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Little is known on the control of lymphomas by NK cells. Here, we study the role of the NK group 2D (NKG2D) receptor for the immunosurveillance of lymphoma. By using transplantable tumors as well as a λ-myc-transgenic model of endogenously arising lymphoma and NKG2D-deficient mice, we show that NK cells eliminate tumor cells in vivo after receiving two signals. One step involved the activation of NK cells giving rise to IFN-γ expression, which was effected by MHCI(low) tumor cells or DCs. However, this was necessary but not sufficient to mediate cytotoxicity. Triggering cytotoxicity additionally required a second step, which could be mediated by engagement of the NKG2D receptor. Thus, NKG2D-deficient NK cells could become activated in vivo, but they were not able to reject transplanted lymphomas or to degranulate in animals bearing autochthonous lymphomas. Tumor growth in NKG2D-deficient λ-myc-transgenic mice was significantly accelerated compared to NKG2D-competent animals. Whereas the latter developed tumors that lost expression of NKG2D ligands (NKG2D-L) in late disease stages, this did not occur in NKG2D-deficient mice. This indicates that NK cells and the NKG2D receptor play a role for control of lymphomas and that selection for NKG2D-L loss mutants provides a mechanism of tumor escape.

Es gibt zahlreiche Bemühungen, neue Immuntherapien zur Behandlung von malignen Tumoren zu entwickeln, da die Prognose vieler Krebserkrankungen immer noch schlecht ist. Dazu muss das Verständnis, wie die verschiedenen Immunzellen innerhalb des Tumormilieus miteinander interagieren, verbessert werden. Mausmodelle für Spontantumoren spiegeln die klinische Situation besser wider als transplantierbare Tumoren und stellen somit eine gute Möglichkeit dar, die während der Tumorentwicklung stattfindenden Immunreaktionen zu analysieren. In der vorliegenden Dissertation wurde mit Mäusen gearbeitet, in deren B-Zellen das Onkogen c-MYC konstitutiv exprimiert wird und die nach einigen Wochen spontan B-Zell-Lymphome entwickeln. Frühere Arbeiten haben bereits gezeigt, dass natürliche Killerzellen (NK-Zellen) aus c-MYC-Tumoren im Vergleich zu Organen aus Wildtyp (wt)-Mäusen kaum Interferon-gamma (IFN-) produzierten und die Fähigkeit, Zielzellen zu töten, stark reduziert war. Dementsprechend sezernierten Tumor-infiltrierende dendritische Zellen (TIDZ) geringere Mengen Interleukin-12 (IL-12), das für die Induktion einer Th1 (T-Helferzelle 1) / ZTL (zytotoxischer T-Lymphozyt)-Antwort essenziell ist, aber vermehrt das immuninhibierende Zytokin IL-10. Für die Aktivierung von naiven T-Zellen ist die Hilfe von NK-Zellen und DZ notwendig, die in c-MYC-Mäusen offenbar nicht gegeben war. Es wurde daher erwartet, dass intratumorale T-Zellen nicht bzw. nur ungenügend aktiviert werden. Überraschenderweise wiesen Tumor-infiltrierende T-Zellen jedoch einen aktivierten Phänotyp auf, zeigten zum Teil sogar eine erhöhte IFN--Produktion, konnten degranulieren und proliferierten in vivo. Trotzdem übernahmen intratumorale T-Zellen im Gegensatz zu NK-Zellen keine immunüberwachende Funktion über die Lymphomentstehung, da c-MYC-Mäuse nach Depletion der T-Zell-Population nicht früher erkrankten als unbehandelte Tiere. Offenbar wurden T-Zellen in c-MYC-Tumoren Antigen-spezifisch aktiviert, was dazu führte, dass sie aufgrund der langanhaltenden Stimulation in einen Erschöpfungszustand geraten sind. Dies spiegelte sich in einer hohen Expression des Erschöpfungsmarkers PD-1 (Programmed Cell Death 1) wider. Die Interaktion des koinhibitorischen Rezeptors PD-1 mit dem entsprechenden Liganden PD-L1, der vor allem auf DZ in c-MYC-Tumoren detektiert wurde, führt in T-Effektorzellen zur Inhibierung des aktivierenden T-Zell-Rezeptor (TZR)-Signals. So konnten T-Zellen aus c-MYC-Tumoren im Vergleich zu T-Zellen aus normalen Mäusen in vitro über den TZR tatsächlich nicht mehr stimuliert werden, was ebenfalls für eine Erschöpfung sprach. Zudem exprimierten intratumorale T-Zellen neben PD-1 die koinhibitorischen Moleküle CTLA-4 (Cytotoxic T-Lymphocyte-Associated Antigen 4) und LAG-3 (Lymphocyte Activation Gene 3). Die Stimulierbarkeit der T-Zellen in vitro konnte durch Zugabe blockierender Antikörper (AK) gegen PD-1 und CTLA-4 verbessert werden. Aufgrund dieser Beobachtung wurden junge, noch gesunde c-MYC-Mäuse mit diesen AK behandelt. Durch die PD-1/CTLA-4-Blockade in vivo zeigten die Tiere ein signifikant verlängertes Überleben. Neben CD4+ T-Helferzellen und CD8+ zytotoxischen T-Lymphozyten wurde in c-MYC-Tumoren innerhalb der CD4+ T-Zellpopulation ein sehr hoher Anteil Foxp3+ regulatorischer T-Zellen (Treg) detektiert. Diese waren aktiviert, proliferierten in vivo und produzierten IL-10. Die koinhibitorischen Moleküle, welche auch auf erschöpften T-Zellen zu finden waren (PD-1, LAG-3 und CTLA-4), wurden ebenfalls von Treg exprimiert, was bekanntlich zur Verstärkung ihrer suppressiven Aktivität führt. Es wurden vor allem Helios-exprimierende natürliche Treg (nTreg) detektiert. Doch auch IL-10-produzierende, regulatorische