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Godt, Johannes ; Scheidig, Franziska ; Grosse-Siestrup, Christian ; Esche, Vera ; Brandenburg, Paul ; Reich, Andrea ; Groneberg, Jan David Alexander
Cadmium (Cd) has been in industrial use for a long period of time. Its serious toxicity moved into scientific focus during the middle of the last century. In this review, we discuss historic and recent developments of toxicological and epidemiological questions, including exposition sources, resorption pathways and organ damage processes.
Wagner, Ulrich ; Staats, Petra ; Fehmann, Hans-Christoph ; Fischer, Axel ; Welte, Tobias ; Groneberg, Jan David Alexander
Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20–25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion.
In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD.
Introduction: In order to assess the significance of drug levels measured in intensive care medicine, clinical and forensic toxicology, as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. Therefore, it makes sense to offer a carefully referenced compilation of therapeutic and toxic plasma concentration ranges, as well as half-lives, of a large number of drugs and other xenobiotics for quick and comprehensive information.
Methods: Data have been abstracted from original papers and text books, as well as from previous compilations, and have been completed with data collected in our own forensic and clinical toxicology laboratory. The data presented in the table and corresponding annotations have been developed over the past 20 years and longer. A previous compilation has been completely revised and updated. In addition, more than 170 substances, especially drugs that have been introduced to the market since 2003 as well as illegal drugs, which became known to cause intoxications, were added. All data were carefully referenced and more than 200 new references were included. Moreover, the annotations providing details were completely revised and more than 100 annotations were added.
Results: For nearly 1,000 drugs and other xenobiotics, therapeutic ("normal") and, if data were available, toxic and comatose-fatal blood-plasma concentrations and elimination half-lives were compiled in a table.
Conclusions: In case of intoxications, the concentration of the ingested substances and/or metabolites in blood plasma better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment and monitoring of acute and chronic intoxications, and to support forensic and clinical expert opinions.
Lahut, Suna ; Ömür, Özgür ; Uyan, Özgün ; Ağım, Zeynep Sena ; Özoğuz, Aslihan ; Parman, Yeşim ; Deymeer, Feza ; Oflazer, Piraye ; Koç, Filiz ; Özçelik, Hilmi ; Auburger, Georg ; Başak, Ayşe Nazlı
Expansions of the polyglutamine (polyQ) domain (≥34) in Ataxin-2 (ATXN2) are the primary cause of spinocerebellar ataxia type 2 (SCA2). Recent studies reported that intermediate-length (27–33) expansions increase the risk of Amyotrophic Lateral Sclerosis (ALS) in 1–4% of cases in diverse populations. This study investigates the Turkish population with respect to ALS risk, genotyping 158 sporadic, 78 familial patients and 420 neurologically healthy controls. We re-assessed the effect of ATXN2 expansions and extended the analysis for the first time to cover the ATXN2 locus with 18 Single Nucleotide Polymorphisms (SNPs) and their haplotypes. In accordance with other studies, our results confirmed that 31–32 polyQ repeats in the ATXN2 gene are associated with risk of developing ALS in 1.7% of the Turkish ALS cohort (p = 0.0172). Additionally, a significant association of a 136 kb haplotype block across the ATXN2 and SH2B3 genes was found in 19.4% of a subset of our ALS cohort and in 10.1% of the controls (p = 0.0057, OR: 2.23). ATXN2 and SH2B3 encode proteins that both interact with growth receptor tyrosine kinases. Our novel observations suggest that genotyping of SNPs at this locus may be useful for the study of ALS risk in a high percentage of individuals and that ATXN2 and SH2B3 variants may interact in modulating the disease pathway.
The neural correlates of developmental dyslexia have been investigated intensively over the last two decades and reliable evidence for a dysfunction of left-hemispheric reading systems in dyslexic readers has been found in functional neuroimaging studies. In addition, structural imaging studies using voxel-based morphometry (VBM) demonstrated grey matter reductions in dyslexics in several brain regions. To objectively assess the consistency of these findings, we performed activation likelihood estimation (ALE) meta-analysis on nine published VBM studies reporting 62 foci of grey matter reduction in dyslexic readers. We found six significant clusters of convergence in bilateral temporo-parietal and left occipito-temporal cortical regions and in the cerebellum bilaterally. To identify possible overlaps between structural and functional deviations in dyslexic readers, we conducted additional ALE meta-analyses of imaging studies reporting functional underactivations (125 foci from 24 studies) or overactivations (95 foci from 11 studies ) in dyslexics. Subsequent conjunction analyses revealed overlaps between the results of the VBM meta-analysis and the meta-analysis of functional underactivations in the fusiform and supramarginal gyri of the left hemisphere. An overlap between VBM results and the meta-analysis of functional overactivations was found in the left cerebellum. The results of our study provide evidence for consistent grey matter variations bilaterally in the dyslexic brain and substantial overlap of these structural variations with functional abnormalities in left hemispheric regions.
Volpato, Virginie ; Macchiarelli, Roberto ; Guatelli-Steinberg, Debbie ; Fiore, Ivana ; Bondioli, Luca ; Frayer, David W.
We describe and analyze a Neandertal postcranial skeleton and dentition, which together show unambiguous signs of right-handedness. Asymmetries between the left and right upper arm in Regourdou 1 were identified nearly 20 years ago, then confirmed by more detailed analyses of the inner bone structure for the clavicle, humerus, radius and ulna. The total pattern of all bones in the shoulder and arm reveals that Regourdou 1 was a right-hander. Confirmatory evidence comes from the mandibular incisors, which display a distinct pattern of right oblique scratches, typical of right-handed manipulations performed at the front of the mouth. Regourdou's right handedness is consistent with the strong pattern of manual lateralization in Neandertals and further confirms a modern pattern of left brain dominance, presumably signally linguistic competence. These observations along with cultural, genetic and morphological evidence indicate language competence in Neandertals and their European precursors.
Visual perception is highly variable and can be influenced by the surrounding world. Previous research has revealed that body perception can be biased due to adaptation to thin or fat body shapes. The aim of the present study was to show that adaptation to certain body shapes and the resulting perceptual biases transfer across different identities of adaptation and test stimuli. We designed two similar adaptation experiments in which healthy female participants adapted to pictures of either thin or fat bodies and subsequently compared more or less distorted pictures of their own body to their actual body shape. In the first experiment (n = 16) the same identity was used as adaptation and test stimuli (i.e. pictures of the participant’s own body) while in the second experiment (n = 16) we used pictures of unfamiliar thin or fat bodies as adaptation stimuli. We found comparable adaptation effects in both experiments: After adaptation to a thin body, participants rated a thinner than actual body picture to be the most realistic and vice versa. We therefore assume that adaptation to certain body shapes transfers across different identities. These results raise the questions of whether some type of natural adaptation occurs in everyday life. Natural and predominant exposure to certain bodily features like body shape – especially the thin ideal in Western societies – could bias perception for these features. In this regard, further research might shed light on aspects of body dissatisfaction and the development of body image disturbances in terms of eating disorders.
Wohlfahrt, Georg ; Brilli, Federico ; Hörtnagl, Lukas ; Xu, Xiaobin ; Bingemer, Heinz ; Hansel, Armin ; Loreto, Francesco
The theoretical basis for the link between the leaf exchange of carbonyl sulfide (COS), carbon dioxide (CO2) and water vapour (H2O) and the assumptions that need to be made in order to use COS as a tracer for canopy net photosynthesis, transpiration and stomatal conductance, are reviewed. The ratios of COS to CO2 and H2O deposition velocities used to this end are shown to vary with the ratio of the internal to ambient CO2 and H2O mole fractions and the relative limitations by boundary layer, stomatal and internal conductance for COS. It is suggested that these deposition velocity ratios exhibit considerable variability, a finding that challenges current parameterizations, which treat these as vegetation-specific constants. COS is shown to represent a better tracer for CO2 than H2O. Using COS as a tracer for stomatal conductance is hampered by our present poor understanding of the leaf internal conductance to COS. Estimating canopy level CO2 and H2O fluxes requires disentangling leaf COS exchange from other ecosystem sources/sinks of COS. We conclude that future priorities for COS research should be to improve the quantitative understanding of the variability in the ratios of COS to CO2 and H2O deposition velocities and the controlling factors, and to develop operational methods for disentangling ecosystem COS exchange into contributions by leaves and other sources/sinks. To this end, integrated studies, which concurrently quantify the ecosystem-scale CO2, H2O and COS exchange and the corresponding component fluxes, are urgently needed.
We investigate the potential of carbonyl sulfide (COS) for being used as a tracer for canopy net photosynthesis, transpiration and stomatal conductance by examining the theoretical basis of the link between leaf COS, carbon dioxide (CO2) and water vapour (H2O) exchange. Our analysis identifies several limitations that need to be overcome to this end, however at present we lack appropriate ecosystem-scale field measurements for assessing their practical significance. It however appears that COS represents a better tracer for CO2 than H2O. Concurrent measurements of ecosystem scale COS, CO2 and H2O exchange are advocated.
Poor condition subarachnoid hemorrhage (SAH) patients present a high mortality and morbidity. In this study, we reviewed the acute interventional (surgical and endovascular) management of 109 SAH-poor condition patients, who were treated as early as logistically possible after confirming stable circulation parameters. Patients over the age of 70 years, without clinical response to painful stimulation were excluded. We recognized at least 3 different postinterventional therapeutic approaches: (1) Norm- or hypovolemic, normotensive hemodilution in 30 patients with space-occupying intracranial hematomas as well as in 31 cases with acute cerebro-spinal-fluid obstruction. (2) Normovolemic, hypertensive hemodilution after unilateral decompressive craniotomy in 23 surgical- and 2 endovascular-treated patients with focalized space occupying lesions and reduced cerebral perfusion. (3) Hypovolemic, normo-, or hypertensive hemodilution after bilateral decompressive craniotomy in 23 cases with massive brain-swelling. We observed a reduced mortality (21%). The overall late outcome was favorable in 56% and unfavorable in 23%. Selective aggressive treatment adapted to increase the cerebral perfusion, seems to be an effective therapy to improve the survival and outcome of several poor condition SAH-patients.
Wolf, Armin ; Jagow, Burkhard von ; Kook, Daniel ; Messmer, Elisabeth M. ; Lackerbauer, Carlo A. ; Kampik, Anselm ; Kohnen, Thomas ; Grüterich, Martin
Background: With increasing numbers of lamellar keratoplasties, eye banks are challenged to deliver precut lamellar donor tissue. In Europe, the most common technique of corneal storage is organ culture which requires a deswelling process before surgical processing. The aim of this study was to investigate the influence of different deswelling times on the cutting plane quality after microkeratome-assisted lamellar dissection.
Methods: Eight paired donor corneas (16 specimens) not suitable for transplantation were organ cultured under standard conditions at the Eye Bank of the Ludwig-Maximilians Universität, Munich, Germany. Pairs of corneal buttons were analyzed during the deswelling process in dextrane-containing medium. While one cornea was cut at an early time point during the deswelling process and put back into deswelling medium thereafter, the partner cornea was completely deswollen and dissected after 72 hours. Specimens were then further processed for scanning electron microscopy. Surface quality was assessed both digitally using Scanning Probe Imaging Processing software, and manually by three blinded graders.
Results: The corneal buttons processed at the beginning of the deswelling process had a smoother surface when compared to the partner cornea that was cut at the end of the deswelling process. In our setting, no relevant difference was detectable between manual and automated microkeratome dissection.
Conclusion: For lamellar keratoplasty, organ-cultured corneas should be processed at an early stage during the deswelling process. We interpret the smoother dissection plane during early deswelling as a result of mechanical properties in a highly hydrated cornea.
Family members provide most of the patient care and administer most of the treatments to patients with Alzheimer’s disease (AD). Family caregivers have an important impact on clinical outcomes, such as quality of life (QoL). As a consequence of this service, family caregivers suffer high rates of psychological and physical illness as well as social and financial burdens. Hence, it is important to involve family caregivers in multimodal treatment settings and provide interventions that are both suitable and specifically tailored to their needs. In recent years, several clinical guidelines have been presented worldwide for evidence-based treatment of AD and other forms of dementia. Most of these guidelines have considered family advice as integral to the optimal clinical management of AD. This article reviews current and internationally relevant guidelines with emphasis on recommendations concerning family advice.
Makino, Takuya ; Otomatsu, Toshihiko ; Shindo, Kazutoshi ; Kitamura, Emi ; Sandmann, Gerhard ; Harada, Hisashi ; Misawa, Norihiko
Background: Cyanobacteria possess several cytochrome P450s, but very little is known about their catalytic functions. CYP110 genes unique to cyanaobacteria are widely distributed in heterocyst-forming cyanobacteria including nitrogen-fixing genera Nostoc and Anabaena. We screened the biocatalytic functions of all P450s from three cyanobacterial strains of genus Nostoc or Anabaena using a series of small molecules that contain flavonoids, sesquiterpenes, low-molecular-weight drugs, and other aromatic compounds.
Results: Escherichia coli cells carrying each P450 gene that was inserted into the pRED vector, containing the RhFRed reductase domain sequence from Rhodococcus sp. NCIMB 9784 P450RhF (CYP116B2), were co-cultured with substrates and products were identified when bioconversion reactions proceeded. Consequently, CYP110E1 of Nostoc sp. strain PCC 7120, located in close proximity to the first branch point in the phylogenetic tree of the CYP110 family, was found to be promiscuous for the substrate range mediating the biotransformation of various small molecules. Naringenin and (hydroxyl) flavanones were respectively converted to apigenin and (hydroxyl) flavones, by functioning as a flavone synthase. Such an activity is reported for the first time in prokaryotic P450s. Additionally, CYP110E1 biotransformed the notable sesquiterpene zerumbone, anti-inflammatory drugs ibuprofen and flurbiprofen (methylester forms), and some aryl compounds such as 1-methoxy and 1-ethoxy naphthalene to produce hydroxylated compounds that are difficult to synthesize chemically, including novel compounds.
