of CRISPR nucleases for eukaryotic applications.

    Ran, F Ann

    Analytical biochemistry

    2017  Volume 532, Page(s) 90–94

    Language English
    Publishing date 2017-09-01
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1110-1
    ISSN 1096-0309 ; 0003-2697
    ISSN (online) 1096-0309
    ISSN 0003-2697
    DOI 10.1016/j.ab.2016.10.018
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  2. Article ; Online: RNA-responsive elements for eukaryotic translational control.

    Zhao, Evan M / Mao, Angelo S / de Puig, Helena / Zhang, Kehan / Tippens, Nathaniel D / Tan, Xiao / Ran, F Ann / Han, Isaac / Nguyen, Peter Q / Chory, Emma J / Hua, Tiffany Y / Ramesh, Pradeep / Thompson, David B / Oh, Crystal Yuri / Zigon, Eric S / English, Max A / Collins, James J

    Nature biotechnology

    2021  Volume 40, Issue 4, Page(s) 539–545

    Abstract: The ability to control translation of endogenous or exogenous RNAs in eukaryotic cells would facilitate a variety of biotechnological applications. Current strategies are limited by low fold changes in transgene output and the size of trigger RNAs ( ... ...

    Abstract The ability to control translation of endogenous or exogenous RNAs in eukaryotic cells would facilitate a variety of biotechnological applications. Current strategies are limited by low fold changes in transgene output and the size of trigger RNAs (trRNAs). Here we introduce eukaryotic toehold switches (eToeholds) as modular riboregulators. eToeholds contain internal ribosome entry site sequences and form inhibitory loops in the absence of a specific trRNA. When the trRNA is present, eToeholds anneal to it, disrupting the inhibitory loops and allowing translation. Through optimization of RNA annealing, we achieved up to 16-fold induction of transgene expression in mammalian cells. We demonstrate that eToeholds can discriminate among viral infection status, presence or absence of gene expression and cell types based on the presence of exogenous or endogenous RNA transcripts.
    MeSH term(s) Animals ; Mammals/genetics ; Protein Biosynthesis/genetics ; RNA ; RNA, Viral/genetics
    Chemical Substances RNA, Viral ; RNA (63231-63-0)
    Language English
    Publishing date 2021-10-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1311932-1
    ISSN 1546-1696 ; 1087-0156
    ISSN (online) 1546-1696
    ISSN 1087-0156
    DOI 10.1038/s41587-021-01068-2
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  3. Article ; Online: Abl Kinases Regulate HGF/Met Signaling Required for Epithelial Cell Scattering, Tubulogenesis and Motility.

    Ran Li / Jennifer F Knight / Morag Park / Ann Marie Pendergast

    PLoS ONE, Vol 10, Iss 5, p e

    2015  Volume 0124960

    Abstract: Tight regulation of receptor tyrosine kinases (RTKs) is crucial for normal development and homeostasis. Dysregulation of RTKs signaling is associated with diverse pathological conditions including cancer. The Met RTK is the receptor for hepatocyte growth ...

    Abstract Tight regulation of receptor tyrosine kinases (RTKs) is crucial for normal development and homeostasis. Dysregulation of RTKs signaling is associated with diverse pathological conditions including cancer. The Met RTK is the receptor for hepatocyte growth factor (HGF) and is dysregulated in numerous human tumors. Here we show that Abl family of non-receptor tyrosine kinases, comprised of Abl (ABL1) and Arg (ABL2), are activated downstream of the Met receptor, and that inhibition of Abl kinases dramatically suppresses HGF-induced cell scattering and tubulogenesis. We uncover a critical role for Abl kinases in the regulation of HGF/Met-dependent RhoA activation and RhoA-mediated actomyosin contractility and actin cytoskeleton remodeling in epithelial cells. Moreover, treatment of breast cancer cells with Abl inhibitors markedly decreases Met-driven cell migration and invasion. Notably, expression of a transforming mutant of the Met receptor in the mouse mammary epithelium results in hyper-activation of both Abl and Arg kinases. Together these data demonstrate that Abl kinases link Met activation to Rho signaling and Abl kinases are required for Met-dependent cell scattering, tubulogenesis, migration, and invasion. Thus, inhibition of Abl kinases might be exploited for the treatment of cancers driven by hyperactivation of HGF/Met signaling.
    Keywords Medicine ; R ; Science ; Q
    Subject code 571
    Language English
    Publishing date 2015-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: RNA-guided genome editing of mammalian cells.

