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Cryo-electron tomography provides a snapshot of the cellular proteome. With template matching, the spatial positions of various macromolecular complexes within their native cellular context can be detected. However, the growing awareness of the reference bias introduced by the cross-correlation based approaches, and more importantly the lack of a reliable confidence measurement in the selection of these macromolecular complexes, has restricted the use of these applications. Here we propose a heuristic, in which the reference bias is measured in real space in an analogous way to the R-free value in X-ray crystallography. We measure the reference bias within the mask used to outline the area of the template, and do not modify the template itself. The heuristic works by splitting the mask into a working and a testing area in a volume ratio of 9:1. While the working area is used during the calculation of the cross-correlation function, the information from both areas is explored to calculate the M-free score. We show using artificial data, that the M-free score gives a reliable measure for the reference bias. The heuristic can be applied in template matching and in sub-tomogram averaging. We further test the applicability of the heuristic in tomograms of purified macromolecules, and tomograms of whole Mycoplasma cells.
Correlative microscopy incorporates the specificity of fluorescent protein labeling into high-resolution electron micrographs. Several approaches exist for correlative microscopy, most of which have used the green fluorescent protein (GFP) as the label for light microscopy. Here we use chemical tagging and synthetic fluorophores instead, in order to achieve protein-specific labeling, and to perform multicolor imaging. We show that synthetic fluorophores preserve their post-embedding fluorescence in the presence of uranyl acetate. Post-embedding fluorescence is of such quality that the specimen can be prepared with identical protocols for scanning electron microscopy (SEM) and transmission electron microscopy (TEM); this is particularly valuable when singular or otherwise difficult samples are examined. We show that synthetic fluorophores give bright, well-resolved signals in super-resolution light microscopy, enabling us to superimpose light microscopic images with a precision of up to 25 nm in the x-y plane on electron micrographs. To exemplify the preservation quality of our new method we visualize the molecular arrangement of cadherins in adherens junctions of mouse epithelial cells.
Bacteria have adapted their NhaA Na(+)/H(+) exchangers responsible for salt homeostasis to their different habitats. We present an electrophysiological and kinetic analysis of NhaA from Helicobacter pylori and compare it to the previously investigated exchangers from Escherichia coli and Salmonella typhimurium. Properties of all three transporters are described by a simple model using a single binding site for H(+) and Na(+). We show that H.pylori NhaA only has a small acidic shift of its pH-dependent activity profile compared to the other transporters and discuss why a more drastic change in its pH activity profile is not physiologically required.
Survivin is a well-established target in experimental cancer therapy. The molecule is over-expressed in most human tumors, but hardly detectable in normal tissues. Multiple functions in different subcellular compartments have been assigned. It participates in the control of cell division, apoptosis, the cellular stress response, and also in the regulation of cell migration and metastasis. Survivin expression has been recognized as a biomarker: high expression indicates an unfavorable prognosis and resistance to chemotherapeutic agents and radiation treatment. Survivin is an unconventional drug target and several indirect approaches have been exploited to affect its function and the phenotype of survivin-expressing cells. Interference with the expression of the survivin gene, the utilization of its messenger RNA, the intracellular localization, the interaction with binding partners, the stability of the survivin protein, and the induction of survivin-specific immune responses have been taken into consideration. A direct strategy to inhibit survivin has been based on the identification of a specifically interacting peptide. This peptide can recognize survivin intracellularly and cause the degradation of the ligand–survivin complex. Technology is being developed that might allow the derivation of small molecular-weight, drug-like compounds that are functionally equivalent to the peptide ligand.
Die Naturwissenschaften waren von den teilweise gewalttätigen Auseinandersetzungen der Studentenproteste Ende der 1960er Jahre nicht an erster Stelle betroffen. Insbesondere das Pharmaziestudium mit seinem zeitintensiven, streng geregelten und durch Laborpraktika dominierten Arbeitsalltag bot wenig Raum für politische Agitationen. Andererseits waren die Studierenden auch nicht mit den Herausforderungen einer sich entwickelnden Massenuniversität konfrontiert. Nichtsdestoweniger mussten sich auch die Hochschullehrer der naturwissenschaftlichen Fakultät mit den zeitgenössischen Reformvorschlägen auseinandersetzen. Der pharmazeutische Chemiker Herbert Oelschläger, eine der prägenden Persönlichkeiten der Frankfurter Pharmazie, scheute diese Auseinandersetzungen nicht und wurde deshalb zu einer beliebten Zielscheibe des AStA.
