Entwicklung neuer Adenin- und Adenosin-Rezeptorliganden als pharmakologische Werkzeuge und Proteomik-Methoden zur Identifizierung des humanen Adeninrezeptors

Im Rahmen dieser Arbeit wurde eine Serie von N6-, 8- und 9-substituierten Adeninderivaten als Adeninrezeptorliganden und 1,8-disubstituierten Xanthinderivaten als A2B-Rezeptorliganden synthetisiert. Die neu dargestellten Verbindungen wurden im Arbeitskreis in Radioligand-Rezeptor-Bindungsstudien und funktionellen Experimenten auf ihre pharmakologischen Eigenschaften untersucht. Unter den Adeninderivaten, die entwickelt wurden, befinden sich der erste in der Literatur bekannte Adeninrezeptor-Antagonist und die erste Serie von Adeninrezeptor-Agonisten mit nanomolaren Affinitäten. Die dargestellten Xanthinderivate zeigen größtenteils subnanomolare Affinitäten am A2B-Rezeptor und ein sehr gutes Selektivitätsprofil gegenüber den anderen bekannten Adenosinrezeptor-Subtypen, sodass in dieser Arbeit der affinste bislang bekannte A2B-Rezeptor-Antagonist und der erste in der Literatur beschriebene spezifische A2B-Rezeptor-Antagonist dargestellt werden konnten. Auf der Basis dieser Daten wurde ferner der erste A2B-spezifische Radioligand entwickelt. In einem weiteren Projekt wurden im Rahmen eines sechsmonatigen Forschungsaufenthalts in der Arbeitsgruppe von Dr. Sonja Hess am California Institute of Technology (Pasadena, CA, USA) Proteomik-Methoden entwickelt, um den humanen Adeninrezeptor spezifisch mittels Liganden-Affinitätschromatographie aus HEK293-Zellen anzureichern und die Proteinsequenz nach proteolytischem Verdau massenspektrometrisch zu analysieren. Ferner wurden Proteomik-Methoden entwickelt, um Transmembranproteine, palmitoylierte Proteine sowie glycosylierte Proteine aus HEK293-Zellen anzureichern und massenspektrometrisch zu analysieren

Experimental characterization of the COndensation PArticle counting System for high altitude aircraft-borne application

A characterization of the ultra-fine aerosol particle counter COPAS (COndensation PArticle counting System) for operation on board the Russian high altitude research aircraft M-55 Geophysika is presented. The COPAS instrument consists of an aerosol inlet and two dual-channel continuous flow Condensation Particle Counters (CPCs) operated with the chlorofluorocarbon FC-43. It operates at pressures between 400 and 50 hPa for aerosol detection in the particle diameter (dp) range from 6 nm up to 1 micro m. The aerosol inlet, designed for the M-55, is characterized with respect to aspiration, transmission, and transport losses. The experimental characterization of counting efficiencies of three CPCs yields dp50 (50% detection particle diameter) of 6 nm, 11 nm, and 15 nm at temperature differences (DeltaT) between saturator and condenser of 17°C, 30°C, and 33°C, respectively. Non-volatile particles are quantified with a fourth CPC, with dp50=11 nm. It includes an aerosol heating line (250°C) to evaporate H2SO4-H2O particles of 11 nm<dp<200 nm at pressures between 70 and 300 hPa. An instrumental in-flight inter-comparison of the different COPAS CPCs yields correlation coefficients of 0.996 and 0.985. The particle emission index for the M-55 in the range of 1.4–8.4×10 16 kg -1 fuel burned has been estimated based on measurements of the Geophysika's own exhaust

Chemical composition of ambient aerosol, ice residues and cloud droplet residues in mixed-phase clouds: single particle analysis during the Cloud and Aerosol Characterization Experiment (CLACE 6)

