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Henig J.,University of Tübingen | Mamedov I.,Max Planck Institute For Biologische Kybernetik | Fouskova P.,CNRS Center for Molecular Biophysics | Toth E.,CNRS Center for Molecular Biophysics | And 4 more authors.
Inorganic Chemistry | Year: 2011

A novel class of 1,4,7,10-tetraazacyclododecane-1,4,7- tris(methylenecarboxylic) acid (DO3A)-based lanthanide complexes with relaxometric response to Ca2+ was synthesized, and their physicochemical properties were investigated. Four macrocyclic ligands containing an alkyl-aminobis(methylenephosphonate) side chain for Ca 2+-chelation have been studied (alkyl is propyl, butyl, pentyl, and hexyl for L1, L2, L3, and L4, respectively). Upon addition of Ca2+, the r1 relaxivity of their Gd3+ complexes decreased up to 61% of the initial value for the best compounds GdL3 and GdL4. The relaxivity of the complexes was concentration dependent (it decreases with increasing concentration). Diffusion NMR studies on the Y3+ analogues evidenced the formation of agglomerates at higher concentrations; the aggregation becomes even more important in the presence of Ca2+. 31P NMR experiments on EuL1 and EuL4 indicated the coordination of a phosphonate to the Ln3+ for the ligand with a propyl chain, while phosphonate coordination was not observed for the analogue bearing a hexyl linker. Potentiometric titrations yielded protonation constants of the Gd 3+ complexes. log KH1 values for all complexes lie between 6.12 and 7.11 whereas log KH2 values are between 4.61 and 5.87. Luminescence emission spectra recorded on the Eu3+ complexes confirmed the coordination of a phosphonate group to the Ln3+ center in EuL1. Luminescence lifetime measurements showed that Ca-induced agglomeration reduces the hydration number which is the main cause for the change in r1. Variable temperature 17O NMR experiments evidenced high water exchange rates on GdL1, GdL2, and GdL3 comparable to that of the aqua ion. © 2011 American Chemical Society.


Ziegler A.,Harvard University | Kunth M.,Leibniz Institute for Molecular Pharmacology | Mueller S.,Charité - Medical University of Berlin | Bock C.,Alfred Wegener Institute for Polar and Marine Research | And 4 more authors.
Zoomorphology | Year: 2011

Magnetic resonance imaging (MRI) is a noninvasive imaging technique that today constitutes one of the main pillars of preclinical and clinical imaging. MRI's capacity to depict soft tissue in whole specimens ex vivo as well as in vivo, achievable voxel resolutions well below (100 μm)3, and the absence of ionizing radiation have resulted in the broad application of this technique both in human diagnostics and studies involving small animal model organisms. Unfortunately, MRI systems are expensive devices and have so far only sporadically been used to resolve questions in zoology and in particular in zoomorphology. However, the results from two recent studies involving systematic scanning of representative species from a vertebrate group (fishes) as well as an invertebrate taxon (sea urchins) suggest that MRI could in fact be used more widely in zoology. Using novel image data derived from representative species of numerous higher metazoan clades in combination with a comprehensive literature survey, we review and evaluate the potential of MRI for systematic taxon scanning. According to our results, numerous animal groups are suitable for systematic MRI scanning, among them various cnidarian and arthropod taxa, brachiopods, various molluscan taxa, echinoderms, as well as all vertebrate clades. However, various phyla in their entirety cannot be considered suitable for this approach mainly due to their small size (e. g., Kinorhyncha) or their unfavorable shape (e. g., Nematomorpha), while other taxa are prone to produce artifacts associated either with their biology (e. g., Echiura) or their anatomy (e. g., Polyplacophora). In order to initiate further uses of MRI in zoology, we outline the principles underlying various applications of this technique such as the use of contrast agents, in vivo MRI, functional MRI, as well as magnetic resonance spectroscopy. Finally, we discuss how future technical developments might shape the use of MRI for the study of zoological specimens. © 2011 Springer-Verlag.