Der "diskus" war in den 1970er Jahren mehr als eine Studentenzeitung. Die Blattmacher boten der linken Sponti-Szene in Frankfurt, aber auch Schriftstellern wie Erich Fried dort ein publizistisches Forum. Das Themenspektrum reichte von dem Häuserkampf im Westend bis zur Situation der linken Intellektuellen in der Bundesrepublik, nachdem sich das innenpolitische Klima infolge der RAF-Anschläge verschärft hatte.
War "68" nur der mythologische Name für Ereignisse und Entwicklungen, die schon viel früher begannen und sich deutlich länger hinzogen? Fühlte sich die immobil gewordene Gesellschaft in der Phase nach dem Wiederaufbau durch die Studentenrevolte von sich selbst befreit? Was hat die "Bewegungsgesellschaft" ab den 1970er Jahren mit "68" zu tun? Diesen Fragen geht der Soziologe Heinz Bude in seinem Essay nach.
Philologe im "Kriegseinsatz" : der Frankfurter Germanist Julius Petersen und der Erste Weltkrieg
(2014)
Vorlesungen für Studenten und Bildungsangebote für Bürger – wie lässt sich dieser Anspruch der jungen Stiftungsuniversität auch in Zeiten des Krieges realisieren, wenn Professoren wie Studenten ins Feld ziehen müssen? Das Beispiel des Germanisten Julius Petersen zeigt, welche Anstrengungen zwischen 1914 und 1918 unternommen wurden, um "Volksbildung" und "Vaterländischen Unterricht" zu ermöglichen. Dazu gehörten Vorträge an der Front ebenso wie Bürgervorlesungen in der Heimat.
Chronic ethanol abuse is known to increase susceptibility to infections after injury, in part, by modification of macrophage function. Several intracellular signalling mechanisms are involved in the initiation of inflammatory responses, including the nuclear factor-κB (NF-κB) pathway. In this study, we investigated the systemic and hepatic effect of chronic ethanol feeding on in vivo activation of NF-κB in NF-κB(EGFP) reporter gene mice. Specifically, the study focused on Kupffer cell proinflammatory cytokines IL-6 and TNF-α and activation of NF-κB after chronic ethanol feeding followed by in vitro stimulation with lipopolysaccharide (LPS). We found that chronic ethanol upregulated NF-κB activation and increased hepatic and systemic proinflammatory cytokine levels. Similarly, LPS-stimulated IL-1 β release from whole blood was significantly enhanced in ethanol-fed mice. However, LPS significantly increased IL-6 and TNF-α levels. These results demonstrate that chronic ethanol feeding can improve the responsiveness of macrophage LPS-stimulated IL-6 and TNF-α production and indicate that this effect may result from ethanol-induced alterations in intracellular signalling through NF-κB. Furthermore, LPS and TNF-α stimulated the gene expression of different inflammatory mediators, in part, in a NF-κB-dependent manner.
Der folgende kleine Aufsatz lobt einen Wissenschaftler, der noch lebt: Prof. Dr. Heiko Braak. Und seine Frau, Prof. Dr. Eva Braak, die leider schon gestorben ist. Die beiden Braaks waren Hirnforscher an der Dr. Senckenbergischen Anatomie der Goethe-Universität. Da hat der Autor des Aufsatzes, Helmut Wicht, sie kennengelernt, als er selbst noch ein junger Anatom war. Und hat die Braaks, ihre Forschung, aber auch die ästhetische Attitüde, mit der vor allem Herr Braak die Sache anging, ebenso wie die Schönheit des Gehirns zu schätzen gelernt. Davon, von der Schönheit, handelt der Aufsatz.
