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Additional file 1: Supplement Figure 1. Detection of adipocytes in unfixed granulation tissue. Intra-vital confocal microscopy single channel images of unfixed granulation tissue compared with subcutaneous fat tissue (merge displayed in Fig. 1b) stained with BODIPY-493/503 to highlight lipid droplets, wheat germ agglutinin (CF®555 WGA) to highlight ECM substrates and cell morphology (N-acetyl-D-glucosamine and sialic acid present in hyaluronan and other heterogeneous polysaccharides), and Hoechst 33342 staining for nuclei. Supplement Figure 2. PPARG overexpression in day 3 differentiated cells. Representative immunoblotting of PPARG- or puromycin overexpressing human ASC subjected to in vitro differentiation for 3 days in the presence of macrophage-CM. Supplement Figure 3. Numbers of NCT-regulated cytokines. Comparison of cytokines with greater than two-fold change in response to NCT-treatment in various CM. Shown are the total number of regulated cytokines per CM (Set Size), and the number of regulated cytokines found exclusively in one CM or shared between different CM types (Intersection Size). Intersections between different CM types are indicated with connected black dots, single dots indicate a single CM. As shown, 22, 7, 6 and 2 cytokines were found exclusively regulated by M(IFNG/LPS), Mo, M0 and M(IL4/IL13) respectively. Four cytokines were similarly regulated in M(IFNG/LPS) and Mo, 3 in M(IFNG/LPS) and M0, 2 in M0 and M(IL4/IL13), 1 in M(IFNG/LPS) and M(IL4/IL13), and 2 in M(IFNG/LPS), M0 and M(IL4/IL13). Supplement Figure 4. Efficacy of IL1RA to inhibit anti-adipogenic effect of IL1B. IL1B receptor mediated signaling was inhibited by the addition of 100ng/ml recombinant IL1RA. Effect on adipocyte differentiation was evaluated by flow cytometry assessing numbers of lipid-laden cells. Values depict the percentage of lipid-laden adipocytes as a percentage of untreated control cells (0ng IL1B) that emit green fluorescence after staining with BODIPY-493/503, n=3. Statistical significance was determined by using non parametric unpaired Student’s t-test. Data are shown as mean ± SEM. Asterisks indicate p-values < 0.05 (*). Supplement Table 1. Table with log2 cytokine protein expression levels used to generate the heatmap in Fig. 2c. (1) and (2) depict values obtained from two independent measurements. Supplement Table 2. Regulation of cytokines by NCT co-treatment in various CM. Contains log2 fold change (M) and log2 average (A) values representing the extent of regulation, and average expression, of cytokines following NCT co-treatment of CM (e.g. a comparison of NCT co-treated Mo cells against untreated Mo cells). Supplement Table 3. List of Primers used for quantitative RT-PCR.

Hybrid imaging combining the beneficial properties of radioactivity and optical imaging within one imaging probe has gained increasing interest in radiopharmaceutical research. In this study, we modified the macrocyclic gallium-68 chelator fusarinine C (FSC) by conjugating a fluorescent moiety and tetrazine (Tz) moieties. The resulting hybrid imaging agents were used for pretargeting applications utilizing click reactions with a trans-cyclooctene (TCO) tagged targeting vector for a proof of principle both in vitro and in vivo. Starting from FSC, the fluorophores Sulfocyanine-5, Sulfocyanine-7, or IRDye800CW were conjugated, followed by introduction of one or two Tz motifs, resulting in mono and dimeric Tz conjugates. Evaluation included fluorescence microscopy, binding studies, logD, protein binding, in vivo biodistribution, &micro, PET (micro-positron emission tomography), and optical imaging (OI) studies. 68Ga-labeled conjugates showed suitable hydrophilicity, high stability, and specific targeting properties towards Rituximab-TCO pre-treated CD20 expressing Raji cells. Biodistribution studies showed fast clearance and low accumulation in non-targeted organs for both SulfoCy5- and IRDye800CW-conjugates. In an alendronate-TCO based bone targeting model the dimeric IRDye800CW-conjugate resulted in specific targeting using PET and OI, superior to the monomer. This proof of concept study showed that the preparation of FSC-Tz hybrid imaging agents for pretargeting applications is feasible, making such compounds suitable for hybrid imaging applications.

Dissertation, Universität Duisburg-Essen, 2021

Perspektive Bibliothek, Bd. 8 Nr. 1 (2019)

Despite extensive efforts to optimize laser therapy, i.e., the current gold standard treatment, a majority of port wine stain (PWS) patients responds suboptimally to laser therapy. This paper describes the niceties of a novel PWS treatment modality termed site-specific pharmaco-laser therapy (SSPLT). In contrast to the classic approach of enhancing the extent of intravascular photocoagulation (the photothermal response), SSPLT focuses on optimization of post-irradiation thrombus formation (i.e., the hemodynamic response) by combining conventional laser therapy with the administration of thermosensitive drug delivery systems that encapsulate prothrombotic and antifibrinolytic drugs. The aim of SSPLT is to instill complete lumenal occlusion in target vessels, which has been linked to optimal PWS blanching. Relevance for patients: The current treatment options for PWS patients are limited in efficacy. Novel therapeutic modalities are needed to more effectively treat patients with recalcitrant PWSs. SSPLT is an experimental-stage treatment modality that could serve as an adjuvant to pulsed dye laser therapy for a selected group of patients whose PWS is ill-responsive to standard treatment. The expected clinical result of SSPLT is improved lesional blanching.

