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Article ; Online: ISG15/USP18/STAT2 is a molecular hub regulating IFN I-mediated control of Dengue and Zika virus replication.

Espada, Constanza Eleonora / da Rocha, Edroaldo Lummertz / Ricciardi-Jorge, Taissa / Dos Santos, Adara Aurea / Soares, Zamira Guerra / Malaquias, Greicy / Patrício, Daniel Oliveira / Gonzalez Kozlova, Edgar / Dos Santos, Paula Fernandes / Bordignon, Juliano / Sanford, Thomas J / Fajardo, Teodoro / Sweeney, Trevor R / Báfica, André / Mansur, Daniel Santos

Frontiers in immunology

2024 Volume 15, Page(s) 1331731

Abstract: The establishment of a virus infection is the result of the pathogen's ability to replicate in a hostile environment generated by the host's immune system. Here, we found that ISG15 restricts Dengue and Zika viruses' replication through the stabilization ...

Abstract	The establishment of a virus infection is the result of the pathogen's ability to replicate in a hostile environment generated by the host's immune system. Here, we found that ISG15 restricts Dengue and Zika viruses' replication through the stabilization of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signaling. Moreover, USP18 competes with NS5-mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the STAT2's stability and restrict virus growth, suggesting that the IFNAR-mediated ISG15 activity is also antiviral. Our results add a novel layer of complexity in the virus/host interaction interface and suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing host's IFN-I mediated response and promoting virus replication.
MeSH term(s)	Humans ; Zika Virus ; Interferon Type I/metabolism ; Zika Virus Infection/genetics ; Virus Replication ; Dengue/genetics ; Ubiquitins/metabolism ; Cytokines/metabolism ; Ubiquitin Thiolesterase/metabolism ; STAT2 Transcription Factor/genetics ; STAT2 Transcription Factor/metabolism
Chemical Substances	Interferon Type I ; ISG15 protein, human (60267-61-0) ; Ubiquitins ; Cytokines ; USP18 protein, human (EC 3.4.19.12) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; STAT2 protein, human ; STAT2 Transcription Factor
Language	English
Publishing date	2024-02-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2024.1331731
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Article ; Online: PKR-mediated stress response enhances dengue and Zika virus replication.

Ricciardi-Jorge, Taissa / da Rocha, Edroaldo Lummertz / Gonzalez-Kozlova, Edgar / Rodrigues-Luiz, Gabriela Flavia / Ferguson, Brian J / Sweeney, Trevor / Irigoyen, Nerea / Mansur, Daniel Santos

mBio

2023 Volume 14, Issue 5, Page(s) e0093423

Abstract: Importance: One of the fundamental features that make viruses intracellular parasites is the necessity to use cellular translational machinery. Hence, this is a crucial checkpoint for controlling infections. Here, we show that dengue and Zika viruses, ... ...

Abstract	Importance: One of the fundamental features that make viruses intracellular parasites is the necessity to use cellular translational machinery. Hence, this is a crucial checkpoint for controlling infections. Here, we show that dengue and Zika viruses, responsible for nearly 400 million infections every year worldwide, explore such control for optimal replication. Using immunocompetent cells, we demonstrate that arrest of protein translations happens after sensing of dsRNA and that the information required to avoid this blocking is contained in viral 5'-UTR. Our work, therefore, suggests that the non-canonical translation described for these viruses is engaged when the intracellular stress response is activated.
MeSH term(s)	Animals ; Humans ; A549 Cells ; Chlorocebus aethiops ; Dengue/immunology ; Dengue/virology ; Dengue Virus/physiology ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism ; Eukaryotic Initiation Factor-2/metabolism ; Gene Deletion ; Protein Biosynthesis/genetics ; Protein Biosynthesis/immunology ; Stress, Physiological/genetics ; Stress, Physiological/immunology ; Vero Cells ; Virus Replication/genetics ; Virus Replication/immunology ; Zika Virus/physiology ; Zika Virus Infection/immunology ; Zika Virus Infection/virology ; RNA, Double-Stranded/metabolism
Chemical Substances	eIF-2 Kinase (EC 2.7.11.1) ; Eukaryotic Initiation Factor-2 ; RNA, Double-Stranded
Language	English
Publishing date	2023-09-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.00934-23
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Article ; Online: Integrated transcriptomics uncovers an enhanced association between the prion protein gene expression and vesicle dynamics signatures in glioblastomas.

