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  1. Article ; Online: Heterogeneity of the GFP fitness landscape and data-driven protein design.

    Gonzalez Somermeyer, Louisa / Fleiss, Aubin / Mishin, Alexander S / Bozhanova, Nina G / Igolkina, Anna A / Meiler, Jens / Alaball Pujol, Maria-Elisenda / Putintseva, Ekaterina V / Sarkisyan, Karen S / Kondrashov, Fyodor A

    eLife

    2022  Volume 11

    Abstract: Studies of protein fitness landscapes reveal biophysical constraints guiding protein evolution and empower prediction of functional proteins. However, generalisation of these findings is limited due to scarceness of systematic data on fitness landscapes ... ...

    Abstract Studies of protein fitness landscapes reveal biophysical constraints guiding protein evolution and empower prediction of functional proteins. However, generalisation of these findings is limited due to scarceness of systematic data on fitness landscapes of proteins with a defined evolutionary relationship. We characterized the fitness peaks of four orthologous fluorescent proteins with a broad range of sequence divergence. While two of the four studied fitness peaks were sharp, the other two were considerably flatter, being almost entirely free of epistatic interactions. Mutationally robust proteins, characterized by a flat fitness peak, were not optimal templates for machine-learning-driven protein design - instead, predictions were more accurate for fragile proteins with epistatic landscapes. Our work paves insights for practical application of fitness landscape heterogeneity in protein engineering.
    MeSH term(s) Genetic Fitness ; Models, Genetic ; Mutation ; Proteins/genetics
    Chemical Substances Proteins
    Language English
    Publishing date 2022-05-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.75842
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Efficient delivery and functional expression of transfected modified mRNA in human embryonic stem cell-derived retinal pigmented epithelial cells.

    Hansson, Magnus L / Albert, Silvia / González Somermeyer, Louisa / Peco, Rubén / Mejía-Ramírez, Eva / Montserrat, Núria / Izpisua Belmonte, Juan Carlos

    The Journal of biological chemistry

    2015  Volume 290, Issue 9, Page(s) 5661–5672

    Abstract: Gene- and cell-based therapies are promising strategies for the treatment of degenerative retinal diseases such as age-related macular degeneration, Stargardt disease, and retinitis pigmentosa. Cellular engineering before transplantation may allow the ... ...

    Abstract Gene- and cell-based therapies are promising strategies for the treatment of degenerative retinal diseases such as age-related macular degeneration, Stargardt disease, and retinitis pigmentosa. Cellular engineering before transplantation may allow the delivery of cellular factors that can promote functional improvements, such as increased engraftment or survival of transplanted cells. A current challenge in traditional DNA-based vector transfection is to find a delivery system that is both safe and efficient, but using mRNA as an alternative to DNA can circumvent these major roadblocks. In this study, we show that both unmodified and modified mRNA can be delivered to retinal pigmented epithelial (RPE) cells with a high efficiency compared with conventional plasmid delivery systems. On the other hand, administration of unmodified mRNA induced a strong innate immune response that was almost absent when using modified mRNA. Importantly, transfection of mRNA encoding a key regulator of RPE gene expression, microphthalmia-associated transcription factor (MITF), confirmed the functionality of the delivered mRNA. Immunostaining showed that transfection with either type of mRNA led to the expression of roughly equal levels of MITF, primarily localized in the nucleus. Despite these findings, quantitative RT-PCR analyses showed that the activation of the expression of MITF target genes was higher following transfection with modified mRNA compared with unmodified mRNA. Our findings, therefore, show that modified mRNA transfection can be applied to human embryonic stem cell-derived RPE cells and that the method is safe, efficient, and functional.
    MeSH term(s) Active Transport, Cell Nucleus ; Blotting, Western ; Cell Differentiation/genetics ; Cell Line ; Cell Nucleus/metabolism ; Embryonic Stem Cells/cytology ; Embryonic Stem Cells/metabolism ; Epithelial Cells/metabolism ; Epithelial Cells/ultrastructure ; Gene Expression ; HEK293 Cells ; Humans ; Interferon Regulatory Factor-3/genetics ; Interferon Regulatory Factor-3/metabolism ; Microphthalmia-Associated Transcription Factor/genetics ; Microphthalmia-Associated Transcription Factor/metabolism ; Microscopy, Confocal ; Microscopy, Electron, Transmission ; Otx Transcription Factors/genetics ; Otx Transcription Factors/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Retinal Pigment Epithelium/cytology ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factor RelA/genetics ; Transcription Factor RelA/metabolism ; Transfection/methods ; cis-trans-Isomerases/genetics ; cis-trans-Isomerases/metabolism
    Chemical Substances IRF3 protein, human ; Interferon Regulatory Factor-3 ; MITF protein, human ; Microphthalmia-Associated Transcription Factor ; OTX2 protein, human ; Otx Transcription Factors ; RELA protein, human ; RNA, Messenger ; Transcription Factor RelA ; retinoid isomerohydrolase (EC 3.1.1.64) ; cis-trans-Isomerases (EC 5.2.-)
    Language English
    Publishing date 2015-01-02
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M114.618835
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.108: Show issues Location:
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  3. Article ; Online: Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice.

