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k-MED entwickelte sich von einem fachbezogenen Projekt im Jahr 1999 zu einem e-Learning-Dienstleister mit umfangreichen Lehr-Lernangeboten sowie einer technischen und organisatorischen Infrastruktur für Autoren und Nutzer. Es bietet heute – Mitte 2006 – 5000 Studierenden, v.a. der Humanmedizin, ca. 170 Lernkurse aus 16 medizinischen Fächern. Das Projekt umfasst erfahrenes Fachpersonal und nutzt eine eigene Online-Autorenumgebung sowie eine internetbasierte Lernplattform, deren Funktionalitäten in Abstimmung mit evaluierten Lehr- und Lern-Szenarien ständig weiter entwickelt werden. Die wichtigste Aufgabe ist die Vollversorgung von Bildungseinrichtungen, darunter vor allem medizinische Fakultäten, mit Lehr-Lern- und Kommunikationsinstrumenten. Aktuelle Informationen sind zu finden unter http://www.k-med.org.
Background: The APOBEC3G protein represents a novel innate defense mechanism against retroviral infection. It facilitates the deamination of the cytosine residues in the single stranded cDNA intermediate during early steps of retroviral infection. Most poxvirus genomes are relatively A/T-rich, which may indicate APOBEC3G-induced mutational pressure. In addition, poxviruses replicate exclusively in the cytoplasm where APOBEC3G is located. It was therefore tempting to analyze whether vaccinia virus replication is affected by APOBEC3G.
Results: The replication of vaccinia virus, a prototype poxvirus, was not, however, inhibited in APOBEC3G-expressing cells, nor did other members of the APOBEC3 family alter vaccinia virus replication. HIV counteracts APOBEC3G by inducing its degradation. However, Western blot analysis showed that the levels of APOBEC3G protein were not affected by vaccinia virus infection.
Conclusion: The data indicate that APOBEC3G is not a restriction factor for vaccinia virus replication nor is vaccinia virus able to degrade APOBEC3G.
Following publication of the data presented by von Minckwitz and colleagues it has been brought to our attention that some patients should be scored differently. Stable disease was seen in three of the eighteen patients instead of two of the eighteen patients: one patient with transitional cell carcinoma treated at 4 µg/kg scFv(FRP5)-ETA per day, and two breast cancer patients treated at 4 and 12.5 µg/kg scFv(FRP5)-ETA per day. Disease progression occured in 9 of the eighteen patients evaluated (see corrected Table 2 overleaf). This does not affect the conclusions of our study. In addition we would like to correct the following errors: patient IDs for patients U01 and U02 in the original Table 2 were interchanged. In addition, patient N03 had a grade 3 elevation of gamma-glutamyl transferase, and not grade 2 (see corrected Table 2 overleaf).
Im Februar ist Universitätspräsident Prof. Rudolf Steinberg mit großer Mehrheit für weitere sechs Jahre in seinem Amt bestätigt worden. Zu Beginn seiner zweiten Amtszeit in diesem Monat wirft er im Gespräch mit dem UniReport einen Blick zurück auf die wichtigsten Entwicklungen und Ereignisse an der Goethe-Universität in seiner ersten Amtszeit und zeigt, wohin die Reise in den kommenden sechs Jahren gehen soll.
Im Mittelpunkt magnetischer Momente : Frankfurt führt das europäische Zentrum für Kernspinresonanz
(2006)
Die Kernspinresonanz (NMR) ist ein Phänomen, das einen präzisen Blick in das Innere der Materie erlaubt. Für Chemiker und Biologen hat ihre Messung im Laufe der vergangenen 50 Jahre immer mehr Bedeutung gewonnen. Die analytische Präzision hat ihren Preis: Ein hochauflösendes NMR-Spektrometer kostet 6,4 Millionen Euro. Auch deshalb haben sich fünf europäische NMR-Zentren jetzt zu einem Großforschungsverbund zusammengeschlossen; unter Federführung Frankfurts und gefördert von der Europäischen Union – damit die Spitzenstellung Europas auf dem Gebiet der NMR-Forschung erhalten und ausgebaut werden kann.
Wieviel Sexualität verträgt eine Universität? Wieviel Sexualität braucht eine Universität? Natürlich nur auf streng wissenschaftlicher Ebene. Seit Monaten ist das am Zentrum für Gesundheitswissenschaften des Klinikums angesiedelte Institut für Sexualwissenschaft in der Diskussion. Der Grund dafür: das Ausscheiden des derzeitigen Direktors, Prof. Volkmar Sigusch, im Herbst. Zu eng scheint der Bestand des Instituts mit der Person des anerkannten Fachmanns mit weltweitem Renommee verknüpft.
Seine seit Jahren herausragenden Leistungen in der Vermittlung wissenschaftlicher Arbeit in der Öffentlichkeit findet mit der Zuerkennung des mit 50.000 Euro dotierten »Communicator-Preises – Wissenschaftspreis des Stifterverbandes« eine verdiente Würdigung. Prof. Friedemann Schrenk ist der diesjährige Preisträger des renommierten, seit 1999 vergebenen Preises, der ihm an seinem 50. Geburtstag von den Präsidenten der Deutschen Forschungsgemeinschaft (DFG) und des Stifterverbandes für die Deutsche Wissenschaft am 18. Juli 2006 in einer Festveranstaltung während des Wissenschaftssommers in München verliehen wird.
Prof. Wolf Lauterbach : 65. Geburtstag [des Professors für klinische Psychologie und Psychotherapie]
(2006)
Der Zugang des Frankfurter Afrikaforschers Leo Frobenius zu Afrika war die Expedition. In insgesamt zwölf »Deutschen Inner-Afrika Expeditionen «, die teilweise vom exilierten Kaiser Wilhelm II. finanziert wurden, bereiste und erforschte er weite Gebiete des Kontinents.
"... der Wissenschaft einen Tempel bauen" : zum 300. Geburtstag Johann Christian Senckenbergs
(2006)
Bilder der Anderen : die Digitalisierung des ethnographischen Bildarchivs des Frobenius-Instituts
(2006)
Symposiumsbeitrag zu: Georg Simmel, Gesamtausgabe. Herausgegeben von Otthein Rammstedt. Band 1: Das Wesen der Materie nach Kant's Physischer Monadologie. Abhandlungen 1882-1884. Rezensionen 1883-1901. Herausgegeben von Klaus Christian Köhnke. Frankfurt am Main: Suhrkamp 2000, 527 S., kt. EURO 16,50 Band 12: Aufsätze und Abhandlungen 1909-1918, Band I. Herausgegeben von Klaus Latzel. Frankfurt am Main: Suhrkamp 2001, 586 S., kt. EURO 18,- Band 13: Aufsätze und Abhandlungen 1909-1918, Band II. Herausgegeben von Klaus Latzel. Frankfurt am Main: Suhrkamp 2000, 432 S., kt. EURO 15,- Band 15: Goethe. Deutschlands innere Wandlung. Das Problem der historischen Zeit. Rembrandt. Herausgegeben von Uta Kösser, Hans-Martin Kruckis und Otthein Rammstedt. Frankfurt am Main: Suhrkamp 2003, 678 S., kt. EURO 18,- Band 19: Französisch- und italienischsprachige Veröffentlichungen. Mélanges de philosophie relativiste. Herausgegeben von Christian Papilloud, Angela Rammstedt und Patrick Watier. Frankfurt am Main: Suhrkamp 2002, 464 S., kt. EURO 18,- Band 20: Postume Veröffentlichungen. Schulpädagogik. Herausgegeben von Torge Karlsruhen und Otthein Rammstedt. Frankfurt am Main: Suhrkamp 2004, 627 S., kt. EURO 19,- Rezensent: Klaus Lichtblau, Prof. Dr., Universität Frankfurt, FB Gesellschaftswissenschaften, Institut für Gesellschafts- und Politikanalyse
Die Postmoderne beschreibt die Fragmentierung der Gesellschaft, in der Systemrationalitäten miteinander kollidieren. Diese Diagnose kann für die Konzeption der Grundrechte nicht folgenlos bleiben. Der Aufsatz fokussiert zwei Ansätze einer neuen Verfassungstheorie. Grundlagen sind Karl-Heinz Ladeurs Kritik der Abwägung und Gunther Teubners Konzept einer Zivilverfassung vor dem Hintergrund seines Matrixmodells.
