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  1. Article: Abrogation of Rb Tumor Suppression Initiates GBM in Differentiated Astrocytes by Driving a Progenitor Cell Program.

    Adhikari, Amit S / Sullivan, Teresa / Bargaje, Rhishikesh / Lu, Lucy / O'Sullivan, T Norene / Song, Yurong / Van Dyke, Terry

    Frontiers in oncology

    2022  Volume 12, Page(s) 904479

    Abstract: Glioblastoma (GBM) remains lethal with no effective treatments. Despite the comprehensive identification of commonly perturbed molecular pathways, little is known about the disease's etiology, particularly in early stages. Several studies indicate that ... ...

    Abstract Glioblastoma (GBM) remains lethal with no effective treatments. Despite the comprehensive identification of commonly perturbed molecular pathways, little is known about the disease's etiology, particularly in early stages. Several studies indicate that GBM is initiated in neural progenitor and/or stem cells. Here, we report that differentiated astrocytes are susceptible to GBM development when initiated by perturbation of the RB pathway, which induces a progenitor phenotype.
    Language English
    Publishing date 2022-06-24
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2022.904479
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Taking Systems Medicine to Heart.

    Trachana, Kalliopi / Bargaje, Rhishikesh / Glusman, Gustavo / Price, Nathan D / Huang, Sui / Hood, Leroy E

    Circulation research

    2018  Volume 122, Issue 9, Page(s) 1276–1289

    Abstract: Systems medicine is a holistic approach to deciphering the complexity of human physiology in health and disease. In essence, a living body is constituted of networks of dynamically interacting units (molecules, cells, organs, etc) that underlie its ... ...

    Abstract Systems medicine is a holistic approach to deciphering the complexity of human physiology in health and disease. In essence, a living body is constituted of networks of dynamically interacting units (molecules, cells, organs, etc) that underlie its collective functions. Declining resilience because of aging and other chronic environmental exposures drives the system to transition from a health state to a disease state; these transitions, triggered by acute perturbations or chronic disturbance, manifest as qualitative shifts in the interactions and dynamics of the disease-perturbed networks. Understanding health-to-disease transitions poses a high-dimensional nonlinear reconstruction problem that requires deep understanding of biology and innovation in study design, technology, and data analysis. With a focus on the principles of systems medicine, this Review discusses approaches for deciphering this biological complexity from a novel perspective, namely, understanding how disease-perturbed networks function; their study provides insights into fundamental disease mechanisms. The immediate goals for systems medicine are to identify early transitions to cardiovascular (and other chronic) diseases and to accelerate the translation of new preventive, diagnostic, or therapeutic targets into clinical practice, a critical step in the development of personalized, predictive, preventive, and participatory (P4) medicine.
    MeSH term(s) Biomarkers ; Cardiovascular Diseases/diagnosis ; Cardiovascular Diseases/physiopathology ; Cardiovascular Diseases/prevention & control ; Cardiovascular Diseases/therapy ; Chronic Disease ; Diagnostic Techniques, Cardiovascular ; Disease Progression ; Early Diagnosis ; Environmental Exposure ; Forecasting ; Genome-Wide Association Study ; Genomics ; Humans ; In Vitro Techniques ; Industrial Development ; Models, Cardiovascular ; Precision Medicine ; Systems Analysis ; Translational Research, Biomedical
    Chemical Substances Biomarkers
    Language English
    Publishing date 2018-04-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 80100-8
    ISSN 1524-4571 ; 0009-7330 ; 0931-6876
    ISSN (online) 1524-4571
    ISSN 0009-7330 ; 0931-6876
    DOI 10.1161/CIRCRESAHA.117.310999
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Consensus miRNA expression profiles derived from interplatform normalization of microarray data.

    Bargaje, Rhishikesh / Hariharan, Manoj / Scaria, Vinod / Pillai, Beena

    RNA (New York, N.Y.)

    2009  Volume 16, Issue 1, Page(s) 16–25

    Abstract: Eukaryotic gene expression is controlled at the post-transcriptional level by small noncoding RNAs called microRNAs (miRNA). miRNAs play important roles during early development and participate in gene regulatory circuits in the cell. Different high- ... ...