A number of prostate cancer (PCa)-specific genomic aberrations (denominated BRCAness genes) have been discovered implicating sensitivity to PARP inhibition within the concept of synthetic lethality. Recent clinical studies show favorable results for the PARP inhibitor olaparib used as single agent for treatment of metastatic castration-resistant PCa. Using 2D and 3D cell culture models mimicking the different treatment and progression stages of PCa, we evaluated a potential use for olaparib in combination with first-line endocrine treatments, androgen deprivation, and complete androgen blockade, and as a maintenance therapy following on from endocrine therapy. We demonstrate that the LNCaP cell line, possessing multiple aberrations in BRCAness genes, is sensitive to olaparib. Additive effects of olaparib combined with endocrine treatments in LNCaP are noted. In contrast, we find that the TMPRSS2:ERG fusion-positive cell lines VCaP and DuCaP do not show signs of synthetic lethality, but are sensitive to cytotoxic effects caused by olaparib. In consequence, additive effects of olaparib with endocrine therapy were not observable in these cell lines, showing the need for synthetic lethality in combination treatment regimens. Additionally, we show that PCa cells remain sensitive to olaparib treatment after initial androgen deprivation implicating a possible use of olaparib as maintenance therapy. In sum, our preclinical data recommend olaparib as a synthetic lethal treatment option in combination or sequenced to first-line endocrine therapy for PCa patients with diagnosed BRCAness.

An accurate transmission measurement of thin foils (usually made of elemental metals and/or semiconductors), which routinely are used as attenuators in soft x-ray beamlines, end-stations and instruments, represents a long standing problem over the wide experimentation field with photon beams, see for example [1-4]. Such foils are also frequently utilized for blocking long wavelength emission, i.e., UV-Vis-IR radiation, from plasma and high order harmonic sources, whilst soft x-rays emitted from the source pass through the foil with only a slight attenuation. Despite the enormous amount of data available in the literature, e.g., Henke’s tables [5], measurements made on real foils often provide surprising results. In this study, a procedure based on the ablation imprints method is utilized for determination of soft x-ray filter transmission, namely the f-scan technique [6,7]. This technique combines the GMD (Gas Monitor Detector) pulse energy measurement and attenuation of the beam by foils (made of different metallic/semiconducting elements of varying thickness) with areas of ablation imprints created on a suitable target, e.g. PMMA – Poly(methyl methacrylate). The results show only a partial overlap with transmission values found in Henke’s tables. Nevertheless, a good agreement with transmission values determined by conventional radiometry techniques at synchrotron radiation beamlines has been found. Such a difference between the experimentally obtained values and transmissions calculated for a pure element is usually explained by spontaneous formation of oxidized layers on the filter surface and in the near-surface layer and their possible alteration by intense FEL radiation. The first results obtained with Al, Nb, Zr and Si filters at FLASH/FLASH2 (Free-electron LASer in Hamburg tuned to 13.5 nm) facilities will be shown and discussed in this presentation.

Perspektive Bibliothek, Bd. 7, Nr. 2 (2018)

Despite extensive efforts to optimize laser therapy, i.e., the current gold standard treatment, a majority of port wine stain (PWS) patients responds suboptimally to laser therapy. This paper describes the niceties of a novel PWS treatment modality termed site-specific pharmaco-laser therapy (SSPLT). In contrast to the classic approach of enhancing the extent of intravascular photocoagulation (the photothermal response), SSPLT focuses on optimization of post-irradiation thrombus formation (i.e., the hemodynamic response) by combining conventional laser therapy with the administration of thermosensitive drug delivery systems that encapsulate prothrombotic and antifibrinolytic drugs. The aim of SSPLT is to instill complete lumenal occlusion in target vessels, which has been linked to optimal PWS blanching. Relevance for patients: The current treatment options for PWS patients are limited in efficacy. Novel therapeutic modalities are needed to more effectively treat patients with recalcitrant PWSs. SSPLT is an experimental-stage treatment modality that could serve as an adjuvant to pulsed dye laser therapy for a selected group of patients whose PWS is ill-responsive to standard treatment. The expected clinical result of SSPLT is improved lesional blanching.