Die Rechtspraxis setzt etwas voraus, das sie nicht nur begründet oder ergänzt, sondern grundsätzlich in Frage stellt. So macht der Zwang, in einem Verfahren zu entscheiden und zu begründen, zugleich deutlich, dass jede Form der Entscheidung unangemessen, unbegründet und in ganz anderer Weise neu herzustellen ist. Das ist das juridische Supplement im Geiste von Jacques Derrida. Supplementiert wird die Wahrheit des Rechts in anderen Medien: in Drama, Film und Literatur etwa. Dort wird in Szene gesetzt, was in der real erlebbaren Rechtswelt nicht wirklich erlebt werden kann, was aber doch – wie kein Amtsträger bestreiten würde – zum Verfahrensergebnis gehört.
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. 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 (3-D) models for further data interpretation.
In general, the magnitude of the apparent fractionation constants (i.e., apparent isotope effects) increases continuously with altitude and decreases from the equator to the North Pole. Only the latter observation can be understood qualitatively by the interplay between the time-scales of N2O photochemistry and transport in a Rayleigh fractionation framework. Deviations from Rayleigh fractionation behavior also occur where polar vortex air mixes with nearly N2O-free upper stratospheric/mesospheric air (e.g., during the boreal winters 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 two-end-member mixing, but could be explained by continuous weak mixing between intravortex and extravortex air (Plumb et al., 2000). However, it appears that none of the simple approaches described here can capture all features of the stratospheric N2O isotope distribution, again justifying the use of 3-D models. 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 (possibly up to 100% for N2O mixing ratios above 300 nmol mol−1). Towards higher altitudes, the temperature dependence of these isotope correlations becomes visible in the stratospheric observations.
Balloon-borne stratospheric BrO measurements: comparison with Envisat/SCIAMACHY BrO limb profiles
(2006)
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.
During SPURT (Spurenstofftransport in der Tropopausenregion, trace gas transport in the tropopause region) we performed measurements of a wide range of trace gases with different lifetimes and sink/source characteristics in the northern hemispheric upper troposphere (UT) and lowermost stratosphere (LMS). A large number of in-situ instruments were deployed on board a Learjet 35A, flying at altitudes up to 13.7 km, at times reaching to nearly 380 K potential temperature. Eight measurement campaigns (consisting of a total of 36 flights), distributed over all seasons and typically covering latitudes between 35° N and 75° N in the European longitude sector (10° W–20° E), were performed. Here we present an overview of the project, describing the instrumentation, the encountered meteorological situations during the campaigns and the data set available from SPURT. Measurements were obtained for N2O, CH4, CO, CO2, CFC12, H2, SF6, NO, NOy, O3 and H2O. We illustrate the strength of this new data set by showing mean distributions of the mixing ratios of selected trace gases, using a potential temperature – equivalent latitude coordinate system. The observations reveal that the LMS is most stratospheric in character during spring, with the highest mixing ratios of O3 and NOy and the lowest mixing ratios of N2O and SF6. The lowest mixing ratios of NOy and O3 are observed during autumn, together with the highest mixing ratios of N2O and SF6 indicating a strong tropospheric influence. For H2O, however, the maximum concentrations in the LMS are found during summer, suggesting unique (temperature- and convection-controlled) conditions for this molecule during transport across the tropopause. The SPURT data set is presently the most accurate and complete data set for many trace species in the LMS, and its main value is the simultaneous measurement of a suite of trace gases having different lifetimes and physical-chemical histories. It is thus very well suited for studies of atmospheric transport, for model validation, and for investigations of seasonal changes in the UT/LMS, as demonstrated in accompanying and elsewhere published studies.
During several balloon flights inside the Arctic polar vortex in early 2003, unusual trace gas distributions were observed, which indicate a strong influence of mesospheric air in the stratosphere. The tuneable diode laser (TDL) instrument SPIRALE (Spectroscopie InFrarouge par Absorption de Lasers Embarqués) measured unusually high CO values (up to 600 ppb) on 27 January at about 30 km altitude. The cryosampler BONBON sampled air masses with very high molecular Hydrogen, extremely low SF6 and enhanced CO values on 6 March at about 25 km altitude. Finally, the MIPAS (Michelson Interferometer for Passive Atmospheric Sounding) Fourier Transform Infra-Red (FTIR) spectrometer showed NOy values which are significantly higher than NOy* (the NOy derived from a correlation between N2O and NOy under undisturbed conditions), on 21 and 22 March in a layer centred at 22 km altitude. Thus, the mesospheric air seems to have been present in a layer descending from about 30 km in late January to 25 km altitude in early March and about 22 km altitude on 20 March. We present corroborating evidence from a model study using the KASIMA (KArlsruhe Simulation model of the Middle Atmosphere) model that also shows a layer of mesospheric air, which descended into the stratosphere in November and early December 2002, before the minor warming which occurred in late December 2002 lead to a descent of upper stratospheric air, cutting of a layer in which mesospheric air is present. This layer then descended inside the vortex over the course of the winter. The same feature is found in trajectory calculations, based on a large number of trajectories started in the vicinity of the observations on 6 March. Based on the difference between the mean age derived from SF6 (which has an irreversible mesospheric loss) and from CO2 (whose mesospheric loss is much smaller and reversible) we estimate that the fraction of mesospheric air in the layer observed on 6 March, must have been somewhere between 35% and 100%.