Foxp3- Tr1-Zellen (T Regulatory Type 1 Zelle), die zu den induzierten Treg (iTreg) zählen, waren in c-MYC-Tumoren zu finden. Schließlich fanden sich auch T-Zellen, die sowohl IFN- als auch IL-10 produzierten. Diese könnten aus Th1-Zellen entstanden sein, welche die Zytokinexpression umgestellt haben. Treg unterdrückten in c-MYC-Tieren anscheinend eine effektive Antitumor-Immunantwort. Daher wurden Foxp3+ Treg in DEREG/c-MYC-Mäusen, die einen transgenen Diphtherietoxin (DT)-Rezeptor tragen, spezifisch durch DT-Injektionen in vivo depletiert. Erstmals wurde der DEREG-Mechanismus zur Treg-Depletion in einem endogenen Tumormodell angewandt. Die Depletion der Foxp3+ Treg verschaffte den DEREG/c-MYC-Mäusen einen leichten Überlebensvorteil. Diese Ergebnisse sind relevant für die Entwicklung neuer immuntherapeutischer Verfahren zur Behandlung maligner Erkrankungen in der Klinik., The prognosis for many cancers is still poor. Therefore, much effort is made to develop new strategies for immunotherapy targeting malignant tumours. For this purpose, the understanding of how immune cells in tumour microenvironments interact with each other has to be improved. Mouse models of spontaneously arising tumours reflect the clinical situation better than transplantable tumours. So, these models provide a good tool for analysing the occurring immune reactions. In the present work mice that constitutively express the oncogene c-MYC in their B cells and that develop B-cell lymphomas after a few weeks served as a tumour model. Former work has already demonstrated that natural killer (NK) cells derived from c-MYC tumours rarely produced interferon-gamma (IFN-) compared to NK cells from wildtype (wt) mice and showed strongly diminished killing of target cells. Accordingly, tumour-infiltrating dendritic cells (TIDC) only secreted low levels of interleukin-12 (IL-12) required for the induction of a Th1 (T-helper cell 1) / CTL (cytotoxic T lymphocyte)-response. Instead, TIDC increased the production of the immunosuppressing cytokine IL-10. A proper NK-cell and DC help that was obviously missing in c-MYC mice is required for activating naïve T cells. Hence, it was expected that intratumoural T cells are not or only insufficiently activated. Surprisingly, tumour infiltrating T cells exhibited an activated phenotype, partly even showed an increased IFN- production, could degranulate and proliferated in vivo. However, in contrast to NK cells, intratumoural T cells did not exert a tumour-protective function during lymphoma formation, since c-MYC mice did not develop lymphomas earlier after T-cell depletion. T cells in c-MYC tumours were activated through their specific antigen. However, due to prolonged stimulation, T cells got into an exhausted state. This was reflected by high expression of the exhaustion marker PD-1. The interaction of the coinhibitory receptor PD-1 (Programmed Cell Death 1) with the corresponding ligand PD-L1, which was detected mainly on DC in c-MYC tumours, leads to the inhibition of the activating T-cell receptor (TCR) signal in T-effector cells. Thus, in contrast to wt-T cells, T cells derived from c-MYC tumours could not be stimulated in vitro through the TCR. This also argued for T-cell exhaustion. In addition to PD-1, intratumoural T cells also expressed the coinhibitory molecules CTLA-4 (Cytotoxic T-Lymphocyte-Associated Antigen 4) and LAG-3 (Lymphocyte Activation Gene 3). T-cell stimulation in vitro could be improved through the addition of blocking antibodies (Ab) targeting PD-1 and CTLA-4. Based on this observation c-MYC mice that did not yet show clinical signs of tumour growth were treated with these Abs. As a result of the PD-1/CTLA-4 blockade, animals showed a significantly longer survival. Besides CD4+ T-helper cells and CD8+ cytotoxic T lymphocytes an augmented fraction of Foxp3+ regulatory T cells (Treg) within the CD4+ T-cell population was detected in tumour-bearing c-MYC animals. These cells were activated, proliferated in vivo and produced IL-10. The coinhibitory molecules that were found on exhausted T cells (PD-1, LAG-3 and CTLA-4) were also expressed on Treg. It is known that this increases the suppressive activity of Treg. Mainly Helios expressing natural Treg (nTreg) were detected. However, IL-10 producing regulatory Foxp3- Tr1 (T Regulatory Type 1) cells that belong to the induced Treg population (iTreg) were also found in c-MYC tumours. Finally, T cells producing IFN- as well as IL-10 were detected. These could originate from Th1 cells that switched their cytokine expression. Treg in c-MYC tumours apparently suppress an effective anti-tumour immune response. Therefore, Foxp3+ Treg were specifically depleted in vivo in DEREG/c-MYC mice carrying a transgenic diphtheria-toxin (DT) receptor by the injection of DT. For the first time, this DEREG mechanism is utilised in an endogenous tumour model. The depletion of Foxp3+ Treg provided a survival benefit for the DEREG/c-MYC mice. These results are relevant for the development of new immunotherapeutic approaches for treating malignant disease in the clinic.

