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Schnitzbauer, Andreas ; Zuelke, Carl ; Graeb, Christian ; Rochon, Justine ; Bilbao, Itxarone ; Burra, Patrizia ; de Jong, Koert P. ; Duvoux, Christophe ; Kneteman, Norman M. ; Adam, Rene ; Bechstein, Wolf Otto ; Becker, Thomas ; Beckebaum, Susanne ; Chazouilleres, Olivier ; Cillo, Umberto ; Colledan, Michele ; Fandrich, Fred ; Gugenheim, Jean ; Hauss, Johann P. ; Heise, Michael ; Hidalgo, Ernest ; Jamieson, Neville ; Königsrainer, Alfred ; Lamby, Philipp E. ; Lerut, Jan P. ; Makisalo, Heikki ; Margreiter, Raimund ; Mazzaferro, Vincenzo ; Mutzbauer, Ingrid ; Otto, Gerd ; Pageaux, Georges-Philippe ; Pinna, Antonio D. ; Pirenne, Jacques ; Rizell, Magnus ; Rossi, Giorgio ; Rostaing, Lionel ; Roy, Andre ; Turrion, Victor Sanchez ; Schmidt, Jan ; Troisi, Roberto I. ; Hoek, Bart van ; Valente, Umberto ; Wolf, Philippe ; Wolters, Heiner ; Mirza, Darius F. ; Scholz, Tim ; Steininger, Rudolf ; Soderdahl, Gunnar ; Strasser, Simone I. ; Jauch, Karl-Walter ; Neuhaus, Peter ; Schlitt, Hans J. ; Geissler, Edward K.
Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. Methods: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 3-year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. (trial registered at www.clinicaltrials.gov: NCT00355862) (EudraCT Number: 2005-005362-36)
On the observation of mesospheric air inside the arctic stratospheric polar vortex in early 2003
(2005)
Engel, Andreas ; Möbius, Tanja ; Haase, Hans-Peter ; Bönisch, Harald ; Wetter, Thomas ; Schmidt, Ulrich ; Levin, Ingeborg ; Reddmann, Thomas ; Oelhaf, Hermann ; Wetzel, Gerald ; Grunow, Katja ; Huret, Nathalie ; Pirre, Michel
During several balloon flights inside the Arctic polar vortex in early 2003, unusual trace gas distributions were observed, which indicate a strong influence of mesospheric air in the stratosphere. The tuneable diode laser (TDL) instrument SPIRALE (Spectroscopie InFrarouge par Absorption de Lasers Embarqués) measured unusually high CO values (up to 600 ppb) on 27 January at about 30 km altitude. The cryosampler BONBON sampled air masses with very high molecular Hydrogen, extremely low SF6 and enhanced CO values on 6 March at about 25 km altitude. Finally, the MIPAS (Michelson Interferometer for Passive Atmospheric Sounding) Fourier Transform Infra-Red (FTIR) spectrometer showed NOy values which are significantly higher than NOy* (the NOy derived from a correlation between N2O and NOy under undisturbed conditions), on 21 and 22 March in a layer centred at 22 km altitude. Thus, the mesospheric air seems to have been present in a layer descending from about 30 km in late January to 25 km altitude in early March and about 22 km altitude on 20 March. We present corroborating evidence from a model study using the KASIMA (KArlsruhe Simulation model of the Middle Atmosphere) model that also shows a layer of mesospheric air, which descended into the stratosphere in November and early December 2002, before the minor warming which occurred in late December 2002 lead to a descent of upper stratospheric air, cutting of a layer in which mesospheric air is present. This layer then descended inside the vortex over the course of the winter. The same feature is found in trajectory calculations, based on a large number of trajectories started in the vicinity of the observations on 6 March. Based on the difference between the mean age derived from SF6 (which has an irreversible mesospheric loss) and from CO2 (whose mesospheric loss is much smaller and reversible) we estimate that the fraction of mesospheric air in the layer observed on 6 March, must have been somewhere between 35% and 100%.
Harbeck, Nadia ; Saupe, Steffen ; Jäger, Elke ; Schmidt, Marcus ; Kreienberg, Rolf ; Müller, Lothar ; Otremba, Burkhard ; Waldenmaier, Dirk ; Dorn, Julia ; Warm, Mathias ; Scholz, Michael ; Untch, Michael ; Wit, Maike de ; Barinoff, Jana ; Lück, Hans-Joachim ; Harter, Philipp ; Augustin, Doris ; Harnett, Paul ; Beckmann, Matthias Wilhelm ; Batran, Salah-Eddin al-
Purpose: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).
Methods: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).
Results: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).
Conclusion: Both PLD and capecitabine are effective first-line agents for MBC.
Wienen-Schmidt, Barbara ; Jonker, Hendrik R. A. ; Wulsdorf, Tobias ; Gerber, Hans-Dieter ; Saxena, Krishna ; Kudlinzki, Denis ; Sreeramulu, Sridhar ; Parigi, Giacomo ; Luchinat, Claudio ; Heine, Andreas ; Schwalbe, Harald ; Klebe, Gerhard
Biophysical parameters can accelerate drug development; e.g., rigid ligands may reduce entropic penalty and improve binding affinity. We studied systematically the impact of ligand rigidification on thermodynamics using a series of fasudil derivatives inhibiting protein kinase A by crystallography, isothermal titration calorimetry, nuclear magnetic resonance, and molecular dynamics simulations. The ligands varied in their internal degrees of freedom but conserve the number of heteroatoms. Counterintuitively, the most flexible ligand displays the entropically most favored binding. As experiment shows, this cannot be explained by higher residual flexibility of ligand, protein, or formed complex nor by a deviating or increased release of water molecules upon complex formation. NMR and crystal structures show no differences in flexibility and water release, although strong ligand-induced adaptations are observed. Instead, the flexible ligand entraps more efficiently water molecules in solution prior to protein binding, and by release of these waters, the favored entropic binding is observed.
