Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation.

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation, which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL ALK(+)). However, little is known about the molecular features and tumour drivers in ALK-negative ALCL (ALCL ALK(-)), which is characterized by a worse prognosis. We found that ALCL ALK(-), in contrast to ALCL ALK(+), lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPβ and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPβ and SOCS1. In murine engraftment models of ALCL ALK(-), we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1).This work was supported by the SCRI-LIMCR GmbH, the “Jubiläumsfond der Österreichischen Nationalbank” (grant-no. 14856 to O.M.), R.G. was supported by grant SFB P021 from the Austrian Science Funds (FWF), L.K. was supported by grant FWF, P26011, R.M. was supported by FWF grants SFB F28 and SFB F47. S.D.T. is a Senior Lecturer supported with funding from Leukemia and Lymphoma Research.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/path.453

Hub Cover and Hub Center Problems

Using covering problems (CoP) combined with binary search is a well-known and successful solution approach for solving continuous center problems. In this paper, we show that this is also true for center hub location problems in networks. We introduce and compare various formulations for hub covering problems (HCoP) and analyse the feasibility polyhedron of the most promising one. Computational results using benchmark instances are presented. These results show that the new solution approach performs better in most examples

Semen Refinement: Microfluidic separation techniques for the removal of micro-organisms from semen for the veterinary industry

In the veterinary industry, artificial insemination is widely applied to produce offspring. Although the spread of diseases is minimized by artificial insemination, micro-organisms are still found in semen. Apart from spreading diseases to recipient female, the presence of micro-organisms in semen decreases semen quality and therewith fertilization rates are reduced. Currently, antibiotics are applied to every semen dose to kill bacteria and screening techniques are performed frequently to detect viruses in semen. However, these processes have several disadvantages such as the emergence of antibiotic resistant bacteria as well as the time duration and working hours before a test results is known. The aim of the doctoral thesis is to develop a microfluidic device for the reduction of micro-organisms from semen for the daily semen processing in the veterinary industry. It has been shown that the viability of spermatozoa after microfluidic processing is maintained for both porcine and bovine spermatozoa. The size-based separation technique pinched-flow fractionation has been applied to remove viruses from semen while maintaining high spermatozoa recoveries. For the separation of bacteria from semen, a separation technique using acoustic waves, known as acoustophoresis, has been applied. The need to process several hundreds of milliliter within an acceptable amount of time is challenging as most microfluidic applications process smaller sample volumes. Concepts to increase the sample throughput are formed to close the gap between the proof-of-principle and the actual application in industry

Hub Cover and Hub Center Problems

Using covering problems (CoP) combined with binary search is a well-known and successful solution approach for solving continuous center problems. In this paper, we show that this is also true for center hub location problems in networks. We introduce and compare various formulations for hub covering problems (HCoP) and analyse the feasibility polyhedron of the most promising one. Computational results using benchmark instances are presented. These results show that the new solution approach performs better in most examples

Effects of stress on human extinction memory

Akuter Stress beeinflusst mittels neuroendokriner Botenstoffe Lern- und Gedächtnisprozesse. In dieser Arbeit wurde anhand zweier experimenteller Paradigmen (prädiktives Lernen und Furchtkonditionierung) in fünf Studien der Einfluss von Stress auf das Extinktionsgedächtnis untersucht. Dabei wurde der Zeitpunkt der Stressinduktion systematisch variiert, um gedächtnisphasenspezifische Stresseffekte feststellen zu können. Im Fokus standen das kontextabhängige Wiederauftreten der konditionierten Reaktion (Renewal) sowie eine mögliche Interaktion von Kontext- und Stresseffekten. Es zeigte sich, dass in Abhängigkeit von der Gedächtnisphase distinkte Stresseffekte auftreten und sowohl der Erregungsgrad, der durch die Aufgabe vermittelt wird, als auch der Kontext eine wichtige Rolle spielen. Insgesamt scheint Stress die Konsolidierung des Extinktionsgedächtnis kontextabhängig zu stärken, während der Abruf der erregenderen Erinnerung unter Stress beeinträchtigt wird.Acute stress modulates learning and memory processes via neuroendocrine messengers. In this thesis, a predictive learning task and a fear conditioning paradigm were applied to investigate the effects of stress on extinction memory in five studies. In order to examine effects of stress on specific memory phases, the timing of stress induction was varied systematically. All studies focused on the context-dependent renewal of conditioned responses, thus also allowing to test for potential interactions between contextual modulation and stress. Results showed that the effects of stress differed depending on the affected memory phase. Moreover, the arousal conveyed by the experimental paradigm as well as the contextual modulation played an important role. Taken together, the findings indicate that stress enhances the consolidation of extinction memory in a context-dependent fashion while impairing retrieval of the more arousing memory

Microbial pathogen removal from porcine semen with acoustophoresis

Microbial pathogens in semen used for artificial insemination (AI) do not only transmit diseases, but also reduce semen quality. A continuous pathogen removal separation technique overcomes the limits of current processing and separation techniques. We have applied acoustophoresis to separate bacteria and viruses from porcine semen while maintaining spermatozoa viability and achieved high spermatozoa recovery

Effect of microfluidic processing on the viability of boar and bull spermatozoa

The use of microfluidics in artificial reproductive technologies for manipulation or assessment of spermatozoa is unique in the sense that it is not always an end point measurement and the sample may be used afterward. During microfluidic processing, spermatozoa are exposed to shear stress, which may harm viability and functioning of spermatozoa. The shear stresses during general microfluidic processing steps were calculated and compared to estimated shear stresses during ejaculation. The viability of boar and bull spermatozoa after microfluidic processing was studied and compared to the typical handling method (centrifugation) and to a control (the sample in a tube at the same temperature). The boar spermatozoa showed a small but significant decrease in viability of 6% after microfluidic handling. Bull spermatozoa proved to be less susceptible to shear stress and were not significantly affected by microfluidic processing. These data indicate that the impact of microfluidic processing on the viability of boar and bull spermatozoa is less than the literature values reported for flow cytometry and comparable to the impact of centrifugatio