Conclusion: We elucidated that the CYP110E1 gene, C-terminally fused to the P450RhF RhFRed reductase domain sequence, is functionally expressed in E. coli to synthesize a robust monooxygenase, which shows promiscuous substrate specificity (affinity) for various small molecules, allowing the biosynthesis of not only flavones (from flavanones) but also a variety of hydroxyl-small molecules that may span pharmaceutical and nutraceutical industries.
Dambek, Michael ; Eilers, Ulrike ; Breitenbach, Jürgen ; Steiger, Sabine ; Büchel, Claudia ; Sandmann, Gerhard
The biosynthesis pathway to diadinoxanthin and fucoxanthin was elucidated in Phaeodactylum tricornutum by a combined approach involving metabolite analysis identification of gene function. For the initial steps leading to β-carotene, putative genes were selected from the genomic database and the function of several of them identified by genetic pathway complementation in Escherichia coli. They included genes encoding a phytoene synthase, a phytoene desaturase, a ζ-carotene desaturase, and a lycopene β-cyclase. Intermediates of the pathway beyond β-carotene, present in trace amounts, were separated by TLC and identified as violaxanthin and neoxanthin in the enriched fraction. Neoxanthin is a branching point for the synthesis of both diadinoxanthin and fucoxanthin and the mechanisms for their formation were proposed. A single isomerization of one of the allenic double bounds in neoxanthin yields diadinoxanhin. Two reactions, hydroxylation at C8 in combination with a keto-enol tautomerization and acetylation of the 3′-HO group results in the formation of fucoxanthin.
Background: Hydrolysates of plant biomass used for the production of lignocellulosic biofuels typically contain sugar mixtures consisting mainly of D-glucose and D-xylose, and minor amounts of L-arabinose. The yeast Saccharomyces cerevisiae is the preferred microorganism for the fermentative production of ethanol but is not able to ferment pentose sugars. Although D-xylose and L-arabinose fermenting S. cerevisiae strains have been constructed recently, pentose uptake is still a limiting step in mixed sugar fermentations.
Results: Here we described the cloning and characterization of two sugar transporters, AraT from the yeast Scheffersomyces stipitis and Stp2 from the plant Arabidopsis thaliana, which mediate the uptake of L-arabinose but not of D-glucose into S. cerevisiae cells. A yeast strain lacking all of its endogenous hexose transporter genes and expressing a bacterial L-arabinose utilization pathway could no longer take up and grow with L-arabinose as the only carbon source. Expression of the heterologous transporters supported uptake and utilization of L-arabinose especially at low L-arabinose concentrations but did not, or only very weakly, support D-glucose uptake and utilization. In contrast, the S. cerevisiae D-galactose transporter, Gal2, mediated uptake of both L-arabinose and D-glucose, especially at high concentrations.
Conclusions: Using a newly developed screening system we have identified two heterologous sugar transporters from a yeast and a plant which can support uptake and utilization of L-arabinose in L-arabinose fermenting S. cerevisiae cells, especially at low L-arabinose concentrations.
Mocroft, Amanda ; Neuhaus, Jacqueline ; Peters, Lars ; Ryom, Lene ; Bickel, Markus ; Grint, Daniel ; Koirala, Janak ; Szymczak, Aleksandra ; Lundgren, Jens ; Ross, Michael J. ; Wyatt, Christina M.
Chronic kidney disease (CKD) is an important cause of morbidity and mortality in HIV-positive individuals. Hepatitis C (HCV) co-infection has been associated with increased risk of CKD, but prior studies lack information on potential mechanisms. We evaluated the association between HCV or hepatitis B (HBV) co-infection and progressive CKD among 3,441 antiretroviral-treated clinical trial participants. Progressive CKD was defined as the composite of end-stage renal disease, renal death, or significant glomerular filtration rate (eGFR) decline (25% decline to eGFR <60 mL/min/1.73 m2 or 25% decline with a baseline <60). Generalized Estimating Equations were used to model the odds of progressive CKD. At baseline, 13.8% and 3.3% of participants were co-infected with HCV and HBV, respectively. Median eGFR was 111, and 3.7% developed progressive CKD. After adjustment, the odds of progressive CKD were increased in participants with HCV (OR 1.72, 95% CI 1.07–2.76) or HBV (OR 2.26, 95% CI 1.15–4.44). Participants with undetectable or low HCV-RNA had similar odds of progressive CKD as HCV seronegative participants, while participants with HCV-RNA >800,000 IU/ml had increased odds (OR 3.07; 95% CI 1.60–5.90). Interleukin-6, hyaluronic acid, and the FIB-4 hepatic fibrosis index were higher among participants who developed progressive CKD, but were no longer associated with progressive CKD after adjustment. Future studies should validate the relationship between HCV viremia and CKD.
Lange, Christian ; Bibert, Stephanie ; Kutalik, Zoltán ; Burgisser, Philippe ; Cerny, Andreas ; Dufour, Jean-Francois ; Geier, Andreas ; Gerlach, Tilman J. ; Heim, Markus H. ; Malinverni, Raffaele ; Negro, Francesco ; Regenass, Stephan ; Badenhoop, Klaus ; Bojunga, Jörg ; Sarrazin, Christoph ; Zeuzem, Stefan ; Müller, Tobias ; Berg, Thomas ; Bochud, Pierre-Yves ; Moradpour, Darius
Background: To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C.
Methodology/Principal Findings: Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061–2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D3<20 ng/mL) during all seasons, but 25(OH)D3 serum levels were not associated with treatment outcome.
Conclusions/Significance: Our study suggests a role of bioactive vitamin D (1,25[OH]2D3, calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D3 is not a suitable predictor of treatment outcome.
Torbensen, Rasmus ; Møller, Henrik Devitt ; Gresham, David ; Alizadeh, Sefa ; Ochmann, Doreen ; Boles, Eckhard ; Regenberg, Birgitte
Amino acids can induce yeast cell adhesion but how amino acids are sensed and signal the modulation of the FLO adhesion genes is not clear. We discovered that the budding yeast Saccharomyces cerevisiae CEN.PK evolved invasive growth ability under prolonged nitrogen limitation. Such invasive mutants were used to identify amino acid transporters as regulators of FLO11 and invasive growth. One invasive mutant had elevated levels of FLO11 mRNA and a Q320STOP mutation in the SFL1 gene that encodes a protein kinase A pathway regulated repressor of FLO11. Glutamine-transporter genes DIP5 and GNP1 were essential for FLO11 expression, invasive growth and biofilm formation in this mutant. Invasive growth relied on known regulators of FLO11 and the Ssy1-Ptr3-Ssy5 complex that controls DIP5 and GNP1, suggesting that Dip5 and Gnp1 operates downstream of the Ssy1-Ptr3-Ssy5 complex for regulation of FLO11 expression in a protein kinase A dependent manner. The role of Dip5 and Gnp1 appears to be conserved in the S. cerevisiae strain ∑1278b since the dip5 gnp1 ∑1278b mutant showed no invasive phenotype.
Secondly, the amino acid transporter gene GAP1 was found to influence invasive growth through FLO11 as well as other FLO genes. Cells carrying a dominant loss-of-function PTR3647::CWNKNPLSSIN allele had increased transcription of the adhesion genes FLO1, 5, 9, 10, 11 and the amino acid transporter gene GAP1. Deletion of GAP1 caused loss of FLO11 expression and invasive growth. However, deletions of FLO11 and genes encoding components of the mitogen-activated protein kinase pathway or the protein kinase A pathway were not sufficient to abolish invasive growth, suggesting involvement of other FLO genes and alternative pathways. Increased intracellular amino acid pools in the PTR3647::CWNKNPLSSIN-containing strain opens the possibility that Gap1 regulates the FLO genes through alteration of the amino acid pool sizes.
Vermehren, Johannes ; Schlosser, Beate ; Domke, Diana ; Elanjimattom, Sandra ; Müller, Christian ; Hintereder, Gudrun ; Hensel-Wiegel, Karin ; Tauber, Rudolf ; Berger, Annemarie ; Haas, Norbert ; Walcher, Felix ; Möckel, Martin ; Lehmann, Ralf ; Zeuzem, Stefan ; Sarrazin, Christoph ; Berg, Thomas
Background and Aims: The prevalence of hepatitis C virus (HCV) antibodies in Germany has been estimated to be in the range of 0.4–0.63%. Screening for HCV is recommended in patients with elevated ALT levels or significant risk factors for HCV transmission only. However, 15–30% of patients report no risk factors and ALT levels can be normal in up to 20–30% of patients with chronic HCV infection. The aim of this study was to assess the HCV seroprevalence in patients visiting two tertiary care emergency departments in Berlin and Frankfurt, respectively.
Methods: Between May 2008 and March 2010, a total of 28,809 consecutive patients were screened for the presence of anti-HCV antibodies. Anti-HCV positive sera were subsequently tested for HCV-RNA.
Results: The overall HCV seroprevalence was 2.6% (95% CI: 2.4–2.8; 2.4% in Berlin and 3.5% in Frankfurt). HCV-RNA was detectable in 68% of anti-HCV positive cases. Thus, the prevalence of chronic HCV infection in the overall study population was 1.6% (95% CI 1.5–1.8). The most commonly reported risk factor was former/current injection drug use (IDU; 31.2%) and those with IDU as the main risk factor were significantly younger than patients without IDU (p<0.001) and the male-to-female ratio was 72% (121 vs. 46 patients; p<0.001). Finally, 18.8% of contacted HCV-RNA positive patients had not been diagnosed previously.
Conclusions: The HCV seroprevalence was more than four times higher compared to current estimates and almost one fifth of contacted HCV-RNA positive patients had not been diagnosed previously.
König, Klemens ; Köhler, David ; Granja, Tiago ; Jennewein, Carla ; Tran, Thi Hoai Nguyen ; Mirakaj, Valbona ; Kröhnert, Friedemann ; Rosenberger, Peter
Recent evidence has demonstrated additional roles for the neuronal guidance protein receptor UNC5B outside the nervous system. Given the fact that ischemia reperfusion injury (IRI) of the liver is a common source of liver dysfunction and the role of UNC5B during an acute inflammatory response we investigated the role of UNC5B on acute hepatic IRI. We report here that UNC5B+/− mice display reduced hepatic IRI and neutrophil (PMN) infiltration compared to WT controls. This correlated with serum levels of lactate dehydrogenase (LDH), aspartate- (AST) and alanine- (ALT) aminotransferase, the presence of PMN within ischemic hepatic tissue, and serum levels of inflammatory cytokines. Moreover, injection of an anti-UNC5B antibody resulted in a significant reduction of hepatic IR injury. This was associated with reduced parameters of liver injury (LDH, ALT, AST) and accumulation of PMN within the injured hepatic tissue. In conclusion our studies demonstrate a significant role for UNC5B in the development of hepatic IRI and identified UNC5B as a potential drug target to prevent liver dysfunction in the future.
Bender, Stephan ; Rellum, Thomas ; Freitag, Christine M. ; Resch, Franz ; Rietschel, Marcella ; Treutlein, Jens ; Jennen-Steinmetz, Christine ; Brandeis, Daniel ; Banaschewski, Tobias ; Laucht, Manfred
Background: Dopamine plays an important role in orienting and the regulation of selective attention to relevant stimulus characteristics. Thus, we examined the influences of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of visual processing in a contingent negative variation (CNV) task.
Methods: 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as preceding visual evoked potential components were assessed.
Results: Significant additive main effects of DAT1 and COMT on the occipito-temporal early CNV were observed. In addition, there was a trend towards an interaction between the two polymorphisms. Source analysis showed early CNV generators in the ventral visual stream and in frontal regions. There was a strong negative correlation between occipito-temporal visual post-processing and the frontal early CNV component. The early CNV time interval 500–1000 ms after the visual cue was specifically affected while the preceding visual perception stages were not influenced.
Conclusions: Late visual potentials allow the genomic imaging of dopamine inactivation effects on visual post-processing. The same specific time-interval has been found to be affected by DAT1 and COMT during motor post-processing but not motor preparation. We propose the hypothesis that similar dopaminergic mechanisms modulate working memory encoding in both the visual and motor and perhaps other systems.
The Arabidopsis arenosa complex is closely related to the model plant Arabidopsis thaliana. Species and subspecies in the complex are mainly biennial, predominantly outcrossing, herbaceous, and with a distribution range covering most parts of latitudes and the eastern reaches of Europe. In this study we present the first comprehensive evolutionary history of the A. arenosa species complex, covering its natural range, by using chromosome counts, nuclear AFLP data, and a maternally inherited marker from the chloroplast genome [trnL intron (trnL) and trnL/F intergenic spacer (trnL/F-IGS) of tRNALeu and tRNAPhe, respectively]. We unravel the broad-scale cytogeographic and phylogeographic patterns of diploids and tetraploids. Diploid cytotypes were exclusively found on the Balkan Peninsula and in the Carpathians while tetraploid cytotypes were found throughout the remaining distribution range of the A. arenosa complex. Three centers of genetic diversity were identified: the Balkan Peninsula, the Carpathians, and the unglaciated Eastern and Southeastern Alps. All three could have served as long-term refugia during Pleistocene climate oscillations. We hypothesize that the Western Carpathians were and still are the cradle of speciation within the A. arenosa complex due to the high species number and genetic diversity and the concurrence of both cytotypes there.
