Suche nach pflanzlichen Thrombininhibitoren - Gerbstoffe und Fettsäuren im Fokus

Etwa eine halbe Millionen Menschen in Deutschland werden mit Antikoagulantien behandelt. Nach Schätzungen wird sich der Markt für antithrombotische Medikamente bis 2010 verdoppeln. Die derzeit verwendeten Antikoagulantien weisen Nachteile wie fehlende orale Verfügbarkeit oder schmale therapeutische Fenster auf. Naturstoffe sind traditionell eine reiche Quelle für neue Leitstrukturen. Auch innerhalb der Gruppe der Antikoagulantien leiten sich viele Wirkstoffe von Naturstoffen ab. Unter den verschiedenen Naturstoffklassen bieten Pflanzenextrakte die einfachste Möglichkeit die wirksame Substanz durch Upscaling zu isolieren. Daher bildeten sie den Ausgangspunkt für die Suche nache Thrombininhibitoren. Ziel dieser Arbeit war die Isolierung von Thrombininhibitoren aus Pflanzen. In einem ersten Schritt wurden dazu Methanol- und Dichlormethanextrakte von 78 verschiedenen Arzneidrogen hergestellt und mittels eines amidolytischen Testsystems auf ihre Thrombin hemmende Wirkung untersucht. Um eine ausschließlich durch bestimmte Substanzklassen verursachte Hemmung auszuschließen, wurde auf Gerbstoffe, Makromoleküle und "promiscuous inhibitors" getestet. Am Ende der Testserien wurde Adonidis herba für die weitere Bearbeitung ausgewählt. Durch die Bestimmung der Hemmung von Thrombin vor und nach der Entfernung von Gerbstoffen, kann die Aussage getroffen werden, ob die Hemmung ausschließlich von Gerbstoffen ausgeht. Aufgrund der großen Probenanzahl erschien die Verwendung einer Fällungsmethode vorteilhaft. Verbreitet als Gerbstofffällungsreagenzien sind Coffein, Polyvinylpyrrolidon, Gelatine und Bleiacetat. Diese vier Gerbstofffällungsreagenzien wurden untereinander in ihrer Beeinflussbarkeit durch den pH-Wert, verschiedene Lösungsmittel und die Konzentration des Gerbstofffällungsreagenzes verglichen. Desweiteren wurde ihr Einfluss auf die Fällung anderer Phenolklassen und Thrombin untersucht. Polyvinylpyrrolidon zeigte sich am besten geeignet, um unter den verwendeten Testbedingungen Gerbstoffe zu entfernen. Bleiacetat erwies sich als ungeeignet. Gerbstoffen werden im Allgemeinen eine hohe Reaktivität und damit eine unspezifische Hemmwirkung nachgesagt. Um diese Aussage zu überprüfen, wurde getestet, ob kondensierte Gerbstoffe selektiv mit unterschiedlichen Proteinen reagieren. Dazu wurden die kondensierten Gerbstoffe aus Cinnamomi cortex isoliert und mit unterschiedlichen Proteinen gefällt. Nach der Fällung wurden die kondensierten Gerbstoffe abgebaut und die Abbaumuster miteinander verglichen. Es zeigte sich, dass kondensierte Gerbstoffe durchaus spezifisch mit unterschiedlichen Proteinen reagieren. Das Thrombin hemmende Prinzip in Adonidis herba wurde gefunden. Es zeigte sich, daß die Fettsäuren Linol- und Linolensäure, die neben Palmitinsäure in Adonis vernalis enthalten sind, für die Wirkung verantwortlich sind. Zwei weitere aktive Drogen, Semen Erucae und Flores Sambuci wurden ebenfalls untersucht. Auch hier waren Fettsäuren die wirksamen Verbindungen. Zusätzlich zu Linol- und Linolensäure waren Öl- und Eicosensäure wirksam. Eine synergistische Hemmung von Thrombin durch die Mischung der Fettsäuren wurde nicht beobachtet. Eine erweiterte Untersuchung der Hemmung von Thrombin durch Fettsäuren brachte das Ergebniss, dass auch Vaccensäure, Eicosatriensäure, Ricinolsäure und Arachidonsäure Thrombin hemmen. Die Hemmung von Thrombin erfolgte zeitabhängig und abhängig von der Inkubationszeit. Letzeres jedoch nur, wenn die Reaktion durch die Zugabe von Substrat gestartet wurde. Aufgrund weiterer Experimente erscheint die Blockade der Bindetasche jedoch weniger wahrscheinlich. Ein Zusammenhang zwischen physikochemischen Parametern und der Hemmwirkung konnte nicht gefunden werden. Die übliche Vorgehensweise zur Isolierung von Inhibitoren aus einer Pflanze ist die wirkorientierte Fraktionierung. Seit mehreren Jahren wird das "Ligandenfischen" verwendet um die wirkorientierte Fraktionierung zu beschleunigen. Mittlerweile wurden ähnliche Methoden publiziert, die alle die Abtrennung eines Enzym-Ligand-Komplexes gemeinsam haben. Durch anschließende Analyse dieses Komplexes erhält man Informationen wie die Retentionszeit und das UV-Spektrum des Inhibitors. Diese Informationen erlauben eine gezieltere Isolierung. Im Rahmen dieser Doktorarbeit wurde gezeigt, daß die Wechselwirkungen zwischen Thrombin und Gerbstoffen ebenfalls genutzt werden können, um einen Inhbitor als Enzym-Inhibitor-Komplex von einer Matrix abzutrennen. Die Methode gelang mit einfachen Mitteln, war kostengünstig, schnell und mittels analytischer HPLC durchzuführen