Boccacino, Jacqueline Marcia / Dos Santos Peixoto, Rafael / Fernandes, Camila Felix de Lima / Cangiano, Giovanni / Sola, Paula Rodrigues / Coelho, Bárbara Paranhos / Prado, Mariana Brandão / Melo-Escobar, Maria Isabel / de Sousa, Breno Pereira / Ayyadhury, Shamini / Bader, Gary D / Shinjo, Sueli Mieko Oba / Marie, Suely Kazue Nagahashi / da Rocha, Edroaldo Lummertz / Lopes, Marilene Hohmuth

BMC cancer

2024 Volume 24, Issue 1, Page(s) 199

Abstract: Background: Glioblastoma (GBM) is an aggressive brain tumor that exhibits resistance to current treatment, making the identification of novel therapeutic targets essential. In this context, cellular prion protein (PrP: Methods: To elucidate the ... ...

Abstract	Background: Glioblastoma (GBM) is an aggressive brain tumor that exhibits resistance to current treatment, making the identification of novel therapeutic targets essential. In this context, cellular prion protein (PrP Methods: To elucidate the implications of PRNP/PrP Results: Functional profiling revealed that vesicular dynamics signatures are strongly correlated with PRNP/PrP Conclusions: Together, our findings shed light on a novel role for PrP
MeSH term(s)	Humans ; Gene Expression ; Gene Expression Profiling ; Glioblastoma/genetics ; Glioblastoma/pathology ; Prion Proteins/genetics ; Prion Proteins/metabolism ; Prions/genetics ; Prions/metabolism ; rab GTP-Binding Proteins/genetics ; Synaptophysin/metabolism
Chemical Substances	Prion Proteins ; Prions ; rab GTP-Binding Proteins (EC 3.6.5.2) ; RAB31 protein, human ; Synaptophysin ; SYPL1 protein, human (159447-27-5) ; PRNP protein, human
Language	English
Publishing date	2024-02-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2041352-X
ISSN	1471-2407 ; 1471-2407
ISSN (online)	1471-2407
ISSN	1471-2407
DOI	10.1186/s12885-024-11914-6
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Article ; Online: Lifelong multilineage contribution by embryonic-born blood progenitors.

Patel, Sachin H / Christodoulou, Constantina / Weinreb, Caleb / Yu, Qi / da Rocha, Edroaldo Lummertz / Pepe-Mooney, Brian J / Bowling, Sarah / Li, Li / Osorio, Fernando G / Daley, George Q / Camargo, Fernando D

Nature

2022 Volume 606, Issue 7915, Page(s) 747–753

Abstract: Haematopoietic stem cells (HSCs) arise in the embryo from the arterial endothelium through a process known as the endothelial-to-haematopoietic transition (EHT) ...

Abstract	Haematopoietic stem cells (HSCs) arise in the embryo from the arterial endothelium through a process known as the endothelial-to-haematopoietic transition (EHT)
MeSH term(s)	Aging ; Animals ; Cell Lineage ; Embryo, Mammalian/cytology ; Hematopoiesis ; Hematopoietic Stem Cells/cytology ; Mice ; Multipotent Stem Cells/cytology
Language	English
Publishing date	2022-06-15
Publishing country	England
Document type	Journal Article
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-022-04804-z
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Article ; Online: Evaluating the transcriptional fidelity of cancer models.

Peng, Da / Gleyzer, Rachel / Tai, Wen-Hsin / Kumar, Pavithra / Bian, Qin / Isaacs, Bradley / da Rocha, Edroaldo Lummertz / Cai, Stephanie / DiNapoli, Kathleen / Huang, Franklin W / Cahan, Patrick

Genome medicine

2021 Volume 13, Issue 1, Page(s) 73

Abstract: Background: Cancer researchers use cell lines, patient-derived xenografts, engineered mice, and tumoroids as models to investigate tumor biology and to identify therapies. The generalizability and power of a model derive from the fidelity with which it ... ...

