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Berlin Brandenburg

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  • 1
    Language: English
    In: Nature, 18 September 2019
    Description: A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.
    Keywords: Brain Tumors ; Neurons ; Receptors ; Convulsions & Seizures ; Science ; Brain Cancer ; Calcium ; Cell Culture ; Communication ; Anesthesia ; Cell Interactions ; Anesthesia ; Glutamic Acid Receptors ; Glioma Cells ; Calcium ; Calcium ; Patients ; Neurons ; Α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid ; Neurons ; Tumors ; Gene Expression ; Organic Chemistry ; Glutamatergic Transmission ; Autocrine Signalling ; Cell Adhesion & Migration ; Α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid Receptors ; Ultrastructure ; Perturbation ; Brain Tumors ; Microscopy ; Anesthesia ; Tumors ; Paracrine Signalling ; Synapses ; Epilepsy ; Invasiveness;
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 2
    Language: English
    In: Neuron, 05 August 2015, Vol.87(3), pp.521-533
    Description: Mover, a member of the exquisitely small group of vertebrate-specific presynaptic proteins, has been discovered as an interaction partner of the scaffolding protein Bassoon, yet its function has not been elucidated. We used adeno-associated virus (AAV)-mediated shRNA expression to knock down Mover in the calyx of Held in vivo. Although spontaneous synaptic transmission remained unaffected, we found a strong increase of the evoked EPSC amplitude. The size of the readily releasable pool was unaltered, but short-term depression was accelerated and enhanced, consistent with an increase in release probability after Mover knockdown. This increase in release probability was not caused by alterations in Ca influx but rather by a higher Ca sensitivity of the release machinery, as demonstrated by presynaptic Ca uncaging. We therefore conclude that Mover expression in certain subsets of synapses negatively regulates synaptic release probability, constituting a novel mechanism to tune synaptic transmission. In this study, Körber et al. show that knockdown of the presynaptic protein Mover in the calyx of Held increases the vesicular release probability by decreasing the calcium sensitivity of release.
    Keywords: Biology ; Anatomy & Physiology
    ISSN: 0896-6273
    E-ISSN: 1097-4199
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  • 3
    Language: English
    In: Nature, 03 December 2015, Vol.528(7580), pp.93-8
    Description: Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.
    Keywords: Astrocytoma -- Pathology ; Brain Neoplasms -- Pathology ; Gap Junctions -- Metabolism
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 4
    Language: English
    In: Nature methods, April 2016, Vol.13(4), pp.319-21
    Description: Super-resolution fluorescence microscopy has become a widely used tool in many areas of research. However, designing and validating super-resolution experiments to address a research question in a technically feasible and scientifically rigorous manner remains a fundamental challenge. We developed SuReSim, a software tool that simulates localization data of arbitrary three-dimensional structures represented by ground truth models, allowing users to systematically explore how changing experimental parameters can affect potential imaging outcomes.
    Keywords: Software ; Image Processing, Computer-Assisted -- Methods ; Imaging, Three-Dimensional -- Methods ; Microscopy, Fluorescence -- Methods ; Synaptic Vesicles -- Ultrastructure
    ISSN: 15487091
    E-ISSN: 1548-7105
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  • 5
    Language: English
    In: Molecular Pain, 25 September 2013, Vol.9
    Description: Background Cancer-associated pain is a major cause of poor quality of life in cancer patients and is frequently resistant to conventional therapy. Recent studies indicate that some hematopoietic growth factors, namely granulocyte macrophage colony stimulating factor (GMCSF) and granulocyte colony stimulating factor (GCSF), are abundantly released in the tumor microenvironment and play a key role in regulating tumor-nerve interactions and tumor-associated pain by activating receptors on dorsal root ganglion (DRG) neurons. Moreover, these hematopoietic factors have been highly implicated in postsurgical pain, inflammatory pain and osteoarthritic pain. However, the molecular mechanisms via which G-/GMCSF bring about nociceptive sensitization and elicit pain are not known. Results In order to elucidate G-/GMCSF mediated transcriptional changes in the sensory neurons, we performed a comprehensive, genome-wide analysis of changes in the transcriptome of DRG neurons brought about by exposure to GMCSF or GCSF. We present complete information on regulated genes and validated profiling analyses and report novel regulatory networks and interaction maps revealed by detailed bioinformatics analyses. Amongst these, we validate calpain 2, matrix metalloproteinase 9 (MMP9) and a RhoGTPase Rac1 as well as Tumor necrosis factor alpha (TNFα) as transcriptional targets of G-/GMCSF and demonstrate the importance of MMP9 and Rac1 in GMCSF-induced nociceptor sensitization. Conclusion With integrative approach of bioinformatics, in vivo pharmacology and behavioral analyses, our results not only indicate that transcriptional control by G-/GMCSF signaling regulates a variety of established pain modulators, but also uncover a large number of novel targets, paving the way for translational analyses in the context of pain disorders.
