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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Background: To determine the general appearance of normal axillary lymph nodes (LNs) in real-time tissue sonoelastography and to explore the method's potential value in the prediction of LN metastases.
Methods: Axillary LNs in healthy probands (n=165) and metastatic LNs in breast cancer patients (n=15) were examined with palpation, B-mode ultrasound, Doppler and sonoelastography (assessment of the elasticity of the cortex and the medulla). The elasticity distributions were compared and sensitivity (SE) and specificity (SP) were calculated. In an exploratory analysis, positive and negative predictive values (PPV, NPV) were calculated based upon the estimated prevalence of LN metastases in different risk groups.
Results: In the elastogram, the LN cortex was significantly harder than the medulla in both healthy (p=0.004) and metastatic LNs (p=0.005). Comparing healthy and metastatic LNs, there was no difference in the elasticity distribution of the medulla (p=0.281), but we found a significantly harder cortex in metastatic LNs (p=0.006). The SE of clinical examination, B-mode ultrasound, Doppler ultrasound and sonoelastography was revealed to be 13.3%, 40.0%, 14.3% and 60.0%, respectively, and SP was 88.4%, 96.8%, 95.6% and 79.6%, respectively. The highest SE was achieved by the disjunctive combination of B-mode and elastographic features (cortex >3mm in B-mode or blue cortex in the elastogram, SE=73.3%). The highest SP was achieved by the conjunctive combination of B-mode ultrasound and elastography (cortex >3mm in B-mode and blue cortex in the elastogram, SP=99.3%).
Conclusions: Sonoelastography is a feasible method to visualize the elasticity distribution of LNs. Moreover, sonoelastography is capable of detecting elasticity differences between the cortex and medulla, and between metastatic and healthy LNs. Therefore, sonoelastography yields additional information about axillary LN status and can improve the PPV, although this method is still experimental.
Background
To determine the general appearance of normal axillary lymph nodes (LNs) in real-time tissue sonoelastography and to explore the method′s potential value in the prediction of LN metastases.
Methods
Axillary LNs in healthy probands (n=165) and metastatic LNs in breast cancer patients (n=15) were examined with palpation, B-mode ultrasound, Doppler and sonoelastography (assessment of the elasticity of the cortex and the medulla). The elasticity distributions were compared and sensitivity (SE) and specificity (SP) were calculated. In an exploratory analysis, positive and negative predictive values (PPV, NPV) were calculated based upon the estimated prevalence of LN metastases in different risk groups.
Results
In the elastogram, the LN cortex was significantly harder than the medulla in both healthy (p=0.004) and metastatic LNs (p=0.005). Comparing healthy and metastatic LNs, there was no difference in the elasticity distribution of the medulla (p=0.281), but we found a significantly harder cortex in metastatic LNs (p=0.006). The SE of clinical examination, B-mode ultrasound, Doppler ultrasound and sonoelastography was revealed to be 13.3%, 40.0%, 14.3% and 60.0%, respectively, and SP was 88.4%, 96.8%, 95.6% and 79.6%, respectively. The highest SE was achieved by the disjunctive combination of B-mode and elastographic features (cortex >3mm in B-mode or blue cortex in the elastogram, SE=73.3%). The highest SP was achieved by the conjunctive combination of B-mode ultrasound and elastography (cortex >3mm in B-mode and blue cortex in the elastogram, SP=99.3%).
Conclusions
Sonoelastography is a feasible method to visualize the elasticity distribution of LNs. Moreover, sonoelastography is capable of detecting elasticity differences between the cortex and medulla, and between metastatic and healthy LNs. Therefore, sonoelastography yields additional information about axillary LN status and can improve the PPV, although this method is still experimental.
Objectives-The purpose of this study was to determine the dependence of breast tissue elasticity on the menstrual cycle of healthy volunteers by means of real-time sonoelastography.
Methods-Twenty-two healthy volunteers (aged 18-33 years) were examined once weekly during two consecutive menstrual cycles using sonoelastography. Group 1 (n = 10) was not taking hormonal medication; group 2 (n = 12) was taking oral contraceptives.
