Research Area E - Publications 2016

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Am 02.02.2017 durften 22 naturwissenschaftlich besonders interessierte Schüler/innen der Unterstufe des Ernst Mach Gymnasiums zusammen mit ihren Lehrerinnen eine Exkursion zum CIPSM machen.

This is their resume:

„Das Erlebnis startete schon frühmorgens um rechtzeitig am Campus anzukommen. An der Universität wurden wir sehr herzlich empfangen.

Dr. Oliver Baron ...

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Molecular & Cellular Oncology, 4:1, e1263713, DOI:10.1080/23723556.2016.1263713
Molecular & Cellular Oncology, online article

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Stalling of the DNA replication machinery activates the ATR checkpoint kinase, which coordinates the cellular responses to replication stress. New studies identify a novel ATR activator, ETAA1, which is indispensable for the maintenance of genome integrity. Dysregulation of ETAA1 may contribute to the development of pancreatic cancer.
 

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Chem. Commun., DOI: 10.1039/C6CC07517G
Chem. Commun., online article

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A deeper investigation of the chemistry that occurs on the newly discovered epigenetic DNA bases 5-hydroxymethyl-(hmdC), 5-formyl-(fdC), and 5-carboxy-deoxycytidine (cadC) requires chemical tool compounds, which are able to dissect the different potential reaction pathways in cells. Here we report that the 2′-(R)-fluorinated derivatives F-hmdC, F-fdC, and F-cadC, ...

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Chem. Commun., 53, 107-110, DOI: 10.1039/C6CC08365J
Chem. Commun., online article

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Ramariolides A–D are natural products with antibacterial activity. To exploit their cellular mechanism, we here devise the first total synthesis and prepare a photoprobe for target identification. Antibacterial testing against several pathogenic strains including Mycobacterium tuberculosis revealed the highest potency for ramariolide A. Chemical proteomics ...

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Nature Cell Biology, 18, 1357–1366, doi:10.1038/ncb3436
Nature Cell Biology, online article

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DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions, whose accurate repair by non-homologous end-joining (NHEJ) or homologous recombination (HR) is crucial for genome integrity and is strongly influenced by the local chromatin environment1, 2. Here, we identify SCAI (suppressor of cancer cell invasion) as a 53BP1-interacting chromatin-associated ...

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J. Proteome Res., 15 (12), pp 4490–4504, DOI: 10.1021/acs.jproteome.6b00621
J. Proteome Res., online article

 

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Although substantial progress has been made regarding the use of molecularly targeted cancer therapies, resistance almost invariably develops and presents a major clinical challenge. The tumor microenvironment can rescue cancer cells from kinase inhibitors by growth-factor-mediated induction of pro-survival pathways. Here we show that epidermal growth factor ...

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Chem. Sci., DOI: 10.1039/C6SC03438A
Chem. Sci., online article

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Caseinolytic proteases (ClpP) are important for recognition and controlled degradation of damaged proteins. While the majority of bacterial organisms utilize only a single ClpP, Listeria monocytogenes expresses two isoforms (LmClpP1 and LmClpP2). LmClpPs assemble into either a LmClpP2 homocomplex or a LmClpP1/2 heterooligomeric complex. The heterocomplex in ...

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Mar. Drugs, 14(11), 200; doi:10.3390/md14110200
Mar. Drugs, online article

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The glycogen-synthase-kinase 3 (GSK-3) is an important target in drug discovery. This enzyme is involved in the signaling pathways of type 2 diabetes, neurological disorders, cancer, and other diseases. Therefore, inhibitors of GSK-3 are promising drug candidates for the treatment of a broad range of diseases. Here we report pannorin, alternariol, and ...

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Angew. Chem. Int. Ed., 55, 1 – 7, DOI: 10.1002/anie.201607338
Angew. Chem. Int. Ed., online article

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Gram-negative bacteria represent a challenging task for antibacterial drug discovery owing to their impermeable cell membrane and restricted uptake of small molecules. We herein describe the synthesis of natural-product-derived epoxycyclohexenones and explore their antibiotic activity against several pathogenic bacteria. A compound with activity against ...

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ACS Chem. Biol., 11 (12), pp 3400–3411, DOI: 10.1021/acschembio.6b00709
ACS Chem. Biol., online article

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The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis, and treatment resistance, yet therapeutic targeting, drug discovery, or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical proteomics to survey 235 clinical kinase ...

