FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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References
Sensitivity enhancement of (Hyper-)CEST image series by exploiting redundancies in the spectral domain
Döpfert, J., Witte, C., Kunth, M.; Schröder, L.
Contrast media & molecular imaging, 9:100-107
(2014)

Tags: Molecular Imaging (Schröder)

Abstract: CEST has proven to be a valuable technique for the detection of hyperpolarized xenon-based functionalized contrast agents. Additional information can be encoded in the spectral dimension, allowing the simultaneous detection of multiple different biosensors. However, owing to the low concentration of dissolved xenon in biological tissue, the signal-to-noise ratio (SNR) of Hyper-CEST data is still a critical issue. In this work, we present two techniques aiming to increase SNR by exploiting the typically high redundancy in spectral CEST image series: PCA-based post-processing and sub-sampled acquisition with low-rank reconstruction. Each of them yields a significant SNR enhancement, demonstrating the feasibility of the two approaches. While the first method is directly applicable to proton CEST experiments as well, the second one is particularly beneficial when dealing with hyperpolarized nuclei, since it distributes the non-renewable initial polarization more efficiently over the sampling points. The results obtained are a further step towards the detection of xenon biosensors with spectral Hyper-CEST imaging in vivo.

Fast gradient-encoded CEST spectroscopy of hyperpolarized xenon
Döpfert, J., Witte, C.; Schröder, L.
Chemphyschem, 15:261-264
(2014)

Tags: Molecular Imaging (Schröder)

Abstract: Breaking speed limits: The acquisition of xenon-129 Hyper-CEST spectra is drastically accelerated by utilizing gradients to encode the chemical shift dimension. The signal is increased by using repeated spin-echo refocussing. The additional application of a variable flip angle makes the experiment independent from a constant Xe redelivery.

Ultrafast CEST imaging
Döpfert, J., Zaiss(*), M., Witte, C.; Schröder, L.
J Magn Reson, 243:47-53
(2014)

Tags: Molecular Imaging (Schröder)

Abstract: We describe a new MR imaging method for the rapid characterization or screening of chemical exchange saturation transfer (CEST) contrast agents. It is based on encoding the chemical shift dimension with an additional gradient as proposed in previous ultrafast CEST spectroscopy approaches, but extends these with imaging capabilities. This allows us to investigate multiple compounds simultaneously with an arbitrary sample tube arrangement. The technique requires a fast multislice readout to ensure the saturation is not lost during data acquisition due to T1 relaxation. We therefore employ radial subsampling, acquiring only 10 projections per CEST image with a 128x128 matrix. To recover the images, we use a heuristic reconstruction algorithm that incorporates low rank and limited object support as prior knowledge. This way, we are able to acquire a spectral CEST data set consisting of 15 saturation offsets more than 16 times faster than compared with conventional CEST imaging.

Flexible, polymer-supported synthesis of sphingosine derivatives provides ceramides with enhanced biological activity
El-Dahshan, A., Al-Gharabli(*), S. I., Radetzki, S., Al-Tel(*), T. H., Kumar(*), P.; Rademann, J.
Bioorg Med Chem, 22:5506-5512
(2014)

Tags: Medicinal Chemistry (Rademann), Screening Unit (von Kries)

Abstract: A polymer-supported route for the synthesis of sphingosine derivatives is presented based on the C-acylation of polymeric phosphoranylidene acetates with an Fmoc-protected amino acid. The approach enables the flexible variation of the sphingosine tail through a deprotection-decarboxylation sequence followed by E-selective Wittig olefination cleavage. d-Erythro-sphingosine analogs have been synthesized by diastereoselective reduction of the keto group employing LiAlH(O-tBu)3 as reducing agent. The effect of ceramides and keto-ceramides on the proliferation of three cancer cell lines HEP G-2, PC-12 and HL-60 was investigated and a ceramide containing an aromatic sphingosine tail was identified as being most active.

Proteome analysis of the HIV-1 Gag interactome
Engeland(*), C. E., Brown(*), N. P., Borner(*), K., Schümann, M., Krause, E., Kaderali(*), L., Müller(*), G. A.; Kräusslich(*), H. G.
Virology, 460-461:194-206
(2014)

Tags: Mass Spectrometry (Krause, E.)

Abstract: Human immunodeficiency virus Gag drives assembly of virions in infected cells and interacts with host factors which facilitate or restrict viral replication. Although several Gag-binding proteins have been characterized, understanding of virus-host interactions remains incomplete. In a series of six affinity purification screens, we have identified protein candidates for interaction with HIV-1 Gag. Proteins previously found in virions or identified in siRNA screens for host factors influencing HIV-1 replication were recovered. Helicases, translation factors, cytoskeletal and motor proteins, factors involved in RNA degradation and RNA interference were enriched in the interaction data. Cellular networks of cytoskeleton, SR proteins and tRNA synthetases were identified. Most prominently, components of cytoplasmic RNA transport granules were co-purified with Gag. This study provides a survey of known Gag-host interactions and identifies novel Gag binding candidates. These factors are associated with distinct molecular functions and cellular pathways relevant in host-pathogen interactions.