    Keywords: Medicine ; Anatomy & Physiology
    ISSN: 1744-8069
    E-ISSN: 1744-8069
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  • 6
    Language: English
    In: Scientific Reports, 01 April 2018, Vol.8(1), pp.1-7
    Description: Abstract With continuing advances in the resolving power of super-resolution microscopy, the inefficient labeling of proteins with suitable fluorophores becomes a limiting factor. For example, the low labeling density achieved with antibodies or small molecule tags limits attempts to reveal local protein nano-architecture of cellular compartments. On the other hand, high laser intensities cause photobleaching within and nearby an imaged region, thereby further reducing labeling density and impairing multi-plane whole-cell 3D super-resolution imaging. Here, we show that both labeling density and photobleaching can be addressed by repetitive application of trisNTA-fluorophore conjugates reversibly binding to a histidine-tagged protein by a novel approach called single-epitope repetitive imaging (SERI). For single-plane super-resolution microscopy, we demonstrate that, after multiple rounds of labeling and imaging, the signal density is increased. Using the same approach of repetitive imaging, washing and re-labeling, we demonstrate whole-cell 3D super-resolution imaging compensated for photobleaching above or below the imaging plane. This proof-of-principle study demonstrates that repetitive labeling of histidine-tagged proteins provides a versatile solution to break the ‘labeling barrier’ and to bypass photobleaching in multi-plane, whole-cell 3D experiments.
    Keywords: Biology
    E-ISSN: 2045-2322
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  • 7
    Language: English
    In: Methods in molecular biology (Clifton, N.J.), 2017, Vol.1538, pp.169-184
    Description: Central nervous system tissue contains a high density of synapses each composed of an intricate molecular machinery mediating precise transmission of information. Deciphering the molecular nanostructure of pre- and postsynaptic specializations within such a complex tissue architecture poses a particular challenge for light microscopy. Here, we describe two approaches suitable to examine the molecular nanostructure of synapses at 20-30 nm lateral and 50-70 nm axial resolution within an area of 500 μm × 500 μm and a depth of 0.6 μm to several micrometers. We employ single-molecule localization microscopy (SMLM) on immunolabeled fixed brain tissue slices. tomoSTORM utilizes array tomography to achieve SMLM in 40 nm thick resin-embedded sections. dSTORM of cryo-sectioned slices uses optical sectioning in 0.1-4 μm thick hydrated sections. Both approaches deliver 3D nanolocalization of two or more labeled proteins within a defined tissue volume. We review sample preparation, data acquisition, analysis, and interpretation.
    Keywords: Brain Tissue Fixation ; Storm-Data Postprocessing ; Super-Resolution Microscopy ; Thin Sectioning ; Dstorm ; Tomostorm ; Brain -- Diagnostic Imaging ; Imaging, Three-Dimensional -- Methods ; Microscopy, Fluorescence -- Methods ; Molecular Imaging -- Methods ; Single Molecule Imaging -- Methods ; Tomography -- Methods
    E-ISSN: 1940-6029
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 8
    Language: English
    In: Frontiers in Neuroscience, Jan 10, 2019
    Description: Diffuse tumor infiltration into the adjacent parenchyma is an effective dissemination mechanism of brain tumors. We have previously developed correlated high field magnetic resonance imaging and ultramicroscopy (MR-UM) to study neonangiogenesis in a glioma model. In the present study we used MR-UM to investigate tumor infiltration and neoangiogenesis in a translational approach. We compare infiltration and neoangiogenesis patterns in four brain tumor models and the human disease: whereas the U87MG glioma model resembles brain metastases with an encapsulated growth and extensive neoangiogenesis, S24 experimental gliomas mimic IDH1 wildtype glioblastomas, exhibiting infiltration into the adjacent parenchyma and along white matter tracts to the contralateral hemisphere. MR-UM resolves tumor infiltration and neoangiogenesis longitudinally based on the expression of fluorescent proteins, intravital dyes or endogenous contrasts. Our study demonstrates the huge morphological diversity of brain tumor models regarding their infiltrative and neoangiogenic capacities and further establishes MR-UM as a platform for translational neuroimaging.