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Nature Microbiology 2, Article number: 16189, doi:10.1038/nmicrobiol.2016.189
Nature Microbiology, online article

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Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here, we identify members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as receptors of H. pylori and show that HopQ is the surface-exposed adhesin that specifically binds human ...

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Chem. Eur. J.,22, 16433 – 16436,  DOI: 10.1002/chem.201604237
Chem. Eur. J., online article

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The first example of a bis-hemithioindigo (bis-HTI)-based molecular receptor was realized. Its folding and selective binding affinity for aromatic guest molecules can be precisely controlled by visible light and heat. The thermodynamically stable state of the bis-HTI is the s-shaped planar Z,Z-configuration. After irradiation with 420 nm light only the ...

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Nature Cell Biology, 18, 1196–1207, doi:10.1038/ncb3422
Nature Cell Biology, online article

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Activation of the ATR kinase following perturbations to DNA replication relies on a complex mechanism involving ATR recruitment to RPA-coated single-stranded DNA via its binding partner ATRIP and stimulation of ATR kinase activity by TopBP1. Here, we discovered an independent ATR activation pathway in vertebrates, mediated by the uncharacterized protein ETAA1 ...

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ChemBioChem, DOI: 10.1002/cbic.201600483
ChemBioChem, online article

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The receptor tyrosine kinase EPHA2 is overexpressed in several cancer entities (breast, head and neck, non-small cell lung cancer). Small molecule-based inhibition of the activity of the EPHA2 kinase domain (KD) has been seen as an important strategy for achieving therapeutic intervention. However, obtaining structural information by protein crystallography or by ...

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Eur. J. Inorg. Chem., DOI: 10.1002/ejic.201600811
Eur. J. Inorg. Chem., online article

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Self-assembled coordination cages are interesting as drug-delivery systems. Therefore, the synthesis of new M2L4 (M = Pd, Pt) molecular cages derived from highly fluorescent, rigid polyaromatic ligands is reported herein, and the first Pt2L4 cage with a ligand consisting of three pyridine moieties is described. The photophysical properties were examined, and they ...

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Cell Press, Volume 45, Issue 4, p761–773, http://dx.doi.org/10.1016/j.immuni.2016.08.010
Cell Press, online article

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Imiquimod is a small-molecule ligand of Toll-like receptor-7 (TLR7) that is licensed for the treatment of viral infections and cancers of the skin. Imiquimod has TLR7-independent activities that are mechanistically unexplained, including NLRP3 inflammasome activation in myeloid cells and apoptosis induction in cancer cells. We investigated the mechanism ...

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Nature Communications, 7, Article number: 12852, doi:10.1038/ncomms12852
Nature Communications, online article

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Dissecting cellular signalling requires the analysis of large number of proteins. The DigiWest approach we describe here transfers the western blot to a bead-based microarray platform. By combining gel-based protein separation with immobilization on microspheres, hundreds of replicas of the initial blot are created, thus enabling the comprehensive analysis of ...

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Biological Chemistry, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/hsz-2016-0198
Biological Chemistry, online article

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Helicobacter pylori infects the stomach of 50% of the population worldwide, thus causing chronic gastritis. Although this infection can be cured by antibiotic treatment, therapeutic options are increasingly limited due to the development of resistances. The γ-glutamyltranspeptidase (gGT) of Helicobacter pylori (HpgGT) is a virulence factor important for ...

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Chem. Eur. J., 22, 1 – 11, DOI: 10.1002/chem.201602784
Chem. Eur. J., online article

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Structural features and internal dynamics of inosine-containing RNAs are poorly understood. NMR studies of such RNAs require 13C,15N-labeling, which cannot be achieved using in vitro transcription as inosine and guanosine are not distinguished by RNA polymerase. Herein, we report the synthesis of an inosine phosphoramidite with selective 13C8 and 15N7-isotope ...

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Bioconjugate Chem., 27 (10), pp 2359–2371, DOI: 10.1021/acs.bioconjchem.6b00369
Bioconjugate Chem., online article

 

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The Ornithodoros moubata Complement Inhibitor (OmCI) binds complement component 5 (C5) with high affinity and, thus, selectively prevents proteolytic activation of the terminal lytic complement pathway. A recombinant version of OmCI (also known as Coversin and rEV576) has proven efficacious in several animal models of complement-mediated diseases and successfully ...