Die Erkenntnis, dass das Gehirn Hormone produziert, gehört heute zum Allgemeingut des biomedizinischen Wissens. Ausgangspunkt der modernen Neuroendokrinologie ist das weit gespannte biologische Konzept der Neurosekretion, das Ernst und Berta Scharrer in den 1930er Jahren aus einer Reihe von fundamentalen Einzelentdeckungen entwickelten. Das Fundament dieses Konzeptes legte das Paar am Neurologischen Institut (Edinger Institut) in Frankfurt am Main.
Zu den exzellenten Frankfurter Neurowissenschaftlern des 20. Jahrhunderts zählt Kurt Goldstein. Er durchlief die harte Schule von Ludwig Edinger. Bekannt wurde er jedoch durch einen eigenständigen Ansatz, der mit dem Schlagwort ganzheitliche Neurologie charakterisiert werden kann. Er wandte sich gegen die Auffassung, »Funktionen« im Gehirn exakt lokalisieren zu können, ohne den lokalisatorischen Ansatz vollständig zu verwerfen. Besondere Aufmerksamkeit schenkte er den Kompensationsreaktionen des Gehirns und des »ganzen« Menschen. » […] he never forgot that he addressed an individual, not a brain«, brachte es sein Schüler Walther Riese auf den Punkt.
Unter den zahlreichen Traditionen, an die in Frankfurt am Main stolz erinnert wird, bleibt eine bislang eigentümlich unterbelichtet: die Geschichte der Hirnforschung. Gerald Kreft gibt einen Überblick über dieses faszinierende Kapitel der lokalen Wissenschaftsentwicklung und stellt zugleich das Museumsprojekt zur Geschichte der Hirnforschung in Frankfurt vor, das die Ludwig Edinger-Stiftung realisieren will. Hier wirkt jener Geist fort, der 1914 zur Eröffnung der Goethe-Universität führte. Der Hirnforscher Ludwig Edinger (1855-1918) war der einzige Wissenschaftler unter den elf Unterzeichnern des Stiftungsvertrags, der an der Universität forschte und lehrte.
Was für den Laien unscheinbar aussieht, kann für den Geologen ein wertvolles Fundstück sein. Um ihren Blick zu schulen, arbeiten Studierende nicht nur im Gelände, sondern auch mit den Objekten der geowissenschaftlichen Sammlungen. Für die Forschung sind die Fundstücke ein steinernes Gedächtnis der Erdgeschichte.
Das Sofa Arthur Schopenhauers, Millionen Jahre alte Fossilien, japanische Mangas, physikalische Geräte, illustrierte Inkunabeln, hauchdünne Hirnschnitte, Kopien afrikanischer Felsbilder, Herbarbelege von James Cook, Klavierrollen mit Einspielungen von Camille Saint Saens ... Was sich liest wie das schillernde Inventar eines Universalmuseums zur Erd- und Menschheitsgeschichte der vergangenen 4,6 Milliarden Jahre ist das dingliche Reservoir der historischen und aktuellen Forschung und Lehre an der Goethe-Universität. Eine Ausstellung im Museum Giersch zeigt anlässlich der 100-Jahr-Feier ausgewählte Schätze aus 40 Sammlungen für ein breites Publikum.
Neue Forschungsmethoden verändern oft auch die Bedeutung von Fachsammlungen. Häufig verläuft dieser Wandel zu einer Sammlung von nunmehr historischem Wert schleichend. Manchmal werden Sammlungen auch durch neue Fragestellungen für andere Fachwissenschaften unerwartet wertvoll. Gastautor Jochen Hennig, Sammlungsbeauftragter des Präsidiums der Humboldt-Universität zu Berlin, plädiert dafür, den Bedeutungswandel von Universitätssammlungen aktiv zu begleiten.
Wissenschaft findet nicht nur im Labor statt. Sie ist eingebettet in ein soziales und wirtschaftliches Gefüge. Dieses kommt besonders dann zum Ausdruck, wenn Kontroversen über die Interpretation von Experimenten entstehen. Ein Beispiel dafür ist Prof. Dr. Rolf Marschaleks Theorie zur Entstehung bestimmter Leukämien. Der Frankfurter Forscher hält die über viele Jahre als richtig akzeptierte Theorie seiner bekannten amerikanischen Kollegin Janet Rowley für zu eng gefasst – und macht sich damit in der Fachwelt jenseits des Atlantiks nicht nur Freunde.