Reichert, Carolin F. ; Maire, Micheline ; Gabel, Virginie ; Hofstetter, Marcel ; Viola, Antoine U. ; Kolodyazhniy, Vitaliy ; Strobel, Werner ; Goetz, Thomas ; Bachmann, Valérie ; Landolt, Hans-Peter ; Cajochen, Christian ; Schmidt, Christina
Sleep is regulated in a time-of-day dependent manner and profits working memory. However, the impact of the circadian timing system as well as contributions of specific sleep properties to this beneficial effect remains largely unexplored. Moreover, it is unclear to which extent inter-individual differences in sleep-wake regulation depend on circadian phase and modulate the association between sleep and working memory. Here, sleep electroencephalography (EEG) was recorded during a 40-h multiple nap protocol, and working memory performance was assessed by the n-back task 10 times before and after each scheduled nap sleep episode. Twenty-four participants were genotyped regarding a functional polymorphism in adenosine deaminase (rs73598374, 12 G/A-, 12 G/G-allele carriers), previously associated with differences in sleep-wake regulation. Our results indicate that genotype-driven differences in sleep depend on circadian phase: heterozygous participants were awake longer and slept less at the end of the biological day, while they exhibited longer non rapid eye movement (NREM) sleep and slow wave sleep concomitant with reduced power between 8–16 Hz at the end of the biological night. Slow wave sleep and NREM sleep delta EEG activity covaried positively with overall working memory performance, independent of circadian phase and genotype. Moreover, REM sleep duration benefitted working memory particularly when occurring in the early morning hours and specifically in heterozygous individuals. Even though based on a small sample size and thus requiring replication, our results suggest genotype-dependent differences in circadian sleep regulation. They further indicate that REM sleep, being under strong circadian control, boosts working memory performance according to genotype in a time-of-day dependent manner. Finally, our data provide first evidence that slow wave sleep and NREM sleep delta activity, majorly regulated by sleep homeostatic mechanisms, is linked to working memory independent of the timing of the sleep episode within the 24-h cycle.
Blood vessels form de novo through the tightly regulated programs of vasculogenesis and angiogenesis. Both processes are distinct but one of the steps they share is the formation of a central lumen, when groups of cells organized as vascular cords undergo complex changes to achieve a tube-like morphology. Recently, a protein termed epidermal growth factor-like domain 7 (EGFL7) was described as a novel endothelial cell-derived factor involved in the regulation of the spatial arrangement of cells during vascular tube assembly. With its impact on tubulogenesis and vessel shape EGFL7 joined the large family of molecules governing blood vessel formation. Only recently, the molecular mechanisms underlying EGFL7's effects have been started to be elucidated and shaping of the extracellular matrix (ECM) as well as Notch signaling might very well play a role in mediating its biological effects. Further, findings in knock-out animal models suggest miR-126, a miRNA located within the egfl7 gene, has a major role in vessel development by promoting VEGF signaling, angiogenesis and vascular integrity. This review summarizes our current knowledge on EGFL7 and miR-126 and we will discuss the implications of both bioactive molecules for the formation of blood vessels.
Pätz, Hans-Werner ; Volz-Thomas, Andreas ; Hegglin, Michaela I. ; Brunner, Dominik ; Fischer, Herbert ; Schmidt, Ulrich
Two aircraft instruments for the measurement of total odd nitrogen (NOy) were compared side by side aboard a Learjet A35 in April 2003 during a campaign of the AFO2000 project SPURT (Spurengastransport in der Tropopausenregion). The instruments albeit employing the same measurement principle (gold converter and chemiluminescence) had different inlet configurations. The ECO-Physics instrument operated by ETH-Zürich in SPURT had the gold converter mounted outside the aircraft, whereas the instrument operated by FZ-Jülich in the European project MOZAIC III (Measurements of ozone, water vapour, carbon monoxide and nitrogen oxides aboard Airbus A340 in-service aircraft) employed a Rosemount probe with 80 cm of FEP-tubing connecting the inlet to the gold converter. The NOy concentrations during the flight ranged between 0.3 and 3 ppb. The two data sets were compared in a blind fashion and each team followed its normal operating procedures. On average, the measurements agreed within 7%, i.e. within the combined uncertainty of the two instruments. This puts an upper limit on potential losses of HNO3 in the Rosemount inlet of the MOZAIC instrument. Larger transient deviations were observed during periods after calibrations and when the aircraft entered the stratosphere. The time lag of the MOZAIC instrument observed in these instances is in accordance with the time constant of the MOZAIC inlet line determined in the laboratory for HNO3.
Pätz, Hans-Werner ; Volz-Thomas, Andreas ; Hegglin, Michaela I. ; Brunner, Dominik ; Fischer, Herbert ; Schmidt, Ulrich
Two aircraft instruments for the measurement of total odd nitrogen (NOy) were compared side by side aboard a Learjet A35 in April 2003 during a campaign of the AFO2000 project SPURT (Spurengastransport in der Tropopausenregion). The instruments albeit employing the same measurement principle (gold converter and chemiluminescence) had different inlet configurations. The ECO-Physics instrument operated by ETH-Zürich in SPURT had the gold converter mounted outside the aircraft, whereas the instrument operated by FZ-Jülich in the European project MOZAIC III (Measurements of ozone, water vapour, carbon monoxide and nitrogen oxides aboard Airbus A340 in-service aircraft) employed a Rosemount probe with 80 cm of FEP-tubing connecting the inlet to the gold converter. The NOy concentrations during the flight ranged between 0.3 and 3 ppb. The two data sets were compared in a blind fashion and each team followed its normal operating procedures. On average, the measurements agreed within 6%, i.e. within the combined uncertainty of the two instruments. This puts an upper limit on potential losses of HNO3 in the Rosemount inlet of the MOZAIC instrument. Larger transient deviations were observed during periods after calibrations and when the aircraft entered the stratosphere. The time lag of the MOZAIC instrument observed in these instances is in accordance with the time constant of the MOZAIC inlet line determined in the laboratory for HNO3.