    Pyzocha, Neena K / Ran, F Ann / Hsu, Patrick D / Zhang, Feng

    Methods in molecular biology (Clifton, N.J.)

    2013  Volume 1114, Page(s) 269–277

    Abstract: The microbial CRISPR-Cas adaptive immune system can be harnessed to facilitate genome editing in eukaryotic cells (Cong L et al., Science 339, 819-823, 2013; Mali P et al., Science 339, 823-826, 2013). Here we describe a protocol for the use of the RNA- ... ...

    Abstract The microbial CRISPR-Cas adaptive immune system can be harnessed to facilitate genome editing in eukaryotic cells (Cong L et al., Science 339, 819-823, 2013; Mali P et al., Science 339, 823-826, 2013). Here we describe a protocol for the use of the RNA-guided Cas9 nuclease from the Streptococcus pyogenes type II CRISPR system to achieve specific, scalable, and cost-efficient genome editing in mammalian cells.
    MeSH term(s) Animals ; Cell Line ; Cloning, Molecular ; DNA End-Joining Repair ; Gene Order ; Gene Targeting/methods ; Genetic Vectors ; Genome ; Humans ; RNA Editing ; Transfection ; RNA, Small Untranslated
    Chemical Substances RNA, Small Untranslated
    Language English
    Publishing date 2013-11-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-62703-761-7_17
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  5. Article ; Online: Abl Kinases Regulate HGF/Met Signaling Required for Epithelial Cell Scattering, Tubulogenesis and Motility.

    Li, Ran / Knight, Jennifer F / Park, Morag / Pendergast, Ann Marie

    PloS one

    2015  Volume 10, Issue 5, Page(s) e0124960

    Abstract: Tight regulation of receptor tyrosine kinases (RTKs) is crucial for normal development and homeostasis. Dysregulation of RTKs signaling is associated with diverse pathological conditions including cancer. The Met RTK is the receptor for hepatocyte growth ...

    Abstract Tight regulation of receptor tyrosine kinases (RTKs) is crucial for normal development and homeostasis. Dysregulation of RTKs signaling is associated with diverse pathological conditions including cancer. The Met RTK is the receptor for hepatocyte growth factor (HGF) and is dysregulated in numerous human tumors. Here we show that Abl family of non-receptor tyrosine kinases, comprised of Abl (ABL1) and Arg (ABL2), are activated downstream of the Met receptor, and that inhibition of Abl kinases dramatically suppresses HGF-induced cell scattering and tubulogenesis. We uncover a critical role for Abl kinases in the regulation of HGF/Met-dependent RhoA activation and RhoA-mediated actomyosin contractility and actin cytoskeleton remodeling in epithelial cells. Moreover, treatment of breast cancer cells with Abl inhibitors markedly decreases Met-driven cell migration and invasion. Notably, expression of a transforming mutant of the Met receptor in the mouse mammary epithelium results in hyper-activation of both Abl and Arg kinases. Together these data demonstrate that Abl kinases link Met activation to Rho signaling and Abl kinases are required for Met-dependent cell scattering, tubulogenesis, migration, and invasion. Thus, inhibition of Abl kinases might be exploited for the treatment of cancers driven by hyperactivation of HGF/Met signaling.
    MeSH term(s) Actin Cytoskeleton/metabolism ; Animals ; Cell Line, Tumor ; Cell Movement ; Dogs ; Epithelial Cells/physiology ; HEK293 Cells ; Hepatocyte Growth Factor/metabolism ; Humans ; Madin Darby Canine Kidney Cells ; Mice ; Proto-Oncogene Proteins c-abl/metabolism ; Proto-Oncogene Proteins c-met/metabolism ; Signal Transduction
    Chemical Substances Hepatocyte Growth Factor (67256-21-7) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1) ; Proto-Oncogene Proteins c-abl (EC 2.7.10.2)
    Language English
    Publishing date 2015-05-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0124960
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  6. Article ; Online: Whole Clinic Research Enrollment in Parkinson's Disease: The Molecular Integration in Neurological Diagnosis (MIND) Study.