Inter- und Transdisziplinarität sind ein Versuch, das Spezialwissen verschiedener Disziplinen miteinander zu verbinden, um die komplexen Fragestellungen unserer Zeit beantworten zu können. Beate Meichsner hat im Gespräch mit Wissenschaftlern unterschiedlichster Disziplinen Chancen und Grenzen, Möglichkeiten und Stolpersteine interdisziplinärer und transdisziplinärer Forschung eruiert.
Die Mathematik ist die einzige Wissenschaft, in der Wissen nicht veraltet. Das hängt damit zusammen, dass sie ein geistiges Konstrukt ist, das zuallererst im Kopf der Mathematiker entsteht. Zwar gibt es heute manche Teilgebiete wie die angewandte Mathematik, die praxisbezogene Probleme unter Aufwendung großer Rechnerleistungen lösen, doch Gebiete wie die reine Mathematik benötigen den PC nur zum Testen von Hypothesen. Dennoch hat sich die Arbeitsweise der Mathematiker in den letzten Jahrzehnten verändert.
Manche Wissenschaftler haben die Gabe, andere zu inspirieren. Sie ziehen talentierte junge Menschen an, sind gut vernetzt und bringen wiederum erfolgreiche Forscher hervor. Heike Jüngst spürt dem Erfolgsrezept der Begründer wissenschaftlicher Schulen an einem historischen und einem zeitgenössischen Beispiel nach.
Als Rainer Forst, Professor für politische Theorie und Philosophie an der Frankfurter Universität, 2012 den Leibniz-Preis erhielt, hieß es in der Laudatio, er führe die »philosophische Tradition der Frankfurter Schule mit Jürgen Habermas und Axel Honneth auf höchstem Niveau« fort. In diesem Jahr wird das Frankfurter Institut für Sozialforschung 90 Jahre alt, und die Anfänge der »Frankfurter Schule« liegen ungefähr 85 Jahre zurück – Anlässe genug, um zu fragen: Wie hat sich die »Frankfurter Schule« gewandelt?
Ein neophytisches Schaumkraut, das sich am Bodenseeufer massiv ausgebreitet hat und in jüngster Zeit vielfach auch in Belgien und den Niederlanden beobachtet wurde, konnte als Unkraut in einem Gartencenter, einem Baumarkt und auf drei Friedhöfen in Aachen nachgewiesen werden. Die Art wird als Japanisches Reisfeld-Schaumkraut, Cardamine flexuosa auct., Asian C. flexuosa, C. flexuosa subsp. debilis und aktuell als C. hamiltonii bezeichnet. Offenbar handelt es sich um Erstnachweise für Nordrhein-Westfalen.
Es ist 18:50 Uhr an einem Mittwochabend. Das PA-Gebäude auf dem Campus Westend ist hell erleuchtet. Während draußen die ersten Gäste stehen, ist im Innern ein junger Mann in Hemd und Sakko damit beschäftigt, einen roten Teppich von den letzten Flusen zu befreien. In wenigen Minuten werden die ersten Besucher der Ausstellung »36 Stifter für eine Idee« in den Saal treten, über den frisch gesaugten Teppich laufen und das Ergebnis von drei Jahren Arbeit begutachten.
Erinnerungsorte
(2014)
Immatrikulationsfeiern gehörten zum festen Ritual der universitären Kultur, bis in den 1960er Jahren bewusst mit dieser Tradition gebrochen wurde. Heute werden die Studierenden an der Goethe-Universität beim "unistart" begrüßt. Ist diese Veranstaltung ein Brückenschlag zwischen Gegenwart und alten Zeiten oder eher ein Spiegel des sich wandelnden universitären Selbstverständnisses?