Background: Although childhood sexual and/or physical abuse (CSA/CPA) is known to have severe psychopathological consequences, there is little evidence on psychotherapeutic interventions for adolescents and young adults suffering from post-traumatic stress disorder (PTSD). Equally sparse are data on moderators of treatment response on PTSD-related epigenetic changes, health care costs and loss of productivity, alterations in cognitive processing, and on how successful interventions affect all of these factors. Early treatment may prevent later (co)morbidity. In this paper, we present a study protocol for the evaluation of a newly developed psychotherapeutic manual for PTSD after CSA/CPA in adolescents and young adults – the Developmentally Adapted Cognitive Processing Therapy (D-CPT).
Methods/design: In a multicenter randomized controlled trial (RCT) D-CPT is compared to treatment as usual (TAU). A sample of 90 adolescent outpatients aged 14 to 21 years will be randomized to one of these conditions. Four assessments will be carried out at baseline, at end of treatment, and 3 and 6 months after end of therapy. Each time, patients will be assessed via clinical interviews and a wide range of questionnaires. In addition to PTSD symptoms and comorbidities, we will evaluate moderators of treatment response, epigenetic profiles, direct and indirect costs of this disorder, and neurophysiological processing of threat cues in PTSD and their respective changes in the course of these two treatments (D-CPT and TAU).
Discussion: The study will provide new insights in the understudied field of PTSD in adolescents and young adults. A newly developed intervention will be evaluated in this therapeutically underserved population. Results will provide data on treatment efficacy, direct and indirect treatment costs, as well as on associations of treatment outcome and PTSD intensity both to epigenetic profiles and to the neurobiological processing of threat cues. Besides, they will help to learn more about the psychopathology and possible new objective correlates of PTSD.
Trial registration: Germanctr.de identifier: DRKS00004787.
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.
Fischer, Caroline ; Endle, Heiko ; Schumann, Lana ; Wilken-Schmitz, Annett ; Kaiser, Julia ; Gerber, Susanne ; Vogelaar, Christina F. ; Schmidt, Mirko Hans Heinrich ; Nitsch, Robert ; Snodgrass, Isabel ; Thomas, Dominique Jeanette ; Vogt, Johannes ; Tegeder, Irmgard
Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2−/− mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2−/− mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2−/− mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2−/− mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2−/− were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2−/− phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions.
Göbel, Kathrin ; Heil, Michael ; Bott, Lukas ; Brandenburg, Leonard ; Caesar, Christoph ; Deuter, Isabell ; Grein, Alexander ; Keliç-Heil, Aleksandra ; Körper, Daniel ; Löher, Bastian ; Reifarth, René ; Savran, Deniz ; Schulte, Hendrik ; Simon, Haik ; Törnqvist, Hans Toshihide ; Almusidi, Tahani ; Álvarez-Pol, Héctor ; Atkins, Liam ; Aumann, Thomas ; Bemmerer, Daniel ; Benlliure Anaya, Jose Fernando ; Boretzky, Konstanze ; Brückner, Benjamin ; Cabanelas Eiras, Pablo ; Casarejos Ruiz, Enrique ; Cederkäll, Joakim ; Chulkov, Leonid V. ; Cortina Gil, Dolores ; Danilov, Andrey ; Erbacher, Philipp ; Escribano Rodriguez, Sonia ; Fülöp, Zsolt ; Falduto, Ashton ; Fiebiger, Stefan ; Gašparić, Igor ; Garcia Borge, Maria José ; Gernhäuser, Roman ; Glorius, Jan ; Gonzales Caamaño, David ; Hartig, Anna-Lena ; Heftrich, Tanja ; Heggen, Henning ; Heine, Marcel ; Heinz, Andreas ; Hensel, Thomas ; Holl, Matthias ; Johansson, Håkan T. ; Jonson, Björn ; Kalantar-Nayestanaki, Nasser ; Kamenyero, Armel ; Khasawneh, Kafa al- ; Kiselev, Oleg A. ; Klenze, Philipp ; Kohls, Marvin ; Kröll, Thorsten ; Kresan, Dmytro ; Kurtulgil, Cem Deniz ; Kurz, Nikolaus ; Langer, Christoph ; Lehr, Christopher ; Litvinov, Yuri A. ; Lorenz, Enis ; Murillo Morales, Silvia ; Nácher González, Enrique ; Nilsson, Thomas ; Park, Joochun ; Paschalis, Stefanos ; Perea Martinez, Angel ; Petri, Marina ; Plag, Ralf ; Ponnath, Lukas ; Popočovski, Romana ; Reich, Markus ; Rhee, Han-Bum ; Rodriguez Sanchez, Jose Luis ; Rossi, Dominic M. ; Scheit, Heiko ; Schmidt, Konrad ; Slavkovská, Zuzana ; Starostin, Viktor ; Storck, Sonja ; Sürder, Christian ; Tanaka, Junki ; Tengblad, Olof ; Thomas, Benedikt ; Typel, Stefan ; Varga, László ; Volk, Klaus ; Volknandt, Meiko ; Wagner, Vadim ; Wamers, Felix ; Weigand, Mario ; Zanetti, Lorenzo
We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(α,γ)16O fusion reaction and to reach lower center-ofmass energies than measured so far.
The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-to-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.
