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  1. Article ; Online: robustica

    Miquel Anglada-Girotto / Samuel Miravet-Verde / Luis Serrano / Sarah A. Head

    BMC Bioinformatics, Vol 23, Iss 1, Pp 1-

    customizable robust independent component analysis

    2022  Volume 9

    Abstract: Abstract Background Independent Component Analysis (ICA) allows the dissection of omic datasets into modules that help to interpret global molecular signatures. The inherent randomness of this algorithm can be overcome by clustering many iterations of ... ...

    Abstract Abstract Background Independent Component Analysis (ICA) allows the dissection of omic datasets into modules that help to interpret global molecular signatures. The inherent randomness of this algorithm can be overcome by clustering many iterations of ICA together to obtain robust components. Existing algorithms for robust ICA are dependent on the choice of clustering method and on computing a potentially biased and large Pearson distance matrix. Results We present robustica, a Python-based package to compute robust independent components with a fully customizable clustering algorithm and distance metric. Here, we exploited its customizability to revisit and optimize robust ICA systematically. Of the 6 popular clustering algorithms considered, DBSCAN performed the best at clustering independent components across ICA iterations. To enable using Euclidean distances, we created a subroutine that infers and corrects the components’ signs across ICA iterations. Our subroutine increased the resolution, robustness, and computational efficiency of the algorithm. Finally, we show the applicability of robustica by dissecting over 500 tumor samples from low-grade glioma (LGG) patients, where we define two new gene expression modules with key modulators of tumor progression upon IDH1 and TP53 mutagenesis. Conclusion robustica brings precise, efficient, and customizable robust ICA into the Python toolbox. Through its customizability, we explored how different clustering algorithms and distance metrics can further optimize robust ICA. Then, we showcased how robustica can be used to discover gene modules associated with combinations of features of biological interest. Taken together, given the broad applicability of ICA for omic data analysis, we envision robustica will facilitate the seamless computation and integration of robust independent components in large pipelines.
    Keywords Bioinformatics ; Independent component analysis ; Clustering ; Unsupervised learning ; Low-grade glioma ; Python ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
    Subject code 006
    Language English
    Publishing date 2022-12-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Modulation of the Endomembrane System by the Anticancer Natural Product Superstolide/ZJ-101

    Phillip R. Sanchez / Sarah A. Head / Shan Qian / Haibo Qiu / Avishek Roy / Zhendong Jin / Wei Zheng / Jun O. Liu

    International Journal of Molecular Sciences, Vol 24, Iss 9575, p

    2023  Volume 9575

    Abstract: Marine natural products represent a unique source for clinically relevant drugs due to their vast molecular and mechanistic diversity. ZJ-101 is a structurally simplified analog of the marine natural product superstolide A, isolated from the New ... ...

    Abstract Marine natural products represent a unique source for clinically relevant drugs due to their vast molecular and mechanistic diversity. ZJ-101 is a structurally simplified analog of the marine natural product superstolide A, isolated from the New Caledonian sea sponge Neosiphonia Superstes . The mechanistic activity of the superstolides has until recently remained a mystery. Here, we have identified potent antiproliferative and antiadhesive effects of ZJ-101 on cancer cell lines. Furthermore, through dose–response transcriptomics, we found unique dysregulation of the endomembrane system by ZJ-101 including a selective inhibition of O-glycosylation via lectin and glycomics analysis. We applied this mechanism to a triple-negative breast cancer spheroid model and identified a potential for the reversal of 3D-induced chemoresistance, suggesting a potential for ZJ-101 as a synergistic therapeutic agent.
    Keywords natural product ; superstolide ; glycomics ; transcriptomics ; phenotypic analysis ; 3D spheroid ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2023-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Silencing of SRRM4 suppresses microexon inclusion and promotes tumor growth across cancers.