Kollektives und kulturelles Erinnern : Erinnerungskulturen leben von der Dynamik der Gegenwart
(2014)
Keine Gemeinschaft kommt ohne kollektive Erinnerungen aus, dazu gehören Gedenkfeiern und Denkmäler ebenso wie Mythen und Rituale oder die Identifikation mit großen Ereignissen oder Persönlichkeiten. Erinnern ist nicht nur identitätsstiftend, es bedeutet auch, sich vergangene Erlebnisse zu vergegenwärtigen – oder wie Marcel Proust es ausdrückt: "Erst im Gedächtnis formt sich die Wirklichkeit." Wenn die Erinnerungskultur ihre Dynamik aus der Aktualität verliert, ist sie tot.
»Königliche Universität zu Frankfurt a. M.« – mit diesem Namen konnten sich auch die Frankfurter Stifter arrangieren, formalrechtlich hätte Wilhelm II. den Vortritt gehabt. Goethe, natürlich immer fester Bestandteil des philologischen
Bildungskanons, rückte der Universität verhalten näher: zunächst mit seinem Relief über dem historischen Haupteingang, bis es zu seinem 100. Todestag 1932 an der Zeit schien, die Universität nach dem Dichterfürsten zu benennen.
Das Verhältnis zwischen den Frankfurtern und ihrer Universität ist ein wechselvolles: gestiftet und großzügig unterstützt von Bürgern und Stadtpolitikern, gepflegt in den harten Jahren der Inflation, gleichgeschaltet und wissenschaftlich ausgehungert während des Nationalsozialismus, entfremdet und abgelehnt nach der Studentenrevolte in den 1960er und 1970er Jahren, wiederentdeckt ab den 1980er Jahren, geschätzt und gefördert seit der (Rück-)Verwandlung in eine Stiftungsuniversität (2008).
Wie nehmen Sie die Goethe-Universität heute in Zeiten des stärkeren nationalen und internationalen Wettbewerbs der Hochschulen wahr?
Was war rückblickend die wichtigste Veränderung, die Sie während Ihrer Amtszeit initiieren konnten?
Wenn Sie Ihre Zeit als Präsident noch einmal Revue passieren lassen, welche Episode lässt Sie heute noch schmunzeln?
Sie hätten die Chance, 2015 nochmal als Präsident anzutreten, welche Impulse würden Sie dann setzen wollen?
Was wünschen Sie der Goethe-Universität für die nächsten 50 Jahre?
Eine weltoffene, tolerante und liberale Intellektualität prägt die Frankfurter Universität – abgesehen von dem dunklen Kapitel während des Nationalsozialismus – seit ihrer Gründung 1914. Gegründet und gestiftet von wohlhabenden und engagierten Bürgern der Stadt, war sie von Beginn an etwas Besonderes in der deutschen Universitätslandschaft.
Examining event-related potential (ERP) correlates of decision bias in recognition memory judgments
(2014)
Memory judgments can be based on accurate memory information or on decision bias (the tendency to report that an event is part of episodic memory when one is in fact unsure). Event related potentials (ERP) correlates are important research tools for elucidating the dynamics underlying memory judgments but so far have been established only for investigations of accurate old/new discrimination. To identify the ERP correlates of bias, and observe how these interact with ERP correlates of memory, we conducted three experiments that manipulated decision bias within participants via instructions during recognition memory tests while their ERPs were recorded. In Experiment 1, the bias manipulation was performed between blocks of trials (automatized bias) and compared to trial-by-trial shifts of bias in accord with an external cue (flexibly controlled bias). In Experiment 2, the bias manipulation was performed at two different levels of accurate old/new discrimination as the memory strength of old (studied) items was varied. In Experiment 3, the bias manipulation was added to another, bottom-up driven manipulation of bias induced via familiarity. In the first two Experiments, and in the low familiarity condition of Experiment 3, we found evidence of an early frontocentral ERP component at 320 ms poststimulus (the FN320) that was sensitive to the manipulation of bias via instruction, with more negative amplitudes indexing more liberal bias. By contrast, later during the trial (500–700 ms poststimulus), bias effects interacted with old/new effects across all three experiments. Results suggest that the decision criterion is typically activated early during recognition memory trials, and is integrated with retrieved memory signals and task-specific processing demands later during the trial. More generally, the findings demonstrate how ERPs can help to specify the dynamics of recognition memory processes under top-down and bottom-up controlled retrieval conditions.