Abstract	Background: Cancer researchers use cell lines, patient-derived xenografts, engineered mice, and tumoroids as models to investigate tumor biology and to identify therapies. The generalizability and power of a model derive from the fidelity with which it represents the tumor type under investigation; however, the extent to which this is true is often unclear. The preponderance of models and the ability to readily generate new ones has created a demand for tools that can measure the extent and ways in which cancer models resemble or diverge from native tumors. Methods: We developed a machine learning-based computational tool, CancerCellNet, that measures the similarity of cancer models to 22 naturally occurring tumor types and 36 subtypes, in a platform and species agnostic manner. We applied this tool to 657 cancer cell lines, 415 patient-derived xenografts, 26 distinct genetically engineered mouse models, and 131 tumoroids. We validated CancerCellNet by application to independent data, and we tested several predictions with immunofluorescence. Results: We have documented the cancer models with the greatest transcriptional fidelity to natural tumors, we have identified cancers underserved by adequate models, and we have found models with annotations that do not match their classification. By comparing models across modalities, we report that, on average, genetically engineered mice and tumoroids have higher transcriptional fidelity than patient-derived xenografts and cell lines in four out of five tumor types. However, several patient-derived xenografts and tumoroids have classification scores that are on par with native tumors, highlighting both their potential as faithful model classes and their heterogeneity. Conclusions: CancerCellNet enables the rapid assessment of transcriptional fidelity of tumor models. We have made CancerCellNet available as a freely downloadable R package ( https://github.com/pcahan1/cancerCellNet ) and as a web application ( http://www.cahanlab.org/resources/cancerCellNet_web ) that can be applied to new cancer models that allows for direct comparison to the cancer models evaluated here.
MeSH term(s)	Animals ; Cell Line, Tumor ; Disease Models, Animal ; Genetic Engineering ; Humans ; Neoplasms/genetics ; Neoplasms/pathology ; Organoids/pathology ; Species Specificity ; Transcription, Genetic ; Xenograft Model Antitumor Assays
Language	English
Publishing date	2021-04-29
Publishing country	England
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.
ZDB-ID	2484394-5
ISSN	1756-994X ; 1756-994X
ISSN (online)	1756-994X
ISSN	1756-994X
DOI	10.1186/s13073-021-00888-w
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Article ; Online: RUNX1 mutations mitigate quiescence to promote transformation of hematopoietic progenitors in Fanconi anemia.

Leukemia

2023 Volume 37, Issue 8, Page(s) 1698–1708

Abstract: Many inherited bone marrow failure syndromes (IBMFSs) present a high risk of transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). During transformation of IBMFSs, hematopoietic stem and progenitor cells (HSPCs) with poor ... ...

Abstract	Many inherited bone marrow failure syndromes (IBMFSs) present a high risk of transformation to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). During transformation of IBMFSs, hematopoietic stem and progenitor cells (HSPCs) with poor fitness gain ectopic, dysregulated self-renewal secondary to somatic mutations via undefined mechanisms. Here, in the context of the prototypical IBMFS Fanconi anemia (FA), we performed multiplexed gene editing of mutational hotspots in MDS-associated genes in human induced pluripotent stem cells (iPSCs) followed by hematopoietic differentiation. We observed aberrant self-renewal and impaired differentiation of HSPCs with enrichment of RUNX1 insertions and deletions (indels), generating a model of IBMFS-associated MDS. We observed that compared to the failure state, FA MDS cells show mutant RUNX1-mediated blunting of the G
MeSH term(s)	Humans ; Fanconi Anemia/genetics ; Fanconi Anemia/pathology ; Fanconi Anemia/therapy ; Congenital Bone Marrow Failure Syndromes/complications ; Core Binding Factor Alpha 2 Subunit/genetics ; Induced Pluripotent Stem Cells/pathology ; Myelodysplastic Syndromes/pathology ; Mutation ; Leukemia, Myeloid, Acute/pathology
Chemical Substances	Core Binding Factor Alpha 2 Subunit ; RUNX1 protein, human
Language	English
Publishing date	2023-06-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-023-01945-6
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Zs.A 2295: Show issues

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Article ; Online: Effects of Magnetite Nanoparticles and Static Magnetic Field on Neural Differentiation of Pluripotent Stem Cells.

Semeano, Ana T / Tofoli, Fabiano A / Corrêa-Velloso, Juliana C / de Jesus Santos, Ana P / Oliveira-Giacomelli, Ágatha / Cardoso, Rafaela R / Pessoa, Mateus A / da Rocha, Edroaldo Lummertz / Ribeiro, Gustavo / Ferrari, Merari F R / Pereira, Lygia V / Teng, Yang D / Petri, Denise F S / Ulrich, Henning

Stem cell reviews and reports

2022 Volume 18, Issue 4, Page(s) 1337–1354

Abstract: Neurodevelopmental processes of pluripotent cells, such as proliferation and differentiation, are influenced by external natural forces. Despite the presence of biogenic magnetite nanoparticles in the central nervous system and constant exposure to the ... ...