Zusammenfassung Das Hauptsubstrat der Gerinnung ist Fibrinogen (FI). Bei akuter Blutung ist es zumeist der erste Gerinnungsfaktor, der kritische Grenzwerte erreicht (150–200 mg/dl). FI kann hervorragend mittels point-of-care-tauglicher viskoelastischer Methoden (Thrombelstographie oder Thrombelastometrie) monitiert werden. Die Substitution kann mittels Frischplasma, Cryopräzipitat oder Fibrinogenkonzentrat erfolgen. Frischplasma ist nicht besonders effektiv, mit einer erhöhten Morbidität, insbesondere bei kritisch Kranken, sowie mit Volumenbelastung assoziiert. Cryopräzipitat wird in einigen europäischen Ländern nicht angeboten. Die Gabe von Fibrinogenkonzentrat wird in verschiedenen Leitlinien empfohlen. Als Akut-Phase-Protein kann FI physiologischerweise bei Entzündungsprozessen, schweren Verletzungen sowie nach großen Operationen in kurzer Zeit auf über 1000 mg/dl ansteigen; wobei hier Fibrinogenspaltprodukte anti-inflammatorische und sogar antibakterielle Eigenschaften haben.

Perspektive Bibliothek, Bd. 7, Nr. 1 (2018)

The three-dimensional architecture of the pancreatic islet is integral to beta cell function, but the process of islet formation remains poorly understood due to the difficulties of imaging internal organs with cellular resolution. Within transparent zebrafish larvae, the developing pancreas is relatively superficial and thus amenable to live imaging approaches. We performed in vivo time-lapse and longitudinal imaging studies to follow islet development, visualizing both naturally occurring islet cells and cells arising with an accelerated timecourse following an induction approach. These studies revealed previously unappreciated fine dynamic protrusions projecting between neighboring and distant endocrine cells. Using pharmacological compound and toxin interference approaches, and single-cell analysis of morphology and cell dynamics, we determined that endocrine cell motility is regulated by phosphoinositide 3-kinase (PI3K) and G-protein-coupled receptor (GPCR) signaling. Linking cell dynamics to islet formation, perturbation of protrusion formation disrupted endocrine cell coalescence, and correlated with decreased islet cell differentiation. These studies identified novel cell behaviors contributing to islet morphogenesis, and suggest a model in which dynamic exploratory filopodia establish cell-cell contacts that subsequently promote cell clustering., Summary: Pancreatic endocrine cells extend previously unrecognized dynamic, flexible, fine projections to guide clustering into a compacted islet in a process regulated by PI3K and GPCR.

Perspektive Bibliothek, Bd. 6, Nr. 1 (2017)

Objective: To investigate the relationship between climatic factors and daily numbers of completed suicide in the area of Split-Dalmatia County in the years 2011 to 2015. Subjects and methods: Retrospective analysis of all suicides between 1st of January 2011 and 31st of December 2015. Weather variables of interest were sunshine duration, atmospheric pressure, temperature, relative humidity, wind direction (Bura/Jugo) and wind speed. Data was collected on the weather station Split Marjan and compared on a day-to-day basis with daily number of suicides. Timelines for each variable were created and Pearson correlation coefficients were calculated to demonstrate possible associations. Calculations were repeated distinguishing between male and female suicides. To reduce seasonality, data on weather and suicides were differenced. Results: Positive weak correlation was found between sunshine duration and number of daily suicides (r=0.057; P=0.015) and conversely weak negative correlation between cloud coverage and number of daily suicides (r=-0.052; P=0.057). These associations were found in the whole sample as well as only in men. When comparing male to female suicides, these results were not reproducible in the female population. Conclusion: This study confirms the hypothesis that sunshine may facilitate suicide and conversely cloud coverage can be seen as protective factor. Associations with other climatic factors may be present but due to the complexity of the interaction between weather and human behaviour and health, difficult to demonstrate., Cilj: Istražiti povezanost klimatskih čimbenika i broja samoubojstava u Splitsko-dalmatinskoj županiji u razdoblju 2011. - 2015. godine. Ispitanici i metode: Ovo istraživanje predstavlja retrospektivnu analizu stope samoubojstava između 1. siječnja 2011. i 31. prosinca 2015. Vremenske varijable koje su se analizirale su trajanje sunca, atmosferski pritisak, temperatura, relativna vlažnost te smjer i brzina vjetra. Podaci su prikupljeni s vremenske postaje Split-Marjan i uspoređeni na dnevnoj bazi sa stopom samoubojstava. Za svaku varijablu je izračunat Pearsonov koeficijent s ciljem utvrđivanja mogućih povezanosti. Izračuni su ponavljani i s ciljem utvrđivanja razlike po spolu. Kako bi se izbjegla sezonalnost podaci su diferencirani. Rezultati: Pozitivna korelacija je utvrđena između trajanja sunca u danu i broja samoubojstava po danu (r=0.057; P=0.015) i posljedično negativna korelacija između oblačnog vremena i stope samoubojstava (r=-0.052; P=0.057). Ove povezanosti su utvrđene u cijelom uzorku, i kod mušaraca. Uspoređujući muška i ženska samoubojstva, rezultati se ne mogu primijeniti na žensku populaciju. Zaključak: Ovo istraživanje potvrđuje hipotezu da sunce može potaknuti samoubojstva i da je oblačno vrijeme zaštitni čimbenik. Povezanosti s ostalim klimatskim čimbenicima mogu biti prisutne, ali zbog kompleksnosti interakcija vremena, ljudskog ponašanja i zdravlja se otežano pokazuju.

Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of male cancer death in Western nations. Thus, new treatment modalities are urgently needed. Elevated production of reactive oxygen species (ROS) by NADPH oxidase (Nox) enzymes is implicated in tumorigenesis of the prostate and other tissues. However, the identity of the Nox enzyme(s) involved in prostate carcinogenesis remains largely unknown. Analysis of radical prostatectomy tissue samples and benign and malignant prostate epithelial cell lines identified Nox5 as an abundantly expressed Nox isoform. Consistently, immunohistochemical staining of a human PCa tissue microarray revealed distinct Nox5 expression in epithelial cells of benign and malignant prostatic glands. shRNA-mediated knockdown of Nox5 impaired proliferation of Nox5-expressing (PC-3, LNCaP) but not Nox5-negative (DU145) PCa cell lines. Similar effects were observed upon ROS ablation via the antioxidant N-acetylcysteine confirming ROS as the mediators. In addition, Nox5 silencing increased apoptosis of PC-3 cells. Concomitantly, protein kinase C zeta (PKCζ) protein levels and c-Jun N-terminal kinase (JNK) phosphorylation were reduced. Moreover, the effect of Nox5 knockdown on PC-3 cell proliferation could be mimicked by pharmacological inhibition of JNK. Collectively, these data indicate that Nox5 is expressed at functionally relevant levels in the human prostate and clinical PCa. Moreover, findings herein suggest that Nox5-derived ROS and subsequent depletion of PKCζ and JNK inactivation play a critical role in modulating intracellular signaling cascades involved in the proliferation and survival of PCa cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.

Tissue immunosurveillance is an important mechanism to prevent cancer. Skin treatment with the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), followed by the tumor promoter 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), is an established murine model for squamous cell carcinoma (SCC). However, the innate immunological events occurring during the initiation of chemical carcinogenesis with DMBA remain elusive. Here, we discovered that natural killer (NK) cells and Langerhans cells (LC) cooperate to impair this oncogenic process in murine skin. The depletion of NK cells or LC caused an accumulation of DNA-damaged, natural killer group 2D-ligand (NKG2D-L) expressing keratinocytes and accelerated tumor growth. Notably, the secretion of TNFα mainly by LC promoted the recruitment of NK cells into the epidermis. Indeed, the TNFα-induced chemokines CCL2 and CXCL10 directed NK cells to DMBA-treated epidermis. Our findings reveal a novel mechanism how innate immune cells cooperate in the inhibition of cutaneous chemical carcinogenesis.

Perspektive Bibliothek, Bd. 5, Nr. 1 (2016), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Perspektive Bibliothek, Bd. 4, Nr. 1 (2015), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Perspektive Bibliothek, Bd. 4, Nr. 2 (2015), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Background\ud Many diseases and pathological conditions are characterized by transient or constitutive overproduction of reactive oxygen species (ROS). ROS are causal for ischemia/reperfusion (IR)-associated tissue injury (IRI), a major contributor to organ dysfunction or failure. Preventing IRI with antioxidants failed in the clinic, most likely due to the difficulty to timely and efficiently target them to the site of ROS production and action. IR is also characterized by changes in the activity of intracellular signaling molecules including the stress kinase p38MAPK. While ROS can cause the activation of p38MAPK, we recently obtained in vitro evidence that p38MAPK activation is responsible for elevated mitochondrial ROS levels, thus suggesting a role for p38MAPK upstream of ROS and their damaging effects.\ud Results\ud Here we identified p38MAPKα as the predominantly expressed isoform in HL-1 cardiomyocytes and siRNA-mediated knockdown demonstrated the pro-oxidant role of p38MAPKα signaling. Moreover, the knockout of the p38MAPK effector MAPKAP kinase 2 (MK2) reproduced the effect of inhibiting or knocking down p38MAPK. To translate these findings into a setting closer to the clinic a stringent kidney clamping model was used. p38MAPK activity increased upon reperfusion and p38MAPK inhibition by the inhibitor BIRB796 almost completely prevented severe functional impairment caused by IR. Histological and molecular analyses showed that protection resulted from decreased redox stress and apoptotic cell death.\ud \ud Conclusions\ud These data highlight a novel and important mechanism for p38MAPK to cause IRI and suggest it as a potential therapeutic target for prevention of tissue injury.