Background: Hepatitis delta frequently leads to liver cirrhosis and hepatic decompensation. As treatment options are limited, there is a need for biomarkers to determine disease activity and to predict the risk of disease progression. We hypothesized that anti-HDV IgM could represent such a marker.
Methods: Samples of 120 HDV-infected patients recruited in an international multicenter treatment trial (HIDIT-2) were studied. Anti-HDV IgM testing was performed using ETI-DELTA-IGMK-2-assay (DiaSorin). In addition, fifty cytokines, chemokines and angiogenetic factors were measured using multiplex technology (Bio-Plex System). A second independent cohort of 78 patients was studied for the development of liver-related clinical endpoints (decompensation, HCC, liver transplantation or death; median follow up of 3.0 years, range 0.6–12).
Results: Anti-HDV IgM serum levels were negative in 18 (15%), low (OD<0.5) in 76 (63%), and high in 26 (22%) patients of the HIDIT-2 cohort. Anti-HDV IgM were significantly associated with histological inflammatory (p<0.01) and biochemical disease activity (ALT, AST p<0.01). HDV replication was independent from anti-HDV IgM, however, low HBV-DNA levels were observed in groups with higher anti-HDV IgM levels (p<0.01). While high IP-10 (CXCL10) levels were seen in greater groups of anti-HDV IgM levels, various other antiviral cytokines were negatively associated with anti-HDV IgM. Associations between anti-HDV IgM and ALT, AST, HBV-DNA were confirmed in the independent cohort. Clinical endpoints occurred in 26 anti-HDV IgM positive patients (39%) but in only one anti-HDV IgM negative individual (9%; p = 0.05).
Conclusions: Serum anti-HDV IgM is a robust, easy-to-apply and relatively cheap marker to determine disease activity in hepatitis delta which has prognostic implications. High anti-HDV IgM levels may indicate an activated interferon system but exhausted antiviral immunity.
Higher N170 amplitudes to words and to faces were recently reported for faster readers of German. Since the shallow German orthography allows phonological recoding of single letters, the reported speed advantages might have their origin in especially well-developed visual processing skills of faster readers. In contrast to German, adult readers of Hebrew are forced to process letter chunks up to whole words. This dependence on more complex visual processing might have created ceiling effects for this skill. Therefore, the current study examined whether also in the deep Hebrew orthography visual processing skills as reflected by N170 amplitudes explain reading speed differences. Forty university students, native speakers of Hebrew without reading impairments, accomplished a lexical decision task (i.e., deciding whether a visually presented stimulus represents a real or a pseudo word) and a face decision task (i.e., deciding whether a face was presented complete or with missing facial features) while their electroencephalogram was recorded from 64 scalp positions. In both tasks stronger event related potentials (ERPs) were observed for faster readers in time windows at about 200 ms. Unlike in previous studies, ERP waveforms in relevant time windows did not correspond to N170 scalp topographies. The results support the notion of visual processing ability as an orthography independent marker of reading proficiency, which advances our understanding about regular and impaired reading development.
MicroRNAs are key modulators at molecular level in different biological processes, including determination of cell fate and differentiation. Herein, microRNA expression profiling experiments were performed on syngeneic cardiac (CStC) and bone marrow (BMStC) mesenchymal stromal cells cultured in standard growth medium and then in vitro exposed to adipogenic, osteogenic, cardiomyogenic and endothelial differentiation media. Analysis identified a tissue-specific microRNA signature composed of 16 microRNAs that univocally discriminated cell type of origin and that were completely unaffected by in vitro differentiation media: 4 microRNAs were over-expressed in cardiac stromal cells, and 12 were overexpressed or present only in bone marrow stromal cells. Further, results revealed microRNA subsets specifically modulated by each differentiation medium, irrespective of the cell type of origin, and a subset of 7 microRNAs that were down-regulated by all media with respect to growth medium. Finally, we identified 16 microRNAs that were differentially modulated by the media when comparing the two tissues of origin. The existence of a tissue-specific microRNA signature surviving to any differentiation stimuli, strongly support the role if microRNAs determining cell identity related to tissue origin. Moreover, we identified microRNA subsets modulated by different culture conditions in a tissue-specific manner, pointing out their importance during differentiation processes.
