Protective activity of aromatic amines and imines against oxidative nerve cell death

Oxidative stress is a widespread phenomenon in the pathology of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Neuronal cell death due to oxidative stress may causally contribute to the pathogeneses of these diseases. Therefore, neuroprotective antioxidants are considered to be a promising approach to slow down disease progression. We have investigated different aromatic amine and imine compounds for neuroprotective antioxidant functions in cell culture, and found that these compounds possess excellent cytoprotective potential in diverse paradigms of oxidative neuronal cell death, including clonal cell lines, primary cerebellar neurons, and organotypic hippocampal slice cultures. Aromatic amines and imines are effective against oxidative glutamate toxicity, glutathione depletion, and hydrogen peroxide toxicity. Their mode of action as direct antioxidants; was experimentally confirmed by electron spin resonance spectroscopy, cell-free brain lipid peroxidation assays, and intracellular peroxide measurements. With half-maximal effective concentrations of 20-75 nm in different neuroprotection experiments, the aromatic imines phenothiazine, phenoxazine, and iminostilbene proved to be about two orders of magnitude more effective than common phenolic antioxidants. This remarkable efficacy could be directly correlated to calculated properties of the compounds by means of a novel, quantitative structure-activity relationship model. We conclude that bridged bisarylimines with a single free NH-bond, such as iminostilbene, are superior neuroprotective antioxidants, and may be promising lead structures for rational drug development

Retracing labial-velar consonants in Mbum (Adamawa): Between genetic transmission and language contact

Labial-velar consonants, which are typologically rather rare in the languages of the world, have been used for both genealogical and areal classification purposes. The claim that their occurrence mainly signals areal contact (e.g. Güldemann 2008), has been criticized by scholars (cf. Cahill 2017, Childs 2017) who point out a possible genealogical development in multiple language families of Africa. In this paper, we analyse contemporary and historical data on Mbum varieties from the Adamawa plateau in Cameroon and closely related languages of the Kebi-Benue family to approach the question whether labial-velars are transmitted merely through contact in these languages or warrant a genealogical explanation. The bottom-up approach leads to an interpretation of the current distribution of labial-velars that has both elements in it: There are arguments for reconstructing labial-velars for the Proto-Kebi-Benue level, but certain specifics of their geographical distribution also hint at a contact explanation.Labial-velar consonants, which are typologically rather rare in the languages of the world, have been used for both genealogical and areal classification purposes. The claim that their occurrence mainly signals areal contact (e.g. Güldemann 2008), has been criticized by scholars (cf. Cahill 2017, Childs 2017) who point out a possible genealogical development in multiple language families of Africa. In this paper, we analyse contemporary and historical data on Mbum varieties from the Adamawa plateau in Cameroon and closely related languages of the Kebi-Benue family to approach the question whether labial-velars are transmitted merely through contact in these languages or warrant a genealogical explanation. The bottom-up approach leads to an interpretation of the current distribution of labial-velars that has both elements in it: There are arguments for reconstructing labial-velars for the Proto-Kebi-Benue level, but certain specifics of their geographical distribution also hint at a contact explanation.Labial-velar consonants, which are typologically rather rare in the languages of the world, have been used for both genealogical and areal classification purposes. The claim that their occurrence mainly signals areal contact (e.g. Güldemann 2008), has been criticized by scholars (cf. Cahill 2017, Childs 2017) who point out a possible genealogical development in multiple language families of Africa. In this paper, we analyse contemporary and historical data on Mbum varieties from the Adamawa plateau in Cameroon and closely related languages of the Kebi-Benue family to approach the question whether labial-velars are transmitted merely through contact in these languages or warrant a genealogical explanation. The bottom-up approach leads to an interpretation of the current distribution of labial-velars that has both elements in it: There are arguments for reconstructing labial-velars for the Proto-Kebi-Benue level, but certain specifics of their geographical distribution also hint at a contact explanation