Perspektive Bibliothek, Bd. 3, Nr. 1 (2014), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Perspektive Bibliothek, Bd. 3, Nr. 2 (2014), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Includes bibliographical references., This thesis proposes a new counter-narrative to the neo-liberal agenda that combines two seemingly disparate bodies of work: New Governance and Nancy Fraser’s theory of justice. New Governance is a new and rapidly growing strand of legal thought and practi ce that has simultaneously developed a following in Europe and the United States. In short, legal scholars in this field of research are advocating a shift away from long-standing command-style, fixed-rule regulation toward more collaborative, bottom-up, and flexible modes of regulation.

Perspektive Bibliothek, Bd. 2, Nr. 2 (2013), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Perspektive Bibliothek, Bd. 2, Nr. 1 (2013), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Perspektive Bibliothek, Bd. 1, Nr. 1 (2012), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Patron-Driven Acquisition (PDA), die kundengesteuerte E-Book-Erwerbung, erfreut sich in den letzten Jahren an Bibliotheken im In- und Ausland immer größerer Beliebtheit. Trotz der offensichtlichen Vorteile der kundenorientierten E-Book-Erwerbung zögern heute immer noch viele wissenschaftliche Bibliotheken in Deutschland, PDA in ihre Erwerbungsstrategie aufzunehmen. Die größte Sorge stellt dabei die vorzeitige Erschöpfung bzw. die Überziehung des zur Verfügung stehenden Budgets dar. Der Artikel geht von der Grundannahme aus, dass eine vorausschauende, angemessene Budgetierung möglich ist und sie einer der wichtigsten Gesichtspunkte bei der Einführung von PDA ist. Zunächst wird die Funktionsweise von PDA zusammenfassend vorgestellt und ein knapper Überblick über die üblicherweise gehandelten Vorteile und Ängste gegeben. Danach beschäftigt sich der Beitrag ausführlich mit den Parametern, deren Berücksichtigung für einen sinnvollen Einsatz und die richtige Budgetierung von PDA wesentlich sind. Hierbei wird insbesondere auf Erfahrungswerte und Studien aus dem Ausland verwiesen. Auf dieser Grundlage setzt sich der Artikel zum Schluss kurz mit budgetrelevanten Sachverhalten der PDA-Projekte an den Bibliotheken in Bielefeld, Dresden und Mannheim auseinander., Perspektive Bibliothek, Bd. 1, Nr. 2 (2012), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Die Darstellung von Bibliotheken und Bibliothekaren ist von den Anfängen des Kinos bis zur Gegenwart ein fester Bestandteil der Filmgeschichte. Dennoch ist der Darstellung der Institution Bibliothek in der akademischen Diskussion bisher wenig Beachtung geschenkt worden. Die wenigen Beiträge sind sich in ihrer Betrachtung von Bibliotheken im Film erstaunlicherweise darin einig, dass Bibliotheken vorrangig die Funktion einer atmosphärischen Kulisse einnehmen und darüber hinaus nur selten eine weitergehende, für die Handlung erhebliche Bedeutung erfahren. Diese undifferenzierte Sicht auf Bibliotheken im Film wird der Fülle und Vielfalt der Darstellungen jedoch nicht gerecht. Um die Vielschichtigkeit der Thematik besser zu erfassen, wird in diesem Artikel ein Analysemodell vorgeschlagen, das eine strukturierte Einordnung von Bibliotheksdarstellungen im Film erlaubt. Anhand vier filmischer Beispiele – Indiana Jones and the Last Crusade (1989), Misery (1990), City of Angels (1998) und The Shawshank Redemption (1994) – werden unterschiedliche Ausprägungsformen von Bibliothekdarstellungen im Film aufgezeigt. Diese Fallbeispiele verdeutlichen, dass die Funktionen und Bedeutungen von Bibliotheken im Film wesentlich vielfältiger sind als bisher allgemein angenommen. Es lässt sich in zudem in Ansätzen herausarbeiten, mit welchen Attributen und Werten Bibliotheken konventionell in Verbindung gebracht werden., Perspektive Bibliothek, Bd. 1, Nr. 1 (2012), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Perspektive Bibliothek, Bd. 1, Nr. 2 (2012), Beginn und Erscheinungsfrequenz: Nummer: 1, Jahr: 2012, Bände pro Jahr: 1

Hintergrund: Auf der Webseite [link:http://www.jeder-fehler-zaehlt.de/#http://www.jeder-fehler-zaehlt.de/] berichten Hausärzte auch von Fehlern und Beinahefehlern beim Impfen. In dieser repräsentativen Querschnittstudie von Hausärzten der KV[for full text, please go to the a.m. URL], 45. Kongress für Allgemeinmedizin und Familienmedizin, Forum Medizin 21

Pyruvate kinase M2 (M2-PK) controls the rate-limiting step at the end of the glycolytic pathway in normal proliferating and tumor cells. Other functions of M2-PK in addition to its role in glycolysis are little understood. The aim of this study was to identify new cellular interaction partners of M2-PK in order to discover novel links between M2-PK and cellular functions. Here we show that the SUMO E3 ligase protein PIAS3 (inhibitor of activated STAT3) physically interacts with M2-PK and its isoenzyme M1-PK. Moreover, we demonstrate that endogenous SUMO-1-M2-PK conjugates exist in mammalian cells. Furthermore, we show that transient expression of PIAS3 but not the RING domain mutant PIAS3 (C299S, H301A) is consistent with nuclear localization of M2-PK and PIAS3 and M2-PK partially colocalize in the nucleus of these cells. This study suggests a link between PIAS3 and nuclear pyruvate kinase.