    Tropea, Thomas F / Amari, Noor / Han, Noah / Rick, Jacqueline / Suh, EunRan / Akhtar, Rizwan S / Dahodwala, Nabila / Deik, Andres / Gonzalez-Alegre, Pedro / Hurtig, Howard / Siderowf, Andrew / Spindler, Meredith / Stern, Matthew / Thenganatt, Mary Ann / Weintraub, Daniel / Willis, Allison W / Van Deerlin, Vivianna / Chen-Plotkin, Alice

    Journal of Parkinson's disease

    2021  Volume 11, Issue 2, Page(s) 757–765

    Abstract: Background: Observational studies in Parkinson's disease (PD) have focused on relatively small numbers of research participants who are studied extensively. The Molecular Integration in Neurological Diagnosis Initiative at the University of Pennsylvania ...

    Abstract Background: Observational studies in Parkinson's disease (PD) have focused on relatively small numbers of research participants who are studied extensively. The Molecular Integration in Neurological Diagnosis Initiative at the University of Pennsylvania aims to characterize molecular and clinical features of PD in every patient in a large academic center.
    Objective: To determine the feasibility and interest in a global-capture biomarker research protocol. Additionally, to describe the clinical characteristics and GBA and LRRK2 variant carrier status among participants.
    Methods: All patients at UPenn with a clinical diagnosis of PD were eligible. Informed consent included options for access to the medical record, future recontact, and use of biosamples for additional studies. A blood sample and a completed questionnaire were obtained from participants. Targeted genotyping for four GBA and eight LRRK2 variants was performed, with plasma and DNA banked for future research.
    Results: Between September 2018 and December 2019, 704 PD patients were approached for enrollment; 652 (92.6%) enrolled, 28 (3.97%) declined, and 24 (3.41%) did not meet eligibility criteria. Median age was 69 (IQR 63_75) years, disease duration was 5.41 (IQR 2.49_9.95) years, and 11.10%of the cohort was non-white. Disease risk-associated variants in GBA were identified in 39 participants (5.98%) and in LRRK2 in 16 participants (2.45%).
    Conclusions: We report the clinical and genetic characteristics of PD patients in an all-comers, global capture protocol from an academic center. Patient interest in participation and yield for identification of GBA and LRRK2 mutation carriers is high, demonstrating feasibility of PD clinic-wide molecular characterization.
    MeSH term(s) Aged ; Cohort Studies ; Glucosylceramidase/genetics ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Mutation ; Parkinson Disease/diagnosis ; Parkinson Disease/genetics
    Chemical Substances Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; Glucosylceramidase (EC 3.2.1.45)
    Language English
    Publishing date 2021-02-11
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2620609-2
    ISSN 1877-718X ; 1877-7171
    ISSN (online) 1877-718X
    ISSN 1877-7171
    DOI 10.3233/JPD-202406
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    Zs.A 6964: Show issues Location:
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  7. Article ; Online: UD-MIL: Uncertainty-Driven Deep Multiple Instance Learning for OCT Image Classification.

    Wang, Xi / Tang, Fangyao / Chen, Hao / Luo, Luyang / Tang, Ziqi / Ran, An-Ran / Cheung, Carol Y / Heng, Pheng-Ann

    IEEE journal of biomedical and health informatics

    2020  Volume 24, Issue 12, Page(s) 3431–3442

    Abstract: Deep learning has achieved remarkable success in the optical coherence tomography (OCT) image classification task with substantial labelled B-scan images available. However, obtaining such fine-grained expert annotations is usually quite difficult and ... ...

