Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results:A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies

Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1

Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo

Regionale Standards: Ausgabe 2013

"Die 'Regionalen Standards' gehen zurück auf die Initiative eines gemeinsamen Arbeitskreises, bestehend aus Vertretern des Statistischen Bundesamtes, der Arbeitsgemeinschaft Sozialwissenschaftlicher Institute e.V. (ASI) und des ADM Arbeitskreis Deutscher Markt- und Sozialforschungsinstitute e.V. Sie stellen ein Angebot für die Forschung in der Bundesrepublik Deutschland dar. Die 'Regionalen Standards' beschreiben Gebietsabgrenzungen und Instrumente zur Typisierung von Regionen, wie sie in der Bundesrepublik Deutschland von der amtlichen Statistik und/oder der Markt- und Sozialforschung in gewisser Regelmäßigkeit eingesetzt werden. Zusätzlich werden Datensätze aus unterschiedlichen Quellen vorgestellt, die für die Regionalisierung von Bevölkerungsumfragen genutzt werden können und für die Forschung (teils jedoch mit Einschränkungen) zur Verfügung stehen. Ergänzt werden die 'Regionalen Standards' durch eine jährlich aktualisierte Tabellenanalyse aus dem Mikrozensus, zu beziehen über die Internetseiten www.destatis.de, www.gesis.org und www.adm-ev.de." (Autorenreferat

Mobility in a Globalised World 2016

The term mobility has different meanings in the following science disciplines. In economics, mobility is the ability of an individual or a group to improve their economic status in relation to income and wealth within their lifetime or between generations. In information systems and computer science, mobility is used for the concept of mobile computing, in which a computer is transported by a person during normal use. Logistics creates by the design of logistics networks the infrastructure for the mobility of people and goods. Electric mobility is one of today’s solutions from engineering perspective to reduce the need of energy resources and environmental impact. Moreover, for urban planning, mobility is the crunch question about how to optimise the different needs for mobility and how to link different transportation systems. In this publication we collected the ideas of practitioners, researchers, and government officials regarding the different modes of mobility in a globalised world, focusing on both domestic and international issues

Optimization of Primary Human Bronchial Epithelial 3D Cell Culture with Donor-Matched Fibroblasts and Comparison of Two Different Culture Media

In vitro airway models are increasingly important for pathomechanistic analyses of respiratory diseases. Existing models are limited in their validity by their incomplete cellular complexity. We therefore aimed to generate a more complex and meaningful three-dimensional (3D) airway model. Primary human bronchial epithelial cells (hbEC) were propagated in airway epithelial cell growth (AECG) or PneumaCult ExPlus medium. Generating 3D models, hbEC were airlifted and cultured on a collagen matrix with donor-matched bronchial fibroblasts for 21 days comparing two media (AECG or PneumaCult ALI (PC ALI)). 3D models were characterized by histology and immunofluorescence staining. The epithelial barrier function was quantified by transepithelial electrical resistance (TEER) measurements. The presence and function of ciliated epithelium were determined by Western blot and microscopy with high-speed camera. In 2D cultures, an increased number of cytokeratin 14-positive hbEC was present with AECG medium. In 3D models, AECG medium accounted for high proliferation, resulting in hypertrophic epithelium and fluctuating TEER values. Models cultured with PC ALI medium developed a functional ciliated epithelium with a stable epithelial barrier. Here, we established a 3D model with high in vivo–in vitro correlation, which has the potential to close the translational gap for investigations of the human respiratory epithelium in pharmacological, infectiological, and inflammatory research

Biological Models of the Lower Human Airways—Challenges and Special Requirements of Human 3D Barrier Models for Biomedical Research

In our review, we want to summarize the current status of the development of airway models and their application in biomedical research. We start with the very well characterized models composed of cell lines and end with the use of organoids. An important aspect is the function of the mucus as a component of the barrier, especially for infection research. Finally, we will explain the need for a nondestructive characterization of the barrier models using TEER measurements and live cell imaging. Here, organ-on-a-chip technology offers a great opportunity for the culture of complex airway models