Staurosporine induces necroptotic cell death under caspase-compromised conditions in U937 cells
(2012)
Dunai, Zsuzsanna A. ; Imre, Gergely ; Barna, Gabor ; Korcsmaros, Tamas ; Petak, Istvan ; Bauer, Pal I. ; Mihalik, Rudolf
For a long time necrosis was thought to be an uncontrolled process but evidences recently have revealed that necrosis can also occur in a regulated manner. Necroptosis, a type of programmed necrosis is defined as a death receptor-initiated process under caspase-compromised conditions. The process requires the kinase activity of receptor-interacting protein kinase 1 and 3 (RIPK1 and RIPK3) and mixed lineage kinase domain-like protein (MLKL), as a substrate of RIPK3. The further downstream events remain elusive. We applied known inhibitors to characterize the contributing enzymes in necroptosis and their effect on cell viability and different cellular functions were detected mainly by flow cytometry. Here we report that staurosporine, the classical inducer of intrinsic apoptotic pathway can induce necroptosis under caspase-compromised conditions in U937 cell line. This process could be hampered at least partially by the RIPK1 inhibitor necrotstin-1 and by the heat shock protein 90 kDa inhibitor geldanamycin. Moreover both the staurosporine-triggered and the classical death ligand-induced necroptotic pathway can be effectively arrested by a lysosomal enzyme inhibitor CA-074-OMe and the recently discovered MLKL inhibitor necrosulfonamide. We also confirmed that the enzymatic role of poly(ADP-ribose)polymerase (PARP) is dispensable in necroptosis but it contributes to membrane disruption in secondary necrosis. In conclusion, we identified a novel way of necroptosis induction that can facilitate our understanding of the molecular mechanisms of necroptosis. Our results shed light on alternative application of staurosporine, as a possible anticancer therapeutic agent. Furthermore, we showed that the CA-074-OMe has a target in the signaling pathway leading to necroptosis. Finally, we could differentiate necroptotic and secondary necrotic processes based on participation of PARP enzyme.
Rogne, Per ; Ozdowy, Przemysław ; Richter, Christian ; Saxena, Krishna ; Schwalbe, Harald ; Kuhn, Lars T.
Atomic-level analyses of non-native protein ensembles constitute an important aspect of protein folding studies to reach a more complete understanding of how proteins attain their native form exhibiting biological activity. Previously, formation of hydrophobic clusters in the 6 M urea-denatured state of an ultrafast folding mini-protein known as TC5b from both photo-CIDNP NOE transfer studies and FCS measurements was observed. Here, we elucidate the structural properties of this mini-protein denatured in 6 M urea performing 15N NMR relaxation studies together with a thorough NOE analysis. Even though our results demonstrate that no elements of secondary structure persist in the denatured state, the heterogeneous distribution of R2 rate constants together with observing pronounced heteronuclear NOEs along the peptide backbone reveals specific regions of urea-denatured TC5b exhibiting a high degree of structural rigidity more frequently observed for native proteins. The data are complemented with studies on two TC5b point mutants to verify the importance of hydrophobic interactions for fast folding. Our results corroborate earlier findings of a hydrophobic cluster present in urea-denatured TC5b comprising both native and non-native contacts underscoring their importance for ultra rapid folding. The data assist in finding ways of interpreting the effects of pre-existing native and/or non-native interactions on the ultrafast folding of proteins; a fact, which might have to be considered when defining the starting conditions for molecular dynamics simulation studies of protein folding.
Sponges play a key role in Antarctic marine benthic community structure and dynamics and are often a dominant component of many Southern Ocean benthic communities. Understanding the drivers of sponge distribution in Antarctica enables us to understand many of general benthic biodiversity patterns in the region. The sponges of the Antarctic and neighbouring oceanographic regions were assessed for species richness and biogeographic patterns using over 8,800 distribution records. Species-rich regions include the Antarctic Peninsula, South Shetland Islands, South Georgia, Eastern Weddell Sea, Kerguelen Plateau, Falkland Islands and north New Zealand. Sampling intensity varied greatly within the study area, with sampling hotspots found at the Antarctic Peninsula, South Georgia, north New Zealand and Tierra del Fuego, with limited sampling in the Bellingshausen and Amundsen seas in the Southern Ocean. In contrast to previous studies we found that eurybathy and circumpolar distributions are important but not dominant characteristics in Antarctic sponges. Overall Antarctic sponge species endemism is ~43%, with a higher level for the class Hexactinellida (68%). Endemism levels are lower than previous estimates, but still indicate the importance of the Polar Front in isolating the Southern Ocean fauna. Nineteen distinct sponge distribution patterns were found, ranging from regional endemics to cosmopolitan species. A single, distinct Antarctic demosponge fauna is found to encompass all areas within the Polar Front, and the sub-Antarctic regions of the Kerguelen Plateau and Macquarie Island. Biogeographical analyses indicate stronger faunal links between Antarctica and South America, with little evidence of links between Antarctica and South Africa, Southern Australia or New Zealand. We conclude that the biogeographic and species distribution patterns observed are largely driven by the Antarctic Circumpolar Current and the timing of past continent connectivity.
Bohmann, Ferdinand ; Mirceska, Ana ; Pfeilschifter, Josef ; Lindhoff-Last, Edelgard ; Steinmetz, Helmuth ; Förch, Christian ; Pfeilschifter, Waltraud
Background: Dabigatran etexilate (DE) is a new oral direct thrombin inhibitor. Clinical trials point towards a favourable risk-to-benefit profile of DE compared to warfarin. In this study, we evaluated whether hemorrhagic transformation (HT) occurs after experimental stroke under DE treatment as we have shown for warfarin.
Methods: 44 male C57BL/6 mice were pretreated orally with 37.5 mg/kg DE, 75 mg/kg DE or saline and diluted thrombin time (dTT) and DE plasma concentrations were monitored. Ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO) for 1 h or 3 h. We assessed functional outcome and HT blood volume 24 h and 72 h after tMCAO.
Results: After 1 h tMCAO, HT blood volume did not differ significantly between mice pretreated with DE 37.5 mg/kg and controls (1.5±0.5 µl vs. 1.8±0.5 µl, p>0.05). After 3 h tMCAO, DE-anticoagulated mice did also not show an increase in HT, neither at the dose of 37.5 mg/kg equivalent to anticoagulant treatment in the therapeutic range (1.3±0.9 µl vs. control 2.3±0.5 µl, p>0.05) nor at 75 mg/kg, clearly representing supratherapeutic anticoagulation (1.8±0.8 µl, p>0.05). Furthermore, no significant increase in HT under continued anticoagulation with DE 75 mg/kg could be found at 72 h after tMCAO for 1 h (1.7±0.9 µl vs. control 1.6±0.4 µl, p>0.05).
Conclusion: Our experimental data suggest that DE does not significantly increase hemorrhagic transformation after transient focal cerebral ischemia in mice. From a translational viewpoint, this indicates that a continuation of DE anticoagulation in case of an ischemic stroke might be safe, but clearly, clinical data on this question are warranted.
Temporal variation in the detectability of a species can bias estimates of relative abundance if not handled correctly. For example, when effort varies in space and/or time it becomes necessary to take variation in detectability into account when data are analyzed. We demonstrate the importance of incorporating seasonality into the analysis of data with unequal sample sizes due to lost traps at a particular density of a species. A case study of count data was simulated using a spring-active carabid beetle. Traps were ‘lost’ randomly during high beetle activity in high abundance sites and during low beetle activity in low abundance sites. Five different models were fitted to datasets with different levels of loss. If sample sizes were unequal and a seasonality variable was not included in models that assumed the number of individuals was log-normally distributed, the models severely under- or overestimated the true effect size. Results did not improve when seasonality and number of trapping days were included in these models as offset terms, but only performed well when the response variable was specified as following a negative binomial distribution. Finally, if seasonal variation of a species is unknown, which is often the case, seasonality can be added as a free factor, resulting in well-performing negative binomial models. Based on these results we recommend (a) add sampling effort (number of trapping days in our example) to the models as an offset term, (b) if precise information is available on seasonal variation in detectability of a study object, add seasonality to the models as an offset term; (c) if information on seasonal variation in detectability is inadequate, add seasonality as a free factor; and (d) specify the response variable of count data as following a negative binomial or over-dispersed Poisson distribution.
Background: Adaptation to low oxygen by changing gene expression is vitally important for cell survival and tissue development. The sprouting of new blood vessels, initiated from endothelial cells, restores the oxygen supply of ischemic tissues. In contrast to the transcriptional response induced by hypoxia, which is mainly mediated by members of the HIF family, there are only few studies investigating alternative splicing events. Therefore, we performed an exon array for the genome-wide analysis of hypoxia-related changes of alternative splicing in endothelial cells.
Methodology/Principal findings: Human umbilical vein endothelial cells (HUVECs) were incubated under hypoxic conditions (1% O(2)) for 48 h. Genome-wide transcript and exon expression levels were assessed using the Affymetrix GeneChip Human Exon 1.0 ST Array. We found altered expression of 294 genes after hypoxia treatment. Upregulated genes are highly enriched in glucose metabolism and angiogenesis related processes, whereas downregulated genes are mainly connected to cell cycle and DNA repair. Thus, gene expression patterns recapitulate known adaptations to low oxygen supply. Alternative splicing events, until now not related to hypoxia, are shown for nine genes: six which are implicated in angiogenesis-mediated cytoskeleton remodeling (cask, itsn1, larp6, sptan1, tpm1 and robo1); one, which is involved in the synthesis of membrane-anchors (pign) and two universal regulators of gene expression (cugbp1 and max).
Conclusions/Significance: For the first time, this study investigates changes in splicing in the physiological response to hypoxia on a genome-wide scale. Nine alternative splicing events, until now not related to hypoxia, are reported, considerably expanding the information on splicing changes due to low oxygen supply. Therefore, this study provides further knowledge on hypoxia induced gene expression changes and presents new starting points to study the hypoxia adaptation of endothelial cells.
Michaelis, Martin ; Rothweiler, Florian ; Agha, B. ; Barth, Susanne ; Voges, Yvonne ; Löschmann, Nadine ; Deimling, Andreas von ; Breitling, Rainer ; Doerr, Hans Wilhelm ; Rödel, Franz ; Speidel, Daniel ; Cinatl, Jindrich
Adaptation of wild-type p53 expressing UKF-NB-3 cancer cells to the murine double minute 2 inhibitor nutlin-3 causes de novo p53 mutations at high frequency (13/20) and multi-drug resistance. Here, we show that the same cells respond very differently when adapted to RITA, a drug that, like nutlin-3, also disrupts the p53/Mdm2 interaction. All of the 11 UKF-NB-3 sub-lines adapted to RITA that we established retained functional wild-type p53 although RITA induced a substantial p53 response. Moreover, all RITA-adapted cell lines remained sensitive to nutlin-3, whereas only five out of 10 nutlin-3-adapted cell lines retained their sensitivity to RITA. In addition, repeated adaptation of the RITA-adapted sub-line UKF-NB-3rRITA10 μM to nutlin-3 resulted in p53 mutations. The RITA-adapted UKF-NB-3 sub-lines displayed no or less pronounced resistance to vincristine, cisplatin, and irradiation than nutlin-3-adapted UKF-NB-3 sub-lines. Furthermore, adaptation to RITA was associated with fewer changes at the expression level of antiapoptotic factors than observed with adaptation to nutlin-3. Transcriptomic analyses indicated the RITA-adapted sub-lines to be more similar at the gene expression level to the parental UKF-NB-3 cells than nutlin-3-adapted UKF-NB-3 sub-lines, which correlates with the observed chemotherapy and irradiation sensitivity phenotypes. In conclusion, RITA-adapted cells retain functional p53, remain sensitive to nutlin-3, and display a less pronounced resistance phenotype than nutlin-3-adapted cells.
Uibel, Stefanie ; Takemura, Masaya ; Müller, Daniel ; Quarcoo, David ; Klingelhöfer, Doris ; Groneberg, Jan David Alexander
Urban health is potentially affected by particle emissions. The potential toxicity of nanoparticles is heavily debated and there is an enormous global increase in research activity in this field. In this respect, it is commonly accepted that nanoparticles may also be generated in processes occurring while driving vehicles. So far, a variety of studies addressed traffic-related particulate matter emissions, but only few studies focused on potential nanoparticles. Therefore, the present study analyzed the literature with regard to nanoparticles and cars. It can be stated that, to date, only a limited amount of research has been conducted in this area and more studies are needed to 1) address kind and sources of nanoparticles within automobiles and to 2) analyse whether there are health effects caused by these nanoparticles.
Bicycle traumata are very common and especially neurologic complications lead to disability and death in all stages of the life. This review assembles the most recent findings concerning research in the field of bicycle traumata combined with the factor of bicycle helmet use. The area of bicycle trauma research is by nature multidisciplinary and relevant not only for physicians but also for experts with educational, engineering, judicial, rehabilitative or public health functions. Due to this plurality of global publications and special subjects, short time reviews help to detect recent research directions and provide also information from neighbour disciplines for researchers. It can be stated that to date, that although a huge amount of research has been conducted in this area more studies are needed to evaluate and improve special conditions and needs in different regions, ages, nationalities and to create successful prevention programs of severe head and face injuries while cycling. Focus was explicit the bicycle helmet use, wherefore sledding, ski and snowboard studies were excluded and only one study concerning electric bicycles remained due to similar motion structures within this review. The considered studies were all published between January 2010 and August 2011 and were identified via the online databases Medline PubMed and ISI Web of Science.
Increasing evidence about the central nervous representation of pain in the brain suggests that the operculo-insular cortex is a crucial part of the pain matrix. The pain-specificity of a brain region may be tested by administering nociceptive stimuli while controlling for unspecific activations by administering non-nociceptive stimuli. We applied this paradigm to nasal chemosensation, delivering trigeminal or olfactory stimuli, to verify the pain-specificity of the operculo-insular cortex. In detail, brain activations due to intranasal stimulation induced by non-nociceptive olfactory stimuli of hydrogen sulfide (5 ppm) or vanillin (0.8 ppm) were used to mask brain activations due to somatosensory, clearly nociceptive trigeminal stimulations with gaseous carbon dioxide (75% v/v). Functional magnetic resonance (fMRI) images were recorded from 12 healthy volunteers in a 3T head scanner during stimulus administration using an event-related design. We found that significantly more activations following nociceptive than non-nociceptive stimuli were localized bilaterally in two restricted clusters in the brain containing the primary and secondary somatosensory areas and the insular cortices consistent with the operculo-insular cortex. However, these activations completely disappeared when eliminating activations associated with the administration of olfactory stimuli, which were small but measurable. While the present experiments verify that the operculo-insular cortex plays a role in the processing of nociceptive input, they also show that it is not a pain-exclusive brain region and allow, in the experimental context, for the interpretation that the operculo-insular cortex splay a major role in the detection of and responding to salient events, whether or not these events are nociceptive or painful.