Kim K.I.,Max Planck Institute For Biologische Kybernetik | Kwon Y.,KAIST
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2010

This paper proposes a framework for single-image super-resolution. The underlying idea is to learn a map from input low-resolution images to target high-resolution images based on example pairs of input and output images. Kernel ridge regression (KRR) is adopted for this purpose. To reduce the time complexity of training and testing for KRR, a sparse solution is found by combining the ideas of kernel matching pursuit and gradient descent. As a regularized solution, KRR leads to a better generalization than simply storing the examples as has been done in existing example-based algorithms and results in much less noisy images. However, this may introduce blurring and ringing artifacts around major edges as sharp changes are penalized severely. A prior model of a generic image class which takes into account the discontinuity property of images is adopted to resolve this problem. Comparison with existing algorithms shows the effectiveness of the proposed method. © 2010 IEEE.


Kirschfeld K.,Max Planck Institute For Biologische Kybernetik | Land M.F.,University of Sussex
Ophthalmologe | Year: 2011

Bifocal or multifocal intraocular lenses (IOLs) can be used to replace natural lenses during cataract surgery. These lenses are recommended by cataract surgeons as the replacement lenses of choice when patients wish to avoid wearing spectacles. There are, however, drawbacks to these lenses: one drawback is that the contrast in the images of bifocal and multifocal lenses is reduced as documented in the ophthalmology literature. It is claimed that acuity is similar in multifocal compared to monofocal lenses, however, we show that any loss in contrast inevitably reduces visual acuity. The other drawback is that the sharp in-focus image is always seen superimposed on one or more blurred out of focus images of the same object. In the ophthalmology literature it is assumed that the brain can suppress the undesired blurred image and only perceive the sharp image. We argue that there are no known mechanisms that would make this possible. This means that vision with bifocal or multifocal implanted lenses cannot be as good as vision with monofocal implants supplemented by spectacles, and this should be explained to patients before undergoing surgery for lens replacement. The results also hold for bifocal and multifocal contact lenses. © 2011 Springer-Verlag.


Henig J.,University of Tübingen | Toth E.,CNRS Center for Molecular Biophysics | Engelmann J.,Max Planck Institute For Biologische Kybernetik | Gottschalk S.,Max Planck Institute For Biologische Kybernetik | Mayer H.A.,University of Tübingen
Inorganic Chemistry | Year: 2010

Two macrocyclic ligands, 1,4,7,10-tetraazacyclododecane-1-glutaric-4,7,10- triacetic acid (H5DOTAGA) and the novel 1,4,7,10- tetraazacyclododecane-1-(4-(carboxymethyl)benzoic)-4,7,10-triacetic acid (H 5DOTABA), were prepared and their lanthanide complexes (Ln = Gd 3+, Y3+) attached to an amino-functionalized T 8-silsesquioxane. The novel compounds Gadoxane G (GG) and Gadoxane B (GB) possess eight monohydrated lanthanide complexes each, as evidenced by multinuclear (1H, 13C, 29Si) NMR spectroscopy and high resolution mass spectrometry (HR-MS). Pulsed-field gradient spin echo (PGSE) diffusion 1H NMR measurements revealed hydrodynamic radii of 1.44 nm and global rotational correlation times of about 3.35 ns for both compounds. With regard to potential MRI contrast agent applications, a variable-temperature 17O NMR and 1H nuclear magnetic relaxation dispersion (NMRD) study was carried out on aqueous solutions of the gadolinium(III) complexes of the Gadoxanes and the corresponding monomeric ligands to yield relevant physicochemical properties. The water exchange rates of the inner-sphere water molecules are all very similar (kex 298 between (5.3 ± 0.5) - 106 s?1 and (5.9 ± 0.3) - 106 s?1) and only slightly higher than that reported for the gadolinium(III) complex of 1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid (H4DOTA) (k ex 298 = 4.1 - 106 s?1). Despite their almost identical size and their similar water exchange rates, GB shows a significantly higher longitudinal relaxivity than GG over nearly the whole range of magnetic fields (e.g., 17.1 mM?1 s?1 for GB and 12.1 mM?1 s?1 for GG at 20 MHz and 25 °C). This difference arises from their different local rotational correlation times (τlR 298 = 240 ± 10 ps and 380 ± 20 ps, respectively), because of the higher rigidity of the phenyl ring of GB as compared to the ethylene spacer of GG. A crucial feature of these novel compounds is the lability of the silsesquioxane core in aqueous media. The hydrolysis of the Si?O?Si moieties was investigated by 29Si NMR and PGSE diffusion 1H NMR spectroscopy, electrospray ionization mass spectrometry (ESI-MS), as well as by relaxivity measurements. Although frozen aqueous solutions (pH 7.0) of GG and GB can be stored at ?28 °C for at least 10 months without any decomposition, with increasing temperature and pH the hydrolysis of the silsesquioxane core was observed (e.g., t1/2 = 15 h at pH 7.4 and 55 min at pH 8.1 for GG at 37 °C). No change in relaxivity was detected within the first 3 h, since the hydrolysis of the initial Si?O?Si moieties has no influence on the rotational correlation time. However, the further hydrolysis of the silsesquioxane core leads to smaller fragments and therefore to a decrease in relaxivity. © 2010 American Chemical Society.