    Abstract Deep learning has achieved remarkable success in the optical coherence tomography (OCT) image classification task with substantial labelled B-scan images available. However, obtaining such fine-grained expert annotations is usually quite difficult and expensive. How to leverage the volume-level labels to develop a robust classifier is very appealing. In this paper, we propose a weakly supervised deep learning framework with uncertainty estimation to address the macula-related disease classification problem from OCT images with the only volume-level label being available. First, a convolutional neural network (CNN) based instance-level classifier is iteratively refined by using the proposed uncertainty-driven deep multiple instance learning scheme. To our best knowledge, we are the first to incorporate the uncertainty evaluation mechanism into multiple instance learning (MIL) for training a robust instance classifier. The classifier is able to detect suspicious abnormal instances and abstract the corresponding deep embedding with high representation capability simultaneously. Second, a recurrent neural network (RNN) takes instance features from the same bag as input and generates the final bag-level prediction by considering the individually local instance information and globally aggregated bag-level representation. For more comprehensive validation, we built two large diabetic macular edema (DME) OCT datasets from different devices and imaging protocols to evaluate the efficacy of our method, which are composed of 30,151 B-scans in 1,396 volumes from 274 patients (Heidelberg-DME dataset) and 38,976 B-scans in 3,248 volumes from 490 patients (Triton-DME dataset), respectively. We compare the proposed method with the state-of-the-art approaches, and experimentally demonstrate that our method is superior to alternative methods, achieving volume-level accuracy, F1-score and area under the receiver operating characteristic curve (AUC) of 95.1%, 0.939 and 0.990 on Heidelberg-DME and those of 95.1%, 0.935 and 0.986 on Triton-DME, respectively. Furthermore, the proposed method also yields competitive results on another public age-related macular degeneration OCT dataset, indicating the high potential as an effective screening tool in the clinical practice.
    MeSH term(s) Adolescent ; Adult ; Deep Learning ; Diabetic Retinopathy/diagnostic imaging ; Humans ; Image Interpretation, Computer-Assisted/methods ; Macular Edema/diagnostic imaging ; Retina/diagnostic imaging ; Supervised Machine Learning ; Tomography, Optical Coherence/methods ; Young Adult
    Language English
    Publishing date 2020-12-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2695320-1
    ISSN 2168-2208 ; 2168-2194
    ISSN (online) 2168-2208
    ISSN 2168-2194
    DOI 10.1109/JBHI.2020.2983730
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  8. Article ; Online: Temperamental Shyness and Anger/Frustration in Childhood: Normative Development, Individual Differences, and the Impacts of Maternal Intrusiveness and Frontal Electroencephalogram Asymmetry.

    Liu, Ran / Phillips, Jennifer J / Ji, Feng / Shi, Dexin / Bell, Martha Ann

    Child development

    2021  Volume 92, Issue 6, Page(s) 2529–2545

    Abstract: This study used latent growth curve modeling to identify normative development and individual differences in the developmental patterns of shyness and anger/frustration across childhood. This study also examined the impacts of maternal intrusiveness and ... ...

    Abstract This study used latent growth curve modeling to identify normative development and individual differences in the developmental patterns of shyness and anger/frustration across childhood. This study also examined the impacts of maternal intrusiveness and frontal electroencephalogram (EEG) asymmetry at age 4 on the developmental patterns of shyness and anger/frustration. 180 children (92 boys, 88 girls; M
    MeSH term(s) Anger ; Child ; Child, Preschool ; Electroencephalography ; Female ; Frontal Lobe ; Frustration ; Humans ; Individuality ; Male ; Shyness
    Language English
    Publishing date 2021-07-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 215602-7
    ISSN 1467-8624 ; 0009-3920
    ISSN (online) 1467-8624
    ISSN 0009-3920
    DOI 10.1111/cdev.13621
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  9. Article ; Online: Genome engineering using the CRISPR-Cas9 system.

    Ran, F Ann / Hsu, Patrick D / Wright, Jason / Agarwala, Vineeta / Scott, David A / Zhang, Feng

    Nature protocols

    2013  Volume 8, Issue 11, Page(s) 2281–2308

    Abstract: Targeted nucleases are powerful tools for mediating genome alteration with high precision. The RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system can be used to facilitate ...