Small bowel endoscopy is crucial for diagnosing small bowel Crohn’s disease, and capsule endoscopy is complemented by balloon-assisted enteroscopy to take biopsies and by magnetic resonance imaging to visualize enteral and extra-intestinal involvement. Recently, imaging has also become a key instrument to manage Crohn’s disease patients. Treatment control is advised for patients who have undergone bowel resections and is increasingly used to testify treatment success in non-operated patients, too. In this review we present the modern imaging methods to diagnose and to manage Crohn’s disease with a special focus on the small bowel. Moreover, current knowledge on the impact of diagnostic methods on the patients’ outcome is reported.
Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the ‘mitochondrial infectious damage adaptation’ (MIDA) model according to which a deceleration of fusion–fission cycles reflects a systemic adaptation increasing life span.
Wittmann, Miriam ; Doble, Rosella ; Bachmann, Malte ; Pfeilschifter, Josef ; Werfel, Thomas ; Mühl, Heiko
IL-18 is an important mediator involved in chronic inflammatory conditions such as cutaneous lupus erythematosus, psoriasis and chronic eczema. An imbalance between IL-18 and its endogenous antagonist IL-18 binding protein (BP) may account for increased IL-18 activity. IL-27 is a cytokine with dual function displaying pro- and anti-inflammatory properties. Here we provide evidence for a yet not described anti-inflammatory mode of action on skin resident cells. Human keratinocytes and surprisingly also fibroblasts (which do not produce any IL-18) show a robust, dose-dependent and highly inducible mRNA expression and secretion of IL-18BP upon IL-27 stimulation. Other IL-12 family members failed to induce IL-18BP. The production of IL-18BP peaked between 48–72 h after stimulation and was sustained for up to 96 h. Investigation of the signalling pathway showed that IL-27 activates STAT1 in human keratinocytes and that a proximal GAS site at the IL-18BP promoter is of importance for the functional activity of IL-27. The data are in support of a significant anti-inflammatory effect of IL-27 on skin resident cells. An important novel property of IL-27 in skin pathobiology may be to counter-regulate IL-18 activities by acting on keratinocytes and importantly also on dermal fibroblasts.
Husson, Steven J. ; Liewald, Jana F. ; Schultheis, Christian ; Stirman, Jeffrey N. ; Lu, Hang ; Gottschalk, Alexander
Essentially any behavior in simple and complex animals depends on neuronal network function. Currently, the best-defined system to study neuronal circuits is the nematode Caenorhabditis elegans, as the connectivity of its 302 neurons is exactly known. Individual neurons can be activated by photostimulation of Channelrhodopsin-2 (ChR2) using blue light, allowing to directly probe the importance of a particular neuron for the respective behavioral output of the network under study. In analogy, other excitable cells can be inhibited by expressing Halorhodopsin from Natronomonas pharaonis (NpHR) and subsequent illumination with yellow light. However, inhibiting C. elegans neurons using NpHR is difficult. Recently, proton pumps from various sources were established as valuable alternative hyperpolarizers. Here we show that archaerhodopsin-3 (Arch) from Halorubrum sodomense and a proton pump from the fungus Leptosphaeria maculans (Mac) can be utilized to effectively inhibit excitable cells in C. elegans. Arch is the most powerful hyperpolarizer when illuminated with yellow or green light while the action spectrum of Mac is more blue-shifted, as analyzed by light-evoked behaviors and electrophysiology. This allows these tools to be combined in various ways with ChR2 to analyze different subsets of neurons within a circuit. We exemplify this by means of the polymodal aversive sensory ASH neurons, and the downstream command interneurons to which ASH neurons signal to trigger a reversal followed by a directional turn. Photostimulating ASH and subsequently inhibiting command interneurons using two-color illumination of different body segments, allows investigating temporal aspects of signaling downstream of ASH.
Using an electrophysiological assay the activity of NhaA was tested in a wide pH range from pH 5.0 to 9.5. Forward and reverse transport directions were investigated at zero membrane potential using preparations with inside-out and right side-out-oriented transporters with Na+ or H+ gradients as the driving force. Under symmetrical pH conditions with a Na+ gradient for activation, both the wt and the pH-shifted G338S variant exhibit highly symmetrical transport activity with bell-shaped pH dependences, but the optimal pH was shifted 1.8 pH units to the acidic range in the variant. In both strains the pH dependence was associated with a systematic increase of the Km for Na+ at acidic pH. Under symmetrical Na+ concentration with a pH gradient for NhaA activation, an unexpected novel characteristic of the antiporter was revealed; rather than being down-regulated, it remained active even at pH as low as 5. These data allowed a transport mechanism to advance based on competing Na+ and H+ binding to a common transport site and a kinetic model to develop quantitatively explaining the experimental results. In support of these results, both alkaline pH and Na+ induced the conformational change of NhaA associated with NhaA cation translocation as demonstrated here by trypsin digestion. Furthermore, Na+ translocation was found to be associated with the displacement of a negative charge. In conclusion, the electrophysiological assay allows the revelation of the mechanism of NhaA antiport and sheds new light on the concept of NhaA pH regulation.
Although essential for T cell function, the identity of the T cell receptor (TCR) “inside-out” pathway for the activation of lymphocyte function-associated antigen 1 (LFA-1) is unclear. SKAP1 (SKAP-55) is the upstream regulator needed for TCR-induced RapL-Rap1 complex formation and LFA-1 activation. In this paper, we show that SKAP1 is needed for RapL binding to membranes in a manner dependent on the PH domain of SKAP1 and the PI3K pathway. A SKAP1 PH domain-inactivating mutation (i.e. R131M) markedly impaired RapL translocation to membranes for Rap1 and LFA-1 binding and the up-regulation of LFA-1-intercellular adhesion molecule 1 (ICAM-1) binding. Further, N-terminal myr-tagged SKAP1 for membrane binding facilitated constitutive RapL membrane and Rap1 binding and effectively substituted for PI3K and TCR ligation in the activation of LFA-1 in T cells.
Objectives: Sepsis remains a disease with a high mortality in neonates. Microcirculatory impairment plays a pivotal role in the development of multiorgan failure in septic newborns. The hemodynamic effects of recombinant activated protein C (rhAPC) were tested in an animal model of neonatal septic shock focusing on intestinal microcirculation.
Materials and methods: Endotoxic shock was triggered by intravenous application of Escherichia coli lipopolysaccarides in newborn piglets. Thereafter, five animals received a continuous infusion of 24 µg/kg/h rhAPC, and five received vehicle for control. Over the course of three hours, intestinal microcirculation was assessed by intravital microscopy every 30 min. Macrocirculation and blood counts were monitored simultaneously.
Results: After a short hypotensive period in all animals, the arterial blood pressure returned to baseline in the rhAPC-treated piglets, whereas the hypotension became increasingly severe in the controls. By 90 min, mean blood pressure in the controls was significantly lower than in the treatment group. Similar observations were made regaring microcirculation. After an early impairment in all study animals, functional capillary density and intestinal microcirculatory red blood cell velocity and red blood cell flow recovered in the rhAPC group, but deteriorated further in the control piglets.
Conclusion: Recombinant activated protein C protects macro- and microcirculation from endotoxic shock.
Der verstärkte Umgang mit Wissen in den Wirtschaftswissenschaften ist in den letzten Jahren in den Fokus der Wissenschaftler geraten. Ausgeblendet wurde dabei größtenteils die Kehrseite von Wissen, die Frage nach dem "Nichtwissen". Das Nichtwissen ist aufgrund der vorherrschenden Auffassung des gesellschaftlichen Bildes mit einer negativen Notation behaftet. Die zunehmende Auseinandersetzung des Nichtwissens in den Geisteswissenschaften bringt die positiven Funktionen zur Geltung. Der vorliegende Artikel zeigt zunächst die erfolgsfördernden Funktionen des Nichtwissens auf und implementiert somit Chancen des Nichtwissens in einem wirtschaftwissenschaftlichen Rahmen. Im Anschluss werden empirische Befunde, resultierend aus einer Befragung, die an der Goethe Universität Frankfurt am Main durchgeführt wurde, präsentiert.
EFP1 is an ER stress-induced glycoprotein which interacts with the pro-apoptotic protein Par-4
(2009)
Appel, Sarah ; Vetterkind, Susanne ; Koplin, Ansgar ; Maertens, Barbara ; Boosen, Meike ; Preuss, Ute
We have isolated the rat ortholog of EFP1 (EF-hand binding protein 1) as a novel interaction partner of the pro-apoptotic protein Par-4 (prostate apoptosis response-4). Rat EFP1 contains two thioredoxin domains, the COOH-terminal one harboring a CGFC motif, and has a similar protein domain structure as members of the protein disulfide isomerase (PDI) family. In REF52.2 and CHO cells, EFP1 colocalized with the endoplasmic reticulum (ER) marker PDI. Furthermore, EFP1 possesses catalytic activity as demonstrated by an insulin disulfide reduction assay. Western blot analysis revealed two EFP1 protein bands of approximately 136 and 155 kDa, representing different glycosylation states of the protein. Complex formation between EFP1 and Par-4 was confirmed in vitro and in vivo by co-immunoprecipitation, dot blot overlay and pull-down experiments. In CHO cells, coexpression of EFP1 and Par-4 resulted in enhanced Par-4-mediated apoptosis, which required the catalytic activity of EFP1. Interestingly, EFP1 was specifically upregulated in NIH3T3 cells after induction of ER stress by thapsigargin, tunicamycin, and brefeldin A, but not by agents that induce oxidative stress or ER-independent apoptosis. Furthermore, we could show that the induction of apoptosis by Ca2+ stress-inducing agents was significantly decreased after siRNA oligonucleotide-mediated knockdown of Par-4. Our data suggest that EFP1 might represent a cell-protective enzyme that could play an important role in the decision between survival and initiation of Par-4-mediated apoptosis.
Michel, Sebastian ; Bigdeli, Amir Khosrow ; Beiras Fernández, Andrés ; Schmitz, Christoph ; Wolf, Manuel ; Sodian, Ralf ; Kaczmarek, Ingo
Background: Valvular aortic stenosis is a common disease in the elderly, often in multimorbid patients. It is often associated with coronary artery disease and peripheral artery disease. In this situation, the risk of conventional open-heart surgery is too high, and other treatment strategies have to be evaluated.
Case report: A 79-year-old female patient with severe aortic stenosis, coronary artery disease and end-stage chronic obstructive pulmonary disease suffering from dyspnea at rest and permanently dependent on oxygen was treated in three steps. Firstly, her pulmonary infection was treated with antibiotics for 7 days. Then, the left anterior descending artery was stented (bare-metal stent). In the same session, valvuloplasty of the aortic valve was performed. She was sent to rehabilitation to improve her pulmonary condition and took clopidogrel for 4 weeks. Finally, she underwent transapical aortic valve replacement. She was released to rehabilitation on postoperative day 12.
Conclusion: A combination of modern interventional and minimally invasive surgical techniques to treat aortic stenosis and coronary heart disease can be a viable option for multimorbid patients with extremely high risk in conventional open-heart surgery.
Meyer, Hartwig ; Stöver, Timo ; Fouchet, Florian ; Bastiat, Guillaume ; Saulnier, Patrick ; Bäumer, Wolfgang ; Lenarz, Thomas ; Scheper, Verena
Objective: Sensorineural hearing loss leads to the progressive degeneration of spiral ganglion cells (SGC). Next to postoperative fibrous tissue growth, which should be suppressed to assure a close nerve–electrode interaction, the density of healthy SGC is one factor that influences the efficiency of cochlear implants (CI), the choice of treatment for affected patients. Rolipram, a phosphodiesterase-4 inhibitor, has proven neuroprotective and anti-inflammatory effects and might also reduce SGC degeneration and fibrosis, but it has to pass the cellular membrane to be biologically active.
Methods: Lipidic nanocapsules (LNC) can be used as biodegradable drug carriers to increase the efficacy of conventional application methods. We examined the biological effects of rolipram and LNC's core encapsulated rolipram on SGC and dendritic cell (DC) tumor necrosis factor-α (TNF-α) production in vitro and on SGC survival in systemically-deafened guinea pigs in vivo.
Results: Our results prove that rolipram does not have a beneficial effect on cultured SGC. Incorporation of rolipram in LNC increased the survival of SGC significantly. In the DC study, rolipram significantly inhibited TNF-α in a dose-dependent manner. The rolipram-loaded LNC provided a significant cytokine inhibition as well. In vivo data do not confirm the in vitro results.
Conclusion: By transporting rolipram into the SGC cytoplasm, LNC enabled the neuroprotective effect of rolipram in vitro, but not in vivo. This might be due to dilution of test substances by perilymph or an inadequate release of rolipram based on differing in vivo and in vitro conditions. Nevertheless, based on in vitro results, proving a significantly increased neuronal survival when using LNC-rolipram compared to pure rolipram and pure LNC application, we believe that the combination of rolipram and LNC can potentially reduce neuronal degeneration and fibrosis after CI implantation. We conclude that rolipram is a promising drug that can be used in inner ear therapy and that LNC have potential as an inner ear drug-delivery system. Further experiments with modified conditions might reveal in vivo biological effects.
The most frequent neurodegenerative diseases (NDs) are Alzheimer’s disease (AD), Parkinson’s disease (PD), and frontotemporal lobar degeneration associated with protein TDP-43 (FTLD–TDP). Neuropathologically, NDs are characterized by abnormal intracellular and extra-cellular protein deposits and by disease-specific neuronal death. Practically all terminal stages of NDs are clinically associated with dementia. Therefore, major attention was directed to protein deposits and neuron loss in supratentorial (telencephalic) brain regions in the course of NDs. This was also true for PD, although the pathological hallmark of PD is degeneration of pigmented neurons of the brainstem’s substantia nigra (SN). However, PD pathophysiology was explained by dopamine depletion in the telencephalic basal ganglia due to insufficiency and degeneration of the projection neurons located in SN. In a similar line of argumentation AD- and FTLD-related clinical deficits were exclusively explained by supratentorial allo- and neo-cortical laminar neuronal necrosis. Recent comprehensive studies in AD and PD early stages found considerable and unexpected involvement of brainstem nuclei, which could have the potential to profoundly change our present concepts on origin, spread, and early clinical diagnosis of these diseases. In contrast with PD and AD, few studies addressed brainstem involvement in the course of the different types of FTLD–TDP. Some of the results, including ours, disclosed a higher and more widespread pathology than anticipated. The present review will focus mainly on the impact of brainstem changes during the course of the most frequent NDs including PD, AD, and FTLD–TDP, with special emphasis on the need for more comprehensive research on FTLDs.