Strauch H.,University of Tübingen | Engelmann J.,Max Planck Institute For Biologische Kybernetik | Scheffler K.,Max Planck Institute For Biologische Kybernetik | Scheffler K.,University of Tübingen | Mayer H.A.,University of Tübingen
Dalton Transactions | Year: 2016

A fast and simple route was developed to synthesize a new T8-silsesquioxane based contrast agent for potential application in Magnetic Resonance Imaging. For this purpose the novel C2-thiol-functionalized T8-silsesquioxane (3) was constructed as a carrier molecule as well as the DOTA based gadolinium(iii) complex (11) equipped with allyl terminated linkers was prepared. The linkage of the complexes to the T8-silsesquioxane was performed via an UV-light catalyzed thiol-ene click reaction within one hour which affords the desired product 13 in a yield of 80%. The successful transformation as well as the intactness of the cube was confirmed by spectroscopic methods and mass spectrometry. This new and simple approach offers a highly effective access to T8-silsesquioxanes functionalized with eight metal complexes. Longitudinal relaxivity measurements of compound 13 (9.5 ± 0.9 mM-1 s-1) at 3 T in HEPES buffered cell culture medium (physiological conditions) show a significant enhancement of r1 per 1 mM gadolinium in comparison to the clinically applied contrast agent Dotarem™ (3.4 mM-1 s-1). In relation to the former reported T8-silsesquioxane based contrast agent Gadoxane G (10.6 mM-1 s-1) a similar relaxivity is found. As the T8-core of polyhedral oligosilsesquioxanes (POSS) based contrast agents undergoes a hydrolysis process depending on the pH, long-term r1 measurements in different solutions (water, cell culture medium and HEPES buffered medium) as well as 1H, 1H/29Si HSQC and PGSE diffusion 1H NMR spectroscopic investigations on aqueous solutions were performed. In solutions featuring an approximately neutral pH (D2O, pD = 7.0; water and HEPES buffered medium, pH = 7.4-7.5) contrast agent 13 (t1/2 = 2.4 d, HEPES/medium) shows a slower decomposition of the T8-cage in comparison to the previously synthesized Gadoxane G (t1/2 = 15 ± 3 h, HEPES/medium). However, under more basic conditions (medium, pH = 8.4-8.5) the decomposition process of 13 is considerably accelerated (t1/2 ∼ 55-60 min), indicating a higher sensitivity of the T8-cage to pH shifts into the basic range similar to Gadoxane G. © 2016 The Royal Society of Chemistry.