Two different single particle mass spectrometers were operated in parallel at the Swiss High Alpine Research Station Jungfraujoch (JFJ, 3580 m a.s.l.) during the Cloud and Aerosol Characterization Experiment (CLACE 6) in February and March 2007. During mixed phase cloud events ice crystals from 5–20 micro m were separated from larger ice aggregates, non-activated, interstitial aerosol particles and supercooled droplets using an Ice-Counterflow Virtual Impactor (Ice-CVI). During one cloud period supercooled droplets were additionally sampled and analyzed by changing the Ice-CVI setup. The small ice particles and droplets were evaporated by injection into dry air inside the Ice-CVI. The resulting ice and droplet residues (IR and DR) were analyzed for size and composition by the two single particle mass spectrometers: a custom-built Single Particle Laser-Ablation Time-of-Flight Mass Spectrometer (SPLAT) and a commercial Aerosol Time-of-Flight Mass Spectrometer (ATOFMS, TSI Model 3800). During CLACE 6 the SPLAT instrument characterized 355 individual IR that produced a mass spectrum for at least one polarity and the ATOFMS measured 152 IR. The mass spectra were binned in classes, based on the combination of dominating substances, such as mineral dust, sulfate, potassium and elemental carbon or organic material. The derived chemical information from the ice residues is compared to the JFJ ambient aerosol that was sampled while the measurement station was out of clouds (several thousand particles analyzed by SPLAT and ATOFMS) and to the composition of the residues of supercooled cloud droplets (SPLAT: 162 cloud droplet residues analyzed, ATOFMS: 1094). The measurements showed that mineral dust was strongly enhanced in the ice particle residues. Close to all of the SPLAT spectra from ice residues did contain signatures from mineral compounds, albeit connected with varying amounts of soluble compounds. Similarly, close to all of the ATOFMS IR spectra show a mineral or metallic component. Pure sulfate and nitrate containing particles were depleted in the ice residues. Sulfate and nitrate was found to dominate the droplet residues (~90% of the particles). The results from the two different single particle mass spectrometers were generally in agreement. Differences in the results originate from several causes, such as the different wavelength of the desorption and ionisation lasers and different size-dependent particle detection efficiencies

Atmospheric radiative effects of an in situ measured Saharan dust plume and the role of large particles

This work will present aerosol size distributions measured in a Saharan dust plume between 0.9 and 12 km altitude during the ACE-2 campaign 1997. The distributions contain a significant fraction of large particles of diameters from 4 to 30 μm. Radiative transfer calculations have been performed using these data as input. Shortwave, longwave as well as total atmospheric radiative effects (AREs) of the dust plume are investigated over ocean and desert within the scope of sensitivity studies considering varied input parameters like solar zenith angle, scaled total dust optical depth, tropospheric standard aerosol profiles and particle complex refractive index. The results indicate that the large particle fraction has a predominant impact on the optical properties of the dust. A single scattering albedo of ω&lt;sub&gt;&lt;I&gt;o&lt;/I&gt;&lt;/sub&gt;=0.75&amp;ndash;0.96 at 550 nm was simulated in the entire dust column as well as 0.76 within the Saharan dust layer at ~4 km altitude indicating enhanced absorption. The measured dust leads to cooling over the ocean but warming over the desert due to differences in their spectral surface albedo and surface temperature. The large particles absorb strongly and they contribute at least 20% to the ARE in the dusty atmosphere. &lt;br&gt;&lt;br&gt; From the measured size distributions modal parameters of a bimodal lognormal column volume size distribution were deduced, resulting in a coarse median diameter of ~9 μm and a column single scattering albedo of 0.78 at 550 nm. A sensitivity study demonstrates that variabilities in the modal parameters can cause completely different AREs and emphasises the warming effect of the large mineral dust particles

Integration of Constraints into Digital Building Models for Cooperative Planning Processes