The inability to faithfully segregate chromosomes in mitosis results in chromosome instability, a hallmark of solid tumors. Disruption of microtubule dynamics contributes highly to mitotic chromosome instability. The kinesin-13 family is critical in the regulation of microtubule dynamics and the best characterized member of the family, the mitotic centromere-associated kinesin (MCAK), has recently been attracting enormous attention. MCAK regulates microtubule dynamics as a potent depolymerizer of microtubules by removing tubulin subunits from the polymer end. This depolymerizing activity plays pivotal roles in spindle formation, in correcting erroneous attachments of microtubule-kinetochore and in chromosome movement. Thus, the accurate regulation of MCAK is important for ensuring the faithful segregation of chromosomes in mitosis and for safeguarding chromosome stability. In this review we summarize recent data concerning the regulation of MCAK by mitotic kinases, Aurora A/B, Polo-like kinase 1 and cyclin-dependent kinase 1. We propose a molecular model of the regulation of MCAK by these mitotic kinases and relevant phosphatases throughout mitosis. An ever-increasing quantity of data indicates that MCAK is aberrantly regulated in cancer cells. This deregulation is linked to increased malignance, invasiveness, metastasis and drug resistance, most probably due to increased chromosomal instability and remodeling of the microtubule cytoskeleton in cancer cells. Most interestingly, recent observations suggest that MCAK could be a novel molecular target for cancer therapy, as a new cancer antigen or as a mitotic regulator. This collection of new data indicates that MCAK could be a new star in the cancer research sky due to its critical roles in the control of genome stability and the cytoskeleton. Further investigations are required to dissect the fine details of the regulation of MCAK throughout mitosis and its involvements in oncogenesis.
Large crystals of the methyl ester of the N-a-benzyloxycarbonyl protected Ala-Phe dipeptide (Z-AF-OMe) were obtained after the very slow evaporation of a solution of the corresponding carboxylic acid (Z-AF-OH) in methanol containing an excess of HCl. The structure was confirmed by single crystal X-ray diffraction data. It crystallizes in the orthorhombic space group P212121 with unit cell dimensions a = 5.0655(6) Å, b = 8.4614(8) Å, c = 46.856(5) Å, V = 2008.3(4) Å3, Z = 4. In the crystal, the molecules form hydrogen bonded chains running along the a axis of the unit cell. Other secondary interactions are also discussed.
This study presents a global scale analysis of cropping intensity, crop duration and fallow land extent computed by using the global dataset on monthly irrigated and rainfed crop areas MIRCA2000. MIRCA2000 was mainly derived from census data and crop calendars from literature. Global cropland extent was 16 million km2 around the year 2000 of which 4.4 million km2 (28%) was fallow, resulting in an average cropping intensity of 0.82 for total cropland extent and of 1.13 when excluding fallow land. The lowest cropping intensities related to total cropland extent were found for Southern Africa (0.45), Central America (0.49) and Middle Africa (0.54), while highest cropping intensities were computed for Eastern Asia (1.04) and Southern Asia (1.0). In remote or arid regions where shifting cultivation is practiced, fallow periods last 3–10 years or even longer. In contrast, crops are harvested two or more times per year in highly populated, often irrigated tropical or subtropical lowlands where multi-cropping systems are common. This indicates that intensification of agricultural land use is a strategy that may be able to significantly improve global food security. There exist large uncertainties regarding extent of cropland, harvested crop area and therefore cropping intensity at larger scales. Satellite imagery and remote sensing techniques provide opportunities for decreasing these uncertainties and to improve the MIRCA2000 inventory.
Transition metal nitrides, carbides and borides have a high potential for industrial applications as they not only have a high melting point but are generally harder and less compressible than the pure metals. Here we summarize recent advances in the synthesis of binary transition metal nitrides, carbides and borides focusing on the reaction of the elements at extreme conditions generated within the laser-heated diamond anvil cell. The current knowledge of their structures and high-pressure properties like high-(p; T) stability, compressibility and hardness is described as obtained from experiments.
We report on screening tests of 66 extracts obtained from 35 marine sponge species from the Caribbean Sea (Curaçao) and from eight species from the Great Barrier Reef (Lizard Island). Extracts were prepared in aqueous and organic solvents and were tested for hemolytic, hemagglutinating, antibacterial and anti-acetylcholinesterase (AChE) activities, as well as their ability to inhibit or activate cell protein phosphatase 1 (PP1). The most interesting activities were obtained from extracts of Ircinia felix, Pandaros acanthifolium, Topsentia ophiraphidites, Verongula rigida and Neofibularia nolitangere. Aqueous and organic extracts of I. felix and V. rigida showed strong antibacterial activity. Topsentia aqueous and some organic extracts were strongly hemolytic, as were all organic extracts from I. felix. The strongest hemolytic activity was observed in aqueous extracts from P. acanthifolium. Organic extracts of N. nolitangere and I. felix inhibited PP1. The aqueous extract from Myrmekioderma styx possessed the strongest hemagglutinating activity, whilst AChE inhibiting activity was found only in a few sponges and was generally weak, except in the methanolic extract of T. ophiraphidites.
Spontaneous symmetry breaking is a general principle that constitutes the underlying concept of a vast number of physical phenomena ranging from ferromagnetism and superconductivity in condensed matter physics to the Higgs mechanism in the standard model of elementary particles. I focus on manifestations of spontaneously broken symmetries in systems that are not Lorentz invariant, which include both nonrelativistic systems as well as relativistic systems at nonzero density, providing a self-contained review of the properties of spontaneously broken symmetries specific to such theories. Topics covered include: (i) Introduction to the mathematics of spontaneous symmetry breaking and the Goldstone theorem. (ii) Minimization of Higgs-type potentials for higher-dimensional representations. (iii) Counting rules for Nambu–Goldstone bosons and their dispersion relations. (iv) Construction of effective Lagrangians. Specific examples in both relativistic and nonrelativistic physics are worked out in detail.
Self-organized complexity and Coherent Infomax from the viewpoint of Jaynes’s probability theory
(2012)
This paper discusses concepts of self-organized complexity and the theory of Coherent Infomax in the light of Jaynes’s probability theory. Coherent Infomax, shows, in principle, how adaptively self-organized complexity can be preserved and improved by using probabilistic inference that is context-sensitive. It argues that neural systems do this by combining local reliability with flexible, holistic, context-sensitivity. Jaynes argued that the logic of probabilistic inference shows it to be based upon Bayesian and Maximum Entropy methods or special cases of them. He presented his probability theory as the logic of science; here it is considered as the logic of life. It is concluded that the theory of Coherent Infomax specifies a general objective for probabilistic inference, and that contextual interactions in neural systems perform functions required of the scientist within Jaynes’s theory.
YS-121 [2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid] is the result of target-oriented structural derivatization of pirinixic acid. It is a potent dual PPARα/γ-agonist, as well as a potent dual 5-LO/mPGES-1-inhibitor. Additionally, recent studies showed an anti-inflammatory efficacy in vivo. Because of its interference with many targets, YS-121 is a promising drug candidate for the treatment of inflammatory diseases. Ongoing preclinical studies will thus necessitate huge amounts of YS-121. To cope with those requirements, we have optimized the synthesis of YS-121. Surprisingly, we isolated and characterized byproducts during the resulting from nucleophilic aromatic substitution reactions by different tertiary alkylamines at a heteroaromatic halide. These amines should actually serve as assisting bases, because of their low nucleophilicity. This astonishing fact was not described in former publications concerning that type of reaction and, therefore, might be useful for further reaction improvement in general. Furthermore, we could develop a proposal for the mechanism of that byproduct formation.
El Antri, Ali ; Messouri, Ibtissam ; Bouktaib, Mohamed ; El Alami, Rachid ; Bolte, Michael ; El Bali, Brahim ; Lachkar, Mohammed
Two tetrahydroisoquinoline alkaloids were extracted from the alkaloid fraction of a methanol extract of the seeds of Calycotome Villosa Subsp. intermedia. Their structures were established as (R)-1-hydroxymethyl-7-8-dimethoxy-1,2,3,4-tetrahydro- isoquinoline (1) and (S)-7-hydroxymethyl-2-3-dimethoxy-7,8,9,10-tetrahydroisoquinoline chloride (2) by spectroscopic techniques and X-ray diffraction analysis.
The title thiourea was synthesized by reaction of 3,4,5-trimethoxybenzoyl isothiocyante with 3-fluoroaniline. The 3,4,5-trimethoxybenzoyl isothiocyante was produced in situ by reaction of 3,4,5-trimethoxybenzoyl chloride with ammonium thiocyanate in dry acetonitrile. The structure was confirmed by the spectroscopic, elemental analysis and single crystal X-ray diffraction data. It crystallizes in the monoclinic space group P21/c with unit cell dimensions a = 13.0966(9), b = 16.6460(13), c = 7.8448(5), β = 106.721(5)°, V 1637.9(2) ų, Z = 4.
Nollmann, Friederike I. ; Dowling, Andrea ; Kaiser, Marcel ; Deckmann, Klaus ; Grösch, Sabine ; French-Constant, Richard ; Bode, Helge Björn
The synthesis of the recently characterized depsipeptide szentiamide (1), which is produced by the entomopathogenic bacterium Xenorhabdus szentirmaii, is described. Whereas no biological activity was previously identified for 1, the material derived from the efficient synthesis enabled additional bioactivity tests leading to the identification of a notable activity against insect cells and Plasmodium falciparum, the causative agent of malaria.
Mol-ecules of the title compound, [Zn(8)(C(6)F(5))(8)O(4)(C(4)H(10)O)(4)], are located on a special position of site symmetry [Formula: see text]. As a result, there is just one quarter-mol-ecule in the asymmetric unit. The title compound features a Zn(4)O(4) cube. Each Zn atom in the cube carries a pentafluorophenyl substituent. Each O atom is bonded to a further Zn atom, which is connected to a pentafluorophenyl substituent and the O atom of a diethyl ether mol-ecule. All ether C atoms are disordered over two sets of sites with a site occupation factor of 0.51 (2) for the major occupied site.
Molecules of the title compound, C20H14O2, show approximate C s symmetry with the approximate mirror plane perpendicular to the central ring. The torsion angles about the acyclic bonds are 30.05 (15) and 30.77 (15)° in one half compared to −36.62 (14) and −18.60 (15)° in the other half of the molecule. The central aromatic ring makes dihedral angles of 47.78 (4) and 51.68 (3)° with the two terminal rings.
The title compound, C14H20O5S·0.5H2O, crystallizes with two organic molecules and a solvent water molecule in the asymmetric unit. In both molecules, the hexapyranosyl rings adopt a slightly distorted chair conformation (5 C 2) with four substituents in equatorial positions and one substituent in an axial position. The main difference between the organic molecules is the dihedral angle between the phenyl ring and the best plane defined by the O—C1—C2—C3 atoms (r.m.s deviations = 0.003 and 0.043 Å) of the hexapyranosyl rings [47.4 (4) and 86.5 (4)°]. In the asymmetric unit, molecules are linked by two strong O—H[cdots, three dots, centered]O hydrogen bonds. In the crystal, the components are linked by a total of 10 distinct O—H[cdots, three dots, centered]O hydrogen bonds, resulting in the formation of a two-dimensional network parallel to the ab plane.
The title compound, C15H15BrO2, was synthesized by a Brønsted acid-catalysed domino electrocyclization-halogenation reaction. The five-membered ring is essentially planar (r.m.s. deviation 0.006 Å) and forms a dihedral angle of 72.7 (3)° with the attached phenyl ring. The six-membered heterocycle adopts a half-chair conformation. The crystal packing is stabilized by a C—H[cdots, three dots, centered]O contact.
The title compound, C(21)H(18)ClN, was synthesized by an enanti-oselective Brønsted acid-catalysed transfer hydrogenation reaction. The six-membered heterocycle adopts a half-chair conformation. It has the biphenyl residue in an axial position. The two rings of the biphenyl residue are almost coplanar [dihedral angle = 2.65 (9)°]. The crystal packing is stabilized by N-H⋯Cl hydrogen bonds, which connect the mol-ecules into chains running along the a axis.
The title compound, C25H20N4O2, is a ditopic ortho-hydroquinone-based bis(pyrazol-1-yl)methane ligand. The dihedral angles between the planes of the pyrazole rings and their attached phenyl rings are 17.4 (3) and 5.9 (4)°. The pyrazole rings make a dihedral angle of 87.84 (16)°. One of the two hydroxy groups forms an intramolecular hydrogen bond to the other hydroxy group, whereas the second is involved in an intermolecular O—H[cdots, three dots, centered]N hydrogen bond. As a result of these intermolecular hydrogen bonds, helical chains running along the b axis are formed.
Ihler, Fritz ; Bertlich, Mattis ; Sharaf, Kariem ; Strieth, Sebastian ; Strupp, Michael ; Canis, Martin
Objective: Betahistine is a histamine H1-receptor agonist and H3-receptor antagonist that is administered to treat Menière’s disease. Despite widespread use, its pharmacological mode of action has not been entirely elucidated. This study investigated the effect of betahistine on guinea pigs at dosages corresponding to clinically used doses for cochlear microcirculation.
