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Duplissy, Jonathan ; Enghoff, Martin Bødker ; Aplin, Karen L. ; Arnold, Frank ; Aufmhoff, Heinfried ; Avngaard, Michael ; Baltensperger, Urs ; Bondo, Torsten ; Bingham, Robert ; Carslaw, Kenneth S. ; Curtius, Joachim ; David, André ; Fastrup, Bent ; Gagné, Stéphanie ; Hahn, F. ; Harrison, R. Giles ; Kellett, Barry ; Kirkby, Jasper ; Kulmala, Markku ; Laakso, Lauri ; Laaksonen, Ari ; Lillestol, Egil ; Lockwood, Michael ; Mäkelä, Jyrki ; Makhmutov, Vladimir ; Marsh, Nigel D. ; Nieminen, Tuomo ; Onnela, Antti ; Pedersen, E. ; Pedersen, Jens Olaf Pepke ; Polny, Josef ; Reichl, Ulrike ; Seinfeld, John H. ; Sipilä, Mikko ; Stozhkov, Yuri ; Stratmann, Frank ; Svensmark, Henrik ; Svensmark, J. ; Veenhof, Rob ; Verheggen, Bart ; Viisanen, Yrjö ; Wagner, Paul E. ; Wehrle, Günther ; Weingartner, Ernest ; Wex, Heike ; Wilhelmsson, Mats ; Winkler, Paul M.
During a 4-week run in October–November 2006, a pilot experiment was performed at the CERN Proton Synchrotron in preparation for the CLOUD1 experiment, whose aim is to study the possible influence of cosmic rays on clouds. The purpose of the pilot experiment was firstly to carry out exploratory measurements of the effect of ionising particle radiation on aerosol formation from trace H2SO4 vapour and secondly to provide technical input for the CLOUD design. A total of 44 nucleation bursts were produced and recorded, with formation rates of particles above the 3 nm detection threshold of between 0.1 and 100 cm−3s−1, and growth rates between 2 and 37 nm h−1. The corresponding H2SO4 concentrations were typically around 106 cm−3 or less. The experimentally-measured formation rates and H2SO4 concentrations are comparable to those found in the atmosphere, supporting the idea that sulphuric acid is involved in the nucleation of atmospheric aerosols. However, sulphuric acid alone is not able to explain the observed rapid growth rates, which suggests the presence of additional trace vapours in the aerosol chamber, whose identity is unknown. By analysing the charged fraction, a few of the aerosol bursts appear to have a contribution from ion-induced nucleation and ion-ion recombination to form neutral clusters. Some indications were also found for the accelerator beam timing and intensity to influence the aerosol particle formation rate at the highest experimental SO2 concentrations of 6 ppb, although none was found at lower concentrations. Overall, the exploratory measurements provide suggestive evidence for ion-induced nucleation or ion-ion recombination as sources of aerosol particles. However in order to quantify the conditions under which ion processes become significant, improvements are needed in controlling the experimental variables and in the reproducibility of the experiments. Finally, concerning technical aspects, the most important lessons for the CLOUD design include the stringent requirement of internal cleanliness of the aerosol chamber, as well as maintenance of extremely stable temperatures (variations below 0.1°C).
Duplissy, Jonathan ; Enghoff, Martin Bødker ; Aplin, Karen L. ; Arnold, Frank ; Aufmhoff, Heinfried ; Avngaard, Michael ; Baltensperger, Urs ; Bondo, Torsten ; Bingham, Robert ; Carslaw, Kenneth S. ; Curtius, Joachim ; David, André ; Fastrup, Bent ; Gagné, Stéphanie ; Hahn, F. ; Harrison, R. Giles ; Kellett, Barry ; Kirkby, Jasper ; Kulmala, Markku ; Laakso, Lauri ; Laaksonen, Ari ; Lillestol, Egil ; Lockwood, Michael ; Mäkelä, Jyrki ; Makhmutov, Vladimir ; Marsh, Nigel D. ; Nieminen, Tuomo ; Onnela, Antti ; Pedersen, E. ; Pedersen, Jens Olaf Pepke ; Polny, Josef ; Reichl, Ulrike ; Seinfeld, John H. ; Sipilä, Mikko ; Stozhkov, Yuri ; Stratmann, Frank ; Svensmark, Henrik ; Svensmark, J. ; Veenhof, Rob ; Verheggen, Bart ; Viisanen, Yrjö ; Wagner, Paul E. ; Wehrle, Günther ; Weingartner, Ernest ; Wex, Heike ; Wilhelmsson, Mats ; Winkler, Paul M.