Who Is Alyx? A new Behavioral Biometric Dataset for User Identification in XR

This article presents a new dataset containing motion and physiological data of users playing the game "Half-Life: Alyx". The dataset specifically targets behavioral and biometric identification of XR users. It includes motion and eye-tracking data captured by a HTC Vive Pro of 71 users playing the game on two separate days for 45 minutes. Additionally, we collected physiological data from 31 of these users. We provide benchmark performances for the task of motion-based identification of XR users with two prominent state-of-the-art deep learning architectures (GRU and CNN). After training on the first session of each user, the best model can identify the 71 users in the second session with a mean accuracy of 95% within 2 minutes. The dataset is freely available under https://github.com/cschell/who-is-aly

M+D: conceptual guidelines for compiling a materials library

This article proposes to present a study conducted by the Raw Materials research group, the results of which comprise the conceptual guidelines for compiling an M+D material library. The study includes the topic, materials and design taking the impact of the changes that came into being in the post industrial era on project methodologies and the search for information regarding materials. Taking into account the importance and complexity that these relationships have taken on currently, we have studied the issue of materials based on Manzini (1983) and Ashby and Johnson (2002). Afterward different databases and materials libraries located in the Brazil, the United States, France and Italy geared toward design professionals and students were analyzed to understand what information and means of access to them were available. The project methodologies were approached based on Löbach (1991), Bürdeck (1994), Schulmann (1994), Baxter (1998), Dantas (1998 and 2005) and Papanek (1995 and 2000). This study sought to identify the key elements of the role of materials in the project process today, to serve as a parameter for the analysis of the models studied. A comparative analysis of the models investigated enabled identification of positive and negative aspects to adapt to the needs previously mentioned and identify conceptual guidelines for compiling a collection of materials for use in design projects. Keywords: Design, Materials, Project Methodology, Library</p

Differential interferometric synthetic aperture radar for tide modelling in Antarctic ice-shelf grounding zones