Methods: Thirty healthy Dunkin-Hartley guinea pigs were randomly assigned to five groups to receive betahistine dihydrochloride in a dose of 1,000 mg/kg b. w. (milligram per kilogram body weight), 0.100 mg/kg b. w., 0.010 mg/kg b. w., 0.001 mg/kg b. w. in NaCl 0.9% or NaCl 0.9% alone as placebo. Cochlear blood flow and mean arterial pressure were continuously monitored by intravital fluorescence microscopy and invasive blood pressure measurements 3 minutes before and 15 minutes after administration of betahistine.
Results: When betahistine was administered in a dose of 1.000 mg/kg b. w. cochlear blood flow was increased to a peak value of 1.340 arbitrary units (SD: 0.246; range: 0.933–1.546 arb. units) compared to baseline (p<0.05; Two Way Repeated Measures ANOVA/Bonferroni t-test). The lowest dosage of 0.001 mg/kg b. w. betahistine or NaCl 0.9% had the same effect as placebo. Nonlinear regression revealed that there was a sigmoid correlation between increase in blood flow and dosages.
Conclusions: Betahistine has a dose-dependent effect on the increase of blood flow in cochlear capillaries. The effects of the dosage range of betahistine on cochlear microcirculation corresponded well to clinically used single dosages to treat Menière’s disease. Our data suggest that the improved effects of higher doses of betahistine in the treatment of Menière’s disease might be due to a corresponding increase of cochlear blood flow.
Paulus, Patrick ; Ockelmann, Pia ; Tacke, Sabine ; Karnowski, Nora ; Ellinghaus, Peter ; Scheller, Bertram ; Holfeld, Johannes ; Urbschat, Anja ; Zacharowski, Kai
The main goal of adequate organ preservation is to avoid further cellular metabolism during the phase of ischemia. However, modern preservation solutions do rarely achieve this target. In donor organs hypoxia and ischemia induce a broad spectrum of pathologic molecular mechanisms favoring primary graft dysfunction (PGD) after transplantation. Increased hypoxia-induced transcriptional activity leads to increased vascular permeability which in turn is the soil of a reperfusion edema and the enhancement of a pro-inflammatory response in the graft after reperfusion. We hypothesize that inhibition of the respiration chain in mitochondria and thus inhibition of the hypoxia induced mechanisms might reduce reperfusion edema and consecutively improve survival in vivo. In this study we demonstrate that the rotenoid Deguelin reduces the expression of hypoxia induced target genes, and especially VEGF-A, dose-dependently in hypoxic human lung derived cells. Furthermore, Deguelin significantly suppresses the mRNA expression of the HIF target genes VEGF-A, the pro-inflammatory CXCR4 and ICAM-1 in ischemic lungs vs. control lungs. After lung transplantation, the VEGF-A induced reperfusion-edema is significantly lower in Deguelin-treated animals than in controls. Deguelin-treated rats exhibit a significantly increased survival-rate after transplantation. Additionally, a downregulation of the pro-inflammatory molecules ICAM-1 and CXCR4 and an increase in the recruitment of immunomodulatory monocytes (CD163+ and CD68+) to the transplanted organ involving the IL4 pathway was observed. Therefore, we conclude that ischemic periods preceding reperfusion are mainly responsible for the increased vascular permeability via upregulation of VEGF. Together with this, the resulting endothelial dysfunction also enhances inflammation and consequently lung dysfunction. Deguelin significantly decreases a VEGF-A induced reperfusion edema, induces the recruitment of immunomodulatory monocytes and thus improves organ function and survival after lung transplantation by interfering with hypoxia induced signaling.
Sphingosine kinases (SK) catalyze the phosphorylation of proapoptotic sphingosine to the prosurvival factor sphingosine 1-phosphate (S1P), thereby promoting oncogenic processes. Breast (MDA-MB-231), lung (NCI-H358), and colon (HCT 116) carcinoma cells were transduced with shRNA to downregulate SK-1 expression or treated with a pharmacologic SK-1 inhibitor. The effects of SK-1 targeting were investigated by measuring the level of intracellular sphingosine, the activity of protein kinase C (PKC) and cell cycle regulators, and the mitotic index. Functional assays included measurement of cell proliferation, colony formation, apoptosis, and cell cycle analysis. Downregulation of SK-1 or its pharmacologic inhibition increased intracellular sphingosine and decreased PKC activity as shown by reduced phosphorylation of PKC substrates. In MDA-MB-231 cells this effect was most pronounced and reduced cell proliferation and colony formation, which could be mimicked using exogenous sphingosine or the PKC inhibitor RO 31-8220. SK-1 downregulation in MDA-MB-231 cells increased the number of cells with 4N and 8N DNA content, and similar effects were observed upon treatment with sphingosine or inhibitors of SK-1 or PKC. Examination of cell cycle regulators unveiled decreased cdc2 activity and expression of Chk1, which may compromise spindle checkpoint function and cytokinesis. Indeed, SK-1 kd cells entered mitosis but failed to divide, and in the presence of taxol also failed to sustain mitotic arrest, resulting in further increased endoreduplication and apoptosis. Our findings delineate an intriguing link between SK-1, PKC and components of the cell cycle machinery, which underlines the significance of SK-1 as a target for cancer therapy.
The fused five- and six-membered rings in the title compound, C14H12N2O, are essentially planar, the largest deviation from the mean plane being 0.023 (2) Å. The dihedral angle between the benzimidazole mean plane and the phenyl ring is 68.50 (6)°. In the crystal, each molecule is linked to its symmetry equivalent created by a crystallographic inversion center by pairs of N—H[cdots, three dots, centered]O hydrogen bonds, forming inversion dimers.
In the mol-ecule of the title compound, C(12)H(12)BrN(3)O, the fused-ring system is essentially planar, the largest deviation from the mean plane being 0.0148 (3) Å. The two allyl groups are nearly perpendicular to the imidazo[4,5-b]pyridine plane [C-C-N-C torsion angles of 81.6 (4) and -77.2 (4)°] and point in the same direction. The planes through the atoms forming each allyl group are nearly perpendicular to the imidazo[4,5-b]pyridin-2-one system, as indicated by the dihedral angles between them of 80.8 (5) and 73.6 (5)°.
The two fused five- and six-membered rings building the molecule of the title compound, C13H10BrN3, are approximately planar, the largest deviation from the mean plane being 0.004 (2) Å. The dihedral angle between the imidazo[4,5-b]pyridine mean plane and that of the phenyl ring is 41.84 (11)°. The structure is held together by slipped π–π stacking between symmetry-related molecules, with an interplanar distance of 3.583 (1) Å and a centroid–centroid vector of 3.670 (2) Å.
The structure of the title compound, (C15H15N2O4)[AgI2], consists of an organic 4-[3-(isonicotinoyloxy)propoxycarbonyl]pyridinium cation which has a gauche–gauche (O/C/C/C—O/C/C/C or GG’) conformation and lies on a twofold rotation axis, which passes through the central C atom of the aliphatic chain, and an inorganic [AgI2]− anion. In the complex anion, the Ag+ cation is bound to two I− anions in a linear geometry. The anion was modelled assuming disorder around a crystallographic inversion centre near the location of the Ag+ cation. The crystal packing is stabilized by a strong intermolecular N—H[cdots, three dots, centered]N hydrogen bond, which links the cations into zigzag chains with graph-set notation C(16) running along the face diagonal of the ac plane. The N-bound H atom is disordered over two equally occupied symmetry-equivalent sites, so that the molecule has a pyridinium ring at one end and a pyridine ring at the other.
Rodi, Youssef Kandri ; Chahdi, Fouad Ouazzani ; Essassi, El Mokhtar ; Luis, Santiago V. ; Bolte, Michael ; El Ammari, Lahcen
In the molecular structure of the title compound, C21H18N2O, the fused-ring system is essentially planar, the largest deviation from the mean plane being 0.0121 (9) Å. The O atom and adjacent C atom are located in Wyckoff position 4e on a twofold axis (0, y, 1/4). The two benzyl groups are almost perpendicular to the benzimidazole plane, but point in opposite directions. The dihedral angle between the benzimidazole mean plane and the phenyl ring is 81.95 (5)°, whereas that between the two benzyl groups is 60.96 (7)°.
Rodi, Youssef Kandri ; Chahdi, Fouad Ouazzani ; Essassi, El Mokhtar ; Luis, Santiago V. ; Bolte, Michael ; El Ammari, Lahcen
The asymmetric unit of the title compound, C16H23ClN2O, comtains two independent molecules in which the fused-ring systems are essentially planar, the largest deviation from the mean plane of each molecule being 0.011 (2) Å and 0.016 (2) Å. The benzimidazole rings of the two molecules make a dihedral angle of 66.65 (7)°. The nonyl substituents are almost perpendicular to the benzimidazole planes [C—N—C—C tosrsion angles = 96.0 (3) and 81.0 (2)°]. In the crystal, each independent molecule forms an inversion dimer via a pair of N—H[cdots, three dots, centered]O hydrogen bonds. In one of the independent molecules, the terminal –CH2–CH3 group of the alkyl chain is disordered over two sets of sites with a refined occupancy ratio of 0.746 (7):0.254 (7).
The title compound, [Li4O4(C12H8BO)4(C4H10O)4], features a Li4O4 cube. Each Li atom in the cube is additionally coordinated by a diethyl ether molecule and each O atom in the cube carries a 9-oxa-10-boraanthracene residue. The crystal studied was a non-merohedral twin [twin law (-1 0 0 / 0 0 1 / 0 1 0); the contribution of the major twin component refined to 0.553 (3)] emulating apparent tetragonal symmetry, whereas the actual crystal system is just orthorhombic.
The crystal structure of the title compound, hexa-μ2-bromido-μ4-oxido-tetrakis[(diethyl ether)magnesium], [Mg4Br6O(C4H10O)4], determined from data measured at 173 K, differs from the previously known structure of diethyl ether magnesium oxybromide, which was determined from room-temperature data [Stucky & Rundle (1964 [triangle]). J. Am. Chem. Soc. 86, 4821–4825]. The title compound crystallizes in the tetragonal space group I An external file that holds a picture, illustration, etc. Object name is e-67-m1614-efi7.jpg, whereas the previously known structure crystallizes in a different tetragonal space group, namely P An external file that holds a picture, illustration, etc. Object name is e-67-m1614-efi7.jpg21 c. Both molecules have crystallographic An external file that holds a picture, illustration, etc. Object name is e-67-m1614-efi7.jpg symmetry and show almost identical geometric parameters for the Mg, Br and O atoms. The crystal of the title compound turned out to be a merohedral twin emulating a structure with apparent Laue symmetry 4/mmm, whereas the correct Laue group is just 4/m. The fractional contribution of the minor twin component converged to 0.462 (1).
The title compound, C26H18BrNO4, features a functionalized chromene. The cyclohexene ring adopts a sofa conformation and has the nitro group and the bromophenyl ring in an axial position. The ten atoms of the chromene moiety lie close to a common plane (r.m.s. deviation = 0.066 Å). The attached phenyl ring is twisted by 32.89 (10)° from the chromene plane. The crystal packing is stabilized by C—H[cdots, three dots, centered]O interactions.
Ouzidan, Younes ; Rodi, Youssef Kandri ; Essassi, El Mokhtar ; Luis, Santiago V. ; Bolte, Michael ; El Ammari, Lahcen
The title molecule, C17H25N3O3, is built up from fused six- and five-membered rings linked to a –C10H21 chain. The fused-ring system is essentially planar, the largest deviation from the mean plane being 0.009 (2) Å. The chain is roughly perpendicular to this plane, making a dihedral angle of 79.5 (2)°. In the crystal, N—H[cdots, three dots, centered]O hydrogen bonds build infinite chains along [010]. There are channels in the structure containing disordered hexane. The contribution of this solvent to the scattering power was suppressed using the SQUEEZE option in PLATON [Spek (2009 [triangle]). Acta Cryst. D65, 148–155].
The title compound, C(19)H(14)ClNO(3)·0.2H(2)O, crystallizes with five mol-ecules and a disordered water mol-ecule in the asymmetric unit. Four of the five mol-ecules form hydrogen-bonded dimers via N-H⋯O hydrogen bonds towards another symmetry-independent mol-ecule, whereas the fifth mol-ecule forms a hydrogen-bonded dimer with its symmetry equivalent, also via N-H⋯O hydrogen bonds. The dihedral angle between the planes of the fused benzene ring and the five-membered ring to which it is attached is 79.45 (13), 49.00 (15), 72.49 (16), 81.91 (18) and 76.38 (16)° for the five mol-ecules in the asymmetric unit.
The structure of the title compound, C14H12N2O2 {systematic name: 2,2′-[hydrazinediylidenebis(methanylylidene)]diphenol}, has already been determined in the triclinic space group P An external file that holds a picture, illustration, etc. Object name is e-68-0o255-efi1.jpg with Z = 4 [El-Medani, Aboaly, Abdalla & Ramadan (2004 [triangle]). Spectrosc. Lett. 37, 619–632]. However, the correct space group should be P21/c with Z = 4. This structure is a new polymorph of the already known monoclinic polymorph of salicyladehyde azine, which crystallizes in space group P21/n with Z = 2. The benzene rings form a dihedral angle of 46.12 (9)°. Two intramolucular O—H[cdots, three dots, centered]N hydrogen bonds occur.
In the title compound, C15H14N2O4, (I), the molecule lies on a twofold rotation axis which passes through the central C atom of the aliphatic chain, giving one half-molecule per asymmetric unit. The structure is a monoclinic polymorph of the triclinic structure previously reported [Brito, Vallejos, Bolte & López-Rodríguez (2010). Acta Cryst. E66, o792], (II). The most obvious difference between them is the O/C/C/C—O/C/C/C torsion angle [58.2 (7)° in (I) and 173.4 (3)/70.2 (3)° in (II) for GG and TG conformations, respectively]. Another important difference is observed in the dihedral angle between the planes of the aromatic rings [86.49 (7)° for (I) and 76.4 (3)° for (II)]. The crystal structure features a weak π–π interaction [centroid–centroid distance = 4.1397 (10)Å]; this latter kind of interaction is not evident in the triclinic polymorph.