    Jorge-Torres, Olga C / Szczesna, Karolina / Roa, Laura / Casal, Carme / Gonzalez-Somermeyer, Louisa / Soler, Marta / Velasco, Cecilia D / Martínez-San Segundo, Pablo / Petazzi, Paolo / Sáez, Mauricio A / Delgado-Morales, Raúl / Fourcade, Stephane / Pujol, Aurora / Huertas, Dori / Llobet, Artur / Guil, Sonia / Esteller, Manel

    Cell reports

    2018  Volume 23, Issue 6, Page(s) 1665–1677

    Abstract: Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a ... ...

    Abstract Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763.
    MeSH term(s) Animals ; Biomarkers/metabolism ; Cells, Cultured ; Cerebellum/metabolism ; Cerebellum/pathology ; Dendritic Spines/drug effects ; Dendritic Spines/metabolism ; Dendritic Spines/pathology ; Disease Models, Animal ; Glycogen Synthase Kinase 3 beta/antagonists & inhibitors ; Glycogen Synthase Kinase 3 beta/metabolism ; Humans ; Indoles/pharmacology ; Inflammation/pathology ; Longevity ; Maleimides/pharmacology ; Methyl-CpG-Binding Protein 2/deficiency ; Methyl-CpG-Binding Protein 2/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; NF-kappa B p50 Subunit/metabolism ; Phenotype ; Protein Kinase Inhibitors/pharmacology ; Rett Syndrome/metabolism ; Rett Syndrome/pathology ; Signal Transduction ; Survival Analysis ; Synapses/metabolism ; Up-Regulation/drug effects
    Chemical Substances Biomarkers ; Indoles ; Maleimides ; Mecp2 protein, mouse ; Methyl-CpG-Binding Protein 2 ; NF-kappa B p50 Subunit ; Protein Kinase Inhibitors ; SB 216763 ; Nfkb1 protein, mouse (147257-52-1) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1)
    Language English
    Publishing date 2018-05-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2018.04.010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Genetically encodable bioluminescent system from fungi.

    Kotlobay, Alexey A / Sarkisyan, Karen S / Mokrushina, Yuliana A / Marcet-Houben, Marina / Serebrovskaya, Ekaterina O / Markina, Nadezhda M / Gonzalez Somermeyer, Louisa / Gorokhovatsky, Andrey Y / Vvedensky, Andrey / Purtov, Konstantin V / Petushkov, Valentin N / Rodionova, Natalja S / Chepurnyh, Tatiana V / Fakhranurova, Liliia I / Guglya, Elena B / Ziganshin, Rustam / Tsarkova, Aleksandra S / Kaskova, Zinaida M / Shender, Victoria /
    Abakumov, Maxim / Abakumova, Tatiana O / Povolotskaya, Inna S / Eroshkin, Fedor M / Zaraisky, Andrey G / Mishin, Alexander S / Dolgov, Sergey V / Mitiouchkina, Tatiana Y / Kopantzev, Eugene P / Waldenmaier, Hans E / Oliveira, Anderson G / Oba, Yuichi / Barsova, Ekaterina / Bogdanova, Ekaterina A / Gabaldón, Toni / Stevani, Cassius V / Lukyanov, Sergey / Smirnov, Ivan V / Gitelson, Josef I / Kondrashov, Fyodor A / Yampolsky, Ilia V

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

    2018  Volume 115, Issue 50, Page(s) 12728–12732

    Abstract: Bioluminescence is found across the entire tree of life, conferring a spectacular set of visually oriented functions from attracting mates to scaring off predators. Half a dozen different luciferins, molecules that emit light when enzymatically oxidized, ...

    Abstract Bioluminescence is found across the entire tree of life, conferring a spectacular set of visually oriented functions from attracting mates to scaring off predators. Half a dozen different luciferins, molecules that emit light when enzymatically oxidized, are known. However, just one biochemical pathway for luciferin biosynthesis has been described in full, which is found only in bacteria. Here, we report identification of the fungal luciferase and three other key enzymes that together form the biosynthetic cycle of the fungal luciferin from caffeic acid, a simple and widespread metabolite. Introduction of the identified genes into the genome of the yeast
    MeSH term(s) Amino Acid Sequence ; Animals ; Biosynthetic Pathways/genetics ; Caffeic Acids ; Cell Line ; Cell Line, Tumor ; Female ; Fungi/genetics ; Gene Duplication/genetics ; HEK293 Cells ; HeLa Cells ; Humans ; Luminescent Proteins/genetics ; Mice ; Mice, Inbred BALB C ; Sequence Alignment ; Xenopus laevis
    Chemical Substances Caffeic Acids ; Luminescent Proteins ; caffeic acid (U2S3A33KVM)
    Language English
    Publishing date 2018-11-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1803615115
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Show issues Location:
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