Background: Rapidly increasing temperatures in the mountain region of Nepal and recent reports of dengue fever and lymphatic filariasis cases from mountainous areas of central Nepal prompted us to study the spatio-temporal distribution of the vectors of these two diseases along an altitudinal transect in central Nepal.
Methodology/Principal Findings: We conducted a longitudinal study in four distinct physiographical regions of central Nepal from September 2011 to February 2012. We used BG-Sentinel and CDC light traps to capture adult mosquitoes. We found the geographical distribution of the dengue virus vectors Aedes aegypti and Aedes albopictus along our study transect to extend up to 1,310 m altitude in the Middle Mountain region (Kathmandu). The distribution of the lymphatic filariasis vector Culex quinquefasciatus extended up to at least 2,100 m in the High Mountain region (Dhunche). Statistical analysis showed a significant effect of the physiographical region and month of collection on the abundance of A. aegypti and C. quinquefasciatus only. BG-Sentinel traps captured significantly higher numbers of A. aegypti than CDC light traps. The meteorological factors temperature, rainfall and relative humidity had significant effects on the mean number of A. aegypti per BG-Sentinel trap. Temperature and relative humidity were significant predictors of the number of C. quinquefasciatus per CDC light trap. Dengue fever and lymphatic filariasis cases had previously been reported from all vector positive areas except Dhunche which was free of known lymphatic filariasis cases.
Conclusions/Significance: We conclude that dengue virus vectors have already established stable populations up to the Middle Mountains of Nepal, supporting previous studies, and report for the first time the distribution of lymphatic filariasis vectors up to the High Mountain region of this country. The findings of our study should contribute to a better planning and scaling-up of mosquito-borne disease control programmes in the mountainous areas of Nepal.
Objectives: Low energy shock waves have been shown to induce angiogenesis, improve left ventricular ejection fraction and decrease angina symptoms in patients suffering from chronic ischemic heart disease. Whether there is as well an effect in acute ischemia was not yet investigated.
Methods: Hind-limb ischemia was induced in 10–12 weeks old male C57/Bl6 wild-type mice by excision of the left femoral artery. Animals were randomly divided in a treatment group (SWT, 300 shock waves at 0.1 mJ/mm2, 5 Hz) and untreated controls (CTR), n = 10 per group. The treatment group received shock wave therapy immediately after surgery.
Results: Higher gene expression and protein levels of angiogenic factors VEGF-A and PlGF, as well as their receptors Flt-1 and KDR have been found. This resulted in significantly more vessels per high-power field in SWT compared to controls. Improvement of blood perfusion in treatment animals was confirmed by laser Doppler perfusion imaging. Receptor tyrosine kinase profiler revealed significant phosphorylation of VEGF receptor 2 as an underlying mechanism of action. The effect of VEGF signaling was abolished upon incubation with a VEGFR2 inhibitor indicating that the effect is indeed VEGFR 2 dependent.
Conclusions: Low energy shock wave treatment induces angiogenesis in acute ischemia via VEGF receptor 2 stimulation and shows the same promising effects as known from chronic myocardial ischemia. It may therefore develop as an adjunct to the treatment armentarium of acute muscle ischemia in limbs and myocardium.
Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear.
Plexins are widely expressed transmembrane proteins that mediate the cellular effects of semaphorins. The molecular mechanisms of plexin-mediated signal transduction are still poorly understood. Here we show that signalling via B-family plexins leading to the activation of the small GTPase RhoA requires activation of the IκB kinase (IKK)-complex. In contrast, plexin-B-dependent regulation of R-Ras activity is not affected by IKK activity. This regulation of plexin signalling depends on the kinase activity of the IKK-complex, but is independent of NF-κB activation. We confirm that the IKK-complex is active in tumour cells and osteoblasts, and we demonstrate that plexin-B-dependent tumour cell invasiveness and regulation of osteoblast differentiation require an active IKK-complex. This study identifies a novel, NF-κB-independent function of the IKK-complex and shows that IKK directs plexin-B signalling to the activation of RhoA.