In the title compound, [Ag(BF4)(C14H12N2O4)]n, the coordination of the Ag+ ion is trigonal–bipyramidal with the N atoms of two ethane-1,2-diyl bis(pyridine-3-carboxylate) ligands in the apical positions and three F atoms belonging to different tetrafluoridoborate anions in the equatorial plane. The material consists of infinite chains of [Ag(C14H12N2O4)] units running along [001], held together by BF4 − bridging anions.
Prostate cancer is one of the most common tumor diseases worldwide. Often being non-aggressive, prostate tumors in these cases do not need immediate treatment. However, about 20% of diagnosed prostate cancers tend to metastasize and require treatment. Existing diagnostic methods may fail to accurately recognize the transition of a dormant, non-aggressive tumor into highly malignant prostate cancer. Therefore, new diagnostic tools are needed to improve diagnosis and therapy of prostate carcinoma. This review evaluates existing methods to diagnose prostate carcinoma, such as the biochemical marker prostate-specific antigen (PSA), but also discusses the possibility to use the altered expression of integrins and laminin-332 in prostate carcinomas as diagnostic tools and therapeutic targets of prostate cancer.
Momic, Tatjana ; Arlinghaus, Franziska Therese ; Arien-Zakay, Hadar ; Katzhendler, Jeoshua ; Eble, Johannes A. ; Marcinkiewicz, Cezary ; Lazarovici, Philip
In Israel, Vipera xantina palestinae (V.x.p.) is the most common venomous snake, accounting for several hundred cases of envenomation in humans and domestic animals every year, with a mortality rate of 0.5 to 2%. In this review we will briefly address the research developments relevant to our present understanding of the structure and function of V.x.p. venom with emphasis on venom disintegrins. Venom proteomics indicated the presence of four families of pharmacologically active compounds: (i) neurotoxins; (ii) hemorrhagins; (iii) angioneurin growth factors; and (iv) different types of integrin inhibitors. Viperistatin, a α1β1selective KTS disintegrin and VP12, a α2β1 selective C-type lectin were discovered. These snake venom proteins represent promising tools for research and development of novel collagen receptor selective drugs. These discoveries are also relevant for future improvement of antivenom therapy towards V.x.p. envenomation.
Geiger, Florian ; Beverungen, Mirjam ; Lorenz, Helga ; Wieland, Julia ; Fehr, Michael ; Kasten, Philip
VEGF (vascular endothelial growth factor) promotes vascularization and remodeling of bone substitutes. The aim of this study was to examine the effect of distinct resorbable ceramic carriers on bone forming capacities of VEGF transfected bone marrow stromal cells (BMSC). A critical size defect of the radius in rabbits was filled either by a low surface scaffold called beta-TCP (tricalciumphsphate) or the high surface scaffold CDHA (calcium deficient hydroxy-apatite) loaded with autologous BMSC, which were either transfected with a control plasmid or a plasmid coding for phVEGF165. They were compared to unloaded scaffolds. Thus, six treatment groups (n = 6 in each group) were followed by X-ray over 16 weeks. After probe retrieval, the volume of new bone was measured by micro-CT scans and vascularization was assessed in histology. While only minor bone formation was found in both carriers when implanted alone, BMSC led to increased osteogenesis in both carriers. VEGF promoted vascularization of the scaffolds significantly in contrast to BMSC alone. Bone formation was increased in the beta-TCP group, whereas it was inhibited in the CDHA group that showed faster scaffold degradation. The results indicate that the interaction of VEGF transfected BMSC with resorbable ceramic carrier influences the ability to promote bone healing.
Urban areas develop on formal and informal levels. Informal development is often highly dynamic, leading to a lag of spatial information about urban structure types. In this work, an object-based remote sensing approach will be presented to map the migrant housing urban structure type in the Pearl River Delta, China. SPOT5 data were utilized for the classification (auxiliary data, particularly up-to-date cadastral data, were not available). A hierarchically structured classification process was used to create (spectral) independence from single satellite scenes and to arrive at a transferrable classification process. Using the presented classification approach, an overall classification accuracy of migrant housing of 68.0% is attained.
Quarcoo, David ; Scutaru, Cristian ; Henkel, Ulrich ; Spallek, Michael ; Uibel, Stefanie ; Vitzthum, Karin ; Mache, Stefanie ; Kusma, Bianca ; Groneberg, Jan David Alexander
Background: Professional working at computer notebooks is associated with high requirements on the body posture in the seated position. By the high continuous static muscle stress resulting from this position at notebooks, professionals frequently working at notebooks for long hours are exposed to an increased risk of musculoskeletal complaints. Especially in subjects with back pain, new notebooks should be evaluated with a focus on rehabilitative issues.
Methods: In a field study a new notebook design with adjustable screen was analyzed and compared to standard notebook position.
Results: There are highly significant differences in the visual axis of individuals who are seated in the novel notebook position in comparison to the standard position. Also, differences are present between further alternative notebook positions. Testing of gender and glasses did not reveal influences.
Conclusion: This study demonstrates that notebooks with adjustable screen may be used to improve the posture. Future studies may focus on patients with musculoskeletal diseases.
Speech production involves widely distributed brain regions. This MEG study focuses on the spectro-temporal dynamics that contribute to the setup of this network. In 21 participants performing a cue-target reading paradigm, we analyzed local oscillations during preparation for overt and covert reading in the time-frequency domain and localized sources using beamforming. Network dynamics were studied by comparing different dynamic causal models of beta phase coupling in and between hemispheres. While a broadband low frequency effect was found for any task preparation in bilateral prefrontal cortices, preparation for overt speech production was specifically associated with left-lateralized alpha and beta suppression in temporal cortices and beta suppression in motor-related brain regions. Beta phase coupling in the entire speech production network was modulated by anticipation of overt reading. We propose that the processes underlying the setup of the speech production network connect relevant brain regions by means of beta synchronization and prepare the network for left-lateralized information routing by suppression of inhibitory alpha and beta oscillations.
Bingold, Tobias Michael ; Pullmann, Barbara ; Sartorius, Sven ; Geiger, Emanuel Valentin ; Marzi, Ingo ; Zacharowski, Kai ; Wissing, Heimo ; Scheller, Bertram
Introduction: The triggering receptor expressed on myeloid cells-1 (TREM-1) is known to be expressed during bacterial infections. We investigated whether TREM-1 is also expressed in non-infectious inflammation following traumatic lung contusion.
Methods: In a study population of 45 adult patients with multiple trauma and lung contusion, we obtained bronchoalveolar lavage (BAL) (blind suctioning of 20 ml NaCl (0.9%) via jet catheter) and collected blood samples at two time points (16 hours and 40 hours) after trauma. Post hoc patients were assigned to one of four groups radiologically classified according to the severity of lung contusion based on the initial chest tomography. Concentration of soluble TREM-1 (sTREM-1) and bacterial growth were determined in the BAL. sTREM-1, IL-6, IL-10, lipopolysaccharide binding protein, procalcitonin, C-reactive protein and leukocyte count were assessed in blood samples. Pulmonary function was evaluated by the paO2/FiO2 ratio.
Results: Three patients were excluded due to positive bacterial growth in the initial BAL. In 42 patients the severity of lung contusion correlated with the levels of sTREM-1 16 hours and 40 hours after trauma. sTREM-1 levels were significantly (P < 0.01) elevated in patients with severe contusion (2,184 pg/ml (620 to 4,000 pg/ml)) in comparison with patients with mild (339 pg/ml (135 to 731 pg/ml)) or no (217 pg/ml (97 to 701 pg/ml)) contusion 40 hours following trauma. At both time points the paO2/FiO2 ratio correlated negatively with sTREM-1 levels (Spearman correlation coefficient = -0.446, P < 0.01).
Conclusions: sTREM-1 levels are elevated in the BAL of patients following pulmonary contusion. Furthermore, the levels of sTREM-1 in the BAL correlate well with both the severity of radiological pulmonary tissue damage and functional impairment of gas exchange (paO2/FiO2 ratio).
Cortical neurons are typically driven by several thousand synapses. The precise spatiotemporal pattern formed by these inputs can modulate the response of a post-synaptic cell. In this work, we explore how the temporal structure of pre-synaptic inhibitory and excitatory inputs impact the post-synaptic firing of a conductance-based integrate and fire neuron. Both the excitatory and inhibitory input was modeled by renewal gamma processes with varying shape factors for modeling regular and temporally random Poisson activity. We demonstrate that the temporal structure of mutually independent inputs affects the post-synaptic firing, while the strength of the effect depends on the firing rates of both the excitatory and inhibitory inputs. In a second step, we explore the effect of temporal structure of mutually independent inputs on a simple version of Hebbian learning, i.e., hard bound spike-timing-dependent plasticity. We explore both the equilibrium weight distribution and the speed of the transient weight dynamics for different mutually independent gamma processes. We find that both the equilibrium distribution of the synaptic weights and the speed of synaptic changes are modulated by the temporal structure of the input. Finally, we highlight that the sensitivity of both the post-synaptic firing as well as the spike-timing-dependent plasticity on the auto-structure of the input of a neuron could be used to modulate the learning rate of synaptic modification.
Background: Transfer entropy (TE) is a measure for the detection of directed interactions. Transfer entropy is an information theoretic implementation of Wiener's principle of observational causality. It offers an approach to the detection of neuronal interactions that is free of an explicit model of the interactions. Hence, it offers the power to analyze linear and nonlinear interactions alike. This allows for example the comprehensive analysis of directed interactions in neural networks at various levels of description. Here we present the open-source MATLAB toolbox TRENTOOL that allows the user to handle the considerable complexity of this measure and to validate the obtained results using non-parametrical statistical testing. We demonstrate the use of the toolbox and the performance of the algorithm on simulated data with nonlinear (quadratic) coupling and on local field potentials (LFP) recorded from the retina and the optic tectum of the turtle (Pseudemys scripta elegans) where a neuronal one-way connection is likely present.
Results: In simulated data TE detected information flow in the simulated direction reliably with false positives not exceeding the rates expected under the null hypothesis. In the LFP data we found directed interactions from the retina to the tectum, despite the complicated signal transformations between these stages. No false positive interactions in the reverse directions were detected.
Conclusions: TRENTOOL is an implementation of transfer entropy and mutual information analysis that aims to support the user in the application of this information theoretic measure. TRENTOOL is implemented as a MATLAB toolbox and available under an open source license (GPL v3). For the use with neural data TRENTOOL seamlessly integrates with the popular FieldTrip toolbox.
We conducted measurements of the five important short-lived organic bromine species in the marine boundary layer (MBL). Measurements were made in the Northern Hemisphere mid-latitudes (Sylt Island, North Sea) in June 2009 and in the tropical Western Pacific during the TransBrom ship campaign in October 2009. For the one-week time series on Sylt Island, mean mixing ratios of CHBr3, CH2Br2, CHBr2Cl and CH2BrCl were 2.0, 1.1, 0.2, 0.1 ppt, respectively. We found maxima of 5.8 and 1.6 ppt for the two main components CHBr3 and CH2Br2. Along the cruise track in the Western Pacific (between 41° N and 13° S) we measured mean mixing ratios of 0.9, 0.9, 0.2, 0.1 and 0.1 ppt for CHBr3, CH2Br2, CHBrCl2, CHBr2Cl and CH2BrCl. Air samples with coastal influence showed considerably higher mixing ratios than the samples with open ocean origin. Correlation analyses of the two data sets yielded strong linear relationships between the mixing ratios of four of the five species (except for CH2BrCl). Using a combined data set from the two campaigns and a comparison with the results from two former studies, rough estimates of the molar emission ratios between the correlated substances were: 9/1/0.35/0.35 for CHBr3/CH2Br2/CHBrCl2/CHBr2Cl. Additional measurements were made in the tropical tropopause layer (TTL) above Teresina (Brazil, 5° S) in June 2008, using balloon-borne cryogenic whole air sampling technique. Near the level of zero clear-sky net radiative heating (LZRH) at 14.8 km about 2.25 ppt organic bromine was bound to the five short-lived species, making up 13% of total organic bromine (17.82 ppt). CH2Br2 (1.45 ppt) and CHBr3 (0.56 ppt) accounted for 90% of the budget of short-lived compounds in that region. Near the tropopause (at 17.5 km) organic bromine from these substances was reduced to 1.35 ppt, with 1.07 and 0.12 ppt attributed to CH2Br2 and CHBr3, respectively.
We conducted measurements of up to the five important short-lived brominated species in the marine boundary layer (MBL) of the mid-latitudes (List/Sylt, North Sea) in June 2009 and of the tropical Western Pacific during the TransBrom ship campaign in October 2009. For the one-week time series in List mean mixing ratios of 2.0, 1.1, 0.2, 0.1 ppt were analysed for CHBr3, CH2Br2, CHBr2Cl and CH2BrCl, with maxima of 5.8 and 1.6 ppt for the two main components CHBr3 and CH2Br2. Along the cruise track in the Western Pacific (between 41° N and 13° S) mean mixing ratios of 1.0, 0.9, 0.2, 0.1 and 0.1 ppt for CHBr3, CH2Br2, CHBrCl2, CHBr2Cl and CH2BrCl were determined. Air samples with coastal influence showed considerably higher mixing ratios than the samples with open ocean origin. Correlation analyses of the two datasets yielded strong linear relationships between the mixing ratios of four of the five species (except for CH2BrCl). Using a combined dataset from the two campaigns, rough estimates of the molar emission ratios between the correlated substances were derived as follows: 9/1/0.3/0.3 for CHBr3/CH2Br2/CHBrCl2/CHBr2Cl. Additional measurements were made in the tropical tropopause layer (TTL) above Teresina (Brazil, 5.07° S, 42.87° W) in June 2008, using balloon-borne cryogenic whole air sampling technique. Near the level of zero clear-sky net radiative heating (LZRH) at 14.8 km about 2.25 ppt organic bromine was bound to the five short-lived species, making up 13 % of total organic bromine (17.82 ppt). CH2Br2 (1.45 ppt) and CHBr3 (0.56 ppt) accounted for 90 % of the budget of short-lived compounds in that region. Near the tropopause (at 17.5 km) organic bromine from short-lived substances was reduced to 1.35 ppt, with 1.07 ppt and 0.12 ppt attributed to CH2Br2 and CHBr3 respectively.