This book is a compilation of papers describing the systems participating in the third edition of the EvAAL competition. The first edition in 2011 was centered on indoor localization. The second edition in 2012 included a track on activity recognition. This third edition in 2013 maintained both tracks.

WOS:000324933900040 Heterogeneous N2O5 uptake onto aerosol is the primary nocturnal path for removal of NOx (= NO+NO2) from the atmosphere and can also result in halogen activation through production of ClNO2. The N2O5 uptake coefficient has been the subject of numerous laboratory studies; however, only a few studies have determined the uptake coefficient from ambient measurements, and none has been focused on winter conditions, when the portion of NOx removed by N2O5 uptake is the largest. In this work, N2O5 uptake coefficients are determined from ambient wintertime measurements of N2O5 and related species at the Boulder Atmospheric Observatory in Weld County, CO, a location that is highly impacted by urban pollution from Denver, as well as emissions from agricultural activities and oil and gas extraction. A box model is used to analyze the nocturnal nitrate radical chemistry and predict the N2O5 concentration. The uptake coefficient in the model is iterated until the predicted N2O5 concentration matches the measured concentration. The results suggest that during winter, the most important influence that might suppress N2O5 uptake is aerosol nitrate but that this effect does not suppress uptake coefficients enough to limit the rate of NOx loss through N2O5 hydrolysis. N2O5 hydrolysis was found to dominate the nocturnal chemistry during this study consuming similar to 80% of nocturnal gas phase nitrate radical production. Typically, less than 15% of the total nitrate radical production remained in the form of nocturnal species at sunrise when they are photolyzed and reform NO2.

Contains fulltext : 92201.pdf (Publisher’s version ) (Open Access) 6 p.

Background: It has been suggested that Mycoplasma pneumoniae may play a role in the development of atherosclerosis, but to date this association is still a matter of debate due to conflicting findings. Methods: We have investigated the levels of specific IgA antibodies to M. pneumoniae in 91 patients with internal carotid artery (ICA) stenosis using a commercial kit (SeroMP™ IgA; Savyon Diagnostics, Israel; cut-off value: 20 binding units; BU). All patients underwent surgery for ICA stenosis. From each patient, the first serum sample (S1) was taken before surgery, and the second after an interval of 6 month (S2). Results: The S1 seroprevalence was 18.7% (17/91). Thirteen of the 17 patients with positive S1 levels also remained positive after six month, whereby no decrease of IgA level was seen (median S1 level: 34 BU, range: 22–65 BU; median S2 level: 37 BU, range: 22–58 BU). Specifically, six of the patients showed an increased level after 6 months, and six a decrease, with the level remaining constant in one patient. In contrast, only 3 of the 74 S1 negative patients became positive for anti-M. pneumoniae IgA between the taking of the first and the second serum specimen (p, GMS Krankenhaushygiene Interdisziplinär; 6(1):Doc04; ISSN 1863-5245

Der Einsatz von Virtual-Reality (VR)-Systemen erlaubt - anders als bei der zwei- oder dreidimensionalen Darstellung am Desktop - das "Eintauchen" (Immersion) in die virtuelle Umgebung. Bei der Verifikation des Layouts geplanter Industrieanlagen oder Fabriken können zusätzliche Bewertungsaspekte miteinbezogen werden. Die zunehmende Nutzung der VR-Technologie in der Planungskette liegt daher im Trend. Die "Adapter"-Software" "ImmerVISe" verbindet die Funktionalitäten von VR-Umgebung und modernem Planungswerkzeug und erlaubt die bidirektionale Kommunikation zwischen beiden Systemen.