    Keywords: Brain Tumors -- Diagnosis ; Brain Tumors -- Development And Progression
    ISSN: 1662-453X
    ISSN: 16624548
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  • 9
    Language: English
    In: Atmospheric Chemistry and Physics, May 20, 2016, Vol.16(10), p.6153
    Description: About 70#xE2;#x80;#xAF;% of the anthropogenic carbon dioxide (CO.sub.2) is emitted from the megacities and urban areas of the world. In order to draw effective emission mitigation policies for combating future climate change as well as independently validating the emission inventories for constraining their large range of uncertainties, especially over major metropolitan areas of developing countries, there is an urgent need for greenhouse gas measurements over representative urban regions. India is a fast developing country, where fossil fuel emissions have increased dramatically in the last three decades and are predicted to continue to grow further by at least 6#xE2;#x80;#xAF;% per year through to 2025. The CO.sub.2 measurements over urban regions in India are lacking. To overcome this limitation, simultaneous measurements of CO.sub.2 and carbon monoxide (CO) have been made at Ahmedabad, a major urban site in western India, using a state-of-the-art laser-based cavity ring down spectroscopy technique from November 2013 to May 2015. These measurements enable us to understand the diurnal and seasonal variations in atmospheric CO.sub.2 with respect to its sources (both anthropogenic and biospheric) and biospheric sinks. The observed annual average concentrations of CO.sub.2 and CO are 413.0#xE2;#x80;#xAF;#xC2;#xB1;#xE2;#x80;#xAF;13.7 and 0.50#xE2;#x80;#xAF;#xC2;#xB1;#xE2;#x80;#xAF;0.37#xE2;#x80;#xAF;ppm respectively. Both CO.sub.2 and CO show strong seasonality with lower concentrations (400.3#xE2;#x80;#xAF;#xC2;#xB1;#xE2;#x80;#xAF;6.8 and 0.19#xE2;#x80;#xAF;#xC2;#xB1;#xE2;#x80;#xAF;0.13#xE2;#x80;#xAF;ppm) during the south-west monsoon and higher concentrations (419.6#xE2;#x80;#xAF;#xC2;#xB1;#xE2;#x80;#xAF;22.8 and 0.72#xE2;#x80;#xAF;#xC2;#xB1;#xE2;#x80;#xAF;0.68#xE2;#x80;#xAF;ppm) during the autumn (SON) season. Strong diurnal variations are also observed for both the species. The common factors for the diurnal cycles of CO.sub.2 and CO are vertical mixing and rush hour traffic, while the influence of biospheric fluxes is also seen in the CO.sub.2 diurnal cycle. Using CO and CO.sub.2 covariation, we differentiate the anthropogenic and biospheric components of CO.sub.2 and found significant contributions of biospheric respiration and anthropogenic emissions in the late night (00:00-05:00#xE2;#x80;#xAF;h, IST) and evening rush hours (18:00-22:00#xE2;#x80;#xAF;h) respectively. We compute total yearly emissions of CO to be 69.2#xE2;#x80;#xAF;#xC2;#xB1;#xE2;#x80;#xAF;0.07#xE2;#x80;#xAF;Gg for the study region using the observed CO#xE2;#x80;#xAF;:#xE2;#x80;#xAF;CO.sub.2 correlation slope and bottom-up CO.sub.2 emission inventory. This calculated emission of CO is 52#xE2;#x80;#xAF;% larger than the estimated emission of CO by the emissions database for global atmospheric research (EDGAR) inventory. The observations of CO.sub.2 have been compared with an atmospheric chemistry-transport model (ACTM), which incorporates various components of CO.sub.2 fluxes. ACTM is able to capture the basic variabilities, but both diurnal and seasonal amplitudes are largely underestimated compared to the observations. We attribute this underestimation by the model to uncertainties in terrestrial biosphere fluxes and coarse model resolution. The fossil fuel signal from the model shows fairly good correlation with observed CO.sub.2 variations, which supports the overall dominance of fossil fuel emissions over the biospheric fluxes in this urban region.
    Keywords: Carbon Dioxide ; Atmospheric Chemistry ; Global Temperature Changes ; Fossil Fuels ; Developing Countries ; Greenhouse Gases ; Air Pollution
    ISSN: 1680-7316
    ISSN: 16807324
    E-ISSN: 16807324
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