The uniqueness and the long life cycle of buildings imply a dynamically modifiable building model. The technological foundation for the management of digital building models, a dynamic model management system (MMS), developed by our research group, allows to explicitly access and to modify the object model of the stored planning data. In this paper, the integration of constraints in digital building models will be shown. Constraints are conditions, which apply to the instances of domain model classes, and are defined by the user at runtime of the information system. For the expression of constraints, the Constraint Modelling Language (CML) has been developed and will be described in this paper. CML is a powerful, intuitively usable object-oriented language, which allows the expression of constraints at a high semantic level. A constrained-enabled MMS can verify, whether an instance fulfils the applying constraints. To ensure flexibility, the evaluation of constraints is not implicitly performed by the systems, but explicitly initiated by the user. A classification of constraint types and example usage scenarios are given

Discontinuing atovaquone/proguanil prophylaxis ad-hoc post-exposure and during-travel dose-sparing prophylactic regimens against P. falciparum malaria: an update with pointers for future research

© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)Background: Atovaquone/proguanil (AP) is a highly effective malaria chemoprophylaxis combination. According to current guidelines, AP is taken once daily during, and continued for seven days post exposure. A systematic review by Savelkoel et al. summarised data up to 2017 on abbreviated AP regimens, and concluded that discontinuing AP upon return may be effective, although the available data was insufficient to modify current recommendations. The same applies to other studies evaluating during-travel dose-sparing regimens. Methods: A literature search in Pubmed and Embase was performed including search terms related to AP prophylaxis and pharmacokinetics to search for recent studies on abbreviated AP regimens published since 2017. Results: Since the 2017 review, no new studies assessing discontinuing AP ad-hoc post-exposure prophylaxis have been published. Two new studies were identified assessing other abbreviated AP regimens; one investigated a twice-weekly AP regimen in 32 travellers, and one a three-day AP course in therapeutic dose (1000/400 mg) prior to exposure in 215 travellers. No malaria cases were detected in the study participants adhering to these regimens. Conclusions: Further research would be needed if the research question is considered of sufficient importance to facilitate evidence-based decision-making to modify current guidelines, as efficacy studies in travellers are fraught with confounders. We recommend human challenge trials to study abbreviated AP regimens pertaining to malaria chemoprophylaxis as they allow for rational, subject number, time- and cost-saving trial designs.info:eu-repo/semantics/publishedVersio

Prekäre Lebenslagen von Kindern und Jugendlichen - Herausforderungen für die Kinder- und Jugendhilfe. Expertise zum 9. Kinder- und Jugendbericht des Landes Nordrhein-Westfalen

[Diese Expertise] ist als Beitrag zu einer landesspezifischen Sozialberichterstattung über Kinder, Jugendliche und junge Erwachsene sowie über das Leistungsspektrum der Kinder- und Jugendhilfe zu verstehen. Damit ist sie nach Anspruch und Methode zwischen Wissenschaft, Forschung und Politik zu verorten. Sie basiert großteils auf einer empirisch-quantitativen Datengrundlage [und rückt] auf einer deskriptiven Basis relevante Aspekte der Bedingungen des Aufwachsens, der gegenwärtigen Lebensverhältnisse und der Teilhabechancen von Kindern und Jugendlichen in Nordrhein-Westfalen in den Mittelpunkt. Mit der Fokussierung auf prekäre Lebenslagen werden überwiegend die Lebensbedingungen und Teilhabechancen von Heranwachsenden aus schwierigen sozialen Verhältnissen betrachtet. … In der Expertise werden überwiegend diejenigen Ausschnitte der Lebensbedingungen der nachwachsenden Generation beleuchtet, die sich auf das Aufwachsen in öffentlicher Verantwortung beziehen. Infolgedessen geht es sowohl um eine Ausrichtung an den Akteuren selbst, d.h. den Kindern und Jugendlichen, als auch um eine Berücksichtigung der Institutionen, insbesondere der Einrichtungen der Kinder- und Jugendhilfe. (DIPF/Orig.

