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Yew J.Y.,Institute of Medical Physics and Biophysics | Yew J.Y.,Temasek Life science Laboratory | Yew J.Y.,National University of Singapore | Soltwisch J.,Institute of Medical Physics and Biophysics | And 2 more authors.
Journal of the American Society for Mass Spectrometry | Year: 2011

We recently demonstrated that ultraviolet laser desorption ionization orthogonal time-of-flight mass spectrometry (UV-LDI o-TOF MS) could be used for the matrix-free analysis of cuticular lipids (unsaturated aliphatic and oxygen-containing hydrocarbons and triacylglycerides) directly from individual Drosophila melanogaster fruit flies (Yew, J.Y.; Dreisewerd, K.; Luftmann, H.; Pohlentz, G.; Kravitz, E.A., Curr. Biol. 2009, 19, 1245-1254). In this report, we show that the cuticular hydrocarbon, fatty acid, and triglyceride profiles of other insects and spiders can also be directly analyzed from intact body parts. Mandibular pheromones from the jaw of a queen honey bee are provided as one example. In addition, we describe analytical features and examine mechanisms underlying the methodology. Molecular ions of lipids can be generated by direct UV-LDI when non-endogenous compounds are applied to insect wings or other body parts. Current sensitivity limits are in the 10 pmol range. We show also the dependence of ion signal intensity on collisional cooling gas pressure in the ion source, laser wavelength (varied between 280-380 nm and set to 2.94 μm for infrared LDI), and laser pulse energy. © American Society for Mass Spectrometry, 2011.


News Article | February 23, 2017
Site: www.eurekalert.org

A study led by researchers at the Hospital del Mar Medical Research Institute (IMIM) and the Institute of Medical Physics and Biophysics at the Faculty of Medicine in Charité Hospital, Berlin, published in the journal Nature Communications, demonstrates that the cholesterol present in cell membranes can interfere with the function of an important brain membrane protein, through a previously unknown mode of interaction. Specifically, cholesterol is capable of regulating the activity of the adenosine receptor, by invading it and accessing the active site. This will allow new ways of interacting with these proteins to be devised that in the future could lead to drugs for treating diseases like Alzheimer's. The adenosine receptor belongs to the GPCR family (G Protein-Coupled Receptors), a large group of proteins located in cell membranes, which are key in the transmission of signals and communication between cells. GPCRs are therefore involved in the majority of important physiological processes, including the interpretation of sensory stimuli such as vision, smell, and taste, the regulation of the immune and inflammatory system, and behaviour modulation. "Cholesterol is an essential component of neuronal membranes, where GPCRs reside along with other proteins. Interestingly, the levels of cholesterol in the membrane are altered in diseases such as Alzheimer's, where GPCRs like the adenosine receptor play a key role", explains Jana Selent, head of the GPCR Drug Discovery research group at the GRIB, a joint programme between Hospital del Mar Medical Research Institute (IMIM) and Universitat Pompeu Fabra (UPF). "This study has shown that cholesterol can exert direct action on this important family of proteins in neuronal membranes, the GPCRs, and establishes the basis for a hitherto unknown interaction pathway between the cell membrane and proteins", adds the researcher. Up to now, it was thought that membrane cholesterol could regulate the activity of these proteins through two mechanisms: either by altering the physical properties of the membrane, or by binding to the surface of the protein. In both cases, it was thought that cholesterol could only exercise its modulatory action from outside the protein. However, by using latest-generation molecular simulations the researchers were able to detect the fact that cholesterol can leave the neuronal membrane and get within the adenosine receptor, in particular accessing the receptor's active site. With this information, and in collaboration with Dr. Mairena Martin and Dr. José L. Albasanz from the University of Castilla-La Mancha, we designed an experimental protocol using cell assays to demonstrate that cholesterol is able to modulate the activity of this receptor by accessing its interior. "Cholesterol levels in cell membranes could have a more direct effect than previously thought on the behaviour of key proteins in central nervous system diseases. In particular, high levels of membrane cholesterol like those present in Alzheimer's patients probably block the adenosine receptor, which could in turn be related to certain symptoms observed in this disease", explains Ramón Guixà González, a postdoctoral researcher at the Institute of Medical Physics and Biophysics at the Faculty of Medicine in Charité Hospital in Berlin and first author of the article. "Although other studies are needed to prove this relationship, this work provides key knowledge that could be used in the future in the development of new molecules that, like cholesterol, have the ability to get inside the receptor and modulate its activity", says the researcher. The results from this study represent a paradigm shift in the relationship between membrane cholesterol and GPCRs in the central nervous system, and open up new avenues of research in fields where the cholesterol-GPCR relationship is essential. It also appears that the cholesterol access pathway into the receptor is an evolutionary footprint. It is therefore necessary to discover whether the molecular mechanism described in this paper is present in other GPCRs and therefore potentially involved in a wide range of central nervous system diseases. Guixà-González R, Albasanz JL, Rodríguez-Epigares I, Pastor M, Sanz F, Martí-Solano M, Manna M, Martínez-Seara H, Hildebrand PW, Martí M, Selent J. Membrane cholesterol access into a G-protein-coupled receptor. Nature Communications, 8:14505, 2017. (DOI: doi:10.1038/ncomms14505) Explanatory video in which you can see how cholesterol leaves the neuronal membrane and get within the adenosine receptor: https:/