Background Drug resistance to chemotherapy is often associated with increased malignancy in neuroblastoma (NB). One explanation for the link between resistance and malignancy might be that resistance facilitates cancer progression and invasion. To investigate this hypothesis, adhesion, transendothelial penetration and NCAM (CD56) adhesion receptor expression of drug-resistant versus drug-sensitive NB tumor cells were evaluated. Methods Acquired drug resistance was mimicked by exposing parental UKF-NB-2, UKF-NB-3 or IMR-32 tumor cells to increasing concentrations of vincristine- (VCR) or doxorubicin (DOX) to establish the resistant tumor cell sublines UKF-NB-2VCR, UKF-NB-2DOX, UKF-NB-3VCR, UKF-NB-3DOX, IMR-32VCR and IMR-32DOX. Additionally, the malignant behaviour of UKF-NB-4, which already possessed the intrinsic multidrug resistance (MDR) phenotype, was analyzed. UKF-NB-4 exposed to VCR or DOX were designated UKF-NB-4VCR or UKF-NB-4DOX. Combined phase contrast - reflection interference contrast microscopy was used to separately evaluate NB cell adhesion and penetration. NCAM was analyzed by flow cytometry, western blot and RT-PCR. Results VCR and DOX resistant tumor sublines showed enhanced adhesion and penetration capacity, compared to their drug naive controls. Strongest effects were seen with UKF-NB-2VCR, UKF-NB-3VCR and IMR-32DOX. DOX or VCR treatment also evoked increased invasive behaviour of UKF-NB-4. The process of accelerated tumor invasion was accompanied by decreased NCAM surface and protein expression, and down-regulation of NCAM coding mRNA. Transfection of UKF-NB-4VCR cells with NCAM cDNA led to a significant receptor up-regulation, paralleled by diminished adhesion to an endothelial cell monolayer. Conclusions It is concluded that NB cells resistant to anticancer drugs acquire increased invasive capacity relative to non-resistant parental cells, and that enhanced invasion is caused by strong down-regulation of NCAM adhesion receptors.
Oral presentations Background: We selected peptide ligands for the HIV-1 packaging signal PSI by screening phage displayed peptide libraries. Peptide ligands were optimized by screening spot synthesis peptide membranes. The aim of this study is the functional characterization of these peptide ligands with respect to inhibition of HIV-1 replication. Methods: Phage displayed peptide libraries were screened with PSI-RNA structures. The Trp-rich peptide motifs were optimized for specific binding on spot synthesis peptide membranes. The best binding peptide was expressed intracellularly in fusion with RFP or linked to a protein transduction domain (PTD) for intracellular delivery. The effects on virion production were analyzed using pseudotyped lentiviral particles. Results: After positive and negative selection rounds, phages binding specifically to PSI-RNA were identified by ELISA. Peptide inserts contained conserved motifs of aromatic amino acids known to be implicated in binding of PSI-RNA by the natural Gag ligand. The filter assay identified HKWPWW as the best binding ligand for PSI-RNA, which is delivered into several cell lines by addition of a PTD. Compared to a control peptide, the HKWPWW peptide inhibited HIV-1 replication as deduced from reduced titers of culture supernatants. As HKWPWW also binds to the TAR-RNA like the natural nucleocapsid PSI-RNA ligand, the effect on Tat-TAR inhibition will also be analyzed. Currently T-cell lines are established which stably express HKWPWW as well as a control peptide, which will be infected with HIV-1 to monitor the ability of HKWPWW to inhibit wild type HIV-1 replication. Conclusion: The selection of a peptide ligand for PSI-RNA able to inhibit HIV-1 replication proves the suitability of the phage display technology for the selection of peptides binding to RNA-structures. This enables the indentification of peptides serving as leads to interfere with additional targets in the HIV-1 replication cycle.
Background Anti-angiogenic treatment is believed to have at least cystostatic effects in highly vascularized tumours like pancreatic cancer. In this study, the treatment effects of the angiogenesis inhibitor Cilengitide and gemcitabine were compared with gemcitabine alone in patients with advanced unresectable pancreatic cancer. Methods A multi-national, open-label, controlled, randomized, parallel-group, phase II pilot study was conducted in 20 centers in 7 countries. Cilengitide was administered at 600 mg/m2 twice weekly for 4 weeks per cycle and gemcitabine at 1000 mg/m2 for 3 weeks followed by a week of rest per cycle. The planned treatment period was 6 four-week cycles. The primary endpoint of the study was overall survival and the secondary endpoints were progression-free survival (PFS), response rate, quality of life (QoL), effects on biological markers of disease (CA 19.9) and angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and safety. An ancillary study investigated the pharmacokinetics of both drugs in a subset of patients. Results Eighty-nine patients were randomized. The median overall survival was 6.7 months for Cilengitide and gemcitabine and 7.7 months for gemcitabine alone. The median PFS times were 3.6 months and 3.8 months, respectively. The overall response rates were 17% and 14%, and the tumor growth control rates were 54% and 56%, respectively. Changes in the levels of CA 19.9 went in line with the clinical course of the disease, but no apparent relationships were seen with the biological markers of angiogenesis. QoL and safety evaluations were comparable between treatment groups. Pharmacokinetic studies showed no influence of gemcitabine on the pharmacokinetic parameters of Cilengitide and vice versa. Conclusion There were no clinically important differences observed regarding efficacy, safety and QoL between the groups. The observations lay in the range of other clinical studies in this setting. The combination regimen was well tolerated with no adverse effects on the safety, tolerability and pharmacokinetics of either agent.
Ribosomal proteins are assumed to stabilize specific RNA structures and promote compact folding of the large rRNA. The conformational dynamics of the protein between the bound and unbound state play an important role in the binding process. We have studied those dynamical changes in detail for the highly conserved complex between the ribosomal protein L11 and the GTPase region of 23S rRNA. The RNA domain is compactly folded into a well defined tertiary structure, which is further stabilized by the association with the C-terminal domain of the L11 protein (L11ctd). In addition, the N-terminal domain of L11 (L11ntd) is implicated in the binding of the natural thiazole antibiotic thiostrepton, which disrupts the elongation factor function. We have studied the conformation of the ribosomal protein and its dynamics by NMR in the unbound state, the RNA bound state and in the ternary complex with the RNA and thiostrepton. Our data reveal a rearrangement of the L11ntd, placing it closer to the RNA after binding of thiostrepton, which may prevent binding of elongation factors. We propose a model for the ternary L11–RNA–thiostrepton complex that is additionally based on interaction data and conformational information of the L11 protein. The model is consistent with earlier findings and provides an explanation for the role of L11ntd in elongation factor binding.
Background: Growth rate is central to the development of cells in all organisms. However, little is known about the impact of changing growth rates. We used continuous cultures to control growth rate and studied the transcriptional program of the model eukaryote Saccharomyces cerevisiae, with generation times varying between 2 and 35 hours.
Results: A total of 5930 transcripts were identified at the different growth rates studied. Consensus clustering of these revealed that half of all yeast genes are affected by the specific growth rate, and that the changes are similar to those found when cells are exposed to different types of stress (>80% overlap). Genes with decreased transcript levels in response to faster growth are largely of unknown function (>50%) whereas genes with increased transcript levels are involved in macromolecular biosynthesis such as those that encode ribosomal proteins. This group also covers most targets of the transcriptional activator RAP1, which is also known to be involved in replication. A positive correlation between the location of replication origins and the location of growth-regulated genes suggests a role for replication in growth rate regulation.
Conclusion: Our data show that the cellular growth rate has great influence on transcriptional regulation. This, in turn, implies that one should be cautious when comparing mutants with different growth rates. Our findings also indicate that much of the regulation is coordinated via the chromosomal location of the affected genes, which may be valuable information for the control of heterologous gene expression in metabolic engineering.
