STAT3 regulated ARF expression suppresses prostate cancer metastasis

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

Communicating ASP and the Polynomial Hierarchy

Communicating answer set programming is a framework to represent and reason about the combined knowledge of multiple agents using the idea of stable models. The semantics and expressiveness of this framework crucially depends on the nature of the communication mechanism that is adopted. The communication mechanism we introduce in this paper allows us to focus on a sequence of programs, where each program in the sequence may successively eliminate some of the remaining models. The underlying intuition is that of leaders and followers: each agent’s decisions are limited by what its leaders have previously decided. We show that extending answer set programs in this way allows us to capture the entire polynomial hierarchy.

Genomic Resources Notes Accepted 1 June 2015 - 31 July 2015

This article documents the public availability of (i) microbiomes in diet and gut of larvae from the dipteran Dilophus febrilis using massive parallel sequencing, (ii) SNP and SSR discovery and characterization in the transcriptome of the Atlantic mackerel (Scomber scombrus, L) and (iii) assembled transcriptome for an endangered, endemic Iberian cyprinid fish (Squalius pyrenaicus).

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications

Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68(+) intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.

Carbon and nitrogen uptake of calcareous benthic foraminifera along a depth-related oxygen gradient in the OMZ of the Arabian Sea

Foraminifera are an important faunal element of the benthos in oxygen-depleted settings such as Oxygen Minimum Zones (OMZs) where they can play a relevant role in the processing of phytodetritus. We investigated the uptake of phytodetritus (labeled with 13C and 15N) by cal-careous foraminifera in the 0-1 cm sediment horizon under different oxygen concentrations within the OMZ in the eastern Arabian Sea. The in situ tracer experiments were carried out along a depth transect on the Indian margin over a period of 4 to 10 days. The uptake of phy-todetrital carbon within 4 days by all investigated species shows that phytodetritus is a rele-vant food source for foraminifera in OMZ sediments. The decrease of total carbon uptake from 540 to 1100 m suggests a higher demand for carbon by species in the low-oxygen core region of the OMZ or less food competition with macrofauna. Especially Uvigerinids showed high uptake of phytodetrital carbon at the lowest oxygenated site. Variation in the ratio of phytodetrital carbon to nitrogen between species and sites indicates that foraminiferal carbon and nitrogen use can be decoupled and different nutritional demands are found between spe-cies. Lower ratio of phytodetrital carbon and nitrogen at 540 m could hint for greater demand or storage of food-based nitrogen, ingestion or hosting of bacteria under almost anoxic condi-tions. Shifts in the foraminiferal assemblage structure (controlled by oxygen or food availabil-ity) and in the presence of other benthic organisms account for observed changes in the pro-cessing of phytodetritus in the different OMZ habitats. Foraminifera dominate the short-term processing of phytodetritus in the OMZ core but are less important in the lower OMZ bounda-ry region of the Indian margin as biological interactions and species distribution of foraminifera change with depth and oxygen levels.

Metabolism of mineral-sorbed organic matter depends upon microbial lifestyle in fluvial ecosystems

In fluvial ecosystems mineral erosion, carbon (C) and nitrogen (N) fluxes are linked via organo-mineral complexation, where dissolved organic molecules bind to mineral surfaces. Biofilms and suspended aggregates represent major aquatic microbial lifestyles whose relative importance changes predictably through fluvial networks. We tested how organo-mineral sorption affects aquatic microbial metabolism, using organo-mineral particles containing a mix of ¹³C, ¹⁵N-labelled amino acids. We traced ¹³C and ¹⁵N retention within biofilm and suspended aggregate biomass and its mineralisation. Organo-mineral complexation restricted C and N retention within biofilms and aggregates and also their mineralisation. This reduced the efficiency with which biofilms mineralise C and N by 30 % and 6 %. By contrast, organo-minerals reduced the C and N mineralisation efficiency of suspended aggregates by 41 % and 93 %. Our findings show how organo-mineral complexation affects microbial C:N stoichiometry, potentially altering the biogeochemical fate of C and N within fluvial ecosystems.

MRZ-99030 – a novel modulator of Aβ aggregation: II – reversal of Aβ oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice.

