FMP Publications

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

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References
Biomembrane Interactions of Functionalized Cryptophane-A: Combined Fluorescence and 129Xe NMR Studies of a Bimodal Contrast Agent
Sloniec(*), J., Schnurr, M., Witte, C., Resch-Genger(*), U., Schröder, L.; Hennig(*), A.
Chem-Eur J, 19:3110-3118
(2013)

Tags: Molecular Imaging (Schröder)

Abstract: Fluorescent derivatives of the 129Xe NMR contrast agent cryptophane-A were obtained by functionalization with near infrared fluorescent dyes DY680 and DY682. The resulting conjugates were spectrally characterized, and their interaction with giant and large unilamellar vesicles of varying phospholipid composition was analyzed by fluorescence and NMR spectroscopy. In the latter, a chemical exchange saturation transfer with hyperpolarized 129Xe (Hyper-CEST) was used to obtain sufficient sensitivity. To determine the partitioning coefficients, we developed a method based on fluorescence resonance energy transfer from Nile Red to the membrane-bound conjugates. This indicated that not only the hydrophobicity of the conjugates, but also the phospholipid composition, largely determines the membrane incorporation. Thereby, partitioning into the liquid-crystalline phase of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine was most efficient. Fluorescence depth quenching and flip-flop assays suggest a perpendicular orientation of the conjugates to the membrane surface with negligible transversal diffusion, and that the fluorescent dyes reside in the interfacial area. The results serve as a basis to differentiate biomembranes by analyzing the Hyper-CEST signatures that are related to membrane fluidity, and pave the way for dissecting different contributions to the Hyper-CEST signal.

Monogenic ion channelopathies of the skeleton
Stauber, T., Horn(*), D.; Kornak(*), U.
Med Genet-Berlin, 25:493-500
(2013)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Although ion channels are intuitively more related to the generation of action potentials, they can influence skeletal cells, development, and homeostasis in different ways as demonstrated in this review. All major skeletal cell types, chondrocytes, osteoblasts, osteocytes, and osteoclasts, can be involved in the pathogenesis and often the interaction of these different defects is incompletely understood. Connexin 43 and TRPV4, two of the mentioned membrane proteins, predominantly conduct calcium ions and are the basis of a whole spectrum of skeletal phenotypes. While connexin 43 seems to regulate the function of osteoblasts and osteocytes, TRPV4 is crucial for chondrocytes. The other two examples are chloride-transporting membrane proteins ANO5 and ClC-7, which can cause gnathodiaphyseal dysplasia and osteopetrosis, respectively. Whereas the function of ANO5 is largely unknown, the role of ClC-7 in bone resorbing osteoclasts has been investigated in great detail.

Lipid-Labeling Facilitates a Novel Magnetic Isolation Procedure to Characterize Pathogen-Containing Phagosomes
Steinhäuser(*), C., Heigl(*), U., Tchikov(*), V., Schwarz(*), J., Gutsmann(*), T., Seeger(*), K., Brandenburg(*), J., Fritsch(*), J., Schroeder(*), J., Wiesmüller(*), K. H., Rosenkrands(*), I., Walther(*), P., Pott(*), J., Krause, E., Ehlers(*), S., Schneider-Brachert(*), W., Schütze(*), S.; Reiling(*), N.
Traffic, 14:321-336
(2013)

Tags: Mass Spectrometry (Krause, E.)

Abstract: Here we describe a novel approach for the isolation and biochemical characterization of pathogen-containing compartments from primary cells: We developed a lipid-based procedure to magnetically label the surface of bacteria and visualized the label by scanning and transmission electron microscopy (SEM, TEM). We performed infection experiments with magnetically labeled Mycobacterium avium, M. tuberculosis and Listeria monocytogenes and isolated magnetic bacteria-containing phagosomes using a strong magnetic field in a novel free-flow system. Magnetic labeling of M.tuberculosis did not affect the virulence characteristics of the bacteria during infection experiments addressing host cell activation, phagosome maturation delay and replication in macrophages in vitro. Biochemical analyses of the magnetic phagosome-containing fractions provided evidence of an enhanced presence of bacterial antigens and a differential distribution of proteins involved in the endocytic pathway over time as well as cytokine-dependent changes in the phagosomal protein composition. The newly developed method represents a useful approach to characterize and compare pathogen-containing compartments, in order to identify microbial and host cell targets for novel anti-infective strategies.