Background Reliable taxonomic identification at the species level is the basis for many biological disciplines. In order to distinguish species, it is necessary that taxonomic characters allow for the separation of individuals into recognisable, homogeneous groups that differ from other such groups in a consistent way. We compared here the suitability and efficacy of traditionally used shell morphology and DNA-based methods to distinguish among species of the freshwater snail genus Radix (Basommatophora, Pulmonata). Results Morphometric analysis showed that shell shape was unsuitable to define homogeneous, recognisable entities, because the variation was continuous. On the other hand, the Molecularly defined Operational Taxonomic Units (MOTU), inferred from mitochondrial COI sequence variation, proved to be congruent with biological species, inferred from geographic distribution patterns, congruence with nuclear markers and crossing experiments. Moreover, it could be shown that the phenotypically plastic shell variation is mostly determined by the environmental conditions experienced. Conclusion Contrary to DNA-taxonomy, shell morphology was not suitable for delimiting and recognising species in Radix. As the situation encountered here seems to be widespread in invertebrates, we propose DNA-taxonomy as a reliable, comparable, and objective means for species identification in biological research.
Die Rolle des Kulturbildes im interkulturell motivierten Deutschunterricht am Beispiel des Iran
(2006)
Der Vortrag basiert auf meiner Dissertation über die "Interkulturelle Kommunikation an iranischen Sprachinstituten und Universitäten". Er setzt sich zunächst mit den Vorstellungen über die Kultur des deutschsprachigen Raums im Iran und dessen Reflexion in Unterrichtsprozessen auseinander. In diesem Zusammenhang wird die Rolle der Beziehung zwischen Kultur und Sprache im Fremdsprachenunterricht herausgearbeitet. Daher steht die Beschäftigung mit Kulturfragen im Mittelpunkt. Es handelt sich dabei vor allem um zwei typische Beispiele für "interkulturelle Missverständnisse", die bei iranischen Deutschlernenden in ihrem Verständnis der deutschen Kultur sehr häufig vorkommen. Zwei weitere Beispiele werden gezeigt, in denen die kontrastierten Kulturen miteinander übereinstimmen und somit eine feste und unproblematische Grundlage für den Umgang miteinander darstellen. Im Folgenden soll die Rolle der Deutschlehrer und der institutionellen Bedingungen im Unterricht analysiert werden. Gerade der Deutschunterricht in islamischen Ländern ist darauf angewiesen, dass der Lehrer Sprachsituationen bereitstellt, anhand derer er versucht, die von der Ausgangsgesellschaft stammenden interkulturellen Konflikte aufzugreifen und letztlich zu bewältigen. Meine Unterrichtsanalysen zeigen, dass diese Vorgehensweise der Lehrer ohne Steuerung der Institution nicht möglich ist. Da die interkulturell motivierte Deutschvermittlung institutionelle Voraussetzungen verlangt, stellt der Vortrag auch die Frage, ob eine regionale von den beiden Regierungen unabhängige Institution für die Beschäftigung mit den möglichen interkulturellen Konflikten notwendig ist und warum sie bis jetzt nicht zustande gekommen ist. Trotz der neusten politischen Bemühungen um die kulturellen Annäherungen zwischen beiden Ländern gelten immer noch beide Kulturen als "kontrastiert". Der Deutschunterricht in der iranischen Gesellschaft kann diese Kluft nur dann schmälern, wenn die Deutsch anbietenden Institutionen inter- und transkulturelle Aspekte stärker berücksichtigen.
Background The reciprocal (9;22) translocation fuses the bcr (breakpoint cluster region) gene on chromosome 22 to the abl (Abelson-leukemia-virus) gene on chromosome 9. Depending on the breakpoint on chromosome 22 (the Philadelphia chromosome – Ph+) the derivative 9+ encodes either the p40(ABL/BCR) fusion transcript, detectable in about 65% patients suffering from chronic myeloid leukemia, or the p96(ABL/BCR) fusion transcript, detectable in 100% of Ph+ acute lymphatic leukemia patients. The ABL/BCRs are N-terminally truncated BCR mutants. The fact that BCR contains Rho-GEF and Rac-GAP functions strongly suggest an important role in cytoskeleton modeling by regulating the activity of Rho-like GTPases, such as Rho, Rac and cdc42. We, therefore, compared the function of the ABL/BCR proteins with that of wild-type BCR. Methods We investigated the effects of BCR and ABL/BCRs i.) on the activation status of Rho, Rac and cdc42 in GTPase-activation assays; ii.) on the actin cytoskeleton by direct immunofluorescence; and iii) on cell motility by studying migration into a three-dimensional stroma spheroid model, adhesion on an endothelial cell layer under shear stress in a flow chamber model, and chemotaxis and endothelial transmigration in a transwell model with an SDF-1α gradient. Results Here we show that both ABL/BCRs lost fundamental functional features of BCR regarding the regulation of small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells. Conclusion Our data presented here describe for the first time an analysis of the biological function of the reciprocal t(9;22) ABL/BCR fusion proteins in comparison to their physiological counterpart BCR.
Gute naturwissenschaftliche Vorkenntnisse sind insbesondere für den vorklinischen Studienabschnitt wichtig. Wegen der heterogenen Auswahl von Leistungskursen und Abituranforderungen kann jedoch nicht unbedingt von einem einheitlichen Wissensstand ausgegangen werden. Daher wurde versucht, mit einem Testbogen aus insgesamt 40 Aufgaben zur Biologie, Chemie, Mathematik und Physik den Wissensstand der Studienanfänger in Humanmedizin in Deutschland zu quantifizieren. Der Fragebogen enthielt neben Faktenaufgaben auch Anwendungen vor allem mathematischer und chemischer Prinzipien. Alle Fragen mussten durch Freitextantworten oder Skizzen beantwortet werden. Teilgenommen haben insgesamt 2 935 Studienanfänger des Wintersemesters 2004/2005 von 14 deutschen Universitäten (etwa 40% des Jahrganges). Im Mittel wurden 14,34 der 40 Aufgaben richtig beantwortet; etwas bessere Kenntnisse wurden in den 15 Biologiefragen (6,89) und den 8 Mathematikfragen erreicht (3,23), während vor allem in Chemie (2,18 von 10 Fragen) und Physik (1,55 von 8 Fragen) große Wissenslücken bestehen. Die Ergebnisse bestätigen, dass die naturwissenschaftlichen Vorkenntnisse der Studienanfänger schlecht sind; sie erfordern einen größeren Zeitaufwand für die Vermittlung des Abiturwissens im ersten vorklinischen Semester. Sinnvoll erscheint alternativ die verpflichtende Teilnahme an Zusatzkursen in diesen Fächern vor Aufnahme des eigentlichen Fachstudiums.
Mit der Neuregelung der Studienplatzverteilung von 2005 haben die Universitäten in Deutschland die Möglichkeit, bis zu 60% der Studienplätze nach universitätseigenen Kriterien zu vergeben. Implizit wird vom Gesetzgeber und der öffentlichen Meinung gefordert, nicht-leistungsbezogene Kriterien und Persönlichkeitsmerkmale verstärkt zur Bewerberauswahl einzusetzen (Motivation, Identifikation, Vermeidung von Fehlvorstellungen). Da in Anbetracht der Bewerberzahlen mündliche Auswahlgespräche als ungeeignet erscheinen, wurde vom Fachbereich Medizin der Johann Wolfgang Goethe Universität ein Fragebogen entworfen, um nichtschulische Leistungen zu erfassen. Dieser Fragebogen wurde am Beginn des Wintersemesters 2005/2006 von allen Studienanfängern der JWG-Universität Frankfurt und der Medizinischen Universität Innsbruck ausgefüllt. Entgegen der initialen Erwartungen der Verfasser gaben nur etwa 15% Prozent Medizin-spezifische berufliche Vorerfahrungen an (Rettungsdienst, Ausbildung als Krankenschwester/pfleger oder ähnliches); dagegen wurden von etwa 60% angegeben, mindestens ein Musikinstrument zu spielen oder länger sportlich aktiv gewesen zu sein. Die Zusammenstellung der Selbstangaben zeigt, dass Medizin-relevante Vorkenntnisse nur bei einem kleinen Anteil der Studienbewerber in größerem Umfang vorhanden sind. Aufgrund der großen Streuung in der Art und Dauer der angegebenen Vorleistungen sollte die Erhebung von Parametern zur Beurteilung von soft skills, z.B. durch Online-Fragebogen, als (Vor)Selektionsinstrument nur sehr vorsichtig eingesetzt werden.