The Nicastrin ectodomain adopts a highly thermostable structure

Nicastrin is a type I transmembrane glycoprotein, which is part of the high molecular weight gamma-secretase complex. gamma-Secretase is one of the key players associated with the generation of Alzheimer's disease pathology, since it liberates the neurotoxic amyloid beta-peptide. Four proteins Nicastrin, anterior pharynx-defective-1 (Aph-1), presenilin enhancer-2 (Pen-2) and Presenilin are essential to form the active gamma-secretase complex. Recently it has been shown, that Nicastrin has a key function in stabilizing the mature gamma-secretase complex and may also be involved in substrate recognition. So far no structural data for the Nicastrin ectodomain or any other gamma-secretase component are available. We therefore used Circular Dichroism (CD) spectroscopy to demonstrate that Nicastrin, similar to its homologues, the Streptomyces griseus aminopeptidase (SGAP) and the transferrin receptor (TfR), adopts a thermostable secondary structure. Furthermore, the Nicastrin ectodomain has an exceptionally high propensity to refold after thermal denaturation. These findings provide evidence to further support the hypothesis that Nicastrin may share evolutionary conserved properties with the aminopeptidase and the transferrin receptor family

Data-driven assessment of eQTL mapping methods

<p>Abstract</p> <p>Background</p> <p>The analysis of expression quantitative trait loci (eQTL) is a potentially powerful way to detect transcriptional regulatory relationships at the genomic scale. However, eQTL data sets often go underexploited because legacy QTL methods are used to map the relationship between the expression trait and genotype. Often these methods are inappropriate for complex traits such as gene expression, particularly in the case of epistasis.</p> <p>Results</p> <p>Here we compare legacy QTL mapping methods with several modern multi-locus methods and evaluate their ability to produce eQTL that agree with independent external data in a systematic way. We found that the modern multi-locus methods (Random Forests, sparse partial least squares, lasso, and elastic net) clearly outperformed the legacy QTL methods (Haley-Knott regression and composite interval mapping) in terms of biological relevance of the mapped eQTL. In particular, we found that our new approach, based on Random Forests, showed superior performance among the multi-locus methods.</p> <p>Conclusions</p> <p>Benchmarks based on the recapitulation of experimental findings provide valuable insight when selecting the appropriate eQTL mapping method. Our battery of tests suggests that Random Forests map eQTL that are more likely to be validated by independent data, when compared to competing multi-locus and legacy eQTL mapping methods.</p

Prognostic relevance of MMP-2 (72-kD collagenase IV) in gastric cancer

The association of MMP-2 (matrix metalloproteinase 2, 72-kD collagenase IV) with invasive and metastatic capacity of tumor cells has implicated a potential role in the prognosis for cancer patients. However, no larger study has been done to prove this hypothesis. The present study was therefore designed to investigate the prognostic impact of MMP-2 in a prospective series of 203 gastric cancer patients. MMP-2 expression was measured immunohistochemically and scored semiquantitatively (score 0-3) in carcinoma cells, and results were correlated with clinicopathological tumor parameters and parameters of the urokinase-type plasminogen activator (uPA) system. Survival analyses were done using the Kaplan-Meier method (log-rank statistics) and multivariate Cox analysis. Significant correlations were found for MMP-2 and Lauren's classification, M stage and proteases/inhibitors of the uPA system in the primary tumor. Kaplan-Meier analysis revealed an association of increasing MMP-2 expression with worse prognosis. This was especially seen in patients with a parallel high expression of uPA receptor. However, differences in survival probabilities between low and high MMP-2 levels were not significant. In a separate analysis of diffuse-type cancers, MMP-2 was significantly associated with disease-free (p = 0.0056) and overall survival (p = 0.0426). Multivariately, MMP-2 was not an independent parameter. Our results demonstrate that there is an association of immunohistochemical detection of MMP-2 with prognosis of cancer patients. For diffuse gastric cancers, it is a significant prognostic parameter, however, not of independent impact. The study further suggests that consideration of interrelated tumor-associated proteases like uPA receptor in combination with MMP-2 may improve its prognostic power