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Chem. Commun., 52, 11971-11974, DOI: 10.1039/C6CC05807H
Chem. Commun., online article

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N-Acylhomoserine lactones are autoinducers of quorum sensing (QS) in Gram-negative bacteria. We exploit here the role of structurally related β-lactones in the inhibition of Vibrio harveyi bioluminescence and identify a derivative with nanomolar potency. Surprisingly, QS was not affected and combined proteomic/biochemical studies revealed insights into the ...

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J. Am. Chem. Soc., 138 (37), pp 12219–12227, DOI: 10.1021/jacs.6b05981
J. Am. Chem. Soc., online article

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Controlling the internal motions of molecules by outside stimuli is a decisive task for the generation of responsive and complex molecular behavior and functionality. Light-induced structural changes of photoswitches are of special high interest due to the ease of signal application and high repeatability. Typically photoswitches use one reaction coordinate in ...

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Protein Engineering, Design & Selection, vol. 29 no. 12, pp. 557–562, doi: 10.1093/protein/gzw039
Protein Engineering, Design & Selection, online article

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To facilitate biocatalytic conversion of the biotechnologically accessible dicyclic dialcohol isosorbide into its industrially relevant diamines, we have designed a fusion protein between two homo-oligomeric enzymes: the levodione reductase (LR) from Leifsonia aquatica and the variant L417M of the ω-aminotransferase from Paracoccus denitrificans (PDωAT(L417M)), ...

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Angew. Chem. Int. Ed., Volume 55, Issue 39, Pages 11797–11800, DOI: 10.1002/anie.201605994
Angew. Chem. Int. Ed, online article

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5-Formyl-2′-deoxycytosine (fdC) is a recently discovered epigenetic base in the genome of stem cells, with yet unknown functions. Sequencing data show that the base is enriched in CpG islands of promoters and hence likely involved in the regulation of transcription during cellular differentiation. fdC is known to be recognized and excised by the enzyme ...

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Org. Lett., DOI: 10.1021/acs.orglett.6b02110
Org. Lett., online article

 

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Investigation of the function of the new epigenetic bases requires the development of stabilized analogues that are stable during base excision repair (BER). Here we report the synthesis of 2′-(R)-fluorinated versions of the phosphoramidites of 5-methylcytosine (mC), 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), and 5-carboxycytosine (caC). For ...

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Nature, doi:10.1038/nature19081
Nature, online article

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Hypermethylation of the promoters of tumour suppressor genes represses transcription of these genes, conferring growth advantages to cancer cells. How these changes arise is poorly understood. Here we show that the activity of oxygen-dependent ten-eleven translocation (TET) enzymes is reduced by tumour hypoxia in human and mouse cells. TET enzymes catalyse DNA ...

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PNAS; vol. 113; no.35; E5192-E5201 www.pnas.org/cgi/doi/10.1073/pnas.1603435113
PNAS, online article

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Highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) has developed strategies to inhibit host immune recognition. We identify cellular E3 ubiquitin ligase ring-finger and CHY zinc-finger domain-containing 1 (RCHY1) as an interacting partner of the viral SARS-unique domain (SUD) and papain-like protease (PLpro), and, as a consequence, the ...

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Nature Communications, 7, Article number: 12418, doi:10.1038/ncomms12418
Nature Communications, online article

 

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Methylation at 5-cytosine (5-mC) is a fundamental epigenetic DNA modification associated recently with cardiac disease. In contrast, the role of 5-hydroxymethylcytosine (5-hmC)—5-mC’s oxidation product—in cardiac biology and disease is unknown. Here we assess the hydroxymethylome in embryonic, neonatal, adult and hypertrophic mouse cardiomyocytes, showing that ...

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Biological Chemistry, Band 398, Heft 1, Seiten 39–55, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2016-0195
Biological Chemistry, online article

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Members of the vascular endothelial growth factor receptor (VEGFR) family play a central role in angiogenesis as well as lymphangiogenesis and are crucial for tumor growth and metastasis. In particular, VEGFR-3 expression is induced in endothelial cells during tumor angiogenesis. We report the design of anticalins that specifically recognize the ligand-binding ...