Differential interferometric synthetic aperture radar (DInSAR) is an essential tool for detecting ice-sheet motion near Antarctica's oceanic margin. These space-borne measurements have been used extensively in the past to map the location and retreat of ice-shelf grounding lines as an indicator for the onset of marine ice-sheet instability and to calculate the mass balance of ice sheets and individual catchments. The main difficulty in interpreting DInSAR is that images originate from a combination of several SAR images and do not indicate instantaneous ice deflection at the times of satellite data acquisitions. Here, we combine the sub-centimetre accuracy and spatial benefits of DInSAR with the temporal benefits of tide models to infer the spatio-temporal dynamics of ice–ocean interaction during the times of satellite overpasses. We demonstrate the potential of this synergy with TerraSAR-X data from the almost-stagnant southern McMurdo Ice Shelf (SMIS). We then validate our algorithm with GPS data from the fast-flowing Darwin Glacier, draining the Antarctic Plateau through the Transantarctic Mountains into the Ross Sea. We are able to reconstruct DInSAR-derived vertical displacements to 7 mm mean absolute residual error and generally improve traditional tide-model output by up to 39 % from 10.8 to 6.7 cm RMSE against GPS data from areas where ice is in local hydrostatic equilibrium with the ocean and by up to 74 % from 21.4 to 5.6 cm RMSE against GPS data in feature-rich coastal areas where tide models have not been applicable before. Numerical modelling then reveals Young's modulus of E=1.0±0.56  GPa and an ice viscosity of ν=10±3.65  TPa s when finite-element simulations of tidal flexure are matched to 16 d of tiltmeter data, supporting the hypothesis that strain-dependent anisotropy may significantly decrease effective viscosity compared to isotropic polycrystalline ice on large spatial scales. Applications of our method include the following: refining coarsely gridded tide models to resolve small-scale features at the spatial resolution and vertical accuracy of SAR imagery, separating elastic and viscoelastic contributions in the satellite-derived flexure measurement, and gaining information about large-scale ice heterogeneity in Antarctic ice-shelf grounding zones, the missing key to improving current ice-sheet flow models. The reconstruction of the individual components forming DInSAR images has the potential to become a standard remote-sensing method in polar tide modelling. Unlocking the algorithm's full potential to answer multi-disciplinary research questions is desired and demands collaboration within the scientific community

Inferring Private Personal Attributes of Virtual Reality Users from Head and Hand Motion Data

Motion tracking "telemetry" data lies at the core of nearly all modern virtual reality (VR) and metaverse experiences. While generally presumed innocuous, recent studies have demonstrated that motion data actually has the potential to uniquely identify VR users. In this study, we go a step further, showing that a variety of private user information can be inferred just by analyzing motion data recorded by VR devices. We conducted a large-scale survey of VR users (N=1,006) with dozens of questions ranging from background and demographics to behavioral patterns and health information. We then collected VR motion samples of each user playing the game ``Beat Saber,'' and attempted to infer their survey responses using just their head and hand motion patterns. Using simple machine learning models, many of these attributes could accurately and consistently be inferred from VR motion data alone, highlighting the pressing need for privacy-preserving mechanisms in multi-user VR applications

Who is Alyx? A new behavioral biometric dataset for user identification in XR

Introduction: This paper addresses the need for reliable user identification in Extended Reality (XR), focusing on the scarcity of public datasets in this area.Methods: We present a new dataset collected from 71 users who played the game “Half-Life: Alyx” on an HTC Vive Pro for 45 min across two separate sessions. The dataset includes motion and eye-tracking data, along with physiological data from a subset of 31 users. Benchmark performance is established using two state-of-the-art deep learning architectures, Convolutional Neural Networks (CNN) and Gated Recurrent Units (GRU).Results: The best model achieved a mean accuracy of 95% for user identification within 2 min when trained on the first session and tested on the second.Discussion: The dataset is freely available and serves as a resource for future research in XR user identification, thereby addressing a significant gap in the field. Its release aims to facilitate advancements in user identification methods and promote reproducibility in XR research

Comparison of HER2 Expression in Primary Tumor and Disseminated Tumor Cells in the Bone Marrow of Breast Cancer Patients

Objective: The aim of this study was to measure the human epidermal growth factor receptor 2 (HER2) status of disseminated tumor cells (DTCs) from bone marrow (BM) aspirates and to assess correspondence or discrepancy with the primary tumor. Methods: DTCs were isolated from the BM of 156 breast cancer patients. Cytokeratin-positive DTCs were further analyzed by the chromogenic in situ hybridization method to detect HER2 gene amplification. Results: A significant correlation (p = 0.021) was found between the HER2 status of DTCs and the primary tumors. Sixty-one (68.5%) patients had a corresponding status. However, a shift of phenotype between primary tumor and DTCs was found in the remaining patients. Conclusion: This study showed a significant grade of discordance of the HER2 status between primary tumors and DTCs in the BM of a relevant subgroup of patients. Detection of HER2 amplification on DTCs could therefore help to better stratify patients for a more tailored therapy, since they would benefit from a HER2-targeted therapy. (C) 2016 S. Karger AG, Base