Abstract	Neurodevelopmental processes of pluripotent cells, such as proliferation and differentiation, are influenced by external natural forces. Despite the presence of biogenic magnetite nanoparticles in the central nervous system and constant exposure to the Earth's magnetic fields and other sources, there is scant knowledge regarding the role of electromagnetic stimuli in neurogenesis. Moreover, emerging applications of electrical and magnetic stimulation to treat neurological disorders emphasize the relevance of understanding the impact and mechanisms behind these stimuli. Here, the effects of magnetic nanoparticles (MNPs) in polymeric coatings and the static external magnetic field (EMF) were investigated on neural induction of murine embryonic stem cells (mESCs) and human induced pluripotent stem cells (hiPSCs). The results show that the presence of 0.5% MNPs in collagen-based coatings facilitates the migration and neuronal maturation of mESCs and hiPSCs in vitro. Furthermore, the application of 0.4 Tesla EMF perpendicularly to the cell culture plane, discernibly stimulates proliferation and guide fate decisions of the pluripotent stem cells, depending on the origin of stem cells and their developmental stage. Mechanistic analysis reveals that modulation of ionic homeostasis and the expression of proteins involved in cytostructural, liposomal and cell cycle checkpoint functions provide a principal underpinning for the impact of electromagnetic stimuli on neural lineage specification and proliferation. These findings not only explore the potential of the magnetic stimuli as neural differentiation and function modulator but also highlight the risks that immoderate magnetic stimulation may affect more susceptible neurons, such as dopaminergic neurons.
MeSH term(s)	Animals ; Dopaminergic Neurons ; Humans ; Induced Pluripotent Stem Cells ; Magnetic Fields ; Magnetite Nanoparticles ; Mice ; Pluripotent Stem Cells
Chemical Substances	Magnetite Nanoparticles
Language	English
Publishing date	2022-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2495577-2
ISSN	2629-3277 ; 1558-6804 ; 1550-8943
ISSN (online)	2629-3277 ; 1558-6804
ISSN	1550-8943
DOI	10.1007/s12015-022-10332-0
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Article ; Online: NetDecoder: a network biology platform that decodes context-specific biological networks and gene activities.

da Rocha, Edroaldo Lummertz / Ung, Choong Yong / McGehee, Cordelia D / Correia, Cristina / Li, Hu

Nucleic acids research

2016 Volume 44, Issue 10, Page(s) e100

Abstract: The sequential chain of interactions altering the binary state of a biomolecule represents the 'information flow' within a cellular network that determines phenotypic properties. Given the lack of computational tools to dissect context-dependent networks ...

Abstract	The sequential chain of interactions altering the binary state of a biomolecule represents the 'information flow' within a cellular network that determines phenotypic properties. Given the lack of computational tools to dissect context-dependent networks and gene activities, we developed NetDecoder, a network biology platform that models context-dependent information flows using pairwise phenotypic comparative analyses of protein-protein interactions. Using breast cancer, dyslipidemia and Alzheimer's disease as case studies, we demonstrate NetDecoder dissects subnetworks to identify key players significantly impacting cell behaviour specific to a given disease context. We further show genes residing in disease-specific subnetworks are enriched in disease-related signalling pathways and information flow profiles, which drive the resulting disease phenotypes. We also devise a novel scoring scheme to quantify key genes-network routers, which influence many genes, key targets, which are influenced by many genes, and high impact genes, which experience a significant change in regulation. We show the robustness of our results against parameter changes. Our network biology platform includes freely available source code (http://www.NetDecoder.org) for researchers to explore genome-wide context-dependent information flow profiles and key genes, given a set of genes of particular interest and transcriptome data. More importantly, NetDecoder will enable researchers to uncover context-dependent drug targets.
MeSH term(s)	Algorithms ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Computational Biology/methods ; Databases, Factual ; Dyslipidemias/genetics ; Dyslipidemias/metabolism ; Female ; Gene Regulatory Networks ; Humans ; Protein Interaction Maps ; Signal Transduction ; Software ; Transcriptome
Language	English
Publishing date	2016-06-02
Publishing country	England
Document type	Journal Article
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/gkw166
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Zs.A 1067: Show issues

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Article ; Online: Nanoparticle translocation through a lipid bilayer tuned by surface chemistry.

da Rocha, Edroaldo Lummertz / Caramori, Giovanni Finoto / Rambo, Carlos Renato

Physical chemistry chemical physics : PCCP

2013 Volume 15, Issue 7, Page(s) 2282–2290

Abstract: An enhanced understanding about the interactions between nanomaterials and cell membranes may have important implications for biomedical applications. In this work, coarse-grained molecular dynamics simulations of gold nanoparticles interacting with ... ...