News Article | February 22, 2017
Site: phys.org

Arrestin loops interact directly with the membrane adjacent to the GPCR. Credit: Jana Selent, Pompeu Fabra University. Researchers from Charité – Universitätsmedizin Berlin have been studying two proteins that play a vital role in many bodily processes. The aim of the research was to establish how G-protein-coupled receptors (GPCRs) and arrestin form complexes. The human GPCR family consists of nearly one thousand different types of membrane proteins, with the majority involved in sensory and neuronal processes. Results from this research, which has been published in the current issue of the journal Nature Communications, identify a previously unknown binding element critical to the arrestin - GPCR interaction. As crucial drug targets, G-protein-coupled receptors are responsible for the effectiveness of nearly half of all medicines prescribed today. GPCRs are integral membrane proteins that control and modulate the processing of sensory and physiological stimuli, such as those relevant to our sight and taste, or those involved in controlling our heart rate. Arrestins play a key role in controlling the activity and signal transduction of GPCRs inside the cells of the body. "GPCRs are the target of a wide variety of drug-based treatments, which is why it is so important for us to understand their structure and function, and to fully understand how these membrane proteins interact at the molecular level. In order to develop better drugs with fewer side effects, this knowledge is necessary," explains Dr. Martha Sommer, who chairs the Arrestin Working Group at Charité's Institute of Medical Physics and Biophysics. Some of the side effects that occur with certain medicines (such as morphine-based drugs) are the result of arrestin-dependent signaling pathways. The researchers' close observation of the interactions between arrestins and GPCRs yielded crucial conclusions. "We asked ourselves how these two proteins manage to find each other, and what happens when they come together to form a complex. The recent crystal structure of a GPCR-arrestin complex prompted us to ask whether a section of arrestin called the C-edge might interact with the membrane adjacent to the GPCR," explains Dr. Sommer. "Using a combination of computer simulations, which we conducted in cooperation with Dr. Jana Selent at the UPF Barcelona, and site-directed fluorescence spectroscopy, we were able to show that loops within the C-edge of arrestin binds to the membrane." The existence of this type of interaction was previously unknown, and its discovery opens up a whole new field of research regarding how the membrane influences the function of arrestin. A better understanding of GPCR-arrestin interactions is essential if we are to develop drugs with fewer side effects. Dr. Sommer's team have already begun to explore the role of the membrane on the structure and interactions inside the GPCR-arrestin complex. More information: Ciara C M. Lally et al, C-edge loops of arrestin function as a membrane anchor, Nature Communications (2017). DOI: 10.1038/ncomms14258