    Abstract Eukaryotic gene expression is controlled at the post-transcriptional level by small noncoding RNAs called microRNAs (miRNA). miRNAs play important roles during early development and participate in gene regulatory circuits in the cell. Different high-throughput expression analysis methods including microarrays, bead-based detection, and small RNA cloning have been applied to quantitatively detect miRNAs in various tissues, cell types, and biological conditions. High-throughput expression data was collected from public repositories and processed to create a database of miRNA expression profiles. Several commonly used normalization methods were compared to identify suitable methods for cross-platform comparison of high-throughput miRNA expression data. The database provides interlaboratory and interplatform validated reference expression levels for miRNAs. The normalized expression profiles were validated by querying for well-established features of miRNA expression. Firstly, expression profiles of several tissue-specific miRNAs showed good agreement between the database and previously reported profiles. We have also identified a set of miRNAs that are constitutively expressed across mammalian tissues. Secondly, we used the database to compare the expression patterns of miRNAs belonging to the let-7 family, where the divergence in expression patterns implies that they may have diversified functionally. Lastly, we compared expression profiles of intronic and clustered miRNAs. Expression profiles of intronic miRNAs and clustered miRNAs showed either very good, or in certain cases, very poor correlation with the host gene. Interplatform comparison of miRNA expression profiles thus provides a resource of consensus expression profiles that can be used in the future for studying miRNA function and regulation.
    MeSH term(s) Algorithms ; Animals ; Consensus Sequence/genetics ; Data Interpretation, Statistical ; Gene Expression Profiling/instrumentation ; Gene Expression Profiling/methods ; Gene Expression Profiling/standards ; Humans ; Meta-Analysis as Topic ; MicroRNAs/analysis ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Neoplasms/genetics ; Oligonucleotide Array Sequence Analysis/instrumentation ; Oligonucleotide Array Sequence Analysis/methods ; Oligonucleotide Array Sequence Analysis/standards ; Organ Specificity/genetics ; Reference Values
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2009-11-30
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1241540-6
    ISSN 1469-9001 ; 1355-8382
    ISSN (online) 1469-9001
    ISSN 1355-8382
    DOI 10.1261/rna.1688110
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cell population structure prior to bifurcation predicts efficiency of directed differentiation in human induced pluripotent cells.

    Bargaje, Rhishikesh / Trachana, Kalliopi / Shelton, Martin N / McGinnis, Christopher S / Zhou, Joseph X / Chadick, Cora / Cook, Savannah / Cavanaugh, Christopher / Huang, Sui / Hood, Leroy

    Proceedings of the National Academy of Sciences of the United States of America

    2017  Volume 114, Issue 9, Page(s) 2271–2276

    Abstract: Steering the differentiation of induced pluripotent stem cells (iPSCs) toward specific cell types is crucial for patient-specific disease modeling and drug testing. This effort requires the capacity to predict and control when and how multipotent ... ...

    Abstract Steering the differentiation of induced pluripotent stem cells (iPSCs) toward specific cell types is crucial for patient-specific disease modeling and drug testing. This effort requires the capacity to predict and control when and how multipotent progenitor cells commit to the desired cell fate. Cell fate commitment represents a critical state transition or "tipping point" at which complex systems undergo a sudden qualitative shift. To characterize such transitions during iPSC to cardiomyocyte differentiation, we analyzed the gene expression patterns of 96 developmental genes at single-cell resolution. We identified a bifurcation event early in the trajectory when a primitive streak-like cell population segregated into the mesodermal and endodermal lineages. Before this branching point, we could detect the signature of an imminent critical transition: increase in cell heterogeneity and coordination of gene expression. Correlation analysis of gene expression profiles at the tipping point indicates transcription factors that drive the state transition toward each alternative cell fate and their relationships with specific phenotypic readouts. The latter helps us to facilitate small molecule screening for differentiation efficiency. To this end, we set up an analysis of cell population structure at the tipping point after systematic variation of the protocol to bias the differentiation toward mesodermal or endodermal cell lineage. We were able to predict the proportion of cardiomyocytes many days before cells manifest the differentiated phenotype. The analysis of cell populations undergoing a critical state transition thus affords a tool to forecast cell fate outcomes and can be used to optimize differentiation protocols to obtain desired cell populations.
    Language English
    Publishing date 2017-02-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1621412114
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Incomplete penetrance and variable expressivity: is there a microRNA connection?

    Ahluwalia, Jasmine K / Hariharan, Manoj / Bargaje, Rhishikesh / Pillai, Beena / Brahmachari, Vani

    BioEssays : news and reviews in molecular, cellular and developmental biology

    2009  Volume 31, Issue 9, Page(s) 981–992

    Abstract: Incomplete penetrance and variable expressivity are non-Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells ... ...