Engel, Andreas ; Möbius, Tanja ; Haase, Hans-Peter ; Bönisch, Harald ; Wetter, Thomas ; Schmidt, Ulrich ; Levin, Ingeborg ; Reddmann, Thomas ; Oelhaf, Hermann ; Wetzel, Gerald ; Grunow, Katja ; Huret, Nathalie ; Pirre, Michel
During several balloon flights inside the Arctic polar vortex in early 2003, unusual trace gas distributions were observed, which indicate a strong influence of mesospheric air in the stratosphere. The tuneable diode laser (TDL) instrument SPIRALE (Spectroscopie InFrarouge par Absorption de Lasers Embarqués) measured unusually high CO values (up to 600 ppb) on 27 January at about 30 km altitude. The cryosampler BONBON sampled air masses with very high molecular Hydrogen, extremely low SF6 and enhanced CO values on 6 March at about 25 km altitude. Finally, the MIPAS (Michelson Interferometer for Passive Atmospheric Sounding) Fourier Transform Infra-Red (FTIR) spectrometer showed NOy values which are significantly higher than NOy* (the NOy derived from a correlation between N2O and NOy under undisturbed conditions), on 21 and 22 March in a layer centred at 22 km altitude. Thus, the mesospheric air seems to have been present in a layer descending from about 30 km in late January to 25 km altitude in early March and about 22 km altitude on 20 March. We present corroborating evidence from a model study using the KASIMA (KArlsruhe Simulation model of the Middle Atmosphere) model that also shows a layer of mesospheric air, which descended into the stratosphere in November and early December 2002, before the minor warming which occurred in late December 2002 lead to a descent of upper stratospheric air, cutting of a layer in which mesospheric air is present. This layer then descended inside the vortex over the course of the winter. The same feature is found in trajectory calculations, based on a large number of trajectories started in the vicinity of the observations on 6 March. Based on the difference between the mean age derived from SF6 (which has an irreversible mesospheric loss) and from CO2 (whose mesospheric loss is much smaller and reversible) we estimate that the fraction of mesospheric air in the layer observed on 6 March, must have been somewhere between 35% and 100%.
The introduction of a common currency as well as the harmonization of rules and regulations in Europe has significantly reduced distance in all its guises. With reduced costs of overcoming space, this emphasizes centripetal forces and it should foster consolidation of financial activity. In a national context, as a rule, this led to the emergence of one financial center. Hence, Europeanization of financial and monetary affairs could foretell the relegation of some European financial hubs such as Frankfurt and Paris to third-rank status. Frankfurt’s financial history is interesting insofar as it has lost (in the 1870s) and regained (mainly in the 1980s) its preeminent place in the German context. Because Europe is still characterized by local pockets of information-sensitive assets as well as a demand for variety the national analogy probably does not hold. There is room in Europe for a number of financial hubs of an international dimension, including Frankfurt.
Slik, J. W. Ferry ; Franklin, Janet ; Arroyo-Rodríguez, Víctor ; Field, Richard ; Aguilar, Salomon ; Aguirre, Nikolay ; Ahumada, Jorge ; Aiba, Shin-Ichiro ; Alves, Luciana F. ; Anitha, Kamalakumari ; Avella, Andres ; Mora, Francisco ; Aymard, Gerardo A. ; Báez, Selene ; Balvanera, Patricia ; Bastian, Meredith L. ; Bastin, Jean-François ; Bellingham, Peter ; van den Berg, Eduardo ; da Conceição Bispo, Polyanna ; Boeckx, Pascal ; Böhning-Gaese, Katrin ; Bongers, Frans ; Boyle, Brad ; Brambach, Fabian ; Brearley, Francis Q. ; Brown, Sandra ; Chai, Shauna-Lee ; Chazdon, Robin L. ; Chen, Shengbin ; Chhang, Phourin ; Chuyong, George ; Ewangog, Corneille ; Coronado, Indiana ; Cristóbal-Azkarate, Jurgi ; Culmsee, Heike ; Damas, Kipiro ; Dattaraja, Handanakere Shivaramaiah ; Davidar, Priya ; DeWalt, Saara J. ; Din, Hazimah ; Drake, Donald R. ; Duque, Alvaro ; Durigan, Giselda ; Eichhorn, Karl ; Schmidt Eler, Eduardo ; Enoki, Tsutomu ; Ensslin, Andreas ; Fandohan, Adandé Belarmain ; Farwig, Nina ; Feeley, Kenneth J. ; Fischer, Markus ; Forshed, Olle ; Garcia, Queila Souza ; Garkoti, Satish Chandra ; Gillespie, Thomas William ; Gillet, Jean-Francois ; Gonmadje, Christelle ; Granzow-de la Cerda, Iñigo ; Griffith, Daniel M. ; Grogan, James ; Hakeem, Khalid Rehman ; Harris, David J. ; Harrison, Rhett D. ; Hector, Andy ; Hemp, Andreas ; Homeier, Jürgen ; Hussain, M. Shah ; Ibarra Manríquez, Guillermo ; Hanum, I. Faridah ; Imai, Nobuo ; Jansen, Patrick A. ; Joly, Carlos Alfredo ; Joseph, Shijo ; Kartawinata, Kuswata ; Kearsley, Elizabeth ; Kelly, Daniel L. ; Kessler, Michael ; Killeen, Timothy J. ; Kooyman, Robert ; Laumonier, Yves ; Laurance, Susan G. ; Laurance, William F. ; Lawes, Michael J. ; Letcher, Susan G. ; Lindsell, Jeremy ; Lovett, Jon ; Lozada, Jose ; Lu, Xinghui ; Lykke, Anne Mette ; Bin Mahmud, Khairil ; Mahayani, Ni Putu Diana ; Mansor, Asyraf ; Marshall, Andrew R. ; Martin, Emanuel H. ; Leal Matos, Darley Calderado ; Meave, Jorge A. ; Melo, Felipe P. L. ; Aguirre Mendoza, Zhofre ; Metali, Faizah ; Medjibe, Vincent P. ; Metzger, Jean Paul ; Metzker, Thiago ; Mohandass, Dharmalingam ; Munguía-Rosas, Miguel A. ; Muñoz, Rodrigo ; Nurtjahy, Eddy ; Lenza de Oliveira, Eddie ; Onrizal, Onrizal ; Parolin, Pia ; Parren, Marc ; Parthasarathy, Narayanaswamy ; Paudel, Ekananda ; Perez, Rolando ; Pérez-García, Eduardo A. ; Pommer, Ulf ; Poorter, Lourens ; Qi, Lan ; F. Piedade, Maria Teresa ; Rodrigues Pinto, José Roberto ; Dalberg Poulsen, Axel ; Poulsen, John R. ; Powers, Jennifer S. ; Prasad, Rama Chandra ; Puyravaud, Jean-Philippe ; Rangel, Orlando ; Reitsma, Jan ; S. B. Rocha, Diogo ; Rolim, Samir ; Rovero, Francesco ; Rozak, Andes ; Ruokolainen, Kalle ; Rutishauser, Ervan ; Rutten, Gemma ; Mohd. Said, Mohd. Nizam ; Saiter, Felipe Z. ; Saner, Philippe ; Santos, Braulio ; dos Santos, João Roberto ; Sarker, Swapan Kumar ; Schmitt, Christine B. ; Schöngart, Jochen ; Schulze, Mark ; Sheil, Douglas ; Sist, Plinio ; Souza, Alexandre F. ; Spironello, Wilson Roberto ; Sposito, Tereza ; Steinmetz, Robert ; Stevart, Tariq ; Suganuma, Marcio Seiji ; Sukri, Rahayu ; Sultana, Aisha ; Sukumar, Raman ; Sunderland, Terry ; Supriyadi, Agus ; Suresh, Hebbalalu S. ; Suzuki, Eizi ; Tabarelli, Marcelo ; Tang, Jianwei ; Tanner, Edmund V. J. ; Targhetta, Natalia ; Theilade, Ida ; Thomas, Duncan ; Timberlake, Jonathan ; de Morisson Valeriano, Márcio ; Valkenburg, Johan van ; Do, Tran Van ; Sam, Hoang Van ; Vandermeer, John H. ; Verbeeck, Hans ; Vetaas, Ole Reidar ; Adekunle, Victor ; Vieira, Simone A. ; Webb, Campbell O. ; Webb, Edward L. ; Whitfeld, Timothy ; Wich, Serge ; Williams, John ; Wiser, Susan ; Wittmann, Florian ; Yang, Xiaobo ; Adou Yao, C. Yves ; Yap, Sandra L. ; Zahawie, Rakan A. ; Zakaria, Rahmad ; Zang, Runguo
Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.
Ziegler, Christiane ; Richter, Jan ; Mahr, Marina ; Gajewska, Agnes ; Schiele, Miriam A. ; Gehrmann, Andrea ; Schmidt, Brad ; Lesch, Klaus-Peter J. ; Lang, Thomas ; Helbig-Lang, Sylvia ; Pauli, Paul ; Kircher, Tilo ; Reif, Andreas ; Rief, Winfried ; Voßbeck-Elsebusch, Anna Nicola ; Arolt, Volker ; Wittchen, Hans-Ulrich ; Hamm, Alfons ; Deckert, Jürgen ; Domschke, Katharina
Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
Borsch, Thomas ; Stevens, Albert-Dieter ; Häffner, Eva ; Güntsch, Anton ; Berendsohn, Walter G. ; Appelhans, Marc Sebastian ; Barilaro, Christina ; Beszteri, Bánk ; Blattner, Frank R. ; Bossdorf, Oliver ; Dalitz, Helmut ; Dressler, Stefan ; Duque-Thüs, Rhinaixa ; Esser, Hans-Joachim ; Franzke, Andreas ; Goetze, Dethardt ; Grein, Michaela ; Grünert, Uta ; Hellwig, Frank ; Hentschel, Jörn ; Hörandl, Elvira ; Janßen, Thomas ; Jürgens, Norbert ; Kadereit, Gudrun ; Karisch, Timm ; Koch, Marcus ; Müller, Frank ; Müller, Jochen ; Ober, Dietrich ; Porembski, Stefan ; Poschlod, Peter ; Printzen, Christian ; Röser, Martin ; Sack, Peter ; Schlüter, Philipp M. ; Schmidt, Marco ; Schnittler, Martin ; Scholler, Markus ; Schultz, Matthias ; Seeber, Elke ; Simmel, Josef ; Stiller, Michael ; Thiv, Mike ; Thüs, Holger ; Tkach, Natalia ; Triebel, Dagmar ; Warnke, Ursula ; Weibulat, Tanja ; Wesche, Karsten ; Yurkov, Andrey ; Zizka, Georg
Plants, fungi and algae are important components of global biodiversity and are fundamental to all ecosystems. They are the basis for human well-being, providing food, materials and medicines. Specimens of all three groups of organisms are accommodated in herbaria, where they are commonly referred to as botanical specimens.The large number of specimens in herbaria provides an ample, permanent and continuously improving knowledge base on these organisms and an indispensable source for the analysis of the distribution of species in space and time critical for current and future research relating to global biodiversity. In order to make full use of this resource, a research infrastructure has to be built that grants comprehensive and free access to the information in herbaria and botanical collections in general. This can be achieved through digitization of the botanical objects and associated data.The botanical research community can count on a long-standing tradition of collaboration among institutions and individuals. It agreed on data standards and standard services even before the advent of computerization and information networking, an example being the Index Herbariorum as a global registry of herbaria helping towards the unique identification of specimens cited in the literature.In the spirit of this collaborative history, 51 representatives from 30 institutions advocate to start the digitization of botanical collections with the overall wall-to-wall digitization of the flat objects stored in German herbaria. Germany has 70 herbaria holding almost 23 million specimens according to a national survey carried out in 2019. 87% of these specimens are not yet digitized. Experiences from other countries like France, the Netherlands, Finland, the US and Australia show that herbaria can be comprehensively and cost-efficiently digitized in a relatively short time due to established workflows and protocols for the high-throughput digitization of flat objects.Most of the herbaria are part of a university (34), fewer belong to municipal museums (10) or state museums (8), six herbaria belong to institutions also supported by federal funds such as Leibniz institutes, and four belong to non-governmental organizations. A common data infrastructure must therefore integrate different kinds of institutions.Making full use of the data gained by digitization requires the set-up of a digital infrastructure for storage, archiving, content indexing and networking as well as standardized access for the scientific use of digital objects. A standards-based portfolio of technical components has already been developed and successfully tested by the Biodiversity Informatics Community over the last two decades, comprising among others access protocols, collection databases, portals, tools for semantic enrichment and annotation, international networking, storage and archiving in accordance with international standards. This was achieved through the funding by national and international programs and initiatives, which also paved the road for the German contribution to the Global Biodiversity Information Facility (GBIF).Herbaria constitute a large part of the German botanical collections that also comprise living collections in botanical gardens and seed banks, DNA- and tissue samples, specimens preserved in fluids or on microscope slides and more. Once the herbaria are digitized, these resources can be integrated, adding to the value of the overall research infrastructure. The community has agreed on tasks that are shared between the herbaria, as the German GBIF model already successfully demonstrates.We have compiled nine scientific use cases of immediate societal relevance for an integrated infrastructure of botanical collections. They address accelerated biodiversity discovery and research, biomonitoring and conservation planning, biodiversity modelling, the generation of trait information, automated image recognition by artificial intelligence, automated pathogen detection, contextualization by interlinking objects, enabling provenance research, as well as education, outreach and citizen science.We propose to start this initiative now in order to valorize German botanical collections as a vital part of a worldwide biodiversity data pool.