Im Rahmen dieser Arbeit wurden epitaktische AlN-Schichten untersucht. Diese konnten unter Stickstoff-reichen Wachstumsbedingungen effizient und homogen mit Silizium bis zu einer Konzentration von 5.2 × 1021 cm-3 dotiert werden. Dabei wirkt Silizium in einer Konzentration von ca. (5±3) × 1020 cm-3 optimal als Surfactant, was sich in Form einer deutlich verringerten Oberflächenrauigkeit und Schraubenversetzungsdichte sowie einer höheren lateralen Kristallitgröße von mehr als 1 µm bemerkbar macht. Aufgrund dieser Wirkung des Siliziums wird eine biaxiale kompressive Verspannung von mehr als 2 GPa induziert. Diese führt zu einer Zunahme der Aktivierungsenergie des Silizium-Donators bzw. der elektrischen Leitfähigkeit auf mehr als 500 meV. Mit steigender Dotierkonzentration nimmt die Wahrscheinlichkeit für die Bildung von AlxSiyN-Clustern zu. Dies wirkt sich in vielfältiger Weise aus: Zum einen bildet sich in der polykristallinen Schicht ein Störband aus, zum anderen zeigen Messungen des Absorptionskoeffizienten bzw. der Bandkanten-nahen Lumineszenz eine Abnahme der Bandlücke um mehr als 80 meV, welche auf die Bildung von Bandausläufern (band tails) zurückgeführt werden kann. Within this work, epitaxial AlN layers were investigated. Efficient and homogeneous doping was achieved under nitrogen rich growth conditions for silicon concentrations up to 5.2 × 1021 cm-3. During growth silicon acts most effective as a surfactant at a concentration of (5±3) × 1020 cm-3, which leads to a significant reduction of the surface roughness and the screw dislocation density, accompanied by an increase of the lateral crystal size tomore than 1 µm. Due to this effect of the silicon, a biaxial compressive stress of more than 2 GPa is induced. This leads to an increase of the activation energy of the silicon donor or the electric conductivity to more than 500 meV. With increasing donor concentration the probability for the formation of AlxSiyN clusters increases strongly, which leads to manifold effects: An impurity band is formed within the polycrystalline layer, and measurements of the absorption coefficient and the near bandgap luminescence show a decrease of the bandgap by more than 80 meV, which can be ascribed to the formation of band tails.

Background. The Dickkopf (Dkk) family comprises four members Dkk-1, -2, -3 and - 4. Dkk-3, the most divergent family member, unlike the others does not modulate Wnt signaling. Dkk-3 is proposed to function as a secreted tumor suppressor since it is downregulated in a number of cancer cells and prostate cancer tissue and thus may be a promising candidate molecule for therapeutic interference. Methods. The in situ tissue localization of Dkk-3 protein in normal prostate (NP), benign prostate hyperplasia (BPH) and prostate carcinoma (PCa) was investigated by immunohistochemistry/immunofluorescence. In addition, biological function of Dkk-3 in terms of proliferation and viability was evaluated in primary prostate basal epithelial cells, stromal cells and established human PCa cell lines by treatment with recombinant protein or by overexpression. Results. Stimulation with purified recombinant protein and overexpression of Dkk-3 did not significantly alter in vitro cell proliferation in any primary or tumor cell line evaluated. Dkk-3 was expressed in both the basal and secretory epithelium of NP. In BPH expression was restricted to defined basal cells and was absent in tumor cells of high grade PCa. In contrast to normal prostatic tissue, Dkk-3 was upregulated in subglandular blood vessels of BPH and in the reactive stroma of PCa tissue. Conclusions. Our results indicate that Dkk-3 expression in the normal epithelium of the prostate is lost during benign and malignant transformation and differentiation processes. The loss of expression seems to be counterbalanced by upregulation of Dkk-3 expression in the blood vessels of the remodeled tissue.