Development and initial validation of the Falls Efficacy Scale-International (FES-I)

Background: there is a need for a measure of fear of falling that assesses both easy and difficult physical activities and social activities and is suitable for use in a range of languages and cultural contexts, permitting direct comparison between studies and populations in different countries and settings. Objective: to develop a modified version of the Falls Efficacy Scale to satisfy this need, and to establish its psychometric properties, reliability, and concurrent validity (i.e. that it demonstrates the expected relationship with age, falls history and falls risk factors). Design: cross-sectional survey. Setting: community sample. Method: 704 people aged between 60 and 95 years completed The Falls Efficacy Scale-International (FES-I) either in postal self-completion format or by structured interview. Results: the FES-I had excellent internal and test-retest reliability (Cronbach's α=0.96, ICC=0.96). Factor analysis suggested a unitary underlying factor, with two dimensions assessing concern about less demanding physical activities mainly in the home, and concern about more demanding physical activities mainly outside the home. The FES-I had slightly better power than the original FES items to discriminate differences in concern about falling between groups differentiated by sex, age, occupation, falls in the past year, and falls risk factors (chronic illness, taking multiple or psychoactive medications, dizziness). Conclusions: the FES-I has close continuity with the best existing measure of fear of falling, excellent psychometric properties, and assesses concerns relating to basic and more demanding activities, both physical and social. Further research is required to confirm cross-cultural and predictive validit

No influence of CO2 on stable isotope analyses of soil waters with OA-ICOS

Acknowledgements We are thankful for the support by Audrey Innes with the stable isotope, LOI, and GWC analysis. We thank Jonathan Dick for suggesting that we use sparkling water to generate different CO2 concentrations in the headspace and Claire Tunaley for proof reading. We further highly appreciate the help of David Galloway and Michael Mcgibbon from the School of Biological Sciences, University of Aberdeen, with the CO2 analysis. We are also thankful for the support by Robert Provencal and Doug S. Baer regarding the technical aspects of the isotope analyzer. We would also like to thank the European Research Council (ERC, Project No. GA 335910 VeWa) and the Natural Environment Research Council (NERC, Project No. NE/K000268/1) for funding. We thank three anonymous reviewers for their valuable feedback that helped to improve the manuscript.Peer reviewedPublisher PD

RETRATO INFANTIL [Material gráfico]

INCLUIDAS EN EL PEQUEÑO ÁLBUM FOTOGRÁFICO FAMILIAR DE LA COLECCIÓN LUIS SUÁREZ GALVÁNCopia digital. Madrid : Ministerio de Educación, Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 201

Unterstützung der ukrainischen Genehmigungsbehörde NARU beim Aufbau eines technischen Systems zur verbesserten betrieblichen Überwachung des KKW Saporoshje (4. Realisierungsstufe)

Das vor zwei Jahren im KKW Saporoshje in Betrieb genommene System zur verbesserten betrieblichen Überwachung wurde an die Kiewer Zentrale der ukrainischen Aufsichtsbehörde angeschlossen. Dazu wurden die für den Anschluß und die Ausstattung dieser Zentrale in der ersten Ausbaustufe unbedingt erforderlichen technischen Mittel einvernehmlich spezifiziert, in Deutschland beschafft, im notwendigen Umfang erprobt, in die Ukraine überführt und dem Partner am Einsatzort unentgeltlich überlassen. Bei der Erprobung des Informationstransfers aus dem KKW Saporoshje in die Kiewer Zentrale wurde nachgewiesen, daß die von der ukrainischen Behörde gemietete Standleitung die notwendigen technischen Anforderungen erfüllt. Bei Funktionstests Mitte Januar 1998 wurden On-line-Daten aus dem Saporoger System der verbesserten betrieblichen Überwachung fehlerfrei nach Kiew übertragen. Ferner sind der ukrainischen Seite zum Anschluß des KKW Rovno an die Kiewer Zentrale die gleichen technischen Mittel zur Verfügung gestellt worden