    Sarah A Head / Xavier Hernandez-Alias / Jae-Seong Yang / Ludovica Ciampi / Violeta Beltran-Sastre / Antonio Torres-Méndez / Manuel Irimia / Martin H Schaefer / Luis Serrano

    PLoS Biology, Vol 19, Iss 2, p e

    2021  Volume 3001138

    Abstract: RNA splicing is widely dysregulated in cancer, frequently due to altered expression or activity of splicing factors (SFs). Microexons are extremely small exons (3-27 nucleotides long) that are highly evolutionarily conserved and play critical roles in ... ...

    Abstract RNA splicing is widely dysregulated in cancer, frequently due to altered expression or activity of splicing factors (SFs). Microexons are extremely small exons (3-27 nucleotides long) that are highly evolutionarily conserved and play critical roles in promoting neuronal differentiation and development. Inclusion of microexons in mRNA transcripts is mediated by the SF Serine/Arginine Repetitive Matrix 4 (SRRM4), whose expression is largely restricted to neural tissues. However, microexons have been largely overlooked in prior analyses of splicing in cancer, as their small size necessitates specialized computational approaches for their detection. Here, we demonstrate that despite having low expression in normal nonneural tissues, SRRM4 is further silenced in tumors, resulting in the suppression of normal microexon inclusion. Remarkably, SRRM4 is the most consistently silenced SF across all tumor types analyzed, implying a general advantage of microexon down-regulation in cancer independent of its tissue of origin. We show that this silencing is favorable for tumor growth, as decreased SRRM4 expression in tumors is correlated with an increase in mitotic gene expression, and up-regulation of SRRM4 in cancer cell lines dose-dependently inhibits proliferation in vitro and in a mouse xenograft model. Further, this proliferation inhibition is accompanied by induction of neural-like expression and splicing patterns in cancer cells, suggesting that SRRM4 expression shifts the cell state away from proliferation and toward differentiation. We therefore conclude that SRRM4 acts as a proliferation brake, and tumors gain a selective advantage by cutting off this brake.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2021-02-01T00:00:00Z
    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: Itraconazole Inhibits Enterovirus Replication by Targeting the Oxysterol-Binding Protein

    Jeroen R.P.M. Strating / Lonneke van der Linden / Lucian Albulescu / Joëlle Bigay / Minetaro Arita / Leen Delang / Pieter Leyssen / Hilde M. van der Schaar / Kjerstin H.W. Lanke / Hendrik Jan Thibaut / Rachel Ulferts / Guillaume Drin / Nina Schlinck / Richard W. Wubbolts / Navdar Sever / Sarah A. Head / Jun O. Liu / Philip A. Beachy / Maria A. De Matteis /
    Matthew D. Shair / Vesa M. Olkkonen / Johan Neyts / Frank J.M. van Kuppeveld

    Cell Reports, Vol 10, Iss 4, Pp 600-

    2015  Volume 615

    Abstract: Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, we identify ITZ as a broad-spectrum inhibitor of enteroviruses (e.g., poliovirus, coxsackievirus, enterovirus-71, rhinovirus). We demonstrate that ITZ ... ...

    Abstract Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, we identify ITZ as a broad-spectrum inhibitor of enteroviruses (e.g., poliovirus, coxsackievirus, enterovirus-71, rhinovirus). We demonstrate that ITZ inhibits viral RNA replication by targeting oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4). Consistently, OSW-1, a specific OSBP/ORP4 antagonist, also inhibits enterovirus replication. Knockdown of OSBP inhibits virus replication, whereas overexpression of OSBP or ORP4 counteracts the antiviral effects of ITZ and OSW-1. ITZ binds OSBP and inhibits its function, i.e., shuttling of cholesterol and phosphatidylinositol-4-phosphate between membranes, thereby likely perturbing the virus-induced membrane alterations essential for viral replication organelle formation. ITZ also inhibits hepatitis C virus replication, which also relies on OSBP. Together, these data implicate OSBP/ORP4 as molecular targets of ITZ and point to an essential role of OSBP/ORP4-mediated lipid exchange in virus replication that can be targeted by antiviral drugs.
    Keywords Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2015-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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