The etiology of retinal detachment in central serous retinopathy (CSR) is unknown; however, three facts are generally accepted: (1) the serous exudate which raises the layers of the receptors/pigment epithelium is formed due to hyperpermeability in the choriocapillaries, (2) patients frequently suffer from headaches and (3) stress promotes the incidence of CSR. A high blood plasma histamine concentration can cause the abovementioned symptoms which suggests that histamine might provoke CSR. Within 1 week after administration of the antihistamine loratadin a considerable reduction in the retinal exudate and restoration of vision were observed. This supports the hypothesis that histamine could be involved in the process of retinal detachment. Further investigations and large scale clinical trials should clarify if this hypothesis can be proved or disproved and whether antihistamines can be used for age-related macular degeneration (AMD). © 2014, ©The Author (2014) This article is published with open access at Springerlink.com.


Feldmann V.,University of Tübingen | Engelmann J.,Max Planck Institute For Biologische Kybernetik | Gottschalk S.,Max Planck Institute For Biologische Kybernetik | Mayer H.A.,University of Tübingen
Journal of Colloid and Interface Science | Year: 2012

Spherical, nonporous and monodisperse silica nanoparticles (NPs) with a diameter of about 100nm were synthesized and covalently functionalized with lanthanoid(III) (Ln=Gd or Y) chelate complexes, which serve as contrast agents (CAs) for magnetic resonance imaging (MRI). The materials were fully characterized after each synthetic step by different analytical methods, such as dynamic light scattering, scanning electron microscopy, DRIFT and NMR spectroscopy, thermogravimetry and elemental analysis, as well as zetapotential measurements. High surface concentrations of Gd(III) complexes (up to 50μmolg -1) were determined by ICP-AES and T 1-measurements, respectively. MRI experiments show the typical concentration-dependent increase of the longitudinal relaxation rate. T 1-weighted images of samples with more than 25μg NPs per 100μL agar display a clear contrast enhancement in the agar layer. The transverse relaxivities r 2 of the materials are significantly higher than r 2 of the corresponding free Gd(III) complexes in water and medium, whereas the longitudinal relaxivities r 1 are slightly increased. Due to the high loading of Gd(III) complexes, the relaxivities per particle are remarkably high (up to 2.78×10 5mM -1s -1 for r 1). Thus, new hybrid materials, based on nonporous silica NPs with high local relaxivity values were synthesized, which can serve as very effective CAs for MRI. © 2011 Elsevier Inc.


PubMed | Max Planck Institute For Biologische Kybernetik
Type: Journal Article | Journal: Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft | Year: 2015

The etiology of retinal detachment in central serous retinopathy (CSR) is unknown; however, three facts are generally accepted: (1) the serous exudate which raises the layers of the receptors/pigment epithelium is formed due to hyperpermeability in the choriocapillaries, (2) patients frequently suffer from headaches and (3) stress promotes the incidence of CSR. A high blood plasma histamine concentration can cause the abovementioned symptoms which suggests that histamine might provoke CSR. Within 1 week after administration of the antihistamine loratadin a considerable reduction in the retinal exudate and restoration of vision were observed. This supports the hypothesis that histamine could be involved in the process of retinal detachment. Further investigations and large scale clinical trials should clarify if this hypothesis can be proved or disproved and whether antihistamines can be used for age-related macular degeneration (AMD).


PubMed | Max Planck Institute For Biologische Kybernetik
Type: Journal Article | Journal: Biophysics of structure and mechanism | Year: 2012

The photoreceptors in the flys ommatidia contain a bistable visual pigment, which can be shifted back and forth by means of light of appropriate wavelengths. The situation is complicated, however, by the presence of photostable pigments. One of them (located in rhabdomeres no. 1-6) absorbs in the UV, another one (in rhabdomeres no. 7y) in the blue spectral range. Such pigments act as (dichroic) colour filters that modify the spectral and polarisation sensitivity of the photoreceptors by means of absorption. It could be shown furthermore that such pigments can also act as sensitizing pigments that modify spectral sensitivities due to sensitization.

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