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  1. Article ; Online: Review of the state of science and evaluation of currently available in silico prediction models for reproductive and developmental toxicity: A case study on pesticides.

    Weyrich, Anastasia / Joel, Madeleine / Lewin, Geertje / Hofmann, Thomas / Frericks, Markus

    Birth defects research

    2022  Volume 114, Issue 14, Page(s) 812–842

    Abstract: Background: In silico methods for toxicity prediction have increased significantly in recent years due to the 3Rs principle. This also applies to predicting reproductive toxicology, which is one of the most critical factors in pesticide approval. The ... ...

    Abstract Background: In silico methods for toxicity prediction have increased significantly in recent years due to the 3Rs principle. This also applies to predicting reproductive toxicology, which is one of the most critical factors in pesticide approval. The widely used quantitative structure-activity relationship (QSAR) models use experimental toxicity data to create a model that relates experimentally observed toxicity to molecular structures to predict toxicity. Aim of the study was to evaluate the available prediction models for developmental and reproductive toxicity regarding their strengths and weaknesses in a pesticide database.
    Methods: The reproductive toxicity of 315 pesticides, which have a GHS classification by ECHA, was compared with the prediction of different in silico models: VEGA, OECD (Q)SAR Toolbox, Leadscope Model Applier, and CASE Ultra by MultiCASE.
    Results: In all models, a large proportion (up to 77%) of all pesticides were outside the chemical space of the model. Analysis of the prediction of remaining pesticides revealed a balanced accuracy of the models between 0.48 and 0.66.
    Conclusion: Overall, predictions were only meaningful in rare cases and therefore always require evaluation by an expert. The critical factors were the underlying data and determination of molecular similarity, which offer great potential for improvement.
    MeSH term(s) Computer Simulation ; Databases, Factual ; Pesticides/toxicity ; Quantitative Structure-Activity Relationship ; Reproduction
    Chemical Substances Pesticides
    Language English
    Publishing date 2022-06-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2104792-3
    ISSN 2472-1727
    ISSN (online) 2472-1727
    DOI 10.1002/bdr2.2062
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 749: Show issues Location:
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  2. Book ; Online ; Thesis: Challenges and solution approaches for an improved assessment of reproductive toxicity – species differences and in silico predictions

    Weyrich, Anastasia [Verfasser] / Richling, Elke [Akademischer Betreuer]

    2022  

    Author's details Anastasia Weyrich ; Betreuer: Elke Richling
    Keywords Biowissenschaften, Biologie ; Life Science, Biology
    Subject code sg570
    Language English
    Publisher Technische Universität Kaiserslautern
    Publishing place Kaiserslautern
    Document type Book ; Online ; Thesis
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  3. Article ; Online: Synthetic protein switches: Combinatorial linker engineering with iFLinkC.

    Gräwe, Alexander / Ranglack, Jan / Weyrich, Anastasia / Stein, Viktor

    Methods in enzymology

    2020  Volume 647, Page(s) 231–255

    Abstract: Linker engineering constitutes a critical, yet frequently underestimated aspect in the construction of synthetic protein switches and sensors. Notably, systematic strategies to engineer linkers by predictive means remain largely elusive to date. This is ... ...

    Abstract Linker engineering constitutes a critical, yet frequently underestimated aspect in the construction of synthetic protein switches and sensors. Notably, systematic strategies to engineer linkers by predictive means remain largely elusive to date. This is primarily due to our insufficient understanding how the biophysical properties that underlie linker functions mediate the conformational transitions in artificially engineered protein switches and sensors. The construction of synthetic protein switches and sensors therefore heavily relies on experimental trial-and-error. Yet, methods for effectively generating linker diversity at the genetic level are scarce. Addressing this technical shortcoming, iterative functional linker cloning (iFLinkC) enables the combinatorial assembly of linker elements with functional domains from sequence verified repositories that are developed and stored in-house. The assembly process is highly scalable and given its recursive nature generates linker diversity in a combinatorial and exponential fashion based on a limited number of linker elements.
    MeSH term(s) Biophysics ; Protein Engineering ; Proteins/genetics ; Synthetic Biology
    Chemical Substances Proteins
    Language English
    Publishing date 2020-10-17
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1557-7988
    ISSN (online) 1557-7988
    DOI 10.1016/bs.mie.2020.09.009
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  4. Article ; Online: iFLinkC: an iterative functional linker cloning strategy for the combinatorial assembly and recombination of linker peptides with functional domains.

    Gräwe, Alexander / Ranglack, Jan / Weyrich, Anastasia / Stein, Viktor

    Nucleic acids research

    2020  Volume 48, Issue 4, Page(s) e24

    Abstract: Recent years have witnessed increasing efforts to engineer artificial biological functions through recombination of modular-organized toolboxes of protein scaffolds and parts. A critical, yet frequently neglected aspect concerns the identity of peptide ... ...