During a 4-week run in October–November 2006, a pilot experiment was performed at the CERN Proton Synchrotron in preparation for the Cosmics Leaving OUtdoor Droplets (CLOUD) experiment, whose aim is to study the possible influence of cosmic rays on clouds. The purpose of the pilot experiment was firstly to carry out exploratory measurements of the effect of ionising particle radiation on aerosol formation from trace H2SO4 vapour and secondly to provide technical input for the CLOUD design. A total of 44 nucleation bursts were produced and recorded, with formation rates of particles above the 3 nm detection threshold of between 0.1 and 100 cm -3 s -1, and growth rates between 2 and 37 nm h -1. The corresponding H2O concentrations were typically around 106 cm -3 or less. The experimentally-measured formation rates and htwosofour concentrations are comparable to those found in the atmosphere, supporting the idea that sulphuric acid is involved in the nucleation of atmospheric aerosols. However, sulphuric acid alone is not able to explain the observed rapid growth rates, which suggests the presence of additional trace vapours in the aerosol chamber, whose identity is unknown. By analysing the charged fraction, a few of the aerosol bursts appear to have a contribution from ion-induced nucleation and ion-ion recombination to form neutral clusters. Some indications were also found for the accelerator beam timing and intensity to influence the aerosol particle formation rate at the highest experimental SO2 concentrations of 6 ppb, although none was found at lower concentrations. Overall, the exploratory measurements provide suggestive evidence for ion-induced nucleation or ion-ion recombination as sources of aerosol particles. However in order to quantify the conditions under which ion processes become significant, improvements are needed in controlling the experimental variables and in the reproducibility of the experiments. Finally, concerning technical aspects, the most important lessons for the CLOUD design include the stringent requirement of internal cleanliness of the aerosol chamber, as well as maintenance of extremely stable temperatures (variations below 0.1 °C)
Mourão-Miranda, Janaina ; Hardoon, David Roi ; Hahn, Tim ; Marquand, Andre F. ; Williams, Steve C. R. ; Shawe-Taylor, John ; Brammer, Michael
Pattern recognition approaches, such as the Support Vector Machine (SVM), have been successfully used to classify groups of individuals based on their patterns of brain activity or structure. However these approaches focus on finding group differences and are not applicable to situations where one is interested in accessing deviations from a specific class or population. In the present work we propose an application of the one-class SVM (OC-SVM) to investigate if patterns of fMRI response to sad facial expressions in depressed patients would be classified as outliers in relation to patterns of healthy control subjects. We defined features based on whole brain voxels and anatomical regions. In both cases we found a significant correlation between the OC-SVM predictions and the patients' Hamilton Rating Scale for Depression (HRSD), i.e. the more depressed the patients were the more of an outlier they were. In addition the OC-SVM split the patient groups into two subgroups whose membership was associated with future response to treatment. When applied to region-based features the OC-SVM classified 52% of patients as outliers. However among the patients classified as outliers 70% did not respond to treatment and among those classified as non-outliers 89% responded to treatment. In addition 89% of the healthy controls were classified as non-outliers.
Survival according to BRAF-V600 tumor mutations : an analysis of 437 patients with primary melanoma
(2014)
Meckbach, Diana ; Bauer, Jürgen ; Pflugfelder, Annette ; Meier, Friedegund ; Busch, Christian ; Eigentler, Thomas Kurt ; Capper, David ; Deimling, Andreas von ; Mittelbronn, Michel Guy André ; Perner, Sven ; Ikenberg, Kristian ; Hantschke, Markus ; Büttner, Petra ; Garbe, Claus ; Weide, Benjamin
The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease-free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant-metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies.
Mäder, Lisa ; Blank, Anna-Eva ; Capper, David ; Jansong, Janina ; Baumgarten, Peter ; Wirsik, Naita M. ; Zachskorn, Cornelia ; Ehlers, Jakob ; Seifert, Michael ; Klink, Barbara ; Liebner, Stefan ; Niclou, Simone P. ; Naumann, Ulrike ; Harter, Patrick Nikolaus ; Mittelbronn, Michel Guy André
Epithelial-to-mesenchymal transition (EMT) is supposed to be responsible for increased invasion and metastases in epithelial cancer cells. The activation of EMT genes has further been proposed to be important in the process of malignant transformation of primary CNS tumors. Since the cellular source and clinical impact of EMT factors in primary CNS tumors still remain unclear, we aimed at deciphering their distribution in vivo and clinico-pathological relevance in human gliomas.
We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR-amplification, IDH-1 (R132H) mutation and 1p/19q LOH. Furthermore, transcriptional cluster and survival analyses were performed.
Our data illustrate that SLUG and TWIST are overexpressed in gliomas showing vascular proliferation such as pilocytic astrocytomas and glioblastomas. EMT factors are exclusively expressed by non-neoplastic pericytes/vessel-associated mural cells (VAMCs). They are not associated with patient survival but correlate with pericytic/VAMC genes in glioblastoma cluster analysis.