    Abstract Targeted nucleases are powerful tools for mediating genome alteration with high precision. The RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system can be used to facilitate efficient genome engineering in eukaryotic cells by simply specifying a 20-nt targeting sequence within its guide RNA. Here we describe a set of tools for Cas9-mediated genome editing via nonhomologous end joining (NHEJ) or homology-directed repair (HDR) in mammalian cells, as well as generation of modified cell lines for downstream functional studies. To minimize off-target cleavage, we further describe a double-nicking strategy using the Cas9 nickase mutant with paired guide RNAs. This protocol provides experimentally derived guidelines for the selection of target sites, evaluation of cleavage efficiency and analysis of off-target activity. Beginning with target design, gene modifications can be achieved within as little as 1-2 weeks, and modified clonal cell lines can be derived within 2-3 weeks.
    MeSH term(s) Base Sequence ; Cell Culture Techniques ; Cell Line ; Clustered Regularly Interspaced Short Palindromic Repeats ; DNA End-Joining Repair ; DNA Mutational Analysis ; DNA Repair ; Deoxyribonucleases/chemistry ; Deoxyribonucleases/genetics ; Genetic Engineering/methods ; Genome ; Genotyping Techniques ; HEK293 Cells ; Humans ; Molecular Sequence Data ; Mutagenesis ; Transfection
    Chemical Substances Deoxyribonucleases (EC 3.1.-)
    Language English
    Publishing date 2013-10-24
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2244966-8
    ISSN 1750-2799 ; 1754-2189
    ISSN (online) 1750-2799
    ISSN 1754-2189
    DOI 10.1038/nprot.2013.143
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  10. Article ; Online: Virtual screening for small-molecule pathway regulators by image-profile matching.

    Rohban, Mohammad H / Fuller, Ashley M / Tan, Ceryl / Goldstein, Jonathan T / Syangtan, Deepsing / Gutnick, Amos / DeVine, Ann / Nijsure, Madhura P / Rigby, Megan / Sacher, Joshua R / Corsello, Steven M / Peppler, Grace B / Bogaczynska, Marta / Boghossian, Andrew / Ciotti, Gabrielle E / Hands, Allison T / Mekareeya, Aroonroj / Doan, Minh / Gale, Jennifer P /
    Derynck, Rik / Turbyville, Thomas / Boerckel, Joel D / Singh, Shantanu / Kiessling, Laura L / Schwarz, Thomas L / Varelas, Xaralabos / Wagner, Florence F / Kafri, Ran / Eisinger-Mathason, T S Karin / Carpenter, Anne E

    Cell systems

    2022  Volume 13, Issue 9, Page(s) 724–736.e9

    Abstract: Identifying the chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions of candidate small molecules are tested in target-based biochemical screens or ... ...

    Abstract Identifying the chemical regulators of biological pathways is a time-consuming bottleneck in developing therapeutics and research compounds. Typically, thousands to millions of candidate small molecules are tested in target-based biochemical screens or phenotypic cell-based screens, both expensive experiments customized to each disease. Here, our uncustomized, virtual, profile-based screening approach instead identifies compounds that match to pathways based on the phenotypic information in public cell image data, created using the Cell Painting assay. Our straightforward correlation-based computational strategy retrospectively uncovered the expected, known small-molecule regulators for 32% of positive-control gene queries. In prospective, discovery mode, we efficiently identified new compounds related to three query genes and validated them in subsequent gene-relevant assays, including compounds that phenocopy or pheno-oppose YAP1 overexpression and kill a Yap1-dependent sarcoma cell line. This image-profile-based approach could replace many customized labor- and resource-intensive screens and accelerate the discovery of biologically and therapeutically useful compounds.
    MeSH term(s) Cell Line ; Prospective Studies ; Retrospective Studies
    Language English
    Publishing date 2022-09-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2854138-8
    ISSN 2405-4720 ; 2405-4712
    ISSN (online) 2405-4720
    ISSN 2405-4712
    DOI 10.1016/j.cels.2022.08.003
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