Basal mass balance and prevalence of ice tongues in the Western ross sea

Ice tongues at the fringes of the Antarctic ice sheet lose mass primarily through both basal melting and calving. They are sensitive to ocean conditions which can weaken the ice both mechanically or through thinning. Ice tongues, which are laterally unconfined, are likely to be particularly sensitive to ocean-induced stresses. Here we examine ice tongues in the Western Ross Sea, by looking into the factors affecting their stability. We calculate the basal mass change of twelve Antarctic ice tongues using a flux gate approach, deriving thickness from ICESat-2 height measurements and ice surface velocities from Sentinel-1 feature-tracking over the same period (October 2018 to December 2021). The basal mass balance ranges between −0.14 ± 0.07 m yr−1 and −1.50 ± 1.2 m yr−1. The average basal mass change for all the ice tongues is −0.82 ± 0.68 m of ice yr−1. Low values of basal melt suggest a stable mass balance condition in this region, with low thermal ocean forcing, as other studies have shown. We found a heterogeneous basal melt pattern with no latitudinal gradient and no clear driver in basal melt indicating that local variables are important in the persistence of ice tongues in the absence of a strong oceanographic melting force. Moreover, thanks to the temporal resolution of the data we were able to resolve the seasonal variability of Drygalski and Aviator Ice Tongues, the two largest ice tongues studied

Pooled Analysis of the Prognostic Relevance of Disseminated Tumor Cells in the Bone Marrow of Patients With Ovarian Cancer

Objective: Detection of disseminated tumor cells (DTCs) in the bone marrow (BM) of patients with breast cancer is associated with poor outcomes. Recent studies demonstrated that DTCs may serve as a prognostic factor in ovarian cancer. The aim of this 3-center study was to evaluate the impact of BM status on survival in a large cohort of patients with ovarian cancer. Materials and Methods: Four hundred ninety-five patients with primary ovarian cancer were included in this 3-center prospective study. Bone marrow aspirates were collected intraoperatively from the iliac crest. Disseminated tumor cells were identified by antibody staining and by cytomorphology. Clinical outcome was correlated with the presence of DTCs. Results: Disseminated tumor cells were detected in 27% of all BM aspirates. The number of cytokeratin-positive cells ranged from 1 to 42 per 2 x 10(6) mononuclear cells. Disseminated tumor cell status did correlate with histologic subtype but not with any of the other established clinicopathologic factors. The overall survival was significantly shorter among DTC-positive patients compared to DTC-negative patients (51 months; 95% confidence interval, 37-65 months vs 33 months; 95% confidence interval, 23-43 months; P = 0.023). In the multivariate analysis, BM status, International Federation of Gynecology and Obstetrics stage, nodal status, resection status, and age were independent predictors of reduced overall survival, whereas only BM status, International Federation of Gynecology and Obstetrics stage, and resection status independently predicted progression-free survival. Conclusions: Tumor cell dissemination into the BM is a common phenomenon in ovarian cancer. Disseminated tumor cell detection has the potential to become an important biomarker for prognostication and disease monitoring in patients with ovarian cancer

On the interpretation of ice-shelf flexure measurements

Tidal flexure in ice shelf grounding zones has been used extensively in the past to determine grounding line position and ice properties. Although the rheology of ice is viscoelastic at tidal loading frequencies, most modelling studies have assumed some form of linear elastic beam approximation to match observed flexure profiles. Here we use density, radar and DInSAR measurements in combination with full-Stokes viscoelastic modelling to investigate a range of additional controls on the flexure of the Southern McMurdo Ice Shelf. We find that inclusion of observed basal crevasses and density dependent ice stiffness can greatly alter the flexure profile and yet fitting a simple elastic beam model to that profile will still produce an excellent fit. Estimates of the effective Young's modulus derived by fitting flexure profiles are shown to vary by over 200% depending on whether these factors are included, even when the local thickness is well constrained. Conversely, estimates of the grounding line position are relatively insensitive to these considerations for the case of a steep bed slope in our study region. By fitting tidal amplitudes only, and ignoring phase information, elastic beam theory can provide a good fit to observations in a wide variety of situations. This should, however, not be taken as an indication that the underlying rheological assumptions are correct