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Chem. Eur. J., Volume 22, Issue 31, Pages 10782–10785, DOI : 10.1002/chem.201602438
Chem. Eur. J., online article

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Heterocyclic aromatic amines react with purine bases and result in bulky DNA adducts that cause mutations. Such structurally diverse lesions are substrates for the nucleotide excision repair (NER). It is thought that the NER machinery recognises and verifies distorted DNA conformations, also involving the xeroderma pigmentosum group A and C proteins (XPA, XPC) ...

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J Nucl Med 2016; 57:1971–1977, DOI: 10.2967/jnumed.116.176784
J Nucl Med, online article

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Antibodies have become an established treatment modality in cancer therapy during the last decade. However, these treatments often suffer from insufficient and heterogeneous response despite validated antigen or target receptor expression in the tumor. In fact, therapeutic success depends both on the presence and accessibility of the tumor antigen by the ...

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Proteins, Volume 84, Issue 10, Pages 1390–1407, DOI: 10.1002/prot.25084
Proteins, online article

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Substrate binding to Hsp70 chaperones is involved in many biological processes, and the identification of potential substrates is important for a comprehensive understanding of these events. We present a multi-scale pipeline for an accurate, yet efficient prediction of peptides binding to the Hsp70 chaperone BiP by combining sequence-based prediction with ...

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Nature Medicine, 22, 735–743, doi:10.1038/nm.4128
Nature Medicine, online article

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Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate ...

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Diabetologia, Volume 59, Issue 9, pp 2005–2012, DOI: 10.1007/s00125-016-4004-6
Diabetologia, online article

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Aims/hypothesis
Recombinant leptin offers a viable treatment for lipodystrophy (LD) syndromes. However, due to its short plasma half-life, leptin replacement therapy requires at least daily subcutaneous (s.c.) injections. Here, we optimised this treatment strategy in LD mice by using a novel leptin version with extended plasma half-life using PASylation ...

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Protein Engineering, Design & Selection, vol. 29 no. 7, pp. 263–270, doi: 10.1093/protein/gzw016
Protein Engineering, Design & Selection, online article

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ANTICALIgN is an interactive software developed to simultaneously visualize, analyze and modify alignments of DNA and/or protein sequences that arise during combinatorial protein engineering, design and selection. ANTICALIgN combines powerful functions known from currently available sequence analysis tools with unique features for protein engineering, in ...

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Science, Vol. 352, Issue 6287, pp. 833-836, DOI: 10.1126/science.aad2808

Science, online article

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The origin of life is believed to have started with prebiotic molecules reacting along unidentified pathways to produce key molecules such as nucleosides. To date, a single prebiotic pathway to purine nucleosides had been proposed. It is considered to be inefficient due to missing regioselectivity and low yields. We report that the condensation of ...

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Proteomics, Volume 16, Issue 10, Pages 1447–1456, DOI 10.1002/pmic.201500523
Proteomics, online article

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Phosphorylation is a reversible posttranslational protein modification which plays a pivotal role in intracellular signaling. Despite extensive efforts, phosphorylation site mapping of proteomes is still incomplete motivating the exploration of alternative methods that complement existing workflows. In this study, we compared tandem mass spectrometry (MS/MS) on ...

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Biochemical Journal, 473, 1563–1578, doi:10.1042/BCJ20160114
Biochemical Journal, online article

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Amyloid beta (Aβ) peptides, in particular Aβ42 and Aβ40, exert neurotoxic effects and their overproduction leads to amyloid deposits in the brain, thus constituting an important biomolecular target for treatments ofAlzheimer’s disease (AD).We describe the engineering of cognate Anticalins as a novel type of neutralizing protein reagent based on the human ...

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PROTEINS, Volume 84, Issue 6, Pages 855–858, DOI: 10.1002/prot.25010
PROTEINS, online article

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Spirochaeta thermophila secretes seven glycoside hydrolases for plant biomass degradation that carry a carbohydrate-binding module 64 (CBM64) appended at the C-terminus. CBM64 adsorbs to various β1-4-linked pyranose substrates and shows high affinity for cellulose. We present the first crystal structure of a CBM64 at 1.2 Å resolution, which reveals a ...

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Nature Genetics, doi:10.1038/ng.3522

Nature Genetics, online article

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The vertebrate body plan and organs are shaped during a conserved embryonic phase called the phylotypic stage. However, the mechanisms that guide the epigenome through this transition and their evolutionary conservation remain elusive. Here we report widespread DNA demethylation of enhancers during the phylotypic period in zebrafish, Xenopus tropicalis and mouse. ...