Maßgeblich unter dem wachsenden externen Druck hat die didaktische Qualifizierung in den medizinischen Fakultäten an Bedeutung gewonnen. Im Rahmen der Professionalisierung der medizinischen Aus-, Fort- und Weiterbildung ist eine pädagogisch-didaktische Ausbildung der Lehrenden unumgänglich. Um Orientierung und Argumentationshilfe zu geben, werden in einer dreiteiligen Artikelfolge Stellenwert der Medizindidaktik, Anforderungsprofil der Angebote und Konzepte zur Implementierung und zur Erfolgsmessung für den deutschsprachigen Raum beleuchtet. In Teil II beleuchten wir den Ausbildungsbedarf und erstellen ein Anforderungsprofil für ein strukturiertes systematisches Qualifizierungsangebot. Der Hauptbedarf besteht in der Qualifizierung der Lehrenden, die den täglichen Unterricht durchführen. Insbesondere sie brauchen das Handwerkszeug, das ihnen erlaubt, ihre verschiedenen Lehraufgaben effizienter zu bewältigen. Seitens der Fakultät und der Studierenden bestehen Ansprüche an qualifizierte Lehrende; ebenso bestehen Forderungen seitens der Lehrenden an adäquat qualifizierende Kurse. Zur Umsetzung dieser berechtigten Ansprüche sind modular aufgebaute Programme nötig, die eine zumindest national qualitativ und quantitativ vergleichbare Ausbildung gewährleisten. Anforderungen an derartige Kurse sind bereits definiert und lokal zum Beispiel in Baden-Württemberg und zum Teil auch in Nordrhein-Westfalen umgesetzt. Es gilt nun, diese auf breiter Basis in die Praxis umzusetzen.
Alle Leistungsnachweise des klinischen Studienabschnittes nach neuer Ärztlicher Approbationsordnung müssen benotet werden; hierzu sind in der Regel schriftliche Prüfungen notwendig. Bisher erprobte Methoden beinhalten die Prüfung passiven Wissens (Einfachauswahlfragen, multiple choice-Fragen, progress test-Fragen) und aktiven Wissens (short essay questions, long essay questions). Vor- und Nachteile dieser Verfahren werden diskutiert, sowie die zur Erstellung, Durchführung und Auswertung schriftlicher Prüfungen notwendigen Ressourcen.
Maßgeblich unter dem wachsenden externen Druck hat die didaktische Qualifizierung in den medizinischen Fakultäten an Bedeutung gewonnen. Im Rahmen der Professionalisierung der medizinischen Aus-, Fort- und Weiterbildung ist eine pädagogisch-didaktische Ausbildung der Lehrenden unumgänglich. Um Orientierung und Argumentationshilfe zu geben, werden in einer dreiteiligen Artikelfolge Stellenwert der Medizindidaktik, Anforderungsprofil der Angebote und Konzepte zur Implementierung und zur Erfolgsmessung für den deutschsprachigen Raum beleuchtet. In Teil I geben wir eine Bestandsaufnahme zur Medizindidaktik. Aktuell gibt es bundesweit ein breit gefächertes Qualifizierungsangebot. Es reicht von einfachen unstrukturierten Kurzfortbildungen wie zum Beispiel Vorträgen und Seminaren, die inhaltlich, formal und qualitativ eine große Beliebigkeit zeigen, bis hin zu umfassenden mehrjährigen (Aufbau-)Studiengängen mit "Master-Degree". Im internationalen Vergleich fehlt in Deutschland ein allgemein verbindliches "Basis-Programm", das die täglich Lehrenden systematisch auf ihre Ausbildungsaufgaben vorbereitet. Dies ist bisher nur lokal umgesetzt wie zum Beispiel in Baden-Württemberg mit dem ministeriell zertifizierten Programm der Medizindidaktischen Qualifikation I und II. Vergleichbares ist in Nordrhein-Westfalen und Bayern im Aufbau.
The interaction of T cells and antigen-presenting cells is central to adaptive immunity and involves the formation of immunological synapses in many cases. The surface molecules of the cells form a characteristic spatial pattern whose formation mechanisms and function are largely unknown. We perform computer simulations of recent experiments on geometrically repatterned immunological synapses and explain the emerging structure as well as the formation dynamics. Only the combination of in vitro experiments and computer simulations has the potential to pinpoint the kind of interactions involved. The presented simulations make clear predictions for the structure of the immunological synapse and elucidate the role of a self-organizing attraction between complexes of T cell receptor and peptide–MHC molecule, versus a centrally directed motion of these complexes.
Aim of the study: Investigation, whether water-filtered infrared-A (wIRA) irradiation during moderate bicycle ergometer endurance exercise has effects especially on local fat reduction and on weight reduction beyond the effects of ergometer exercise alone.
Methods: Randomised controlled study with 40 obese females (BMI 30-40 (median: 34.5), body weight 76-125 (median: 94.9) kg, age 20-40 (median: 35.5) years, isocaloric nutrition), 20 in the wIRA group and 20 in the control group. In both groups each participant performed 3 times per week over 4 weeks for 45 minutes bicycle ergometer endurance exercise with a constant load according to a lactate level of 2 mmol/l (aerobic endurance load, as determined before the intervention period). In the wIRA group in addition large parts of the body (including waist, hip, and thighs) were irradiated during all ergometries of the intervention period with visible light and a predominant part of water-filtered infrared-A (wIRA), using the irradiation unit “Hydrosun® 6000” with 10 wIRA radiators (Hydrosun® Medizintechnik, Müllheim, Germany, radiator type 500, 4 mm water cuvette, yellow filter, water-filtered spectrum 500-1400 nm) around a speed independent bicycle ergometer.
Main variable of interest: change of “the sum of circumferences of waist, hip, and both thighs of each patient” over the intervention period (4 weeks). Additional variables of interest: body weight, body mass index BMI, body fat percentage, fat mass, fat-free mass, water mass (analysis of body composition by tetrapolar bioimpedance analysis), assessment of an arteriosclerotic risk profile by blood investigation of variables of lipid metabolism (cholesterol, triglycerides, high density lipoproteins HDL, low density lipoproteins LDL, apolipoprotein A1, apolipoprotein B), clinical chemistry (fasting glucose, alanin-aminotransferase ALT (= glutamyl pyruvic transaminase GPT), gamma-glutamyl-transferase GGT, creatinine, albumin), endocrinology (leptin, adiponectin (= adipo Q), homocysteine, insulin). All variables were at least measured before and after the intervention period. Ergometry (ECG, blood pressure behaviour, lactate curve with power at 2, 3 and 4 mmol/l) before the intervention period. In addition: nutrition training ahead of and during the intervention period with a nutrition protocol over one week for assessment of the daily energy intake; calculation of basic metabolic rate and total energy requirement. Assessment of undesired effects.