Stein, Stefan ; Ott, Marion Gabriele ; Schultze-Straßer, Stephan ; Jauch, Anna ; Burwinkel, Barbara ; Kinner, Andrea ; Schmidt, Manfred ; Krämer, Alwin ; Schwäble, Joachim ; Glimm, Hanno ; Köhl, Ulrike ; Preiss, Carolin ; Ball, Claudia ; Martin, Hans ; Göhring, Gudrun ; Schwarzwaelder, Kerstin ; Hofmann, Wolf-Karsten ; Karakaya, Kadin ; Tchatchou, Sandrine ; Yang, Rongxi ; Reinecke, Petra ; Kühlcke, Klaus ; Schlegelberger, Brigitte ; Thrasher, Adrian J. ; Hoelzer, Dieter ; Seger, Reinhard ; Kalle, Christof von ; Grez, Manuel
Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.
Reifarth, René ; Altstadt, Sebastian ; Göbel, Kathrin ; Heftrich, Tanja ; Heil, Michael ; Koloczek, Alexander ; Langer, Christoph ; Plag, Ralf ; Pohl, M. ; Sonnabend, Kerstin ; Weigand, Mario ; Adachi, T. ; Aksouh, Farouk ; Al-Khalili, J. ; AlGarawi, M. ; AlGhamdi, S. ; Alkhazov, G. ; Alkhomashi, N. ; Alvarez-Pol, Héctor ; Alvarez-Rodriguez, R. ; Andreev, V. ; Andrei, B. ; Atar, Leyla ; Aumann, Thomas ; Avdeichikov, Vladimir ; Bacri, C. ; Bagchi, S. ; Barbieri, Carlo ; Beceiro, Saul ; Beck, C. ; Beinrucker, Clemens ; Belier, Gilbert ; Bemmerer, Daniel ; Bendel, M. ; Benlliure Anaya, Jose Fernando ; Benzoni, G. ; Berjillos, R. ; Bertini, D. ; Bertulani, Carlos A. ; Bishop, S. ; Blasi, N. ; Bloch, T. ; Blumenfeld, Y. ; Bonaccorso, A. ; Boretzky, Konstanze ; Botvina, Alexander ; Boudard, A. ; Boutachkov, P. ; Boztosun, I. ; Bracco, A. ; Brambilla, S. ; Monago, J.Briz ; Caamano, Manuel ; Caesar, Christoph ; Camera, F. ; Casarejos Ruiz, Enrique ; Catford, Wilton N. ; Cederkäll, Joakim ; Cederwall, B. ; Chartier, Marielle ; Chatillon, Audrey ; Cherciu, M. ; Chulkov, Leonid V. ; Coleman-Smith, P. ; Cortina Gil, Dolores ; Crespi, F. ; Crespo, Raquel ; Cresswell, J. ; Csatlós, Margit ; Déchery, F. ; Davids, B. ; Davinson, Thomas ; Derya, Vera ; Detistov, P. ; Díaz Fernández, Paloma ; DiJulio, D. ; Dmitry, S. ; Doré, D. ; Dueñas, J. ; Dupont, Emmeric ; Egelhof, Peter ; Egorova, I. ; Elekes, Zoltán ; Enders, Joachim ; Endres, Janis ; Ershov, S. ; Ershova, Olga ; Fernández Domínguez, Beatriz ; Fetisov, A. ; Fiori, Enrico ; Fomichev, A. ; Fonseca, M. ; Fraile, L. ; Freer, Martin ; Friese, Jürgen ; Garcia Borge, Maria José ; Galaviz Redondo, Daniel ; Gannon, S. ; Garg, U. ; Gašparić, Igor ; Gasques, L. ; Gastineau, B. ; Geissel, Hans ; Gernhäuser, Roman ; Ghosh, T. ; Gilbert, M. ; Glorius, Jan ; Golubev, Pavel ; Gorshkov, Alexander ; Gourishetty, A. ; Grigorenko, Leonid V. ; Gulyas, J. ; Haiduc, Maria ; Hammache, F. ; Harakeh, Muhsin N. ; Hass, M. ; Heine, Marcel ; Hennig, Andreas ; Henriques, Ana ; Herzberg, Rolf-Dietmar ; Holl, Matthias ; Ignatov, Alexander ; Ignatyuk, A. ; Ilieva, Stoyanka ; Ivanov, Marian ; Iwasa, N. ; Jakobsson, B. ; Johansson, Håkan T. ; Jonson, Björn ; Joshi, P. ; Junghans, Arnd Rudolf ; Jurado Apruzzese, Beatriz ; Körner, G. ; Kalantar, N. ; Kanungo, Rituparna ; Kelic-Heil, Aleksandra ; Kezzar, K. ; Khan, E. ; Khanzadeev, Alexei ; Kiselev, Oleg A. ; Kogimtzis, M. ; Körper, D. ; Kräckmann, S. ; Kröll, Thorsten ; Krücken, Reiner ; Krasznahorkay, Attila ; Kratz, Jens-Volker ; Kresan, Dmytro ; Krings, Thomas ; Krumbholz, A. ; Krupko, S. ; Kulessa, Reinhard ; Kumar, Shyam ; Kurz, Nikolaus ; Kuzmin, E. ; Labiche, Marc ; Langanke, Karlheinz ; Lazarus, I. ; Bleis, T.Le ; Lederer, Claudia ; Lemasson, A. ; Lemmon, Roy Crawford ; Liberati, V. ; Litvinov, Yuri A. ; Löher, Bastian ; Herraiz, J.Lopez ; Münzenberg, G. ; Machado, Jorge ; Maev, E. ; Mahata, Kripamay ; Mancusi, D. ; Marganiec, Justyna ; Perez, M.Martinez ; Marusov, V. ; Mengoni, D. ; Million, B. ; Morcelle, V. ; Moreno, O. ; Movsesyan, Alina ; Nácher González, Enrique ; Najafi, Mohammad Ali ; Nakamura, T. ; Naqvi, F. ; Nikolski, E. ; Nilsson, Thomas ; Nociforo, Chiara ; Nolan, P. ; Novatsky, B. ; Nyman, Göran Hugo ; Ornelas, A. ; Palit, R. ; Pandit, S. ; Panin, Valerii ; Paradela Dobarro, Carlos ; Parkar, V. ; Paschalis, Stefanos ; Pawłowski, P. ; Perea Martinez, Angel ; Pereira, J. ; Petrache, C. ; Petri, Marina ; Pickstone, Simon Glynn ; Pietralla, Norbert ; Pietri, Stephane ; Pivovarov, Y. ; Potlog, P. ; Prokofiev, Andrey ; Rastrepina, G. ; Rauscher, Thomas ; Ribeiro Jimenez, Guillermo ; Ricciardi, Maria Valentina ; Richter, Achim ; Rigollet, Catherine ; Riisager, Karsten ; Rios, A. ; Ritter, C. ; Rodríguez Frutos, Tomás Raúl ; Rodríguez Vignote, Javier ; Röder, Marko ; Romig, Christopher ; Rossi, Dominic M. ; Roussel-Chomaz, P. ; Rout, Prakash Chandra ; Roy, S. ; Söderström, P. ; Saha Sarkar, Maitreyee ; Sakuta, S. ; Salsac, M. ; Sampson, J. ; Sanchez, J. ; Saez, del Rio ; Rosado, J.Sanchez ; Sanjari, Mohammad Shahab ; Sarriguren, P. ; Sauerwein, Anne ; Savran, Deniz ; Scheidenberger, Christoph ; Scheit, Heiko ; Schmidt, Stefan ; Schmitt, C. ; Schnorrenberger, Linda ; Schrock, P. ; Schwengner, R. ; Seddon, D. ; Sherrill, B. ; Shrivastava, A. ; Sidorchuk, S. ; Silva, Joel ; Simon, Haik ; Simpson, E. ; Singh, P. ; Slobodan, D. ; Sohler, D. ; Spieker, Mark-Christoph ; Stach, D. ; Stan, E. ; Stanoiu, M. ; Stepantsov, S. ; Stevenson, P. ; Strieder, F. ; Stuhl, László ; Suda, T. ; Sümmerer, Klaus ; Streicher, Branislav ; Taieb, Julien ; Takechi, M. ; Tanihata, I. ; Taylor, J. ; Tengblad, Olof ; Ter-Akopian, G. ; Terashima, S. ; Teubig, P. ; Thies, Ronja ; Thoennessen, M. ; Thomas, T. ; Thornhill, J. ; Thungstrom, G. ; Timar, J. ; Togano, Yasuhiro ; Tomohiro, U. ; Tornyi, T. ; Tostevin, J. ; Townsley, C. ; Trautmann, Wolfgang ; Trivedi, T. ; Typel, Stefan ; Uberseder, E. ; Udias, J. ; Uesaka, T. ; Uvarov, L. ; Vajta, Z. ; Velho, Paulo ; Vikhrov, V. ; Volknandt, Meiko ; Volkov, Vasily ; Neumann-Cosel, Peter von ; Schmid, Mirko von ; Wagner, A. ; Wamers, Felix ; Weick, Helmut ; Wells, D. ; Westerberg, L. ; Wieland, Oliver ; Wiescher, Michael ; Wimmer, Christine ; Wimmer, K. ; Winfield, John S. ; Winkel, M. ; Woods, Philip John ; Wyss, R. ; Yakorev, Dmitry ; Yavor, M. ; Zamora Cardona, Juan Carlos ; Zartova, I. ; Zerguerras, T. ; Zgura, M. ; Zhdanov, A. ; Zhukov, Mikhail V. ; Zieblinski, M. ; Zilges, Andreas ; Zuber, Kai
The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process flow and r-process β-decay chains. These nuclei are attributed to the p and rp process.
For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections.
The Facility for Antiproton and Ion Research (FAIR) will offer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes.
The influence of temperatur and pressure on the fluorescence quantum yield of N-methylacridone (9,10-dihydro-9-oxo-10-methyl-acridine) in toluene in the range of 283-313 K and 1 bar to 2.5 kbar, respectively, has been investigated. Treatment of the data in terms of the Eyring transition-state theory leads to a consistent interpretation of the observed effect. The unusually large increase of the quantum yield with increasing pressure is attributed to a positive volume of activation, ⊿V≠, for the thermally activated S1-T2 intersystem crossing which is known to be the only deactivation process (of the Si-state) competing with fluorescence. Comparison of the values for ⊿H≠, the activation enthalpy of this process, determined at various pressures, indicates a decrease in ⊿H≠ at elevated pressures. Since ⊿H≠ can be associated with the S1-T2 energy gap involved in intersystem crossing, this result further confirms the conclusion that the change in Franck-Condon factors alone cannot account for the decrease in the intersystem crossing rate with increasing pressure.