News Article | February 22, 2017
Site: www.eurekalert.org

Researchers from Charité - Universitätsmedizin Berlin have been studying two proteins that play a vital role in many bodily processes. The aim of the research was to establish how G-protein-coupled receptors (GPCRs) and arrestin form complexes. The human GPCR family consists of nearly one thousand different types of membrane proteins, with the majority involved in sensory and neuronal processes. Results from this research, which has been published in the current issue of the journal Nature Communications*, identify a previously unknown binding element critical to the arrestin - GPCR interaction. As crucial drug targets, G-protein-coupled receptors are responsible for the effectiveness of nearly half of all medicines prescribed today. GPCRs are integral membrane proteins that control and modulate the processing of sensory and physiological stimuli, such as those relevant to our sight and taste, or those involved in controlling our heart rate. Arrestins play a key role in controlling the activity and signal transduction of GPCRs inside the cells of the body. "GPCRs are the target of a wide variety of drug-based treatments, which is why it is so important for us to understand their structure and function, and to fully understand how these membrane proteins interact at the molecular level. In order to develop better drugs with fewer side effects, this knowledge is necessary," explains Dr. Martha Sommer, who chairs the Arrestin Working Group at Charité's Institute of Medical Physics and Biophysics. Some of the side effects that occur with certain medicines (such as morphine-based drugs) are the result of arrestin-dependent signaling pathways. The researchers' close observation of the interactions between arrestins and GPCRs yielded crucial conclusions. "We asked ourselves how these two proteins manage to find each other, and what happens when they come together to form a complex. The recent crystal structure of a GPCR-arrestin complex prompted us to ask whether a section of arrestin called the C-edge might interact with the membrane adjacent to the GPCR," explains Dr. Sommer. "Using a combination of computer simulations, which we conducted in cooperation with Dr. Jana Selent at the UPF Barcelona, and site-directed fluorescence spectroscopy, we were able to show that loops within the C-edge of arrestin binds to the membrane." The existence of this type of interaction was previously unknown, and its discovery opens up a whole new field of research regarding how the membrane influences the function of arrestin. A better understanding of GPCR-arrestin interactions is essential if we are to develop drugs with fewer side effects. Dr. Sommer's team have already begun to explore the role of the membrane on the structure and interactions inside the GPCR-arrestin complex. Dr. Martha Sommer Institute of Medical Physics and Biophysics / Chair of the Arrestin Working Group (AG Arrestin) Charité - Universitätsmedizin Berlin Tel: +49 30 450 524 200 Email: martha.sommer@charite.de


Li Z.,Center for Nanotechnology ech | Huve J.,Center for Nanotechnology ech | Huve J.,Institute of Medical Physics and Biophysics | Krampe C.,Center for Nanotechnology ech | And 8 more authors.
Small | Year: 2013

Information about the mechanisms underlying the interactions of nanoparticles with living cells is crucial for their medical application and also provides indications of the putative toxicity of such materials. Here the uptake and intracellular delivery of disc-shaped zeolite L nanocrystals as porous aminosilicates with well-defined crystal structure, uncoated as well as with COOH-, NH2-, polyethyleneglycol (PEG)- and polyallylamine hydrochloride (PAH) surface coatings are reported. HeLa cells are used as a model system to demonstrate the relation between these particles and cancer cells. Interactions are studied in terms of their fates under diverse in vitro cell culture conditions. Differently charged coatings demonstrated dissimilar behavior in terms of agglomeration in media, serum protein adsorption, nanoparticle cytotoxicity and cell internalization. It is also found that functionalized disc-shaped zeolite L particles enter the cancer cells via different, partly not yet characterized, pathways. These in vitro results provide additional insight about low-aspect ratio anisotropic nanoparticle interactions with cancer cells and demonstrate the possibility to manipulate the interactions of nanoparticles and cells by surface coating for the use of nanoparticles in medical applications. Interaction of zeolite L nanocontainers with cancer cells. By inhibition and colocalization experiments, the route of uptake and the intracellular fate of functionalized zeolite L nanoparticles in Hela cancer cells are described. According to their surface charge, zeolites are selectively engulfed and intracellularly targeted. The results show how the destiny of nanoparticles in cancer cells can be altered by surface functionalization. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | Chubu University, Institute of Medical Physics and Biophysics and University of Munster
Type: | Journal: Cerebral cortex (New York, N.Y. : 1991) | Year: 2016

During the development of the mammalian neocortex, the generation of neurons by neural progenitors and their migration to the final position are closely coordinated. The highly polarized radial glial cells (RGCs) serve both as progenitor cells to generate neurons and as support for the migration of these neurons. After their generation, neurons transiently assume a multipolar morphology before they polarize and begin their migration along the RGCs. Here, we show that Rap1 GTPases perform essential functions for cortical organization as master regulators of cell polarity. Conditional deletion of Rap1 GTPases leads to a complete loss of cortical lamination. In RGCs, Rap1 GTPases are required to maintain their polarized organization. In newborn neurons, the loss of Rap1 GTPases prevents the formation of axons and leading processes and thereby interferes with radial migration. Taken together, the loss of RGC and neuronal polarity results in the disruption of cortical organization.