Results-The breast parenchyma appeared softer than the dermis and harder than the adipose tissue, and elasticity varied over the menstrual cycle and between groups. Group 1 (no hormone intake) showed continuously increasing elasticity with relatively soft breast parenchyma in the menstrual and follicular phases and harder parenchyma in the luteal phase (P = .012). Group 2 (oral contraceptives) showed no statistically significant changes in breast parenchymal elasticity according to sonoelastography. The parenchyma was generally softer in group 1 compared with group 2 throughout the menstrual cycle (P = .033). The dermis, the subcutaneous adipose tissue, and the pectoralis major muscle showed no changes in elasticity. Comparison of measurements made during the first and the second menstrual cycles showed similar patterns of elasticity in both groups.
Conclusions-Sonoelastography is a reproducible method that can be used to determine the dependence of breast parenchyma elasticity on the menstrual cycle and on the intake of hormonal contraceptives.
Galaxies are surrounded by large reservoirs of gas, mostly hydrogen, that are fed by inflows from the intergalactic medium and by outflows from galactic winds. Absorption-line measurements along the lines of sight to bright and rare background quasars indicate that this circumgalactic medium extends far beyond the starlight seen in galaxies, but very little is known about its spatial distribution. The Lyman-alpha transition of atomic hydrogen at a wavelength of 121.6 nanometres is an important tracer of warm (about 104 kelvin) gas in and around galaxies, especially at cosmological redshifts greater than about 1.6 at which the spectral line becomes observable from the ground. Tracing cosmic hydrogen through its Lyman-a emission has been a long-standing goal of observational astrophysics(1-3), but the extremely low surface brightness of the spatially extended emission is a formidable obstacle. A new window into circumgalactic environments was recently opened by the discovery of ubiquitous extended Lyman-alpha emission from hydrogen around high-redshift galaxies(4,5). Such measurements were previously limited to especially favourable systems(6-8) or to the use of massive statistical averaging(9,10) because of the faintness of this emission. Here we report observations of low-surface-brightness Lyman-alpha emission surrounding faint galaxies at redshifts between 3 and 6. We find that the projected sky coverage approaches 100 per cent. The corresponding rate of incidence (the mean number of Lyman-alpha emitters penetrated by any arbitrary line of sight) is well above unity and similar to the incidence rate of high-column-density absorbers frequently detected in the spectra of distant quasars(11-14). This similarity suggests that most circumgalactic atomic hydrogen at these redshifts has now been detected in emission.
Plans are currently being drafted for the next decade of action on biodiversity-both the post-2020 Global Biodiversity Framework of the Convention on Biological Diversity (CBD) and Biodiversity Strategy of the European Union (EU). Freshwater biodiversity is disproportionately threatened and underprioritized relative to the marine and terrestrial biota, despite supporting a richness of species and ecosystems with their own intrinsic value and providing multiple essential ecosystem services. Future policies and strategies must have a greater focus on the unique ecology of freshwater life and its multiple threats, and now is a critical time to reflect on how this may be achieved. We identify priority topics including environmental flows, water quality, invasive species, integrated water resources management, strategic conservation planning, and emerging technologies for freshwater ecosystem monitoring. We synthesize these topics with decades of first-hand experience and recent literature into 14 special recommendations for global freshwater biodiversity conservation based on the successes and setbacks of European policy, management, and research. Applying and following these recommendations will inform and enhance the ability of global and European post-2020 biodiversity agreements to halt and reverse the rapid global decline of freshwater biodiversity.
The precise and accurate assessment of carbon dioxide (CO2) exchange is crucial to identify terrestrial carbon (C) sources and sinks and for evaluating their role within the global C budget. The substantial uncertainty in disentangling the management and soil impact on measured CO2 fluxes are largely ignored especially in cropland. The reasons for this lies in the limitation of the widely used eddy covariance as well as manual and automatic chamber systems, which either account for short-term temporal variability or small-scale spatial heterogeneity, but barely both. To address this issue, we developed a novel robotic chamber system allowing for dozens of spatial measurement repetitions, thus enabling CO2 exchange measurements in a sufficient temporal and high small-scale spatial resolution. The system was tested from 08th July to 09th September 2019 at a heterogeneous field (100 m x 16 m), located within the hummocky ground moraine landscape of northeastern Germany (CarboZALF-D). The field is foreseen for a longer-term block trial manipulation experiment extending over three erosion induced soil types and was covered with spring barley. Measured fluxes of nighttime ecosystem respiration (R-eco) and daytime net ecosystem exchange (NEE) showed distinct temporal patterns influenced by crop phenology, weather conditions and management practices. Similarly, we found clear small-scale spatial differences in cumulated (gap-filled) R-eco, gross primary productivity (GPP) and NEE fluxes affected by the three distinct soil types. Additionally, spatial patterns induced by former management practices and characterized by differences in soil pH and nutrition status (P and K) were also revealed between plots within each of the three soil types, which allowed compensating for prior to the foreseen block trial manipulation experiment. The results underline the great potential of the novel robotic chamber system, which not only detects short-term temporal CO2 flux dynamics but also reflects the impact of small-scale spatial heterogeneity.