Impact and mitigation of borehole related effects in permanent crosshole resistivity imaging: An example from the Ketzin CO2 storage site

Geoelectrical methods are particularly suited for CO2 injection monitoring due to their high sensitivity to fluid displacement processes in porous rock formations. The use of borehole electrodes is favorable for deep storage horizons. Yet data acquisition based on permanently installed borehole electrodes can be challenged by the finite extent of the electrodes, unintended borehole deviation and complex borehole completion. Such conditions can lead to systematic errors in the electrical data sets, distortions of tomograms, and ultimately misinterpretations. We systematically analyze the effects of different borehole related error sources on tomographic inversion results and present respective methods for mitigation. Specifically, we incorporate the finite extent of the ring electrodes and the borehole completion into the electrical finite-element models and discuss the opportunity to infer borehole deviations solely based on geoelectrical data by means of a coupled inversion. While the finite extent of ring electrodes can be neglected if the electrode spacing is sufficiently large (> 5 m), different borehole completion materials used to fill the well annulus can cause potentially strong resistivity contrasts between the borehole completion and the rock formation, i.e., close to the electrodes. Resulting inversion artifacts are generally less severe when the borehole completion is more resistive compared to the surrounding rock. It is also shown that 2.5D inversion approaches are not adequate for imaging injection experiments in the presence of borehole completion. Unintended borehole deviation can result in geometric errors. Especially, vertical electrode shifts cause strong and localized inversion artifacts. Coupled inverse schemes potentially provide the opportunity to infer electrode shifts solely based on geoelectrical data provided the availability of high quality measurements (< 5% data error). After discussing the effects of the different borehole related error sources, the mitigation methods are validated using synthetic data sets. Subsequently, relevant methods are applied to a field data set from the Ketzin CO2 storage site, Germany, where crosshole electrical resistivity imaging is used for CO2 migration monitoring. The mitigation methods presented can improve estimates of the subsurface resistivity distribution, which, in our particular example, is an essential basis for the quantification of CO2 saturation from time-lapse geoelectrical measurements.ISSN:0926-9851ISSN:1879-185

The assessment of CO2 backproduction as a technique for potential leakage remediation at the Ketzin pilot site in Germany

As part of the license application, CO 2 storage projects must develop a corrective measures plan, which describes the steps that can be taken when the plume in the subsurface behaves in an unpredicted and undesired manner. One possible technique in the toolbox of corrective measures is CO 2 backproduction, which has the potential for both pressure management and plume steering in the reservoir. The feasibility of this technique has recently been tested during a field experiment at the Ketzin pilot site in Germany. In this paper, the authors describe an assessment of backproduction using coupled flow and geomechanical modelling. In line with the field observations, the simulation results obtained also suggest that it is a stable and promising remediation technique

Computer implementation of the international standards for neurological classification of spinal cord injury for consistent and efficient derivation of its subscores including handling of data from not testable segments

The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), defined by the American Spinal Injury Association (ASIA), and particularly the ASIA Impairment Scale (AIS) are widely used for research and clinical purposes. Although detailed procedures for scaling, scoring, and classification have been defined, misclassifications remain a major problem, especially for cases with missing (i.e., not testable [NT]) data. This work aimed to implement computer-based classification algorithms that included rules for handling NT data. A consistent and structured algorithmic scoring, scaling, and classification scheme, and a computerized application have been developed by redefining logical/mathematical imprecisions. Existing scoring rules are extended for handling NT segments. Design criterion is a pure logical approach so that substitution of non-testability for all valid examination scores leads to concordant results. Nine percent of 5542 datasets from 1594 patients in the database of the European Multicenter Study of Human Spinal Cord Injury (EM-SCI) contained NT segments. After adjusting computational algorithms, the classification accuracy was equivalent between clinical experts and the computational approach and resulted in 84% valid AIS classifications within datasets containing NT. Additionally, the computational method is much more efficient, processing approximately 200,000 classifications/sec. Computational algorithms offer the ability to classify ISNCSCI subscores efficiently and without the risk of human-induced errors. This is of particular clinical relevance, since these scores are used for early predictions of neurological recovery and functional outcome for patients with spinal cord injuries