    Abstract Incomplete penetrance and variable expressivity are non-Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells manifests as variations in penetrance and expressivity of mutations between individuals of the same genotype. These phenomena are seen most often in dominantly inherited diseases, implying that they are sensitive to concentration of the gene product. In this framework and the advances in understanding the role of microRNA (miRNA) in fine-tuning gene expression at translational level, we propose miRNA-mediated regulation as a mechanism for incomplete penetrance and variable expressivity. The presence of miRNA binding sites at 3' UTR, co-expression of target gene-miRNA pairs for genes showing incomplete penetrance and variable expressivity derived from available data lend support to our hypothesis. Single nucleotide polymorphisms in the miRNA target site facilitate the implied differential targeting of the transcripts from homologous alleles.
    MeSH term(s) Alleles ; Animals ; Gene Expression ; Humans ; MicroRNAs/genetics ; Penetrance ; Polymorphism, Genetic
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2009-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 50140-2
    ISSN 1521-1878 ; 0265-9247
    ISSN (online) 1521-1878
    ISSN 0265-9247
    DOI 10.1002/bies.200900066
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Incomplete penetrance and variable expressivity: is there a microRNA connection

    Ahluwalia, Jasmine K / Hariharan, Manoj / Bargaje, Rhishikesh / Pillai, Beena / Brahmachari, Vani

    BioEssays. 2009 Sept., v. 31, no. 9

    2009  

    Abstract: Incomplete penetrance and variable expressivity are non-Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells ... ...

    Abstract Incomplete penetrance and variable expressivity are non-Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells manifests as variations in penetrance and expressivity of mutations between individuals of the same genotype. These phenomena are seen most often in dominantly inherited diseases, implying that they are sensitive to concentration of the gene product. In this framework and the advances in understanding the role of microRNA (miRNA) in fine-tuning gene expression at translational level, we propose miRNA-mediated regulation as a mechanism for incomplete penetrance and variable expressivity. The presence of miRNA binding sites at 3' UTR, co-expression of target gene-miRNA pairs for genes showing incomplete penetrance and variable expressivity derived from available data lend support to our hypothesis. Single nucleotide polymorphisms in the miRNA target site facilitate the implied differential targeting of the transcripts from homologous alleles.
    Language English
    Dates of publication 2009-09
    Size p. 981-992.
    Publishing place Wiley-VCH Verlag
    Document type Article
    ZDB-ID 50140-2
    ISSN 1521-1878 ; 0265-9247
    ISSN (online) 1521-1878
    ISSN 0265-9247
    DOI 10.1002/bies.200900066
    Database NAL-Catalogue (AGRICOLA)

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  7. Article ; Online: Proximity of H2A.Z containing nucleosome to the transcription start site influences gene expression levels in the mammalian liver and brain.

    Bargaje, Rhishikesh / Alam, Mohammad Parwez / Patowary, Ashok / Sarkar, Maharnob / Ali, Tamer / Gupta, Shivani / Garg, Manali / Singh, Meghna / Purkanti, Ramya / Scaria, Vinod / Sivasubbu, Sridhar / Brahmachari, Vani / Pillai, Beena

    Nucleic acids research

    2012  Volume 40, Issue 18, Page(s) 8965–8978

    Abstract: Nucleosome positioning maps of several organisms have shown that Transcription Start Sites (TSSs) are marked by nucleosome depleted regions flanked by strongly positioned nucleosomes. Using genome-wide nucleosome maps and histone variant occupancy in the ...

    Abstract Nucleosome positioning maps of several organisms have shown that Transcription Start Sites (TSSs) are marked by nucleosome depleted regions flanked by strongly positioned nucleosomes. Using genome-wide nucleosome maps and histone variant occupancy in the mouse liver, we show that the majority of genes were associated with a single prominent H2A.Z containing nucleosome in their promoter region. We classified genes into clusters depending on the proximity of H2A.Z to the TSS. The genes with no detectable H2A.Z showed lowest expression level, whereas H2A.Z was positioned closer to the TSS of genes with higher expression levels. We confirmed this relation between the proximity of H2A.Z and expression level in the brain. The proximity of histone variant H2A.Z, but not H3.3 to the TSS, over seven consecutive nucleosomes, was correlated with expression. Further, a nucleosome was positioned over the TSS of silenced genes while it was displaced to expose the TSS in highly expressed genes. Our results suggest that gene expression levels in vivo are determined by accessibility of the TSS and proximity of H2A.Z.
    MeSH term(s) Animals ; Brain/metabolism ; Chromatin Immunoprecipitation ; Female ; Gene Expression Regulation ; Gene Silencing ; Histones/analysis ; Liver/metabolism ; Mice ; Nucleosomes/chemistry ; Nucleosomes/metabolism ; Transcription Initiation Site
    Chemical Substances Histones ; Nucleosomes
    Language English
    Publishing date 2012-07-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gks665
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Identification of novel targets for miR-29a using miRNA proteomics.

    Bargaje, Rhishikesh / Gupta, Shivani / Sarkeshik, Ali / Park, Robin / Xu, Tao / Sarkar, Maharnob / Halimani, Mahantappa / Roy, Soumya Sinha / Yates, John / Pillai, Beena

    PloS one

    2012  Volume 7, Issue 8, Page(s) e43243

    Abstract: MicroRNAs (miRNAs) are short regulatory RNA molecules that interfere with the expression of target mRNA by binding to complementary sequences. Currently, the most common method for identification of targets of miRNAs is computational prediction based on ... ...