PI3K class II alpha controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function
Franco(*), I., Gulluni(*), F., Campa(*), C. C., Costa(*), C., Margaria(*), J. P., Ciraolo(*), E., Martini(*), M., Monteyne(*), D., De Luca(*), E., Germena(*), G., Posor, Y., Maffucci(*), T., Marengo(*), S., Haucke, V., Falasca(*), M., Perez-Morga(*), D., Boletta(*), A., Merlo(*), G. R.; Hirsch(*), E.
Dev Cell, 28:647-658
(2014)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Multiple phosphatidylinositol (PtdIns) 3-kinases (PI3Ks) can produce PtdIns3P to control endocytic trafficking, but whether enzyme specialization occurs in defined subcellular locations is unclear. Here, we report that PI3K-C2alpha is enriched in the pericentriolar recycling endocytic compartment (PRE) at the base of the primary cilium, where it regulates production of a specific pool of PtdIns3P. Loss of PI3K-C2alpha-derived PtdIns3P leads to mislocalization of PRE markers such as TfR and Rab11, reduces Rab11 activation, and blocks accumulation of Rab8 at the primary cilium. These changes in turn cause defects in primary cilium elongation, Smo ciliary translocation, and Sonic Hedgehog (Shh) signaling and ultimately impair embryonic development. Selective reconstitution of PtdIns3P levels in cells lacking PI3K-C2alpha rescues Rab11 activation, primary cilium length, and Shh pathway induction. Thus, PI3K-C2alpha regulates the formation of a PtdIns3P pool at the PRE required for Rab11 and Shh pathway activation.

EU-OPENSCREEN--a European infrastructure of open screening platforms for chemical biology
Frank, R.
ACS Chem Biol, 9:853-854
(2014)

Tags: Chemical Systems Biology (Frank)

Live Cell NMR
Freedberg(*), D. I.; Selenko, P.
Annu Rev Biophys, 43:171-192
(2014)

Tags: In-Cell NMR (Selenko)

Abstract: Ever since scientists realized that cells are the basic building blocks of all life, they have been developing tools to look inside them to reveal the architectures and mechanisms that define their biological functions. Whereas "looking into cells" is typically said in reference to optical microscopy, high-resolution in-cell and on-cell nuclear magnetic resonance (NMR) spectroscopy is a powerful method that offers exciting new possibilities for structural and functional studies in and on live cells. In contrast to conventional imaging techniques, in-and on-cell NMR methods do not provide spatial information on cellular biomolecules. Instead, they enable atomic-resolution insights into the native cell states of proteins, nucleic acids, glycans, and lipids. Here we review recent advances and developments in both fields and discuss emerging concepts that have been delineated with these methods.

Non-stoichiometric O-acetylation of Shigella flexneri 2a O-specific polysaccharide: synthesis and antigenicity
Gauthier(*), C., Chassagne(*), P., Theillet, F. X., Guerreiro(*), C., Thouron(*), F., Nato(*), F., Delepierre(*), M., Sansonetti(*), P. J., Phalipon(*), A.; Mulard(*), L. A.
Organic & Biomolecular Chemistry, 12:4218-4232
(2014)

Tags: In-Cell NMR (Selenko)

Abstract: Synthetic functional mimics of the O-antigen from Shigella flexneri 2a are seen as promising vaccine components against endemic shigellosis. Herein, the influence of the polysaccharide non-stoichiometric di-O-acetylation on antigenicity is addressed for the first time. Three decasaccharides, representing relevant internal mono-and di-O-acetylation profiles of the O-antigen, were synthesized from a pivotal protected decasaccharide designed to tailor late stage site-selective O-acetylation. The latter was obtained via a convergent route involving the imidate glycosylation chemistry. Binding studies to five protective mIgGs showed that none of the acetates adds significantly to broad antibody recognition. Yet, one of the five antibodies had a unique pattern of binding. With IC50 in the micromolar to submicromolar range mIgG F22-4 exemplifies a remarkable tight binding antibody against diversely O-acetylated and non-O-acetylated fragments of a neutral polysaccharide of medical importance.

Reporter assay for endo/lysosomal escape of toxin-based therapeutics
Gilabert-Oriol(*), R., Thakur(*), M., von Mallinckrodt(*), B., Bhargava(*), C., Wiesner, B., Eichhorst, J., Melzig(*), M. F., Fuchs(*), H.; Weng(*), A.
Toxins (Basel), 6:1644-1666
(2014)

Tags: Cellular Imaging (Wiesner)

Abstract: Protein-based therapeutics with cytosolic targets are capable of exhibiting their therapeutic effect once they have escaped from the endosomes or lysosomes. In this study, the reporters-horseradish peroxidase (HRP), Alexa Fluor 488 (Alexa) and ricin A-chain (RTA)-were investigated for their capacity to monitor the endo/lysosomal escape of the ribosome-inactivating protein, saporin. The conjugates-saporin-HRP, (Alexa)saporin and saporin-KQ-RTA-were constructed, and the endo/lysosomal escape of these conjugates alone (lack of endo/lysosomal release) or in combination with certain structurally-specific triterpenoidal saponins (efficient endo/lysosomal escape) was characterized. HRP failed in reporting the endo/lysosomal escape of saporin. Contrastingly, Alexa Fluor 488 successfully allowed the report of the process at a toxin concentration of 1000 nM. In addition, single endo/lysosome analysis facilitated the determination of the amount of (Alexa)saporin released from each vesicle. RTA was also successful in reporting the endo/lysosomal escape of the enzymatically inactive mutant, saporin-KQ, but in this case, the sensitivity of the method reached a toxin concentration of 10 nM. In conclusion, the simultaneous usage of Alexa Fluor 488 and RTA as reporters may provide the possibility of monitoring the endo/lysosomal escape of protein-based therapeutics in the concentration range of 10-1000 nM.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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13125 Berlin, Germany
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