Only methods of non-parametric statistics were used, both descriptive (median, percentiles of 25 and 75 (= interquartile range), minimum, maximum) and confirmatory (two-sided Mann-Whitney U test for unpaired samples for the only one main variable of interest). Total error probability: .05 (5%). An intention to treat analysis ITT with last observed carry forward method was used preferably (presented results) and in addition an on treatment analysis OT. Only 2 (treatment group) and 4 (control group) drop-outs occurred (mostly due to lack of time).
Results: The “sum of circumferences of waist, hip, and both thighs of each patient” decreased during the 4 weeks significantly more (p<.001) in the wIRA group than in the control group: medians and interquartile ranges: -8.0 cm (-10.5 cm/-4.1 cm) vs. -1.8 cm (-4.4 cm/0.0 cm).
As well “body weight of each patient” decreased during the 4 weeks markedly more in the wIRA group than in the control group: medians and interquartile ranges: -1.9 kg (-4.0 kg/0.0 kg) vs. 0.0 kg (-1.5 kg/+0.4 kg); median of body weight changed from 99.3 kg to 95.6 kg (wIRA) vs. 89.9 kg to 89.6 kg (control). A similar effect showed the body mass index BMI.
Blood variables of interest remained unchanged or showed some slight improvements during the treatment period, concerning most variables with no obvious differences between the two groups; insulin showed a slight trend to decrease in the wIRA group and to increase in the control group.
Undesired effects of the treatment were not seen.
Discussion: The results of the study suggest, that wIRA – during moderate bicycle ergometer endurance exercise as lipolytic stimulus – increases local lipolysis with a local fat reduction (thighs) in the otherwise bradytrophic fatty tissue. The presumably underlying mechanisms of wIRA have already been proven: wIRA acts both by thermal effects and by non-thermal effects. Thermal effects of wIRA are the generation of a therapeutic field of warmth with the increase of tissue temperature, tissue oxygen partial pressure, and tissue blood flow, and by this regional metabolism. As fatty tissue normally has a slow metabolism (bradytrophic and hypothermic tissue) with a low rate of lipolysis, wIRA can increase lipolysis in fatty tissue and the mobilized fats are burned in musculature during the ergometer exercise.
Conclusion: The results of the study indicate, that wIRA irradiation during moderate ergometer endurance exercise can be used – in combination with an appropriate nutrition – to improve body composition, especially local fat distribution, and the reduction of fat and body weight in obese persons.
RNA interference (RNAi) has emerged as a powerful tool to induce loss-of-function phenotypes by post-transcriptional silencing of gene expression. In this study we wondered whether inducible RNAi-cassettes integrated into cellular DNA possess the power to trigger neoplastic growth. For this purpose inducible RNAi vectors containing tetracycline (Tet)-responsive derivatives of the H1 promoter for the conditional expression of short hairpin RNA (shRNA) were used to target human polo-like kinase 1 (Plk1), which is overexpressed in a broad spectrum of human tumors. In the absence of doxycycline (Dox) HeLa clones expressing TetR, that carry the RNAi-cassette stably integrated, exhibited no significant alteration in Plk1 expression levels. In contrast, exposure to Dox led to marked downregulation of Plk1 mRNA to 3% and Plk1 protein to 14% in cell culture compared to mismatch shRNA/Plk1-expressing cells. As a result of Plk1 depletion cell proliferation decreased to 17%. Furthermore, for harnessing RNAi for silencing disease-related genes in vivo we transplanted inducible RNAi-HeLa cells onto nude mice. After administration of Dox knockdown of Plk1 expression was observed correlating to a significant inhibition of tumor growth. Taken together, our data revealed that genomically integrated RNAi-elements are suitable to hamper tumor growth by conditional expression of shRNA.
Natural objects provide partially redundant information to the brain through different sensory modalities. For example, voices and faces both give information about the speech content, age, and gender of a person. Thanks to this redundancy, multimodal recognition is fast, robust, and automatic. In unimodal perception, however, only part of the information about an object is available. Here, we addressed whether, even under conditions of unimodal sensory input, crossmodal neural circuits that have been shaped by previous associative learning become activated and underpin a performance benefit. We measured brain activity with functional magnetic resonance imaging before, while, and after participants learned to associate either sensory redundant stimuli, i.e. voices and faces, or arbitrary multimodal combinations, i.e. voices and written names, ring tones, and cell phones or brand names of these cell phones. After learning, participants were better at recognizing unimodal auditory voices that had been paired with faces than those paired with written names, and association of voices with faces resulted in an increased functional coupling between voice and face areas. No such effects were observed for ring tones that had been paired with cell phones or names. These findings demonstrate that brief exposure to ecologically valid and sensory redundant stimulus pairs, such as voices and faces, induces specific multisensory associations. Consistent with predictive coding theories, associative representations become thereafter available for unimodal perception and facilitate object recognition. These data suggest that for natural objects effective predictive signals can be generated across sensory systems and proceed by optimization of functional connectivity between specialized cortical sensory modules.
Background The proto-oncogene pituitary tumor-transforming gene (PTTG) has been shown to be abundantly overexpressed in a large variety of neoplasms likely promoting neo-vascularization and tumor invasiveness. In this study, we investigated a potential role for PTTG mRNA expression as a marker to evaluate the future clinical outcome of patients diagnosed with primary cancer of the head and neck. Methods Tumor samples derived from primary tumors of 89 patients suffering from a squamous cell carcinoma were analyzed for PTTG mRNA-expression and compared to corresponding unaffected tissue. Expression levels were correlated to standard clinico-pathological parameters based on a five year observation period. Results In almost all 89 tumor samples PTTG was found to be overexpressed (median fold increase: 2.1) when compared to the unaffected tissue specimens derived from the same patient. The nodal stage correlated with PTTG transcript levels with significant differences between pN0 (median expression: 1.32) and pN+ (median expression: 2.12; P = 0.016). In patients who developed a tumor recurrence we detected a significantly higher PTTG expression in primary tumors (median expression: 2.63) when compared to patients who did not develop a tumor recurrence (median expression: 1.29; P = 0.009). Since the median expression of PTTG in patients with tumor stage T1/2N0M0 that received surgery alone without tumor recurrence was 0.94 versus 3.82 in patients suffering from a tumor recurrence (P = 0.006), PTTG expression might provide a feasible mean of predicting tumor recurrence. Conclusion Elevated PTTG transcript levels might be used as a prognostic biomarker for future clinical outcome (i.e. recurrence) in primary squamous cell carcinomas of the head and neck, especially in early stages of tumor development.
Background: PPARs exhibit anti-inflammatory capacities and are potential modulators of the inflammatory response. We hypothesized that their expression and/or function may be altered in cystic fibrosis (CF), a disorder characterized by an excessive host inflammatory response.
Methods: PPARα, β and γ mRNA levels were measured in peripheral blood cells of CF patients and healthy subjects via RT-PCR. PPARα protein expression and subcellular localization was determined via western blot and immunofluorescence, respectively. The activity of PPARα was analyzed by gel shift assay.