Organised by: Cranfield University A consistent and accurate digital data model takes a major role during the whole product life cycle of production facilities. This article introduces both technologies: 3D laser scanning for acquisition of 3D geometry date and motion capturing for real motion data with focus on the application in the product life cycle of production facilities. It gives an overview and comparison of different hard- and software solutions. Workflows for concrete tasks in the planning process show how both technologies can be combined and how the acquired data needs to be handled for the integration with CAD tools or Virtual Reality systems. Finally this article gives an outlook on the possible future development of these technologies. Mori Seiki – The Machine Tool Company

Massively deployed wireless sensor and actuator networks (WSAN), co-existing with RFID technology, can bring clear benefits to large-scale enterprise systems, by delegating parts of the business functionality closer to the point of action. However, a major impediment in the integration process is represented by the variety of customized WSAN platforms and proprietary technologies. In this paper, we present a three-layer service-oriented architecture that accommodates different sensor platforms and exposes their functionality in a uniform way to the business application. Our work is motivated by real business cases from the oil\&gas industry. In our implementation, we use three sensor platforms (Particle, $\mu$Node and Sindrion) integrated through the UPnP standard and incorporated into SAP enterprise software. The practical tests and application trials confirm the feasibility of our solution, but also reveal a number of challenges to be taken into account when deploying WSAN on industrial sites.

BOREXINO, a real-time device for low energy neutrino spectroscopy is nearing completion of construction in the underground laboratories at Gran Sasso, Italy (LNGS). The experiment's goal is the direct measurement of the flux of 7Be solar neutrinos of all flavors via neutrino-electron scattering in an ultra-pure scintillation liquid. Seeded by a series of innovations which were brought to fruition by large scale operation of a 4-ton test detector at LNGS, a new technology has been developed for BOREXINO. It enables sub-MeV solar neutrino spectroscopy for the first time. This paper describes the design of BOREXINO, the various facilities essential to its operation, its spectroscopic and background suppression capabilities and a prognosis of the impact of its results towards resolving the solar neutrino problem. BOREXINO will also address several other frontier questions in particle physics, astrophysics and geophysics.

Percutaneous dilatational tracheostomy is an increasingly accepted procedure for bed-side tracheostomy. The exact positioning of the endotracheal tube, the localization of the point for puncturing the trachea and damage to the endotracheal tube and the cuff as well as to the bronchoscope due to the puncturing process are technical problems which can endanger the course of the operation. In a prospective randomized study, we examined whether use of the laryngeal mask airway (LMA) is a real alternative to the endotracheal tube during tracheostomy. Of 48 consecutive patients only 43 fulfilled all criteria for this study: PaO2100 mmHg, PaCO245 mmHg (in patients with head injury35 mmHg) under intermittent positive pressure ventilation (IPPV) with a mean ventilation pressure of25 mmHg and an FiO2 of 1.0. Patients with intestinal obstruction, hemorrhages of the mouth and nose and unfavourable anatomic conditions were not included in this study. Three more patients had to be excluded from the study because of technical problems. In 21 patients tracheostomy was performed using an endotracheal tube (ET group) and in 19 patients using a LMA (LM group). After positioning of the endotracheal tube or the LMA, tracheostomy was performed in the usual way. Arterial blood gases (PaO2 and PaCO2) were investigated before positioning of the endotracheal tube or the LMA, five minutes after this procedure and five minutes after the end of tracheostomy. Mean arterial pressure (MAP), heart frequency (HF) and peripheral oxygen saturation (SpO2), endexpiratory CO2 partial pressure (PetCO2) and minute ventilation volume (MVV) were registered every 60 seconds. The ET group and LM group did not differ regarding basic diseases, age and severity of illness. Before the beginning of tracheostomy, there were no differences in MAP, HF, SpO2, PetCO2 and PaCO2 between the two groups. Before tracheostomy, only PaO2 was significantly higher in the LM group than in the ET group. Immediately before the insertion of the tracheal cannula and five minutes after the end of tracheostomy, there were no differences in the measured parameters of the two groups. An increase in PetCO2 and a decrease in minute ventilation volume were observed in both groups. Regarding technical complications, the LMA is a safe alternative to the endotracheal tube. The choice of method should depend on the basic disease and the patient's ventilation requirements at the time of tracheostomy, while there is still a call for safe instruments guaranteeing sufficient sealing of the respiratory tract during the dilatational tracheostomy and simultaneous avoidance of technical problems during puncturing of the trachea and widening of the point of puncturing.