In the framework of the European ACTS (Advanced Communication Technologies and Services) programme, the largeproject AMUSE has been established involving 25 partners from 8 European countries and Israel. The project aims todevelop, specify, implement and trial advanced multimedia services to test these new services under real conditions infield trials in several locations based on Hybrid Fibre Coax (HFC), Asymmetrical Digital Subscriber Line (ADSL) andFibre to the Curb/Building (FTTCIFTTB) technologies and finally to show the implementation of an end-to-end ATMinfrastructure for various types of access networks. This paper describes the first of a series of the project's HFC trialswhich has been carried out in the city of Munich, Germany.1 Introduction In the framework of the European ACTS programme [9], the large project AMUSE [8] has been established involving25 partners from 8 European countries and Israel. With an effort of more than 1500 man months corresponding to abudget of around 17 million ECU the consortium merely aims

1. Eine Versuchsmethode wird beschrieben, mit der die Veranderungen der Riechleistung der Bienenarbeiterin nach vorangegangener Geruchsermudung qualitativ erfast werden konnen. 2. Bienenarbeiterinnen werden auf aliphatische (Caprylsaure, Octanal, 2-Methyl-Undecanal, Octadecanal) und aromatische (Anisaldehyd, Benzylazetat, p-Tolyl-aldehyd) Verbindungen dressiert, danach fur 1 Std einem Adaptationsduft ausgesetzt und mit dem Dressurduft getestet. 3. Innerhalb der aliphatischen und aromatischen Stoffgruppe wurden jeweils Kreuzadaptationen gefunden, zwischen den Stoffgruppen aber nicht. 4. Die Erholungsphase nach einem adaptierenden Reiz dauert 2–5 Std.

Artificial magnetic fields (MF) influence physiological processes in bees. 1. An inhomogeneous, static magnetic field (IMF) reduces the flying activity of bees and increases their life span by more than 60%. 2. The content of the ageing pigment lipofuscin in brain and, to a lesser extent, in thorax muscles increases with the physiological age. The content of lipofuscin of the thorax muscle is only 1/5 that of the brain. 3. Despite their increased chronological age (60–74%) brain lipofuscin of bees under conditions of an inhomogeneous, static magnetic field is slightly reduced compared with bees in natural earth's magnetic field (EMF) conditions. No effects could be registered in the muscle lipofuscin of the thorax. 4. There was no correlation between the content of lipofuscin and the chronological age. 5. Flying activity is also reduced by horizontal magnetic fields (0.40–1.45 Oe). 6. Dance tempo is reduced in compensated EMF and amplified static magnetic fields (0.84 Oe). Dance tempo is drastically reduced if compensation of the EMF is followed by application of a 5 Hz magnetic field with 1.04 Oepp, directed E-W.

The response of a bristle field sensillum inApis mellifica may be described as follows. 1. Distinct artificial magnetic fields (especially tilting of the static vector) influence the impulse frequency of the sensory cell. 2. At certain hours of the day characteristic changes of the impulse frequency occur. 3. Under predominantly natural magnetic field (MF) conditions there are significant correlations between the variation of selected MF components and impulse frequency (IMP). However, when a spatially oscillating MF-vector is applied, the IMP course does not always show a formal coincidence with MF variation. 4. Our hypothesis is that in this case the trigonometric constellation of sun (S) and moon (M) becomes the dominant guiding factor. 5. IMP frequency — with a given total azimuthal shift of the SM-system — may be calculated by the following equation using S and M azimuth and height data: $$IMP_{freq} = \pm (0.46 \cdot (\sin Az_S + \sin h_S ) + (sin Az_M + \sin h_M ))/\Delta t$$ Az=azimuth (in angular degrees),h=height (in angular degrees). 6. A quantization of the space in 90° steps and the preference of the north-south direction in this orientation system are evident. MF influences are discussed in relation to nuclear magnetic resonance; effects caused by the sun-moon constellation seem to be a gravitational modulation. A partial synthesis of both parameters is possible. Those results are discussed from a quantum mechanical point of view.

When mushroom-bodies of time-trained honeybees are translocated according to the geographical longitude — the latitude remains nearly the same — and are implanted to naive host animals the information on time is transferred as an information on local time, i.e. the time-signal learned by the donor animal breaks through in the host animal isochronous with local time and not as an endogenously driven circadian rhythm.

The misdirection (“Misweisung”) which indicates a definite direction in the bee's dance is correlated to daily variations of the total intensity (ΔF) of the earth's magnetic field (EMF). It depends on the orientation of the dancing place with regard to the EMF coordinates. The distance of the feeding place, however, is insignificant. There exists a positive correlation between the efficiency ofΔF and a progressive tilting of the comb toward the horizontal position. No difference is observed in the intensity and exactness of the bees' dancing whether they are dancing on the lower side of the oblique comb in a somewhat ‘hanging’ attitude or on the upper side. The efficiency ofΔF is comparable on both sides of the comb. Bees dancing on a horizontal comb orient primarily to the main first-order directions of the EMF and, to a lesser extent, to the second-order directions regardless of the direction of the feeding place.