Exome sequencing reveals new causal mutations in children with epileptic encephalopathies
Veeramah(*), K. R., Johnstone(*), L., Karafet(*), T. M., Wolf(*), D., Sprissler(*), R., Salogiannis(*), J., Barth-Maron(*), A., Greenberg(*), M. E., Stuhlmann, T., Weinert, S., Jentsch, T. J., Pazzi(*), M., Restifo(*), L. L., Talwar(*), D., Erickson(*), R. P.; Hammer(*), M. F.
Epilepsia, 54:1270-1281
(2013)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Purpose: The management of epilepsy in children is particularly challenging when seizures are resistant to antiepileptic medications, or undergo many changes in seizure type over time, or have comorbid cognitive, behavioral, or motor deficits. Despite efforts to classify such epilepsies based on clinical and electroencephalographic criteria, many children never receive a definitive etiologic diagnosis. Whole exome sequencing (WES) is proving to be a highly effective method for identifying de novo variants that cause neurologic disorders, especially those associated with abnormal brain development. Herein we explore the utility of WES for identifying candidate causal de novo variants in a cohort of children with heterogeneous sporadic epilepsies without etiologic diagnoses. Methods: We performed WES (mean coverage approximately 403) on 10 trios comprised of unaffected parents and a child with sporadic epilepsy characterized by difficult-to-control seizures and some combination of developmental delay, epileptic encephalopathy, autistic features, cognitive impairment, or motor deficits. Sequence processing and variant calling were performed using standard bioinformatics tools. A custom filtering system was used to prioritize de novo variants of possible functional significance for validation by Sanger sequencing. Key Findings: In 9 of 10 probands, we identified one or more de novo variants predicted to alter protein function, for a total of 15. Four probands had de novo mutations in genes previously shown to harbor heterozygous mutations in patients with severe, early onset epilepsies (two in SCN1A, and one each in CDKL5 and EEF1A2). In three children, the de novo variants were in genes with functional roles that are plausibly relevant to epilepsy (KCNH5, CLCN4, and ARHGEF15). The variant in KCNH5 alters one of the highly conserved arginine residues of the voltage sensor of the encoded voltage-gated potassium channel. In vitro analyses using cell-based assays revealed that the CLCN4 mutation greatly impaired ion transport by the ClC-4 2Cl(-)/H+-exchanger and that the mutation in ARHGEF15 reduced GEF exchange activity of the gene product, Ephexin5, by about 50%. Of interest, these seven probands all presented with seizures within the first 6 months of life, and six of these have intractable seizures. Significance: The finding that 7 of 10 children carried de novo mutations in genes of known or plausible clinical significance to neuronal excitability suggests that WES will be of use for the molecular genetic diagnosis of sporadic epilepsies in children, especially when seizures are of early onset and difficult to control.

Visualizing Brain Inflammation with a Shingled-Leg Radio-Frequency Head Probe for F-19/H-1 MRI
Waiczies(*), H., Lepore(*), S., Drechsler(*), S., Qadri(*), F., Purfurst(*), B., Sydow, K., Dathe, M., Kühne(*), A., Lindel(*), T., Hoffmann(*), W., Pohlmann(*), A., Niendorf(*), T.; Waiczies(*), S.
Sci Rep-Uk, 3
(2013)

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe)

Abstract: Magnetic resonance imaging (MRI) provides the opportunity of tracking cells in vivo. Major challenges in dissecting cells from the recipient tissue and signal sensitivity constraints albeit exist. In this study, we aimed to tackle these limitations in order to study inflammation in autoimmune encephalomyelitis. We constructed a very small dual-tunable radio frequency (RF) birdcage probe tailored for F-19 (fluorine) and H-1 (proton) MR mouse neuroimaging. The novel design eliminated the need for extra electrical components on the probe structure and afforded a uniform B-1(+)-field as well as good SNR. We employed fluorescently-tagged F-19 nanoparticles and could study the dynamics of inflammatory cells between CNS and lymphatic system during development of encephalomyelitis, even within regions of the brain that are otherwise not easily visualized by conventional probes. F-19/H-1 MR Neuroimaging will allow us to study the nature of immune cell infiltration during brain inflammation over an extensive period of time.

Exploiting Specific Interactions toward Next-Generation Polymeric Drug Transporters
Wieczorek(*), S., Krause, E., Hackbarth(*), S., Röder(*), B., Hirsch(*), A. K. H.; Börner(*), H. G.
J. Am. Chem. Soc., 135:1711-1714
(2013)

Tags: Mass Spectrometry (Krause, E.)

Abstract: A generic method describes advanced tailoring of polymer drug carriers based on polymer-block-peptides. Combinatorial means are used to select suitable peptide segments to specifically complex small-molecule drugs. The resulting specific drug formulation agents render insoluble drugs water-soluble and enable precise adjustment of drug-release profiles beyond established block-copolymer carriers. While proof of principle is shown on chlorin as a partially approved drug for photodynamic cancer therapy, the concept is universal and applies to a broad spectrum of difficult drugs.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de

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