β-amyloid1-42 (Aβ1-42) is a major endogenous pathogen underlying the aetiology of Alzheimer's disease (AD). Recent evidence indicates that soluble Aβ oligomers, rather than plaques, are the major cause of synaptic dysfunction and neurodegeneration. Small molecules that suppress Aβ aggregation, reduce oligomer stability or promote off-pathway non-toxic oligomerization represent a promising alternative strategy for neuroprotection in AD. MRZ-99030 was recently identified as a dipeptide that modulates Aβ1-42 aggregation by triggering a non-amyloidogenic aggregation pathway, thereby reducing the amount of intermediate toxic soluble oligomeric Aβ species. The present study evaluated the relevance of these promising results with MRZ-99030 under pathophysiological conditions i.e. against the synaptotoxic effects of Aβ oligomers on hippocampal long term potentiation (LTP) and two different memory tasks. Aβ1-42 interferes with the glutamatergic system and with neuronal Ca2+ signalling and abolishes the induction of LTP. Here we demonstrate that MRZ-99030 (100–500 nM) at a 10:1 stoichiometric excess to Aβ clearly reversed the synaptotoxic effects of Aβ1-42 oligomers on CA1-LTP in murine hippocampal slices. Co-application of MRZ-99030 also prevented the two-fold increase in resting Ca2+ levels in pyramidal neuron dendrites and spines triggered by Aβ1-42 oligomers. In anaesthetized rats, pre-administration of MRZ-99030 (50 mg/kg s.c.) protected against deficits in hippocampal LTP following i.c.v. injection of oligomeric Aβ1-42. Furthermore, similar treatment significantly ameliorated cognitive deficits in an object recognition task and under an alternating lever cyclic ratio schedule after the i.c.v. application of Aβ1-42 and 7PA2 conditioned medium, respectively. Altogether, these results demonstrate the potential therapeutic benefit of MRZ-99030 in AD.

Production of extended-spectrum β-lactamases and the potential indirect pathogenic role of Prevotella isolates from the cystic fibrosis respiratory microbiota

Extended-spectrum β-lactamase (ESBL) production and the prevalence of the β-lactamase-encoding gene blaTEM were determined in Prevotella isolates (n=50) cultured from the respiratory tract of adults and young people with cystic fibrosis (CF). Time-kill studies were used to investigate the concept of passive antibiotic resistance and to ascertain whether a β-lactamase-positive Prevotella isolate can protect a recognised CF pathogen from the action of ceftazidime in vitro. The results indicated that approximately three-quarters (38/50; 76%) of Prevotella isolates produced ESBLs. Isolates positive for ESBL production had higher minimum inhibitory concentrations (MICs) of β-lactam antibiotics compared with isolates negative for production of ESBLs (P<0.001). The blaTEM gene was detected more frequently in CF Prevotella isolates from paediatric patients compared with isolates from adults (P=0.002), with sequence analysis demonstrating that 21/22 (95%) partial blaTEM genes detected were identical to blaTEM-116. Furthermore, a β-lactamase-positive Prevotella isolate protected Pseudomonas aeruginosa from the antimicrobial effects of ceftazidime (P=0.03). Prevotella isolated from the CF respiratory microbiota produce ESBLs and may influence the pathogenesis of chronic lung infection via indirect methods, including shielding recognised pathogens from the action of ceftazidime.

Local object gist: meaningful shapes and spatial layout at a very early stage of visual processing

In his introduction, Pinna (2010) quoted one of Wertheimer’s observations: “I stand at the window and see a house, trees, sky. Theoretically I might say there were 327 brightnesses and nuances of color. Do I have ‘327’? No. I have sky, house, and trees.” This seems quite remarkable, for Max Wertheimer, together with Kurt Koffka and Wolfgang Koehler, was a pioneer of Gestalt Theory: perceptual organisation was tackled considering grouping rules of line and edge elements in relation to figure-ground segregation, i.e., a meaningful object (the figure) as perceived against a complex background (the ground). At the lowest level – line and edge elements – Wertheimer (1923) himself formulated grouping principles on the basis of proximity, good continuation, convexity, symmetry and, often forgotten, past experience of the observer. Rubin (1921) formulated rules for figure-ground segregation using surroundedness, size and orientation, but also convexity and symmetry. Almost a century of research into Gestalt later, Pinna and Reeves (2006) introduced the notion of figurality, meant to represent the integrated set of properties of visual objects, from the principles of grouping and figure-ground to the colour and volume of objects with shading. Pinna, in 2010, went one important step further and studied perceptual meaning, i.e., the interpretation of complex figures on the basis of past experience of the observer. Re-establishing a link to Wertheimer’s rule about past experience, he formulated five propositions, three definitions and seven properties on the basis of observations made on graphically manipulated patterns. For example, he introduced the illusion of meaning by comics-like elements suggesting wind, therefore inducing a learned interpretation. His last figure shows a regular array of squares but with irregular positions on the right side. This pile of (ir)regular squares can be interpreted as the result of an earthquake which destroyed part of an apartment block. This is much more intuitive, direct and economic than describing the complexity of the array of squares.