    Abstract Recent years have witnessed increasing efforts to engineer artificial biological functions through recombination of modular-organized toolboxes of protein scaffolds and parts. A critical, yet frequently neglected aspect concerns the identity of peptide linkers or spacers connecting individual domains which remain poorly understood and challenging to assemble. Addressing these limitations, iFlinkC comprises a highly scalable DNA assembly process that facilitates the combinatorial recombination of functional domains with linkers of varying length and flexibility, thereby overcoming challenges with high GC-content and the repeat nature of linker elements. The capacity of iFLinkC is demonstrated in the construction of synthetic protease switches featuring PDZ-FN3-based affinity clamps and single-chain FKBP12-FRB receptors as allosteric inputs. Library screening experiments demonstrate that linker space is highly plastic as the induction of allosterically regulated protease switches can vary from >150-fold switch-ON to >13-fold switch-OFF solely depending on the identity of the connecting linkers and relative orientation of functional domains. In addition, Pro-rich linkers yield the most potent switches contradicting the conventional use of flexible Gly-Ser linkers. Given the ease and efficiency how functional domains can be readily recombined with any type of linker, iFLinkC is anticipated to be widely applicable to the assembly of any type of fusion protein.
    MeSH term(s) Base Composition/genetics ; Cloning, Molecular/methods ; DNA/genetics ; Peptides/genetics ; Protein Domains/genetics ; Proteins/genetics ; Recombination, Genetic/genetics ; TOR Serine-Threonine Kinases/genetics
    Chemical Substances Peptides ; Proteins ; DNA (9007-49-2) ; TOR Serine-Threonine Kinases (EC 2.7.1.1)
    Language English
    Publishing date 2020-01-10
    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/gkz1210
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1067: Show issues Location:
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  5. Article ; Online: Ontogeny of renal, hepatic, and placental expression of ATP-binding cassette and solute carrier transporters in the rat and the rabbit.

    Weyrich, Anastasia / Frericks, Markus / Eichenlaub, Michael / Schneider, Steffen / Hofmann, Thomas / Van Cruchten, Steven / van Ravenzwaay, Bennard

    Reproductive toxicology (Elmsford, N.Y.)

    2021  Volume 107, Page(s) 1–9

    Abstract: Species differences in developmental toxicity can be due to varying expression of xenobiotic transporters. Hence, knowledge on the ontogeny of these transporters, especially in human, rat and rabbit, is pivotal. Two superfamilies of transporters, the ATP- ...

    Abstract Species differences in developmental toxicity can be due to varying expression of xenobiotic transporters. Hence, knowledge on the ontogeny of these transporters, especially in human, rat and rabbit, is pivotal. Two superfamilies of transporters, the ATP-binding cassette (ABC) and the solute carrier (SLC) transporters, are well known for their role in the absorption, distribution and/or elimination of xenobiotics and endogenous substances. The aim of this study was to compare the expression levels of these xenobiotic transporters in liver, kidney and placenta of man, Wistar rat and New Zealand White rabbit during pre- and postnatal development. For this purpose, qPCR experiments were performed for rat and rabbit tissues and the gene expression profiles were compared with literature data from man, rat and rabbit. Data analysis showed large differences in transporter expression in development and between species. These results can be used to better understand developmental toxicity findings in non-clinical species and their relevance for man.
    MeSH term(s) ATP-Binding Cassette Transporters/genetics ; Animals ; Embryo, Mammalian ; Female ; Fetus ; Humans ; Kidney/metabolism ; Liver/metabolism ; Male ; Placenta/metabolism ; Pregnancy ; Rabbits ; Rats, Wistar ; Solute Carrier Proteins/genetics ; Species Specificity ; Rats
    Chemical Substances ATP-Binding Cassette Transporters ; Solute Carrier Proteins
    Language English
    Publishing date 2021-10-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639342-1
    ISSN 1873-1708 ; 0890-6238
    ISSN (online) 1873-1708
    ISSN 0890-6238
    DOI 10.1016/j.reprotox.2021.10.005
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    Zs.A 2316: Show issues Location:
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  6. Article ; Online: Interference with SAMHD1 Restores Late Gene Expression of Modified Vaccinia Virus Ankara in Human Dendritic Cells and Abrogates Type I Interferon Expression.

    Sliva, Katja / Martin, Judith / von Rhein, Christine / Herrmann, Tobias / Weyrich, Anastasia / Toda, Masako / Schnierle, Barbara S

    Journal of virology

    2019  Volume 93, Issue 22

    Abstract: Attenuated poxviruses like modified vaccinia virus Ankara (MVA) are promising vectors for vaccines against infectious diseases and cancer. However, host innate immune responses interfere with the viral life cycle and also influence the immunogenicity of ... ...

    Abstract Attenuated poxviruses like modified vaccinia virus Ankara (MVA) are promising vectors for vaccines against infectious diseases and cancer. However, host innate immune responses interfere with the viral life cycle and also influence the immunogenicity of vaccine vectors. Sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1 (SAMHD1) is a phosphohydrolase and reduces cellular deoxynucleoside triphosphate (dNTP) concentrations, which impairs poxviral DNA replication in human dendritic cells (DCs). Human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus (SIV) encode an accessory protein called viral protein X (Vpx) that promotes proteasomal degradation of SAMHD1, leading to a rapid increase in cellular dNTP concentrations. To study the function of SAMHD1 during MVA infection of human DCs, the SIV
    MeSH term(s) A549 Cells ; Animals ; Cell Line ; Dendritic Cells/metabolism ; Dendritic Cells/virology ; Gene Expression Regulation, Viral ; HEK293 Cells ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Interferon Type I/genetics ; Interferon Type I/metabolism ; Monomeric GTP-Binding Proteins/metabolism ; Proteolysis ; SAM Domain and HD Domain-Containing Protein 1/genetics ; SAM Domain and HD Domain-Containing Protein 1/metabolism ; Simian Immunodeficiency Virus/physiology ; Vaccinia virus/genetics ; Vaccinia virus/metabolism ; Viral Regulatory and Accessory Proteins/metabolism ; Virus Replication/physiology
    Chemical Substances Interferon Type I ; VPX protein, Simian immunodeficiency virus ; Viral Regulatory and Accessory Proteins ; SAM Domain and HD Domain-Containing Protein 1 (EC 3.1.5.-) ; SAMHD1 protein, human (EC 3.1.5.-) ; Monomeric GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2019-10-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80174-4
    ISSN 1098-5514 ; 0022-538X
    ISSN (online) 1098-5514
    ISSN 0022-538X
    DOI 10.1128/JVI.01097-19
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