Tula virus (TULV) is a vole-associated hantavirus with low or no pathogenicity to humans. In the present study, 686 common voles (Microtus arvalis), 249 field voles (Microtus agrestis) and 30 water voles (Arvicola spec.) were collected at 79 sites in Germany, Luxembourg and France and screened by RT-PCR and TULV-IgG ELISA. TULV-specific RNA and/or antibodies were detected at 43 of the sites, demonstrating a geographically widespread distribution of the virus in the studied area. The TULV prevalence in common voles (16.7 %) was higher than that in field voles (9.2 %) and water voles (10.0 %). Time series data at ten trapping sites showed evidence of a lasting presence of TULV RNA within common vole populations for up to 34 months, although usually at low prevalence. Phylogenetic analysis demonstrated a strong genetic structuring of TULV sequences according to geography and independent of the rodent species, confirming the common vole as the preferential host, with spillover infections to co-occurring field and water voles. TULV phylogenetic clades showed a general association with evolutionary lineages in the common vole as assessed by mitochondrial DNA sequences on a large geographical scale, but with local-scale discrepancies in the contact areas.
Im Bereich der medizinischen Diagnostik spielen DNA-Chips eine immer wichtigere Rolle. Dabei werden Glas- oder Silikon-Oberflächen mit Tausenden von einzelsträngigen DNA-Fragmenten, sog. Sonden, bestückt, die mit den passenden DNA-Fragmenten in der zugefügten Patientenprobe verschmelzen. Die Auswertung solcher Messungen liefert die Diagnose für Krankheiten wie z.B. Krebs, Alzheimer oder für den Nachweis pathogener Erreger. Durch fortschreitende Miniaturisierung dieser Meßsysteme können bis zu 40.000 Genfragmente des Menschen in einer einzigen Messung analysiert werden. Neben den DNA-Fragmenten können Bio-Chips auch für andere biologische Komponenten wie Antikörper und Proteine eingesetzt werden, wobei bei letzteren neben der Bindung auch die Aktivität ein wichtiger Diagnoseparamter ist. Am Fraunhofer-Institut für medizinische Technik und am Lehrstuhl für Analytische Biochemie der Universität Potsdam wurden im Rahmen einer Doktorarbeit Methoden entwickelt, die es ermöglichen auf nukleinsäuremodifizierten Sensoroberflächen die Aktivität von Proteinen zu messen. Es wurden Nukleinsäuren auf Oberflächen optischer Sensoren verankert. Diese fungierten als Rezeptor für die Proteine sowie auch als Substrat für Restriktionsenzyme, die Nukleinsäuren schneiden und Polymerasen, die Nukleinsäuren synthetisieren und verlängern können. Seine Anwendung fand diese Messmethode in der Messung der Aktivität des Proteins Telomerase, das in 90% aller Tumore erhöhte Aktivität gegenüber gesunden Zellen aufweist. Die Vorteile dieses neuen Assays gegenüber älteren Methoden liegt im Verzicht auf radioaktiv-markierten Komponenten und einer deutlich verkürzten Analysezeit. Die Arbeit schliesst mit einem funktionsfähigen Nachweis der Telomeraseaktivität im Zellextrakt von gesunden und kranken Zellen. Der direkte Einfluß von Hemmstoffen auf die Aktivität konnte sichtbar gemacht werden, und steht daher bei der Entwicklung neuer Tumor-Diagnostika und Therapeutika zur Verfügung.