In summary, the upregulation of EMT genes in pilocytic astrocytomas and glioblastomas reflects the level of activation of pericytes/VAMCs in newly formed blood vessels. Our results underscore that the negative prognostic potential of the EMT signature in the group of diffuse gliomas of WHO grade II-IV does most likely not derive from glioma cells but rather reflects the degree of proliferating mural cells thereby constituting a potential target for future alternative treatment approaches.
EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors
(2018)
Dudvarski Stanković, Nevenka ; Bicker, Frank ; Keller, Stefanie ; Jones, David T. W. ; Harter, Patrick Nikolaus ; Kienzle, Arne ; Gillmann, Clarissa ; Arnold, Philipp ; Golebiewska, Anna ; Keunen, Olivier ; Giese, Alf ; Deimling, Andreas von ; Bäuerle, Tobias ; Niclou, Simone P. ; Mittelbronn, Michel Guy André ; Ye, Weilan ; Pfister, Stefan ; Schmidt, Mirko Hans Heinrich
Glioblastoma (GBM) is a typically lethal type of brain tumor with a median survival of 15 months postdiagnosis. This negative prognosis prompted the exploration of alternative treatment options. In particular, the reliance of GBM on angiogenesis triggered the development of anti‐VEGF (vascular endothelial growth factor) blocking antibodies such as bevacizumab. Although its application in human GBM only increased progression‐free periods but did not improve overall survival, physicians and researchers still utilize this treatment option due to the lack of adequate alternatives. In an attempt to improve the efficacy of anti‐VEGF treatment, we explored the role of the egfl7 gene in malignant glioma. We found that the encoded extracellular matrix protein epidermal growth factor‐like protein 7 (EGFL7) was secreted by glioma blood vessels but not glioma cells themselves, while no major role could be assigned to the parasitic miRNAs miR‐126/126*. EGFL7 expression promoted glioma growth in experimental glioma models in vivo and stimulated tumor vascularization. Mechanistically, this was mediated by an upregulation of integrin α5β1 on the cellular surface of endothelial cells, which enhanced fibronectin‐induced angiogenic sprouting. Glioma blood vessels that formed in vivo were more mature as determined by pericyte and smooth muscle cell coverage. Furthermore, these vessels were less leaky as measured by magnetic resonance imaging of extravasating contrast agent. EGFL7‐inhibition using a specific blocking antibody reduced the vascularization of experimental gliomas and increased the life span of treated animals, in particular in combination with anti‐VEGF and the chemotherapeutic agent temozolomide. Data allow for the conclusion that this combinatorial regimen may serve as a novel treatment option for GBM.
Schleinkofer, Nicolai ; Raddatz, Jacek ; Freiwald, André ; Evans, David ; Beuck, Lydia ; Rüggeberg, Andres ; Liebetrau, Volker
Here we present a comprehensive attempt to correlate aragonitic Na∕Ca ratios from Desmophyllum pertusum (formerly known as Lophelia pertusa), Madrepora oculata and a caryophylliid cold-water coral (CWC) species with different seawater parameters such as temperature, salinity and pH. Living CWC specimens were collected from 16 different locations and analyzed for their Na∕Ca ratios using solution-based inductively coupled plasma-optical emission spectrometry (ICP-OES) measurements.
The results reveal no apparent correlation with salinity (30.1–40.57 g kg−1) but a significant inverse correlation with temperature (−0.31±0.04 mmolmol−1∘C−1). Other marine aragonitic organisms such as Mytilus edulis (inner aragonitic shell portion) and Porites sp. exhibit similar results highlighting the consistency of the calculated CWC regressions. Corresponding Na∕Mg ratios show a similar temperature sensitivity to Na∕Ca ratios, but the combination of two ratios appears to reduce the impact of vital effects and domain-dependent geochemical variation. The high degree of scatter and elemental heterogeneities between the different skeletal features in both Na∕Ca and Na∕Mg, however, limit the use of these ratios as a proxy and/or make a high number of samples necessary. Additionally, we explore two models to explain the observed temperature sensitivity of Na∕Ca ratios for an open and semi-enclosed calcifying space based on temperature-sensitive Na- and Ca-pumping enzymes and transport proteins that change the composition of the calcifying fluid and consequently the skeletal Na∕Ca ratio.