1. Es wurde eine Methode erarbeitet, die im Verhaltensversuch eine reversible Sperrung der Geruchsrezeptoren fur eine oder mehrere Duftstoffklassen erlaubt. 2. Mit Hilfe dieser temporaren Sperrung wurden drei bei den Bienen wirksame Duftstoffklassen gefunden; wahrscheinlich existieren noch zwei weitere. Es sind dies die Duftstoffklassen der a) kettenformigen Molekulstrukturen; b) Aromate und Hydroaromate mit maximal drei Substituenten und Verbindungen, die aus zwei einfachen Sechsringstrukturen — direkt oder indirekt gekoppelt — aufgebaut sind; c) Aromate und Hydroaromate mit 4–6 Substituenten; d) Derivate der bicyclischen Terpene (campherartige) und e) makrocyclische (moschusartige) Verbindungen mit ca. 12–17 C-Atomen im Ring. 3. Jeder Duftstoffklasse ist ein spezifisches Enzym am Rezeptor zugeordnet. Die Wirkungsplastizitat der Enzyme last unter bestimmten strukturellen Voraussetzungen der Qualitaten Ubergange von einer Klasse zu einer anderen moglich erscheinen. Das Klassen-Erkennen stellt den ersten Schritt in der Reaktionskette der Primarprozesse dar. 4. Bei einem Uberangebot von Duftmolekulen einer Qualitat — z.B. durch Injektion — wird das entsprechende klassenspezifische Enzym verstarkt produziert. Dies fuhrt nach dem Abbau des Uberschusses an Duftmolekulen zu einer Sensibilisierung der Rezeptoren fur die betreffenden Qualitaten und die ihr nachststehenden Homologen. 5. Das Enzym fur eine Klasse konnte von sensibilisierten Tieren auf andere Individuen ubertragen werden. Die Empfanger waren dann ebenfalls sensibilisiert; jedoch ist damit ein Wirkungsverlust der Sensibilisierung von ca. 30% verbunden.

Magnetic field (MF) bursts at a frequency of 250 Hz oriented parallel to the field-lines of the EMF induce unequivocal ‘jumps’ of misdirection of up to +10°. The regression of burst intensity (BI inγ; for a range of 10–1400γ) and the size of the induced jumps of misdirection (DMID in angular degrees) follow the equation: DMID= −1+ln BI. Compensation (

1. Durch aktive gerichte Antennenbewegung bringen die Bienen ihre Chemorezeptoren in direkten Kontakt mit dem duftenden Untergrund und vollziehen damit physiologisch eine Kontakt-Chemorezeption. 2. Diese Kontakt-Chemorezeption schafft die physiologische Grundlage zu einer prazisen topochemischen Orientierung. Sie zeichnet sich durch folgende Leistungen aus: Normale Bienen: a). Die Tiere lernen eine „Duftorgel“ qualitativ-sukzessiv nach ihren einzelnen, raumlich getrennten Duftkomponenten in richtiger Reihenfolge aufzulosen (Abb. 3). b). Zwei verschiedene, raumlich nahe beieinander liegende Duftkomponenten werden qualitativ-simultan aufgelost. Damit ist ein neuer Nachweis der Osmotropotaxis mit Hilfe der Kontakt-Chemorezeption erbracht (vgl. Martin 1964) (Abb. 22). Partiell antennenamputierte Bienen: c). Nach partieller Antennenamputation geht das raumlich qualitativsukzessive Auflosungsvermogen vollkommen verloren (Abb. 4 und 8). d). Das raumlich qualitativ-simultane Auflosungsvermogen erfahrt bei solchen amputierten Bienen einen erheblichen Leistungsruckgang (Abb. 22). 3. Zwingt man die Bienen beim Ruckweg vom Ziel, die Duftorgel in umgekehrter Reihenfolge zu durchlaufen, dann sind die Ergebnisse etwa um 20% schlechter als ohne Gegendressur (wenn der Ruckweg keine Duftmarken bietet). 4. Die Kontakt-Chemorezeption leistet gleichviel in einer Duftorgel, die eine „hangende“ oder eine „stehende“ Blute als Vorbild nimmt. 5. Der Lern Vorgang zur raumlich qualitativ-sukzessiven Auflosung von Duftmarken in der Duftorgel ist mit kinasthetischer Orientierungsleistung verknupft. 6. Normale Bienen konnen mit ihren Antennen verschieden strukturierte Oberflachen unterscheiden. Die Dressur wird jedoch auserst erschwert, wenn das gebotene mechanische Muster nicht auch die erwarteten Duftmarken bietet — wie das im normalen Lebensraum der Bienen stets der Fall ist. 7. Nach partieller Antennenamputation — es genugt bereits die Amputation eines einzigen Gliedes — werden die verschiedenen Oberflachenstrukturen nicht mehr unterschieden. 8. Bei Duft-Struktur-Konkurrenzversuchen sticht die olfaktorische Information eindeutig die mechano-rezeptorische aus. Sogar spontan gebotene Duftqualitaten uben noch etwa die gleiche Attraktivitat aus wie eine in mehreren Tagen erlernte Oberflachenstruktur.