Characterization of TRIB2 following PI3K inhibition

Dissertação de mestrado, Oncobiologia,(Mecanismos Moleculares do Cancro), Departamento de Ciências Biomédicas e Medicina, Universidade do Algarve, 2015

Evaluation an der FH Bund - Konzepte und Ergebnisse aus den Fachbereichen

Dulisch, Linssen und Reiter (2001) legten ein umfassendes Evaluationskonzept für die FH Bund vor. In den zehn Fachbereichen und im Zentralbereich der FH Bund erfolgt/e eine Diskussion, Modifikation und konkrete Anpassung an die Belange vor Ort. Dieser Prozess wurde in einer Evaluationtagung an der FH Bund im Juni 2003 gebündelt. Die Tagung zeigte, dass alle Fachbereiche und der Zentralbereich Fortschritte machen, wenn auch in unterschiedlichem Tempo. Dieser Band dokumentiert den Status Quo der Evaluation in den Fachbereichen und dem Zentralbereich und folgt damit § 6 Hochschulrahmengesetz (HRG), wonach die Arbeit der Hochschulen bewertet und das Ergebnis der Bewertung veröffentlicht werden soll. Inhaltsübersicht: - Evaluation an Fachhochschulen - Überblick - Empfehlungen des Benchmarking Clubs - Evaluationstagung der FH Bund 2003 - Zentralbereich - Allgemeine und Innere Verwaltung - Arbeitsverwaltung - Auswärtige Angelegenheiten - Bundesgrenzschutz - Bundeswehrverwaltung - Finanzen - Landwirtschaftliche Sozialversicherung - Öffentliche Sicherheit - Gesamtkonzept - Öffentliche Sicherheit - Abteilung Kriminalpolizei - Sozialversicherung - Wetterdienst

Fahrplan zur Facharbeit : Ideen finden, erfolgreich recherchieren, richtig zitieren

Der Fahrplan zur Facharbeit soll ein hilfreicher Begleiter bei der Facharbeit sein, wertvolle Tipps bei den wichtigen Punkten Vorbereitung, Recherche und Verarbeitung von Rechercheergebnissen geben.

Bestimmung des Kostenverlaufs von Molkereiabteilungen in Abhängigkeit von der Kapazitätsgröße und -auslastung. I. Modellbeschreibung und -abgrenzung

In dieser Arbeit werden die Grundlagen zur Bestimmung des Kostenverlaufs einzelner ausgewählter Molkereibetriebsabteilungen bei unterschiedlichen Kapazitätsgrößen und -auslastungen bestimmt. Den Produkten (Abteilungen) werden die mengenproportionalen Produkteinzelkosten zugerechnet sowie die Gemeinkosten der Abteilung, die sich aus jahresfixen, tagesfixen und chargenfixen Kosten zusammensetzen. Für Energie werden lediglich mengenproportionale Kosten in Ansatz gebracht. Die sonstigen Kosten der Hilfskostenstellen werden grundsätzlich nicht auf die Produkte bzw. Abteilungen umgelegt; sie werden im letzten Teil dieser Veröffentlichungsreihe behandelt. Die objektive Vergleichbarkeit der Kosten kann so gewährleistet werden. Ein wichtiger Bestandteil dieser Arbeit war die Entwicklung eines für alle Abteilungen brauchbaren Simulationsmodells, das für den Einsatz in der EDV konzipiert wurde. Neben der Berechnung der anfallenden Kosten bei unterschiedlichen Anlagengrößen sind bei dem Computermodell beliebige Variationen der folgenden Faktoren möglich. Dadurch können die Auswirkungen eines veränderten Beschäftigungsgrades bzw. einer anderen Kapazitätsauslastung auf die Stückkosten der einzelnen Produkte ermittelt werden. Es ist vorgesehen, die Daten über Jahre hinaus auf dem neuesten Stand zu halten und zu veröffentlichen.

La flûte enchantée. Ah! l'ingrat par son silence : air de Pamina / Mozart, comp.. Roméo et Juliette. Ah! je veux vivre dans le rêve : valse / Gounod, comp. ; Mme Ritter Ciampi, S ; accompagnement d'orchestre

Comprend : La flûte enchantée ; Roméo et Juliette