Schleinkofer, Nicolai ; Raddatz, Jacek ; Freiwald, André ; Evans, David ; Beuck, Lydia ; Rüggeberg, Andres ; Liebetrau, Volker
Here we present a comprehensive attempt to correlate aragonitic Na / Ca ratios from Lophelia pertusa, Madrepora oculata and a caryophylliid cold-water coral (CWC) species with different seawater parameters such as temperature, salinity and pH. Living CWC specimens were collected from 16 different locations and analyzed for their Na / Ca content using solution-based inductively coupled plasma-optical emission spectrometry (ICP-OES) measurements. The results reveal no apparent correlation with salinity (30.1–40.57 g/kg) but a significant inverse correlation with temperature (−0.31 mmol/mol/°C). Other marine aragonitic organisms such as Mytilus edulis (inner aragonitic shell portion) and Porites sp. exhibit similar results highlighting the consistency of the calculated CWC regressions. Corresponding Na / Mg ratios show a similar temperature sensitivity to Na / Ca ratios, but the combination of two ratios appear to reduce the impact of vital effects and domain-dependent geochemical variation. The high degree of scatter and elemental heterogeneities between the different skeletal features in both Na / Ca and Na / Mg however limit the use of these ratios as a proxy and/or make a high number of samples necessary. Additionally, we explore two models to explain the observed temperature sensitivity of Na / Ca ratios for an open and semi-enclosed calcifying space based on temperature sensitive Na and Ca pumping enzymes and transport proteins that change the composition of the calcifying fluid and consequently the skeletal Na / Ca ratio.
Torres-Odio, Sylvia ; Key, Jana ; Höpken, Hans-Hermann ; Canet Pons, Júlia ; Valek, Lucie ; Roller, Bastian ; Walter, Michael ; Morales-Gordo, Blas ; Meierhofer, David ; Harter, Patrick Nikolaus ; Mittelbronn, Michel Guy André ; Tegeder, Irmgard ; Gispert, Suzana ; Auburger, Georg
Background: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types.
Methods: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts.
Results: In a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”. Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3, and Nfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance. Immunohistochemistry showed pronounced cellular response of Iba1-positive microglia and GFAP-positive astrocytes; brain lipidomics observed increases of ceramides as neuroinflammatory signs at old age.
In a second approach, we assessed PINK1 deficiency in the presence of a stressor. Marked dysregulations of microbial defense factors Ifit3 and Rsad2 were consistently observed upon five analyses: (1) Pink1 −/− primary neurons in the first weeks after brain dissociation, (2) aged Pink1 −/− midbrain with transgenic A53T-alpha-synuclein overexpression, (3) human neuroblastoma cells with PINK1-knockdown and murine Pink1 −/− embryonal fibroblasts undergoing acute starvation, (4) triggering mitophagy in these cells with trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP), and (5) subjecting them to pathogenic RNA-analogue poly(I:C). The stress regulation of MAVS, RSAD2, DDX58, IFIT3, IFIT1, and LRRK2 was PINK1 dependent. Dysregulation of some innate immunity genes was also found in skin fibroblast cells from PARK6 patients.
Conclusions: Thus, an individual biomarker with expression correlating to progression was not identified. Instead, more advanced disease stages involved additional pathways. Hence, our results identify PINK1 deficiency as an early modulator of innate immunity in neurons, which precedes late stages of neuroinflammation during alpha-synuclein spreading.
Ilina, Elena ; Armento, Angela ; Sanchez, Leticia ; Reichlmeir, Marina ; Braun, Yannick ; Penski, Cornelia ; Capper, David ; Sahm, Felix ; Jennewein, Lukas ; Harter, Patrick Nikolaus ; Zukunft, Sven ; Fleming, Ingrid ; Schulte, Dorothea ; Guerroué, Francois ; Behrends, Christian ; Ronellenfitsch, Michael Wilfried ; Naumann, Ulrike ; Mittelbronn, Michel Guy André
Carboxypeptidase E (CPE) has recently been described as a multifunctional protein that regulates proliferation, migration and survival in several tumor entities. In glioblastoma (GBM), the most malignant primary brain tumor, secreted CPE (sCPE) was shown to modulate tumor cell migration. In our current study, we aimed at clarifying the underlying molecular mechanisms regulating anti-migratory as well as novel metabolic effects of sCPE in GBM. Here we show that sCPE activates mTORC1 signaling in glioma cells detectable by phosphorylation of its downstream target RPS6. Additionally, sCPE diminishes glioma cell migration associated with a negative regulation of Rac1 signaling via RPS6, since both inhibition of mTOR and stimulation of Rac1 results in a reversed effect of sCPE on migration. Knockdown of CPE leads to a decrease of active RPS6 associated with increased GBM cell motility. Apart from this, we show that sCPE enhances glucose flux into the tricarboxylic acid cycle at the expense of lactate production, thereby decreasing aerobic glycolysis, which might as well contribute to a less invasive behavior of tumor cells. Our data contributes to a better understanding of the complexity of GBM cell migration and sheds new light on how tumor cell invasion and metabolic plasticity are interconnected.