Online single particle analysis of ice particle residuals from mountain-top mixed-phase clouds using laboratory derived particle type assignment

In situ single particle analysis of ice particle residuals (IPRs) and out-of-cloud aerosol particles was conducted by means of laser ablation mass spectrometry during the intensive INUIT-JFJ/CLACE campaign at the high alpine research station Jungfraujoch (3580 m a.s.l.) in January–February 2013. During the 4-week campaign more than 70 000 out-of-cloud aerosol particles and 595 IPRs were analyzed covering a particle size diameter range from 100 nm to 3 µm. The IPRs were sampled during 273 h while the station was covered by mixed-phase clouds at ambient temperatures between −27 and −6 °C. The identification of particle types is based on laboratory studies of different types of biological, mineral and anthropogenic aerosol particles. The outcome of these laboratory studies was characteristic marker peaks for each investigated particle type. These marker peaks were applied to the field data. In the sampled IPRs we identified a larger number fraction of primary aerosol particles, like soil dust (13 ± 5 %) and minerals (11 ± 5 %), in comparison to out-of-cloud aerosol particles (2.4 ± 0.4 and 0.4 ± 0.1 %, respectively). Additionally, anthropogenic aerosol particles, such as particles from industrial emissions and lead-containing particles, were found to be more abundant in the IPRs than in the out-of-cloud aerosol. In the out-of-cloud aerosol we identified a large fraction of aged particles (31 ± 5 %), including organic material and secondary inorganics, whereas this particle type was much less abundant (2.7 ± 1.3 %) in the IPRs. In a selected subset of the data where a direct comparison between out-of-cloud aerosol particles and IPRs in air masses with similar origin was possible, a pronounced enhancement of biological particles was found in the IPRs

The realization of autonomous, aircraft-based, real-time aerosol mass spectrometry in the upper troposphere and lower stratosphere

We report on the developments that enabled the field deployment of a fully automated aerosol mass spectrometer, especially designed for high-altitude measurements on unpressurized aircraft. The merits of the two main categories of real-time aerosol mass spectrometry, i.e. (a) single-particle laser desorption and ionization and (b) continuous thermal desorption and electron impact ionization of aerosols, have been integrated into one compact apparatus with the aim to perform in situ real-time analysis of aerosol chemical composition. The demonstrated instrument, named the ERICA (European Research Council Instrument for Chemical composition of Aerosols), operated successfully aboard the high-altitude research aircraft M-55 Geophysica at altitudes up to 20 km while being exposed to ambient conditions of very low atmospheric pressure and temperature. A primary goal of those field deployments was the in situ study of the Asian tropopause aerosol layer (ATAL). During 11 research flights, the instrument operated for more than 49 h and collected chemical composition information of more than 150 000 single particles combined with quantitative chemical composition analysis of aerosol particle ensembles. This paper presents in detail the technical characteristics of the main constituent parts of the instrument, as well as the design considerations for its integration into the aircraft and its autonomous operation in the upper troposphere and lower stratosphere (UTLS). Additionally, system performance data from the first field deployments of the instrument are presented and discussed, together with exemplary mass spectrometry data collected during those flights

On the potential for discontinuing atovaquone-proguanil (AP) ad-hoc post-exposure and other abbreviated AP-regimens: Pharmacology, pharmacokinetics and perspectives

According to current guidelines, atovaquone-proguanil (AP) malaria chemoprophylaxis should be taken once daily starting one day before travel and continued for seven days post-exposure. However, drug-sparing regimens, including discontinuing AP after leaving malaria-endemic areas are cost-saving and probably more attractive to travelers, and may thus enhance adherence. AP has causal prophylactic effects, killing malaria parasites during the hepatic stage. If early hepatic stages were already targeted by AP, AP could possibly be discontinued upon return. Pharmacokinetic data and studies on drug-sparing AP regimens suggest this to be the case. Nevertheless, the evidence is weak and considered insufficient to modify current recommendations. Field trials require large numbers of travelers and inherently suffer from the lack of a control group. Safely-designed controlled human malaria infection trials could significantly reduce study participant numbers and safely establish an effective AP abbreviated regimen which we propose as the optimal trial design to test this concept