Results: In lymphocytes, the expression of PPARα mRNA, but not of PPARβ, was reduced (-37%; p < 0.002) in CF patients compared with healthy persons and was therefore further analyzed. A similar reduction of PPARα was observed at protein level (-26%; p < 0.05). The transcription factor was mainly expressed in the cytosol of lymphocytes, with low expression in the nucleus. Moreover, DNA binding activity of the transcription factor was 36% less in lymphocytes of patients (p < 0.01). For PPARα and PPARβ mRNA expression in monocytes and neutrophils, no significant differences were observed between CF patients and healthy persons. In all cells, PPARγ mRNA levels were below the detection limit.
Conclusion: Lymphocytes are important regulators of the inflammatory response by releasing cytokines and antibodies. The diminished lymphocytic expression and activity of PPARα may therefore contribute to the inflammatory processes that are observed in CF.
In den Jahren 1992-1999, 2001 und 2002 wurden vom Landesmuseum Kärnten am Zollfeld (KG Maria Saal, pol. Bez. Klagenfurt Land) archäologische Untersuchungen im westlichen Stadtrandbereich des Municipium Claudium Virunum durchgeführt. Dabei wurde der Ostteil zweier Insulae erfasst, die durch den Ost-West verlaufenden Cardo Maximus voneinander getrennt werden. Im Zuge der Ausgrabungen konnte auch eine große Zahl an Wandmalereifragmenten geborgen werden. Der überwiegende Teil kam zwar nur noch in Form von klein- bis kleinstteiligen Fragmenten zu Tage, die Menge der Fundstücke und die Tatsache, dass es sich bei diesen um die ersten stratifizierbaren Wandmalereien der Provinzhauptstadt Noricums handelt, machte eine ausführliche Bearbeitung des Materials notwendig. Im Zuge der Bearbeitung konnten auch zwei Rekonstruktionsversuche erarbeitet werden, die hier im Anschluss vorgestellt werden sollen
Hazar Lake sunken city
(2006)
Background While there is enough convincing evidence in childhood acute lymphoblastic leukemia (ALL), the data on the pre-natal origin in childhood acute myeloid leukemia (AML) are less comprehensive. Our study aimed to screen Guthrie cards (neonatal blood spots) of non-infant childhood AML and ALL patients for the presence of their respective leukemic markers. Methods We analysed Guthrie cards of 12 ALL patients aged 2–6 years using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements (n = 15) and/or intronic breakpoints of TEL/AML1 fusion gene (n = 3). In AML patients (n = 13, age 1–14 years) PML/RARalpha (n = 4), CBFbeta/MYH11 (n = 3), AML1/ETO (n = 2), MLL/AF6 (n = 1), MLL/AF9 (n = 1) and MLL/AF10 (n = 1) fusion genes and/or internal tandem duplication of FLT3 gene (FLT3/ITD) (n = 2) were used as clonotypic markers. Assay sensitivity determined using serial dilutions of patient DNA into the DNA of a healthy donor allowed us to detect the pre-leukemic clone in Guthrie card providing 1–3 positive cells were present in the neonatal blood spot. Results In 3 patients with ALL (25%) we reproducibly detected their leukemic markers (Ig/TCR n = 2; TEL/AML1 n = 1) in the Guthrie card. We did not find patient-specific molecular markers in any patient with AML. Conclusion In the largest cohort examined so far we used identical approach for the backtracking of non-infant childhood ALL and AML. Our data suggest that either the prenatal origin of AML is less frequent or the load of pre-leukemic cells is significantly lower at birth in AML compared to ALL cases.
Background: Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties. Methods and Findings: Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318–510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one. Conclusions: The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. At the same time, synergy between CR3014 and CR3022 may allow for a lower total antibody dose to be administered for passive immune prophylaxis of SARS-CoV infection.
In Zeiten des nahezu uneingeschränkten Computereinsatzes gewinnen die Software – Sicherheit und Software – Verlässlichkeit immer mehr an Bedeutung. Dies trifft sowohl für die Neuentwicklung als auch für die Wartung und Pflege von Software – Systemen zu. In sicherheitsrelevanten, lebenserhaltenden Systemen, wie beispielsweise im medizinischen Bereich, im Bereich der Steuerung von Sicherheitssystemen in Kraftfahrzeugen, in technischen Anwendungen mit Mikroprozessunterstützung und ähnlichen Anwendungsgebieten ist es notwendiger denn je, äußerst stabile, sichere und verlässliche Software - Systeme einzusetzen. ...
Antileukoproteinase (ALP) is a physiological inhibitor of granulocytic serine proteases that has been shown to have anti-inflammatory properties in addition to its antiproteolytic activity. On the basis of its potential to block anti-collagen type II (CII) antibody-induced arthritis (CAIA) and to suppress the conformational activation of β2-integrins in leukocytes, the present study was undertaken to investigate its interference with leukocyte adherence to cytokine-activated endothelium. The potential of recombinant ALP to block the interactions of leukocytes with the endothelial lining was concomitantly investigated in vitro and in vivo. Thus, intravital fluorescence microscopic imaging of leukocyte rolling and firm adhesion to postcapillary venules were performed in the knee joints of DBA1/J mice after intravenous injection of anti-CII mAbs. An IL-1β-activated endothelial layer formed by a murine glomerular cell line (glEND.2) was used to assay the interaction with human leukocytes in vitro. Electromobility shift and luciferase reporter gene assays permitted the analysis of cytokine-induced activation of the NF-κB pathway. Fluorescence-activated cell sorting was applied to determine endothelial E-selectin expression. Leukocyte rolling and firm adhesion to the synovial endothelium in an early response to the anti-CII antibody transfer were significantly decreased in ALP-pretreated mice. Concomitantly, ALP suppressed the IL-1β-induced NF-κB activation and the upregulation of E-selectin expression in glEND.2 cells in vitro. These findings support the notion that the newly uncovered properties of ALP to interfere with cytokine signalling and upregulation of adhesion molecules in endothelial cells are likely to contribute to the therapeutic potential of ALP in immune-complex-induced tissue injury.
Introduction: Intoxications with carbachol, a muscarinic cholinergic receptor agonist are rare. We report an interesting case investigating a (near) fatal poisoning. Methods: The son of an 84-year-old male discovered a newspaper report stating clinical success with plant extracts in Alzheimer's disease. The mode of action was said to be comparable to that of the synthetic compound 'carbamylcholin'; that is, carbachol. He bought 25 g of carbachol as pure substance in a pharmacy, and the father was administered 400 to 500 mg. Carbachol concentrations in serum and urine on day 1 and 2 of hospital admission were analysed by HPLC-mass spectrometry. Results: Minutes after oral administration, the patient developed nausea, sweating and hypotension, and finally collapsed. Bradycardia, cholinergic symptoms and asystole occurred. Initial cardiopulmonary resuscitation and immediate treatment with adrenaline (epinephrine), atropine and furosemide was successful. On hospital admission, blood pressure of the intubated, bradyarrhythmic patient was 100/65 mmHg. Further signs were hyperhidrosis, hypersalivation, bronchorrhoea, and severe miosis; the electrocardiographic finding was atrio-ventricular dissociation. High doses of atropine (up to 50 mg per 24 hours), adrenaline and dopamine were necessary. The patient was extubated 1 week later. However, increased dyspnoea and bronchospasm necessitated reintubation. Respiratory insufficiency was further worsened by Proteus mirabilis infection and severe bronchoconstriction. One week later, the patient was again extubated and 3 days later was transferred to a peripheral ward. On the next day he died, probably as a result of heart failure. Serum samples from the first and second days contained 3.6 and 1.9 mg/l carbachol, respectively. The corresponding urine concentrations amounted to 374 and 554 mg/l. Conclusion: This case started with a media report in a popular newspaper, initiated by published, peer-reviewed research on herbals, and involved human failure in a case history, medical examination and clinical treatment. For the first time, an analytical method for the determination of carbachol in plasma and urine has been developed. The analysed carbachol concentration exceeded the supposed serum level resulting from a therapeutic dose by a factor of 130 to 260. Especially in old patients, intensivists should consider intoxications (with cholinergics) as a cause of acute cardiovascular failure.