Amygdalin, a natural compound, has been used by many cancer patients as an alternative approach to treat their illness. However, whether or not this substance truly exerts an anti-tumor effect has never been settled. An in vitro study was initiated to investigate the influence of amygdalin (1.25–10 mg/ml) on the growth of a panel of bladder cancer cell lines (UMUC-3, RT112 and TCCSUP). Tumor growth, proliferation, clonal growth and cell cycle progression were investigated. The cell cycle regulating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1, p19, p27 as well as the mammalian target of rapamycin (mTOR) related signals phosphoAkt, phosphoRaptor and phosphoRictor were examined. Amygdalin dose-dependently reduced growth and proliferation in all three bladder cancer cell lines, reflected in a significant delay in cell cycle progression and G0/G1 arrest. Molecular evaluation revealed diminished phosphoAkt, phosphoRictor and loss of Cdk and cyclin components. Since the most outstanding effects of amygdalin were observed on the cdk2-cyclin A axis, siRNA knock down studies were carried out, revealing a positive correlation between cdk2/cyclin A expression level and tumor growth. Amygdalin, therefore, may block tumor growth by down-modulating cdk2 and cyclin A. In vivo investigation must follow to assess amygdalin's practical value as an anti-tumor drug.
Background: Low Emission Zones (LEZs) are areas where the most polluting vehicles are restricted from entering. The effectiveness of LEZs to lower ambient exposures is under debate. This study focused on LEZs that restricted cars of Euro 1 standard without appropriate retrofitting systems from entering and estimated LEZ effects on NO2, NO, and NOx ( = NO2+NO).
Methods: Continuous half-hour and diffuse sampler 4-week average NO2, NO, and NOx concentrations measured inside and outside LEZs in 17 German cities of 6 federal states (2005–2009) were analysed as matched quadruplets (two pairs of simultaneously measured index values inside LEZ and reference values outside LEZ, one pair measured before and one after introducing LEZs with time differences that equal multiples of 364 days) by multiple linear and log-linear fixed-effects regression modelling (covariables: e.g., wind velocity, amount of precipitation, height of inversion base, school holidays, truck-free periods). Additionally, the continuous half-hour data was collapsed into 4-week averages and pooled with the diffuse sampler data to perform joint analysis.
Results: More than 3,000,000 quadruplets of continuous measurements (half-hour averages) were identified at 38 index and 45 reference stations. Pooling with diffuse sampler data from 15 index and 10 reference stations lead to more than 4,000 quadruplets for joint analyses of 4-week averages. Mean LEZ effects on NO2, NO, and NOx concentrations (reductions) were estimated to be at most −2 µg/m3 (or −4%). The 4-week averages of NO2 concentrations at index stations after LEZ introduction were 55 µg/m3 (median and mean values) or 82 µg/m3 (95th percentile).
Conclusions: This is the first study investigating comprehensively the effectiveness of LEZs to reduce NO2, NO, and NOx concentrations controlling for most relevant potential confounders. Our analyses indicate that there is a statistically significant, but rather small reduction of NO2, NO, and NOx concentrations associated with LEZs.
The genetic treatment of neurodegenerative diseases still remains a challenging task since many approaches fail to deliver the therapeutic material in relevant concentrations into the brain. As viral vectors comprise the risk of immune and inflammatory responses, human serum albumin (HSA) nanoparticles were found to represent a safer and more convenient alternative. Their ability to cross the blood-brain barrier (BBB) and deliver drugs into the brain in order to enhance gene-based therapy has been previously demonstrated. The present study deals with the development of pGL3-PEI-coated HSA nanoparticles and subsequent in vitro testing in cerebellar granular and HeLa cells. The luciferase control vector pGL3 was chosen as reporter plasmid encoding for the firefly luciferase protein, linear polyethylenimine (22 kDa) as endosomolytic agent for enhancing the cells’ transfection. Studies on particle characteristics, their cellular uptake into aforementioned cell lines and on subcellular localisation, and transfection efficiency in the cerebellar cells proved the feasibility of nanoparticle-based gene delivery.