Balloon-borne stratospheric BrO measurements : comparison with Envisat/SCIAMACHY BrO limb profiles
(2005)
Dorf, Marcel ; Bösch, Hartmut ; Butz, Andre ; Camy-Peyret, Claude C. ; Chipperfield, Martyn P. ; Engel, Andreas ; Goutail, Florence ; Grunow, Katja ; Hendrick, François ; Hrechanyy, Serhiy ; Naujokat, Barbara ; Pommereau, Jean-Pierre ; Roozendael, Michel van ; Sioris, Christopher E. ; Stroh, Fred ; Weidner, Frank ; Pfeilsticker, Klaus
For the first time, results of all four existing stratospheric BrO profiling instruments, are presented and compared with reference to the SLIMCAT 3-dimensional chemical transport model (3-D CTM). Model calculations are used to infer a BrO profile validation set, measured by 3 different balloon sensors, for the new Envisat/SCIAMACHY (ENVIronment SATellite/SCanning Imaging Absorption spectroMeter for Atmospheric CHartographY) satellite instrument. The balloon observations include (a) balloon-borne in situ resonance fluorescence detection of BrO, (b) balloon-borne solar occultation DOAS measurements (Differential Optical Absorption Spectroscopy) of BrO in the UV, and (c) BrO profiling from the solar occultation SAOZ (Systeme d'Analyse par Observation Zenithale) balloon instrument. Since stratospheric BrO is subject to considerable diurnal variation and none of the measurements are performed close enough in time and space for a direct comparison, all balloon observations are considered with reference to outputs from the 3-D CTM. The referencing is performed by forward and backward air mass trajectory calculations to match the balloon with the satellite observations. The diurnal variation of BrO is considered by 1-D photochemical model calculation along the trajectories. The 1-D photochemical model is initialised with output data of the 3-D model with additional constraints on the vertical transport, the total amount and photochemistry of stratospheric bromine as given by the various balloon observations. Total [Bry]=(20.1±2.8)pptv obtained from DOAS BrO observations at mid-latitudes in 2003, serves as an upper limit of the comparison. Most of the balloon observations agree with the photochemical model predictions within their given error estimates. First retrieval exercises of BrO limb profiling from the SCIAMACHY satellite instrument agree to <±50% with the photochemically-corrected balloon observations, and tend to show less agreement below 20 km.
Contribution of sulfuric acid and oxidized organic compounds to particle formation and growth
(2012)
Riccobono, Francesco ; Rondo, Linda ; Sipilä, Mikko ; Barmet, Peter ; Curtius, Joachim ; Dommen, Josef ; Ehn, Mikael ; Ehrhart, Sebastian ; Kulmala, Markku ; Kürten, Christoph Andreas ; Mikkilä, Jyri ; Petäjä, Tuukka ; Weingartner, Ernest ; Baltensperger, Urs
Lack of knowledge about the mechanisms underlying new particle formation and their subsequent growth is one of the main causes for the large uncertainty in estimating the radiative forcing of atmospheric aerosols in global models. We performed chamber experiments designed to study the contributions of sulfuric acid and organic vapors to formation and to the early growth of nucleated particles, respectively. Distinct experiments in the presence of two different organic precursors (1,3,5-trimethylbenzene and α-pinene) showed the ability of these compounds to reproduce the formation rates observed in the low troposphere. These results were obtained measuring the sulfuric acid concentrations with two Chemical Ionization Mass Spectrometers confirming the results of a previous study which modeled the sulfuric acid concentrations in presence of 1,3,5-trimethylbenzene.
New analysis methods were applied to the data collected with a Condensation Particle Counter battery and a Scanning Mobility Particle Sizer, allowing the assessment of the size resolved growth rates of freshly nucleated particles. The effect of organic vapors on particle growth was investigated by means of the growth rate enhancement factor (Γ), defined as the ratio between the measured growth rate in the presence of α-pinene and the kinetically limited growth rate of the sulfuric acid and water system. The observed Γ values indicate that the growth is dominated by organic compounds already at particle diameters of 2 nm. Both the absolute growth rates and Γ showed a strong dependence on particle size supporting the nano-Köhler theory. Moreover, the separation of the contributions from sulfuric acid and organic compounds to particles growth reveals that the organic contribution seems to be enhanced by the sulfuric acid concentration. The size resolved growth analysis finally indicates that both condensation of oxidized organic compounds and reactive uptake contribute to particle growth.
A comprehensive set of stratospheric balloon and aircraft samples was analyzed for the position-dependent isotopic composition of nitrous oxide (N2O). Results for a total of 220 samples from between 1987 and 2003 are presented, nearly tripling the number of mass-spectrometric N2O isotope measurements in the stratosphere published to date. Cryogenic balloon samples were obtained at polar (Kiruna/Sweden, 68° N), mid-latitude (southern France, 44° N) and tropical sites (Hyderabad/India, 18° N). Aircraft samples were collected with a newly-developed whole air sampler on board of the high-altitude aircraft M55 Geophysica during the EUPLEX 2003 campaign. All samples were analyzed by laboratory mass spectrometry for their 18O/16O and position-dependent 15N/14N isotope ratios with very high precision (standard deviation about 0.15 per mil for 18O/16O and average 15N/14N ratios, about 0.5 per mil for 15NNO/14NNO and N15NO/N14NO ratios). For mixing ratios above 200 nmol mol−1, relative isotope enrichments (δ values) and mixing ratios display a compact relationship, which is nearly independent of latitude and season and which can be explained equally well by Rayleigh fractionation or mixing. However, for mixing ratios below 200 nmol mol−1 this compact relationship gives way to meridional, seasonal and interannual variations. A comparison to a previously published mid-latitude balloon profile even shows large zonal variations, justifying the use of three-dimensional models for further data interpretation.
In general, the magnitude of the apparent fractionation constants (apparent isotope effects) increases continuously with altitude and decreases from the equator to the North pole, which can be qualitatively understood by the interplay between the time-scales of N2O photochemistry and transport. Deviations from this behavior occur where polar vortex air mixes with nearly N2O-free upper stratospheric/mesospheric air (e.g., during the boreal winter of 2003 and possibly 1992). Aircraft observations in the polar vortex at mixing ratios below 200 nmol mol−1 deviate from isotope variations expected for both Rayleigh fractionation and end-member mixing, but could be explained by continuous weak mixing between intravortex and extravortex air (Plumb et al., 2000). Finally, correlations between 18O/16O and average 15N/14N isotope ratios or between the position-dependent 15N/14N isotope ratios show that photo-oxidation makes a large contribution to the total N2O sink in the lower stratosphere (up to 100%). Towards higher altitudes, the temperature dependence of these isotope correlations becomes visible in the stratospheric observations.
Klein, Holger ; Nickovic, Slobodan ; Haunold, Werner ; Bundke, Ulrich ; Nillius, Björn ; Ebert, Martin ; Weinbruch, Stephan ; Schuetz, Lothar ; Levin, Zev ; Barrie, Leonard A. ; Bingemer, Heinz
Surface measurements of aerosol and ice nuclei (IN) at a Central European mountain site during an episode of dust transport from the Sahara are presented. Transport is simulated by the Eulerian regional dust model DREAM. Ice nuclei and mineral dust are significantly correlated. The highest correlation is found between IN concentration and aerosol surface area. The ice nucleating characteristics of the aerosol with respect to temperature and supersaturation are similar during the dust episode than during the course of the year. This suggests that dust is always a dominant constituent of ice nucleating aerosols in Central Europe.
Klein, Holger ; Nickovic, Slobodan ; Haunold, Werner ; Bundke, Ulrich ; Nillius, Björn ; Ebert, Martin ; Weinbruch, Stephan ; Schuetz, Lothar ; Levin, Zev ; Barrie, Leonard A. ; Bingemer, Heinz
Surface measurements of aerosol and ice nuclei (IN) at a Central European mountain site during an episode of dust transport from the Sahara are presented. Ice nuclei were sampled by electrostatic precipitation on silicon wafers and were analyzed in an isothermal static vapor diffusion chamber. The transport of mineral dust is simulated by the Eulerian regional dust model DREAM. Ice nuclei and mineral dust are significantly correlated, in particular IN number concentration and aerosol surface area. The ice nucleating characteristics of the aerosol as analyzed with respect to temperature and supersaturation are similar during the dust episode than during the course of the year. This suggests that dust may be a main constituent of ice nucleating aerosols in Central Europe.
The isotopic composition of methane in the stratosphere : high-altitude balloon sample measurements
(2011)
The isotopic composition of stratospheric methane has been determined on a large suite of air samples from stratospheric balloon flights covering subtropical to polar latitudes and a time period of 16 yr. 154 samples were analyzed for δ13C and 119 samples for δD, increasing the previously published dataset for balloon borne samples by an order of magnitude, and more than doubling the total available stratospheric data (including aircraft samples) published to date. The samples also cover a large range in mixing ratio from tropospheric values near 1800 ppb down to only 250 ppb, and the strong isotope fractionation processes accordingly increase the isotopic composition up to δ13C = −14‰ and δD = +190‰, the largest enrichments observed for atmospheric CH4 so far. When analyzing and comparing kinetic isotope effects (KIEs) derived from single balloon profiles, it is necessary to take into account the residence time in the stratosphere in combination with the observed mixing ratio and isotope trends in the troposphere, and the range of isotope values covered by the individual profile. The isotopic composition of CH4 in the stratosphere is affected by both chemical and dynamical processes. This severely hampers interpretation of the data in terms of the relative fractions of the three important sink mechanisms (reaction with OH, O(1D) and Cl). It is shown that a formal sink partitioning using the measured data severely underestimates the fraction removed by OH, which is likely due to the insensitivity of the measurements to the kinetic fractionation in the lower stratosphere. Full quantitative interpretation of the CH4 isotope data in terms of the three sink reactions requires a global model.
The isotopic composition of methane in the stratosphere : high-altitude balloon sample measurements
(2011)
The isotopic composition of stratospheric methane has been determined on a large suite of air samples from stratospheric balloon flights covering subtropical to polar latitudes and a time period of 16 yr. 154 samples were analyzed for δC and 119 samples for δD, increasing the previously published dataset for balloon borne samples by an order of magnitude, and more than doubling the total available stratospheric data (including aircraft samples) published to date. The samples also cover a large range in mixing ratio from tropospheric values near 1800 ppb down to only 250 ppb, and the strong isotope fractionation processes accordingly increase the isotopic composition up to δ13C=−14‰ and δD= +190‰, the largest enrichments observed for atmospheric CH4 so far. When analyzing and comparing kinetic isotope effects (KIEs) derived from single balloon profiles, it is necessary to take into account the residence time in the stratosphere in combination with the observed mixing ratio and isotope trends in the troposphere, and the range of isotope values covered by the individual profile. Temporal isotope trends can also be determined in the stratosphere and compare reasonably well with the tropospheric trends. The effects of chemical and dynamical processes on the isotopic composition of CH4 in the stratosphere are discussed in detail. Different ways to interpret the data in terms of the relative fractions of the three important sink mechanisms (reaction with OH, O(1D)) and Cl, respectively), and their limitations, are investigated. The classical approach of using global mean KIE values can be strongly biased when profiles with different minimum mixing ratios are compared. Approaches for more local KIE investigations are suggested. It is shown that any approach for a formal sink partitioning from the measured data severely underestimates the fraction removed by OH, which is likely due to the insensitivity of the measurements to the kinetic fractionation in the lower stratosphere. Attempts can be made to correct for the lower stratospheric sink bias, but full quantitative interpretation of the CH4 isotope data in terms of the three sink reactions requires a global model.
Pison, Isabelle C. ; Fortems-Cheiney, Audrey ; Schmidt, Martina ; Chevallier, Frédéric ; Ramonet, Michel ; Jordan, Armin ; Søvde, Ole Amund ; Engel, Andreas ; Fisher, Rebecca E. ; Lowry, David ; Nisbet, Euan G. ; Levin, Ingeborg ; Hammer, Samuel ; Necki, Jaroslaw ; Bartyzel, J. ; Reimann, Stefan ; Vollmer, Martin K. ; Steinbacher, Martin ; Aalto, Tuula ; Maione, Michela ; Arduini, Jgor ; O'Doherty, Simon ; Grant, Aoife ; Sturges, William T. ; Forster, Grant L. ; Lunder, Chris Rene ; Privalov, Viacheslav I. ; Paramonova, Nina N. ; Werner, A. ; Bousquet, Philippe
This paper presents an analysis of the recent tropospheric molecular hydrogen (H2) budget with a particular focus on soil uptake and European surface emissions. A variational inversion scheme is combined with observations from the RAMCES and EUROHYDROS atmospheric networks, which include continuous measurements performed between mid-2006 and mid-2009. Net H2 surface flux, then deposition velocity and surface emissions and finally, deposition velocity, biomass burning, anthropogenic and N2 fixation-related emissions were simultaneously inverted in several scenarios. These scenarios have focused on the sensibility of the soil uptake value to different spatio-temporal distributions. The range of variations of these diverse inversion sets generate an estimate of the uncertainty for each term of the H2 budget. The net H2 flux per region (High Northern Hemisphere, Tropics and High Southern Hemisphere) varies between −8 and +8 Tg yr−1. The best inversion in terms of fit to the observations combines updated prior surface emissions and a soil deposition velocity map that is based on bottom-up and top-down estimations. Our estimate of global H2 soil uptake is −59±9 Tg yr−1. Forty per cent of this uptake is located in the High Northern Hemisphere and 55% is located in the Tropics. In terms of surface emissions, seasonality is mainly driven by biomass burning emissions. The inferred European anthropogenic emissions are consistent with independent H2 emissions estimated using a H2/CO mass ratio of 0.034 and CO emissions within the range of their respective uncertainties. Additional constraints, such as isotopic measurements would be needed to infer a more robust partition of H2 sources and sinks.