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Nanoscale, 2016, 8, 8101-8110, DOI: 10.1039/C5NR08163G

Nanoscale, online article

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Effective and controlled drug delivery systems with on-demand release and targeting abilities have received enormous attention for biomedical applications. Here, we describe a novel enzyme-based cap system for mesoporous silica nanoparticles (MSNs) that is directly combined with a targeting ligand via bio-orthogonal click chemistry. The capping system is based on ...

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ACS Chem. Biol., 11 (5), pp 1245–1254, DOI: 10.1021/acschembio.5b01063
ACS Chem. Biol., online article

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Many protein kinases are valid drug targets in oncology because they are key components of signal transduction pathways. The number of clinical kinase inhibitors is on the rise, but these molecules often exhibit polypharmacology, potentially eliciting desired and toxic effects. Therefore, a comprehensive assessment of a compound’s target space is desirable for a ...

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PLOS ONE, DOI:10.1371/journal.pone.0148608
PLOS ONE, online article

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The aim of this study was to design, synthesize and validate a multifunctional antidepressant probe that is modified at two distinct positions. The purpose of these modifications was to allow covalent linkage of the probe to interaction partners, and decoration of probe-target complexes with fluorescent reporter molecules. The strategy for the design of such a ...

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Quarterly Reviews of Biophysics, 49, e5, pages 1 of 32, doi:10.1017/S0033583515000268

Quarterly Reviews of Biophysics, online article

 

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Nucleotide excision repair (NER) is a highly versatile and efficient DNA repair process, which is responsible for the removal of a large number of structurally diverse DNA lesions. Its extreme broad substrate specificity ranges from DNA damages formed upon exposure to ultraviolet radiation to numerous bulky DNA adducts induced by mutagenic environmental chemicals ...

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Molecular & Cellular Proteomics, 15, 1424-1434. doi: 10.1074/mcp.M115.052175
Molecular & Cellular Proteomics, online article

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The study of male infertility after spinal cord injury (SCI) has enhanced the understanding of seminal plasma (SP) as an important regulator of spermatozoa function. However, the most important factors leading to the diminished sperm motility and viability observed in semen of men with SCI remained unknown. Thus, to explore SP related molecular mechanisms ...

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ACS Chem. Biol., 2016, 11 (4), pp 1082–1089, DOI: 10.1021/acschembio.5b00905
ACS Chem. Biol., online article

 

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The epipolythiodioxopiperazine (ETP) gliotoxin mediates toxicity via its reactive thiol groups and thereby contributes to virulence of the human pathogenic fungus Aspergillus fumigatus. Self-intoxication of the mold is prevented either by reversible oxidation of reduced gliotoxin or by irreversible conversion to bis(methylthio)gliotoxin. The latter is produced by ...

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Protein Engineering, Design & Selection, vol. 29 no. 3, pp. 105–115, doi: 10.1093/protein/gzv065
Protein Engineering, Design & Selection, online article

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Although prostate carcinoma (PCa) is by far the most commonly diagnosed neoplasia in men, corresponding diagnostic and therapeutic modalities have limited efficacy at present. Anticalins comprise a novel class of binding proteins based on a non-immunoglobulin scaffold that can be engineered to specifically address molecular targets of interest. Here we report the ...

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Chem. Eur. J., Volume 22, Issue 14, Pages 4666–4678, DOI: 10.1002/chem.201504419
Chem. Eur. J., online article

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Biological selection makes natural products promising scaffolds for drug development and the ever growing number of newly identified, structurally diverse molecules helps to fill the gaps in chemical space. Elucidating the function of a small molecule, such as identifying its protein binding partners, its on- and off-targets, is becoming increasingly important. ...

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Chem. Eur. J., Volume 22, Issue 5, Pages 1622–1630, DOI: 10.1002/chem.201503981
Chem. Eur. J., online article

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Methicillin-resistant Staphylococcus aureus (MRSA) causes severe infections with only few effective antibiotic therapies currently available. To approach this challenge, chemical entities with a novel and resistance-free mode of action are desperately needed. Here, we introduce a new hydroxyamide compound that effectively reduces the expression of devastating ...

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