Background Fermentation of lignocellulosic biomass is an attractive alternative for the production of bioethanol. Traditionally, the yeast Saccharomyces cerevisiae is used in industrial ethanol fermentations. However, S. cerevisiae is naturally not able to ferment the pentose sugars D-xylose and L-arabinose, which are present in high amounts in lignocellulosic raw materials. Results We describe the engineering of laboratory and industrial S. cerevisiae strains to co-ferment the pentose sugars D-xylose and L-arabinose. Introduction of a fungal xylose and a bacterial arabinose pathway resulted in strains able to grow on both pentose sugars. Introduction of a xylose pathway into an arabinose-fermenting laboratory strain resulted in nearly complete conversion of arabinose into arabitol due to the L-arabinose reductase activity of the xylose reductase. The industrial strain displayed lower arabitol yield and increased ethanol yield from xylose and arabinose. Conclusion Our work demonstrates simultaneous co-utilization of xylose and arabinose in recombinant strains of S. cerevisiae. In addition, the co-utilization of arabinose together with xylose significantly reduced formation of the by-product xylitol, which contributed to improved ethanol production.
Background: Particle Swarm Optimization (PSO) is an established method for parameter optimization. It represents a population-based adaptive optimization technique that is influenced by several "strategy parameters". Choosing reasonable parameter values for the PSO is crucial for its convergence behavior, and depends on the optimization task. We present a method for parameter meta-optimization based on PSO and its application to neural network training. The concept of the Optimized Particle Swarm Optimization (OPSO) is to optimize the free parameters of the PSO by having swarms within a swarm. We assessed the performance of the OPSO method on a set of five artificial fitness functions and compared it to the performance of two popular PSO implementations. Results: Our results indicate that PSO performance can be improved if meta-optimized parameter sets are applied. In addition, we could improve optimization speed and quality on the other PSO methods in the majority of our experiments. We applied the OPSO method to neural network training with the aim to build a quantitative model for predicting blood-brain barrier permeation of small organic molecules. On average, training time decreased by a factor of four and two in comparison to the other PSO methods, respectively. By applying the OPSO method, a prediction model showing good correlation with training-, test- and validation data was obtained. Conclusion: Optimizing the free parameters of the PSO method can result in performance gain. The OPSO approach yields parameter combinations improving overall optimization performance. Its conceptual simplicity makes implementing the method a straightforward task.
The existence of a mean-square continuous strong solution is established for vector-valued Itö stochastic differential equations with a discontinuous drift coefficient, which is an increasing function, and with a Lipschitz continuous diffusion coefficient. A scalar stochastic differential equation with the Heaviside function as its drift coefficient is considered as an example. Upper and lower solutions are used in the proof.
In November 2005, a survey was begun of the wells in and around Hagia Sophia Church in Istanbul. The long-term goal of the survey is the understanding of the function of the tunnels and the water systems used for Hagia Sophia and its surroundings during the Byzantine and the Ottoman periods. Alternate research methods, such as geophysical research, will be used in future surveys. The 2005 survey examined the channels that run from under the narthex and continue northwards and the southwards of the building as well as channels that run towards the atrium, hippodrome, and garden in the north. The survey resulted in the first photos of the well-bottoms in the history of Hagia Sophia.
Gene trapping is a method of generating murine embryonic stem (ES) cell lines containing insertional mutations in known and novel genes. A number of international groups have used this approach to create sizeable public cell line repositories available to the scientific community for the generation of mutant mouse strains. The major gene trapping groups worldwide have recently joined together to centralize access to all publicly available gene trap lines by developing a user-oriented Website for the International Gene Trap Consortium (IGTC). This collaboration provides an impressive public informatics resource comprising ~45 000 well-characterized ES cell lines which currently represent ~40% of known mouse genes, all freely available for the creation of knockout mice on a non-collaborative basis. To standardize annotation and provide high confidence data for gene trap lines, a rigorous identification and annotation pipeline has been developed combining genomic localization and transcript alignment of gene trap sequence tags to identify trapped loci. This information is stored in a new bioinformatics database accessible through the IGTC Website interface. The IGTC Website (www.genetrap.org) allows users to browse and search the database for trapped genes, BLAST sequences against gene trap sequence tags, and view trapped genes within biological pathways. In addition, IGTC data have been integrated into major genome browsers and bioinformatics sites to provide users with outside portals for viewing this data. The development of the IGTC Website marks a major advance by providing the research community with the data and tools necessary to effectively use public gene trap resources for the large-scale characterization of mammalian gene function.
Das Projekt LaMedica (http://www.lamedica.de) hat zum Ziel, eine multimediale Lehr- und Lernplattform zu entwickeln, Inhalte für die Medizin zu erstellen und diese in die Lehre zu implementieren. Es wurde eine on-line Autorenumgebung geschaffen, die sehr unterschiedliche didaktische Ansätze unterstützt: systematische und vernetzte Wissensvermittlung, fallbasiertes Lernen, Erstellung von Vorlesungen und Lernerfolgskontrolle. Die Lehrinhalte können zielgruppenspezifisch aufbereitet und dargestellt werden und richten sich insbesondere an Studenten, Ärzte in der Weiterbildung und Fachärzte. Eine on-line Medien-Datenbank unterstützt die Wiederverwendung und den Austausch von Inhalten auf der Basis eines Content-Management-Systems durch Verwendung des Learning Objects Metadata Standards (LOM). Die Förderung erfolgt durch das BMBF (FKZ NM054A).
Celiac disease
(2006)
Celiac disease is a chronic intestinal disease caused by intolerance to gluten. It is characterized by immune-mediated enteropathy, associated with maldigestion and malabsorption of most nutrients and vitamins. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. The main symptoms are: stomach pain, gas, and bloating, diarrhea, weight loss, anemia, edema, bone or joint pain. Prevalence for clinically overt celiac disease varies from 1:270 in Finland to 1:5000 in North America. Since celiac disease can be asymptomatic, most subjects are not diagnosed or they can present with atypical symptoms. Furthermore, severe inflammation of the small bowel can be present without any gastrointestinal symptoms. The diagnosis should be made early since celiac disease causes growth retardation in untreated children and atypical symptoms like infertility or neurological symptoms. Diagnosis requires endoscopy with jejunal biopsy. In addition, tissue-transglutaminase antibodies are important to confirm the diagnosis since there are other diseases which can mimic celiac disease. The exact cause of celiac disease is unknown but is thought to be primarily immune mediated (tissue-transglutaminase autoantigen); often the disease is inherited. Management consists in life long withdrawal of dietary gluten, which leads to significant clinical and histological improvement. However, complete normalization of histology can take years.