PubMed | Chubu University, Institute of Medical Physics and Biophysics, University of Munster and Max Planck Institute for Molecular Biomedicine
Type: Journal Article | Journal: PloS one | Year: 2016

The establishment of a polarized morphology is essential for the development and function of neurons. During the development of the mammalian neocortex, neurons arise in the ventricular zone (VZ) from radial glia cells (RGCs) and leave the VZ to generate the cortical plate (CP). During their migration, newborn neurons first assume a multipolar morphology in the subventricular zone (SVZ) and lower intermediate zone (IZ). Subsequently, they undergo a multi-to-bipolar (MTB) transition to become bipolar in the upper IZ by developing a leading process and a trailing axon. The small GTPases Rap1A and Rap1B act as master regulators of neural cell polarity in the developing mouse neocortex. They are required for maintaining the polarity of RGCs and directing the MTB transition of multipolar neurons. Here we show that the Rap1 guanine nucleotide exchange factor (GEF) C3G (encoded by the Rapgef1 gene) is a crucial regulator of the MTB transition in vivo by conditionally inactivating the Rapgef1 gene in the developing mouse cortex at different time points during neuronal development. Inactivation of C3G results in defects in neuronal migration, axon formation and cortical lamination. Live cell imaging shows that C3G is required in cortical neurons for both the specification of an axon and the initiation of radial migration by forming a leading process.


Boening D.,Max Planck Institute for Biophysical Chemistry | Boening D.,Institute of Medical Physics and Biophysics | Groemer T.W.,Max Planck Institute for Biophysical Chemistry | Groemer T.W.,Friedrich - Alexander - University, Erlangen - Nuremberg | And 2 more authors.
Optics Express | Year: 2010

In this work we systematically explored performance of an EMCCD as a detector for spatially resolved total internal reflection image correlation spectroscopy (TIR-ICS) with respect to adjustable parameters. We show that variations in the observation volume (pixel binning) can be well described by a simple structural term D. To test the sensitivity of camera-based TIR-ICS we measured diffusion coefficients and particle numbers (PN) of fluorescent probes of different sizes (Fluorospheres, GFP and labeled antibodies) at varying viscosities, concentrations, and sampling rates. TIR-ICS allowed distinguishing between different probe concentrations with differences in PN of 5% and differences of 6% in D by acquiring only 15 independent measurement runs. © 2010 Optical Society of America.


PubMed | Institute of Medical Physics and Biophysics and University of Munster
Type: Journal Article | Journal: Angewandte Chemie (International ed. in English) | Year: 2015

Gold nanoparticles (AuNPs) are subjects of broad interest in scientific community due to their promising physicochemical properties. Herein we report the facile and controlled light-mediated preparation of gold nanoparticles through a Norrish typeI reaction of photoactive polymers. These carefully designed polymers act as reagents for the photochemical reduction of gold ions, as well as stabilizers for the in situ generated AuNPs. Manipulating the length and composition of the photoactive polymers allows for control of AuNP size. Nanoparticle diameter can be controlled from 1.5nm to 9.6nm.


Samanta A.,University of Munster | Tesch M.,University of Munster | Keller U.,Institute of Medical Physics and Biophysics | Klingauf J.,Institute of Medical Physics and Biophysics | And 2 more authors.
Journal of the American Chemical Society | Year: 2015

Polymer-shelled vesicles are prepared by using cyclodextrin vesicles as supramolecular templates and an adamantane-functionalized poly(acrylic acid) additive anchored via host-guest recognition, followed by cross-linking of carboxylic acid groups on the polymer. The polymer-shelled nanocontainers are highly stable and effective for encapsulating small hydrophilic molecules. We also show that a hollow cross-linked polymer cage can be obtained after dissolution of the template vesicles. The size and shell thickness of the polymer cage can be tuned by variation of template size and polymer length. © 2015 American Chemical Society.

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