The photochemical cleavage of the endoperoxides of anthradichromene and benzodixanthene into the parent hydrocarbon and oxygen is shown to be an adiabatic photoreaction originating from an upper excited singlet state. This photochemical behaviour is described by a theory for the photochemistry of endoperoxides developed by Kearns and Khan.
Stecher, Melanie ; Schommers, Philipp Frederik ; Kollan, Christian ; Stoll, Matthias ; Kuhlendahl, Frieder ; Stellbrink, Hans‑Jürgen ; Wasmuth, Jan‑Christian ; Stephan, Christoph ; Hamacher, Laura ; Lehmann, Clara ; Boesecke, Christoph ; Bogner, Johannes ; Esser, Stefan ; Fritzsche, Carlos ; Haberl, Annette ; Hofmann, Christian ; Jensen, Björn ; Schwarze‑Zander, Carolynne ; Platten, Martin ; Fätkenheuer, Gerd ; Schmidt, Daniel ; Gunsenheimer-Bartmeyer, Barbara ; Vehreschild, Jörg Janne
Objective: Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving.
Methods: We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan–Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data.
Results: We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male (n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59–66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39–0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011–2017), being on a multi-tablet regimen (MTR).
Conclusions: Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.
Stecher, Melanie ; Schommers, Philipp Frederik ; Kollan, Christian ; Stoll, Matthias ; Kuhlendahl, Frieder-Johan ; Stellbrink, Hans‑Jürgen ; Wasmuth, Jan‑Christian ; Stephan, Christoph ; Hamacher, Laura ; Lehmann, Clara ; Boesecke, Christoph ; Bogner, Johannes ; Esser, Stefan ; Fritzsche, Carlos ; Haberl, Annette ; Schürmann, Dirk ; Degen, Olaf ; Horst, Heinz August ; Hoffmann, Christian ; Jensen, Björn-Erik Ole ; Schwarze-Zander, Carolynne ; Platten, Martin ; Fätkenheuer, Gerd ; Schmidt, Daniel ; Gunsenheimer-Bartmeyer, Barbara ; Vehreschild, Jörg Janne
Correction to: Infection (2020) 48:723–733 https://doi.org/10.1007/s15010-020-01469-6. The original version of this article unfortunately contained a mistake. In this article the authors Dirk Schürmann at affiliation Charité, University Medicine, Berlin, Olaf Degen at affiliation University Clinic Hamburg Eppendorf, Hamburg and Heinz-August Horst at affiliation University Hospital Schleswig–Holstein, Kiel, Germany were missing from the author list. The original article has been corrected.
Schmidt-Hieber, Martin ; Silling, Gerda ; Schalk, Enrico ; Heinz, Werner ; Panse, Jens ; Penack, Olaf ; Christopeit, Maximilian ; Buchheidt, Dieter ; Meyding-Lamadé, Uta ; Hähnel, Stefan ; Wolf, Hans-Heinrich ; Ruhnke, Markus ; Schwartz, Stefan ; Maschmeyer, Georg
Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases.
No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors
(2019)
Hopfner, Franziska ; Müller, Stefanie H. ; Steppat, Dagmar ; Miller, Joanna ; Schmidt, Nele ; Wandinger, Klaus-Peter ; Leypoldt, Frank ; Berg, Daniela ; Franke, Andre ; Lieb, Wolfgang ; Tittmann, Lukas ; Balzer-Geldsetzer, Monika ; Baudrexel, Simon ; Dodel, Richard ; Hilker-Roggendorf, Rüdiger ; Kalbe, Elke ; Kassubek, Jan ; Klockgether, Thomas ; Liepelt-Scarfone, Inga ; Mollenhauer, Brit ; Neuser, Petra ; Reetz, Kathrin ; Riedel, Oliver ; Schulte, Claudia ; Schulz, Jörg B. ; Spottke, Annika ; Storch, Alexander ; Trenkwalder, Claudia ; Wittchen, Hans-Ulrich ; Witt, Karsten ; Wüllner, Ullrich ; Deuschl, Günther ; Kuhlenbäumer, Gregor
Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.
Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.
Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.
Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
Thill, Marc ; Friedrich, Michael ; Kolberg-Liedtke, Cornelia ; Albert, Ute-Susann ; Banys-Paluchowski, Maggie ; Bauerfeind, Ingo ; Blohmer, Jens-Uwe ; Budach, Wilfried ; Dall, Peter ; Fallenberg, Eva Maria ; Fasching, Peter Andreas ; Fehm, Tanja ; Gerber, Bernd ; Gluz, Oleg ; Harbeck, Nadia ; Heil, Jörg ; Huober, Jens ; Jackisch, Christian ; Kreipe, Hans-H. ; Krug, David ; Kühn, Thorsten ; Kümmel, Sherko ; Loibl, Sibylle ; Lüftner, Diana ; Lux, Michael Patrick ; Maass, Nicolai ; Mundhenke, Christoph ; Nitz, Ulrike ; Park-Simon, Tjoung-Won ; Reimer, Toralf ; Rhiem, Kerstin ; Rody, Achim ; Schmidt, Marcus ; Schneeweiss, Andreas ; Schütz, Florian ; Sinn, Peter ; Solbach, Christine ; Solomayer, Erich-Franz ; Stickeler, Elmar ; Thomssen, Christoph ; Untch, Michael ; Witzel, Isabell ; Wöckel, Achim ; Müller, Volkmar ; Janni, Wolfgang ; Ditsch, Nina