    Abstract MicroRNAs (miRNAs) are short regulatory RNA molecules that interfere with the expression of target mRNA by binding to complementary sequences. Currently, the most common method for identification of targets of miRNAs is computational prediction based on free energy change calculations, target site accessibility and conservation. Such algorithms predict hundreds of targets for each miRNA, necessitating tedious experimentation to identify the few functional targets. Here we explore the utility of miRNA-proteomics as an approach to identifying functional miRNA targets. We used Stable Isotope Labeling by amino acids in cell culture (SILAC) based proteomics to detect differences in protein expression induced by the over-expression of miR-34a and miR-29a. Over-expression of miR-29a, a miRNA expressed in the brain and in cells of the blood lineage, resulted in the differential expression of a set of proteins. Gene Ontology based classification showed that a significant sub-set of these targets, including Voltage Dependent Anion Channel 1 and 2 (VDAC1 and VDAC2) and ATP synthetase, were mitochondrial proteins involved in apoptosis. Using reporter assays, we established that miR-29a targets the 3' Untranslated Regions (3' UTR) of VDAC1 and VDAC2. However, due to the limited number of proteins identified using this approach and the inability to differentiate between primary and secondary effects we conclude that miRNA-proteomics is of limited utility as a high-throughput alternative for sensitive and unbiased miRNA target identification. However, this approach was valuable for rapid assessment of the impact of the miRNAs on the cellular proteome and its biological role in apoptosis.
    MeSH term(s) 3' Untranslated Regions ; ATP Synthetase Complexes/metabolism ; Algorithms ; Apoptosis ; Cell Culture Techniques ; Computer Simulation ; Gene Expression Profiling ; Gene Expression Regulation ; HEK293 Cells ; Humans ; MicroRNAs/biosynthesis ; MicroRNAs/metabolism ; Models, Genetic ; Proteomics/methods ; Voltage-Dependent Anion Channel 1/metabolism ; Voltage-Dependent Anion Channel 2/metabolism
    Chemical Substances 3' Untranslated Regions ; MIRN29a microRNA, human ; MicroRNAs ; VDAC1 protein, human ; VDAC2 protein, human ; Voltage-Dependent Anion Channel 2 ; Voltage-Dependent Anion Channel 1 (EC 1.6.-) ; ATP Synthetase Complexes (EC 2.7.4.-)
    Language English
    Publishing date 2012-08-27
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0043243
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Identification of novel targets for miR-29a using miRNA proteomics.

    Rhishikesh Bargaje / Shivani Gupta / Ali Sarkeshik / Robin Park / Tao Xu / Maharnob Sarkar / Mahantappa Halimani / Soumya Sinha Roy / John Yates / Beena Pillai

    PLoS ONE, Vol 7, Iss 8, p e

    2012  Volume 43243

    Abstract: MicroRNAs (miRNAs) are short regulatory RNA molecules that interfere with the expression of target mRNA by binding to complementary sequences. Currently, the most common method for identification of targets of miRNAs is computational prediction based on ... ...

    Abstract MicroRNAs (miRNAs) are short regulatory RNA molecules that interfere with the expression of target mRNA by binding to complementary sequences. Currently, the most common method for identification of targets of miRNAs is computational prediction based on free energy change calculations, target site accessibility and conservation. Such algorithms predict hundreds of targets for each miRNA, necessitating tedious experimentation to identify the few functional targets. Here we explore the utility of miRNA-proteomics as an approach to identifying functional miRNA targets. We used Stable Isotope Labeling by amino acids in cell culture (SILAC) based proteomics to detect differences in protein expression induced by the over-expression of miR-34a and miR-29a. Over-expression of miR-29a, a miRNA expressed in the brain and in cells of the blood lineage, resulted in the differential expression of a set of proteins. Gene Ontology based classification showed that a significant sub-set of these targets, including Voltage Dependent Anion Channel 1 and 2 (VDAC1 and VDAC2) and ATP synthetase, were mitochondrial proteins involved in apoptosis. Using reporter assays, we established that miR-29a targets the 3' Untranslated Regions (3' UTR) of VDAC1 and VDAC2. However, due to the limited number of proteins identified using this approach and the inability to differentiate between primary and secondary effects we conclude that miRNA-proteomics is of limited utility as a high-throughput alternative for sensitive and unbiased miRNA target identification. However, this approach was valuable for rapid assessment of the impact of the miRNAs on the cellular proteome and its biological role in apoptosis.
    Keywords Medicine ; R ; Science ; Q
    Subject code 500
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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