Abstract	An enhanced understanding about the interactions between nanomaterials and cell membranes may have important implications for biomedical applications. In this work, coarse-grained molecular dynamics simulations of gold nanoparticles interacting with lipid bilayers were performed to evaluate the effect of hydrophobicity, charge density and ligand length on lipid bilayers. The simulations accomplished indicate that hydrophobic and anionic nanoparticles do not exhibit significant interactions and different charge densities may induce pore formation or nanoparticle wrapping, resembling first stages of endocytosis. The suggested interplay between charge density and ligand length has important implications when designing nanoparticles for drug and gene delivery applications. Moreover, control of charge densities may induce internalization of nanoparticles into cells through different mechanisms such as passive translocation, for nanoparticles with low charge density, or endocytosis for higher charge densities, highlighting the role of surface chemistry in nanoparticle-cell interactions.
MeSH term(s)	1,2-Dipalmitoylphosphatidylcholine/chemistry ; Anions/chemistry ; Drug Carriers/chemistry ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/chemistry ; Molecular Dynamics Simulation ; Nanoparticles/chemistry ; Phosphatidylglycerols/chemistry ; Surface Properties
Chemical Substances	Anions ; Drug Carriers ; Lipid Bilayers ; Phosphatidylglycerols ; 1,2-Dipalmitoylphosphatidylcholine (2644-64-6) ; 1,2-dipalmitoylphosphatidylglycerol (VA9U6BR3SB)
Language	English
Publishing date	2013-02-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1476244-4
ISSN	1463-9084 ; 1463-9076
ISSN (online)	1463-9084
ISSN	1463-9076
DOI	10.1039/c2cp44035k
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Article ; Online: A network-based phenotype mapping approach to identify genes that modulate drug response phenotypes.

Cairns, Junmei / Ung, Choong Yong / da Rocha, Edroaldo Lummertz / Zhang, Cheng / Correia, Cristina / Weinshilboum, Richard / Wang, Liewei / Li, Hu

Scientific reports

2016 Volume 6, Page(s) 37003

Abstract: To better address the problem of drug resistance during cancer chemotherapy and explore the possibility of manipulating drug response phenotypes, we developed a network-based phenotype mapping approach (P-Map) to identify gene candidates that upon ... ...

Abstract	To better address the problem of drug resistance during cancer chemotherapy and explore the possibility of manipulating drug response phenotypes, we developed a network-based phenotype mapping approach (P-Map) to identify gene candidates that upon perturbed can alter sensitivity to drugs. We used basal transcriptomics data from a panel of human lymphoblastoid cell lines (LCL) to infer drug response networks (DRNs) that are responsible for conferring response phenotypes for anthracycline and taxane, two common anticancer agents use in clinics. We further tested selected gene candidates that interact with phenotypic differentially expressed genes (PDEGs), which are up-regulated genes in LCL for a given class of drug response phenotype in triple-negative breast cancer (TNBC) cells. Our results indicate that it is possible to manipulate a drug response phenotype, from resistant to sensitive or vice versa, by perturbing gene candidates in DRNs and suggest plausible mechanisms regulating directionality of drug response sensitivity. More important, the current work highlights a new way to formulate systems-based therapeutic design: supplementing therapeutics that aim to target disease culprits with phenotypic modulators capable of altering DRN properties with the goal to re-sensitize resistant phenotypes.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Algorithms ; Anthracyclines/toxicity ; Antineoplastic Agents/toxicity ; Bridged-Ring Compounds/toxicity ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics ; Gene Regulatory Networks/drug effects ; Humans ; Nucleoside-Diphosphate Kinase/genetics ; Nucleoside-Diphosphate Kinase/metabolism ; Phenotype ; RNA Interference ; RNA, Small Interfering/metabolism ; Receptors, Interleukin-1 Type I/genetics ; Receptors, Interleukin-1 Type I/metabolism ; Taxoids/toxicity
Chemical Substances	Adaptor Proteins, Signal Transducing ; Anthracyclines ; Antineoplastic Agents ; Bridged-Ring Compounds ; EPS8 protein, human ; IL1R1 protein, human ; RNA, Small Interfering ; Receptors, Interleukin-1 Type I ; Taxoids ; taxane (1605-68-1) ; NME7 protein, human (EC 2.7.4.6) ; Nucleoside-Diphosphate Kinase (EC 2.7.4.6)
Language	English
Publishing date	2016-11-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep37003
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